LTFU_HSCT_guidelines

FRED HUTCHINSON CANCER CENTER

December 20, 2023

LONG-TERM FOLLOW-UP AFTER HEMATOPOIETIC STEM CELL TRANSPLANT

GENERAL GUIDELINES FOR REFERRING PHYSICIANS

These guidelines and the information they contain are copyrighted material of Fred Hutchinson

referring physicians who are involved in the care of patients who have had an hematopoietic

stem cell transplant at Fred Hutch. They may not be used for any other purpose, and Fred Hutch

disclaims all liability for the use of these guidelines except as expressly permitted by Fred Hutch.

No portion of these guidelines may be copied, displayed for redistribution to third parties for

commercial purposes or for any non-permitted use without the prior written permission of Fred

Hutch.

These guidelines describe generally accepted practices for medical care after hematopoietic stem

cell transplantation. Care has been taken to assure that the information in these guidelines is

current and accurate based on the available literature and the experience of physicians and

patients at Fred Hutch. Recommendations in these guidelines must be implemented in a

medically reasonable way that accounts for the specific situation of the individual patient.

Recommendations for patients who are enrolled in specific protocols may differ from the

recommendations in these guidelines and will be communicated separately. Questions

concerning the recommendations in these guidelines or their application to particular patients

should be directed to the LTFU office. See Section I of the guidelines for information on how to

contact the LTFU office.

Contributions to these updated guidelines were made by: Paul Carpenter, M.D.; Michael Boeckh,

M.D.; Joachim Deeg, M.D.; Guang-Shing Cheng, MD; Jean Stern, M.S.R.D.; and Leona

Holmberg, M.D., P.H.D.

TABLE OF CONTENTS

Page

I. How to Contact the LTFU Office at Fred Hutch 5

II. Frequency of Office Visits 6

III. Laboratory Tests 7-9

A. Complete Blood cell counts

B. Liver function tests

C. Renal function tests

D. Drug levels

E. Fasting Lipids Profile

F. Thyroid Function in Blood

G. Blood cultures

H. CMV monitoring

I. CMV, EBV and Adenovirus monitoring after treatment with ATG (ATGAM or

Thymoglobulin)

J. Disease monitoring of Blood and Bone marrow

IV. Infections Prophylaxis, Pre-emptive Therapy, and Intravenous Immunoglobulin 10-22

A. Pneumocystis carinii

B. Varicella zoster

C. Encapsulated bacteria

D. Cytomegalovirus

E. Fungal organisms

F. Intravenous immunoglobulin (IVIG and CMV IG)

V.Fever of Unknown Etiology 23

VI. Evaluation of Respiratory Problems and Lung Infiltrates 24-26

A. Diagnostic evaluation

B. Bronchoalveolar lavage (Tests recommended for BAL and transbronchial biopsy specimens)

C. Thoracoscopic lung biopsy (Evaluation of pulmonary nodules or persistent infiltrates with negative BAL)

VII. Evaluation of Diarrhea and Other GI Problems 27-29

A. Diagnostic evaluation and initial management

B. Procedures for gastrointestinal endoscopic biopsy

C. Algorithm for Evaluation of Acute Onset Diarrhea in Transplant

VIII. Treatment of Specific Infections 30-31

A. Cytomegalovirus

B. Varicella zoster

C. Pneumocystis carinii

IX. Vaccinations 32-41

X.Chronic Graft-Versus-Host Disease (GVHD) 42-52

A. Categories of acute and chronic GVHD (Table 1)

B. Signs and symptoms of chronic GVHD (Table 2)

C. How to diagnosis chronic GVHD

D. How to score each organ/site affected by chronic GVHD (Appendix D)

E. How to assess overall severity of chronic GVHD – Global assessment of

chronic GVHD severity (Table 3)

F. Other Laboratory testing and diagnostic indicators used in chronic GVHD

G. Monitoring and other chronic GVHD information

H. Guidelines for treatment of chronic GVHD

I. Monitoring and Management of Bronchiolitis Obliterans Syndrome after HCT

XI. General Guidelines for Prevention of Osteoporosis and Glucocorticosteroid Induced

Osteoporosis 53-59

A. Patient monitoring

B. Elemental Calcium requirements

C. Vitamin D requirements

D. Magnesium

E. Exercise

F. Gonadal hormone replacement

G. Other treatments

1. Bisphosphonates

2. Rank Land Inhibitors

3. Calcitonin

4. Low Sodium Diet

5. Endocrinology

XII. Hyperlipidemia 60-66

XIII. Hypertension 67-70

XIV. Recurrent Malignancy 71

XV. Secondary Malignancies 72

XVI. Other Complications 73-84

A. Gonadal hormone insufficiency

B. Endocrine abnormalities

C. Ocular complications

D. Oral complications and guidelines for dental care

E. Renal insufficiency

F. Neurological complications

G. Bone complications

H. Chronic Pulmonary complications

I. Hepatobiliary complications

J. Gastrointestinal complications

XVII. Blood Product Transfusion 85

XVIII. Viral Hepatitis 86-88

A. Hepatitis B

B. Hepatitis C

XIX. Iron Overload 90-98

A. Evaluation of iron overload after HSC Transplant

B. Phlebotomy after transplant

C. Chelation therapy

XX. Vitamins, Mineral Supplements 99-101

A. Calcium and Vitamin D

B. Magnesium

XXI. Diets and Other Nutritional Guidelines 102-104

A. Diet for immunosuppressive patients

B. Additional dietary recommendations

1. Diet for patients receiving treatment with corticosteroids

2. Diet for patients with GVHD of gastrointestinal tract

XXII. Naturopathic (Herbal and Nutrient supplement preparations) 105

XXIII. Return to Seattle for Long-Term Follow-Up Evaluation 106

XXIV. How to Send Specimens for Testing at Fred Hutch 107

XXV. References 108-112

APPENDICES

A. FAX Consult Request 114

B. LTFU Alert 115

C. Skin Assessment Form 116

D. Chronic GVHD Scoring Form 117-119

E. Skin Thickness Assessment (patients with scleroderma) 120

F. Flexibility 121

I. HOW TO CONTACT THE LONG-TERM FOLLOW-UP OFFICE AT THE FRED

HUTCHINSON CANCER CENTER

We offer telephone consultation to all physicians caring for patients who have been

transplanted at the Fred Hutchinson Cancer Center (Fred Hutch). We have developed a

Consultation FAX form (Appendix A) in order to facilitate communication between your

office and the LTFU office. This form can be filed in your medical records and sent to 1-

800-376-8197 (toll-free, USA and Canada) whenever you need assistance. All efforts will be

made to respond within 48 hours on regular workdays. For urgent questions from 8:00 a.m.

to 4:00pm Pacific Time on workdays, you can call (206) 667-4415. For urgent questions after

hours and on weekend and holidays, please call (206) 606-7600 and ask for the transplant

charge nurse. The nurse will triage the call and page the appropriate physician to assist you.

For non-urgent inquiries, you may also contact our LTFU Office at [email protected].

Please include the patient identification and your phone number to contact you back.

Information about LTFU services can be accessed on our website at;

http://www.fhcrc.org/science/clinical/ltfu/contact.html .

You can also find us on Google by typing FHCRC.LTFU, then clicking in the "Information

for Physician" in the left hand navigation column.

We also request that you notify us immediately after certain types of events. We have

developed an LTFU Alert FAX form in order to facilitate the notification from your office to

the LTFU office (Appendix B). This form can be filed in your medical records and sent to

1-800-376-8197 (toll-free, USA and Canada) to report the following events:

1. Death of the patient

2. Diagnosis or change in therapy of chronic GVHD

3. Recurrent malignancy

4. Diagnosis of myelodysplasia or secondary malignancy

5. Surgery or biopsy planned for evaluation of suspected secondary malignancy

6. Change of M.D.

7. Change of M.D. office address

8. Change of patient name or address

9. Requests from patients that we refrain from contacting them

II. FREQUENCY OF OFFICE VISITS

After returning home, hematopoietic transplant patients should be followed with weekly office

visits for one month. The interval time between visits can be extended to 2 weeks for 2 months

and then monthly for 6-12 months if the patient's medical condition remains stable. Vital signs

and body weight should be monitored at each clinic visit. Weight and height should be recorded

at monthly intervals for assessment of growth and development in pediatric patients. Patients

who have had an allogeneic hematopoietic stem cell transplant should be monitored for

development of chronic graft-versus-host disease (GVHD). Helpful tips on how to assess and

score chronic GVHD can be found at http://www.fhcrc.org/ltfu by clicking on "Information for

Physicians" in the left hand navigation column. Then click on the right blue “GVHD Tips &

Forms" button. Here you will find the Chronic GVHD Assessment and Scoring form (Appendix

D), Range of Motion Assessment form (Appendix F), Skin Thickness Assessment form/ Rodnan

Score for patients with sclerosis or fasciitis (Appendix E) and other helpful information. More

detailed information about chronic GVHD is outlined in Section X.

If manifestations of chronic GVHD develop or worsen, please contact the LTFU office

(Appendix A).

III. LABORATORY TESTS

A. Complete blood cell counts (CBC), differential and platelet counts should be measured at

each office visit. Patients receiving ganciclovir (or ValGANCiclovir), daily

Trimethoprim/Sulfamethoxazole (TMP/SMX), Cellcept (mycophenolate mofetil), and other

myelosuppressive medication should have a CBC at weekly intervals or more often when

counts are low.

B. Liver function tests (LFT's) (alkaline phosphatase, ALT, AST, LDH and total bilirubin)

should be measured at each office visit. Patients receiving immunosuppressive medications

or other hepatotoxic drugs such as itraconazole, voriconazole, INH, should have LFT's

measured at two-week intervals or more often when abnormalities are present. If drug

toxicity suspected, blood levels should be checked if available.

C. Renal function tests (serum creatinine, BUN, and magnesium) should be measured at each

office visit. Patients receiving cyclosporine, tacrolimus (formerly known as FK506),

amphotericin or other nephrotoxic drugs should have renal function monitored at weekly

intervals or more often when abnormalities are present. Dose adjustment may be needed for

medications such as cyclosporine, tacrolimus, ganciclovir, valacyclovir, acyclovir, among

others.

D. Drug levels:

Cyclosporine or tacrolimus (FK506) blood levels should be monitored at least twice monthly

until levels remain stable within the therapeutic range. Sirolimus (rapamycin) should be

monitored weekly until levels remain stable within levels maintained no higher than 10

ng/dL). Sirolimus, cyclosporine or tacrolimus (FK506) levels should be checked more

frequently when toxicity is suspected (i.e., new onset of thrombocytopenia, worsening

anemia, abnormal renal function, abnormal LFT's, development of tremors or other

neurological symptoms), when blood levels are outside the therapeutic range or when

manifestations of GVHD is not under control.

Note: If patients is on immunosuppressive therapy like Cyclosporine, Tacrolimus, or

Sirolimus with Maribavir because of drug-drug interaction, check two times per week

immunosuppressive drug levels for the first two weeks at start of Maribavir and for two weeks

after stopping of Maribavir. Otherwise, monitor immunosuppressive drug levels at least once

a week or as clinically indicated. Adjust immunosuppressive drug dose as needed.

Itraconazole blood levels should be monitored at monthly intervals until levels remain stable

within the therapeutic range. Itraconazole levels should be checked more frequently when

results are outside the therapeutic range and when results of LFT's are abnormal. Voriconazole,

posaconazole and the other azoles should be used with caution during treatment with sirolimus.

If treatment with azoles is warranted please contact the LTFU office to discuss sirolimus dose

adjustment.

E. Fasting lipids profile is recommended periodically due to increased risk of cardiovascular

disease and increased risk of metabolic syndrome in transplant survivors. In patients receiving

sirolimus, tacrolimus or cyclosporine, monthly fasting lipids profile is recommended until

acceptable values are achieved, thereafter, monitoring may be decreased to every 3 to 6

months, or more often if clinically indicated.

F. Thyroid function in blood should be monitored yearly due to increased thyroid disease

after transplant. For patients who received radiolabeled iodine antibody therapy, thyroid

function should be checked sooner at 3 and 6 months within the first year after transplant,

and other times as clinically indicated.

G. Blood cultures should be drawn whenever clinically indicated. For high risk patients

(i.e., treatment with prednisone at a dose of more than 1 mg/kg/day), weekly surveillance

blood cultures may be beneficial.

H CMV monitoring in blood should be instituted for all patients who are at risk of CMV

disease after transplant. PCR is the standard assay for CMV surveillance.

Initial CMV Monitoring

CMV seropositive recipients of non-cord blood allogeneic transplants or CD34 selected

autologous transplants should have CMV monitored in blood weekly until day 100 after

transplant. CMV seropositive cord blood recipients should have CMV monitored twice

weekly until day 100 after transplant. CMV seronegative recipients of cord blood should

have CMV monitored weekly until day 100 days after transplant. CMV

seronegative/seronegative non-cord blood allogeneic or seronegative unmodified

autologous transplant recipients should be monitored weekly until day 60 after transplant.

After day 100 to one year post transplant, CMV monitoring

CMV blood testing should be continued, initially weekly, until 1 year after transplant for

allogeneic recipients at risk of late CMV disease which include:

• Patients treated for CMV viremia in the first 100 days after transplantation

• Cord blood transplant recipients who were CMV seropositive

• Patients who received Letermovir prophylaxis beyond day +60 after transplant

• For non-malignant patients except Sickle cell and Thalassemia that received either Anti-

Human Thymocyte Globulin or Campath in transplant conditioning or for GVHD should

have weekly CMV blood testing for at least 6 months after the last serotherapy dose or

until absolute CD4 count is > 200 cells/microliters, whichever is later

• All other patients who received Anti-Human Thymocyte Globulin in conditioning or for

GVHD should have weekly CMV blood testing for at least 6 months after the last dose of

ATG or absolute lymphocyte count >300 cells/microliters, whichever is later (see Section

• Patients treated with > 0.5 mg/kg/day prednisone or prednisone equivalent or other agents (e.g.,

MMF, ibrutinib, etc.) for either late acute or chronic GVHD.

Changes in initial surveillance frequency > 100 days after transplant and before one

year post transplant for NON-CORD BLOOD transplant patients:

The weekly frequency of CMV blood surveillance after day 100 posttransplant may be

changed for non-cord blood transplant ONLY as follows:

• Non-Cord Blood patients can be changed to every other week surveillance if on < 0.5

mg/kg/day prednisone or prednisone equivalent and on stable doses or tapering doses of other

immunosuppressive agents AND have had three consecutive negative surveillance tests (PCR

for CMV DNA)

• Surveillance may be stopped entirely after 2 additional negative tests if tapering of

immunosuppression continues.

• Resume weekly CMV surveillance testing if treatment with immunosuppression is increased or

re-initiated for GVHD.

CMV monitoring after one year post transplant

CMV monitoring as clinically indicated based on history of prolonged CMV prophylaxis,

repeated episodes of CMV reactivation, or ongoing active GVHD requiring systemic

immunosuppressive therapy.

I. CMV, EBV and Adenovirus Monitoring After Treatment with Anti-Human Thymocyte

Globulin (ATG) (ATGAM or Thymoglobulin) Unless Specified Differently per Protocol

• For non-malignant patients except sickle cell and Thalassemia that received either Anti-

Human Thymocyte Globulin or Campath in transplant conditioning or for GVHD should

have weekly blood monitoring by PCR for EBV, adenovirus, and CMV for at least 6

months after the last serotherapy dose or until absolute CD4 count is > 200

cells/microliters, whichever is later.

• All other patients who received Anti-Human Thymocyte Globulin in conditioning or for

GVHD should have weekly blood monitoring by PCR for EBV, adenovirus, and CMV

for at least 6 months after last dose of ATG or absolute lymphocyte count > 300 cells/

microliter, whichever is later.

J. Disease Monitoring of Blood and Bone marrow.

Bone Marrow:

Bone marrow should be evaluated at one year after transplant. Testing should include

evaluation of morphology and immunophenotyping, cytogenetics and molecular testing

as applicable. Subsequent bone marrow evaluations should be done as clinically

indicated such as:

• The CBC or platelet count shows any abnormalities

• If the most recent marrow evaluation or other testing showed any evidence of

persistent malignancy

• If the patient has a disease for which maintenance treatment would be indicated if

disease were discovered after a previous evaluation with no evidence of malignant

cells.

Blood:

Patients transplanted for chronic myeloid leukemia (CML) or Philadelphia chromosome-

positive acute lymphocytic leukemia (Ph-positive ALL) should have blood tested for

BCR/abl transcripts at 6 month intervals for the first 2 years after transplant and then at

yearly intervals. When BCR/abl transcripts are detected in the blood, a marrow aspirate

should be evaluated by cytogenetic testing, morphology and molecular testing.

If recurrent malignancy occurs, please contact the LTFU office for consultation for

specific treatment and follow-up recommendations (Appendix A).

IV. INFECTIONS PROPHYLAXIS, PREEMPTIVE THERAPY AND INTRAVENOUS

IMMUNOGLOBULIN

All transplant recipients have some degree of immunodeficiency, especially during the first

6-12 months after the transplant. Bacterial, fungal and viral infections occur most frequently

during this time interval. In the absence of GVHD, most patients have adequate immune

reconstitution by one year after the transplant. Patients with chronic GVHD remain

immunodeficient and have a high risk of infections.

A. Pneumocystis jiroveci pneumonia (PCP)

All patients should receive prophylaxis against PCP for at least 6 months after the

transplant or until all immunosuppressive medications have been discontinued, whichever

occur later. The preferred drug is trimethoprim-sulfamethoxazole administered according

to the following regimen:

• Adults: 1 double strength tablet p.o. b.i.d. on 2 consecutive days weekly

• Children > 20 kg: 1 single strength tablet p.o. b.i.d. on 2 consecutive days weekly

• Children < 20 kg: and 5 mg/kg/day of trimethoprim component in two divided doses on

2 consecutive days weekly.

Patients who are allergic to sulfa should be desensitized whenever possible. If

desensitization is not feasible, Dapsone should be administered at a dose of 50 mg p.o.

b.i.d. daily for adults and 1 mg/kg/day in two divided doses (up to 100 mg/day) for

children. Before starting treatment with Dapsone, patients must be tested to rule out G-6-

PD deficiency. For patients who cannot tolerate Bactrim or dapsone, atovaquone or

pentamidine IV may be given.

Atovaquone:

Dosing

Adults and pediatric patients > 50 kg:

1500 mg oral suspension, once daily, to be taken with a meal.

Pediatric patients less than or equal to 50 kg:

30 mg/kg, once daily, to be taken with a meal.

Pentamidine

Dosing

Pediatric:

Children < 24 months:

4 mg/kg/dose (max 300 mg) IV over 90 minutes every two weeks.

Children > 2 years:

4 mg/kg/dose (max 300 mg) IV over 90 minutes every four weeks.

Adult:

300 mg IV over 90 minutes, every four weeks.

B. Varicella-zoster virus

All VZV-seropositive patients (via vaccine or via disease) should receive prophylaxis

with acyclovir or valacyclovir throughout the first year after the transplant or until 8

months after systemic immunosuppression ends, whichever is longer.

Acyclovir should be administered according to the following regimen (assuming

adequate renal function):

• Weight > 40 kg, receiving < 0.5 mg/kg/day of corticosteroids: 800 mg P.O. B.I.D.*

• Weight < 40kg, receiving < 0.5 mg/kg/day of corticosteroids: 600 mg/ m

P.O. B.I.D.

Alternatively, valacyclovir should be administered according to the following regimen:

• Weight > 40 kg, receiving > 0.5 mg/kg/day of corticosteroids: 500 mg P.O. B.I.D*.

• Weight < 40 kg, receiving > 0.5 mg/kg/day of corticosteroids: 250 mg P.O. B.I.D.

*Note: In VZV seropositive/HSV seronegative, patients > 40 kg, lower doses of prophylaxis

are sufficient, 800 mg/day of acyclovir or 500 mg/day of valacyclovir. For patients < 40 kg,

the dose of acyclovir should be 300 mg/m

(maximum 400 mg) P.O. B.I.D.

It is difficult to prevent VZV transmission to susceptible patients because infected

individuals are contagious for 24-48 hours before the rash appears. The incubation period

of VZV is 10-21 days. Individuals with VZV (chickenpox or shingles) remain contagious

until all skin lesions have crusted.

All patients exposed to chickenpox or zoster during the first year after the transplant or

during treatment with immunosuppressive medications should be evaluated. VZV-

seronegative patients and those not receiving prophylactic acyclovir should be treated

with valacyclovir from days 3 to 22 after exposure unless treatment with ganciclovir,

foscarnet or cidofovir is being given for another reason. Valacyclovir should be given at

a dose of 1gm p.o. t.i.d. for patients > 40 kg and at a dose of 500 mg p.o. t.i.d. for patients

< 40 kg. In adults and children without adequate oral intake, acyclovir can be

administered at a dose of 500mg/m

IV every 8 hours if renal function is normal. In

seronegative recipients, administration of VZIG within 96 hours of exposure should also

be used, if available, in addition to valcyclovir as outlined above. Patients exposed to

chickenpox or zoster during prophylaxis with acyclovir or valacyclovir must be followed

closely for the development of VZV infection.

Vaccination against VZV should be delayed (See vaccination Section IX for details).

C. Encapsulated bacteria

Patients with chronic GvHD are highly susceptible to recurrent bacterial infections,

especially with encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus

influenzae and Neisseria meningitidis as they are functionally asplenic. Susceptibility to

these organisms may be due to persistent low levels of opsonizing antibodies, low CD4

counts, poor reticuloendothelial function, and long-term use of immunosuppressive

therapy, especially corticosteroids, with their suppressive effects on

Encapsulated bacteria (continued)

phagocytosis. Long-term chemoprophylaxis is recommended in this setting due to

unpredictable protection provided by vaccination, which is also recommended after

transplant. Due to the emergence of penicillin resistance (and the concomitant need for

PCP prophylaxis in these patients), trimethoprim-sulfamethoxazole (TMP-SMX) is

recommended as first-line drug for chemoprophylaxis for infections with encapsulated

bacteria. If TMP-SMX is not tolerated, the traditional penicillin-based prophylaxis

should be substituted for encapsulated bacteria and dapsone also should be prescribed to

provide PCP prophylaxis.

Other patient groups who should be considered for encapsulated organism prophylaxis

include those who are:

• Without GVHD but are receiving glucocorticoid or other immunosuppressive

medications.

• With persistent or recurrent manifestations of chronic GVHD without ongoing use of

immunosuppressive medications

• Being treated for relapsed or progressive malignancy after transplant

• Surgically and/or functionally asplenic (see below for more details).

• Patients who are age> 65 years old post-allogeneic stem cell transplantation.

Patients receiving systemic immunosuppressive therapy for chronic GVHD should

receive antibiotic prophylaxis against infection with encapsulated bacteria for at least 6

months after discontinuation of all immunosuppressive medications. Double-strength

(DS) trimethoprim-sulfamethoxazole (800mg sulfamethoxazole) given as a single dose

daily is adequate for prevention of infection with both PCP and encapsulated bacteria in

adults.

In patients with sulfa allergies, Penicillin VK (Pen-Vee-K) should be given for

encapsulated bacteria prophylaxis (see Table below). Children < 30 kg who do not

tolerate daily trimethoprim-sulfamethoxazole (TMP/SMX) should receive Penicillin VK

(See Table below).

Additional medication is required for PCP prophylaxis in patients who receive

penicillin instead of daily trimethoprim-sulfamethoxazole (TMP/SMX). (See Section

IV.A)

Table - Penicillin VK dosing for encapsulated bacterial prophylaxis:

Adults and Children ( > 60 kg)

500 mg PO BID

Adults ( < 60 kg) and

Children (> 3 years and < 60 kg)

250 mg PO BID

Children (< 3 years)

125 mg PO BID

For more information, see the Standard Practice Guideline section “Antibiotic

Prophylaxis for Encapsulated Bacteria in Allogeneic Patients with Chronic GVHD

Requiring Immunosuppressive Therapy”

Antimicrobial prophylaxis for asplenic patients

Patient education is paramount to prevent fatal infections in asplenic patients. Studies

have shown that 11% to 50% of postsplenectomy patients remain unaware of their

increased risk for serious infection or the appropriate health precautions that should be

undertaken. Important education points include the following:

• Persons without a functioning spleen are more susceptible to certain infections.

• The risk of infection is life-long, but it is highest in the first year or two after the

surgery.

• If unwell (particularly in case of fever associated with rigors), patients should seek

prompt medical attention. Infections can be rapidly progressive and life-

threatening in a matter of hours. The use of prophylactic or preemptive measures

should never be allowed to engender a false sense of security.

• Travel-related infections (such as babesiosis and malaria) are particularly important;

adherence to antimalarial prophylaxis cannot be overemphasized.

• All physicians caring for the patient should be informed of the condition, no matter

how long after the splenectomy.

Antimicrobial regimens are the same as for prevention of encapsulated bacteria in patients

with chronic GVHD, and include daily Trimethoprim/Sulfamethoxazole (TMP/SMX) or

twice-daily Penicillin VK therapy. Penicillin VK provides no protection against PCP; thus

dapsone or other PCP prophylaxis must be added.

The duration of antibiotic prophylaxis in the asplenic patient after transplant is dependent of

the presence of chronic GVHD (See Table below).

Table - Duration of propylaxis for encapsualted organism in asplenic patients according

to chronic GVHD

HCT recipients with chronic GVHD

Until 6 months after immunosuppression d/c’d

OR until age 6 OR 2 years after splenectomy

(whichever occurs later)

All HCT receipients without chronic

GVHD (allo, auto, syngenic)

1 year after BMT OR until age 6 OR 2 years after

splenectomy (whichever occurs later)

Note:

Sickle Cell: All Sickle cell patients should receive prophylactic penicillin daily for two years

post transplant or until their tenth birthday, whichever is longer. The dose is 125 mg PO

BID for patients < 3 years old and 250 mg PO BID for patients > 3 years.

Antimicrobial prophylaxis should also be considered for patients AT ANY TIME post-

splenectomy during travel to sites where medical care will not be rapidly accessible.

Preemptive therapy for the post-splenectomy patient with fever and rigors

Another strategy that has been advocated is the provision of "standby" antipneumococcal

antibiotics; this strategy may be particularly relevant for patients who are not receiving

prophylaxis. Under this strategy, the patient retains a personal supply of antibiotics to be

taken at the first sign of respiratory illness, fever, or rigors, particularly if there is likely

to be a delay in medical evaluation. There is currently no evidence that such early self-

treatment will lower the mortality associated with post splenectomy sepsis (PSS). In fact,

the literature series with the lowest mortality reported to date emphasized patient

education, close follow-up, and prompt physician intervention at the earliest sign of even

minor infection. Thus, even if patients have their own supply of antibiotics, medical help

should be sought immediately, at which time a physician should decide whether to

continue antibiotic therapy.

Recommended antibiotics and doses that may be useful in preemptive approaches include

the following:

• Adults: Amoxicillin 500 mg tablets; take 4 tablets (2 grams) and

report immediately for medical attention

Levofloxacin 750 mg tablets; take 1 tablet and report

immediately for medical attention

• Children 20-40 kg: Amoxicillin 250 mg tablets; take 4 tablets (1 gram) and

report immediately for medical attention

• Children < 20 kg: Amoxicillin 50 mg/kg administered as chewable tablets

and report immediately for medical attention

For penicillin-allergic children, consider Bactrim or other drugs as clinically indicated.

Empiric therapy for post-splenectomy sepsis (PSS) or other serious infections

Early recognition of infection followed by aggressive intervention is the cornerstone of

PSS management. Initial empiric antimicrobial therapy for the splenectomized patient

with unexplained fever, rigors, and other systemic symptoms should always include a

broad-spectrum antibiotic active against S. pneumoniae, H. influenzae, and N.

meningitidis such as ceftriaxone. In areas with high-level penicillin-resistant

pneumococci, vancomycin may be added empirically, particularly in cases with suspected

or proven meningitis

Patients with splenectomy post transplant

Also see Vaccination Section IX

D. Cytomegalovirus (CMV)

(See Section III, subsections H. and I for CMV monitoring frequency). `

1. Table 1. Threshold CMV Viral Load for Preemptive Therapy

All transplants that do not

meet above criteria

CMV seropositive CD34-

selected autologous

recipients

DAY 0-60

DAY >100

≥ 50 IU/ mL

(1.70 log10)

≥ 500 IU/ mL

(2.70 log10)

If protocol requires testing beyond day 100 > 500 IU/ mL (2.70 log 10)

Or rising DNA levels >5x baseline within 1 month

PATIENT

POPULATION

Unmodified autologous,

< 1 mg/kg steroids

≥ 150 IU/ mL

(2.18 log10)

DAY 0-100

Post Transplant

2. Preemptive Therapy

Table 2. Pre-emptive Induction Treatment Regimen for CMV Reactivation with Adequate

Renal Function After Transplant

Acyclovir/valAcyclovir used for CMV prophylaxis should be discontinued when pre-emptive therapy is

started. Acyclovir/valAcyclovir should be continued, for HSV/VZV prophylaxis, if maribavir is initiated or

restarted when ganciclovir or foscarnet is completed if indicated.

INDUCTION

Preferred

Alternative

ValGANCiclovir*

** (ONLY for patients with good

oral intake, no active gut GVHD,

no significant liver

disease and no severe diarrhea):

Adults and Peds > 50 kg:

900 mg PO Q 12 hrs

Peds ≥ 40 to < 50kg:

675 mg PO Q 12 hrs

Peds ≥ 30 to < 40kg:

450 mg PO Q 12 hrs

Peds ≥20 to <30 kg:

450 mg PO Q 12 hrs or

Liquid 14 mg/kg Q 12 hrs

Peds ≥ 15 to <20 kg:

225 mg PO Q12 hrs (= ½ pill) or

Liquid 14 mg/kg Q12 hrs

Peds ≥10 to < 15 kg:

Liquid 14 mg/kg Q12 hrs

Ganciclovir**

5 mg/kg IV Q 12hrs

Foscarnet**

90 mg/kg

IV Q 12hrs

Maribavir*,***, **** 400mg

PO BID

(Age ≥ 12 years and

weight ≥ 35kg )

Duration of Induction:

• For Non-Cord blood transplant, a switch to maintenance dosing may be made if CMV DNA levels are declining (at

least 1-log reduction) after 7 days; if not declining at day 7 of treatment, continue twice daily induction dosing until

CMV DNA levels have decreased over the course of 1 week; at which point transition to maintenance dosing can

occur.

• For Cord blood transplant, CMV DNA levels must be negative at one week in order to transition to maintenance

dosing. Otherwise, continue induction dosing until CMV DNA levels are negative at which point a transition to

maintenance is appropriate.

• All patients failing induction should be considered to switch therapy and do UL97/UL54 resistance testing

* ValGANCiclovir absorption is significantly enhanced when taken with food; thus patients should be

instructed to take ValGANCiclovir with food. Patients with poor oral intake, severe diarrhea/gut GVHD

are NOT good candidates for ValGANCicovir or Maribavir and should receive IV ganciclovir daily.

**Use actual weight unless actual weight is above 150% of ideal weight. For patients who are > 150% ideal body

weight, the weight used should be capped at 150% of ideal body weight.

***Maribavir to be considered in failure/intolerance of “Preferred” agents ; screen for drug-drug interactions.

****Because of drug-drug interaction, Maribavir should not be given simultaneously with CYP3 substrates like

Cytoxan and a 48-hour washout period is recommended.

Table 3: Preemptive Maintenance Treatment Regimen for CMV Reactivation with Adequate

Renal Function After Transplant

MAINTENANCE

Preferred

Alternative

ValGANCiclovir*

** (ONLY for patients with good oral intake, no

active gut GVHD,

no significant liver disease and no severe diarrhea):

Adults and peds > 50 kg:

900 mg PO Q Day

Peds ≥ 40 to < 50 kg:

675 mg PO Q Day

Peds ≥30 to < 40 kg:

450 mg PO Q Day

Peds ≥20 to <30 kg:

450 mg PO Q Day or

Liquid 14 mg/kg QD

Peds ≥ 15 to <20 kg:

225 mg PO QD (= ½ pill)

or Liquid 14 mg/kg QD

Peds ≥10 to < 15kg:

Liquid 14 mg/kg QD

Ganciclovir**

5 mg/kg IV Q DAY

Foscarnet**

90 mg/kg

IV Q DAY

Maribavir*,***, **** 400mg

PO BID

(Age ≥ 12 years and

weight ≥ 35kg )

Duration of Maintenance therapy:

• Maintenance therapy should be given for at least 2 weeks after induction therapy has been completed.

• Preemptive therapy may be discontinued when the surveillance test is negative after a minimum of 3 weeks

of therapy (at least one week induction). Shorter courses may be appropriate for subsequent episodes of

CMV reactivation. Please consult the LTFU office for questions (206-667-4415)

* ValGANCiclovir absorption is significantly enhanced when taken with food; thus patients should be instructed to

take ValGANCiclovir with food. Patients with poor oral intake, severe diarrhea/gut GVHD are NOT good

candidates for ValGANCiclovir or Maribavir and should receive IV ganciclovir daily.

**Use actual weight unless actual weight is above 150% of ideal weight. For patients who are > 150% ideal body

weight, the weight used should be capped at 150% of ideal body weight.

***Maribavir to be considered in failure/intolerance of “Preferred” agents ; screen for drug-drug interactions.

****Because of drug-drug interaction, Maribavir should not be given simultaneously with CYP3 substrates like

Cytoxan and a 48-hour washout period is recommended.

Note: Any questions on maintenance therapy, including drug resistance, Contact the LTFU office

(Appendix A).

Monitoring during treatment:

• CBC and differential must be measured within 24 hours before initiating treatment.

• CBC and differential must be measured 2-3 times weekly during treatment with

ValGANCiclovir or ganciclovir.

• Daily CBC is mandatory if the absolute neutrophil count (ANC) is <1,500/mm

• If ANC <1,000/mm

before ValGANCiclovir or ganciclovir is started, alternative

therapy is foscarnet.

• Renal function tests must be measured at least weekly.

Dose adjustment and other precautions during treatment:

• STOP ValGANCiclovir or ganciclovir if the ANC is below 1,000/mm

and consider foscarnet.

• AVOID using ValGANCiclovir, ganciclovir and foscarnet concurrently with acyclovir.

Please contact the LTFU office (Appendix A) for consultation.

• ValGANCiclovir, ganciclovir and foscarnet MUST be adjusted for renal dysfunction.

3. CMV Prophylaxis After Day 100 in Seropositive Cord Blood Transplant Recipients

CMV seropositive cord blood transplant recipients remain at significantly increased risk for CMV

reactivation after day 100 after transplant. Therefore, antiviral prophylaxis and continued close

monitoring after day 100 (see Table 3 below) are recommended for all CMV seropositive cord

blood transplant recipients.

Table 3: CMV Prophylaxis and Monitoring after Day 100 to 1 Year for CMV-seropositive Cord Blood

Recipients with Prior Posttransplant CMV Reactivation

DOSING

PREFERRED

ALTERNATIVE

MONITORING

BLOOD

Able to tolerate PO

Unable to

tolerate PO

Able to tolerate

Adult or Pediatric ≥50 kg

ValGANCiclovir

†

900mg PO QD

Ganciclovir

5 mg/kg IV

Q DAY

Valacyclovir*

2 grams PO TID

Weekly:

CMV PCR,

Creatinine,

CBC with

Differential.

Pediatric ≥40 to <50 kg

ValGANCiclovir

†

675 mg PO QD(=1½ pills)

Valacyclovir*

2 grams PO TID

Pediatric ≥30 to <40 kg

ValGANCiclovir

†

450 mg PO QD

Valacyclovir*

1 gram PO TID

Pediatric ≥20 to < 30 kg

ValGANCiclovir

†

450 mg PO QD)

or Liquid 14 mg/kg QD

Valacyclovir*

1 gram PO TID

Pediatric ≥15 to < 20 kg

ValGANCiclovir

†

225 mg PO QD(= ½ pill)

or Liquid 14 mg/kg QD

Acyclovir*

600 mg/m

QID

Pediatric ≥10 to < 15 kg

ValGANCiclovir

†

Liquid 14 mg/kg QD

Acyclovir*

600 mg/m

PO QID

† Absorption of ValGANCiclovir is significantly enhanced when taken with food; thus patients should be instructed to take ValGANCiclovir

with food. Patients with poor oral intake, severe diarrhea/gut GVHD are NOT good candidates for ValGANCiclovir and should receive IV

ganciclovir daily.

* Valacyclovir tablets should NOT be crushed. Oral acyclovir suspension has poor bioavailability and is not a preferred choice.

Use actual weight unless actual weight is above 150% of ideal weight. For patients who are > 150% ideal body

weight, the weight used should be capped at 150% of ideal body weight.

Table 4: CMV Prophylaxis and Monitoring after Day 100 for CMV-seropositive Cord Blood

Recipients without Prior Posttransplant CMV Reactivation

DOSING

PREFERRED

ALTERNATIVE

MONITORING

BLOOD

Able to tolerate

PO intake

Unable to

tolerate PO

intake

Adult or Pediatric ≥50 kg

Valacyclovir*

2 grams PO TID

Acyclovir

‡

500 mg/m

IV Q 8 hr

Ganciclovir

5 mg/kg

IV Q DAY

Weekly:

CMV by PCR

Creatinine and

CBC with

Differential

Pediatric ≥40 to <50 kg

Valacyclovir*

2 grams PO TID

Pediatric ≥30 to <40 kg

Valacyclovir*

1 gram PO TID

Pediatric ≥20 to < 30 kg

Valacyclovir*

1 gram PO TID

Pediatric ≥15 to < 20 kg

Acyclovir

600 mg/m

PO QID

Pediatric ≥10 to < 15 kg

Acyclovir

600 mg/m

PO QID

* Oral Valacyclovir is the preferred agent and is available in tablets or compounded liquid formulation for

children.

Crushing tablets is NOT recommended.

‡

If patients cannot tolerate oral tablets or liquid formulation, they should receive IV Acyclovir (adjusted to

ideal body weight). Oral acyclovir suspension has poor bioavailability, thus not a preferred choice.

Use actual weight unless actual weight is above 150% of ideal weight. For patients who are > 150%

ideal body weight, the weight used should be capped at 150% of ideal body weight.

Dose adjustment and other precautions during treatment:

• STOP ganciclovir or ValGANCiclovir if the ANC is below 1,000/mm

and consider

acyclovir, valacyclovir or foscarnet, as clinically indicated.

• AVOID using ganciclovir, ValGANCiclovir, foscarnet and valacyclovir concurrently

with acyclovir. Please contact the LTFU office (Appendix A) for consultation.

• Ganciclovir, foscarnet, ValGANCiclovir, valacyclovir and acyclovir MUST be adjusted

for renal dysfunction.

E. Fungal organisms

The current standard practice for antifungal prophylaxis is to administer fluconazole (400

mg/day) until day 75 after an allogeneic or CD34 selected autologous transplant or until

engraftment and resolution of mucositis after an unselected autologous transplant. This

strategy has been shown to reduce the incidence of candidemia and candidiasis-related

mortality. Fluconazole does not prevent infection with Aspergillus and other mold

species.

F. Intravenous immunoglobulin (IVIG) replacement and adjunctive therapy

A) Use of IVIG after hematopoietic cell transplantation (HCT) from day 100

through 1 year.

Reported IVIG studies are listed in the end of the LTFU general guidelines

[1-9]

. For

information regarding IVIG administration before100 days after transplant see

Standard Practice Committee guidelines.

1. Dosing and administration of prophylactic IVIG:

a. For allogeneic patients transplanted for myeloma, low grade lymphoma or CLL,

Administer IVIG 400 mg/kg at monthly intervals to maintain serum IgG levels above

400 mg/dL for 10 months after transplant prior to start of vaccinations.

b. For primary immune deficiency disease (PID):

Pre-infusion IgG serum level

(mg/dL)

IVIG dosing regimen

1,2

600 – 1000

Begin at 200 mg/kg/every 2 weeks and

wean to 400 mg/kg/every 4 weeks if

troughs remain satisfactory

< 600

300 mg/kg/every 2weeks up to 500 mg/kg

every week

>1000

400 mg/kg/every 4 weeks until B cell

function fully restored

When low levels are attributable to increased losses (e.g. chronic diarrhea) both IVIG dose and

frequency should be increased.

For pediatric patients the maximum dose of IVIG is 40 grams.

For pediatric patients whose central line is only being used for IVIG

prophylaxis, transition to subcutaneous human immunoglobulin preparation

(Hizentra



) may be considered under the approval and guidance of Pediatric

Immunology Service.

c. Other than above diseases, for allogeneic patients with haploidentical donors

or cord blood transplant, pediatric patients with unrelated donors or for

patients with ongoing infections or chronic GVHD with severe

hypogammaglobulinemia:

Continue to check IVIG levels monthly and administer IVIG 400 mg/kg at monthly

intervals to maintain serum IgG levels above 400 mg/dL. Continue for 10 months

after transplant prior to anticipated start of routine vaccinations.

d. IVIG should be held two months before the annual posttransplant evaluation to assess

immune reconstitution. (e.g. serum immunoglobulins levels and other immunological

panel).

e. Select immunoglobulin product according to precautions to decrease adverse effects

as applicable (see cautionary note below).

B) Use of IVIG after hematopoietic cell transplantation (HCT) > 1 year

Dosing and administration of prophylactic IVIG beyond 1 year

For allogeneic patients with Chronic GVHD beyond 1 year with recurrent

sinopulmonary infections and persistent hypogammaglobulinemia

Recommend to check IgG level monthly and administer IVIG 400mg/kg at

monthly intervals to maintain serum IgG levels > 400mg/dl

C) IVIG for treatment of CMV pneumonia:

There is no convincing efficacy data to add standard IVIG to antiviral therapy for

CMV pneumonia after HCT. The overall benefit of CMV IgG combined with

antiviral for treatment of CMV pneumonia has been reported by some but not all

investigators. Due to high mortality associated with CMV pneumonia, some experts

recommends antiviral therapy combine with CMV IgG as follows:

• CMV-IVIG may be administered at 150mg/kg every other day for 2 weeks (7

doses) followed by weekly administration for 4 additional weeks in combination

with anti-CMV medication.

• When high titer CMV-IVIG product (CytoGam) is not available, some experts has

recommended using standard IVIG at 500mg/kg given at the same schedule as

described above for CMV IgG.

D) Premedications before IVIG administration:

Given the high incidence of side effects of IVIG infusion (i.e., fever, chills, nausea,

emesis, headache, myalgias, rash and hypotension without anaphylaxis),

premedication with acetoaminophen and anti-histaminices (i.e., diphenhydramine) is

recommended.

E) Contraindication for IVIG:

1. Antibodies to IgA present

2. Anaphylaxis or severe prior reaction to immunoglobulin or serum therapy.

F) Cautionary note about IVIG:

IgA deficiency: IgA deficiency is considered a contraindication for IVIG use because

patients may develop IgE antibodies to IgA which increases their risk of anaphylaxis

if exposed to a product containing significant quantities of IgA. IVIG formulation

products with the lowest IgA content available should be given to patients known to

be deficient in IgA who require IVIG and who do not have detectable antibodies to

IgA. All patients with absent pre-transplant serum IgA levels should be evaluated for

the presence of anti-IgA antibodies. (see table below)

Renal insufficiency (creatinine clearance less than 60 ml/min):

Sucrose-free containing IVIG products should ONLY be used in the setting of renal

insufficiency. (see table below)

Continued F: Cautionary note about IVIG, Renal insufficiency:

IVIG Preparations

Preparation

Sugar Content

IgA Content

CMV IVIG

Cytogam

5% Sucrose

IVIG

Carimune

5% Sucrose

720mcg/ml

Panoglobulin

5% Sucrose

720mcg/ml

Gammar

5% Sucrose

Sandoglobulin

5% Sucrose

Octagam

10% Maltose

<200 mcg/ml

Venoglobulin

5% Sorbitol

15-50mcg/ml

Flebogamma

5% Sorbitol

<50mcg/ml

Gammar

5% Glucose

<25 mcg/ml

Iveegam

5% Glucose

<10mcg/ml

Low IgA containing IVIG

Polygam

2% Glucose

<3.7mcg/ml

Gammagard SD (powder)

2% Glucose

<1 mcg

Sugar Free IVIG

Gamunex

45mcg/ml

Gammagard 10% (liquid)

37 mcg/ml

Privigen

<25mcg/ml

Gammaplex

V. FEVER OF UNKNOWN ETIOLOGY

Fever should be considered a sign of infection until proven otherwise. The following

evaluation should be instituted promptly in all patients with fever.

1. Complete physical examination including the perineal and rectal area.

2. Blood culture

3. Urine culture

4. Cultures from any site suspicious for infection

5. Chest X-ray. CT of the chest should be obtained if respiratory symptoms are

present even if the chest x-ray is negative.

6. Sinus CT scan should be obtained if respiratory symptoms are present.

Empiric treatment with antibiotics may be indicated after cultures have been obtained.

Sudden, overwhelming sepsis syndrome with Pneumococcus or other encapsulated

organisms can occur, especially in patients who have poor compliance with antibiotic

prophylaxis. Organisms should be tested for antibiotic susceptibility. Please contact the

LTFU office (Appendix A) for consultation or assistance regarding specific treatment and

other evaluation as needed.

VI. EVALUATION OF RESPIRATORY PROBLEMS AND LUNG INFILTRATES

If the patient develops respiratory problems that do not resolve after initial diagnostic

evaluation and treatment, we urge you to contact the LTFU office (Appendix A) to discuss

further evaluation and management.

A. Diagnostic Evaluation

1. Chest x-ray PA and lateral

2. Lung CT scan if respiratory symptoms persist

3. Sinus CT scan if symptomatic or suspected sinus infection

4. Blood culture (always)

5. Nasopharynx culture for pertussis if clinically indicated

6. Bronchoalveolar Lavage (BAL) is recommended for patients with pulmonary

symptoms or pulmonary infiltrates to rule out infectious complication.

7. Transbronchial or thoracoscopic biopsy if BAL is negative with persistent pulmonary infiltrates

B. Tests Recommended for BAL and Transbronchial Biopsy Specimens

See algorithm on the end of this section for overview.

1. Bacterial, fungal, mycobacterial, and Legionella cultures

2. Stains specific for viral inclusions and general morphology to rule out malignancy

(Papanicolaou, Wright-Giemsa, Hematoxylin & Eosin)

3. Methenamine silver, Kinyoun AFB, modified Gimenez and Gram stains, KOH

4. for BAL Aspergillus Galactomannan Enzyme Immunoassay (GM EIA) (fluid only) or aspergillus by PCR

5. CMV shell vial test

6. DFA (direct fluorescent antibody) staining for herpes viruses (HSV, VZV),

7. PCR for respiratory viruses (RSV, influenzae A and B, parainfluenzae, adenovirus)

8. DFA (direct fluorescent antibody) for Legionella or PCR for Legionella

9. If clinically indicated, PCR or IHC for EBV.

C. Evaluation of Pulmonary Nodules or Persistent Infiltrates with a Negative BAL

1. Thoracoscopic biopsy or open lung biopsy is recommended for patients with nodular

infiltrates to rule out fungal, malignancy, bronchiolitis obliterans syndrome (BOS),

cryptogenic organizing pneumonia (COP)or other processes. Thoracoscopic lung

biopsy generally causes less morbidity than open lung biopsy. Fresh tissue should be

submitted for microbiologic and pathologic evaluation.

2. Tests recommended for lung tissue

a) Fresh samples should be obtained for DFA and culture or PCR for Legionella.

b) Imprints of the frozen section and permanent section should be made and evaluated

for morphology and assessment of viral inclusions and possible malignancy by

using Papanicolaou, Wright-Giemsa, hematoxylin and eosin stains. Specimens

should be evaluated for Pneumocystis, fungi, mycobacteria, Legionella and other

bacteria by using methenamine silver, Kinyoun AFB, modified Gimenez and

tissue Gram stains. Warthin-Starry stain should be done if needed. When

available, immunohistochemistry staining and in situ hybridization are

recommended for detection of viral infection.

c) Samples should be submitted for microbiologic evaluation to detect fungi,

mycobacteria, and other bacterial organisms.

d) Aspergillus by PCR

e) Samples should be submitted for viral cultures, in addition:

-DFA staining for herpes viruses (HSV, VZV)

-PCR for respiratory viruses (RSV, influenzae A and B, parainfluenzae,

adenovirus)

-Shell vial testing for CMV or PCR testing for CMV, VZV, HSV, EBV, HHV-6,

depending on the level of clinical suspicion.

3. If Infections Ruled Out, Then Consider BOS After Allogeneic Transplant

See section X, I for work up and treatment

Tests Recommended for Bronchoalveolar Lavage Fluid or

Lung Biopsy Specimens

ALWAYS:

• Bacteria & fungal cultures

• Gram Stains, KOH

• Histology / cytology

(H & E, silver stain)

STRONGLY RECOMMENDED:

• Legionella (culture & DFA or PCR)

• AFB (culture & stain)

• Modified Gimenez stain

• Viral cultures

• Aspergillus by PCR

• Aspergillus Galactomannan Enzyme

Immunoassay (GM EIA) (fluid only)

• Keep material in the refrigerator / freezer until a definitive diagnosis is made.

• If any of the tests above is not available locally, please contact the LTFU office (Appendix A).

During respiratory season:

• RSV and others respiratory virus

(for example influenzae A & B, parainfluenzae,

adenovirus) by PCR

If VZV is suspected (skin lesions, hepatitis):

• DFA or PCR

If HSV is suspected:

• DFA or PCR

If patient or donor are CMV seropositive:

• Shell vial cultures for CMV

If EBV is suspected:

• EBV by PCR or immuno-histo-

chemistry, IHC

SPECIFIC SITUATIONS

VII. EVALUATION OF DIARRHEA AND OTHER GI COMPLICATIONS

If the patient develops diarrhea or other gastrointestinal complications that do not resolve

after initial diagnostic evaluation and treatment (see algorithm on the end of this section), we

urge you to contact the LTFU office (Appendix A) to discuss further evaluation and

management.

A. Diagnostic Evaluation and Initial Management

1. Diarrhea caused by oral magnesium supplementation should be ruled out. If

necessary, patients should receive IV replacement of magnesium.

2. The clinical evaluation of diarrhea depends on its duration and volume, the presence of

blood, and the occurrence of fever and other constitutional symptoms. Normal stool

volume is <200 ml/day. Volumes >1000 ml/day indicate a small intestinal source

(GVHD, magnesium effect, enteric virus, giardiasis or cryptosporidiosis). Bloody

diarrhea suggests a bacterial enteric pathogen, GVHD or CMV enteritis. A more

directed approach can be taken if there is a history of foreign travel or history of

exposure to children from day-care setting. An algorithm for evaluation of diarrhea is

summarized on the following page.

3. Patients should remain NPO for 24-48 hours and IV fluids should be given to prevent

volume depletion. Special diets are recommended for patients with diarrhea caused by

GVHD (Section XX).

4. Immunosuppressive medications should be given IV if the volume of diarrhea exceeds

1.5 liter/day in adults of if diarrhea persists for more than 3 days. Contact the LTFU

office (Appendix A) for IV doses of immunosuppressive medications.

5. Monitor creatinine closely, and check the cyclosporine or tacrolimus (FK506) level weekly.

6. Avoid treatment with anti-diarrhea agents containing atropine-like drugs (e.g. Loperimide).

7. If the diarrhea does not resolve with these measures or recurs after the patient resumes oral

medications, a search for enteric pathogens including, for example, norovirus, c. difficile,

adenovirus and for children, rotavirus and endoscopy with biopsies is recommend.

Adequate platelet count and coagulation parameters should exist to do biopsy safely.

B. Procedures for Gastrointestinal Endoscopic Biopsies

1. Maintain platelet counts >50,000 before and for 3 - 4 days after the procedure.

2. Esophagogastroduodenoscopy should be carried out with multiple biopsies. Biopsy

of any erosion or ulcerations is indicated. If there are no macroscopic abnormalities

found, we suggest 6-8 biopsies of the gastric antrum. To minimize the risk of

bleeding, avoid biopsies of the duodenum unless this is the only site of abnormalities.

3. When diarrhea is the major GI symptom in a patient without other manifestations of

GVHD, either upper endoscopy or colonoscopy may be indicated to rule out CMV

infection or occult GVHD. All infections other than CMV can be identified from

stool samples. Biopsies obtained from the gastric antrum are usually sufficient to

diagnose GVHD, even in cases where the major symptom is diarrhea.

4. Biopsies samples (n = 4) should be placed in fresh buffered formalin.

5. Fresh biopsy samples (gastric, rectal or colon) should be placed in viral transport

medium and sent to a virology lab to perform rapid testing (shell vial) for CMV and

Varicella zoster as well as HSV if there are esophageal lesions. The last stomach

sample should be placed in CLO media to test for H. Pylori.

6. Please send slides and biopsy blocks to the address below if you wish our pathologists

to review the specimen. Because GVHD may be found in one but not all sites, it is

important to send as many slides or blocks as possible.

7. Please label the material with the patient’s name, the date obtained and sites.

8. Send the material to the following address:

Fred Hutchinson Cancer Center

825 Eastlake Ave. E. / Attn: LTFU G-1500

PO Box 19023

Seattle, WA 98109-1023

9. Please call (206) 667-4415 to notify our office when to expect the arrival of shipments.

C. Algorithm for Evaluation of Acute Onset Diarrhea in Transplant Survivors*

*In all patients with diarrhea, oral administration of Mg

should be discontinued, and IV

administration should be substituted.

Severity of illness

Asymptomatic or other symptoms limited

to anorexia, nausea or vomiting

Chronic GVHD

in other organs?

Yes

Test stool for C.

difficile, giardia

antigen, O&P

Other family

members ill with

similar symptoms?

Pos

Neg

Treat

Consider need to

document intestinal

GVHD and to R/O

CMV by biopsy

Yes

Fever, rigors or

bloody diarrhea

Test stool for

• enteric bacterial pathogens:

Salmonella

Shigella

C. fetus jejuni

H7:0157 E. coli

Yersinia

Aeromonas

• C. difficile

• viral culture-including

adenovirus and norovirus

• E. histolytica

• Rotavirus EIA

Neg

Pos

Treat

Endoscopic biopsies

and cultures

CMV

GVHD

Another Dx

Treat

Watchful

waiting

VIII. TREATMENT OF SPECIFIC INFECTIONS

Please contact the LTFU office (Appendix A) to discuss the most appropriate therapy in

patients developing any of the infections described below.

A. Cytomegalovirus (CMV)

Late onset CMV infections have become an increasingly difficult problem for patients

who have had a hematopoietic stem cell transplant. Reconstitution of the T cells that

respond to CMV is slow and may be delayed by prophylactic use of ganciclovir during

the first 3 months after the transplant. Patients at risk of CMV infection should be

monitored closely and should receive prophylactic antiviral treatment to prevent CMV

disease. Note that some patients present with nausea and vomiting as initial

manifestations of CMV infection, in the absence of CMV viremia. To obtain

recommendations for treatment of patients who develop CMV pneumonia or other

diseases caused by this virus, we urge you to contact the LTFU office (Appendix A).

B. Varicella zoster

Varicella zoster virus (VZV) infection occurs in 40-50% of patients during the first year

after the transplant (peak risk 2-8 months) when prophylactic acyclovir is not given. In

approximately 10% of patients, VZV infection presents with abdominal distension or

pain in the abdomen or back, often accompanied by increased serum ALT, before the

development of any skin lesions. Visceral VZV is frequently fatal if treatment is delayed.

If prodromal zoster or documented VZV infection occurs during the first year after the

transplant or at any time during continued treatment with immunosuppressive

medications, parenteral treatment should be started immediately with high dose acyclovir,

and blood should be sent to confirm the diagnosis by a VZV PCR test.

Patients should be treated according to the following recommendations.

1. Fluids should be administered at twice the daily maintenance level during treatment

with high dose acyclovir.

2. Prophylactic treatment with acyclovir or valacyclovir should be resumed after high–

dose treatment has been completed.

3. Renal function tests must be followed closely during treatment with high dose

acyclovir.

4. Doses of acyclovir must be decreased in patients with renal impairment.

Disseminated zoster:

IV acyclovir 500 mg/m

administered as a one hour IV infusion q 8 hr until there is no

evidence of new lesions for 72 hours. Treatment may then be continued with

valacyclovir 1 gm t.i.d. p.o. for patients > 40 kg and 500 mg t.i.d. p.o. for patients < 40

kg to complete the course of treatment (generally 10-14 days).

Localized zoster:

IV acyclovir 500 mg/m

administered as a one hour IV infusion q 8 hr for three doses,

then change to oral valacyclovir as outlined above to complete the course of treatment.

Dose adjustment is necessary in patients with impaired renal function.

C. Pneumocystis Carinii Pneumonia (PCP)

All patients should receive trimethoprim-sulfamethoxazole prophylaxis (Section IV A).

Patients who do not comply with the recommended prophylactic regimen may develop

PCP and will require appropriate treatment. Trimethoprim-sulfamethoxazole should be

given at a dose of 15-20 mg/kg/day of the trimethoprim component in divided doses every

6-8 hr for 14-21 days for treatment of PCP pneumonia.

IX. VACCINATIONS

Antibody titers to vaccine-preventable diseases (e.g. tetanus, polio, measles, mumps,

rubella, and encapsulated organisms) decline between 1 and 4 years after allogeneic or

autologous HCT if the recipient is not revaccinated. The clinical relevance of reduced

antibody titers to these diseases is not readily apparent because only a limited number

of vaccine-preventable diseases have been reported among HCT recipients.

Nonetheless, vaccine-preventable diseases continue to pose risks to the population.

Additionally, there is evidence that infections with encapsulated organisms, measles,

varicella and influenzae can pose risk to HCT recipients. Therefore, HCT recipients

should be routinely vaccinated after HCT so that they can experience immunity to the

same vaccine-preventable diseases as others.

Guidelines for vaccination after HCT have been published by relevant societies

1,2,3,

well as the Advisory Committee on Immunization Practices (ACIP) within the Centers

for Disease Control and Prevention (CDC)

and provides the foundation for our

vaccination practices explained elsewhere in further detail.

Vaccination begins at 3

months for SARS-CoV-2, and 6 months for influenza (or 3-4 months when seasonal

prevalence is high). Other non-live routine childhood vaccinations that must be

repeated after HCT, may begin as early as 6 months in Non-Primary Immune

Deficiency patients but should be considered in conjunction with factors that

significantly delay immune reconstitution. Live vaccines (MMR or MMR-V) are

generally not administered before 2 years after HCT.

See tables for recommendation for vaccinations for adult and pediatric patients:

IX.A1 Adult Vaccination Schema-Non-Live Vaccines: Vaccination before

12 months (if eligible)

IX.A2 Adult Vaccination Schema- Non-Live Vaccines: Standard

vaccination schedule

IX.A3 - Adult Vaccination Schema- For MMR(V) and Zoster Vaccines

IX.P1 Pediatric Vaccination Schema: Vaccination before 12 months (if

eligible)

IX.P2 Pediatric Vaccination Schema: If patient not vaccinated before 12

months

IX.P3: Pediatric Vaccination Schema: For MMR (V) and Zoster Vaccines

Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) recommend that vaccine providers should strongly consider observing patients for 15

minutes after they are vaccinated. If syncope develops, patients should be observed until the symptoms resolve.

Table IX.A1: Adult Vaccination Schema for Non-Live Vaccines: starting before 12 months (if eligible)

1,2

Vaccine

>3m

~4m

~5m

>6m

>7m

>8m

>10m

>12m

>13m

>14m

>18m

>24m

Influenzae (IIV4)

(Sept –

March), non-adjuvanted

IIV4 (Flu)

High-

Dose

IIV4 (Flu)

High-

Dose

Pentacel

(DTaP-

IPV/Hib)

4,5

Pentacel

 titers

Meningococcal ACWY

(MenQuadfi, Menveo,

MCV4)

MCV4

Meningococcal Group B

(Bexsero

)

Bexsero

Pneumococcal-conjugate

(Prevnar 20™)

 titers

PCV20

 titers

Hepatitis A

HAV

Hepatitis B

10,11

HBV

 titers

HPV (Gardasil), 9 to 45 y

HPV

SARS-CoV-2

(Moderna or Pfizer)

COVID

Abbreviations: DTaP, Diphtheria-Tetanus-acellular Pertussis; Hib, H. Influenzae type B; HPV, human papilloma virus; IPV, inactivated polio vaccine; MCV4, meningococcal

conjugate vaccine

Footnotes:

1 For adults transplanted for immunodeficiency disorders, refer to the following section, “Posttransplant Vaccination of Primary Immunodeficiency Disorders.”

2 For non-live vaccine, vaccination may be deferred if receiving ongoing immunoglobulin replacement for delayed immune reconstitution or other factors in Table

IX.1 are present.

3 Ideally start the 2-dose series at 6 months but during high prevalence influenza outbreaks may start as early as 3 months. If non-adjuvanted, high-dose

quadrivalent inactivated influenza vaccine is unavailable, then give standard-dose formulation. The 2-dose series does not apply if no longer on

immunosuppressive therapy and >2y post-HCT.

4 Separate component vaccines (shots) may be used instead for DTaP, IPV, and Hib if Pentacel

is unavailable.

5 If not using Pentacel

and DTaP is unavailable, then may use Adacel

= Tdap (age ≥ 10 y through 64 y) or Boostrix

= Tdap (age ≥ 10 y).

6 Check anti-tetanus toxoid and anti-Hib titers if not done at 12 months.

7 Recommended for patients with anatomic or functional asplenia condition (i.e., chronic GVHD) or increased environmental risk. Trumenba® can be substituted for

Bexsero® (3 doses: 0, 2 and 6 months apart).

8 Check baseline titers for S. Pneumonia (IgG, 23 serotypes) before beginning PCV20 vaccination.

9 Check titers for S. Pneumonia (IgG, 23 serotypes) 1-2 months after each PCV20 is given. A positive response to PCV20 is defined: as achieving a seroprotective IgG level

against S. pneumoniae in ≥15 out of 20 PCV20 serotypes at 1-2 months post-vaccination. A positive response requires no further PCV20 vaccination.

10 A complete series of Hepatitis B vaccination is accomplished preferably with a total of 4 x single 0.5 mL doses of Heplisav-B

based on data extrapolated from patients with

chronic kidney disease or on hemodialysis for ESRF. Alternatively, a total of 4 x double (2 mL total) doses of Engerix-B

may be given. Post-vaccination testing for antibody

to hepatitis B surface antigen is recommended 1-2 months after the 4th dose to ensure protection (Check titers at 24-month visit if not done at 20 months). Patients who do not

respond to the primary vaccine series should receive an additional 1-3 doses of the same vaccine or, alternatively, repeat series with a different vaccine brand (e.g., double

doses of Engerix-B

if did not respond to Heplisav-B

or single doses of Heplisav-B

if did not respond to Engerix-B

11 If NOT administering hepatitis B series using Heplisav-B

, Twinrix

can be administered on days when HAV and HBV are given together. (Twinrix

approved for age ≥ 18 y)

12 Dose 1 of the SARS-CoV-2 vaccination series should begin at > day +90. For allogeneic transplant patients, the initial dose should be arranged to be given

as part of the day +80 work up. Communications with referring provider should be done to advise when subsequent doses are due.

13 Dose 3 is preferably given 2 months after dose 2 but may be given as early as 1 month after dose 2 to avoid a missed vaccination opportunity; Dose 4 is 2

months after Dose 3.

Table IX.A2: Adult Vaccination Schema for Non-Live Vaccines: Standard vaccination schedule

1,2

Abbreviations: DTaP, Diphtheria-Tetanus-acellular Pertussis; Hib, H. Influenzae type B; HPV, human papilloma virus; IPV, inactivated polio vaccine; MCV4, meningococcal conjugate vaccine.

Footnotes:

1 For adults transplanted for immunodeficiency disorders, refer to the following section, “Posttransplant Vaccination of Primary Immunodeficiency

Disorders.”

2 For non-live vaccine, vaccination may be deferred if receiving ongoing immunoglobulin replacement for delayed immune reconstitution or other factors in

Table IX.1 are present.

3 Ideally start the 2-dose series at 6 months but during high prevalence influenza outbreaks may start as early as 3 months. If non-adjuvanted, high-dose

quadrivalent inactivated influenza vaccine is unavailable then give standard-dose formulation. The 2-dose series does not apply if no longer on

immunosuppressive therapy and >2y post-HCT.

4 Separate component vaccines (shots) may be used instead for DTaP, IPV, and Hib if Pentacel

is unavailable.

5 If not using Pentacel

and DTaP is unavailable, then may use Adacel

= Tdap (age ≥ 10 y through 64 y) or Boostrix

= Tdap (age ≥ 10 y).

6 Check anti-tetanus toxoid and anti-Hib titers.

7 Recommended for patients with anatomic or functional asplenia condition (i.e., chronic GVHD) or increased environmental risk). Trumenba® can be

substituted for Bexsero® (3 doses: 0, 2 and 6 months apart).

8 Check baseline titers for S. Pneumonia (IgG, 23 serotypes) before beginning PCV20 vaccination.

9 Check titers for S. Pneumonia (IgG, 23 serotypes) 1-2 months after each PCV20. A positive response to PCV20 is defined: as achieving a seroprotective

IgG level against S. pneumoniae in ≥ 15 out of 20 PCV20 serotypes at 1-2 months post-vaccination. A positive response requires no further PCV20

vaccinations.

10 A complete series of Hepatitis B vaccination is accomplished preferably with a total of 4 x single 0.5 mL doses of Heplisav-B

based on data

extrapolated from patients with chronic kidney disease or on hemodialysis for ESRF. Alternatively, a total of 4 x double (2 mL total) doses of Engerix-

may be given. Post-vaccination testing for antibody to hepatitis B surface antigen is recommended 1-2 months after the 4th dose to ensure protection

(Check titers at 24-month visit if not done at 20 months). Patients who do not respond to the primary vaccine series should receive an additional 1-3

doses of the same vaccine or, alternatively, repeat series with a different vaccine brand (e.g., double doses of Engerix-B

if did not respond to Heplisav-

or single doses of Heplisav-B

if did not respond to Engerix-B

11 If NOT administering hepatitis B series using Heplisav-B

, Twinrix

can be administered on days when HAV and HBV are given together. (Twinrix

approved for age ≥ 18 y).

12 Dose 1 of the SARS-CoV-2 vaccination series should begin at > day +90. For allogeneic transplant patients, the initial dose should be arranged to be

given as part of the day +80 work up. Communications with referring provider should be done to advise when subsequent doses are due.

13 Dose 3 is preferably given 2 months after dose 2 but may be given as early as 1 month after dose 2 to avoid a missed vaccination opportunity; Dose 4 is

2 months after Dose 3.

Vaccine

>3m

~4m

>6m

>7m

>8m

>12m

>13m

>14m

>16m

>18m

>24m

Influenzae (IIV4)

(Sept –

March), non-adjuvanted

IIV4 (Flu)

High-Dose

IIV4 (Flu)

High-Dose

Pentacel

(DTaP-

IPV/Hib)

4,5

Pentacel

 titers

Meningococcal ACWY

(MenQuadfi, Menveo,

MCV4)

MCV4

Meningococcal Group B

(Bexsero

)

Bexsero

Pneumococcal-conjugate

(Prevnar 20™)

 titers

PCV20

 titers

Hepatitis A

HAV

Hepatitis B

10, 11

HBV



titers

HPV (Gardasil), 9 to 45 y

HPV

SARS-CoV-2

(Moderna or Pfizer)

COVID

Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) recommend that vaccine providers should strongly consider observing patients for 15 minutes after

they are vaccinated. If syncope develops, patients should be observed until the symptoms resolve.

Table IX.A3: Adult Vaccination Schema: For MMR(V)

and Zoster (SHINGRIX)

A) Live MMR or Varicella Vaccines

~24 m

24 m

>25m

~27m

Measles/Mumps/Rubella (MMR)

2-1-8 Rule

No Live Vaccines are given

until at least 2 yr post-HCT

and then only when certain

other criteria are met

MMR

Varicella-Zoster (Varivax)

Seronegative ONLY and 2-1-8 Rule

First dose may be given with MMR

 titers

VZV

 titers

a. 2-1-8 Rule = Not until 2 years post HCT plus > 1 year off all immunosuppressive therapy (IST) plus >8 months since last dose of IVIG/VZIG or most recent plasma transfusion.

b. Check baseline varicella serology at least 8 months off IVIG/VZIG when ready to vaccinate to determine if necessary.

c. Check at least 1-2 months after Varivax to ensure seroconversion of the VZV seronegative patient.

B) Non-Live Shingles Vaccine

~12 m

>12m

>14m

ALLOGENEIC and AUTOLOGOUS

recipients AGE >18 y ONLY:

VZV Seropositive ONLY

SHINGRIX is not given until at least 1-y post-HCT

and then only when certain other criteria are met

 titers

SHINGRIX

1. Allogeneic recipients must also be age >18 y and >1 y after HCT, >8 m off immunosuppressive therapy without GVHD flare-ups. Autologous recipients must have also completed maintenance

immunotherapy (e.g. PD-1 inhibitors, proteosome inhibitors, daratumumab) which also prolongs duration of acyclovir/valacyclovir.

2. Patients should have VZV serology checked prior to vaccination (at least at least 8 months off IVIG/VZIG) to ensure still VZV-seropositive. If patient is VZV seronegative, do not give SHINGRIX but

follow the table above and offer Varivax while still following the 2-1-8 Rule.

3. Continue acyclovir or valacyclovir until one month after second Shingrix vaccination.

Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) recommend that vaccine providers should strongly consider observing patients for

15 minutes after they are vaccinated. If syncope develops, patients should be observed until the symptoms resolve.

Table IX.P1: Pediatric Vaccination Schema: Vaccination before 12 months (if eligible)

1,2

Vaccine

>3m

~4m

~5m

>6m

>7m

>8m

>10m

>12m

>14m

>18m

>24m

IIV4 – Age 6 m to <5 y

(September –March)

IIV4 (Flu)

Std-Dose

IIV4 (Flu)

Std-Dose

IIV4 – Age ≥5 y

(September –March)

IIV4 (Flu)

High-Dose

IIV4 (Flu)

High-Dose

Pentacel® (DTaP-IPV/Hib)

4,5

Pentacel

Pentacel®

 titers

Meningococcal ACWY

(MenQuadfi, Menveo, MCV4)

MCV4

Meningococcal Group B

(Bexsero®)

Bexsero®

Pneumococcal-conjugate

(Prevnar 20™)

PCV20

 titers

PCV20

 titers

Hepatitis A

HAV

Hepatitis B

HBV

 titers

HPV9 (Gardasil), 9 to 45 years

HPV

SARS-CoV-2 – Age ≥6 m

Pfizer or Moderna

COVID

Abbreviations: DTaP, Diphtheria-Tetanus-acellular Pertussis; Hib, H. Influenzae type B; HPV, human papilloma virus; IIV4, inactivated quadrivalent influenza

vaccine; IPV, inactivated polio vaccine; MCV4, meningococcal conjugate vaccine; PCV13, Prevnar 13; PPSV23, Pneumovax.

Footnotes:

1. For patients transplanted for immunodeficiency disorders see following section, “Posttransplant Vaccination of Primary Immunodeficiency Disorders”.

2. For non-live vaccine, vaccination may be deferred if receiving ongoing immunoglobulin replacement for delayed immune reconstitution or other factors in

Table IX.1 are present.

3. Ideally start the 2-dose series at 6 months but during high-prevalence influenza outbreaks may start as early as 3 months. If non-adjuvanted, high-dose

quadrivalent inactivated influenza vaccine is unavailable for children ≥ 5 years then give standard-dose based on Pediatric HCT Flu Study. The 2-dose series

does not apply if no longer on immunosuppressive therapy and >2y post-HCT.

4. Different combination vaccines may be used if Pentacel® is unavailable: Infanrix or Daptacel (= DTaP for age < 7 y), Pediarix = DTaP/HBV/IPV (age < 7 y).

5. If not using Pentacel® and DTaP is unavailable then may use Adacel = Tdap (age ≥ 10 y through 64 y ) or Boostrix = Tdap (age > 10 y).

6. Check Anti-tetanus toxoid and anti-Hib titers.

7. Recommended for anatomic or functional asplenia (i.e. chronic GVHD) or increased environmental risk. If patient is ≥10y, Trumenba® can be substituted for

Bexero® (3 doses: 0, 2, and 6 months apart).

8. Check titers for S. Pneumonia (IgG, 23 serotypes) to determine if an additional dose of PCV20 should be given.

9. If using Hepatitis B vaccine Recombivax HBR, dosing schedule is 0, 1 and 6 months if patient is 0 to 19 years of age.

10. Titer at 24-month visit if not done at 20 months. Post-vaccination testing for antibody to hepatitis B surface antigen is recommended 1-2 months after the 3

dose to ensure protection. Patients who do not respond to the primary vaccine series should receive an additional 1-3 double-doses of the same vaccine (or 4-

single dose series of Heplisav-B if age >18y).

11. Dose 1 of the SARS-CoV-2 vaccination series should begin at > day + 90. For allogeneic transplant patients as part of the day+ 80 work up, the initial dose

should be arranged to be given by the appropriate OPD Team). Communications with referring provider should be done to advise when subsequent doses are

due.

12. Dose 3 is preferably given 2 months after dose 2 but may be given as early as 1 month after dose 2 to avoid a missed vaccination opportunity; Dose 4 is 2

months after Dose 3.

Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) recommend that vaccine providers should strongly consider observing patients for

15 minutes after they are vaccinated. If syncope develops, patients should be observed until the symptoms resolve.

Table IX.P2: Pediatric Vaccination Schema: If patient not routinely vaccinated before 12 months

1,2;

Vaccine

>3m

~4m

~5m

>6m

>7m

>8m

>12m

>14m

>16m

>18m

>24m

IIV4 – Age 6 m to <5 y

(September –March)

IIV4 (Flu)

Std-Dose

IIV4 (Flu)

Std-Dose

IIV4 – Age ≥5 y

(September –March)

IIV4 (Flu)

High-Dose

IIV4 (Flu)

High-Dose

Pentacel® (DTaP-IPV/Hib)

4.5

Pentacel®

 titers

Meningococcal ACWY

(MenQuadfi, Menveo, MCV4)

MCV4

Meningococcal Group B

(Bexsero®)

Bexsero®

Pneumococcal-conjugate

(Prevnar 20™)

PCV20

 titers

PCV20

Hepatitis A

HAV

Hepatitis B

HBV

 titers

HPV9 (Gardasil), 9 to 45 y

HPV

SARS-CoV-2 – Age ≥ 6 m

Pfizer or Moderna

COVID

Abbreviations: DTaP, Diphtheria-Tetanus-acellular Pertussis; Hib, H. Influenzae type B; HPV, human papilloma virus; IIV4, inactivated quadrivalent influenza

vaccine; IPV, inactivated polio vaccine; MCV4, meningococcal conjugate vaccine; PCV13, Prevnar 13; PPSV23, Pneumovax.

Footnotes:

1. For patients transplanted for immunodeficiency disorders see following section, “Posttransplant Vaccination of Primary Immunodeficiency Disorders”.

2. For non-live vaccine, vaccination may be deferred if receiving ongoing immunoglobulin replacement for delayed immune reconstitution or other factors in

Table IX.1 are present.

3. Ideally start the 2-dose series at 6 months but during high-prevalence influenza outbreaks may give as early as 3 months. If non-adjuvanted, high-dose

quadrivalent inactivated influenza vaccine is unavailable for children ≥ 5 years, then give standard-dose based on Pediatric HCT Flu Study. The 2-dose series

does not apply if no longer on immunosuppressive therapy and >2y post-HCT.

4. Different combination vaccines may be used if Pentacel® is unavailable: Infanrix or Daptacel (= DTaP for age < 7 y), Pediarix = DtaP/HBV/IPV (age < 7 y).

5. If not using Pentacel® and DtaP is unavailable, then may use Adacel = Tdap (age ≥ 10 y through 64 y ) or Boostrix = Tdap (age > 10 y).

6. Check Anti-tetanus toxoid and anti-Hib titers.

7. Recommended for anatomic or functional asplenia (i.e. chronic GVHD) or increased environmental risk. If patient is ≤10y, Trumenba® can be substituted for

Bexero® (3 doses: 0, 2 and 6 months apart).

8. Check titers for S. Pneumonia (IgG, 23 serotypes) about 2 months after vaccine to determine if an additional dose of PCV20 should be given.

9. If using Hepatitis B vaccine Recombivax HBR, dosing schedule is 0, 1 and 6 months if patient is 0 to 19 years of age.

10. Titer at 24-month visit if not done at 20 months. Post-vaccination testing for antibody to hepatitis B surface antigen is recommended 1-2 months after the 3rd

dose to ensure protection. Patients who do not respond to the primary vaccine series should receive an additional 1-3 double-doses of the same vaccine (or 4-

single dose series of Heplisav-B if age >18y).

11. Dose 1 of the SARS-CoV-2 vaccination series should begin at > day + 90. For allogeneic transplant patients as part of the day+ 80 work up, the initial dose

should be arranged to be given by the appropriate OPD Team). Communications with referring provider should be done to advise when subsequent doses are

due.

12. Dose 3 is preferably given 2 months after dose 2 but may be given as early as 1 month after dose 2 to avoid a missed vaccination opportunity; Dose 4 is 2

months after Dose 3.

Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) recommend that vaccine providers should strongly consider observing patients for 15

minutes after they are vaccinated. If syncope develops, patients should be observed until the symptoms resolve.

Table IX.P3: Pediatric Vaccination Schema: For MMR(V) and Zoster (SHINGRIX)

1. 2-1-8 Rule = Not until 2 years post HCT plus > 1 year off all immunosuppressive therapy (IST) plus >8 months since last dose of IVIG/VZIG or most recent plasma transfusion.

2. Check baseline varicella serology at least 8 months off IVIG/VZIG when ready to vaccinate to determine if necessary.

3. Check at least 1-2 months after Varivax to ensure seroconversion of the VZV seronegative patient.

B) Non-Live Shingles Vaccine

<12m

~12 m

>12m

>14m

ALLOGENEIC and AUTOLOGOUS

recipients AGE >18 y ONLY:

VZV Seropositive ONLY

SHINGRIX is not given until at least 1 yr post-

HCT and then only when certain other criteria

are met

 titers

SHINGRIX

a. Allogeneic recipients must also be age >18 y and >1 y after HCT, >8 m off immunosuppressive therapy without GVHD flare-ups. Autologous recipients must have also completed maintenance

immunotherapy (e.g. PD-1 inhibitors, proteasome inhibitors, daratumumab) which also prolongs duration of acyclovir/valacyclovir.

b. Patients should have VZV serology checked prior to vaccination (at least 8 months off IVIG/VZIG) to ensure still VZV-seropositive. If patient is VZV seronegative, do not give SHINGRIX but

follow the table above and offer Varivax while still following the 2-1-8 Rule.

c. Continue acyclovir or valacyclovir until one month after second Shingrix vaccination

A) Live MMR or Varicella Vaccines

~24 m

24 m

>25m

~27m

Measles/Mumps/Rubella (MMR)

2-1-8 Rule

No Live Vaccines are given until at least 2 yr

post-HCT and then only when certain other

criteria are met

MMR

Varicella-Zoster (Varivax)

Seronegative ONLY and 2-1-8 Rule

First dose may be given with MMR

 titers

VZV

 titers

Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) recommend that vaccine providers should strongly consider observing patients for 15 minutes

after they are vaccinated. If syncope develops, patients should be observed until the symptoms resolve.

• Please keep records of all vaccinations (dates and types of all vaccines) given to the patient

after the transplant and report any toxicity to the LTFU.

Posttransplant Vaccination of Primary Immunodeficiency Disorders (PID):

❖ From a practical standpoint, patients with primary immunodeficiency disorders (PID) are not

candidates for the Standard Practice early vaccination policy that begins at 6 months after

transplant. Exceptions may be made for epidemics (e.g. seasonal influenza) or novel pandemics

(e.g. COVID-19), per pediatric attending recommendations.

❖ PID patients will first be considered as candidates for vaccination at 1 year after transplant if they

satisfy the following criteria:

A. It is reasonable to attempt a 3-month trial off IgG replacement therapy based on a

negative history of patient infections in the past 6 months and

B. The prevalence of community infections with influenza, RSV, metapneumovirus, or

parainfluenza during the planned trial off IgG therapy is low and

C. All of the following laboratory criteria:

Criteria

Comment

1. Trough IgG > 600 mg/dL

on standard IVIG dosing

Suggests numeric IgG reconstitution

2. Detectable serum IgA (>

6 mg/dL)

A detectable IgA level indicates potential ability to

“class switch”

3. Donor

B cell count

> 200 per microliter

Arbitrarily set at 1-log higher than our standard

practice for those transplanted for malignancy

4. Donor

CD4 T cell count

> 200 per microliter

Same as our standard practice for those transplanted

for malignancy

as determined by donor B cell chimerism divided by 100 x total absolute B cell count

as determined by donor CD4 cell chimerism divided by 100 x total absolute CD4 T cell count

Standard Protocol for Re-vaccination with Killed Vaccines after HCT for PID:

1. If patient satisfies criteria A and B above, then obtain results of trough IgG, IgA and IgM

levels, CD19 or CD20 B cell count per microliter and B cell chimerism (% donor), CD4 T cell

donor chimerism and CD4 T cell count per microliter. If patient visit is not timed with the

expected trough following last dose of IVIG, then defer quantitative immunoglobulin testing

until trough levels are expected.

2. If the results of (1) indicate that the patient now satisfies criteria A, B and C then:

o Plan to hold IgG therapy for the next 12 weeks

o Week 0: Give one dose each of: Prevnar, HiB, DTaP (or Tdap) and HBV

(combination vaccines are preferred to limit the number of shots).

o Wks 6-8: Repeat the series given at Week 0

o Week 12: Check antibody response titers including:

Hib, 23-pneumococcal serotypes, tetanus toxoid, and hepatitis B surface antibody

3. Pediatric LTFU Attendings will decide whether patient’s responses to tetanus, HiB and Prevnar

are sufficient for the patient to remain off immunoglobulin therapy and to proceed with

remaining vaccination against pneumococcus, hemophilus influenza Type B, tetanus,

diphtheria, pertussis, and hepatitis B, as well as to begin a standard series of conjugated

meningococcal, hepatitis A and inactivated polio vaccines. Alternatively, if vaccine response is

inadequate then patient will resume IVIG therapy and further vaccination will be deferred.

SARS-CoV-2 and seasonal influenza vaccinations will be given per pediatric LTFU attending

recommendations.

Standard Protocol for Re-vaccination with Live Vaccines after HCT for PID:

1. If patient has responded adequately to killed vaccines the patient may be considered for the live

attenuated measles, mumps and rubella vaccine, and the varicella-zoster vaccine (in VZV

seronegative patients only) assuming the following additional criteria are met:

a. At least 2 years posttransplant

b. At least 1 year off all systemic immunosuppressive therapy

c. At least 8 months after last dose of IVIG therapy

Posttransplant Vaccination of All Other Patients (NON-PID)

Clinically relevant, 2-4-fold rises in specific antibody levels, or a rise from undetectable to a

level considered protective, require at least partial reconstitution of adaptive (T and B cell)

immunity. Therefore, factors that might influence a decision to delay a series of vaccinations

include:

Table IX.1

Delay of T cell recovery

Delay of B cell recovery

• CD4 T cells < 200/microliters

• CD19 or CD20 B cells < 20/microliters

• Active GVHD

• Anti-CD20 antibody ≤ 6 months

• IVIG therapy ≤ 2 months ago

• Moderate to severe GVHD

• Receiving chemotherapy or

biological therapeutic agents

• Receiving chemotherapy or biological

therapeutic agents

*Note Lenalidomide alone maintenance therapy should not affect lymphocyte counts and patients can receive

vaccination per standard schedule.

General Recommendations:

• The “Pink Book” recommends time intervals for pediatric vaccines.

• All patients should receive seasonal flu

and SARS-COV-2 vaccinations per Tables

IX.A1-A2 and Tables IX.P1-P2.

• If patient is on disease-associated maintenance therapy that can affect T or B cell

numbers, then before beginning other vaccinations (Follow Table IX.1 above):

✓ Check CD 19 or CD 20 B cells to determine > 20/microliters and

✓ Check CD4 T cells to determine > 200/microliters.

• Vaccination for S. pneumoniae and H. influenzae is recommended for all transplant

recipients but does not supplant chemoprophylaxis due to variable serologic responses.

• Inactivated vaccine injections should be used for family members who need vaccinations

against polio. Isolation is necessary if live (oral) polio vaccine is administered to family

members or other persons in close contact with the patient during the first year after the

transplant or at any time during treatment with immunosuppressive medications. The

virus can be shed for 8 to 12 weeks after vaccination.

• Influenzae vaccination: Live attenuated influenzae vaccine is not recommended.

• Hepatitis B Vaccination Formulas: In patients > 18 years old who did not respond to

the initial Hepatitis B vaccination series, there is a new Hepatitis B vaccine formulation

with (Toll-like receptor 9) adjuvant ((Heplisav)). However, its safety especially in

allogeneic HCT patients and its impact on GVHD has not been studied. Our Hepatitis B

vaccination policy parallels what is done for patients with chronic kidney disease or on

hemodialysis who are considered immunocompromised.

6-8

•

Smallpox vaccine is comprised of live vaccinia virus. Smallpox vaccination is

contraindicated in HCT recipients because it may result in development of generalized

vaccinia or inadvertent inoculation at other sites such as the face, eyelid, nose, mouth,

genitalia, and rectum. Smallpox vaccine should not be administered to any family

members or other persons who share living space with the patient during the first year after

transplant and beyond one year if the patient continues treatment with immunosuppressive

medications. If smallpox vaccination is administered to these close contacts, then these

individuals should be prevented from having close contact with the immunocompromised

HSCT recipient. See the CDC website for further detailed information

http://www.bt.cdc.gov.

•

Other live vaccines (i.e., BCG, oral polio, yellow fever, typhoid) should not be

administered in patients with active manifestation of GVHD or receiving

immunosuppressive therapy.

•

MMR or Varivax should not be given within 8 months of IVIG and VZIG.

•

Anthrax vaccine is an inactivated, cell-free filtrate vaccine (e.g., no dead or live bacteria in

the preparation). Currently, anthrax vaccination is not routinely recommended for anyone

except certain high-risk groups such as persons working directly with the organism in the

laboratory or certain military personnel. Recommendations for HSCT recipients would be

the same as for other at-risk individuals. Detailed information is available at the CDC

website http://www.bt.cdc.gov

Patients with splenectomy post transplant:

Vaccination recommendations for the post-SCT, post-splenectomy patient are the same as for

the HCT recipient who has an intact spleen (SEE LONG-TERM FOLLOW-UP AFTER

HEMATOPOIETIC STEM CELL TRANSPLANT, GENERAL GUIDELINES FOR

REFERRING PHYSICIANS, SECTION IX VACCINATIONS). Thus, a full series of

vaccination against pneumococcus with PCV20 (Prevnar20®), and against H. influenzae with

3 doses is particularly important. Antibody titers should be checked at least 8 weeks later to

ensure immunization responses.

Vaccination against Neisseria meningidtidis groups A, C, W, Y with two doses of MCV4

Menactra® or Menveo®, (if under 2 years old, discuss with ID) and against serogroup B if ≥ 10y

with two doses of Bexsero® is recommended. If Bexsero is unavailable, vaccination against

serogroup B with the Trumenba vaccine series could be considered, and requires 3

immunizations on a 0, 2, 6 month schedule. Patients should receive a complete series with a

single vaccine type (no mixing between Bexsero® and Trumenba®)

Re- Booster immunizations with MCV4 (Menactra® or Menveo®) and Bexsero® are

recommended every 5 years

and strep pneumonia as clinically indicated.

Note: For non-elective splenectomy, vaccination should begin at or after post-operative

Day 14. Post-transplant with PCV20, H. influenzae B and Neisseria meningidtidis groups

A, C, W, Y, MCV4, and also group B

IX. CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD)

Chronic GVHD is a major complication of allogeneic hematopoietic cell transplantation. The

incidence of chronic GVHD varies between 20 to 85% and depends on many factors such as the

transplant source (blood stem cell vs. marrow vs. umbilical cord), donor type and other

characteristics (previous pregnant female versus male donor), age (older vs. younger) and others

factors. Chronic GVHD syndrome has features resembling autoimmune and other immunologic

disorders such as scleroderma, Sjogren’s syndrome, primary biliary cirrhosis, wasting syndrome,

bronchiolitis obliterans, immune cytopenias, and chronic immunodeficiency. Symptoms usually

present within three years after allogeneic HCT and are often preceded by a history of acute

GVHD. Approximately 50% of patients who develop chronic GVHD are diagnosed by 6 months

after transplant.

Features of chronic GVHD can begin before day 100 after the transplant and manifestations that

are typical or “classical” of acute GVHD can develop or persist long after day 100. Moreover,

chronic and acute GVHD features may present simultaneously

[1,2]

. For this reason, the differential

diagnosis between acute and chronic GVHD cannot be made solely according to the time interval

from transplant

[3,4]

. Criteria to categorize acute and chronic GVHD by the chronic GVHD NIH

consensus working group is outlined in Table 1

[4]

. Helpful tips on how to assess and score chronic

GVHD can be found at http://www.fhcrc.org/ltfu by clicking on "Information for Physicians" in

the left hand navigation column. Then click on the right blue “GVHD Tips & Forms" button. Here

you will find the Chronic GVHD Assessment and Scoring form (Appendix D), Range of Motion

Assessment form (Appendix F), Skin Thickness Assessment form/ Rodnan Score for patients with

sclerosis or fasciitis (Appendix E) and other helpful information.

A. Table 1. Categories of acute and chronic GVHD

[4]

Category

Time of

symptoms

after HCT

or DLI

†

Presence

of Acute

GVHD

Features

Presence of

Chronic

GVHD

Features*

Acute GVHD

Classic acute GVHD

 100 days

Yes

Persistent, recurrent or late onset

acute GVHD

> 100 days

Yes

Chronic GVHD

Classic chronic GVHD

No time limit

Yes

Overlap syndrome

No time limit

Yes

†

DLI (donor lymphocyte infusion)

* See Table 2 below

B. Table 2. Signs and Symptoms of chronic GVHD

[4]

ORGAN

OR SITE

DIAGNOSTIC

(Sufficient to establish

the diagnosis of chronic

GVHD)

DISTINCTIVE

(Seen in chronic GVHD, but

insufficient alone to establish a

diagnosis of chronic GVHD)

OTHER

FEATURES*

COMMON

(Seen with both

acute and

chronic GVHD)

Skin

● Poikiloderma

● Lichen planus-like

features

● Sclerotic features

● Morphea-like

features

● Lichen sclerosus-

like features

● Depigmentation

● Sweat impairment

● Ichthyosis

● Keratosis pilaris

● Hypopigmentation

● Hyperpigmentation

● Erythema

● Maculopapular

rash

● Pruritus

Nails

● Dystrophy

● Longitudinal ridging,

splitting or brittle features

● Onycholysis

● Pterygium unguis

● Nail loss** (usually

symmetric, affects most nails)

Scalp and

Body

Hair

● New onset of scarring or non-

scarring scalp alopecia, (after

recovery from

chemoradiotherapy)

● Scaling, papulosquamous

lesions

● Thinning scalp

hair, typically

patchy, coarse or

dull (not explained

by endocrine or

other causes),

● Premature gray hair

Mouth

● Lichen-type features

● Hyperkeratotic

plaques

● Restriction of mouth

opening from

sclerosis

● Xerostomia

● Mucocele

● Mucosal Atrophy

● Pseudomembranes**

● Ulcers**

● Gingivitis

● Mucositis

● Erythema

● Pain

Eyes

‡

● New onset dry, gritty, or

painful eyes

†

● Cicatricial conjunctivitis

● Keratoconjunctivitis sicca

†

• Confluent areas of punctate

keratopathy

● Photophobia

● Periorbital

hyperpigmentation

● Blepharitis

(erythema of the

eye lids with

edema)

Genitalia

● Lichen planus-like

features

● Vaginal scarring or

stenosis

• Erosions**

• Fissures**

• Ulcers**

GI Tract

• Esophageal web

• Strictures or stenosis in

the upper to mid third of

the esophagus**

• Exocrine

pancreatic

insufficiency

• Anorexia

• Nausea

• Vomiting

• Diarrhea

• Weight loss

• Failure to

thrive (infants

and children

ORGAN

OR SITE

DIAGNOSTIC

(Sufficient to establish

the diagnosis of chronic

GVHD)

DISTINCTIVE

(Seen in chronic GVHD, but

insufficient alone to establish a

diagnosis of chronic GVHD)

OTHER

FEATURES*

COMMON

(Seen with both

acute and

chronic GVHD)

Liver

• Total bilirubin,

alkaline

phosphatase >

2 x upper limit

of normal

†

● ALT or AST >

2x upper limit

of normal

†

Lung

● Bronchiolitis

obliterans diagnosed

with lung biopsy

• Bronchiolitis obliterans

diagnosed with PFTs and

radiology

†

• BOOP

Muscles,

Fascia,

Joints

• Fasciitis

• Joint stiffness or

contractures

secondary to sclerosis

• Myositis or

polymyositis

†

• Edema

• Muscle cramps

• Arthralgia or

arthritis

Hematopoietic

and Immune

• Thrombocytopenia

• Eosinophilia

• Lymphopenia

• Hypo- or hyper-

gammaglobulinemia

• Autoantibodies

(AIHA, ITP)

Other

• Pericardial or pleural

effusions

• Ascites

• Peripheral neuropathy

• Nephrotic syndrome

• Myasthenia gravis

• Cardiac conduction

abnormality or

cardiomyopathy

* Can be acknowledged as part of the chronic GVHD symptomatology if diagnosis is confirmed

** In all cases, infection, drug effect, malignancy or other causes must be excluded.

†

Diagnosis of chronic GVHD requires biopsy or radiology confirmation (or Ophthalmology exam for eyes).

‡

Schirmer’s test with a mean value < 5 mm (average of both eyes) at 5 minutes, or values of 6-10 mm in

patients who have sicca symptoms, or keratitis detected by slit lamp examination are used for the diagnosis of

chronic GVHD or the eyes (again other causes of dry eyes need to be ruled out (e.g., drug effect).

Abbreviations: GVHD (graft versus host disease); ALT (alanine aminotransferase); AST (aspartate

aminotransferase); BOOP (bronchiolitis obliterans organizing pneumonia); PFTs (pulmonary function tests);

AIHA (autoimmune hemolytic anemia); ITP (idiopathic thrombocytopenic purpura).

(continued) Table 2 - Signs and Symptoms of chronic GVHD

[4]

Table 2 - Signs and Symptoms of Chronic GVHD

C. How to diagnosis chronic GVHD

Signs and symptoms of chronic GVHD have been reviewed and reported by the NIH consensus

Working Group to standardize criteria for diagnosis and classification of chronic GVHD for the

purpose of clinical trials (Table 2)

[4]

. The diagnosis of chronic GVHD has no time limit and

requires the presence of at least one diagnostic clinical sign of chronic GVHD (e.g. poikiloderma

or esophageal web) or the presence of at least one distinctive manifestation (e.g.

keratoconjunctivitis sicca) confirmed by pertinent biopsy or other relevant tests in the same or

another organ (Table 2)

The criteria for the diagnosis of chronic GVHD include:

i. Distinction from acute GVHD (Table 1)

ii. Presence of at least one diagnostic clinical manifestation OR at least one distinct

manifestation confirmed by pertinent biopsy or other relevant tests (Table 2)

iii. Exclusion of other possible diagnosis for the clinical manifestation (e.g., infection, drug effect,

others)

D. How to score each organ/site severity with chronic GVHD (Appendix D)

The new scoring system (0-3) has been developed to describe the severity of chronic GVHD for

each organ or site taking functional impact into account

[4]

. Appendix D is a modified chronic

GVHD Scoring and Assessment form to help physicians to evaluate their patients with chronic

GVHD. Appendix E is another tool developed to help physicians to assess skin thickness in

patients with sclerotic features or fasciitis related to chronic GVHD.

E. How to assess overall severity of chronic GVHD - Global Assessment

Manifestations of chronic GVHD may be restricted to a single organ or tissue or may be

widespread. Historically, chronic GVHD was classified as “limited” or “extensive” based on a

small cohort patients reported more than two decades ago

[5]

. Because of inadequacies of the

original classification (e.g., difficulty to apply the historical criteria in patients transplanted with

newer HCT approaches and progress in our understanding of chronic GVHD), overtime, this

widely adopted chronic GVHD classification has proved to have limitation

[3,4]

. The new global

assessment of chronic GVHD severity (mild, moderate or severe) is based on numbers of

organs/sites involved and the degree of involvement in affected organs/sites (Table 3)

[4]

. This new

global assessment of chronic GVHD severity has been developed to replace the historical

“extensive/limited” classification.

Table 3. Global assessment of chronic GVHD severity

Global severity

No. organs/sites affected

Maximum score in all affected organ/site*

Mild

One or two (except lungs

‡

)

‡

Moderate

Three or more

‡

One or more

‡‡

Severe

Any

* See Appendix D.

‡

A lung score of 1 is considered moderate.

‡‡

A lung score of 2 or greater is considered severe.

F. Other laboratory testing and diagnostic indicators used in chronic GVHD

Biopsy (Skin, lip and other tissues). Histological confirmation is necessary in the

absence of diagnostic clinical features or distinctive features confirmed by other

pertinent test (Table 2). Nonetheless, diagnostic histological features of chronic

GVHD are uncommon.

Lung New obstructive lung defect may represent GVHD lung involvement if:

infectious process, asthma or recurrent aspiration from the sinuses or from

gastroesophageal reflux have been ruled out (Table 2 and Appendix D). In the

absence of prior history of chronic GVHD or concomitant GVHD in any other

organ, the diagnosis of bronchiolitis obliterans (BO) requires specific

spirometric criteria with negative workup for infection and evidence of signs of

bronchiolitis by high resolution end-expiratory and end-inspiratory CT scan of

the lungs, or confirmation by lung biopsy.

For information on monitoring of lung function post transplant and treatment of

bronchiolitis obliterans syndrome (BOS), see section I.

Esophagus Esophageal web formation, stricture or dysmotility demonstrated by barium

swallow, endoscopy or manometry.

Muscle Elevated CPK or aldolase, EMG findings consistent with myositis

with biopsy revealing no other etiological process.

Blood Thrombocytopenia (usually 20,000-100,000/microliter), eosinophilia

(> 500/microliter), hypogammaglobulinemia. Hypergammaglobulinemia and

autoantibodies occur in some cases.

G. Monitoring and other chronic GVHD information

Karnofsky or Lansky Clinical Performance scores <60%, >15% weight loss, and recurrent

infections are usually signs of poorly controlled chronic GVHD. Chronic GVHD can lead to

debilitating consequences, e.g., joint contractures, loss of sight, end-stage lung disease, or

mortality resulting from profound chronic immune suppression leading to recurrent or life-

threatening infections. Close monitoring is recommended after allogeneic HCT or donor

lymphocyte infusion so that appropriate treatment and supportive care can be instituted promptly

to prevent serious outcome.

H. Guidelines for treatment of chronic GVHD

We strongly recommend that you consult the LTFU office (Appendix A) before beginning treatment and

before making changes in immunosuppressive treatment for patients with chronic GVHD. Clinical trials

should always be considered because current standard therapies are associated with high morbidity and

decreased survival for patients with high risk chronic GVHD (Section X.A. 2).

Appendix D is a modified chronic GVHD Scoring and Assessment form to help physicians to evaluate

patients for chronic GVHD. Appendix E is another tool developed to help physicians to assess skin

thickness in patients with sclerotic features or fasciitis related to chronic GVHD. Appendix C provides a

cartoon with body area surface to help calculating the percentage of skin involved by GVHD.

Table 4 outlines the criteria currently used for indication of systemic therapy in patients diagnosed

with chronic GVHD according to global severity (Table 3) and risk factors.

Table 4. Indication for systemic treatment for chronic GVHD

Global severity

‡

High risk*

Prolonged systemic therapy

Mild

Yes

‡‡

Moderate

Yes or No

Yes

‡‡

Severe

Yes or No

Yes

‡

See Table 3

* Patients with either thrombocytopenia (<100,000/microliter) or receiving glucocorticoids at time of

diagnosis of chronic GVHD.

‡‡

The benefits of graft-versus-tumor effect and the risk of chronic GVHD require careful consideration

especially in patients transplanted for malignancy with high risk of relapse.

Standard treatment of chronic GVHD usually begins with administration of glucocorticoids

(1mg/kg/day) followed by taper to eventually reach an alternate-day regimen, with or

without daily cyclosporine or tacrolimus (FK506). For information on other medications

used for glucocorticoid-resistant or dependent chronic GVHD or in combination, telephone

consultation with the LTFU medical team is available to you, seven days a week, to discuss

appropriate treatment and provide other follow up recommendations (Appendix A).

The duration of systemic immunosuppressive treatment of chronic GVHD varies but requires at

least one year of therapy. Approximately 80% of patients require systemic immunosuppressive for

2 years and 40% of them requires therapy for at least 4 years.

I. Monitoring and Management of Bronchiolitis Obliterans Syndrome after HCT

Introduction

• Bronchiolitis obliterans syndrome (BOS) is a late non-infectious pulmonary complication that

affects 5.5% of allogeneic HCT recipients and 14% of those with chronic GVHD (7).

• BOS is the clinical correlate of obliterative bronchiolitis which is considered a pulmonary

manifestation of chronic GVHD.

• Lung function impairment is generally irreversible but may stabilize with treatment (8).

• The median time to BOS diagnosis is 1.5 years after HCT (8, 9) and 6 months after diagnosis of

chronic GHVD (10).

Definition of BOS after allogeneic HCT

A. Definition of BOS by NIH Consensus Guidelines (adapted from Reference 11)

1. Significant new obstructive change on spirometry:

a. Decrease of the absolute FEV

(mL) by  10% in comparison in prior 2 years or

pre-transplant baseline

b. FEV

is <75% predicted

c. FEV

/VC

ratio < 0.7 or FEV

/FVC <LLN

d. Meet criteria for obstruction (a-c) after bronchodilator challenge even if there is a

bronchodilator response

2. BOS according to severity is clarified as:

Mild or Asymptomatic = with mild FEV

decline (FEV

>70% predicted)

Moderate/severe or symptomatic = FEV

decline (FEV

<70% predicted)

3. Absence of other conditions that cause airflow obstruction including infection, asthma,

chronic obstructive pulmonary disease (COPD)

4. A history of chronic GHVD, or active chronic GVHD affecting other organs or presence

of a distinctive manifestation of chronic GVHD by 2015 NIH consensus criteria is highly

supportive of BOS if above criteria are met.

5. Other supportive findings:

a. Significant air-trapping: residual volume (RV) > 120%, or RV/TLC > 20% of

predicted value

b. Air-trapping or other features of bronchiolitis including centrilobular nodules,

airway thickening, or bronchiectasis noted on high resolution computed

tomography (HRCT).

B. Lung biopsy showing obliterative bronchiolitis may be required to make the diagnosis of lung

GVHD in patients with no prior history of chronic GVHD or other organ manifestations of

chronic GVHD for the purposes of enrollment into a clinical trial.

C. Diagnostic considerations for BOS:

1. Alternative spirometric phenotype (12)

a. Reduced FVC and FEV

b. Normal FEV

/FVC ratio

c. Normal TLC

2. Patients with baseline pretransplant supranormal FEV

a. FEV

decline >10 % (meets criteria 1a)

b. FEV

/VC <0.7 (meets criteria 1c)

c. FEV

>75% predicted (does not meet criteria 1b)

Monitoring of lung function after day +100 after allogeneic transplant

Slow VC, which is always greater than or equal to FVC, should be used for this calculation if available as per

ATS/ERS guidelines (13). Otherwise FVC is used.

A. Pulmonary function test (PFT) monitoring including spirometry, lung volumes, and DLCO.

1. PFTs for asymptomatic allo-HCT recipients:

a. At 6 months

b. At 1 year

c. Yearly thereafter until 5 years as clinically indicated

d. At diagnosis of chronic GVHD (14)

i. Full PFT testing including: spirometry, lung volumes, and DLCO

ii. Q3 months after diagnosis of chronic GVHD for at least one year.

(spirometry alone may be adequate)

iii. Thereafter, at Q6 months for 1 year (spirometry alone may be adequate)

iv. With at least yearly full PFT testing including: spirometry, lung volumes,

and DLCO until year 5 post HCT

Evaluation and monitoring of new airflow decline detected by PFTs

A. Pulmonary consult should be initiated.

B. New lung function decline:

Airflow obstruction is defined as decline in absolute FEV

>/=10%, with FEV

/VC <0.7. Lung

function decline may be due to obstructive, restrictive, or mixed processes.

a. Evaluate for upper respiratory infection or other etiologies of airflow decline

i. Nasal swab for respiratory virus PCR if indicated by symptoms

ii. Perform high resolution chest CT (HRCT)

o If there are infiltrates, consider bronchoscopy to evaluate for

infection

b. If diagnostic criteria for BOS are met → Start treatment promptly

c. If alternative diagnosis is made, repeat spirometry monthly for at least 3 months

i. If % FEV

stabilizes at 3 months, monitor PFTs every 3 months for one year

ii. If stable at 1 year, q6 month intervals for one year

iii. Thereafter, if stable, yearly.

C. High Resolution CT (HRCT):

1. Indication: Unexplained lung function changes and/or suspicion for BOS

2. Order with inspiratory and expiratory phases

3. Radiographic findings consistent with BOS (15, 16):

a. Mosaic attenuation (indicative of air-trapping)

b. Peripheral ground glass opacities or centrilobular ground glass opacities/nodules

c. Airway thickening or bronchiectasis (usually a late finding)

4. Patient may still have diagnosis of BOS with normal chest CT

D. Bronchoscopy is indicated when there are signs and symptoms of potential infection.

1. Clinical symptoms

Productive cough, fever, runny nose, sore throat

2. Imaging findings

Pulmonary infiltrate including ground glass opacities and/or new pulmonary nodules

Treatment of suspected or confirmed BOS (Figure 1)

A. Prior to specific BOS treatment, all confounding etiologies of airflow obstruction should be

investigated and treated. However, treatment for BOS should not be delayed if suspicion is

strong.

1. Infection: Diagnostic evaluation as directed by clinical symptoms include the following:

a. Sinus CT, nasal washes for respiratory virus PCR panel, sinus aspiration, CXR,

CT chest, sputum culture, bronchoalveolar lavage, and/or surgical lung biopsy.

2. Gastroesophageal reflux

a. Consider treating with proton pump inhibitor if not already on one

b. Lifestyle modifications including elevation of the head of bed

3. Post-nasal drip/sinus symptoms

a. Evaluate for URI

b. Evaluate for environmental allergies/triggers

c. Nasal saline, antihistamine, or steroid as needed

d. Consider ENT evaluation if chronic sinusitis is suspected

B. Initial Treatment

1. Initiate Fluticasone, azithromycin and montelukast (Singulair) (FAM) + Long-Acting

Beta-Agonist (LABA) (9,17,18)

a. FAM = Fluticasone (Flovent) 440 mcg BID + azithromycin 250mg po MWF +

montelukast (Singulair) 10mg po QD

b. LABA = long-acting beta2-agonist (such as salmeterol)

c. For FAM + LABA, inhaled corticosteroid (ICS)/LABA combination may be

prescribed in lieu of separate inhaled medications.

d. Inhaled corticosteroid combinations:

i. First choice: Symbicort HFA 160/4.5 mcg 2 inh BID

ii. Alternatives:

o Advair HFA 230/21mcg 2 inh BID

o Advair Diskus 500/50 mcg 1 inh BID

o Dulera 200/5 mcg 2 inh BID

o Breo Ellipta 200/25 mcg 1 inh QD

e. Treatment should continue without exacerbation after resolution of active chronic

GVHD, which is at least 6 months after discontinuation of all systemic

immunosuppressive treatments for other organ manifestations of chronic GVHD.

2. Prednisone

a. Asymptomatic with mild FEV

decline (FEV

>70% predicted): no new or

increase in prednisone

b. Symptomatic, or with moderate to severe FEV

decline (FEV

<70% predicted):

Start or increase prednisone to 1mg/kg/day x 2 weeks then taper (see below)

c. Other immunosuppressive treatments as indicated to control GVHD in other

organs.

d. After 2 weeks of therapy, begin taper over next 3 weeks to get down to a total

dose of 0.25mg/kg/day or to pre BOS therapy dose by week 5, as tolerated by

stability of FEV

and/or other organ manifestations of chronic GVHD.

e. If prednisone is not required, taper prednisone off within 6-8 weeks as tolerated

(including adrenal insufficiency issues).

C. PFT Monitoring during treatment of BOS

1. After initial diagnosis: Q4-6 weeks x 6 months (Qmonthly) while on prednisone taper.

2. If % FEV

stabilizes after 3 months, space out to q2-3 months for at least a year or longer

per pulmonary recommendations.

3. If % FEV

continues to decrease, see D below.

4. If % FEV

normalizes, see E below

D. Persistent FEV

decline despite initiation of above treatment (FEV

decline of >/= 10%):

1. Rule out infection or other confounding etiologies

2. Consider enrollment in a clinical trial

3. Consider extracorporeal photopheresis (ECP) or other immunosuppression therapies with

LTFU attending

4. If FEV

has stabilized, taper prednisone to 1mg/kg/day x 2 weeks and follow taper

schedule in section B.#2.

Dosages provided are for adult patients. For pediatric patients, please consult pharmacist for dosing.

E. After minimum 6 months of FAM and LABA therapy, a taper of BOS-specific medications can be

considered if all the following conditions are met:

a. Full PFTs with Lung volumes and DLCO remain stable or improved compared with BOS diagnosis

b. There are no new extrapulmonary manifestations of cGVHD requiring an addition or increase in

systemic immunosuppression

c. Patient is on a stable prednisone taper of <10mg/day equivalent

F. Taper Schedule

1. Full PFTs with Lung Volume and DLCO before starting taper.

a. Step 1: D/C Azithromycin first. Ensure that Spirometry without lung volumens are stable over 3

months.

b. Step 2: D/C montelukast. Ensure that Spirometry without lung volumes is stable over 3 months.

c. Step 3: D/C LABA. If Spirometry without lung volumes is stable after stopping azithromycin and

montelukast, drop LABA component of ICS+LABA. This step may be skipped if the patient

prefers to remains on a combination inhaler (such as Symbicort).

d. Steps 4-6: If symptomatically stable after 1 month with stable Spirometry without lung volumes,

drop ICS dose by 50%. If Spirometry without lung volumes is stable after 1 month, continue

tapering ICS to off over 1-2 months.

e. Step 7:Full PFTs with lung volumes and DLCO 1 month after completion of FAM and LABA

therapy.

i. Follow FEV

closely with each step

ii. If FEV

is stable, then next step of taper can proceed.

iii. After FAM+LABA are off, check Spirometry without lung volumes at 1 month 3 months

and 6 months (assuming FEV1 is stable)

iv. Full PFTs with lung volumes and DLCO is recommended at least once a year.

If FEV

decline of >10% occurs during taper:

a. Evaluate for respiratory infection, other exacerbating factors (GERD, post-nasal drip, new cGVHD

manifestations, restrictive lung disease)

b. If a reversible etiology is not identified, stop the taper and resume all components.

G. Supportive treatment

1. Vaccinations

2. Prophylactic antibiotics

3. Treat infections

4. Pulmonary rehabilitation

5. Supplemental oxygen if resting or ambulatory O2 sat </=88%

H. End-stage lung disease from BOS

1. Consider lung transplantation (19)

2. Discuss with UWMC Lung Transplantation service.

3. Basic criteria for referral for lung transplant includes

a. >2 years after HCT without evidence of malignancy

b. Life expectancy <2 years from respiratory failure

c. No other end-organ damage

d. No significant requirement for immunosuppression (prednisone < 20mg/qd

e. BMI >/= 18

f. Appropriate social support and compliance

For details on References, see Section XXV, References, Chronic GVHD

There is no specific FEV

criteria for lung transplant eligibility.

Figure 1. Schema for Treatment of Bronchiolitis Obliterans Syndrome (BOS) according to severity

A. Suspected or

confirmed BOS

Mild or asymptomatic

Moderate/severe or

symptomatic

Start FAM

+LABA

No Prednisone

Start FAM

+LABA

+Prednisone

1mg/kg/d

Stable

Progression

Stable

Progression

Go to B

Continue

FAM + LABA

Continue

FAM + LABA

Taper prednisone

Go to B

Mild or Asymptomatic = with mild FEV

decline (FEV

>70% predicted)

Moderate/severe or symptomatic = FEV

decline (FEV

<70% predicted)

B. Progression of BOS

on treatment

+Infection

No Infection

Treat Infection

Consider other

chronic GVHD

treatments

Inprovement

No Improvement

< 2 years from HCT

Prednisone > 20 mg/qd

> 2 years from HCT

Prednisone < 20 mg/qd

Continue

FAM + LABA

Taper prednisone

Supportive Care

Refer for Lung

Transplantation

Evaluate for

infection

Consider Clinical

Trial

Taper

prednisone

Progression to chronic

respiratory failure

Taper Prednisone

X. GENERAL GUIDELINES FOR PREVENTION OF OSTEOPOROSIS AND

GLUCOCORTICOSTEROID INDUCED OSTEOPOROSIS AFTER HCT

Treatment with glucocorticoids has been recognized as the primary risk factor for

development of osteoporosis after hematopoietic cell transplantation (HCT). Areas of loss

include the femoral neck, vertebrae, ribs. Glucocorticoid myopathy and muscle weakness

may contribute to osteoporosis by removing the normal forces on bone that are produced by

muscle contraction. In HCT recipients, other factors that may contribute to osteoporosis

include electrolyte imbalances, inactivity, significant weight loss, and endocrine deficiencies

(1).

Bone loss can be measured semi-quantitatively using a dual energy x-ray absorptiometry

(DEXA) scan which can compare bone mineral density (BMD) of an individual to an

appropriate normative population using a standard deviation score. BMD-standard deviation

scores have been determined for healthy 30 year old male and female Caucasians (T-scores)

or have been age adjusted (Z-score).

Osteopenia is defined as a bone mineral density T-score of –1 to –2.5 (standard deviations

below the peak mean density of young healthy controls). Osteoporosis is defined by a T-

score of <-2.5. It is also important to evaluate the individuals’ change in BMD over time

when determining appropriate interventions to optimize BMD.

T-scores are used to report bone mineral density for post-menopausal women (regardless of

age) and men >50 years. Z-scores are used to report bone marrow density in all children, pre-

menopausal women, and adult males < 50 years.

T-scores are less appropriate for the interpretation of pediatric DEXA scans, especially in the

very young children where BMD is confounded by normal growth and development.

Therefore, Z-scores are used with children since they are too young to have achieved peak

BMD. Z-scores obtained from the Hologic DEXA scanner (UWMC) for the spine are

available for ages >4 years. Z-scores for the femoral neck are limited to age >12 years. Z-

scores obtained from the General Electric Lunar DEXA scanner for the spine and total body

are available for ages 5 through 19 years. Z-scores

Management of osteopenia and osteoporosis at a minimum includes: (a) minimizing daily

and total cumulative glucocorticoid exposure, (b) optimizing calcium and vitamin D intake,

and (c) participating in weight-bearing exercise. Bone strengthening drugs including

bisphosphonate (5) may also be appropriate for some patients (2,3)

A. Patient Monitoring

Women: Annual measurement of FSH and estradiol for ages > 10 and < 61 years

Men: Annual measurement of:

LH, FSH, and free testosterone for ages ≥ 10 years and < 60 years,

Free testosterone for ages ≥ 60 years

Baseline and followup prostate exam, measurements of PSA and lipid profile in men who are

being treated with testosterone

All patients:

• Height: twice yearly

• Weight: with each clinic visit.

• DEXA SCANS:

a) 1-year after autologous HCT for lymphoma and myeloma in adults.

b) 1-year after allogeneic HCT in adults.

c) 1 year after allogeneic, or autologous-HCT in children

d) Continue annually after allogeneic HCT as clinically indicated for any patient on

steroid therapy >1 year posttransplant after completing initial DEXA scan at 1 year

• Vitamin D (25 Hydroxy) blood level

a) Should be checked at 1-year post transplant for all patients.

b) Are generally rechecked 2-3 months after beginning therapy and target to be within

normal range

• Patients treated with bisphosphonate or rank ligand inhibitors: Recommend liver

function tests, calcium, magnesium, creatinine and electrolytes be measured at baseline

and as clinically indicated.

B. Calcium Requirements

i. FOR PATIENTS ON STEROID THERAPY:

Calcium intake above these levels is not recommended, as it may interfere with the absorption of

other nutrients.

ii. FOR PATIENTS NOT ON STEROIDS

Age

Daily Minimum Requirement

after Transplant (milligrams)

Children 7-12 months

260

Children 1-3 years

700

Children 4-8 years

1000

Children 9-18 years

1300

Adult Males

1000-1200

Adult Females;

On hormone therapy

No hormone therapy

1000-1200

1500

Calcium intake above these levels is not recommended, as it may interfere with the absorption of

other nutrients.

Age

Daily Minimum Requirement

after Transplant (milligrams)

7-12 months:

600

1-3 years:

1000

4-8 years:

1200

> 9 years:

1500

C. Vitamin D Requirement

Table 3: Vitamin D3 (or D2) Supplementation

*,****

Adults (>18 yrs)

Children (<18 yrs)

Treatment of Insufficiency [Vitamin D (25 Hydroxy) levels 20-30 ng/mL] ***

▪ Routine

▪ 25 mcg/day

▪ Age < 1 yr:

─ 10 mcg daily

(20 mcg in dark skinned)

▪ Age 1-8 yr:

─ 15 mcg daily

▪ Age 9-18 yr:

─ 20 mcg daily

▪ Malabsorption syndromes**

▪ 1,250 mcg per week

▪ Age < 1 yr:

─ Consult Endocrinology

▪ Age 1-18 yr:

─ 1,250 mcg per week or

125 mcg daily

▪ Chronic Renal Disease

▪ Consult Nephrology

Treatment of Deficiency [Vitamin D (25 Hydroxy) level <20 ng/mL]***

▪ Uncomplicated

▪ 1,250 mcg per wk x 8 (Repeat

if Vitamin D (25 Hydroxy) level

< 30 ng/mL otherwise treat as

for insufficiency above)

▪ Age 1-12 months:

─ 25-50 mcg daily x 8 wks

▪ Age 1-18 yr:

─ 25-125 mcg daily x 8 wks

1,250 mcg weekly x 8

(Repeat if Vitamin D (25

Hydroxy) level < 30 ng/mL

otherwise treat as for

insufficiency above)

▪ Malabsorption syndromes**

▪ 250-1,250 mcg daily or every

other day

▪ UVB irradiation in patients

also with skin GVHD

▪ Age < 1 yr:

─ Consult Endocrinology

▪ Age 1-18 yr:

─ 1,250 mcg per week

▪ Chronic Renal Disease

▪ Consult Nephrology

Currently there does not seem to be substantive benefit by choosing Vitamin D2 or vitamin D3 over the other

with regard to correcting Vitamin D (25 Hydroxy) levels. The more important decision is prescribing enough.

Dose frequency appears to be less important than cumulative amount so that 50 mcg daily for 50 days is

approximately equivalent to giving 1,250 mcg monthly for 2 months.

Patients who remain deficient or insufficient after adequate therapy are generally treated with hydroxylated

vitamin D metabolites which are more readily absorbed or, if feasible, with sun or sunlamp exposure. While 25-

OH vitamin D (calcidiol) is the most logical choice of activated vitamin D for patients with liver disease,

calcidiol is not readily available in the U.S. The 1,25-OH activated formulation of vitamin D (Calcitriol) is used

most commonly in chronic renal disease when there is secondary hyperparathyroidism. Calcitriol can also be

used in patients with liver disease or severe malabsorption when there is a lack of the 25-OH vitamin D

substrate to be converted to 1,25-OH vitamin D by the kidney.

***

Vitamin D (25 Hydroxy) levels are generally rechecked 2-3 months after beginning therapy and the target level

should be within normal range.

****1000 IU = 25mcg and 50,000 IU = 1,250 mcg

D. Magnesium

Magnesium depletion results in cessation of bone growth, decreased osteoblast and

osteoclast activity. Hypomagnesemia may result in hypocalcemia, peripheral vitamin D

resistance and resistance to parathyroid hormone. Normal serum magnesium levels are

necessary to prevent osteopenia and bone fragility. Patients taking cyclosporine or

tacrolimus should receive adequate magnesium supplementation to maintain normal

concentrations of serum magnesium (see Section XX)

E. Exercise

An exercise program that combines weight bearing (in which bones and muscles work

against gravity as the feet and legs bear the body's weight) and muscle strengthening

exercise is recommended. It is advised that daily duration of these activities be increased

gradually. Thirty to 60 minutes daily has been recommended by the American Heart

Association. Specific time guidelines have not been established for maintenance of bone

density. However, exercise has been shown to minimize bone loss, strengthen skeletal

muscle and prevent falls by improving balance.

Recommended forms of exercise include low-impact walking, low-impact aerobics, stair

climbing, biking (on a stationary bike if the patient has poor balance), Nordic tracking, low

impact dancing or rowing. Weight-lifting can help to improve muscle mass and bone

strength. Speed and duration should be gradually increased. Although high impact exercise

improves bone density more quickly (running, jumping, etc.), it should be avoided during

steroid treatment due to potential harm caused by increased joint stress.

F. Lifestyle

Avoidance of smoking and excessive consumption of alcohol, caffeine, sucrose and animal

protein is recommended as these activities increase urinary calcium excretion and risk of

bone loss.

G. Gonadal hormone replacement

Females: FSH and estradiol levels should be tested annually for ages >10 and <61 years.

(see section XVI about gonadal hormone insufficiency recommendations)

Males: Free testosterone, FSH and LH serum levels should be evaluated as follows:

Male patients  10 and < 60 years: LH, FSH, and free testosterone levels

Male patients  60 years: Free testosterone levels

(see section XVI about gonadal hormone insufficiency recommendations)

Females:

• The use of hormonal therapy is not recommended as the first line of treatment or for

prevention of osteoporosis/osteopenia in women except for children or young adults.

• If estrogen replacement therapy (ERT) is started in an individual, the duration of

therapy should be individualized based on the clinical setting. A consultation is

recommended with the gynecologist.

• Systemic estrogen alone or combined with progesterone should not be prescribed for

patients with a history of thromboembolic diseases (i.e., venous thrombosis,

pulmonary embolism, strokes, etc.), hypercoagulation disorders, breast cancer,

coronary artery disease or active liver disease.

• Transdermal ERT if given is preferred owing to lower risks of thromboembolism

and stroke but like other forms of ERT, should not be used in patients with

unprovoked DVT.

• When ERT is prescribed for women with an intact uterus, low-dose progesterone is

added to prevent endometrial hyperplasia, despite the only slightly increased risk of

breast cancer.

Males:

• Male HCT survivors are at risk for developing hypogonadism which increases the

risk for reduced BMD and fractures.

• If the free serum testosterone level is low, symptoms of hypogonadism are present,

and there are no contraindications, including history or risk of prostate cancer,

testosterone replacement can be considered.

Children:

Gonadal hormone replacement in children needs to be coordinated with age-appropriate

linear growth and pubertal development. Pediatric Endocrinology consultation is advised

for additional work-up as indicated including assessment of gonadal and growth

hormones (See also Section G below).

H. Other treatments

An endocrinology consult may be appropriate for patients at high risk of osteoporosis and

those for whom pharmaceutical therapy is being considered. Therapies to reduce

osteoporosis may include:

Note: For bisphosphonate and rank ligand inhibitor therapy, we recommend adequate

calcium and Vitamin D supplementation.

1. Bisphosphonates are effective for prevention and treatment of post-menopausal and

glucocorticoid-induced osteoporosis (4, 5). Because the risks and benefits of

bisphosphonates during the early posttransplant period are unclear, consideration of

bisphosphonate therapy for osteoporosis is not recommended until at approximately 3

months posttransplant.

Adults with hip or vertebral fractures, or documented osteoporosis (DEXA T score < -

2.5) may receive either oral or intravenous bisphosphonate therapy. Therapy is also

advised for posttransplant patients with osteopenia (T-score -1.0 to -2.5) who are not

receiving hormone replacement therapy and who are to receive prolonged glucocorticoid

therapy. For postmenopausal women, and men age 50 and over, the widely used FRAX®

WHO Fracture Risk Assessment Tool (http://www.shef.ac.uk/FRAX/) can be used to

help guide which patients with osteopenia might benefit from bisphosphonate therapy

based on their estimated 10-year hip fracture probability being ≥ 3% or their 10-year

major osteoporosis related fracture probability being ≥ 20%.

Therapy is usually continued until glucocorticoid therapy has been discontinued and the T-

score enters the normal range (-1.0 to +1.0) or the risk for fractures based on the FRAX®

tool is no longer increased.

In patients taking alendronate for 5 years or more, post-marketing reports have recently

highlighted the occurrence of atypical hip fractures (6). Secondary analyses of the results

from 3 large randomized bisphosphonate trials showed that rates of subtrochanteric or

diaphyseal femoral fractures were very low (1 to 6 cases per 10,000 patient years). While

these analyses did not demonstrate an increase in risk associated with bisphosphonate

use, the study was underpowered for definitive conclusions (7). One approach to consider

for patients at mild risk for fracture is to stop bisphosphonate therapy after 3 to 5 years

and remain off as long as bone mineral density is stable and no fractures occur. Higher

risk patients may be treated longer than 3 to 5 years as clinically indicated and consider

referral to endocrinology for alternative therapy (6).

Children with low bone mineral density (BMD) should be considered for referral to pediatric

endocrinology if they:

a) develop a fracture in the setting of low bone mineral density,

b) have ongoing risk factors for low BMD and/or avascular necrosis (AVN) like steroid

therapy or chronic GVHD , hypogonadism or growth hormone deficiency.

The Pediatric Oncologist and Pediatric Endocrinologist will jointly determine the need for

bisphosphonate therapy. Pediatric Endocrinology will initiate additional work-up as

indicated including assessment of gonadal and growth hormones. In children, initiation of

hormonal therapy may precede bisphosphonate therapy in the appropriate clinical setting.

Children should have an EKG and formal dental evaluation prior to initiation of

bisphosphonate therapy.

For All Patients

• Intravenous bisphosphonates are not recommended for patients with creatinine

clearance <35 ml/minute.

• Oral bisphosphonate therapy can cause esophageal ulceration (pill esophagitis) and

should be discontinued if patients develop esophageal symptoms.

• Due to increased risk of AFF (Atypical Femoral Fractures) and MRO (Osteonecrosis of

the jaw) with prolonged bisphosphonate therapy, after 3 to 5 years of treatment

reassess the risks and benefits of continuing therapy, pursuing a drug holiday or

referring to Endocrinology for consideration of alternative treatment.

Commonly used bisphosphates include:

For Adults

i. Alendronate (Fosamax



)

Osteoporosis treatment: Administer alendronate as a single dose of 70 mg

weekly (or 35 mg twice weekly).

ii. Risedronate (Actonel



)

Osteoporosis treatment: Administer risedronate as a single dose of 35 mg

weekly (or 150 mg monthly).

iii. Pamidronate (Aredia



)

Pamidronate has been used primarily in patients who cannot receive oral

bisphosphonates. In adults a regimen of 60 mg IV for the first dose followed

by 30 mg every 3 months has been used successfully in the nontransplant

setting.

iv. Zoledronate (Reclast®)

Zoledronate may be given as a single 5 mg intravenous dose once a year.

For Children

Drug selection and dosing of bisphosphonate therapy will be determined by

Pediatric Endocrinologist

2. Rank Ligand Inhibitor

Rank Ligand Inhibitors: Denosumab (Prolia®) 60 mg SQ every 6 months for adult

osteoporosis. Denosumab has not been studied to treat osteoporosis in children.

Strongly recommend an endocrinology consult prior to starting rank ligand

inhibitors. Severe hypocalcemia can be seen in patients with renal dysfunction.

Monitor for infection at injection site in patients on immunosuppressive therapy.

Because there is an increased risk for vertebral fracture with discontinuation or

missed doses of denosumab (8, 9), if you are considering discontinuing the drug, we

highly recommend getting an endocrinology consult first.

3. Calcitonin

Calcitonin is secondary therapy for osteoporosis Calcitonin (100-200 International

Units nasal spray daily) may be given if bisphosphonates are inadequate or

contraindicated. There are no data to support the use of calcitonin (salmon) nasal

spray in children. Calcitonin may be given if bisphosphonate of Rank Ligand

Inhibitors are inadequate or contraindicated. Recommend getting an endocrinology

consult prior to starting Calcitonin therapy.

4. Low Sodium Diet

Sodium increases urinary calcium loss. A reduced sodium diet (<4 grams daily) is

encouraged during steroid therapy.

5. Endocrinology

Refer for endocrinology consult if clinically indicated.

XII. HYPERLIPIDEMIA

The syndrome of abdominal obesity, dyslipidemia, hypertension, insulin resistance and

prothrombotic or inflammatory states (metabolic syndrome) is a risk factor for premature

cardiovascular disease. By itself, chronically elevated serum low-density lipoprotein cholesterol

(LDL-C) is also strongly associated with premature cardiovascular disease (< age 55 years) in

the general population. Hyperlipidemia is also associated with reduced survival in the recipients

of solid organ transplants. Chronic immunosuppressive therapy (IST) in hematopoietic cell

transplantation (HCT) or organ transplant recipients may aggravate pre- existing risk factors for

premature cardiovascular disease, or promote development of new risk factors, notably

hyperlipidemia and hypertension. Even after discontinuation of IST, the long-term survivors of

allogeneic HCT appear to be at increased risk relative to their siblings for developing diabetes

and hypertension. Adjustment was made in the analysis for age and gender, and the observation

is independent of obesity.

Based on a retrospective analysis at the Fred Hutch more than half of 349 HCT recipients had

serum cholesterol >200 mg/dL at 75-100 days after HCT. Median cholesterol and triglyceride

levels increased relative to before transplant by 34% and 65% respectively in adults, and 45%

and 125% in children. Marked elevations of serum triglycerides (>750 mg/dL) were observed in

4.8% of adults and 8.1% of children. The prevalence of premature cardiovascular disease after

HCT has not been determined but recent case reports have described premature and fatal

coronary artery disease (CAD) in HCT recipients.

6-10

At least 30 patients who received HCT at

the median age of 35 years (range 4-52 years) at Fred Hutch (08/73-05/98) died at a median of

7.5 years after the transplant due to CAD or heart failure of unspecified etiology. Hyperlipidemia

was present in the majority of patients who had serum lipids levels documented beyond Day 90.

Looking to the future, because the earliest successful HCT were performed in younger patients

just over 40 years ago, it is possible that the prevalence of premature CAD might increase as

earlier transplant survivors mature.

HMG-CoA reductase inhibitors (statins) effectively reduce serum total cholesterol, protect

against premature cardiovascular disease, and improve survival in adults with a wide range of

cholesterol levels whether or not they have a history of coronary artery disease.

2-5

Statin therapy

has been safely administered to solid organ transplant recipients, it has been effective at lowering

serum lipid levels, and appears to protect against premature cardiovascular disease and improve

survival.

11-19

Similar benefits could be expected in HCT recipients with hyperlipidemia.

Pleiotropic effects of statins suggest potential additional roles in mediating improved renal

function, control of hypertension, osteopenia, avascular necrosis, and even control of GVHD.

20-28

The following general guidelines begin with therapeutic lifestyle changes before drug

therapies, in accordance with Adult Treatment Panel III/National Cholesterol Education

Program (ATPIII/NCEP) guidelines for the management of hyperlipidemia in the general

population.

30-31

The risk benefit ratio of drug therapy always needs to be considered and should be

individualized.

A. Working Definitions of Fasting Hyperlipidemia

1. Fasting serum LDL-C > 130 mg/dL or

2. Fasting total cholesterol minus fasting HDL-C >160 and fasting serum triglycerides >

200 mg/dL or

3. Fasting serum triglycerides > 500 mg/dL if >18 years old and > 400mg/dL if ≤18 years

old

4. High-risk or very high-risk category patients with fasting serum LDL-C > 100 mg/dL

Table 1: ATP III Risk Categories and Definitions**

**Electronic 10-year risk calculators are available at https://www.nhlbi.nih.gov/files/docs/guidelines/atglance.pdf

Risk category

Definitions

Very High Risk

1. Established cardiovascular disease and > 2 major risk factors

2. Severe and poorly controlled risk factors,

3. Multiple risk factors of the metabolic syndrome

4. An acute coronary syndrome

High-Risk

(10 yr risk >20%)

CHD or CHD risk equivalents

Moderately High Risk

(10 yr risk 10-20%)

2+ risk factors

Moderate Risk (10 yr

risk < 10%)

2+ risk factors

Low-Risk**

0-1 risk factors

CHD

History of myocardial infarction, stable angina, coronary artery

procedures (angioplasty or bypass surgery) or evidence of clinically

significant myocardial ischemia.

CHD Risk Equivalents

Clinical manifestations of non-coronary forms of atherosclerotic

disease (peripheral arterial disease, abdominal aortic aneurysm and

carotid artery disease), diabetes, and 2+ risk factors.

Metabolic Syndrome

1. Abdominal obesity

2. Elevated triglycerides, small LDL particles and low HDL

3. Hypertension

4. Insulin resistance

5. Prothrombotic and proinflammatory states

Risk Factors

1. Cigarette smoking

2. Hypertension (BP >140/90 mmHg) or on antihypertensive

medication

3. Low HDL cholesterol <40 ml/dL

4. Family History of premature CHD in male first-degree

relative < 55 years of age

5. CHD in female first-degree relative < 65 years of age

6. Age (men > 45 years; women > 55 years)

B. General Guidelines for Management of Hyperlipidemia in HCT Patients

1. Diet: If clinically appropriate, reduce daily fat: saturated fat <7% calories, cholesterol <

200 mg/day [NCEP] or <300 mg /day (American Heart Association).

2. Omega-3-fatty acid supplements may improve triglyceride and LDL-C levels but most

are not regulated and are of variable content. Therefore, consuming a diet rich in these

fatty acids is currently the preferable method of supplementation (major sources include

flaxseed oil, canola oil, walnut oil, wheat germ, soybeans, mackerel, herring, salmon,

sardines in oil, and swordfish).

3. Weight management

4. Regular exercise regimen.

5. Exclude untreated hypothyroidism.

6. Exclude nephrotic syndrome.

7. Exclude obstructive liver disease..

If patient has high CHD risk treat dyslipidemia also with appropriate drugs. If a patient has low to

moderate CHD risk, consider drug therapy based on severity of dyslipidemia, estimated prognosis after

transplant and risk of lipid lowering drug therapy. In patients with low CHD risk that develop secondary

dyslipidemia this must likely can be managed conservatively if immunosuppressive therapy can be

tapered off. Patients with low and moderate risk though with serum triglycerides >500 mg/dL should be

treated to prevent pancreatitis.

C. Important Prescribing Precautions for Hyperlipidemia

Statins are the most widely used class of drugs, but proper selection of statin preparation and

dose are important, as a number of drugs used specifically in the HCT setting can interact with

them. Cyclosporine’s metabolism is by the cytochrome CYP3A4 a key factor in drug-drug

interactions, as it raises levels of statins (for example lovastatin, simvastatin and atorvastatin)

also metabolized by this pathway and thus increases the risk for myopathy

. Tacrolimus and

sirolimus also appear to be metabolized by his pathway

. Cyclosporine can also increase statin

drug levels through inhibition of the member transport OATP1B1. Consequently, cyclosporine

potentially increases the risk for toxicity of any statin

. Other inhibitors of CYP3A4 including

azole antifungals, non-dihydropyridine calcium channel blockers and macrolide antibiotics also

can interact with statins. For other drugs like Ruxolitinib that can impact CYP3A4 metabolism,

contact pharmacy. Since pravastatin, rosuvastatin and fluvastatin are metabolized by

alternative pathways, these statins may be better choices for patients requiring

coadministration of CYP3A4 inhibitory agents.

NOTE: Toxicity may be increased in patients treated with calcineurin inhibitors,

Ruxolitinib, sirolimus, antifungal azoles, or macrolide antibiotics. Patients on these

medications should be started on the lowest dose of statin or fibrate therapy to limit

toxicity. Patients coming to transplant on hyperlipidemia treatment should have their doses

of statin or fibrate therapy reduced prior to start of calcineurin inhibitors, Ruxolitinib,

sirolimus or antifungal azole therapy.

Toxicity related to statins should be discussed before starting therapy:

1. Liver enzyme abnormalities.

2. Rhabdomyolysis with associated renal failure

3. Onset of toxicity may occur weeks to months after initiation of treatment

4. Combination fibrate-statin therapy can be medically appropriate but may increase the

incidence of myopathy.

5. Patients should be advised to report immediately unexplained muscle pain, tenderness,

or weakness, especially when accompanied by fever or malaise.

D. Intervention for Elevated LDL-C with Minimal Elevation of Triglycerides

Any patient who has lifestyle-related risk factors (e.g., obesity, physical inactivity, elevated

triglyceride, low HDL-C, or metabolic syndrome) is a candidate for therapeutic lifestyle changes

to modify these risk factors regardless of LDL-C level.

TABLE 2. ATP III LDL-C Goals and Cut points for TLC and Drug Therapy in

Different Risk Categories and Proposed Modifications (adapted from reference 29) and

Based on Recent Clinical Trial Evidence

Risk Category

LDL-C Goal

Recommendations for Drug

Therapy**

Very high risk

< 70 mg/dL

> 100 mg/dL††

High risk

< 100 mg/dL

> 100 mg/dL††

Moderately high risk

< 130 mg/dL

> 130 mg/dL

Moderate risk

< 130 mg/dL

> 130 mg/dL

Low risk

< 160 mg/dL

> 160 mg/dL

**When LDL-lowering drug therapy is employed, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in

LDL-C levels.

††If a high-risk person has high triglycerides or low HDL-C, combining a fibrate or nicotinic acid with an LDL-lowering drug can be considered.

For persistent and clinically significant elevations of fasting serum LDL-C who have not

responded sufficiently to therapeutic lifestyle changes, treatment with any of the following

statins in Table 3 may be considered.

Table 3. Suggested Medication Options for High LDL-C in Adults* after BMT

Drug

Daily Dose

Class Effects

Precautions

Statins (HMG-CoA

reductase inhibitors)

Start at lowest

doses and rarely

exceed middle of

the dose range

when taking

concomitantly

calcineurin

inhibitors.

LDL 18-55%

HDL 5-15%

TG 7-30%

• Contraindicated in liver disease

• Counsel patient to report muscle pain,

weakness, dark or cola-colored urine,

especially when accompanied by fever

and malaise.

• If myopathy or rhabdomyolysis is

suspected, or if AST/ALT are

significantly elevated stop therapy and

check CK and creatinine.

• Toxicities may occur weeks to many

months after starting therapy.

• Toxicity may be increased in

patients treated with calcineurin

inhibitors, Ruxolitinib,

sirolimus, antifungal azoles, or

macrolide antibiotics. Patients

on these medications should be

started on the lowest dose of

statin therapy to limit toxicity

• Atorvastatin

(Lipitor)

10-80

• Pravastatin

(Pravachol)

10-40

• Simvastatin (Zocor)

5-40

• Rosuvastatin

(Crestor)

5-40

NOTE: Pediatric patients refer to hyperlipidemia specialty clinic.

E. Medical Intervention for Mixed Hyperlipidemia

1. For persistent and clinically significant elevations of fasting serum LDL-C and

triglycerides who have not responded sufficiently to therapeutic lifestyle changes, it is

reasonable to consider initial treatment with a statin.

2. If statin therapy alone does not result in a satisfactory lowering of both LDL-C and

triglycerides then consideration of combination therapy with either a fibrate or ezetimibe

is recommended through consultation with a subspecialty hyperlipidemia clinic,

particularly for children.

F. Medical Intervention for Isolated Hypertriglyceridemia

Fasting serum triglycerides > 800 mg/dL may increase the risk for acute pancreatitis.

Treatment with either of the following fibrates, omega-3-fatty acids, or icosapent ethyl

may be considered at > 500 mg/dL of fasting serum triglycerides.

Fibrates reduce triglycerides by 20-50%. Potential side effects of fibrates include

cholelithiasis, GI upset and myopathy. Risk for myopathy increases when fibrates are

Table 4: Triglycerides Lowering Agent for Adult Patients**

Drug

Daily Dose

Class

Effects

Precautions and Monitoring

Omega-3-Acid

Ethyl Esters

• Lovaza 

4000 Daily

2000 BID

LDL may 

HDL  9%

TG 45%

VLDL40%

• Generally minimal side effects, eructation,

dyspepsia

• May potentiate INR if on warfarin

• Avoid if fish/shellfish allergic

• Monitor AST/ALT periodically

• Has been combined with simvastatin for mixed

hyperlipidemia

Fibric Acids

• Fenofibrate

(Tricor)

• Gemfibrozil

(Lopid)

Start at lowest

doses and

rarely exceed

middle of the

dose range

when taking

concomitantly

calcineurin

inhibitors.

48-145

600-1200

LDL 5-20%

HDL 10-20%

TG 20-50%

• Contraindicated in severe liver or renal disease

• May cause myopathy especially when combined

with statins, and in setting of impaired renal

function in patients receiving cyclosporine or

other drugs that interact with statins

• May cause cholelithiasis and GI symptoms

• May cause reversible increase in serum creatinine

• Fenofibrate-statin combination may be better that

gemofribrozil-statin therapy because gemfibrozil

can increase statin levels by 2-6 fold

• Counsel patient to report muscle pain, weakness,

dark or cola-colored urine, especially when

accompanied by fever and malaise.

• If myopathy or rhabdomyolysis is suspected, or if

AST/ALT are significantly elevated stop therapy

and check CK and creatinine.

• Toxicities may occur weeks to many months after

starting therapy.

Note over the counter omega-3-acid ethyl esters are generally insufficient to significantly lower

triglycerides and VLDLs. Only Lovaza® has been approved for this indication.

**In patients with severe thrombocytopenia, recommend give lower doses.

NOTE: Pediatric patients refer to hyperlipidemia specialty clinic.

Table 5: Summary for Recommendations for Managing Hyperlipidemia

Exclude untreated hypothyroidism, nephrotic syndrome or obstructive liver disease

Adjust Diet to be high in fiber, (fruits, vegetables, whole grains), high in polyunsaturated and

monounsaturated fats and low in saturated fat and devoid of trans fat

Consider referral to dietitian

Add omega 3 fatty acid supplements

Determine Risk of CHD (see Table 1)

If high or very high CHD risk, consider drug therapy

If low to moderate CHD risk, consider drug therapy based on dyslipidemia, estimated

prognosis of treatment, and risk of statins.

If low risk CHD and immunosuppressive therapy can be tapered off, manage conservatively

Assess LDL-C and TG levels to help determine drug therapy.

If elevated LDL-C with minimal elevated TG, statin therapy (Pravastatin, rosuvastatin,

and fluvastatin) preferred because of drug-drug interactions with statins with

calcineurin inhibitors, Ruxolitinib, sirolimus, or antifungal azole therapy. If starting

drug, begin dosing at lowest dose and monitor carefully. If already on drug, consider dose

reducing statins.

If mixed hyperlipidemia and on statin that fails to lower both LDC-C and TG

Add fibrate or ezetimibe

Consider Hyperlipidemia consult

If isolated hypertriglyceridemia (>500 mg/dL), fibrate therapy for adults. For children, refer

to hyperlipidemia specialty clinic.

Begin long term plan for:

Weight management

Regular exercise program

G. Monitoring during treatment with statins or fibrates:

Table 6: Monitoring

CK measure if clinically indicated (i.e. symptoms of myalgia, muscle weakness, etc, develop).

LFT’s at baseline, 2 and 4 weeks after start therapy and monthly while on therapy.

Stop therapy for significantly elevated serum transaminase or if symptoms of myositis or

rhabdomyolysis occur.

1. Serum creatine kinase (CK) should be checked when clinically indicated (i.e. when symptoms

such as myalgia, muscle weakness, etc. develop).

2. Doses of statins or fibrates may be adjusted at four-week intervals as needed.

3. Consultation with a subspecialty hyperlipidemia clinic is generally recommended in patients

taking concomitant immunosuppressive therapy who do not respond adequately to the above

measures.

4. Patients should be advised to report immediately any unexplained muscle pain, tenderness, or

weakness, especially if accompanied by malaise or fever.

5. Statin or fibrate therapy should be withdrawn if serum transaminase concentrations are

significantly elevated or if symptoms of myositis or rhabdomyolysis occur.

6. Liver function tests (LFT) levels should be checked at baseline and at 2 and 4 weeks after

starting statin or fibrate therapy and at least monthly while on immunosuppressive therapy.

XIII. HYPERTENSION

New onset or aggravation of hypertension occurs frequently after hematopoietic cell

transplantation (HCT) with the most common cause of hypertension after allogeneic HCT being

due to treatment with glucorticoids and tacrolimus or cyclosporine. It is important to recognize

also that HCT survivors have a high prevalence metabolic syndrome which represents a cluster

of risk conditions associated with premature coronary heart disease (CHD).

Components of the

metabolic syndrome including hypertension, dyslipidemia, and diabetes occurred with higher

cumulative incidence among HCT survivors compared to a randomly selected matched control.

Thus, adequate control of hypertension is strongly recommended in HCT recipients to minimize

target organ damage and most importantly in the brain, heart and kidneys.

A. Key Points about Hypertension and its treatment

• In uncomplicated hypertension, without diabetes mellitus, renal dysfunction or

cardiac dysfunction the blood pressure (BP) goals are indicated in the table

below

Age (y)

Male

Female

≥18

140/90

132/82

125/80

130/80

124/80

127/79

123/79

125/78

122/78

122/77

121/77

120/76

119/76

117/76

117/75

115/75

115/74

114/75

113/73

112/73

111/72

109/71

110/70

108/70

108/68

106/68

107/65

104/66

105/61

103/63

102/57

101/59

99/52

100/54

Pediatric data based on 90

percentile limits for blood pressure at

The 50

percentile for height (1999-2000 NHANES)

• If an adult patient has a diagnosis of diabetes and/or renal dysfunction, the BP goal is

< 130/80 mm HG. If an adult patient has more than 1 gm of proteinuria, the BP goal is

< 125/75 mm HG.

B. Other key points about control of hypertension and treatment:

• Reductions in myocardial infarctions, stroke incidence and heart failure with BP

lowering below 140/90 mm HG are approximately 25%, 35%, and 50%, respectively.

• Patients with SBP > 160 mm HG and/or DBP > 100 mm HG tend to need two

different agents and it is recommended that two agents are begun at the same time.

• Caffeine intake and nicotine use an hour before blood pressure monitoring may give

falsely elevated readings.

• Referral to a hypertension specialist is advised for patients with poorly controlled

blood pressure.

• In the general population, thiazide diuretics should be used in drug treatment for most

patients with uncomplicated hypertension, alone or combined with drugs from other

classes but the potential of thiazides to aggravate pre-renal azotemia and other

electrolyte abnormalities often limit their use in HCT.

• No single class of drugs has emerged as the standard of care for management of

hypertension in patients receiving calcineurin inhibitors (CNI). Other agents may be

indicated for patients with other co-morbidities (see Table 1).

Table 1 - Antihypertensive Medications According to Clinical Setting

Clinical Setting

Anti-Hypertensive Therapy

Monitoring

Uncomplicated

Hypertension

Options include CCB, beta-

blockers, thiazide diuretics,

ACE-I** or ARBs

• If not on a CNI or at risk for volume depletion,

thiazide diuretics are the treatment of choice. If used

with CNI, limit dose to 12.5-25 mg per day to limit most

metabolic side effects.

• Calcium Channel Blockers (CCB) can affect CNI levels

(cyclosporine and tacrolimus). Check CNI levels with

K and Cr 7-10 days after starting CCB.

• Non-dihydropyridine CCBs (e.g. verapamil, diltiazem)

may potentiate the toxicity of CNI, statins and fibrates

• CCB may worsen proteinuria

• Beta-blockers may diminish sympathetic activity

including CNI induced headaches/migraines and

tachyarrhythmias.

Chronic kidney

disease*, history of

AKI, presence of

proteinuria or

microalbuminuria

(see Table 2)

• ACE-I**/ARB,

• Possibly in combination with CCB if still on CNI.

• Avoid CCB alone due to further increase in proteinuria

• Consider holding during persistent diarrhea, vomiting

or poor fluid intake

• Check serum K and Cr 7-10 days after adding

Diabetes

With or without

proteinuria

Angiotensin converting

enzyme inhibitors (ACE-I**)

or angiotensin II receptor

blockers (ARBs)

• No known interactions with CNI.

• May aggravate hyperkalemia and prerenal azotemia;

avoid in patients with or at risk for volume depletion.

Consider holding during persistent diarrhea, vomiting

or poor fluid intake

• Check serum K and Cr 7-10 days after adding

Heart Failure

• Diuretics

• ACE-I** or ARBs

• Beta-blockers

• Careful to avoid pre-renal azotemia with potent loop

diuretics.

• Consider adding spironolactone or eplerenone if no

hyperkalemia but monitor for subsequent hyperkalemia.

• Carvedilol and metoprolol are beta-blockers of choice

• For those unable to tolerate ACE-I and ARB’s, therapy

with hydralazine plus isosorbide may be beneficial,

particularly in African Americans

Table 1 - Antihypertensive Medications According to Clinical Setting (continued)

Clinical Setting

Anti-Hypertensive Therapy

Monitoring

High-risk for

Coronary Artery

Disease

• ACE-I**, ARBs,

calcium channel blockers

and beta-blockers.

• Diuretic may also be indicated based on risk/benefits

profile

• Calcium Channel Blockers (CCB) can affect CNI levels

(cyclosporine and tacrolimus). Check CNI levels with

K and Cr 7-10 days after starting CCB.

Ischemic Heart

Disease

• Beta blockers

• Carvedilol and metoprolol are the beta-blockers of

choice

History of

Myocardial

Infarction

• ACE-I**, aldosterone

antagonists and the beta-

blockers carvedilol or

metoprolol are indicated.

• Consider adding spironolactone or eplerenone if

hyperkalemia is not present

History of Strokes

• Calcium channel

blockers, thiazides or

ARB.

• Calcium Channel Blockers (CCB) can affect CNI levels

(cyclosporine and tacrolimus). Check CNI levels with

K and Cr 7-10 days after starting CCB.

Hypertensive

Urgency not

requiring

hospitalization

• Clonidine

• Labetatlol

• Hydralazine

• Preferred option is to

consult a hypertension

expert

• Clonidine has rapid onset of action, can cause dry mouth

and somnolence; avoid for general use

• Hydralazine can cause edema and tachycardia

• Evaluate patient every 1-3 days to assess response to

therapy

CCB; calcium channel blockers,

* Definition of chronic kidney disease (CKD) criteria

1. Kidney damage for > 3 months, as defined by structural or functional abnormalities of the kidney, with or

without decreased GFR, manifest by either:

• Pathological abnormalities; or

• Markers of kidney damage, including abnormalities in the composition of the blood or urine, or

abnormalities in imaging tests

2. GFR < 60 mL/min/1.73 m

for > 3 months, with or without kidney damage

**Due to rare, potential complication of angioedema, caution should be exercised with use of

ACE-1 inhibitors in combination with sirolimus. Use of ARB is acceptable.

C. Evaluation for microalbuminuria and additional recommendations

Screening for microalbuminuria before and after transplant is helpful for early diagnosis of

proteinuria and to guide treatment. Microalbuminuria is determined by measuring the

albumin and creatinine ratio in an urine sample.

Table 2. Recommendations based on albumin/creatinine ratio and hypertension

Spot Urine

Albumin/creatinine ratio

ACR

)

Interpretation

Recommendations

Less 30 mg/g

Normal

– Repeat U

ACR

in 1 year

30-300 mg/g

without hypertension and

not on hypertensive

medications

Abnormal

– Repeat U

ACR

in 3-6 months

30-300 mg/g

with hypertension and on

hypertensive medications

Abnormal

– If not already on, consider change to

ACE-I**or ARB therapy

– Repeat U

ACR

in 3-6 months

Greater than 300 mg/g

on hypertensive

medications

Abnormal

– If not already on, consider treating

with ACE-I**or ARB therapy

– Quantify 24-hr total urine protein

– If proteinuria (>1 gram) confirmed,

refer to nephrologist

– Monitor spot U

ACR

in 3 months

**Due to rare, potential complication of angioedema, caution should be exercised with use of

ACE-1 inhibitors in combination with sirolimus. Use of ARB is acceptable.

XIV. RECURRENT MALIGNANCY

In most cases recurrent malignancy occurs within the first 2 years after the transplant, with

few occurring more than 5 years after the transplant.

For patients who had leukemia or other hematological malignancies, peripheral blood counts

should be monitored at least monthly for the first year. Monitoring for minimal residual

disease and recurrent malignancy will vary according to the specific disease and enrollment

in specific protocols. Chimerism testing in blood or bone marrow may be needed to help

establish the diagnosis of recurrent malignancy and to assess options for treatment (adoptive

immunotherapy, biologic response modifiers, gene therapy among others).

If recurrent malignancy is suspected or confirmed, please contact the LTFU office (Appendix

A) promptly to discuss additional diagnostic tests and treatment options.

XV. SECONDARY MALIGNANCIES

Recipients of hematopoietic stem cell transplant have an increased risk of developing

secondary malignancies, including skin cancers, solid tumors, myelodysplastic syndromes,

leukemias and post-transplant lymphoproliferative disorder (PTLD). Solid tumors that occur

at increased frequency include skin cancers (squamous cell, basal cell, malignant melanoma)

and cancers of the buccal cavity, followed by liver, central nervous system, thyroid, bone,

and connective tissue. PTLD generally occurs within the first year after the transplant,

predominantly in patients who received T cell-depleted grafts and in patients treated with

intensive immunosuppressive regimens to control GVHD.

All transplant recipients should have oncologic screening evaluations at annual intervals

throughout life. We recommend the following general guidelines for oncologic screening.

1. Skin exam with the complete physical and history

2. Pap smears & mammogram (women > 35 years) & education to reinforce self breast

exams

3. Prostate exam and PSA (men > 45 years)

4. Occult blood in stool (> 40 years)

5. Colonoscopy (baseline at age 50 years and as clinically indicated thereafter)

6. Oral exam by the dentist at 6 month intervals

7. Complete blood counts, thyroid function, and other tests as applicable

All patients should use sunblocking creams (> 30 SPF – sun protection factor) when outdoors

to prevent skin cancers and to prevent activation of chronic GVHD.

Please contact the LTFU office (Appendix A) if you are planning surgery or a biopsy for

evaluation of suspected secondary malignancy or if secondary malignancy has been

diagnosed.

XVI. OTHER COMPLICATIONS

A. GONADAL HORMONE INSUFFICIENCY

Gonadal hormone insufficiency is related to the age of the patient and the intensity of the

transplant preparative regimen.

MALES:

Post puberty: Men who were past puberty at the time of transplant may develop primary

gonadal failure. Testosterone replacement should also be considered in men who are

receiving corticosteroids for long-term treatment of chronic GVHD (see Section XI). Men

who receive testosterone replacement therapy should have a baseline prostate exam and

measurement of prostate specific antigen (PSA), liver enzymes and serum lipids. Follow-up

monitoring of these parameters may be appropriate.

Prepubertal: For boys without signs of puberty at age 14 years or failure of pubertal

progression or abnormal growth velocity with hypergonadotropic hypogonadism (high FSH

and LH and low free testosterone) should be considered for androgen or gonadotropic

therapy. Initially a lower dose should be considered to accelerate growth velocity without

advancing bone age. Subsequently, the dose can be increased closer to end of growth spurt

when fusion of growth plates is then acceptable. Hormonal replacement in prepubertal boys

should be done in collaboration with a pediatric endocrinologist.

FEMALES: Women often develop primary ovarian failure and have symptoms of premature

menopause. They are also at risk for development of osteoporosis. Permanent ovarian

failure invariably occurs in all female patients who receive busulfan and cyclophosphamide

(BU/CY). Recovery of ovarian function has been observed after transplant in 54% of

younger patients (less than 26 years) conditioned with cyclophosphamide alone. The

probability of ovarian function recovery after fractionated TBI is at least 10% by 6 years

after transplant.

Premature (<40 years) or early (40 – 50 years) onset of menopausal symptoms and

osteoporosis can significantly affect the quality of life of women after a hematopoietic cell

transplant (HCT). During the past 30 years, replacement therapy with estrogen alone (for

patients without a uterus) or combined with progestin (for patients with a uterus) has been

used to prevent or treat menopausal symptoms and to prevent bone loss. In children,

hormonal replacement therapy (HRT) is needed after transplant to promote the development

of secondary sexual characteristics.

Estrogen can treat hot flashes, vaginal and vulvar symptoms, prevent bone loss and improve

the quality of life for HCT recipients who are postmenopausal or who have premature

ovarian failure. The positive effect on cognitive function claimed by many women taking

estrogen remains to be confirmed. In young girls, estrogen replacement therapy is often

critical for the development of secondary sexual characteristics and for the attainment of

peak bone mass in early adulthood.

a) Special Considerations:

It is unclear if estrogen alone or combined with progesterone replacement will add to the

already increased risk of secondary breast cancer in posttransplant women (Friedman et

al.Blood;2008;111:939-944). Among patients who survived for more than 10 years

posttransplant the observed/expected risk ratio is 3.2 for breast cancer (Rizzo et al, Blood

2009; 113: 1175-1193). Radiation has been identified as the primary risk factor associated

generally with the development of solid tumors after a stem cell transplant.

b) Hormonal Replacement Guidelines for Girls:

In young girls, estrogen replacement therapy is often critical for the development of

secondary sexual characteristics during the transitional from adolescence to adulthood and

for the attainment of peak bone mass in early adulthood. Survivors with

hypergonadotrophic (high FSH, low estradiol ) and hypogonadotropic (low FSH, low

estradiol) should be considered for hormone replacement therapy. Initially low dose

hormone therapy should be used . Cyclic dosing should be used at later stages to induce

regular menstrual cycles. It is recommended to hold hormone replacement therapy for 2

months at regular intervals to check for resolution of gonadal insufficiency . Hormonal

replacement in prepubertal girls should be done in collaboration with a pediatric

endocrinologist.

c) Hormonal Replacement Guidelines for Women:

Temporary relief of menopausal symptoms:

Unless medically contraindicated, a finite course of estrogen alone (women without

uterus) or combined with progesterone (women with uterus) may be prescribed for the

temporary relief of menopausal symptoms, provided that patients are frequently

reassessed by their physician to determine the appropriate duration of therapy.

General considerations for posttransplant Gonadal Hormonal Therapy (HRT) include:

• Management of ovarian failure should be tailored according to a patient’s particular

clinical manifestations and individual risks for side effects of HRT such as:

a) history (or family history) of breast cancer

b) history of deep venous thrombosis, stroke or hypercoaguable state

c) history (or family history) of colorectal cancer

d) severe osteoporosis with vertebral crush fractures

e) presence of absence of a uterus

• Overall benefits and risks of long-term HRT should be discussed with each patient.

• Information about non-hormonal alternatives for management of ovarian failure

manifestations should be discussed with all patients.

• A patient and her physician should be able to clearly state the indication (s) for which the

patient is to start (or continue) posttransplant HRT.

• HRT should be prescribed at the lowest effective dose.

• Annual gynecological follow-up evaluation is recommended for all women.

• Monthly self-breast examination is recommended for all women.

• Baseline mammography is recommended for all women from 35-40 years of age. Annual

follow-up is also recommended.

• Yearly re-evaluation of a patient’s ovarian failure management plan is recommended to

determine if it remains the most appropriate plan for that patient.

Specific Contraindications to HRT:

• Systemic estrogen alone or combined with progesterone should not be prescribed for patients

with a history of thromboembolic diseases (i.e., venous thrombosis, pulmonary embolism,

strokes, etc.), hypercoagulation disorders, breast cancer, coronary artery disease, or active

liver disease.

Alternatives to HRT:

• Diet, exercise and other non-hormonal strategies are available for management of hot flashes,

insomnia and mood disturbances.

• Topical estrogen alone may relieve local vaginal/vulva symptoms caused by gonadal

insufficiency.

Use of hormone of supplementation as first line of treatment is not recommended for

osteoporosis/osteopenia except for children or young adults. Please see LTFU Section XI:

General Guidelines For Prevention of Osteoporosis and Glucocorticosteroid Induced

Osteoporosis After HCT

• Difficulties such as decreased libido and/or dyspareunia may be multifactorial in etiology and

may often be managed without the use of systemic conjugated equine estrogen and

medroxyprogesterone.

B. Endocrine Abnormalities

Compensated or overt hypothyroidism, thyroiditis and thyroid neoplasms may develop in

patients who received radiation. The incidence of compensated hypothyroidism after

fractionated total body irradiation (TBI) before transplant ranges between 15-25%.

Patients should be evaluated yearly with physical examination and thyroid function tests.

Growth hormone (GH) deficiency and growth failure (decreased growth rate/year) occurs

in 70-80% of children who received total body irradiation or 1800 cGy cranial

irradiation. The onset of GH deficiency and growth failure varies with the age of the

child at the time of irradiation. The onset of these problems appears to occur later in

younger children than in peri-pubertal children. All children should have height

monitored at least annually, and those <14 years of age should have annual GH testing

until they either develop GH deficiency or are >14 years of age, whichever occurs first.

Among pre-pubertal children, treatment with total body irradiation, busulfan or >2400

cGy testicular irradiation may delay subsequent pubertal development. Children who

received busulfan appear to have the highest risk of delayed or absent pubertal

development. Approximately half of the very young children treated with total body

irradiation progress through pubertal development at an appropriate age, while older

children treated with total body irradiation have a higher risk of delayed pubertal

development. Treatment with cyclophosphamide alone does not delay pubertal

development.

Beginning at age 10, all children should have Tanner development scores determined as

part of an annual physical examination. Children who are Tanner Stage I or II by age 12

years should be referred to a pediatric endocrinologist to evaluate the need for hormonal

supplementation.

C. Ocular complications

An annual eye exam with slit lamp examination is recommended for all patients who

have had an allogeneic transplant and for those who are at risk of cataracts. The risk of

cataracts after transplant is high for patients who received fractionated TBI (30 – 50%)

and for patients treated with corticosteroids after the transplant (45%). In patients who

received neither TBI or prior cranial irradiation, the incidence for cataract is

approximately 15% and, is primarily due to corticosteroids. The median time to develop

cataracts after transplant ranges from 2 to 5 years. Cataract extraction can be performed

safely even when ocular sicca is present. Unanticipated complications after placement of

an intraocular lens have not been reported. Other late complications involving the eyes

are related to chronic GVHD as described in Section X A and B.

D. Oral complications and guidelines for dental care

New oral pain or dryness beyond day + 100 after allogeneic transplant suggests

development of chronic GVHD involving the salivary glands or mucosal surface.

Cultures for candida and DFA or rapid cultures for herpes simplex virus should be

obtained to rule out concomitant infections if clinically indicated. A dental/oral medicine

consultation should be strongly considered in all patients with oral complications. If you

have questions about dental care during treatment for GVHD that are unanswered below,

please call the LTFU office who will provide instructions on how to take oral cavity

photos that you can send to [email protected] with your clinical impression and

question. Our LTFU/Oral Medicine can then review these and provide further advice.

General guidelines for dental care for autologous and allogeneic transplant recipients are

provided in the Table below.

General guidelines for dental care in hematopoietic transplant recipients include (see Table 1):

• Routine dental health examinations (with radiographs as needed) are recommended to

monitor for tooth decay and oral hygiene effectiveness, gingivitis and/or periodontitis.

Dental exams can take place any time after transplant and should be done every 6-12

months for routine oral health assessment, to evaluate/treat chronic GVHD (allogeneic

patients) and to screen for oral cancers. (see Table 1)

• Routine dental exam/cleanings should be delayed for first 6 months after transplant due

to increased risk of bacteremia and pneumonia while patients are still

immunocompromised. After the first 6 months, routine (not deep) cleaning either by

ultrasonic or manual dental scaling are reasonable provided certain other criteria are met

(see Table 1).

• Periodontal therapy (Deep cleaning) can be done after the first 6 months if the additional

criteria over and above those set for routine cleaning are met (see Table 1).

• Elective (non-urgent/non-emergency) restorative dental treatment like fillings and

crowns, or elective surgical procedures like dental extraction of non-infected teeth,

implants and gum graft surgery should be delayed until immunity is recovered and

patient has discontinued systemic immunosuppressive treatments. (see Table 1)

• “Cosmetic” dental care like dentures are considered safe so long as no extractions or

surgeries are needed. Veneers and other elective restorative procedures should be delayed.

Teeth whitening is reasonable beyond 6 months posttransplant. Invisalign therapy is not

recommended within the first 6 months. Traditional orthodontia is deferred until patient has

no active GVHD and is off all systemic immunosuppression. (see Table 1)

• Emergency or Urgent Care should be carefully coordinated between managing

dentist/oral surgeon and medical team so that appropriate supportive and medical care

can be discussed. Important considerations include:

1. Prophylactic and/or therapeutic antibiotics to minimize risk of bacteremia

complications:

a. For patients with an indwelling central venous catheters, follow American Heart

Association (AHA) recommendations for low-moderate endocarditis risk.

b. For short non-surgical/non-invasive surgical procedures, also follow AHA

prophylactic antibiotic recommendations, and extend treatment if there is

significant local dental infection and risk of subsequent spread of infection

(local or disseminated).

2. Other strategies to reduce spread of infection:

a. Chlorhexidine oral rinse for 3 minutes immediately prior to treatment.

b. Minimize aspiration of aerosolized bacteria by using a rubber dam, high

volume suction, minimal air-water sprays during procedures.

3. Platelet support depending on invasiveness of treatment and risk of bleeding.

Other medical support (e.g. stress dose steroids, adjustments to anticoagulation therapy).

Other key points / recommendations:

• More frequent cleanings may be required based on oral health conditions. Ultrasonic

cleaning carries slightly more risk of aspiration than manual scaling but is generally

acceptable.

• Patients should carry out focused and effective oral hygiene (brushing, flossing, etc.) as

good oral hygiene can be protective in preventing oral GVHD flares.

• Patients with dry mouth should be placed on dental decay prevention regimen that

minimally includes daily brush-on prescription-strength fluoride gel or toothpaste or

rinses to reduce the risk of dental decay. Other measures to promote salivation should be

encouraged (oral moisturizing agents, sugar-free gums or candy, and prescription drugs

to stimulate saliva flow).

• Patients who have received bisphosphonate therapy or on or just completed

denosumab therapy are at a risk for osteonecrosis of the jaw (ONJ). Risk depends on

the type of bisphosphonate, dose, frequency, and total duration of treatment. Reclast

(zoledronic acid) is considered to be at very low risk for ONJ. Zometa (another brand of

zoledronic acid) and pamidronate (Aredia) are considered to be at highest risk for

development of ONJ. The risk for MRONJ in patients treated with oral bisphosphonates

increases steadily over time and is of higher concern in those with greater than 3 years of

use. Bisphosphonates will persist in bone for as long as 10-15 years after discontinuation.

Denosumab (Xgeva) has also been associated with ONJ but the risk for ONJ with

denosumab will decrease over 6-7 months after discontinuation. Patients who previously

received bisphosphonates and switched to denosumab may be at an even higher risk for

ONJ compared to either agent used alone.

Recommendations for patients who have received bisphosphonate therapy or on or just

completed denosumab therapy are at a risk for osteonecrosis of the jaw (ONJ:

a. Prevent trauma and irritation from dentures

b. Support excellent dental and periodontal health in order to avoid advancing dental

infections or problems that would ultimately need dental surgery to manage.

c. When patients at risk for ONJ need dental procedures, the least invasive but

effective procedure to solve the problem should be chosen.

Stabilization/restoration of a tooth with a root canal or crown is preferable to

extracting the tooth.

d. Any dental surgery – extractions, implants, periodontal, or endodontic, is

considered high risk for development of ONJ if there has been prior or

ongoing therapy with bisphosphonates or denosumab therapy.

e. If the risk/benefit ratio has been explored and a tooth must be removed, the

procedure should be done by a skilled Oral Surgeon who will use extreme

caution to avoid any excessive trauma to the bone and achieve primary closure

of the site.

• Special attention should be paid to potential head and neck cancers in transplant

survivors – especially lip and oral cavity cancer. Risk is related to cumulative total body

or local irradiation exposure and chronic GVHD.

General guidelines include:

a. Patient counseling to avoid additional risks, specifically, to follow protection

against sun exposure to lips, avoid tobacco products and avoid excess alcohol

beverage intake.

b. Adjunctive examination techniques such as increased uptake of applied toluidine

blue vital dye within dysplastic or neoplastic oral mucosal lesions may be

diagnostically helpful for screening.

c. Serial lesion photographs can be an important component of patient management.

d. Suspicious lesions should be managed comprehensively and followed closely

until resolved or definitive diagnosis is made.

Table 1: Dental Care Guidelines for Autologous and Allogeneic Transplant Recipients

Dental Procedure

Time after Transplant

Until 6 months

After 6 months ****

LOW-RISK HIGH-RISK

Not receiving IST for active GVHD* or

getting maintenance with anti-CD20

therapy or other cytotoxic therapy AND

with ANC >1000, Plts >30K

Receiving IST or

maintenance with anti-CD20

therapy or other cytotoxic

therapy, CD34 selected

transplant or ANC <1000,

Plts <30K

Routine Dental Care

Exam every 6-12 months

YES

Routine Dental Cleanings

YES, with antibiotics if central line still in

place

YES, with antibiotics and/or

IVIG** as clinically

indicated

Periodontal Therapy

Scaling/root planning +/-

curettage (dental deep

cleaning)

YES, for autologous (no contraindications)

YES, for allogeneic with considerations for

additional medical support

Restorative Dental Care***

Crowns

Emergent ONLY

with antibiotics

Emergent ONLY with antibiotics

Emergent ONLY with

antibiotics and/or IVIG

Fillings

Emergent ONLY

with antibiotics

Emergent ONLY with antibiotics

Emergent ONLY with

antibiotics and/or IVIG

Surgical Treatments

Dental extractions

Emergent ONLY

with antibiotics

Emergent ONLY with antibiotics

Emergent ONLY with

antibiotics and/or IVIG

Implants

Autologous – NO

Allogeneic – NO

Gingival grafts

YES, for autologous (no contraindications)

YES, for allogeneic with considerations for

additional medical support

Cosmetic Dental Care

Teeth whitening

YES

Orthodontia

Dentures

YES, if no

surgery needed

YES, if no surgery needed

YES, if no extractions are

needed

Abbreviation: IST = immunosuppression; ANC = absolute neutrophils count, Plts = platelets.

* Prophylactic IST or prednisone dose < 0.5mg/kg/day is OK if GVHD considered inactive

** IVIG should be considered if serum IgG level is below 400 mg/dL

***

If treatment is urgent/or emergency due to overall immune/GVHD status – that is, dental disease is at risk for

seriously compromising patient status, planning should consider strategies to reduce local and systemic infection spread

and bleeding.

****Beyond 1 year posttransplant, all dental procedures without additional precaution are OK, if all conditions

below are met:

– No indwelling central venous catheter

– At least 3 months recovery from the last Rituxan

– No active GVHD defined by discontinuation of all IST at least for 8 months

– IgG level > 400 mg/dL

– ANC >1000 cells/ul

– Platelet count > 30K/ul

– Not receiving cytotoxic therapy as maintenance treatment

E. Renal insufficiency

Nephrotoxic drugs are the most common cause of impaired renal function after a stem

cell transplant. Monitoring renal function and drug levels is recommended for all patients

who are at risk of renal insufficiency (Section III C & D).

F. Neurological Complications

Peripheral neuropathy and central nervous system complications may develop after

transplantation. Neurological complications may be caused by drugs used to control

GVHD (cyclosporine, tacrolimus) (Section X), electrolyte abnormalities, infection

(HHV-6, HSV, VZV, fungal organisms, toxoplasma, among others), prior cranial

irradiation, intrathecal chemotherapy, GVHD and malignancy. The following evaluation

is recommended:

1) Perform neurological examination including mini-mental state exam.

2) Consider

- Medications (CSA, FK506, opiods, benzodiazepines, high-dose steroids, voriconazole, etc) and check

CSA/FK506 levels

- Metabolic abnormalities (hypo/hypernatremia, hypercalcemia, hypercapnia, hyperosmolarity, renal or

hepatic failure, hypothyroidism, adrenal insufficiency, hypoglycemia, etc.)

- Non-CNS infection such as UTI, pneumonia, etc.

- Unremitting pain or insomnia

- Intracranial hemorrhage

- Hypovolemia – due to bleeding or other cause

- Head trauma

- CNS malignancy

- CNS infection

When available, refer to institutional policies on the management of patients with delirium.

If medication/metabolic/endocrine/pain effect/sleep deprivation are felt to be unlikely etiologies OR if symptoms

persist for >24-48 hours despite efforts to correct what’s felt to be underlying cause:

1) Brain Imaging (MRI preferred)

2) Lumbar puncture

Standard: cell count, protein, glucose, cytology, gram stain, bacterial/fungal cultures, HHV-6 PCR (viremia

should not be assumed to be a marker for HHV-6 detection in the CSF), additional CSF saved for future

studies

Additional testing for malignancy of infection (see table below) may be considered as clinically indicated:

3) Consider ID consult for evaluation of infectious etiologies of delirium

4) Consider Neurology consult for evaluation of neurological etiologies of delirium

5) Consider psychiatry consult for evaluation and treatment of delirium

Depending on the clinical scenario, the following additional tests for infectious etiologies

may be considered:

Pathogen

Relative

Frequency

Clinical Setting

Recommended Initial Evaluation

Viruses

HHV-6

Frequent

• Early after transplant

• Temporal lobe contrast-enhancing lesions

• Memory loss characterizing delirium

CSF: HHV-6 PCR

HSV

Occasional

• Temporal lobe contrast-enhancing lesions

• Seropositive and not on ACV/GCV

CSF: HSV PCR

VZV

Occasional

• Seropositive or following significant

exposure and not on ACV/GCV

CSF: VZV PCR

CMV

Rare

• Donor or recipient seropositive and late

after transplant

CSF: CMV PCR

EBV

Occasional

• T-cell depleted, including CD 34+

selected

• Receipt of anti-T cell antibodies

CSF: EBV PCR

Enterovirus

Occasional

• Child

• Summer/fall

CSF: Enterovirus PCR

West Nile Virus*

Occasional

• Donor is from endemic state

• Significant mosquito exposure

• Neuromuscular weakness as component

of meningoencephalitis

CSF: WNV PCR (low sensitivity),

IgM (MAC-ELISA)

Serum: IgM (MAC-ELISA)

Contact Public Health

JC virus

Rare

• Brain imaging: non-enhancing white

matter lesions

• other work-up negative

CSF: JCV PCR

Brain biopsy

Zika virus

Very Rare

• Donor or Recipient from endemic area

ID Consult

Parasites

Toxoplasma

Occasional

• Ring-enhancing lesions

• Seropositive pretransplant and not on

prophylaxis – TMP/SMX, dapsone, etc.

CSF: PCR (low sensitivity)

Plasma: PCR

Fungi

Aspergillus and other

molds

Frequent

• Enhancing brain lesion (s) consistent with

abscess

• Concurrent pulmonary lesions (nodules)

• High degree of immunosuppression, or

neutropenia

CSF: PCR and galactomannan

(unknown sensitivity/specificity),

fungal culture

Plasma: galactomannan

Cryptococcus

Rare

• High degree of immunosuppression, or

neutropenia

• +/- enhancing meningitis or nodule or

hydrocephalus

CSF: cryptococcal antigen, fungal

culture

Serum: cryptococcal antigen

Bacteria

Usual bacterial

pathogens: S.

pneumoniae,

Listeria, GNR,

Nocardia, etc.

Frequent

• Meningitis

• Enhancing brain lesion (s) consistent with

abscess

No additional testing

recommended as these pathogens

should be identified by standard

bacterial culture.

Syphilis

Rare

• Positive pre-transplant serology

• Significant exposure

CSF: VDRL, FTA, or TPPA; IgM

immunoblotting: intrathecal T.

pallium antibody (ITPA) index,

PCR,

Tuberculosis**

Rare

• Meningitis (basilar or diffuse) or ring-

enhancing lesion(s)

• Recipient from endemic area

• Positive PPD pretransplant

• Significant exposure

CSF: AFB stain and culture, PCR

(both, low sensitivity)

* If concerned about other arboviruses, please discuss with Infectious Diseases.

** If concerned about non-tuberculous mycobacteria, please discuss with Infectious Diseases.

If the appropriate test is not locally available, arrangements should be made to send the

specimen to another laboratory. Please contact the LTFU office (see Appendix A)

Some children, especially those given cranial irradiation before the transplant, may have

learning disabilities (particularly in mathematics and abstract thinking). These

abnormalities typically begin to appear 24-42 months after the transplant. When

recognized as a problem, refer for psychological testing. Special educational instruction

should be considered for these children. Short-term memory deficit can occur in adults,

and psychometric testing should be performed as clinically indicated.

Total body irradiation can delay the onset of developmental landmarks in very young

children. These effects are most severe throughout the first year after transplant, and

affected children benefit from occupational therapy to assist their normal development.

After they have achieved appropriate developmental landmarks, further development

appears to proceed normally. IQ and ability to succeed in school do not appear to be

affected by total body irradiation.

G. Bone Complications (see Section XI)

Osteoporosis, fractures and avascular necrosis (AVN) are common complications after

transplantation. Long-term treatment with corticosteroids is the primary risk factor for

these complications, while gonadal failure, electrolyte imbalances, physical inactivity and

treatment with cyclosporine play an additional contributory role. Approximately 50% of

patients receiving long-term corticosteroid therapy will eventually develop bone

fractures. Increased osteoclast-mediated bone resorption and decreased osteoblast-

mediated bone formation cause trabecular bone loss. In HCT recipients, evaluation for

bone loss and osteoporosis includes a careful assessment of risk factors

(www.shef.ac.uk/FRAX/) and exposures in addition to BMD measurement. Bone loss

can be minimized by decreasing glucocorticoid dose, optimizing calcium and vitamin D

intake, participating in weight-bearing exercise, using bone strengthening drugs, and if

clinically indicated by hormonal replacement therapy. Section XI provides detailed

guidelines for preventing and monitoring osteoporosis in patients. Section XX describes

vitamins and other minerals requirements. Section XXI outlines diet for patients treated

with corticosteroids. Section XI outlines hormone replacement therapy.

H. Chronic Pulmonary Complications

Some reports have shown that the FEV

/FVC is less than 70% in 15% of patients by one

year after the transplant and in 30% of patients by three years after an allogeneic

transplant. Among patients with chronic GVHD, 5-10% will develop severe obstructive

airway disease that resembles obliterative bronchiolitis.

Monitoring of lung function after day +100 after allogeneic transplant.

Pulmonary function test (PFT) monitoring including: spirometry, lung volumes, and DLCO.

PFTs for asymptomatic allo-HCT recipients:

a. At 6 months

b. At 1 year

c. Yearly thereafter until 5 years as clinically indicated

d. At diagnosis of chronic GVHD

i. Full PFT testing including: spirometry, lung volumes, and DLCO

ii. Q3 months after diagnosis of chronic GVHD for at least one year.

(spirometry alone may be adequate)

iii. Thereafter, at Q6 months for 1 year (spirometry alone may be

adequate)

iv. With at least yearly full PFT testing including: spirometry, lung

volumes, and DLCO until year 5 post HCT.

(Section X B). If new abnormalities are noted in PFTs please contact the LTFU office to

discuss further recommendations (Appendix A).

Children who received total body irradiation are at risk of delayed onset pulmonary

restrictive disease 5-20 years after the transplant. All patients who were in the pediatric

age group at the time of transplant should have annual pulmonary function tests.

I. Hepatobiliary Complications

(see References, section XXV, Liver)

Elevations of serum ALT, alkaline phosphatase or bilirubin may occur after day 100, even

in patients who had no indication of liver problems earlier. The presentations fall into

four clinical categories.

• Acute hepatitis. Elevations of serum ALT after day 100 are most commonly

caused by drug-induced liver injury (an azole antifungal or trimethoprim-

sulfamethoxazole are the most common causes of Drug Induced Liver Injury (DILI)

in this setting), chronic GVHD, an exacerbation of hepatitis B or C, or a herpesvirus

hepatitis (VZV, HSV).

Four clinical situations demand immediate diagnosis and treatment.

1) Rapidly rising ALT accompanied by anorexia, abdominal distension or pain in

the abdomen or back can be signs of visceral VZV infection (Section VIII B).

2) Patients who have indications of hepatitis B before transplant (HBsAg-positive

or anti-HBc-positive) or who had a donor who was infected with hepatitis B are

at risk of fulminant hepatitis B after the transplant if they did not receive

antiviral prophylaxis.

3) Chronic GHVD can present as an acute hepatitis, usually after tapering or

discontinuation of immunosuppressive medications, particularly cyclosporine or

tacrolimus, or after DLI.

4) In Hepatitis C infected patients, a diagnosis of fulminant immune-rebound

hepatitis should be considered, especially if patient is tapering

immunosuppression, and, if clinically indicated, treatment with Direct Acting

Antiviral (DAA) drugs.

Patients with a rapidly rising ALT and those with ALT values >500 u/L should be

given IV acyclovir until VZV hepatitis is ruled out. An urgent PCR for VZV DNA

in serum is needed to establish the diagnosis. Contact the LTFU office (Appendix

A) for guidance in difficult cases.

• Chronic hepatitis. Chronic fluctuations in serum ALT levels without a discrete

episode of acute hepatitis may represent DILI, hepatitis B or C virus infection

(Section XVII), iron overload (Section XVIII) or cGVHD (Section X).

• Jaundice or signs of cholestasis. Elevated serum bilirubin and elevated alkaline

phosphatase can be caused by chronic GVHD (Section X), drug-induced

cholestasis, acute hepatitis (see above), or biliary obstruction. An ultrasound should

be obtained to evaluate whether the common bile duct is dilated. Liver biopsy

might not be needed in patients who have cholestasis with biopsy-documented

chronic GVHD in other organs. Some patients have liver involvement as the

dominant manifestation of chronic GVHD, and liver biopsy might be needed in

order to establish the diagnosis when other manifestations of chronic GVHD are

absent.

• Hepatomegaly or right upper quadrant pain. The sudden onset of

hepatomegaly suggests acute hepatitis, Epstein-Barr virus-induced

lymphoproliferative disorder involving the liver, or rarely, Budd-Chiari syndrome.

More indolent hepatomegaly can occur with metastatic tumor, leukemia infiltration

or rarely, constrictive pericarditis or mycobacterial infection. Right upper quadrant

pain can be caused by acute cholecystitis, biliary obstruction with cholangitis,

biliary sludge syndrome, or rarely, fungal liver abscess. Liver imaging with helical

CT X-ray or ultrasound is needed to resolve the diagnosis.

Suggestions for liver biopsy and handling of liver tissue. The technique of liver

biopsy depends on the clinical situation (diffuse process vs. focal lesion) and the platelet

count. A percutaneous biopsy is preferred if platelet counts are >100,000/mm

and the

risk of bleeding is small (including normal PT/PTT) but transvenous biopsy through

either the femoral or jugular route is satisfactory for diagnosis of any diffuse hepatitis or

GVHD. Tissue should be cultured for viruses and fungi and should be fixed in freshly-

prepared neutral buffered formalin.

J. Gastrointestinal Complications:

(see References, section XXV, Liver)

GVHD is the most common cause of anorexia, nausea, vomiting and diarrhea after an

allogeneic transplant. However, each of these symptoms has a narrow differential

diagnosis that requires careful evaluation before concluding that GVHD is the sole cause.

Anorexia, nausea and vomiting can be caused by HSV, VZV, and CMV infections and by

certain medications such as trimethoprim-sulfamethoxazole, voriconazole, itraconazole,

mycophenolate mofetil, cyclosporine or tacrolimus. Abdominal pain can be caused by

visceral VZV infection, biliary sludge syndrome, acute cholecystitis, or rarely, Epstein-

Barr virus-induced lymphoproliferative disease. Diarrhea occurring more than 3 months

after transplant is commonly caused by magnesium – containing medications, unresolved

GVHD, or less commonly by an infection (giardiasis, cryptosporidiosis, C. difficile, or

CMV). Section VII provides guidelines for evaluation of diarrhea and endoscopy.

XVII. BLOOD PRODUCT TRANSFUSIONS

All blood products should be irradiated to prevent transfusion related Graft Versus Host Disease

(GVHD), with the exception of pathogen reduced blood products that do not need to be

irradiated. Red blood cells and platelets should also be leukocyte reduced to prevent HLA

alloimmunization and reduce the risk of CMV transmission. Leukocyte reduced blood

components are accepted as “CMV safe” for CMV seronegative patients. Granulocytes are

never leukoreduced.

If the donor and recipient had ABO blood group incompatibility, low-grade hemolysis can

delay erythroid recovery for many months after the transplant. Hemagglutinin titers and

reticulocyte counts should be followed to monitor the change from recipient to donor ABO

type. Type O red cells should be used for patients who have isoagglutinins against donor red

blood cell antigens until the donor blood group type is fully established in the recipient.

Treatment with erythropoietin can be beneficial in some patients. Donor-type platelets

should be used for transfusions.

XVIII. VIRAL HEPATITIS in long term transplant survivors

(see References, section XXV, Liver)

Compared to hepatitis C, hepatitis B is more likely to result in severe clinical hepatitis and

death from post-transplant liver disease, although these outcomes occur only in the minority

of HBV-infected patients. One exception: patients infected by HCV who are receiving

MMF for GVHD prophylaxis may develop a more severe, potentially fatal form of liver

disease called fibrosing cholestatic hepatitis C. In this setting, it should be assessed whether

MMF may be discontinued. Antiviral treatment should be considered for HBV-and HCV-

infected transplant recipients unless contraindications are present. Liver test abnormalities

post-transplant may be caused by hepatic GVHD, HBV, HCV, a herpes virus infection

(VZV, CMV, HSV), adenovirus, or drug-induced injury (Sections I, X and XV). In this

situation, liver biopsy should be performed to determine the dominant pathologic process.

A. Hepatitis B

Even in patients with very low levels of viral replication before transplantation and relatively

normal liver function and histology, impaired cellular immunity can permit reactivation of

HBV. Serological patterns of HBV infection may be atypical in transplant survivors, likely

as a consequence of immunosuppression. Patients with HBV requiring systemic

immunosuppressive medications for control of chronic GVHD remain at risk for acute

exacerbation of hepatitis whenever immunosuppression is tapered or ceased. Such flares

may result in hepatic failure and death. Cirrhosis due to chronic HBV has not emerged as a

major problem after transplantation.

The risk of fatal HBV liver disease among patients who are persistently HBsAg-positive

after transplant and who are not receiving entecavir is approximately 12%. In hematopoietic

cell transplant recipients who are anti-HBc and anti-HBs-positive, but HBsAg-negative,

reactivation of latent infection can occur and may lead to fulminant hepatic failure,

particularly if nucleotide substitutions in the precore region of the genome interfere with

production of HBcAg. Because these patients remain HBcAg-negative despite high levels of

viral replication, monitoring of HBV DNA levels is necessary in these HBsAg-positive

patients.

Posttransplant HBV infection may result from

 Active HBV infection before transplant

 Reactivation of latent HBV infection

 New infection during the transplantation process

o Infected hematopoietic cell product from an infected donor

o Infected blood products (risk estimated in U.S. to be 1 in 500, 000 units).

1) Monitoring of Patients at Risk for HBV Infection

 For allogeneic transplant patients who had a donor who was either HBsAg or

antiHepB core positive:

Serum ALT and HBV DNA monthly to six months post transplant or 6 months

after stopping entecavir (whichever is longer).

 For allogeneic transplant patients where patient is HBsAg positive and on entecavir:

Monitor HBV DNA and serum ALT monthly until 6 months after stopping

entecavir. If increased Serum ALT consider testing for viral resistance and

switching to TAF if checked HBV DNA increased >1.0 log above nadir.

 For allogeneic transplant patients where patient is antiHepB core positive:

Serum ALT and HBV DNA monthly until 6 months after stopping entecavir.

 For autologous transplant patients who is either HBsAg or antiHepB core positive:

o Monitor HBV DNA and Serum ALT monthly until 6 months after stopping

entecavir. If HBV DNA increases > 1.0 log above nadir. Consider testing for

viral resistance and switching if medically indicated to TAF.

2) Treatment

For patients at risk for HBV infection after transplant who are NOT receiving antiviral

prophylaxis, we recommend initiation of antiviral treatment with entecavir when HBV

DNA is first detected after transplant. For patients already on entecavir and not

appropriately responding, consider alternative antiviral therapy. The aim of antiviral

treatment is to suppress viral replication completely, thereby minimizing the risk of viral

mutation. Patients should be treated for 12 months or 6 months after discontinuation of

systemic immunosuppressive treatment, whichever is longer.

3) Other considerations

-Clearance of antigenemia is commonly observed and is particularly likely if the

hematopoietic cell donor was anti-HBs-positive.

- Based on CDC guidelines, vaccination with HAV is considered particularly important

and is strongly recommended for any patient with evidence of infection with HBV to

prevent the development of fulminant liver failure secondary to hepatitis A infection.

(See section IX Vaccinations)

B. Hepatitis C

Infection with HCV virus is more frequent in patients who received blood product transfusions

before 1991 when HCV testing was unavailable than with transfusions given after 1991. The

prevalence of chronic hepatitis C in long-term HCT survivors ranges from 5% to 70%,

depending on the endemic prevalence. Long-term survivors with HCV infection commonly

have fluctuating levels of AST and ALT. During the first 10 years after infection, hepatitis C

has little impact in morbidity or mortality—with the exception possibly of HCV-infected

patients who are receiving MMF. The frequency of cirrhosis and end-stage liver disease caused

by Hepatitis C in 40-year survivors of hematopoietic cell transplant is about 33%.

Regardless of whether HCV infection occurred before or after the transplant, clinical or

biochemical evidence of hepatitis usually coincides with the return of cellular immunity and

the tapering of immunosuppressive drugs used for GVHD prophylaxis. During this time, it

is difficult to differentiate the hepatitic variant of GVHD of the liver from an exacerbation

of HCV. The presence of hepatitis C viremia, even in high titer, is insufficient to make the

distinction between these two disorders. The absence of hepatitis C viremia, however,

means that HCV is not a cause of ALT elevations. Unless there is evidence of active GVHD

in other organs, a liver biopsy may be required before a therapeutic decision is made.

Pathologic distinction between hepatitis C and GVHD may be difficult, since both processes

may be associated with portal lymphoid infiltration and bile duct injury. Marked bile duct

injury with epithelial cell dropout and loss of interlobular bile ducts is more typical of

GVHD. A flare of hepatitis C and hepatic GVHD may occur simultaneously. If the liver

biopsy suggests both processes, immunosuppressive therapy should be administered, since

ongoing lymphocytic attack leading to loss of interlobular bile ducts may result in severe

and progressive cholestasis.

Fulminant immune-rebound hepatitis C has been reported only rarely after withdrawal of

immunosuppression. Patients infected by HCV who are receiving MMF may be at risk to

develop fatal fibrosing cholestatic hepatitis C. After the initial flare of hepatitis during

immune reconstitution, the serum ALT levels may again return to normal, but laboratory

abnormalities often settle into the pattern of chronic hepatitis seen in other patients with

HCV infection.

Monitoring:

 Liver function tests at least weekly to day 100, then bimonthly until 1 year

 HCV RNA should be checked around day 50 post transplant in those rare patients who

were HCV antibody positive but HCV RNA negative pretransplant or whose donor was

HCV RNA positive.

 Patients known to have HCV should be referred to a hepatologist to assess three major

issues: 1) Has the virus infection caused any damage to the liver yet? 2) Are there other

causes of liver damage (i.e., alcohol, medications, chronic GVHD, hemosiderosis or the

hepatitis B virus? 3) Should medications for HCV be instituted?

 All HCV-infected long-term HCT survivors should be evaluated for progression of liver

disease every 6 to 12 months with a hepatic function panel, complete blood count, and

evaluation of prothrombin time/international normalized ratio. If fibrosis is suspected in

long-term HCT survivors, noninvasive tests such as serologic panels and transient

elastography can be used to evaluate for the presence of advanced fibrosis (Scoring System

for Histological Stage Metavir score > F3) and cirrhosis (Metavir score F4).

 For HCV-infected HCT long-term survivors with advanced fibrosis (Metavir score > F3),

surveillance for hepatocellular carcinoma with ultrasonography every 6 months is

recommended. For patients with cirrhosis, endoscopic surveillance for esophageal varices is

recommended.

Therapy

Direct-acting anti-viral therapy for chronic HCV infection should be considered after the

patient has discontinued all immunosuppressive drugs, and has no evidence of active

GVHD. Be aware of possible drug-drug interactions (see References, section XXV,

Liver).`

In patients with concomitant iron overload, phlebotomy or chelation therapy may be

indicated to reduce hepatic iron stores (Section XVIII) before Direct Acting Antiviral

(DAA) therapies. The mobilization of iron after transplant largely depends on the iron

burden, especially cardiac iron. A review of this topic has been published. (see

References, section XXV, Liver)

In all HCT survivors with active HCV infection, cofactors that can lead to fibrosis should be

addressed. Patients should be counseled to avoid excessive weight gain, ethanol and

medications or herbal supplements that are hepatotoxic, as well as on treatment of other

causes of liver disease (nonalcoholic fatty liver disease, hepatitis B virus, HIV, and

extrahepatic obstruction), and mobilization of excess iron.

HCT recipients who develop end-stage liver disease can be considered for liver transplant;

in rare cases, a living donor liver transplant from the original hematopoietic cell donor may

be feasible.

Other Considerations:

- Based on CDC guidelines, vaccination against HAV and HBV are considered

particularly important and are strongly recommended for any patient with evidence of

infection with HCV to prevent the development of fulminant liver failure secondary to

infection with other hepatitis viruses.

(See section IX Vaccinations)

XIX IRON OVERLOAD

A. Summary of evidence

1. Epidemiology

Iron overload occurs frequently in hematopoietic cell transplantation (HCT) patients, often

caused by red cell transfusions prior and during HCT, in addition to ineffective

erythropoiesis with associated intestinal hyperabsorption, and, in some patients, underlying

genetic hemochromatosis. Elevated ferritin estimates 32-58% of HCT survivors may be

overloaded with iron [1, 2, 3]. One autopsy study found 40% of patients with significantly

high liver iron content (LIC) above 5.6mg/g [4]. A cross-sectional study showed 31/56 HCT

recipients had elevated ferritin, and 50% of those with high ferritin had significant liver

siderosis with LIC>6.5mg/g [1].

2. Natural history of iron overload in HCT and its consequences

Once transplant has restored normal hematopoiesis and red cell transfusions are no longer

required, body iron stores decline over several years [5]. Elevated liver iron content (LIC)

defined as >1.8mg/g by T2- magnetic resonance imaging (MRI) was not associated with

survival or complications in adult patients at 1 year post-HCT [6]. High LIC (above 7mg/g)

as determined by magnetic resonance in patients post HCT for myelodysplastic syndromes

or acute myeloid leukemia was a significant risk factor for non-relapse mortality

(particularly in older patients undergoing reduced intensity conditioning), and ferritin above

1,000ng/mL has been associated with decreased survival. [7;8, 9]. Extreme tissue iron

overload (> 15 mg/g dry weight) has been associated with extensive organ toxicity in the

post-transplant survivors of thalassemia, in whom organs at risk include the heart, liver,

pancreas and pituitary gland, resulting in dysrhythmias and cardiac failure, portal fibrosis

and cirrhosis, insulin-dependent diabetes mellitus and other endocrine insufficiencies. Iron

overload increases the susceptibility to mucormycosis, aspergillosis, and infections caused

by Listeria monocytogenes, non-cholera Vibrio species, Yersinia enterocolitica and Yersinia

pseudotubera, among others [2, 4]. In patients with chronic hepatitis C, iron overload may

accelerate the development of cirrhosis.

3. Assessment of iron overload post-HCT

Although ferritin measurement is recommended as part of long-term follow-up post-HCT, it

also changes with inflammation and cell injury. Assessment of body iron by MRI is non-

invasive and has been calibrated with liver biopsies and ex vivo heart tissue iron

measurements, allowing accurate and more frequent assessment of iron overload than liver

biopsy [10]. Liver or marrow iron content correlates poorly with number of transfused red

blood cell units. Marrow and liver iron contents have been determined by spectrophotometry

among 10 consecutive autopsied patients who were transplanted for hematological

malignancy. The median liver iron content (LIC) at 50 to 100 days post-transplant was 4.307

mg/g dry weight (range 1.832-13.120; normal 0.530-0.900) and the median marrow iron

content was 1.999 mg/g dry weight (range 0.932-3.942). Marrow iron content can also be

measured by morphometry based on digital photomicrographs of a Prussian blue-stained

marrow biopsy. Because of correlation between morphometric and spectrophotometric

analyses of marrow iron content (r = 0.8, P= 0.006) and hepatic iron index (r = 0.82, P =

0.004) morphometric analysis of marrow iron content is an acceptable alternative for

quantifying tissue iron stores [11]. Earlier work also demonstrated a close relationship

between biochemical concentration and histologic grading of marrow iron [12] although

histological grading is subject to variation between and within observers [13]. Because the

carrier frequency for homozygous High Fe (HFE) gene mutations is relatively high (0.3 to

0.5%) among individuals of Northern and Western European ancestry, the possibility of

hereditary hemochromatosis (HH) contributing to post-transplant iron overload needs to be

considered in relevant individuals. Two point mutations, C282Y (Cys282Tyr) and H63D

(His63Asp), are the most frequently found within the HFE gene. Homozygosity for C282Y

is associated with hemochromatosis with variable penetrance; the effect of compound

heterozygosity (C282Y/H63D) on iron status in HCT recipients is variable.

4. Management of iron overload post-HCT

Mobilization of iron in heavily overloaded patients improves cardiac function, normalizes

serum alanine aminotransferase (ALT) levels, and results in improved liver histology

[14;15]. Phlebotomies were well-tolerated by 14/16 patients, and they reached the target

ferritin below 500ng/mL after a median of 16.5 phlebotomies in a median of 287 days [3].

Ferritin levels decreased significantly in 49/55 (80%) of patients after a median of 9

phlebotomies in another study [16]. One study showed that recipients of marrows from

donors with mutated HFE had lower reduction in ferritin levels per phlebotomy than those

who received marrow from wild-type donors [16]. A retrospective study found that

deferoxamine use post-HCT in 37 patients was associated with lower ferritin and lower

relapse incidence [17]. Oral chelation with 20-30mg/kg/day of deferasirox has been

evaluated retrospectively and showed a possible association with longer survival after HCT

[18], and a prospective, phase IV, open-label trial showed 10mg/kg/day of deferasirox

provided a significant reduction in serum ferritin and liver iron concentration over one year

of treatment with mild to moderate adverse events [19].

B. Evaluation of Iron Overload after HCT for autologous and allogeneic patients

1. Timepoints of evaluation:

a. at 80-100 days post HCT;

b. 1 year post HCT;

c. at least yearly if still receiving red blood cell transfusions.

2. Laboratory testing:

a. Iron studies (ferritin, iron, total iron-binding capacity [TIBC], and

transferrin saturation [TS])

Biochemical lab tests are non-specific and can be significantly affected by inflammation,

infection (which falsely elevate ferritin and decrease iron, TIBC and TS) and graft versus

host disease (GVHD) (which increases iron absorption), so biochemical tests should NOT

be used as sole criteria to consider the presence of iron overload and should be confirmed

by MRI-T2*.

b. HFE genotype

Consider for patients with:

i. family member with diagnosed hereditary hemochromatosis (HH)

ii. TS > 45% AND Northern or Western European ethnicity.

Genetic analysis for other rare mutations described in association with hemochromatotic

phenotypes such as in HAMP (hepcidin), SLC40A1 (ferroportin), HJV (hemojuvelin),

TFR2 (transferrin receptor 2) genes is recommended on a case-by-case basis.

3. Assessment of Tissue Iron

a. Magnetic resonance - MRI-T2*

All patients should undergo T2*-weighted magnetic resonance imaging test (MRI-T2*) if

there are concerns about iron overload. MRI-T2* is highly accurate in measuring tissue

iron in heart, liver, spleen, and pancreas. Recommend first getting MRI of abdomen for

assessing liver, spleen, and pancreas. If abnormal uptake in pancreas or other high-risk

factors see below, get cardiac MRI.

Cardiac MRI are indicated for patients with the following high-risk factors:

1.Lifetime history of receiving 75 RBC units or more;

2.Thalassemia;

3.Sickle cell disease ;

4.Other congenital anemias (Diamond-Blackfan; hereditary sideroblastic);

5.Associated hereditary hemochromatosis (HH)

b. Endocrine screen: Patients that fulfill criteria for iron overload (LIC>2mg/g),

particularly those with detectable cardiac iron (T2*<20ms) in adult patients, or

below 1 standard deviation or age based references in pediatric patients, may

benefit from earlier screening for endocrine gland abnormalities secondary to iron

overload with fasting glucose, thyroid stimulating hormone (TSH), free thyroxine

(T4), parathyroid hormone (PTH), follicle stimulating hormone (FSH), and

luteinizing hormone (LH).

c. Transient elastography: This is the preferred method if assessment of liver

fibrosis and cirrhosis is a concern, particularly in thrombocytopenic patients for

whom a liver biopsy poses significant risk of bleeding.

d. Liver biopsy: Given the risks of the procedure, risk of sampling variability, and

indolent course of hepatic siderosis, measurement of hepatic iron by

spectrophotometry of liver biopsy should be an exception to be discussed case-by-

case, e.g. in patients with absolute contraindications to MRI.

4. Indication for Iron Mobilization Therapy According to Tissue Iron Content

Cardiac T2*

(ms)

LIC

(mg/g dry weight)

Marrow Iron

Content

Mobilization of Iron

>20ms*

(normal)

>15

Very high

++++

Phlebotomy ± single iron chelator

7 – 15

Moderately high

++ to +++

choice: Phlebotomy

choice: Single iron chelator (especially if

HCV-positive)

2-7

Mildly increased

1) HFE

wildtype

observe

2) HFE

C282Y/C282Y or C282Y/H63D

Phlebotomy aiming at ferritin level <100

3) Hemoglobinopathies and other congenital

anemia disorders

Phlebotomy aiming at ferritin level <500

<20ms*

Any

Phlebotomy + combination iron chelation;

consider admission if symptomatic or T2*<8ms;

consider erythrocytapheresis for faster removal

*For pediatric patients: Use age-based reference ranges for cardiac T2* values. Abnormal

cardiac iron content is defined as below 1 standard deviation for age-based reference

values

C. Phlebotomy for iron overload after HCT

• If indicated, phlebotomy is likely to be the safest and most cost-effective approach for the

mobilization of tissue iron.

• Regular phlebotomy requires adequate venous access, normal hematopoiesis or

hematopoiesis that can respond satisfactorily to weekly or every-other-week

erythropoietic stimulating agents (ESAs).

• Phlebotomy Regimen:

Phlebotomy volume

5 mL/kg as tolerated

Frequency

every 3-4 weeks as tolerated

Monitoring monthly

CBC, ferritin, iron, TIBC, and TS

Discontinue Phlebotomy

Symptomatic anemia with hematocrit below 35%, or

MRI-T2* LIC below 7mg/g (non-HH patients), or

ferritin below 500ng/mL (non-HH patients and patients

with hemoglobinopathies/other congenital anemias), or

ferritin below 100ng/mL (hereditary hemochromatosis

(HH) patients)

• Erythropoietic Stimulating Agents (ESAs) may be administered subcutaneously to

facilitate regular phlebotomy. The smallest number of whole vials should be prescribed

per dose:

Body Weight

(kg)

Erythropoietin

(Units weekly)

Darbepoetin

(micrograms every-other-week)

10-14

6,000 to 8,000

25 to 60

15-20

10,000

21-24

10,000 to 14,000

60 to 100

25-29

14,000

100

30-39

20,000

100

40-60

40,000

200

>60

Use darbepoetin

200

Erythropoetin (Epogen) vial sizes (2,000; 4,000; 10,000; 20,000; 40,000 units)

Darbepoetin (Aranesp) vial sizes (25; 60; 100; 150; 200; 300 micrograms)

• Erythrocytapheresis is a grade 1B recommendation for iron overload in hereditary

hemochromatosis (HH). It has been compared with phlebotomies in two randomized

studies with hereditary hemochromatosis (HH) patients, with faster removal of iron, no

differences in adverse events, and controversial differences in cost [20,21].

Note: Though patients with GVHD continue to hyperabsorb iron from dietary sources and

may be an exception to the normal situation when patients mobilize their excessive iron

stores when effective erythropoiesis returns after HCT.

D. Chelation therapy for iron overload after HCT

If phlebotomy or erythrocytapheresis cannot be performed despite the use of ESAs within

3 - 6 months after transplantation, and if treatment to mobilize iron stores is indicated

(see item 4 above), iron chelation therapy with single agents desferoxamine (DFO) -

Desferal or deferasirox (DFX) - Exjade or Jadenu - should be initiated. Patients with

evidence of cardiac iron overload should undergo combination therapy (DFO and

deferiprone – DFP, Ferriprox).

1. Deferoxamine (DFO) - Desferal

1.1. Administration:

DFO can be administered by continuous subcutaneous or intravenous infusion with less

toxicity if administered subcutaneously.

1.2. Toxicity:

Ocular and auditory abnormalities, sensorimotor neurotoxicity, renal insufficiency,

pulmonary toxicity, and failure of linear growth. In rare cases, treatment with DFO has

enhanced susceptibility to certain microorganisms, such as Vibrio vulnificus, Yersinia

enterocolitica and Yersinia pseudotubera, among others, resulting in generalized

infections by providing these agents with a siderophore otherwise missing.

1.2.1. AVOID ascorbic acid (vitamin C) (>200mg/day) in patients receiving DFO due to

possible impact on left ventricular function. DO NOT administer ascorbic acid with

DFO in patients with heart failure.

1.2.2. Toxicity can be avoided by regular assessment of the body iron stores with annual

MRI-T2*. In general, assessment of body iron stores should also follow when

deferoxamine toxicity occurs.

1.3. Dosing:

20 to 40 mg/kg/day, administered 5-7 days per week by continuous overnight infusion,

typically for 8-12 hours.

Dose should not exceed 50 mg/kg/day

Infusion rate should not exceed 15 mg/kg/hour to avoid hypotension.

1.4. Monitoring:

1.4.1. Prior to starting treatment: obtain baseline CBC, creatinine, ferritin, liver function

tests, audiogram, and eye examinations.

1.4.2. Monthly complete blood count (CBC), ferritin, creatinine, and liver function tests.

1.4.3. Therapeutic index: Most of the toxicity caused by deferoxamine occurs when the

dose exceeds 50 mg/kg/day or when the iron burden is not high. Dose reductions

can be done by aiming at a therapeutic index below 0.025. Therapeutic index is

calculated by: (number of days per week X daily dose in mg/kg) / (7 X serum

ferritin in ng/mL) [22].

1.4.4. Discontinue for six months if LIC <3 mg/g dry weight, or marrow iron content is

not increased or only mildly increased. Thereafter, the dose of DFO should be

adjusted to maintain liver iron content between 3 and 7 mg/g dry weight and

therapeutic index below 0.025.

Suggested monitoring of DFO-related toxicity is shown below.

Toxicity

Tests

Frequency

Alteration In Rx

High frequency

sensorineural hearing

loss

Audiogram

Annually; if

symptomatic, check

immediately

Stop DFO;

repeat audiogram at 3

month intervals until

normal or stable

Retinopathy (pigmentary

degeneration); cataracts;

corneal opacities; visual

impairment

Eye exam

including visual

acuity, slit-lamp

and fundoscopy

Annually; if

symptomatic, check

immediately

Stop desferoxamine if

retinopathy or hearing

impairment

Metaphyseal/Spinal

Plain x-ray of

wrists, knees,

spine; bone age in

children

Annually

Reduce deferoxamine to

20-25 mg/kg/day

Growth retardation

Sitting and

standing height

Every 6 months

Reduce deferoxamine

to 20-25 mg/kg/day;

reassess every 6 months

2. Deferasirox (DFX) - Exjade, Jadenu, or Jadenu Sprinkles

2.1. Contraindications:

a) Serum creatinine greater than two times the age-appropriate upper limit of normal or

creatinine clearance less than 40 mL/min;

b) Poor performance status;

c) High-risk myelodysplastic syndromes;

d) Advanced malignancies;

e) Platelet counts less than 50,000;

f) Known hypersensitivity to DFX or any component of the medication.

2.2. Toxicity:

Gastrointestinal (GI) symptoms (diarrhea, vomiting, nausea, abdominal pain),

headaches, pyrexia, skin rash, increases in serum creatinine, intermittent proteinuria,

cytopenias (including agranulocytosis, neutropenia, and thrombocytopenia), hepatic

dysfunction, auditory disturbances, and ophthalmic disturbances. Post marketing

surveillance has shown cases of acute renal failure or cytopenias with fatal outcomes in

patients taking DFX. The relation to DFX in these cases is uncertain.

2.3. Dosing: see below, items 2.6 and 2.7.

2.4. Monitoring:

2.4.1. Prior to starting treatment: obtain baseline CBC, creatinine with clearance

estimation in duplicate, ferritin, liver function tests, audiogram, and eye

examinations.

2.4.2. Monthly CBC, ferritin, creatinine, urine protein levels, and liver function tests.

2.4.3. Discontinue temporarily if ferritin level falls below 500ng/mL.

Suggested monitoring of DFX-related toxicity is shown below.

Toxicity

Tests

Frequency

Alteration In Rx

High frequency

sensorineural hearing

loss

Audiogram

Annually; if

symptomatic, check

immediately

Stop DFX;

repeat audiogram at 3

month intervals until

normal or stable

Retinopathy (pigmentary

degeneration); cataracts;

corneal opacities; visual

impairment

Eye exam

including visual

acuity, slit-lamp

and fundoscopy

Annually; if

symptomatic, check

immediately

Stop DFX if retinopathy

or hearing impairment

Renal impairment

Creatinine and

protein/creatinine

ratio

Creatinine weekly

for the first month,

then monthly;

Protein/creatinine

ratio every 3 months

See dose modification

below (items 2.5.4 and

2.6.4)

2.5. Specific information about Exjade

2.5.1. Exjade is available in 125mg, 250mg, and 500mg tablets;

2.5.2. Starting dose: 20mg/kg/day.

2.5.3. Dose modification: 5-10mg/kg/day increments every 3-6 months if necessary

depending on serum ferritin trends. Doses should not exceed 40mg/kg/day.

2.5.4. Dose reduction: 50% for starting dose if creatinine clearance 40-60mL/min or

moderate (Child-Pugh B) hepatic impairment. If the serum creatinine level increases

more than 33% over the course of two consecutive visits, the dose should be

reduced by 10mg/kg. For pediatric patients, the dose should be reduced by 10mg/kg

if the serum creatinine is greater than the upper limit of normal on 2 consecutive

visits.

2.5.5. Administration: Exjade should be taken once daily on an empty stomach (at least

30 min prior to eating). Tablets should be completely dispersed by stirring in water,

orange juice, or apple juice until there is a fine suspension. Doses <1 gram should

be dispersed in 3.5 ounces of liquid, and doses 1 gram should be dispersed in 7

ounces of liquid. After swallowing, any residue should be resuspended in a small

volume of liquid and swallowed. Doses should be separated by 2 hours from

aluminum containing antacids.

2.6.Specific information about Jadenu and Jadenu Sprinkles

2.6.1. Jadenu is available in 90mg, 180mg, and 360mg tablets or granules (Jadenu

Sprinkles).

2.6.2. Starting dose: 14mg/kg/day.

2.6.3. Dose modification: 3.5-7mg/kg/day increments every 3-6 months if necessary

depending on serum ferritin trends. Doses should not exceed 28mg/kg/day.

2.6.4. Dose reduction: 50% for starting dose if creatinine clearance 40-

60mL/min/1.73m

or moderate (Child-Pugh B) hepatic impairment. If the serum

creatinine level increases more than 33% over the course of two consecutive visits,

the dose should be reduced by 7mg/kg. For pediatric patients, the dose should be

reduced by 7mg/kg if the serum creatinine is greater than the upper limit of normal

on 2 consecutive visits.

2.6.5. Administration: Jadenu should be taken once daily preferably at the same time of

the day, on an empty stomach or with a light meal (contains less than 7% fat content

and approximately 250 calories). Examples of light meals include 1 whole wheat

English muffin, 1 packet jelly (0.5 ounces), and skim milk (8 fluid ounces) or a

turkey sandwich (2 oz. turkey on whole wheat bread w/ lettuce, tomato, and 1

packet mustard). Jadenu tablets may be crushed and mixed with soft foods (e.g.,

yogurt or apple sauce) immediately prior to use and administered orally.

Commercial crushers with serrated surfaces should be avoided for crushing a single

90 mg tablet. The dose should be immediately and completely consumed and not

stored for future use. Take Jadenu Sprinkles by sprinkling the full dose on soft food

(e.g. yogurt or apple sauce) immediately prior to use and administered orally. Doses

should be separated by 2 hours from aluminum containing antacids.

3. Combination therapy: deferoxamine – Desferal, and deferiprone (DFP) - Ferriprox

3.1. In combination therapy, deferoxamine should be prescribed as above, preferably 7

days a week; if patient is admitted, it may be placed as a 24-hour infusion.

3.2. Deferiprone is an oral medication for iron chelation, available in 500mg tablets and

100mg/mL oral solution.

3.3. Contraindications: severe hepatic impairment, creatinine clearance below

15ml/min/1.73m

, known hypersensitivity to deferiprone or any component of the

medication.

3.4. Toxicity: neutropenia (6.2%), agranulocytosis (1.7%), zinc deficiency, chromaturia

(reddish brown discoloration of the urine), GI symptoms (nausea, vomiting,

abdominal pain or discomfort), joint pain, headache.

3.4.1 Avoid concomitant use of drugs known to be associated with neutropenia

or agranulocytosis if possible.

3.5. Starting dose: 25mg/kg tid (75mg/kg/day daily). Maximum dose is 33mg/kg tid

(daily total 99mg/kg/day).

3.6. Dose reduction: not recommended for mild or moderate liver impairment, or

creatinine clearance above 15ml/min/1.73m

3.7. Administration: take first dose in the morning, second dose at midday, third dose in

the evening, with meal. Allow at least 4-hour intervals between deferiprone and

medications or supplements containing polyvalent cations, e.g. aluminum or zinc.

3.8. Monitoring:

3.8.1. Prior to starting treatment: obtain complete blood count with neutrophil

count, serum transaminases, and zinc levels.

3.8.2. Weekly neutrophil counts

3.8.3. Monthly ferritin, transaminases, and zinc.

3.8.4. Discontinue if ferritin level falls below 500ng/mL.

3.8.5. Management of neutropenia: discontinue DFP and all medications that can

cause neutropenia and follow blood counts daily until recovery. DO NOT

resume DFP in patients who develop agranulocytosis, DO NOT

rechallenge patients with neutropenia above 500 unless benefit outweighs

the risks.

XX. VITAMINS AND OTHER MINERAL SUPPLEMENTS

It is recommended that all allogeneic patients have iron-free multiple vitamin/mineral

supplementation for one year or until all immunosuppressive therapy is discontinued after the

transplant. Autologous patients should continue supplementation for one year if dietary

intake does not meet daily requirements. Iron supplementation should not be used routinely

in any patient unless iron deficiency is clearly documented. Most patients have iron-overload

because of red cell transfusions and increased absorption of iron in the GI tract (see Section

XIX).

A. Calcium and Vitamin D daily intake requirements

Adequate calcium and vitamin D intake are necessary in order to decrease the risk of

bone complications after transplant. Women with ovarian failure and patients who

require long-term treatment with corticosteroids have a high risk of osteoporosis, and

pediatric patients can have poor bone development after chemotherapy and radiation.

Avoidance of sunlight and the use of sunscreen to block UV radiation can contribute to

vitamin D deficiency.

Patients who cannot consume adequate calcium or vitamin D from foods should receive

supplements to meet their daily requirements. Supplemental calcium should be given in

divided doses, preferably as calcium citrate. Some "natural" calcium supplements do not

contain enough bioavailable calcium to prevent osteopenia. The maximum amount that

can be absorbed with each dose is 500 mg. See Section XI for prevention of

osteoporosis.

i. CALCIUM REQUIREMENTS FOR PATIENTS DURING STEROID

THERAPY:

Calcium intake above these levels is not recommended, as it may interfere with the

absorption of other nutrients.

ii. CALCIUM REQUIREMENTS FOR PATIENTS NOT ON STEROIDS

Age

Daily Minimum

Requirement after

Transplant (milligrams)

Children 7-12 months

260

Children 1-3 years

700

Children 4-8 years

1000

Children 9-18 years

1300

Adult Males

1000-1200

Adult Females;

On hormone therapy

No hormone therapy

1000-1200

1500

7-12 months:

600 mg/day

1-3 years:

1000 mg/day

4-8 years:

1200 mg/day

> 9 years:

1500 mg/day

100

iii. Vitamin D requirement

Table 1: Vitamin D3 (or D2) Supplementation

*, ****

Adults (>18 yrs)

Children (<18 yrs)

Treatment of Insufficiency [Vitamin D (25 Hydroxy) levels 20-30 ng/mL]***

▪ Routine

▪ 25 mcg/day

▪ Age < 1 yr:

─ 10 mcg daily

(20 mcg in dark skinned)

▪ Age 1-8 yr:

─ 15 mcg daily

▪ Age 9-18 yr:

─ 20 mcg daily

▪ Malabsorption syndromes**

▪ 1,250 mcg per week

▪ Age < 1 yr:

─ Consult Endocrinology

▪ Age 1-18 yr:

─ 1,250 mcg per week or

─ 125 mcg daily

▪ Chronic Renal Disease

▪ Consult Nephrology

Treatment of Deficiency [Vitamin D (25 Hydroxy) level <20 ng/mL]***

▪ Uncomplicated

▪ 1,250 mcg per wk x 8 (Repeat

if Vitamin D (25 Hydroxy) level

< 30 ng/mL otherwise treat as

for insufficiency above)

▪ Age 1-12 months:

─ 25-50 mcg daily x 8 wks

▪ Age 1-18 yr:

─ 25-125 mcg daily x 8 wks

─ 1,250 mcg weekly x 8