10 On 2020 HSCT WB

HEMATOPOIETIC
STEM CELL TRANSPLANTATION
Lauren Ice, Pharm.D., BCOP, BCPS
Clinical Pharmacy Specialist
Spectrum Health
Grand Rapids, Michigan
LEARNING OBJECTIVES
At the end of the presentation and after reviewing the accompanying reading materials, the participant
should be able to:
1. Design an appropriate patient‐specific treatment, supportive care, and monitoring plan taking
into consideration efficacy and safety outcomes from clinical trials and current guidelines for
patients undergoing hematopoietic stem cell transplantation (HSCT).
2. Apply appropriate strategies to prevent toxicity from chemotherapy agents employed in HSCT
conditioning regimens, and differentiate between myeloablative, non‐myeloablative, and
reduced‐intensity HSCT conditioning regimens.
3. Create a plan for prevention and management of acute and chronic graft‐versus‐host disease
(GVHD) using appropriate systemic and ancillary therapies.
4. Discuss short‐ and long‐term treatment goals, including post‐therapy and survivorship, with the
patient undergoing HSCT and his or her caregiver.
Learner tip: Information in bold is more testable for the BCOP examination. Information in regular font
is either background information or not supported by rigorous clinical trials or guidelines.
©2020 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 1
Patient Case #1: PK is a 61‐year‐old woman with newly diagnosed stage III multiple myeloma. She has
received 6 cycles of lenalidomide, bortezomib, and dexamethasone and attained a very good partial
response to therapy. Her Scr is 2.1 mg/dL and CrCL is 38 mL/min, but otherwise she has no significant
comorbidities.

Question #1: According to the American Society of Clinical Oncology (ASCO) Treatment of Multiple
Myeloma guidelines, what is the most appropriate therapy for PK at this time?
A. Melphalan conditioning followed by autologous HSCT
B. Melphalan conditioning followed by tandem autologous HSCT
C. Melphalan + total body irradiation conditioning followed by an allogeneic HSCT
D. Lenalidomide followed by an autologous HSCT upon progression

I. Background: rationale and indications for transplant1
A. Definition of blood and marrow transplantation or hematopoietic stem cell transplant
(BMT/HSCT): process by which normal hematopoiesis and/or lymphopoiesis is established by the
infusion of an ex vivo pluripotent stem cell from one individual to a different individual
(allogeneic) or the same individual (autologous). Infusion of stem cells typically occurs following
administration of chemotherapy and/or radiation by the recipient.
B. Rationale for use of autologous HSCT
1. To allow dose escalation (intensification) of chemotherapy in order to overcome drug
resistance by bridging hematopoietic failure with infusion of own cells. This only applies
to malignancies with a dose intensity response.
a. Infusion of autologous stem cells serves to rescue the patient from
myelosuppressive effects of high‐dose chemotherapy
b. Other organ toxicities relating to high‐dose therapy become dose‐limiting
C. Rationale for uses of allogeneic HSCT
1. To replace a missing or abnormal hematopoietic or lymphoid component in non‐
malignant disorders (i.e. aplastic anemia or immune disorders)
2. To rescue the recipient from myeloablative therapy given for treatment of malignant
disease (i.e. acute leukemia)
3. To establish a graft‐versus‐leukemia (tumor) effect mediated by donor cell recognition
and destruction or inhibition of residual host malignant cells (i.e. reduced intensity
conditioning and chronic lymphocytic leukemia)
D. Indications for transplant
1. American Society for Blood and Marrow Transplantation (ASBMT) published
guidelines to describe the level of evidence for use of HSCT for treatment of different
diseases2
a. Indications for transplant categorized as: standard of care, standard of care
clinical evidence available, standard of care rare indication, developmental, or
not generally recommended
2. Additional guidelines and evidence regarding the role of HSCT exist for various
malignancies, such as: multiple myeloma3, 4, Hodgkin lymphoma5, and others
Standard of Care Indications for HSCT in Adults2
Autologous Allogeneic
Multiple myeloma3, 4 Acute myeloid leukemia6
 Initial response, sensitive relapse  CR1 (intermediate and high risk), CR2
 Single, upfront transplant should be offered  Therapy‐related
to transplant‐eligible patients; delayed HSCT
may be considered in select patients
Hodgkin lymphoma5 Acute lymphoblastic leukemia7
 Sensitive primary refractory, sensitive first  Ph‐negative: CR1 (high risk and potentially
relapse, second or greater relapse standard risk), ≥CR2
 Ph‐positive: CR1
Diffuse large B‐cell lymphoma8 Myelodysplastic syndrome9
 Sensitive primary refractory, sensitive first  Intermediate‐2/high risk
relapse, second or greater relapse
Follicular lymphoma10 Chronic myeloid leukemia
 Sensitive primary refractory, sensitive first  Accelerated and blast phase, chronic phase
relapse, second or greater relapse 2+ (not as common in current era of TKI
 Transformation to high grade lymphoma therapy)
Mantle cell lymphoma Mantle cell lymphoma
 CR1, PR1, sensitive primary refractory,  Sensitive primary refractory, sensitive first
sensitive first relapse, second or greater relapse
relapse
T cell lymphoma Aplastic anemia
 Sensitive primary refractory, sensitive first  Severe new diagnosis, severe
relapse relapse/refractory
CR1 = first complete response, CR2 = second complete response, PR1 = first partial response

Patient Case #1:
Answer: A. Melphalan conditioning followed by autologous HSCT. For this transplant‐eligible patient, the
ASCO guidelines4 recommend a single, upfront autologous HSCT based on contemporary randomized
controlled trials showing improved progression free survival with early compared to delayed transplant.
High dose melphalan is the recommended conditioning agent in the ASCO guidelines, with no alternative
regimen demonstrating superiority in clinical trials.
Tandem transplant is not routinely recommended per the ASCO guidelines based on a randomized trial
that did not demonstrate any improvement with tandem HSCT compared to single HSCT.
Melphalan + total body irradiation conditioning is a myeloablative conditioning regimen, which when
followed by an allogeneic HSCT is associated with high treatment related mortality. Upfront,
myeloablative allogeneic HSCT for multiple myeloma is not routinely recommended by the ASCO
guidelines.

II. Pre‐HSCT Process
A. Initial referral/consult to establish appropriateness of HSCT
1. Dependent on disease and stage, age, performance status, organ function, and
comorbidities. Several tools are available to assess risk/comorbidities.11, 12
2. In autologous setting, may depend on documentation of chemosensitivity
3. National Marrow Donor Program and American Society for Blood and Marrow
Transplant 2019 Referral Guidelines on Recommended Timing for Transplant
Consultation are available at: (accessed June 22, 2019)
https://bethematchclinical.org/workarea/downloadasset.aspx?id=3545
4. Insurance evaluation for coverage of HSCT
B. Central line placement for: apheresis (if needed), administration of chemotherapy and other
intravenous medications, infusion of stem cells, and other blood products
C. Donor search, evaluation, and selection (allogeneic HSCT only)
1. Multiple factors evaluated including but not limited to: human leukocyte antigen (HLA)
match, age (younger age preferred), sex (male donor preferred), parity of female donors
(multiparous may increase risk for chronic GVHD), blood type and ABO compatibility,
and cytomegalovirus serologic status
2. HLA‐matching and clinical implications for pharmacists13
a. Matching of donor and recipient based on HLA system which determines
compatibility; matches are based on gene expression of alleles (variant copies
of the same gene) for HLA ‐A, ‐B, ‐C, ‐DRB1, ‐DP and –DQ
b. Preferred donor is a 10/10 matched related donor (MRD)
c. Contemporary matched unrelated donor (MUD) outcomes have shown
improved overall survival and reduction in treatment related mortality,
making it a suitable option when an MRD is not available
1) Improved outcomes attributed to better patient selection (transplant
earlier in disease course or lower risk disease), better donor selection
(allele level molecular typing), and improved transplant practices14
2) Grade II – IV acute GVHD remains higher in MUD vs. MRD15‐18
4. No randomized trials to guide selection of alternative immunologic donor
sources when MRD or MUD is not available, including: umbilical cord blood
(UCB), haploidentical (haplo), mismatched unrelated donor (MMUD)

Alternative Donor Sources Compared to MRD/MUD19‐21
UCB Haplo MMUD
Degree of match Match at least 4 of 6 HLA Match at half of HLA One or more HLA
antigens at ‐A, ‐B, and ‐DRB1 markers markers do not match at
–A, ‐B, ‐C, or –DRB1
If using 2 UCB units to achieve
sufficient cell dose, they do not
need to match each other
Advantages Lower risk of GVHD, including Readily available donor Potentially increased
severe and donor lymphocytes availability of grafts,
(most have parent, particularly for minorities
sibling, or child willing to
donate) Lower risk of relapse seen
in some studies
Low donor acquisition
costs Similar engraftment time
Disadvantages Delayed neutrophil and platelet GVHD may be severe, Higher risk of GVHD,
engraftment and higher rate of especially without T cell which may be severe
graft failure depletion/post‐transplant
cyclophosphamide Greater risk of graft
High risk of infection, failure
particularly viral Higher risk of graft
rejection and relapse, Additional donor
Increased costs particularly with T‐cell lymphocytes may be
depletion difficult to obtain
Units for minorities may be
difficult to find High risk of infection Higher TRM

No additional donor Higher TRM
lymphocytes available

Higher TRM
GVHD = graft‐versus‐host disease, TRM = transplant‐related mortality

3. Comparison of anatomic stem cell source in allogeneic HSCT

Comparison of Anatomic Stem Cell Sources: peripheral blood vs. bone marrow in MRD
Bone marrow (BM) vs. peripheral blood (PB) – Matched Related Donor (MRD) setting
Meta‐analysis of 1,111 patients from 9 Randomized trials22

Engraftment Faster with PB: median time to ANC > 0.5 x 109/L was 14 (PB) vs. 21 (BM) days, P <
0.00001; time to platelets > 20 x 109/L was 14 (PB) vs. 22 (BM) days, P < 0.00001. ANC =
Acute GVHD No difference in overall incidence of aGVHD grades I – IV between groups (54%
(aGVHD) PB vs. 53% BM, P = 0.49)
Chronic GVHD Significant increase in the odds of developing both extensive stage
(cGVHD) (OR = 1.89) and overall cGVHD (any stage; OR 1.92) in PB recipients
At 5 years 51% PB vs. 35% BM recipients developed extensive cGVHD and 73% PB
vs. 56% BM developed any stage cGVHD (P = 0.001)
Relapse and Non‐ PB associated with a reduction in relapse at 5 years 23% vs. 32%, P = 0.01 with an
relapse Mortality OR 0.71 in both early and late stage disease.
(NRM) NRM was not different between PB and BM with 30% in both arms
Survival No significant differences in OS between PB and BM in all patients. PB was
associated with a higher 5 year OS in the subgroup with late stage disease, but
not in patients with early stage disease
absolute neutrophil count, OS = overall survival, OR = odds ratio

Comparison of Anatomic Stem Cell Sources: peripheral blood vs. bone marrow in MUD
Bone marrow (BM) vs. peripheral blood (PB) – Matched Unrelated Donor (MUD) setting
N= 551 at 48 centers, prospective, randomized trial23
Engraftment Faster with PB: median time to neutrophil engraftment 5 days shorter with PB (P <
0.001); median time to platelet engraftment 7 days shorter with PB (P < 0.001)
Acute GVHD No difference in overall incidence of aGVHD grades I – IV between groups
(aGVHD) Grade II‐IV aGVHD: no difference, rate 47% PB vs. 56% BM
Grade III‐IV aGVHD: no difference, rate 16% PB vs. 14% BM
Chronic GVHD Less cGVHD in BM; at 2 years 53% PB vs. 41% BM p=0.01
(cGVHD) Among patients alive at 2 years, 57% of PB remained on immunosuppression vs.
37% of BM patients (P = 0.03)
Relapse and Non‐ 28% relapse rate in both groups
relapse Mortality 2 year NRM no difference, rate 26% PB vs. 27% BM
(NRM)
Survival 2 year OS no difference, rate 51% PB vs. 46% BM P = 0.29
Graft Failure Rate 3% PB vs. 9% BM P = 0.002

D. Collection of stem cells
1. Stem cell targets and doses24
a. Minimum recommended dose is 2 x 106 CD34+ cells/kg of recipient body
weight per transplant
b. Ideal recommended target is between 3‐5 x 106 CD34+ cells/kg, although
consideration should be given to balance the number of apheresis sessions
needed to attain the target collection and number of transplants planned.
Compared with doses < 3 x 106CD34+ cells/kg, CD34+ cell doses of 5 x 106
CD34+/kg are associated with improved platelet and neutrophil recovery and
less resource utilization if the higher target can be collected in a few apheresis
sessions.
2. Bone marrow harvest
a. Procured through multiple needle aspirations into the posterior iliac crest
b. Obtained under general or regional anesthesia
c. Volume typically = 10 ‐ 20 mL/kg of recipient weight to achieve final total
nucleated cell (TNC) dose of at least 2 ‐ 4 x 108/kg (maximum volume 1500 mL)
d. Risks minimal; serious adverse events reported in <0.3%

3. Peripheral blood stem cell (PBSC) harvest
a. Collected via one or multiple apheresis procedures; usually requires adequate
central line for autologous collections and venous access for allogeneic donors
b. Volume processed typically 3 ‐ 5 times the blood volume (10 ‐ 30 L)
c. Minimal risks: complications include hypocalcemia, fatigue, nausea/vomiting,
post procedure anemia, thrombocytopenia, hypotension due to fluid shifts,
thrombosis of central line, bleeding; growth factors used may rarely lead to
splenic enlargement and/or rupture
d. Typically a relatively low number of stem cells exist in the peripheral blood;
thus, mobilization of stem cells from bone marrow to peripheral blood is
required
e. Goal of mobilization is to collect adequate stem cells cost‐effectively with
minimization of apheresis sessions and avoidance of mobilization‐related
complications
f. Mobilization strategies24
1) Cytokine mobilization utilizing granulocyte‐colony‐stimulating
factors (GCSF) such as filgrastim, filgrastim‐sndz, and tbo‐filgrastim25
a) Cost‐effective with predictable collection scheduling
b) 5‐38% failure rate of minimum number of CD34+ cells
sufficient to proceed to HSCT
c) Appropriate strategy for healthy donors for allogeneic
collection

Efficacy in Selected Autologous Mobilization Clinical Trials with filgrastim‐sndz and tbo‐filgrastim
Median total Median Percent of
Mobilization
Study design collected apheresis mobilizatio Comments
regimen
(x106 cell/kg) sessions n failures
Prospective 2 gm/m2 Filgrastim‐ 2 days in Filgrastim‐
No difference in
filgrastim‐sndz vs. cyclophosphamide sndz = 11.5 both sndz = 2.5%
hematopoietic
historically matched on day 1 and 2 vs. groups vs. recovery
controls with GCSF followed by GCSF = 12.3 GCSF = 2.7%
parameters and
in MM26 filgrastim‐sndz or transplant‐related
historical GCSF P = 0.51 P = NS P = NS
toxicities
N = 87 5 mcg/kg/day
starting on day +3
Prospective, Cyclophosphamide, Filgrastim‐ 1 day in Filgrastim‐ The adverse event
randomized trial for cytarabine, sndz = 9.1 both sndz = 11% profile was similar
filgrastim‐sndz vs. etoposide, or ESHAP vs. groups vs. between groups
GCSF in NHL, HD, in both groups GCSF = 9.4 GCSF = 9%
MM27 followed by
filgrastim‐sndz or P = NS
N=108 GCSF 10 mcg/kg/day
Prospective, Tbo‐filgrastim 10 Tbo‐ 1 day in 0% in both No difference in
randomized, non‐ mcg/kg/day x 5 days filgrastim = both groups toxicity or
inferiority trial of + plerixafor on day 11.6 groups transplant
tbo‐filgrastim vs. +4 vs. GCSF 10 vs. outcomes between
GCSF in MM, NHL28 mcg/kg/day x 5 days filgrastim = arms
+ plerixafor on day 10.0
N=97 +4 P = NS
GCSF = granulocyte‐colony stimulating factor originator product, filgrastim (Neupogen®); MM = multiple myeloma;
NHL = non‐Hodgkin lymphoma.

2) Chemomobilization using chemotherapy followed by GCSF
administration
a) May be stand‐alone or part of induction or salvage therapy
for autologous patients
b) Shown to generally produce greater CD34+ cell yield than
GCSF alone
c) Similar failure rates of GCSF alone, but can have increased
costs and toxicity and less predictable scheduling
3) Plerixafor plus GCSF
a) Upfront plerixafor has confirmed higher CD34+ cell yields,
lower failure rates (0‐15%), and fewer days of apheresis
compared with GCSF alone, but has increased drug
acquisition costs
b) Preemptive plerixafor is a commonly employed strategy to
optimize costs and resources that involves the addition of
plerixafor only in patients identified as poor mobilizers after
initiation of GCSF, but before starting apheresis based on
circulating peripheral blood CD34+ cell count; this has
similarly shown low mobilization failure rates of <10%
c) Well‐tolerated, most common side effect is diarrhea (30‐40%)
d) Long‐term observational follow‐up study of two phase III
plerixafor trials showed no difference in 5‐year OS or PFS for
MM and NHL patients who received plerixafor compared to
placebo29
4. Cord blood stem cell collection
a. Pregnant women are recruited as potential cord blood donors prior to delivery
b. Consent of the mother is obtained for the collection of the cord blood sample,
processing and freezing the cord unit, maternal infectious disease testing, and
for the storage of both maternal and cord blood samples for possible future
genetic and infectious disease testing
Patient Case #1, Continued: PK is a 61‐year‐old woman with newly diagnosed stage III multiple
myeloma. She has received 6 cycles of lenalidomide, bortezomib, and dexamethasone and attained a
very good partial response to therapy.

Question #2: Which of the following regimens is most appropriate for peripheral blood stem cell
(PBSC) mobilization for PK?
A. Filgrastim
B. Filgrastim‐sndz
C. Filgrastim + plerixafor
D. Filgrastim + sargramostim

E. Stem cell mobilization regimens in autologous HSCT patients30, 31
1. Goal is to increase the number of circulating stem cells to facilitate peripheral blood
stem cell harvesting, thus enabling patients to undergo autologous HSCT
2. Factors that negatively influence patient’s ability to mobilize:24, 30, 32
a. Tumor infiltration in bone marrow
b. Fibrotic bone marrow
c. History of pelvic or abdominal irradiation
d. Bone marrow hypocellularity
e. Diagnosis of non‐Hodgkin lymphoma
f. Prior exposure to chemotherapy including alkylating agents (melphalan,
chlorambucil, busulfan)33, nitrosoureas (carmustine), fludarabine, imatinib, and
lenalidomide (especially >4‐6 cycles)
g. Older age (>60‐70) and low baseline platelet count (i.e., < 150 x 109/L)
h. Number of prior regimens (>6), duration of exposure to chemotherapy (> 12
months), short interval since last chemotherapy (<2‐6 months)
i. Infection, iron overload, diabetes
3. Mobilization guideline recommendations for autologous PBSCT24, 25, 34
a. Multiple myeloma24
1) Single agent GCSF 10‐16 mcg/kg/day, but limited to patients with no
more than 1 previous line of chemotherapy, no prior melphalan, and
no more than 4 cycles of lenalidomide
2) Preemptive plerixafor for patients with low peripheral blood CD34+
counts following 4‐5 days of filgrastim
3) Prior therapy with lenalidomide (or other novel agents known to
impair mobilization)
a) Collect PBSC after 2‐4 cycles of lenalidomide when possible
b) Wait 2‐4 weeks after last lenalidomide dose before start of
apheresis
c) Mobilization with GCSF alone after 4‐6 cycles of
lenalidomide is associated with a higher failure rate and
should be avoided
d) Insufficient data on whether to recommend GCSF +
plerixafor vs. GCSF + chemotherapy‐ both have been shown
to be effective
b. Non‐Hodgkin lymphoma24
1) Single agent GCSF 10‐16 mcg/kg/day, but limited to patients with
low risk for mobilization failure. It may be associated with a higher
failure than other disease states, but it has low toxicity and is easier
to schedule than chemotherapy‐based mobilization.
2) Preemptive plerixafor for patients with low peripheral blood CD34+
counts following 4‐5 days of filgrastim grants successful collection in
majority of cases.
3) Chemotherapy based mobilization, either incorporated into the
initial 3‐6 cycles of planned chemotherapy or as part of a salvage
regimen is appropriate and effective (consider in those patients with
residual disease)
c. General recommendations for all autologous patients24
1) Chemotherapy + GCSF
a) If given as stand‐alone therapy and not needed for disease
control, it is associated with higher costs (hospitalization,
transfusions, and antibiotics) and toxicities than GCSF alone
b) Consider limiting stand‐alone chemotherapy to those who
have not responded optimally to salvage therapy or failed
other mobilization strategies
c) Data to support cyclophosphamide doses above 4 gm/m2 is
limited
2) Upfront plerixafor + GCSF is a suitable initial therapy option for all
patients; however, product cost has limited its universal
implementation for all patients at all centers
a) Consider if:
i. The goal is the highest possible CD34+ yield
ii. Real‐time CD34+ cell counts are not available
iii. Fewer apheresis days is the top priority
b) Preemptive use of plerixafor based on peripheral blood
CD34+ measure is reasonable in other cases
c) Plerixafor may be cost effective in patients with DLBCL
because it enables more patients to undergo PBSCT
3) Plerixafor + GSCF vs. chemotherapy + GCSF – no recommendation
can be made because of lack of data
4) Pegfilgrastim data is limited and mixed; it is not recommended in the
guideline
d. Prevention of stem cell mobilization failure24
1) Monitoring pre‐apheresis peripheral blood CD34+ cell count is
recommended to identify poor mobilizers prior to failure
2) No phase III trials support the recommendation, but preemptive
plerixafor use based on peripheral blood CD34+ cell count may
balance mobilization failure and resource utilization
3) Upfront plerixafor + GCSF is a reliable method to prevent mobilization
failure and need for remobilization
e. Recommendations for remobilization24
1) Avoid regimens with only CSFs
2) Plerixafor should be added if it was not used in the initial
mobilization regimen. This has shown successful remobilization in
~70% of patients with a previous failed mobilization attempt. It may
also be effective in patients who previously failed a plerixafor‐
containing regimen. Plerixafor + chemotherapy + GCSF may be
effective, although data is limited.
3) Chemotherapy + GCSF is an acceptable remobilization strategy for
patients who failed a GCSF monotherapy regimen.
4) Bone marrow harvest is a third line option for patients ineligible for
mobilization clinical trials and autologous PBSCT outweighs the
drawbacks of a bone marrow graft source.
Patient Case #1, Continued:

Answer: C. Filgrastim + plerixafor. Filgrastim + plerixafor is a suitable option for all patients. It should
be considered for initial therapy in patients with more than 4 to 6 cycles of lenalidomide and at centers
where real‐time peripheral blood CD34+ cell counts are not available. Mobilization with filgrastim alone
after 4‐6 cycles of lenalidomide is associated with a higher failure rate and should be avoided.
Filgrastim – sndz is a biosimilar to filgrastim that would similarly be at risk for mobilization failure and
therefore should be avoided as well. There are no randomized trials to support the use of filgrastim +
sargramostim in patients with prior lenalidomide exposure.

F. Mobilization of healthy donors for allogeneic PBSCT31
1. GCSF (10 mcg/kg/day for 4 ‐ 5 days) with apheresis to begin on fifth day of GCSF;
effective in 95% of healthy donors
2. GCSF preferred over GM‐CSF as the latter mobilizes fewer CD34+ cells and donors
require more leukapheresis sessions for adequate PBSC collection
3. Typically requires 1‐2 apheresis procedures; target CD34+ cell dose ranges from 2 ‐ 3 x
106/kg of the recipient body weight to 8 x 106/kg; doses above 8 x 106/kg may increase
risk for chronic GVHD
4. Generally well‐tolerated by donor; reported adverse effects including bone pain, fever,
headaches, myalgia, fatigue, transient thrombocytopenia
5. Serious adverse events occur in 0.6% of healthy donors with filgrastim for PBSC
collection35
G. Processing and storage of stem cells
1. In autologous setting, processed then cryopreserved (frozen) in dimethylsulfoxide
2. In allogeneic setting, may be infused fresh or cryopreserved and then thawed for
infusion
3. Red cell depletion for ABO incompatibility between donor and recipient (allogeneic
HSCT only)
4. May be frozen for years and maintain viability
H. Conditioning regimen (preparative regimen)
1. Myeloablative, nonmyeloablative, and reduced‐intensity conditioning definitions36
a. Myeloablative (MA) regimens cause irreversible cytopenia and stem cell
support is mandatory
1) Used for all autologous transplant and some allogeneic HSCT
b. Nonmyeloablative (NMA) regimens cause minimal cytopenia and can be given
with or without stem cell support. NMA rely on pre‐ and post‐transplant
immunosuppression to allow engraftment and tumor eradication depends on
graft‐versus‐tumor effects.
1) Used for some allogeneic HSCT
2) Regimens generally contain low dose total body irradiation or total
lymphoid irradiation and immunosuppressive chemotherapy
(fludarabine, cyclophosphamide)
c. Reduced intensity conditioning (RIC) regimens do not fit criteria for MA or
NMA regimens. They cause cytopenia of variable duration and should be
given with stem cell support.
1) Used for some allogeneic HSCT
2) Generally accepted criteria for RIC regimens include37
a) 500 cGy or less of total body irradiation (TBI) as a single
fraction or 800 cGy or less if fractionated
b) < 9 mg/kg oral busulfan (or intravenous equivalent)
c) < 140 mg/m2 melphalan (note CIBMTR uses 150 mg/m2)
d) < 10 mg/kg thiotepa

Selected Conditioning Regimens of Differing Dose Intensities38

BU = busulfan; CY = cyclophosphamide; TBI = total body irradiation; FLU= fludarabine; AraC=cytarabine; ATG=anti‐
thymocyte globulin; 131I= Tositumomab
*“High‐dose” TBI (800‐1320 cGy) †“Low‐dose” TBI (200‐400 cGy)
Republished with permission of American Society of Hematology from Who is fit for allogeneic transplantation?,
Deeg et al. 116(23), 2010; permission conveyed through Copyright Clearance Center, Inc.

Selected Myeloablative Conditioning Regimens39
HSCT
PREPARATIVE REGIMEN REGIMEN DAYS
TYPE/DISEASE
BEAM Autologous
BCNU (carmustine) + 300 mg/m2 IV x 1 day ‐6 NHL/HD
Etoposide + 200 mg/m2 IV q24h x 4 days ‐5, ‐4, ‐3, ‐2
Ara‐C (cytarabine) + 200 mg/m2 IV q12h x 4 days ‐5, ‐4, ‐3, ‐2
Melphalan 140 mg/m2 IV x 1 days ‐1
BuCy (BUCY 2)40 Allogeneic >
Busulfan 1 mg/kg/dose PO Q6H x 4 days ‐7 to –4 autologous
OR 0.8 mg/kg/dose IV Q6h x 4 days Hematologic
Cyclophosphamide Cyclophosphamide 60 mg/kg IV QD x ‐3, ‐2 malignancies
2 days
Bu‐Flu + ATG41 Allogeneic
Busulfan (IV) 130 mg/m2 IV QD x 4 days ‐6, ‐5, ‐4, ‐3 Hematological
Fludarabine 40 mg/m2 IV QD x 4 days ‐6, ‐5, ‐4, ‐3 malignancies
+/‐ equine antithymocyte 20 mg/kg IV daily x 3 days ‐3, ‐2, ‐1
globulin
CBV Autologous
Cyclophosphamide 1800 mg/ m2 IV Q24H x 4 days ‐6, ‐5, ‐4, ‐3 NHL/HD
BCNU 450 mg/m2 IV x 1 day ‐3
VP‐16 500 mg/m2 IV Q24H x 4 days ‐6, ‐5, ‐4, ‐3
CE Autologous
Carboplatin 700 mg/m2 x 3 days ‐5, ‐4, ‐3 Germ cell tumor
Etoposide 750 mg/m2 x 3 days ‐5, ‐4, ‐3
Cy/TBI42 Allogeneic
Cyclophosphamide 60 mg/kg/day ‐5, ‐4 Hematological
Total body irradiation 200‐220 cGy BID ‐3, ‐ 2, ‐1 malignancies

Cy/TBI/VP16 Autologous
Etoposide 60 mg/kg IV once ‐4 Lymphoma
Cyclophosphamide 100 mg/kg IV once ‐2
Total body irradiation 120 cGy BID ‐8, ‐7, ‐6, ‐5
Flu/Cy/TBI43 Allogeneic
Cyclophosphamide 60 mg/kg/day ‐5, ‐4 Cord Blood
Fludarabine 25 mg/m2 IV QD x 3 days ‐6, ‐5, ‐4
Total body irradiation 220 cGy BID ‐3, ‐ 2, ‐1
Melphalan Autologous
Melphalan 140 ‐ 200 mg/m2 IV x 1 dose Day ‐2 or ‐1 Multiple
Myeloma
Tandem for MM Autologous
First: Melphalan 140 mg/m2/d IV x 1 day ‐2 Multiple
Second after 3‐ 6 months: myeloma
Melphalan + 140 mg/m2/d IV x 1 day ‐2
Total body irradiation 8 Gy (total) ‐6, ‐5, ‐4, ‐3
NOTE: the accuracy of the doses listed in this table cannot be guaranteed. Always check drug and doses
against the primary reference before prescribing chemotherapy.

Selected Nonmyeloablative and Reduced Intensity Conditioning Regimens39
NONMYELOABLATIVE (NMA)44
HSCT
TYPE/DISEASE
Flu/TBI Allogeneic
TBI + 200 cGy x 1 dose 0 CLL,
Fludarabine 25‐30 mg/m2 IV daily x 3 days ‐4, ‐3, ‐2 Hematological
malignancies
REDUCED INTENSITY CONDITIONING (RIC)44
HSCT
TYPE/DISEASE
Flu/Cy Allogeneic
Cyclophosphamide 60 mg/kg IV QD x 2 days ‐7, ‐6 Hematological
Fludarabine 25 mg/m2 IV QD x 5 days ‐5 to ‐1 malignancies
Flu/Cy/ATG45 Allogeneic
Cyclophosphamide 60 mg/kg/day IV x 2 days ‐7, ‐6 Hematological
Fludarabine 25 mg/m2 QD IV x 5 days ‐5, ‐4, ‐3, ‐2, ‐1 malignancies
ATG (horse) 40 mg/kg QD IV x 4 days ‐5, ‐4, ‐3, ‐2 Aplastic anemia
Flu/Bu46 Allogeneic
Fludarabine 30 mg/m2/d IV Q24H x 6 days ‐10 to –5 Hematological
Busulfan 1 mg/kg/dose PO Q6H x 8 doses ‐6, ‐5 malignancies
+/‐ ATG (Fresenius) 10 mg/kg/d IV Q24H x 4 days ‐4 to –1
Flu/Mel Allogeneic
Fludarabine 25 – 30 mg/m2 IV QD x 4 ‐ 5 days ‐6 to ‐2 (or ‐1) Hematological
Melphalan 100 – 180 mg/m2 IV QD x 1 day ‐2 malignancies
Flu/Cy/TBI47 Allogeneic
Cyclophosphamide 50 mg/kg/day ‐6 Cord Blood
Fludarabine + 40 mg/m2 IV QD x 5 days ‐6, ‐5, ‐4, ‐3, ‐2
Total body irradiation 200 cGy ‐1
Flu/Cy/Thiotepa/TBI48 Allogeneic
Cyclophosphamide 50 mg/kg/day ‐6 Cord Blood
2
Fludarabine 30 mg/m IV QD x 5 days ‐6, ‐5, ‐4, ‐3, ‐2
Thiotepa 5 mg/kg/day ‐5, ‐4
Total body irradiation 200 cGy x 2 days ‐2, ‐1
NOTE: the accuracy of the doses listed in this table cannot be guaranteed. Always check drug and doses
against the primary reference before prescribing chemotherapy.

2. Nonmyeloablative (NMA) and reduced‐intensity (RI) conditioning allogeneic HSCT
a. Designed as an alternative to MA allogeneic HSCT in patients that do not
qualify for conventional allogeneic HSCT due to age or co‐morbidity49
b. Based on the premise that a main therapeutic component of allogeneic HSCT
may be due to T‐cell mediated graft‐versus‐tumor effects rather than to
physical eradication of tumor cells by high‐dose myeloablative preparative
regimens prior to stem cell infusion
c. NMA involves minimization of anti‐tumor intensity and maximization of
immunosuppression
d. Engraftment of donor hematopoietic cells is achieved by suppression of host
immunity rather than myeloablation. NMA is associated with a higher risk of
graft rejection compared with MA conditioning regimens.49
e. A successful outcome may only require partial or mixed, but stable, lympho‐ or
hematopoietic engraftment (chimerism)
f. Post‐transplant immune manipulation may be used to optimize immune
recovery and create a mixed chimeric state. This induces tolerance to prevent
graft rejection and GVHD. An example of post‐transplant immune manipulation
is donor lymphocyte infusion (DLI). Full donor T‐cell chimerism is strongly
correlated with a reduced risk of disease progression or relapse.50
g. Multiple RI and NMA regimens under investigation and use
1) Few prospective randomized comparisons to MA allogeneic HSCT have
been published
Prospective Comparisons of RI vs. MA Regimens
Study design Population OS Relapse Comments
Randomized, N = 272 18‐month OS: Relapse rate: Closed early due to high
phase III trial 78% in MA vs. 13.5% in MA relapse incidence in RI.
(BMT CTN 0901 AML or MDS 68% in RI vs. 48.3% in RI MA conditioning remains the
Scott BL et al.)51 with MRD or standard of care for AML
MUD donors P = 0.07 P < 0.001 patients able to receive.
Randomized, N = 129 2‐year OS: 2‐year relapse‐ Toxicity was similar except
phase III trial 63% in MA vs. free survival: more infections in MA arm.
(Kroger N et MDS or 76% in RI 58% in MA vs. RI may be reasonable
al.)52 secondary AML 62% in RI alternative in MDS.
P = 0.08 P = 0.58

h. NMA/RI aim to exploit graft‐versus‐leukemia or graft‐versus‐tumor (GVT)
potential of HSCT while reducing toxicity
1) GVT sensitivity based on disease response to DLI53
a) Sensitive: CLL, low‐grade lymphoma, CML, and mantle cell
lymphoma
b) Intermediate: AML, intermediate grade lymphoma, MM, HD
c) Insensitive: ALL, high‐grade lymphoma
2) GVT sensitivity based on correlation of greater GVHD with improved
relapse free survival:54
a) Sensitive: CML, myeloproliferative neoplasms, ALL
b) Intermediate: MDS and lymphoproliferative disorders
c) Insensitive: AML and plasma cell disorders
3. The most severe toxicity of chemotherapy used in myeloablative regimens is
myelosuppression; the next most severe toxicity is the dose limiting toxicity. HSCT
allows dose intensification of chemotherapy by 3‐10 fold over standard doses.
4. Overlapping toxicities in a drug regimen should be considered
5. Dosing in hepatic impairment55
a. Standards or dosing guidelines are unable to be made because evidence is
unavailable
b. Current published literature reviewed in publication by Bodge et al.55
6. Dosing in chronic kidney disease56
unavailable
b. Current published literature reviewed in publication by Bodge et al.56
7. Dosing in obesity57
unavailable
b. Current published literature review for dose modification in publication by
Bubalo et al.57
Patient Case #2: JN is a 37‐year‐old female with AML with in first complete remission and is planning to
undergo a matched unrelated donor allogeneic HSCT. She is scheduled to receive busulfan 0.8 mg/kg IV q
6 hours x 4 days + cyclophosphamide 60 mg/kg IV daily x 2 days as conditioning prior to HSCT.

Question #3: Which of the following should she receive to prevent toxicity from the chemotherapy?
A. Continuous bladder irrigation
B. Phenytoin
C. Palifermin
D. Amifostine

I. Chemotherapy used for HSCT conditioning39 (*note this is not all inclusive and is intended to
highlight aspects of chemotherapy that are noteworthy in HSCT)
1. Busulfan
a. Dose limiting toxicities are hepatotoxicity, mucositis, and pulmonary fibrosis.
Doses used in transplant can be up to 7 fold dose increase over standard
doses.58
b. Toxicity is dose related. Many centers do pharmacokinetic dosing based on
area under the curve (AUC), especially with myeloablative doses
1) Validated pharmacokinetic modeling tools are recommended to
personalize doses following the initial high dose of busulfan; test
dose strategies not currently recommended59
2) Study in CML with every 6 hour IV busulfan found the relapse rate
increased with an AUC below 950 micromoles/L x min and the
incidence of veno‐occlusive disease of the liver, gastrointestinal
toxicity, and acute GVHD increased above 1500 micromol/L.60 Other
studies confirm every 6 hour oral busulfan AUC > 1500 micromoles/L
x min increases the risk of veno‐occlusive disease (VOD).61‐63
3) Intravenous busulfan has led to a significant decrease in VOD and
pharmacokinetic (PK) variability – even in the absence of therapeutic
drug monitoring.40, 64 Although no reported differences in overall
survival between formulations, intravenous is commonly preferred
due to convenience and concerns for intrapatient variability.59
4) Once daily intravenous busulfan is a commonly used dosing strategy,
with a goal AUC of 3600‐6000 micromoles/L x min.65 PK study
comparing AUC of 6000 micromoles/L x min x 4 days vs. 130
mg/m2/day x 4 days combined with fludarabine 40 mg/m2/day x 4
days showed improvement in progression free survival (primary
endpoint), overall survival, and a trend for reduced non‐relapse
mortality in patients with AML/MDS.66
5) The need for therapeutic drug monitoring (TDM) in reduced intensity
regimens (total busulfan dose < 9 mg/kg/PO or IV equivalent) is less
well established59
c. Busulfan causes seizures in up to 10% of patients if given no pharmacologic
prophylaxis, therefore seizure prophylaxis is routinely provided67
1) Phenytoin was historically the standard of care and was studied in
most of the studies of busulfan pharmacokinetics
2) Many centers utilize alternatives such as levetiracetam or
benzodiazepines in an attempt to avoid phenytoin induction of
chemotherapy metabolism67
d. Hepatic elimination‐ enzymatic conjugation with glutathione58
e. Drug Interactions68
1) Avoid acetaminophen and metronidazole 72 hours before and after
busulfan – use leads to increased busulfan levels
2) Itraconazole, voriconazole, and posaconazole may increase busulfan
levels (note PK studies were typically done with fluconazole)
3) Induces phenytoin metabolism & vice versa
2. Carboplatin
a. Dose limiting toxicities are hepatic and renal toxicity, ototoxicity, mucositis,
and peripheral neuropathy; 4‐6 fold dose increase over standard dose58
b. Renal elimination‐ consider AUC dosing
c. Drug interactions68
1) Concomitant aminoglycosides increase risk of ototoxicity
2) Case reports of lower phenytoin levels
3. Carmustine
a. Dose limiting toxicity is pulmonary toxicity69‐71; 5.3 fold dose increase over
standard dose58
1) 5 to 60% Incidence, with a higher incidence with higher doses of
carmustine (> 450 mg/m2 =15% incidence)
2) Acute lung injury – cough, dyspnea, fever, minimal radiographic
changes
3) Risk factors: prior chest radiation, smoking, prior bleomycin,
concomitant cyclophosphamide
4) Treatment with early corticosteroids ‐ prednisone 1 mg/kg/day
b. High dose carmustine (>150 mg/m2) is associated with headaches, perioral
paresthesia, and flushing within 2 hours of the infusion due to the alcohol
diluent used in drug reconstitution. Supportive care with acetaminophen,
morphine, hydromorphone, or benzodiazepines diminish the severity of the
reaction.72
c. Hydrolysis, renal elimination
d. Drug Interactions
1) Avoid aldehyde dehydrogenase‐2 inhibitors and drugs that induce
disulfiram reaction due to the alcohol diluent. Most other interactions
are not clinically significant.
4. Cyclophosphamide73
a. Dose limiting toxicity is cardiac74‐76; 8‐10 fold dose increase over standard dose
1) Occurs most often at doses above 150 mg/kg. Causes myocardial
necrosis and acute congestive heart failure; typically occurs in the
first 10 days following administration. Pericarditis has also been
reported.
b. Hemorrhagic cystitis77
1) Incidence ranges from 0.5% to 40%, mortality rates of 2% to 4%
reported
2) Caused by metabolite acrolein
3) Mesna plus saline diuresis or forced saline diuresis is recommended
to decrease the incidence of urothelial toxicity associated with high‐
dose cyclophosphamide; IV hydration with saline > 3 L/m2/d plus IV
furosemide after each dose of cyclophosphamide to maintain urine
output at greater than 100 mL/h
c. May also cause syndrome of inappropriate antidiuretic hormone (SIADH),
pulmonary toxicity
d. Hepatic toxicity
1) Elevated cyclophosphamide metabolite concentrations are associated
with increased risk of hepatic toxicity and non‐relapse mortality
following allogeneic HSCT with a cyclophosphamide 120 mg/kg and
TBI 900‐1440 cGy conditioning regimen78
2) Elevated cyclophosphamide metabolite concentrations were NOT
associated with increased risk of hepatic toxicity, non‐relapse
mortality, relapse or survival79; pharmacokinetic dosing has not been
shown to mitigate toxicity risk 80
3) Administration of Cy before targeted IV busulfan does reduce VOD (0%
vs. 30% in historical control) and day 100 TRM (2% vs. 12%) in patients
with myelofibrosis; no difference in AML/MDS patients (who have an
inherently lower risk for VOD)81
e. Hepatic metabolism; 5‐25% renal elimination
f. Drug interactions
1) Prodrug, metabolized to active and inactive metabolites by CYP3A4,
CYP2B6, CYP2A6, CYP2C8, CYP2C9, and CYP2C19
2) Busulfan or phenytoin increases cyclophosphamide metabolism to
toxic metabolites, therefore some experts suggest administering
cyclophosphamide before busulfan or 12‐18 hours after completion of
busulfan79
3) No significant interaction with aprepitant 125 mg orally on day 1 and
80 mg orally on each consecutive day through day +4 after HSCT with
no significant changes in cyclophosphamide or 2 metabolites
pharmacokinetic parameters82
5. Cytarabine83
a. Dose limiting toxicity is neurotoxicity, but many of the transplant regimens
that include cytarabine are not “high dose” (< 1 gm/m2/dose)
1) Presents with slurred speech, confusion, unsteady gait, coma
2) Risk factors for neurotoxicity include renal dysfunction, age over 40
years, and elevated alkaline phosphatase
3) Please see the Acute Leukemia handout for management of
cytarabine‐induced neurotoxicity
b. Contributes to mucositis; high dose is associated with pulmonary toxicity (non‐
cardiogenic pulmonary toxicity), and hepatic toxicity; conjunctivitis with high‐
dose therapy (see Acute Leukemias section); skin rash
c. Deamination in liver, plasma and peripheral tissues; note neurotoxicity
increased in patients with renal dysfunction & elevated alkaline phosphatase
1) Cytarabine has synergistic activity with several chemotherapy agents,
including cyclophosphamide, cisplatin, purine analogs, methotrexate,
and etoposide
6. Etoposide73
a. Dose limiting toxicity is mucositis; 3‐6 fold dose increase over standard dose
b. Infusion can cause hypotension; associated with metabolic acidosis possibly
due to large dose of ethanol used as excipient
c. Metabolized in liver to glucuronide metabolite and then renally eliminated;
one‐third is excreted by kidney unchanged. Renal elimination increased in
patients with hepatic dysfunction. Consider dose reduction in renal
dysfunction.
1) CYP3A4 substrate‐ any CYP3A4 inducers or inhibitors have potential
for a pharmacokinetic interaction, and caution should be used when
these medications are administered concurrently with etoposide.68
7. Fludarabine
a. Dose limiting toxicity is neurotoxicity
1) The incidence of fludarabine‐related neurotoxicity in HSCT
conditioning regimens doses is 2.4%. Fludarabine dosing of 40‐100
mg/m2/day or a total dose of 200 mg/m2 is associated with an
increased risk of neurotoxicity. The onset of neurotoxicity is
approximately 2 months after receiving fludarabine and it develops
with progressively increasing severity. Neurotoxicity associated with
fludarabine was associated with poor median overall survival
(estimated one year survival of 43%).84
2) Potential risk factors for fludarabine neurotoxicity include: age over 60
years, renal dysfunction contributing to elevated fludarabine
concentrations in the central nervous system (CNS)85, prior high dose
cytarabine, intrathecal therapy, or cranial irradiation and prior HSCT
with fludarabine conditioning84
3) Fludarabine‐induced neurotoxicity may present as cognitive
dysfunction, decreased levels of consciousness, vision changes,
confusion, somnolence, seizure, severe persistent headache, and
blurred vision84
b. Renal elimination
1) Consider dose reduction, especially for regimens with higher doses of
fludarabine (40 mg/m2/day or 200 mg/m2 total dose) for patients with
renal dysfunction85
c. Drug interactions – no significant interactions
8. Ifosfamide58
a. Dose limiting toxicity is renal toxicity and neurotoxicity; 2.7 fold dose increase
over standard dose
1) Please see Sarcoma materials for thorough discussion of neurotoxicity
b. Renal tubular damage may cause Fanconi‐like syndrome (elevated Scr, BUN,
electrolyte wasting)77
c. Hemorrhagic cystitis
1) Caused by metabolite acrolein‐ administer mesna to prevent
2) Toxicity is usually within 4‐6 weeks of administration (if it occurs
later suspect viral cystitis)
3) May present as mild cystitis to massive hemorrhage; patients may
complain of urinary retention, pain with urination; micro or
macroscopic hematuria may be present
d. Hepatic metabolism to active metabolite, renal elimination
e. Drug Interactions
1) Concomitant administration of ifosfamide and CYP3A4 inducers may
increase the metabolism of ifosfamide to its active alkylating
metabolites and may increase the formation of neurotoxic and
nephrotoxic metabolites
2) Concomitant use of CYP3A4 inhibitors and ifosfamide may decrease
the metabolism of ifosfamide to its active alkylating metabolites,
possibly reducing the effectiveness of ifosfamide
9. Melphalan58
a. Dose limiting toxicity is mucositis; 5.6 fold dose increase over standard dose
1) Cryotherapy (ice chips) is effective for prevention of mucositis in
patients with multiple myeloma receiving single agent melphalan86, 87
b. May cause SIADH, pulmonary toxicity, hepatic toxicity, and delayed emesis
c. Primary method of elimination is hydrolysis; renal elimination accounts for
13%
d. Renal dose adjustment has conflicting data‐ some reports indicate safe to use
full dose with renal dysfunction and some describe increased toxicity88‐90
e. No consensus for reduction of melphalan in the setting of renal dysfunction
f. Drug interactions – no significant interactions
10. Thiotepa73
a. Dose limiting toxicity is mucositis and neurotoxicity; 8‐12 fold dose increase
over standard dose
b. Neurotoxicity presents as confusion, somnolence, and coma. May cause
significant elevations in hepatic enzymes, acute erythroderma with
maculopapular dissemination and desquamation, interstitial pneumonitis, and
cardiac toxicity. Skin hyperpigmentation can occur as metabolites can
accumulate in skin folds & dressings.
1) Due to skin excretion at high doses, avoid occlusive dressings and
clean skin twice daily during therapy and for 48 hours after91
c. Oxidative metabolism by CYP2B1, CYP2C11, CYP3A4, and minor by CYP2B6;
metabolized to active metabolite TEPA
1) Inhibitor of CYP2B6‐ cyclophosphamide may not be activated
therefore administer cyclophosphamide before thiotepa.
Patient Case #2:

Answer: B. Phenytoin. Patients receiving busulfan should receive seizure prophylaxis. The optimal
agent has not been determined by randomized trials; phenytoin, levetiracetam, and benzodiazepines
have been used. Patients receiving high‐dose cyclophosphamide as conditioning for HSCT should
receive mesna and saline diuresis (continuous bladder irrigation is not recommended by the American
Society of Clinical Oncology: Use of Chemotherapy and Radiation Therapy Protectants Guidelines77).
Palifermin did not reduce the severity of mucositis in patients receiving busulfan/cyclophosphamide
conditioning in allogeneic stem cell transplants and has no impact on GVHD. Amifostine is not
recommended to prevent toxicity in allogeneic HSCT patients.
J. Immunosuppression (allogeneic HSCT only)
1. Prevention of graft (i.e.; allogeneic stem cell) rejection
a. Achieved with immunosuppressive therapy in conditioning regimen (e.g.
cyclophosphamide, fludarabine, anti‐thymocyte globulin)
b. Required to eradicate host immune system (T‐lymphocytes) and thus allow
acceptance of donor cells; prevents “host‐versus‐graft” reaction
2. Prevention of graft‐versus‐host disease (GVHD)
a. Achieved with long‐term immunosuppressive medications initiated prior to
infusion and continued typically until at least three to six months after HSCT
or until resolution of GVHD. Combination regimens of calcineurin inhibitors
with short course methotrexate (day + 1, 3, 6, +/‐ 11) are standard of care.
b. Required to suppress donor immune system (T‐lymphocytes) and minimize
recognition of host cells as foreign
K. Infusion of stem cells
1. Day of infusion of stem cells referred to as Day 0
2. Infused as fresh (manipulated or unmanipulated) allogeneic stem cells or thawed
cryopreserved (manipulated or unmanipulated) allogeneic or autologous stem cells;
infused via central line; thawed stem cells must be infused rapidly due to limited time of
viability post thawing
3. If cryopreserved, infusion may be associated with dimethyl sulfoxide (DMSO) toxicity
including nausea, bradycardia, and garlic‐like odor from recipient (lasts approximately
24 hours). If multiple bags of CD34+ cells, may separate over several days into different
aliquots to avoid DMSO toxicity.
4. Generally well tolerated; hydration often given to minimize hematuria. Premedication
generally given to prevent infusion reactions (e.g. acetaminophen +/‐ corticosteroid +/‐
diphenhydramine)92
L. Engraftment
1. Sustained ANC >0.5 x 109/L for three consecutive days and platelet count > 20 x 109/L
without transfusion for seven days
III. Post‐HSCT Relapse Prevention
A. Relapse prevention93, 94
1. Relapse is the major cause of death for patients after HSCT
2. Strategies to prevent relapse
a. Improve the conditioning regimen (novel drugs, monoclonal antibodies)
b. Graft engineering (graft depletion of T cells, NK cell enrichment, cytotoxic T
lymphocyte enrichment)
c. Monitor for minimal residual disease and use pre‐emptive therapy
1) Immunologic (e.g. tumor vaccine, genetically modified T cell)
2) Cellular therapy (e.g. donor lymphocyte infusion)
3) Pharmacologic (e.g. imatinib for Philadelphia chromosome‐positive
acute lymphoblastic leukemia)
d. Early withdrawal of immunosuppression to promote graft vs. tumor effect
e. Maintenance therapy post‐HSCT
1) Immunologic (e.g. tumor vaccine, genetically modified T cell)
2) Cellular therapy (e.g. donor lymphocyte infusion)
3) Pharmacologic (e.g. lenalidomide for multiple myeloma)
a) Active in the disease
b) Acceptable non‐hematologic toxicity
c) Acceptable myelotoxicity
d) Minimal drug interactions
e) Will not inhibit graft vs. tumor effect
f) Will not worsen GVHD
g) Other factors: cost, convenience, quality of life impact
h) Doses often lower than in treatment
B. Autologous HSCT maintenance therapies for relapse prevention
1. Lymphoma95
a. Relapse of disease is the primary cause of death in lymphoma patients
following autologous HSCT, with most relapses occurring within 1 – 3 years.
Several pharmacologic maintenance strategies have been studied to lessen this
complication.
b. Joint expert panel from ASBMT, Center for International Blood and Marrow
Transplant Registry (CIBMTR), and European Society for Blood and Marrow
Transplantation (EBMT) provided recommendations based on existing
prospective data and consensus statements when limited data is available.

Joint Consensus Maintenance Therapy Recommendations from ASBMT, CIBMTR, and EBMT for Hodgkin and
non‐Hodgkin Lymphoma post‐HSCT95‐98
Disease Maintenance Agent Consensus Statement Grade of

recommendation
Classic Brentuximab Recommended if brentuximab vedotin‐naïve A
Hodgkin vedotin with at least 1 or more high‐risk features
lymphoma based on AETHERA trial96 (see below)
 Refractory to initial therapy
 Relapse <12 months after initial
therapy
 Extranodal disease at start of pre‐
transplant salvage therapy
Recommended regimen is every 3 weeks for A
16 cycles or until unacceptable toxicity,
disease relapse, or disease progression
(whichever comes first)
Recommended if limited prior exposure to C
brentuximab vedotin (approximately 4 – 6
cycles) with at least 1 or more high‐risk
features, and no evidence of brentuximab
vedotin‐refractory disease
Not recommended if prior evidence of disease C
refractory to brentuximab vedotin
Disease Maintenance Agent Consensus Statement Grade of
recommendation
Diffuse large Rituximab Not recommended, even if disease is A
B‐cell sensitive to rituximab‐based salvage
lymphoma approaches, based on CORAL trial97 (see
below)
Agents other than Not recommended outside of clinical trial C
rituximab
Mantle cell Rituximab Recommended following upfront autologous A
lymphoma HSCT if chemosensitive after 1 line of prior
rituximab and cytarabine‐containing therapy
Recommended regimen is every 2 months for A
3 years as in LYSA trial98 (see below), or until
unacceptable toxicity, disease relapse, or
disease progression (whichever comes first)
Recommended following upfront autologous B
HSCT if chemosensitive regardless of
pretransplant induction
Not recommended if prior evidence of C
rituximab resistance (relapse or progression
while on or within 6 months of rituximab‐
containing regimen)
Recommended following delayed autologous C
HSCT, regardless of history of rituximab
maintenance, if no evidence of rituximab
resistance
rituximab
Follicular Rituximab Recommended every 2 months for 4 doses if A
lymphoma chemosensitive, rituximab‐naïve disease
Recommended if chemosensitive, previously B
rituximab‐ (or other CD20 antibody) treated (lack of
disease without evidence of rituximab prospective data)
resistance
Not recommended if prior evidence of C
rituximab resistance (relapse or progression
while on or within 6 months of rituximab‐
containing regimen)
rituximab
Agency of Healthcare Research and Quality grading of recommendations based on level of evidence:
A, there is good research‐based evidence to support the recommendation;
B, there is fair research‐based evidence to support the recommendation;
C, the recommendation is based on expert opinion and panel consensus;
X, there is evidence of harm from this intervention.

Select Studies on Maintenance Therapy post‐HSCT in Hodgkin and non‐Hodgkin Lymphoma
Disease Study N Maintenance Median PFS OS Comments
Regimen / event free
survival (EFS)
Hodgkin AETHERA, 201596 329 Brentuximab 42.9 No 85% of placebo
lymphoma vedotin 1.8 mg/kg brentuximab difference patients who
Randomized, IV every 21 days vs. 24.1 88% at 2 received therapy
double‐blind, up to 16 cycles months years for progression
placebo‐ starting 30‐45 placebo received
controlled, phase days after HSCT brentuximab
III study of P = 0.0013
brentuximab for PFS
vedotin in high risk
patients
Diffuse CORAL, 201297 242 Rituximab 375 52% No Increased
large B‐ mg/m2 every 2 rituximab vs. difference serious adverse
cell Randomized, months for 1 year 53% at 4 years effects, including
lymphoma multicenter, phase observation infection, in the
III study of rituximab arm
rituximab P = 0.7 for
maintenance vs. EFS at 4
observation years
Mantle LYSA, 201798 240 Rituximab 375 79% 89% All patients
cell mg/m2 every 2 rituximab vs. rituximab received R‐DHAP
lymphoma Randomized, months for 3 61% placebo vs. 80% induction
unblinded, phase years placebo regimen,
III study of P < 0.001 for therefore
rituximab vs. EFS at 4 P = 0.04 unknown
placebo years applicability to
other induction
strategies
R‐DHAP = rituximab, dexamethasone, cytarabine, platinum derivative
2. Multiple myeloma
a. ASCO guidelines for treatment of multiple myeloma include post‐HSCT
maintenance recommendations4
1) Lenalidomide maintenance should be routinely offered to standard‐
risk patients starting approximately 3 months post‐transplant based
on improved progression free and overall survival. The
recommended dose is 10 – 15 mg until progression, or a minimum of
2 years, which is associated with improved overall survival.
a) Recent meta‐analysis confirmed overall survival benefit of
lenalidomide maintenance compared to observation (HR
0.75, 95% CI 0.63 – 0.90, P = 0.001)99 – see table below
b) Lenalidomide 10 mg daily approved by US Food and Drug
Administration for maintenance after HSCT in 2017
2) For patients intolerant of or unable to receive lenalidomide,
bortezomib maintenance every 2 weeks can be considered.
3) In high‐risk patients (decreased creatinine clearance, adverse
chromosome changes, or elevated lactate dehydrogenase),
proteasome inhibitor therapy with or without lenalidomide may be
considered.
Select Studies on Maintenance Therapy post‐HSCT in Multiple Myeloma
Study N Maintenance EFS or PFS OS Comments
Regimen
Lenalidomide (LEN)
CALGB 100104100, 101 460 LEN 10 mg 3 year PFS 5 year OS Discontinuation due
daily vs. 66% LEN 76% LEN to adverse events:
IMIDs or bortezomib in placebo (PBO) 39% PBO 64% PBO 12% LEN vs. 2% PBO
induction regimen in
94% of patients P < 0.001 P = 0.0004 Higher rate of second
followed by single primary cancers:
autologous PBSCT 7.8% LEN vs.
2.6% PBO
IFM 2005‐02102 614 LEN 10‐15 mg 4 year PFS 4 year OS Discontinuation due
daily until PD 43% LEN 73% LEN to adverse events
Bortezomib in or intolerance 22% PBO 75% PBO 27% LEN vs. 15% PBO
induction in 44‐46% of vs. PBO
patients P < 0.001 P = NS Higher rate of second
Single PBSCT in 79%; Maintenance primary cancers:
tandem PBSCT in 21% stopped early 7.5% LEN vs.
because of 2.9% PBO
high rate of
second
primary
cancers
GIMEMA RV‐209103 273 LEN 10 mg PFS 3 year OS 5.2% of LEN patients
for daily days 1‐ 42 mos LEN 88% LEN discontinued
Lenalidomide + dex first 21, repeat q 22 mos none 79% none maintenance
induction x 4 cycles, 28 days until because of adverse
tandem autologous 253 PD or P < 0.001 P = 0.14 effects.
PBSCT vs. MPR for intolerance vs.
(melphalan, secon none 4.3% had second
prednisone, Revlimid), d primary cancers in
then second both LEN
randomization to maintenance and no
lenalidomide or no maintenance groups.
therapy
Meta‐analysis99 1208 LEN 10‐15 mg PFS 79.5 mos Higher rate of
vs. placebo or 52.8 mos LEN follow‐up: second primary
Patient‐level data of observation 23.5 mos NR LEN malignancy in LEN
LEN maintenance vs. (control) control 86 mos arm vs. control
control post‐HSCT control
(included 3 trials listed HR = 0.48 Confirmed OS
above) powered for (95% CI 0.41 P = 0.001 benefit of LEN
primary endpoint of – 0.55) maintenance
OS
NR = not
reached
Regimen
Bortezomib
HOVON‐65/GMMG‐ 827 VAD arm: Median PFS 5 year OS 30% of thalidomide
HD4104 Thalidomide 28 mos VAD 55% VAD and 11% of
50 mg daily or 35 mos PAD 61% PAD bortezomib patients
VAD induction vs. PAD discontinued early
induction followed by PAD arm: P = 0.002 P = 0.07 due to peripheral
autologous PBSCT bortezomib neuropathy.
(~1/3 of patients had 2 1.3 mg/m2 q 2 Note‐ design does
PBSCT) weeks not allow firm
conclusion about
Maintenance x benefit of
2 years maintenance.
PETHEMA/GEM105 386 Interferon 2 year PFS No No maintenance
alfa‐2b (3 MU thalidomide/ difference specific adverse
Induction with 1 of 3 SQ 3 times per bortezomib effects reported
regimens (all had week) vs. 78%
thalidomide, thalidomide thalidomide
bortezomib or both) 100 mg PO 63%
followed by single daily vs. Interferon
autologous PBSCT thalidomide alfa‐2b
100 mg PO 49%
daily +
bortezomib on P = 0.01
days 1, 4, 8,
and 11 every 3
months.
Planned for 3
years
Nordic106 370 Bortezomib 27 mo vs. 20 No Median number of
twice weekly mo difference bortezomib injections
Bortezomib naïve on days 1, 4, 8, P = 0.05 received was 19, and
patients (almost all and 11 in a 3‐ median given dose
had not received novel week schedule was 90%
therapies), received x 2 cycles,
induction and followed by
autologous PBSCT; once weekly
< 10% had 2 PBSCT on days 1, 8,
and 15 in a 4‐
week schedule
x 4 cycles

C. Allogeneic HSCT maintenance therapies for relapse prevention
1. Acute myeloid leukemia/myelodysplastic syndrome
a. Currently insufficient data to recommend for or against maintenance
therapy107
1) Several agents studied, but available data is preliminary, retrospective,
or/and non‐comparative
b. Azacitidine
1) Azacitidine may expand TREG (regulatory T cell) population to
promote graft vs. leukemia while reducing GVHD.108 In the single‐
center RICAZA trial with N=37, azacitidine 36 mg/m2 x 5 days, q 28
days, up to 12 cycles, starting approximately at day 42 was
evaluated109
a) One‐year RFS = 57%, Two‐year RFS 49%
b) One‐year OS = 81%, Two‐year OS 49%
2) In a single center, dose finding study in 47 AML/MDS patients,
azacitidine 32 mg/m2 x 5 days was given q 30 days, x at least 4 cycles,
starting approximately at day 40110
a) One‐year EFS was 58% and overall survival was 77%
c. Decitabine111
1) N=24, dose‐finding study; MTD not identified, recommended dose is
10 mg/m2 IV daily x 5 days q 6 weeks x 8 cycles starting between day
50 and day 100
a) Two‐year OS was 56%, DFS was 48%
d. Sorafenib
1) Retrospective study comparing patients transplanted in CR1 for FLT3‐
internal tandem duplication AML who received sorafenib as
maintenance (N=26) compared to controls who did not (N=43)112
a) Two‐year OS was 81% in the sorafenib group vs. 62% in
control group, P=0.029; 2‐year cumulative incidence of
relapse was 8.2% vs. 37.7%, P = 0.0077
2) Retrospective study in AML patients with FLT3‐internal tandem
duplication compared sorafenib use pre‐HSCT (Group A, N=36), post‐
HSCT (Group B, N=32), and both pre‐ and post‐HSCT (Group C, N=26)
to no sorafenib use (Group D, N=50).113
a) 3‐year leukemia‐free survival rate was shorter in the no
sorafenib group (Group D 34.8%) compared to the sorafenib
groups (Group A 69.4%, Group B 78.1%, Group C 80.4%), P <
0.001.
b) Overall survival was shorter in Group D (50.9%) compared to
Group C (84.6%), but not statistically significantly different
than Groups A or B (74.9% and 78.1%, respectively).
c) Multivariable analysis showed that sorafenib use before
HSCT, after HSCT, and the combined use were protective for a
lower relapse rate and longer leukemia‐free survival.
e. No available data regarding midostaurin use post‐transplant, but phase 2
randomized maintenance trials ongoing
f. Lenalidomide is not recommended as it may promote development of severe
GVHD114
2. Acute lymphoblastic leukemia, Philadelphia chromosome‐positive7
a. Maintence or preemptive MRD‐guided TKI therapy should be considered post
transplant
1) Limited evidence suggests TKI therapies (imatinib, dasatinib, nilotinib)
improve outcomes, including overall survival compared to no
therapy/historical data115‐125
3. Chronic myeloid leukemia126, 127
a. It is not known if all patients should receive a TKI after allogeneic HSCT for CML
or at what level of molecular relapse a TKI should be initiated
b. The optimal agent, dose, or duration of TKI therapy after allogeneic HSCT for
CML has not been determined. Current data suggests it is safe and well
tolerated to administer a TKI post HSCT. Post HSCT TKI therapy has been
associated with a lower incidence of extensive, chronic GVHD.
c. Currently published data includes patients who did not receive a TKI pre‐
transplant or had received imatinib and were not considered resistant or
intolerant to it. This is no longer typical of the patient population currently
undergoing allogeneic HSCT.

Maintenance Therapy post‐HSCT in Chronic Myeloid Leukemia
Regimen
Imatinib for CML 22 Imatinib 300 mg 68% relapsed a 87% at 3 Reduced intensity
in first chronic daily started at day median of 17 years conditioning.
phase128 + 35 in patients months after 50% of patients
with ANC > 1 x HSCT (range: had not received
10^9/L and platelet 13‐29 months) imatinib prior to
count: > 100 x HSCT.
10^9/L. Dose 3/22 patients had
increased to 400 to temporarily
mg daily within 4 hold imatinib
weeks and because of
continued 12 nausea.
months after HSCT.
Imatinib for CML 7 Imatinib 400 mg 2 patients 86% at Myeloablative
beyond first daily started when (29%) relapsed median 1.43 conditioning.
chronic phase115 ANC > 1.2 x 109/L at day 89 and years All patients had
(median day 29) day 180 imatinib before
and continued 12 HSCT.
months after HSCT.
Nilotinib for CML 17 Nilotinib 200 mg 2‐year PFS 56% 2‐year OS Most received
beyond first PO q 12 hours 69% myeloablative
chronic phase120 started after conditioning and
sustained received imatinib
engraftment and prior to HSCT. 7
resolution of patients had also
transplant toxicities received nilotinib.
(median start day
38)

Patient Case #1, Continued: PK is a 61‐year‐old woman with newly diagnosed stage III multiple myeloma.
She is planning to receive high dose melphalan conditioning followed by an autologous PBSCT.

Question #4: What should PK receive to prevent mucositis?
A. Sargramostim mouth rinses
B. Doxepin mouth rinses
C. Ice chips
D. Palifermin

IV. Post‐HSCT Complications
A. Mucositis
1. Most common with myeloablative conditioning, regimens containing total body
irradiation, high dose etoposide or melphalan, and use of methotrexate to prevent
GVHD

MASCC/ISOO Clinical Practice Guidelines for Mucositis86
Mucositis prevention in high‐dose chemotherapy +/‐ TBI in the setting of HSCT
Recommendations for use:
 Palifermin 60 mcg/kg/day x 3 days prior to conditioning treatment and for 3 days post‐
transplant for the prevention of oral mucositis in patients with hematological malignancies
receiving high‐dose chemotherapy therapy and TBI + autologous stem cell transplant
 Low‐level laser therapy to prevent mucositis in patients receiving HSCT, conditioned with high‐
dose chemotherapy, with or without TBI
Suggestions for use:
 Oral care protocols to prevent oral mucositis
 Cryotherapy to prevent oral mucositis in patients receiving high‐dose melphalan, with or
without TBI as conditioning for HSCT
Recommendations against use:
 IV glutamine
 Iseganan antimicrobial mouthwash
Suggestions against use:
 Granulocyte‐macrophage‐colony‐stimulating factor mouthwash
 Pentoxifylline
 Oral pilocarpine
Mucositis/diarrhea treatment in high‐dose chemotherapy +/‐ TBI in the setting of HSCT
Recommendations for use:
 Octreotide at a dose of ≥100 mcg SQ BID to treat diarrhea unresponsive to loperamide
 Patient‐controlled analgesia with morphine to treat pain due to oral mucositis
Suggestions for use:
 Transdermal fentanyl may be effective to treat pain due to oral mucositis
 Doxepin 0.5% mouthwash may be effective to treat pain due to oral mucositis
MASCC = Multinational Association of Supportive Care in Cancer, ISOO = International Society of Oral Oncology

2. Prevention
a. Good oral hygiene. All patients should use saline or sodium bicarbonate
mouthwashes regularly (no benefit to magic mouthwash; chlorhexidine may
cause worse outcomes)86
b. Cryotherapy (ice chips). Cryotherapy leads to vasoconstriction and decreased
blood flow to the oral cavity, which reduces buccal mucosa exposure to
chemotherapy. Use limited to patients with multiple myeloma receiving single
agent melphalan. Compared with usual care, patients using ice chips were less
likely to develop severe mucositis (RR = 0.25, 95% CI = 0.08 to 0.78) and had a
shorter duration of total parenteral nutrition (standardized mean difference = ‐
0.56, 95% CI = ‐0.92 to ‐0.19)87. 2 hours of cryotherapy as effective as 7 hours
for mucositis prevention.129
c. Palifermin
1) Palifermin is a member of the fibroblast growth factor family and has
been shown to protect mucosal tissue
2) Beneficial in autologous HSCT patients with hematologic
malignancies receiving TBI 1200 cGy/cyclophosphamide/etoposide130
conditioning regimen. Grade III/IV mucositis was 63% palifermin vs.
98% placebo; duration of grade III/IV mucositis was 6 days palifermin
vs. 9 days placebo; less TPN use and less opioid use with palifermin131
a) Palifermin 60 mcg/kg/day for 3 consecutive days before and
after myelotoxic therapy for a total of 6 doses
b) Administer the first 3 doses prior to myelotoxic therapy with
the third dose 24 to 48 hours before myelotoxic therapy
c) Administer the last 3 doses after myelotoxic therapy is
complete with the first of these doses on the day of
hematopoietic stem cell infusion after the infusion is
completed, and at least 4 days after the most recent
administration of palifermin
3) Palifermin did not benefit multiple myeloma patients receiving
melphalan 200 mg/m2 when given both pre‐ and post‐transplant or
pre‐transplant only132
4) Palifermin was studied in multiple studies of allogeneic HSCT
patients and did not reduce GVHD.133‐137 The impact on mucositis has
not been shown to be significant in most studies and subgroups of
patients, and is not recommended in the MASCC guidelines.


Answer: C. Ice chips. Sargramostim mouthwashes have been evaluated for prevention of mucositis and
are not recommended by the guidelines. Doxepin mouth rinses are used for treatment of oral mucositis
pain, not for prevention of mucositis. Palifermin did not demonstrate benefit in patients receiving
melphalan conditioning regimens for multiple myeloma. Ice chips are suggested by the guidelines as
they will prevent mucositis related to melphalan.

B. Nausea and Vomiting
1. Follow ASCO guidelines for high‐dose chemotherapy with stem cell transplant,
radiation, and multiday regimens.138 Please refer to the Lung Cancer handout for more
details on these guidelines. Most conditioning regimens are considered moderate or
high emetic risk.
2. 2017 ASCO guideline update states adult patients treated with high‐dose
chemotherapy with stem cell transplantation should receive a three‐drug combination
of a neurokinin 1 receptor antagonist, a 5HT3 receptor antagonist, and
dexamethasone138
a. Randomized controlled trial of dexamethasone + ondansetron 8 mg TID each
day of preparative regimen + 1 additional day +/‐ aprepitant 120 mg day 1, 80
mg all subsequent days of chemotherapy and an additional 3 days139
1) ~50% autologous and 50% allogeneic; conditioning regimens included
Bu/Cy, Cy/TBI, Cy/TBI/etoposide, & carmustine/Cy/etoposide
2) Primary endpoint of no emesis with only grade 1‐2 nausea/vomiting
was achieved in 82% of aprepitant patients and 66% of placebo
patients, P <0.001
3) No difference in 1 year overall survival, PFS, or average nausea score
b. Randomized controlled trial of granisetron 2 mg PO days 1 to 4,
dexamethasone 4 mg PO day 1, 2 mg PO days 2 to 3 +/‐ aprepitant 125 mg PO
day 1, 80 mg PO days 2‐4140
1) Multiple myeloma receiving melphalan 100 mg/m2 IV days 1 & 2
2) Primary endpoint of no emesis and no rescue therapy within 120
hours of melphalan administration in 58% of aprepitant vs. 41% of
placebo, P = 0.0042
3) No effect on overall nausea (85% v 78%, P = 0.106)
4) Quality of life was improved
3. PK study of cyclophosphamide and metabolites and melphalan indicates it is safe to
give aprepitant concomitantly with either agent82, 141
4. Aprepitant may elevate levels of calcineurin inhibitors and sirolimus through CYP3A4
inhibition142, 143
5. Evidence for olanzapine‐based prophylactic regimens in HSCT is currently limited to a
single placebo‐controlled phase III trial144, a small retrospective report145, or use as a
break‐through agent146
6. 2017 ASCO guideline update states patients treated with high‐emetic‐risk radiation
(i.e. total body irradiation) should be offered a two‐drug combination of a 5HT3
receptor antagonist and dexamethasone before each fraction and for one day after
the planned radiation ends138
Patient Case #2, Continued: JN is a 37‐year‐old female with AML who received busulfan and
cyclophosphamide followed by a 10/10 matched unrelated donor allogeneic HSCT. She received
tacrolimus and methotrexate 15 mg/m2 IV on day 1 and 10 mg/m2 IV on days 3, 6, 11 to prevent GVHD.
She presents on day + 35 with a maculopapular skin rash on 45% of her body and had diarrhea with
1200 mL in the past 24 hours. She has a skin biopsy interpreted as GVHD. She is diagnosed with overall
grade III acute GVHD.

Question #5: What is the most appropriate therapy for her at this time?
1. Prednisone 1 mg/kg/day
2. Prednisone 1 mg/kg/day + beclomethasone
3. Methylprednisolone 1 mg/kg IV BID
4. Methylprednisolone 1 mg/kg IV BID + infliximab

C. Graft‐versus‐host disease (GVHD)
1. An immunological disorder affecting multiple organ systems resulting from donor T
cells responding to foreign recipient antigens147, 148
2. Clinical features and presentation determine the classification of acute (aGVHD) or
chronic (cGVHD), not solely the time since transplant147
a. aGVHD features: erythema, maculopapular rash, nausea, vomiting, profuse
diarrhea, ileus, anorexia or cholestatic hepatitis
b. cGVHD features: can occur in a multitude of organs, often characterized by
fibrosis or autoimmune‐like syndromes149 (see cGVHD section below)
c. Overlap syndrome: presence of 1 or more aGVHD manifestation(s) in a patient
with a diagnosis of cGVHD
Types of GVHD147
Presence of Presence of
Time of symptoms
Category Acute GVHD Chronic GVHD
post HSCT or DLI
Features Features
Acute GVHD (aGVHD)
 Classic acute GVHD ≤ 100 days Yes No
 Persistent, recurrent, or late‐ > 100 days Yes No
onset acute GVHD
Chronic GVHD (cGVHD)
 Classic chronic GVHD No time limit No Yes
 Overlap syndrome No time limit Yes Yes
DLI = donor lymphocyte infusion

3. Prevention of GVHD
a. Donor selection based on best histocompatible match
b. Combination immunosuppression
1) Cyclosporine + methotrexate in related donors150
2) Tacrolimus + methotrexate in unrelated donors151
3) Tacrolimus + sirolimus is an acceptable alternative in non‐busulfan
based, myeloablative conditioning regimens with related donors152
4) Mycophenolate is an alternative to methotrexate with reduced
toxicity (decreased mucositis and faster engraftment)153, 154
5) T‐cell depletion in vivo or ex vivo: randomized trials have
demonstrated inconsistent survival outcomes155
a) Antihuman T‐lymphocyte immune globulin (ATG)
i. Several prospective studies in MRD and MUD have
used Fresenius ATG in addition to cyclosporine and
methotrexate in patients receiving myeloablative
conditioning regimens and have shown reduced
incidence of acute and chronic GVHD without
statistically significant decrease in relapse free or
overall survival156‐158
ii. In contrast, a randomized, placebo‐controlled trial of
Fresenius ATG in combination with tacrolimus and
methotrexate in myeloablative MUD showed
decreased rates of acute and chronic GVHD, but
lower rates of progression‐free and overall survival
at 2 years in the ATG arm159
b) ATG use remains controversial, and additional studies needed
to elucidate appropriate place in therapy
6) Post‐transplant cyclophosphamide 50 mg/kg IV on days +3 and +4 in
haploidentical transplants
a) Use in haploidentical transplants, in addition to standard
prophylaxis, has demonstrated acceptable low rates of GVHD,
especially chronic
b) Use as single agent and in combination with other agents
merits further study in MRD and MUD HSCT160
c) A randomized, phase 2 trial in reduced intensity HSCT showed
an improved rate of GVHD‐free, relapse‐free survival in a
tacrolimus, methotrexate, and post‐transplant
cyclophosphamide arm compared to a contemporary control
group that received only tacrolimus and methotrexate (HR
0.72, 90% CI 0.54 – 0.94, P = 0.044).161 A prospective phase 3
trial is currently being conducted.
Select Pivotal Randomized Studies of GVHD Prophylaxis Regimens
Grade II –
Prophylaxis Patients Chronic Overall
Study IV Acute Comments
Regimen (n) GVHD (%) Survival
GVHD (%)
Calcineurin Inhibitor Trials
Ratanathara‐ CSA + MTX 164 44% 56% 57% Myeloablative
thorn et al. 150 MRD conditioning
1998
TAC + MTX 165 32% 49% 47%

MRD
P = 0.01 P = NS P = 0.02
at 2 years at 2 years

Nash et al. 151 CSA + MTX 63 74% 70% 54% Myeloablative
2000 MUD conditioning
Grade II –
GVHD (%)
TAC + MTX 46 56% 78% 50%
MUD
P = 0.002 P = NS at P = NS at
2 years 2 years
Mycophenolate Trials
Bolwell et al. CSA + MMF 21 48% 63% 52% Myeloablative
153
MRD conditioning
2004 MMF
associated with
shorter time to
CSA + MTX 19 37% 64% 68%
neutrophil
MRD
engraftment
P = 0.49 P = NS P = NS at
(11 vs. 18 days)
6 months
and less severe
mucositis
Perkins et al. TAC + MMF 42 78% 38% 54% Mostly
154
MRD myeloablative
2010 MUD conditioning
MMUD MMF
associated with
TAC + MTX 47 79% 45% 42%
less severe
MRD
mucositis;
MUD P = 0.8 P = 0.71 P = 0.58
duration of
MMUD (moderat at 3 years
neutropenia
e or
similar in both
severe at
arms.
1 year)
Sirolimus Trials
Cutler et al. 152 TAC (trough 151 26% 53% 59% Myeloablative
2014 5‐10 ng/mL) MRD conditioing with
+ sirolimus TBI (busulfan
(trough 3‐12 arm closed
ng/mL) early due to
toxicity/ VOD).
TAC (trough 153 34% 45% 63% Trend for more
5‐10 ng/mL) MRD VOD and
and MTX P = 0.48 P = 0.06 P = 0.36 thrombotic
microangio‐
pathy with
sirolimus
Sandmaier et CSA + MMF + 90 26% 49% 64% Nonmyeloablati
al. 162 sirolimus MUD ve conditioning
2019 with
CSA + MMF 77 52% 50% 46%
fludarabine and
MUD
TBI
P = 0.0013 P = 0.74 P = 0.035
at 4 years
Anti‐thymocyte Globulin (ATG) Trials
Grade II –
GVHD (%)
Kroger et al.156 CSA + MTX + 83 10.8% 32.2% 74.1% Myeloablative
2016 ATG‐ MRD conditioning
Fresenius 10 Peripheral
mg/kg IV on blood stem cells
days ‐3, ‐2, ‐1
CSA + MTX 72 18.1% 68.7% 77.9%
MRD
P = 0.013 P < 0.001 P = 0.46
Finke et al.158 CSA + MTX + 103 33% 12.2% 55.2% Myeloablative
2009 ATG‐ MUD conditioning
Socie et al.157 Fresneuis 20 ~80%
2011 mg/kg IV on peripheral
days ‐3, ‐2, ‐1 blood stem cells

CSA + MTX 98 51% 45% 43.3%
MUD
P = 0.011 P < 0.001 P = 0.39
Soiffer et al.159 TAC + MTX + 126 23% 12% 59% Myeloablative
2017 ATG‐ MUD conditioning
Fresneuis 20
mg/kg IV on No difference in
days ‐3, ‐2, ‐1 moderate to
severe cGHVD‐
free survival
between arms
(P = 0.47)

Lower 2‐year
PFS and OS in
ATG arm
CSA = cyclosporine, MMF = mycophenolate, MMUD = mismatched unrelated donor,
MRD = matched related donor, MTX = methotrexate, MUD = matched unrelated donor, TAC = tacrolimus

4. Drug monitoring for medications used to prevent GVHD
a. Cyclosporine and tacrolimus
1) Cyclosporine = 150 ‐ 450 ng/mL; data to suggest low levels (< 200 ‐
300 ng/ml) associated with increased risk of acute GVHD; less data to
correlate levels with toxicity including nephrotoxicity163, 164
2) Tacrolimus = 5 ‐ 20 ng/mL; 5 ‐ 15 ng/mL most commonly used in
clinical practice; levels > 20 ng/mL associated with increased toxicity,
primarily nephrotoxicity. Dose reduction strategies based on levels
and/or serum creatinine.164‐166
a) Target tacrolimus trough levels of 5‐10 ng/mL with
concomitant sirolimus167
3) Dose adjustments for either drug based on nephrotoxicity as
recommended in randomized trials150
a) If creatinine 2 ‐ 2.9 X baseline = at least 25% dose reduction
b) If creatinine > 3 X baseline = at least 50% dose reduction
4) Tapering either medication in patients who do not develop acute
GVHD may be started from day 50‐100 depending on the risk of
relapse. The dose should be reduced by approximately 10% per week
5) Cyclosporine or tacrolimus conversion factors (IV:PO)
a) IV cyclosporine to PO cyclosporine (Sandimmune) = 1:4
b) IV cyclosporine to PO modified cyclosporine (Neoral or
Gengraf) = 1:2‐3
c) IV tacrolimus to PO tacrolimus = 1:3‐4
b. Sirolimus
1) Target trough levels of 3 – 12 ng/mL152, 168
2) Higher levels associated with thrombotic microangiopathy and veno‐
occlusive disease as well as myelosuppression in some studies152, 169,
170

3) Long half‐life (approximately 46 to 78 hours), therefore loading dose
may be considered when starting therapy168
c. Mycophenolate
1) Therapeutic drug monitoring not well established in HSCT
d. Methotrexate (MTX)
1) Standard of care in addition to calcineurin inhibitor167
a) May increase risk for mucositis and pulmonary toxicity
b) May delay time to neutrophil and platelet engraftment (not
as significant with PBSC vs. bone marrow)
2) Dosing
a) 15 mg/m2 IV day 1, 10 mg/m2 IV days 3, 6, 11 established as
standard methotrexate regimen based on randomized trial
(often referred to as short course methotrexate)171
b) 5 mg/m2 IV days 1, 3, 6, + 11 has been evaluated in non‐
randomized studies (often referred to as mini‐
methotrexate)172, 173; overall appears similar to standard dose
methotrexate with less systemic toxicity
c) Assess for dose reduction or elimination on the day each
dose is administered
i. If creatinine > 2 x baseline, transaminases > 200
IU/L, or bilirubin > 5 mg/dL = 50% dose reduction150
ii. If more severe renal or hepatic dysfunction, fluid
third spacing (pleural effusions or ascites), severe
mucositis with threatening airway obstruction –
omit dose150
iii. Leucovorin rescue may be given (not standard of
care) beginning 12 ‐ 24 hrs after MTX x 2‐8 doses;
may ameliorate MTX‐associated toxicities including
delayed engraftment, mucositis; no negative impact
on GVHD or event‐free survival.174, 175 There is no
data to support that leucovorin is helpful in patients
at increased risk for methotrexate toxicity.
5. Manifestations and grading of acute GVHD176
a. Clinical manifestations seen in primarily 3 organs
1) Skin: maculopapular rash, pruritus
2) Gastrointestinal tract: secretory diarrhea, abdominal cramping,
vomiting, nausea, anorexia, dyspepsia
3) Liver: cholestatic hyperbilirubinemia, increased alkaline phosphatase
b. Each organ involved is individually staged from Stage 1 – 4 based on degree and
severity of involvement
c. Staging of each organ is combined to give an overall acute GVHD grade from I
(mild) to IV (life‐threatening)
6. Initial treatment of acute GVHD12, 177‐179
a. First line treatment based on organ involvement and grade
b. Grade I (skin only): topical steroids with continuation or reinitiation of
original immunosuppressive agent
1) Antihistamines as needed for itching
c. Grade II – IV: systemic corticosteroids ± topical steroids with continuation or
reinitiation of original immunosuppressive agent
1) Skin/lower GI/liver: methylprednisolone 1‐2 mg/kg/day (or
equivalent dose prednisone)
2) Upper GI only: methylprednisolone 0.5‐1 mg/kg/day (or equivalent
dose prednisone)
3) Randomized trial in grade II – IV acute GVHD compared 2 mg/kg/day
to 10 mg/kg/day and found no benefit from the higher dose180
4) Complete response rates with durable remission range from 25 to
40%, overall response rate 50 to 65%178
5) Optimal taper schedule has not been defined but factors to be
considered include response, toxicity, and risk for relapse. American
Society of Blood and Marrow Transplant (ASBMT) recommendations
suggest tapering by 0.2 mg/kg/day every 3‐5 days once GVHD
symptoms are under good control; taper should be slowed after the
prednisone dose has been decreased to less than 20‐30 mg/day.178
6) Retrospective data suggests 1 mg/kg/day is similarly effective to 2
mg/kg/day in patients with Grades I‐II GVHD (mostly gut and skin)181;
reduces overall exposure to corticosteroids, produces similar
outcomes with regard to disease control and mortality, and reduces
toxicity (fungal infections and duration of hospitalization). 1mg/kg/day
is recommended for grade II GVHD by British Hematology Guideline179
7) Treatment recommendations from ASBMT suggest initial treatment of
upper GI tract aGVHD with methylprednisolone or prednisone 1
mg/kg/day is reasonable178
d. British Hematology Guidelines suggest ‘nonabsorbable’ steroids (e.g.
beclomethasone or budesonide extended‐release) may be considered for
acute intestinal GVHD in order to reduce the dose of systemic steroids179
1) Budesonide 9 mg orally daily – prospective cohort of patients treated
with budesonide + systemic corticosteroid in stage 2 or higher gut
acute GVHD compared with retrospective cohort182
a) Acute GVHD resolved/no relapse in 77% budesonide group
vs. 32% control (P < 0.01)
2) Beclomethasone 8 mg PO daily ‐ multicenter, randomized trial in stage
1 isolated gut GVHD patients given prednisone 1 – 2 mg/kg/day and
randomized to beclomethasone or placebo183
a) Treatment failure rate at day 50 was primary endpoint and
was not statistically different, but day 80 treatment failure
rate was improved (HR =0.55; P = 0.02)
b) Overall survival at 1 year was 71% in the beclomethasone
group and 58% in the placebo group (HR 0.54; P = 0.04)
c) Drug is not available commercially but is commonly
compounded as 1‐2 mg/mL in corn oil and given as 2 mg PO
four times daily184
e. No additional agent combined in initial therapy with methylprednisolone has
shown benefit, including equine anti‐thymocyte globulin185, basiliximab186,
infliximab187, or mycophenolate188
Answer: C. Methylprednisolone 1 mg/kg IV BID. The most appropriate initial therapy is
methylprednisolone 2 mg/kg/day based on randomized controlled trials. Infliximab added to
methylprednisolone will increase toxicity but not efficacy. Prednisone 1 mg/kg/day represents an
underdose of the required systemic steroid due to the conversion factor between methylprednisolone
and prednisone. Beclomethasone + prednisone may be appropriate for patients with Stage I gut GVHD
alone, but there is no data for patients with both gut and skin GVHD or patients with stage 2 – 4 gut
GVHD.

7. Steroid‐refractory acute GVHD
a. Commonly defined as progression after 3‐5 days of corticosteroid therapy, no
change after 5‐7 days of treatment initiation, or incomplete response after
more than 28 days of methylprednisolone.12, 177, 178 Secondary systemic therapy
may be indicated sooner in patients who do not tolerate high‐dose
glucocorticoids.
b. No standard salvage therapy has been defined as few comparative clinical trials
or prospective case series are available. The available studies often have small
numbers of patients and variable definitions of steroid refractory and response
to therapy. Some reports are of initial therapy after steroids, while others are
after multiple lines of therapy. Use caution when comparing regimens. See
table below for agents with evidence for use.
c. ASBMT and NCCN Guidelines® recommend no specific agent for second line
therapy12, 178, citing lack of comparative studies. The choice of a second‐line
regimen should be guided by the effects of previous treatment(s),
considerations of potential toxicity, interactions with other agents including
those used for prophylaxis, convenience, expense, and prior experience of the
transplant physician/team. Clinical trials should be pursued if available.
d. Ruxolitinib: first FDA‐approved medication for steroid‐refractory GVHD189
1) Mechanism of action
a) Inhibits Janus Associated Kinases (JAK1 and JAK2), decreasing
JAK‐STAT signaling pathways and ultimately decreasing the
development, proliferation, and activation of immune cells
and cytokine production contributing to GVHD
2) Indication and dose
a) FDA‐approved May 24, 2019 for treatment of steroid‐
refractory aGVHD in adult and pediatric patients ≥12 years
of age
b) Approval based on the open‐label, single‐arm, multicenter
REACH1 study results in 71 patients with steroid‐refractory
aGVHD grades II‐IV190
i. 55% overall response rate at day 28, including 27%
complete response
ii. 73% best overall response rate at any time during
treatment, including 56% complete response
c) 5 mg twice daily initial dose, may increase to 10 mg twice
daily after 3 days in the absence of toxicity
i. See table below regarding dose adjustments for
toxicity
ii. Initial dose 5 mg daily for CrCl < 60 mL/min
iii. Dose may be tapered slowly after 6 months in
patients who have successfully discontinued
therapeutic doses of corticosteroids
3) Toxicities
a) Hematologic: anemia (75%); thrombocytopenia (75%);
neutropenia (58%); hemorrhage (49%)
b) Non‐hematologic: infection including bacterial,
mycobacterial, fungal, and viral (55%); edema (51%);
hypertriglyceridemia (11%); fatigue (37%); elevated AST and
ALT (48%)
4) Drug‐drug interactions
a) Substrate of CYP3A4 (primary) and minimally CYP2C9
b) No dose adjustment per package insert for CYP3A4
inhibitors when treating steroid‐refractory aGVHD except
ketoconazole (5 mg daily)

Ruxolitinib Dose Modifications for Toxicity when Treating Steroid‐Refractory aGVHD189
Laboratory Parameter Dose Recommendation
Clinically significant thrombocytopenia after Reduce dose by 1 dose level (e.g. 10 mg twice daily
supportive measures to 5 mg twice daily; 5 mg twice daily to 5 mg daily)
ANC <1 x 10^9/L considered related to Hold for 14 days; resume at 1 dose level lower upon
ruxolitinib recovery
Total bilirubin elevation 3‐5 x ULN: reduce by 1 dose level until recovery
(in absence of liver GVHD) >5‐10 x ULN: hold for up to 14 days until bilirubin
≤1.5 x ULN; resume at current dose upon recovery
>10 x ULN: hold for up to 14 days until bilirubin ≤1.5
x ULN; resume at 1 dose level lower upon recovery
Total bilirubin elevation >3 x ULN: reduce by 1 dose level until recovery
(in presence of liver GVHD)
ANC = absolute neutrophil count, ULN = upper limit of normal

Therapy for Steroid‐Refractory aGVHD12
Organ most
Response
Agent Regimen likely to
Rate
respond
α1‐antitrypsin191 60 mg/kg/day IV every 4 days for CR 35% Skin/gut/liver
up to 4 consecutive weeks/8 doses PR 30%
Alemtuzumab192‐194 10 mg/day x 5 days – higher and 50‐94% Gut/liver
lower doses have been used
Anti‐thymocyte globulin195‐201 10 – 15 mg/kg (equine) QOD x 7‐ 19‐57% Skin
14 days (if using the rabbit
preparation use a dose of 1 ‐ 1.5
mg/kg/dose)
Basiliximab202, 203 20 mg IV daily x 1‐2 consecutive 70‐83% Gut
days, repeated weekly in cases of
persistent GVHD or 20 mg IV on
days 1, 4
Etanercept204 25 mg SQ twice weekly for 4 46% Gut
weeks, then weekly x 4 weeks
Extracorporeal photopheresis ECP on 2 consecutive days at 1‐2 67‐75% Skin and liver
(ECP)205, 206 week intervals until improvement, CR 52‐60%
then every 2‐4 weeks; other
schedules utilized based on
response
Infliximab207‐210 10 mg/kg IV weekly x 3‐ 4 doses 40‐67% Gut or skin
(minimum)
211‐214
Mycophenolate mofetil 1.5 g ‐ 3 g/day 31‐60% Gut
215‐217 2
Pentostatin 1‐1.5 mg/m on days 1 to 3 77‐83% Skin/gut
Ruxolitinib190, 218 5‐10 mg PO twice daily ORR 50‐70% Skin/gut
(Only FDA‐approved agent CR 25‐55%
for steroid‐refractory aGVHD
based on single arm, open‐
label study)
Sirolimus219‐221 Loading dose followed by 57%‐91% Gut or liver
maintenance dose (1‐4 mg/day)
adjusted to target levels of
4‐12 ng/mL
Tocilizumab222‐224 8 mg/kg IV q 2‐4 weeks CR 22‐63% Skin/liver/gut
PR 22‐38%
CR = complete response, ORR = overall response rate, PR = partial response, QOD = every other day

8. Manifestations and grading of chronic GVHD148
a. Time frame: can occur at any point after allogeneic HSCT but typically after
100 days post HSCT (generally between 3 months to 2 years after HSCT, with
2/3 of cases in the first 12 months)225
b. Can present in a multitude of organ systems: skin, nails, mouth, eyes,
genitalia, gastrointestinal tract, liver, lungs, musculoskeletal,
hematologic/immune (see table below)226
c. Often characterized by fibrosis in involved organ(s)
d. National Institutes of Health (NIH) consensus criteria established diagnostic
and distinctive signs to assist diagnosis and classification147
Organ Specific Signs and Symptoms of cGVHD147, 148, 226
Organ Signs / Symptoms
Skin Sclerosis
Erythema
Hypo‐ or hyperpigmentation
Maculopapular rash
Eyes Dry eyes
Photophobia
Keratoconjunctivitis
Mouth Xerostomia
Ulcers
Gingivitis
Erythema
Gastrointestinal Difficulty swallowing
Esophageal strictures
Anorexia
Liver Elevated total bilirubin
Elevated alkaline phosphatase
Fibrosis
Lungs Shortness of breath
Bronchiolitis obliterans
Cryptogenic organizing pneumonia
Musculoskeletal Joint stiffness
Muscle cramps
Decreased range of motion
Hematologic/immune Thrombocytopenia
Hypo‐ or hypergammaglobulinemia

e. Clinical and Global Scoring System for cGVHD147
1) A clinical scoring system (0 – 3) proposed by the NIH Consensus
Development Project enables grading of each individual organ system
and also considers the effect of cGVHD on the patient’s functional
status
2) If the entire abnormality in an organ is noted to be unequivocally
explained by a non‐GVHD documented cause, that organ is not
included for calculation of the global severity
3) If the abnormality in an organ is attributed to multifactorial causes
(GVHD plus other causes) the scored organ will be used for calculation
of the global severity regardless of the contributing causes (no
downgrading of organ severity score)
4) The Global Score considers the number of organs/sites involved and
the severity of clinical scores within those organs/sites to give an
overall rating of mild, moderate, or severe, which dictates
treatment.
f. Measuring therapeutic response227
5) A set of objectives for response has been developed to be used in
GVHD‐related clinical trials. These should be reevaluated every 3
months or whenever a major change in treatment is made.

Patient Case #2, Continued: JN is a 37‐year‐old female with AML who received busulfan and
cyclophosphamide followed by a matched unrelated donor allogeneic HSCT. She received tacrolimus and
methotrexate 15 mg/m2 IV on day 1 and 10 mg/m2 IV on days 3, 6, 11 to prevent GVHD. She was tapered
off all immunosuppression by day + 190. She subsequently developed moderate chronic GVHD involving
her skin and oral mucosa.

Question #6: Which of the following is the most appropriate for JN at this time?
A. Dexamethasone oral rinse and topical triamcinolone
B. Dexamethasone oral rinse, topical triamcinolone and prednisone 1 mg/kg/day
C. Dexamethasone oral rinse, topical triamcinolone and extracorporeal photopheresis
D. Dexamethasone oral rinse, topical triamcinolone, prednisone 1 mg/kg/day and
mycophenolate

9. Initial treatment of chronic GVHD228
a. Indication for treatment: mild disease may be managed with topical therapy.
Moderate to severe cGVHD that involves at least 3 organs or with a score of 2
or greater in any one organ should be considered for systemic therapy. In
some organ sites (mouth, eyes, genital tract), aggressive local therapy alone
may be reasonable.147
b. Consider the presence or absence of high‐risk features (e.g. thrombocytopenia,
progressive onset from acute GVHD, bilirubin > 2 mg/dL) in decision for
systemic vs. local therapy as well as the underlying disease indication for
transplant (malignant vs. non‐malignant disease)229
c. Patients with moderate to severe GVHD will generally require systemic therapy
for at least 1 year229
d. First‐line systemic therapy
1) NCCN Guidelines®: methylprednisolone 0.5‐1 mg/kd/day (or
prednisone equivalent), in addition to continuing or reinitiating
original immunosuppressive agent12
2) ASBMT Guidelines: prednisone 1 mg/kg/day tapering to an every
other day regimen230, 231
3) Prednisone + calcineurin inhibitor
a) May benefit patients with platelet count < 100,000/L230
i. Complete response in 33% of patients receiving
initial therapy
ii. 53% of patients receiving initial therapy survived;
higher than historical control in the azathioprine vs.
prednisone study231; supports combination therapy
for patients with thrombocytopenia
b) Not more effective if platelets are > 100,000/L232
i. TRM was 17% in cyclosporine + prednisone vs. 13%
in prednisone at 5 years, P = 0.11. No difference in
the cumulative incidence of survival, relapse, need
for secondary GVHD treatment, or discontinuation of
immunosuppression.
ii. Survival without recurrent malignancy lower in
combination arm 61% vs. 71%, P = 0.03
iii. Avascular necrosis less in combination 12% vs. 23%,
P = 0.04
4) Other combinations are not beneficial as initial therapy, including,
mycophenolate + calcineurin inhibitor + prednisone233, thalidomide +
cyclosporine + prednisone234, hydroxychloroquine + calcineurin
inhibitor + prednisone235, azathioprine + prednisone231
5) FAM regimen for bronchiolitis obliterans syndrome/BOS (lung
cGVHD)12, 236
a) In addition to systemic corticosteroids, the FAM regimen of
inhaled fluticasone twice daily (or other inhaled
corticosteroid), azithromycin 250 mg 3 times weekly, and
montelukast 10 mg daily was shown to slow progression of
pulmonary function decline in an open label, phase 2 study237
e. Ancillary and supportive care therapies238
1) Due to the refractory nature of cGVHD and the use of prolonged and
high dose immunosuppressant treatments, ancillary and supportive
therapies are paramount to prevent morbidity from cGVHD itself and
treatments of cGVHD
2) Review the NIH Ancillary Therapy and Supportive Care Working
Group Report by Carpenter S et al. (one of recommended readings
for module available at:
http://www.ncbi.nlm.nih.gov/pubmed/25838185), in particular
Table 1
a) Provides organ‐specific recommendations for topical
treatments, infection prevention recommendations, and
other protective measures
10. Steroid‐refractory chronic GVHD
a. There are consensus definitions for response in clinical trials, but they are not
necessarily used to dictate when to modify therapy in clinical practice.
Generally second‐line therapy is considered when:12, 225, 239, 240
1) Progression or development of new clinical manifestations on
prednisone 1 mg/kg/day for 2 weeks
2) No improvement despite treatment for 4‐12 weeks
3) Inability to taper prednisone below 1 mg/kg/day within 3 months or
when symptoms worsen during a taper below 0.5 mg/kg/day
4) Inability to tolerate therapy
b. There is no standard of care (minimal randomized trials have been done, see
table below). Clinical trials should be pursued if available and appropriate.
General considerations include12, 149:
1) History/response with prior therapies
2) Agents with non‐overlapping toxicities
3) Likelihood of response to organ involved
4) History of infectious complications
5) Drug‐drug interactions
6) Patient preference
7) Provider experience
8) Cost

Second‐line Therapy of Chronic GVHD12
Second Line Treatment Response Organ(s) most likely to
Regimen
of Chronic GVHD Rate respond
Extracorporeal Various schedules‐ three times per 60‐70%, CR as Skin is most responsive
photopheresis241‐259 week in week 1, followed by two high as 80% organ, may also be
(randomized study in consecutive days per week in reported. helpful in lung
second line therapy for weeks 2‐12, then twice every Steroid
chronic GVHD)260 month during weeks 12‐24 is sparing effect
common.
Hydroxychloroquine261 800 mg PO daily 53% Skin, oral, and liver

Ibrutinib262 420 mg PO daily 60‐70% Skin, oral, gastrointestinal
(Only FDA‐approved
agent for cGVHD after
failure of 1 or more
lines of systemic
therapy based on
multicenter, open‐label
study) 222
Imatinib263‐267 100 mg PO daily, increase to 400 50‐79% Cutaneous, ocular, and
mg daily if tolerated intestinal GVHD
Mild pulmonary GVHD
may respond, but
moderate and severe are
not likely to respond
Interleukin‐2268 1×106 IU/m2/day 52% Skin and muscle/joints

Mycophenolate 500 mg ‐ 1g PO BID increasing up 40‐57% Gastrointestinal
mofetil211, 213, 214, 269‐275 to 1.5g BID if no initial response or
in some cases based on
therapeutic drug monitoring
Pentostatin276‐279 4 mg/m2 IV every other week x 24 53‐55% **Avoid in pulmonary
weeks GVHD because of high
infection risk
Pomalidomide280 2 mg PO daily PR 56% Skin/oral/eye
Rituximab281‐292 50‐ 375 mg/m2 weekly x 4 – 8 50‐80% Cutaneous or
weeks (meta‐analysis musculoskeletal or
66%) autoimmune cytopenias
Ruxolitinib218, 293 5‐10 mg PO twice daily 78% Skin, liver, lung,
gastrointestinal,
musculoskeletal
Sirolimus294‐296 0.25‐0.5 mg PO daily, titrate to 56‐81% Skin, oral and lower
trough level of 4‐8 ng/mL. gastrointestinal
Loading dose (6‐12 mg) may be
omitted

11. Vaginal cGVHD – Clinical Guidelines for Gynecologic Care after HSCT297
a. Clinical assessment
1) Symptomatic women should be referred to a gynecologist with
experience in GVHD
2) Asymptomatic women should be offered a gynecological exam yearly
3) Yearly gynecological exam should include cervical cytology to assess
for secondary malignancy
4) If treatment of suspected genital chronic GVHD is not successful in 6
– 8 weeks, biopsy should be obtained to avoid incorrect diagnosis
b. Treatment
1) Water only is recommended for genital hygiene; tight clothing and
perfumed products should be avoided
2) Topical estrogen can be used for genital atrophy
3) Topical corticosteroids can be used for rapid control of inflammation
in the setting of genital chronic GVHD
4) Regular intercourse, dilators, and surgery can improve vaginal
narrowing

Answer: B. Dexamethasone oral rinse, topical triamcinolone and prednisone 1 mg/kg/day. The patient
was diagnosed with moderate chronic GVHD involving skin and oral mucosa. Initial therapy should include
both prednisone and topical therapy for both organs. There is no data to indicate extracorporeal
photopheresis could replace prednisone in the first line treatment of chronic GVHD, it would be
appropriate as second line therapy should she not respond to first line therapy. Addition of
mycophenolate in the first line setting as initial therapy has not been shown to be beneficial.

12. Immunosuppressive Agent Toxicity and Drug Monitoring
Immunosuppressive Therapies168, 240, 298‐300
α1‐antitrypsin
Toxicity Generally well‐tolerated
Drug Interactions No known significant interactions
Convenience IV formulation only; dosed at 60 mg/kg twice weekly for 4 weeks
Alemtuzumab
Toxicity Serious and, in rare instances, fatal cytopenia and marrow hypoplasia.
Autoimmune thrombocytopenia and hemolytic anemia have occurred. Higher
incidence of pancytopenia if exceeds single doses >30 mg or cumulative doses
>90 mg per week, which are not recommended, and such doses are unnecessary
to induce profound lymphopenia in GVHD. Prolonged CD4 lymphopenia means
that prophylaxis against Pneumocystis jiroveci pneumonia and herpes virus
infections is advised. Very high risk for viral infections. Weekly PCR monitoring
for EBV, adenovirus, and CMV PCR for at least 6 months after last dose of
alemtuzumab or until absolute lymphocyte count >300 per microliter.
Drug Interactions Not usually clinically significant
Convenience Infusion therapy is given over 2 hours and should not begin at doses >3 mg. If
tolerated, daily doses may increase to 10 mg, but higher doses are not likely to
be necessary for GVHD therapy. The schedule and number of doses for GVHD
therapy is unclear. The overall average half‐life (t1/2) is about 12 days. No longer
commercially available, provided through the Campath Distribution Program free
of charge.
Horse Anti‐thymocyte Globulin
Toxicity Intradermal skin testing advised before the first infusion. Fever 51% and chills
16% (due to release of endogenous leukocyte pyrogens), thrombocytopenia 30%,
leukopenia 14%, and rash 27%. Five to 10 percent of patients experience serum
sickness (lower if premedicated with steroids), dyspnea/apnea, arthralgia, chest,
back, or flank pain, diarrhea, nausea and/or vomiting. Very high risk for viral
infections. Weekly PCR monitoring for EBV, adenovirus, and CMV PCR for at least
6 months after last dose of horse ATG or until absolute lymphocyte count >300
per microliter.
Convenience Intense clinical and vital sign monitoring required; IV infusion only. Regimens
vary for GVHD: 15 mg/kg every other day × 6 doses to 15 mg per kg twice daily ×
5 days

Rabbit Anti‐thymocyte Globulin
Toxicity Skin testing is not considered necessary but must be monitored closely for
anaphylaxis or cytokine release syndrome. Premedication includes
methylprednisolone. Thrombocytopenia and opportunistic infections are
common. Very high risk for viral infections. Weekly PCR monitoring for EBV,
adenovirus, and CMV PCR for at least 6 months after last dose of rabbit ATG or
until absolute lymphocyte count >300 per microliter.
Convenience Intense clinical and vital sign monitoring required; IV infusion only. Variable 4‐ to
7‐dose course with complex schedule for GVHD. It is advisable to start with 0.5
mg/kg for the first infusion and increase to 1‐1.5 mg/kg for subsequent doses
(maximum is 1.5 mg/kg in a given day); total cumulative dose is 6‐7.5 mg/kg.
Basiliximab
Toxicity Hypersensitivity reactions possible although not reported in patients receiving it
for chronic GVHD; bacterial, viral and fungal infections reported
Drug Interactions May increase trough level and toxicity of tacrolimus
Convenience IV formulation only
Cyclosporine
Toxicity Nephrotoxicity, hypertension (generally controlled with non‐dihydropyridine
calcium channel blockers or dose reduction), hypomagnesemia (common; may
be difficult to replete with oral magnesium), tremors of extremities (common,
particularly hands; may limit activity), neurotoxicity (headaches, seizures,
peripheral neuropathy, cortical blindness), hyperkalemia; hyperglycemia,
hirsutism, thrombotic microangiopathy (TMA), allergic reactions (with
intravenous products; related to the diluents)
Drug Interactions Cyclosporine is a substrate for CYP3A4 and P‐glycoprotein so careful attention to
concomitant therapies that interact with CYP3A or P‐glycoprotein is necessary,
including voriconazole and posaconazole.
Convenience Oral and IV formulations available; use modified cyclosporine
Pharmacokinetic monitoring required
Etanercept
Toxicity Risk of infection (viral, fungal, bacterial). Subcutaneous injections are generally
well tolerated.
Convenience Subcutaneous administration given twice weekly for 8 weeks at a dose of 0.4
mg/kg per dose (maximum dose, 25 mg)
Extracorporeal Photopheresis (ECP)
Toxicity Generally well‐tolerated. Blood loss from the extracorporeal circuit,
hypocalcemia due to anticoagulant, mild cytopenia, and catheter‐associated
bacteremia, but overall infection risks do not seem to be increased beyond
standard therapy.
Drug Interactions None
Convenience Requires travel to ECP centers for up to many months. Complex schedule
typically 3 per week (week 1), 2 per week (weeks 2‐12), and 2 per 4 weeks
thereafter.
Glucocorticoids
Toxicity Hyperglycemia, hypertension, insomnia, labile mood, gastritis, osteopenia,
avascular bone necrosis, myopathy, impaired wound healing and secondary
adrenal insufficiency.
Convenience Easy to prescribe

Ibrutinib262
Toxicity Nausea, vomiting, diarrhea, fatigue, rash, bleeding, hypertension, edema,
myelosuppression, second cancers, musculoskeletal pain, infection, atrial
fibrillation, nephrotoxicity
Drug Interactions Ibrutinib is a substrate of CYP3A4 so careful attention to concomitant therapies
that inhibit CYP3A4 is necessary, including azoles. Dose adjustments
recommended for concomitant voriconazole and posaconazole
Convenience Oral formulation only
Imatinib
Toxicity Nausea, vomiting, diarrhea, arthralgia, myalgia, edema, fluid retention,
myelosuppression, rash, hepatotoxicity
Drug Interactions Imatinib is a substrate and inhibitor of CYP3A4 so careful attention to
concomitant therapies that interact with CYP3A4 is necessary, including
cyclosporine, tacrolimus, voriconazole, and posaconazole
Infliximab
Toxicity Generally well tolerated. Anaphylaxis is uncommon. High risk for infections. Very
high risk for viral infections; weekly PCR monitoring for EBV, adenovirus, and
CMV PCR for at least 6 months after last dose of infliximab or until absolute
lymphocyte count >300 per microliter.
Convenience IV formulation only; dosed at 10 mg/kg/week for at least 4 doses
Interleukin‐2
Toxicity Constitutional symptoms (fever, malaise, fatigue), renal dysfunction,
thrombocytopenia
Convenience Daily subcutaneous administration of 1x106 IU/m2
Methotrexate
Toxicity Mucositis, delayed engraftment, hepatotoxicity, pulmonary toxicity and VOD,
myelosuppression
Drug Interactions Penicillin, salicylate, phenytoin, sulfonamides, probenecid, tetracycline,
chloramphenicol (may not be relevant at dosing used for GVHD)
Convenience Oral and IV formulations available
Mycophenolate
Toxicity Dose‐related cytopenia and gastrointestinal toxicity, consider risk: benefit
carefully when treating gastrointestinal GVHD. Enteric‐coated mycophenolic acid
(Myfortic®) may be better tolerated.
Drug Interactions May compound cytopenia when used with other myelosuppressive drugs
Convenience Smallest pill formulations are 250 mg or 180 mg (Myfortic®). IV formulation and
oral suspension are available
Pentostatin
Toxicity Myelosuppression, reversible elevation of liver function test results may occur.
Dose reduction to 0.75 mg/m2 is recommended if creatinine clearance reduced
to between 30 mL/min and 50 mL/min and discontinued if <30 mL/min/1.73 m2.
Stop or withhold therapy for neurotoxicity. Very high risk for viral infections.
Weekly PCR monitoring for EBV, adenovirus and CMV PCR for at least 6 months
after last dose of pentostatin or until absolute lymphocyte count >300 per
microliter.
Convenience IV formulation only and complex schedule: 1.5 mg/m2 on days 1 to 3 and 15 to 17

Pomalidomide
Toxicity Tremors/shakiness, muscle cramps/musculoskeletal pain, fatigue, depression,
anxiety, infection, thrombosis, myelosuppression, hepatotoxicity,
hypersensitivity reactions including skin rash, secondary malignancies, dizziness,
confusion, interstitial lung disease.
Drug Interactions CYP1A2 major substrate
Rituximab
Toxicity Infection, infusion related reaction, late neutropenia/thrombocytopenia
Drug Interactions Not usually clinically significant.
Convenience IV formulation, typically given as 375 mg/m2 IV weekly x 4 weeks
Ruxolitinib 189
Toxicity Hypercholesterolemia, hypertriglyceridemia, myelosuppression, hepatotoxicity,
edema, infection
Drug Interactions Ruxolitinib is a substrate of CYP3A4 so careful attention to concomitant therapies
that inhibit CYP3A4 is necessary, including fluconazole, voriconazole and
posaconazole
Convenience Oral formulation only; may administer through nasogastric tube
Sirolimus
Toxicity Reversible, dose‐related myelosuppression, hypertriglyceridemia, nephrotoxicity,
TMA and neurotoxicity when combined with calcineurin inhibitors. Less common
clinically relevant toxicities are transaminase elevations, edema, arthralgia, and
noninfectious pneumonitis.
Drug Interactions Sirolimus is a substrate for CYP3A4 and P‐glycoprotein. Initial 90% dose reduction
in sirolimus when combining with voriconazole (75% reduction for posaconazole,
25% reduction for fluconazole). Sirolimus may increase the risk for
rhabdomyolysis if used with HMG‐CoA reductase inhibitors. In patients who
develop HUS, calcineurin inhibitor therapy should be stopped, and the dose of
sirolimus should be adjusted to ensure that the trough level <10 ng/mL. In
patients with a serum total bilirubin >2 mg/dL, the sirolimus dose should be
reduced by 30%.
Convenience Oral formulations only: 0.5‐mg, 1‐mg, and 2‐mg tablets as well as a 1‐mg/mL oral
solution. Pharmacokinetic monitoring required.
Tacrolimus
Toxicity Nephrotoxicity, hypertension (generally controlled with non‐dihydropyridine
calcium channel blockers or dose reduction), hypomagnesemia (common; may
be difficult to replete with oral magnesium), tremors of extremities (common,
particularly hands; may limit activity), neurotoxicity (headaches, seizures,
peripheral neuropathy, cortical blindness), hyperkalemia; hyperglycemia,
hyperlipidemia, alopecia, TMA, allergic reactions (with intravenous products‐
related to the diluents).
Drug Interactions Tacrolimus is a substrate for CYP3A4 ‐ reductions are needed, including with
voriconazole and posaconazole
Convenience Oral (0.5 mg, 1 mg, and 5 mg capsules) and IV formulations available
Pharmacokinetic monitoring required
Tocilizumab
Toxicity Hepatotoxicity, hyperlipidemia, infusion related hypersensitivity reactions,
infection, neutropenia, thrombocytopenia, GI perforation
Convenience IV formulations only
Patient Case #2, Continued: JN is a 37‐year‐old female with AML who received cyclophosphamide and
busulfan followed by matched unrelated donor allogeneic HSCT. She received tacrolimus and
methotrexate to prevent GVHD. She was tapered off all immunosuppression by day + 190. She
subsequently developed moderate chronic GVHD involving her skin and oral mucosa and is now
starting prednisone 1 mg/kg/day at day + 240.

Question #7: What is the most appropriate infection prophylaxis for JN at this time?
A. Acyclovir, pentamidine, posaconazole, and penicillin
B. Valganciclovir, pentamidine, fluconazole, and penicillin
C. Valacyclovir, sulfamethoxazole/trimethoprim, voriconazole, and penicillin
D. Acyclovir, sulfamethoxazole/trimethoprim, posaconazole, and penicillin

D. Infection
1. Hematopoietic colony stimulating factors (CSFs)25
a. Autologous
1) Administration of CSFs after autologous HSCT is standard of care to
reduce the duration of severe neutropenia.25 Filgrastim or filgrastim‐
sndz dosing is 5 mcg/kg SQ daily starting between day + 1 and day +5
and continued until ANC is greater than 2‐3 x 109/L25
2) Post‐transplant GCSF is associated with savings in the duration of
hospitalization and overall medical costs301
3) Note most of the data supporting use after autologous HSCT is with
bone marrow, not GCSF‐mobilized peripheral blood stem cells, which
are the current standard stem cell source
b. Allogeneic
1) CSF may be used after allogeneic HSCT to reduce the duration of
severe neutropenia.25 Benefit was shown in patients receiving bone
marrow stem cells, however there are limited data for benefit with
peripheral blood stem cells.302 CSF use is standard of care with cord
blood transplant, but not consistently used for other allogeneic HSCT
patients.
2) Prospective, randomized, placebo‐controlled study in HLA‐identical
bone marrow transplant found improved outcomes in patients
receiving GCSF vs. placebo303
a) Reduced 100‐day non‐relapse mortality (2.9% vs. 11.8%, P =
0.042) in GCSF arm compared to placebo
b) Shorter duration of IV antibiotic therapy (18 vs. 26 days, P =
0.001) and hospitalization (27 vs. 34 days, P = 0.017) in GCSF
arm compared to placebo
c) No difference in grade II‐IV aGVHD (20.3% vs. 23.7%, P = 0.59)
or extensive cGVHD (20.4% vs. 20.7%, P = 0.9) in patients
receiving GCSF compared to placebo
d) No difference in overall survival at 8 years (P = 0.65)
3) Meta‐analysis showed CSFs reduce the rate of documented infection
(RR 0.77 CI 0.64‐0.92, p =0.005) and did not increase the risk of acute
GVHD. Sub‐group analysis showed that patients receiving bone
marrow have reduced rate of documented infection with CSF use, but
patients receiving peripheral blood stem cells do not.302
2. Risk of infection mainly related to time since transplant and presence/absence of
GVHD304

Risk Factors for Infection Based on Impairment of Host Defenses304, 305
Phase of HSCT Impaired host defense as a result of:
Early recovery Neutropenia
Breakdown in oral and gastrointestinal mucosa from chemotherapy
(Pre‐engraftment, or Breakdown in skin barrier (rash, central venous catheter)
conditioning start to Underlying malignancy
around Day 30) Changes in normal microbial flora (due to antibiotic prophylaxis)
Mid recovery Breakdown in mucosal and/or skin barriers due to GVHD
Depressed cellular and humoral immune responses due to recovery of
(2‐3 months post HSCT) donor‐related immune system, immunosuppressive therapy, or aGVHD
Skin barrier compromised by central venous catheter
Late recovery Depressed reticuloendothelial function, functional asplenia due to cGVHD
Persistent depressed cellular and humoral immunity with cGVHD
(> 3 months post HSCT) Immunoglobulin subclass deficiencies
Non‐specific suppressor cells with cGVHD

3. Follow recommendations in global and Infectious Diseases Society of America (IDSA)
guidelines to prevent infection in HSCT patients
a. See antibacterial, Pneumocystis, antifungal, and antiviral prophylaxis tables
below, which summarize recommendations from various guidelines
4. Evidence‐based rating system used in the global HSCT guidelines304
a. Strength of Recommendation ‐ Category Definition
1) A = Both strong evidence for efficacy and substantial clinical benefit
support recommendation for use. Should always be offered.
2) B = Moderate evidence for efficacy—or strong evidence for efficacy,
but only limited clinical benefit—supports recommendation for use.
Should generally be offered.
3) C = Evidence for efficacy is insufficient to support a recommendation
for or against use, or evidence for efficacy might not outweigh adverse
consequences (e.g., drug toxicity, drug interactions), or cost of the
chemoprophylaxis or alternative approaches. Optional.
4) D = Moderate evidence for lack of efficacy or for adverse outcome
supports a recommendation against use. Should generally not be
offered.
5) E = Good evidence for lack of efficacy or for adverse outcome supports
a recommendation against use. Should never be offered.
b. Quality of Evidence Supporting the Recommendation ‐ Category Definition
1) I = Evidence from at least one well‐executed randomized, controlled
trial
2) II = Evidence from at least one well‐designed clinical trial without
randomization; cohort or case‐controlled analytic studies (preferably
from more than one center); multiple time‐series studies; or dramatic
results from uncontrolled experiments
3) III = Evidence from opinions of respected authorities based on clinical
experience, descriptive studies, or reports of expert committees

Antibacterial Prophylaxis
Bacterial prophylaxis per Global Guidelines*304
Day 0 ‐ 100
Strongly consider fluoroquinolone with antipseudomonal activity [levofloxacin
500 mg daily (B1)306 or ciprofloxacin 500 mg BID (BII)] prophylaxis in adult HSCT
patients with anticipated neutropenic period of 7 days or more
Start at time of stem cell infusion and continue until recovery from neutropenia or
initiation of empiric antibacterial therapy for febrile neutropenia
Allogeneic and Monitor for emergence of resistance to fluoroquinolones (AIII)
autologous Alternative prophylaxis option: azithromycin 250 mg daily (CIII)
Addition of anti‐gram‐positive agent to prophylaxis regimen is not indicated (DIII)
Routine gut decontamination is not recommended (DIII)
No recommendation can be made on routine use of colony stimulating factors
(CI). They may shorten duration of neutropenia and may reduce risk of infection
but have no impact on mortality.
Intravenous immune globulin (IVIG) should not routinely be used to prevent
bacterial infection within the first 100 days (DI)
Allogeneic
Consider checking immunoglobulin G (IgG) levels in high risk patients (cord blood
or MUD) and providing IVIG in patients with IgG < 400 mg/dL (CIII)
Day > 100
Prophylaxis against Streptococcus pneumoniae is recommended for allogeneic
recipients with cGVHD as long as active cGVHD treatment is administered and
those with low IgG levels (AIII)
Allogeneic with Antibiotic choice should be guided by local resistance patterns
cGVHD First line preferred regimen: oral penicillin (250‐500 mg BID or 500‐1000 mg daily)
if resistance is not high (AIII)
Alternative prophylaxis options: macrolides, fluoroquinolones, second‐generation
cephalosporin (CIII)
Patients with IgG < 400 mg/dL and bacteremia or recurrent sinopulmonary
Allogeneic and
infections may be considered for IVIG therapy (500 mg/kg q 3‐4 weeks) (CIII)
autologous
Otherwise, routine IVIG prophylaxis is not recommended (DI)
*Global Guidelines include recommendations from the Center for International Blood and Marrow Transplant
Research, the National Marrow Donor Program, the European Blood and Marrow Transplant Group, the American
Society of Blood and Marrow Transplantation, the Canadian Blood and Marrow Transplant Group, the Infectious
Diseases Society of America, the Society for Healthcare Epidemiology of America, the Association of Medical
Microbiology and Infectious Diseases Canada, and the Centers for Disease Control and Prevention304

Pneumocystis Prophylaxis
Pneumocystis jiroveci prophylaxis per Global Guidelines*304
Recommended for all from engraftment until at least 6 months after HSCT, and
Allogeneic longer if patients continue to receive immunosuppressive drugs or have chronic
GVHD (AII)
Consider prophylaxis for patients with certain risk factors: (BIII)
 Underlying hematologic malignancies
 Intense conditioning regimens
 Graft manipulation
Autologous
 High‐dose corticosteroids
 Recent purine analog therapy
Duration of prophylaxis is from engraftment until 3 to 6 months after HSCT, or
longer in patients with ongoing immunomodulatory therapy (CIII)
First line preferred regimen: trimethoprim 80 mg/ sulfamethoxazole 400 mg PO
daily or trimethoprim 160 mg/ sulfamethoxazole 800 mg PO daily or
trimethoprim 160 mg/ sulfamethoxazole 800 mg PO three times per week (AII)
Superior efficacy compared with alternatives
Also protects against Nocardia, Toxoplasma, enteric pathogens, urinary
pathogens, and some respiratory pathogens
Allogeneic and Desensitization is recommended when feasible for patients with allergies (CII)
autologous Alternative prophylaxis options:
 Dapsone 50 mg PO BID or 100 mg PO QD (CII)
 Aerosolized pentamidine 300 mg q 3‐4 weeks (CII) (reported in HSCT with
lowest rates of prevention)307
 Atovaquone 750 mg twice daily or 1500 mg PO daily (CII)
Some recommend prophylaxis for 1‐2 weeks before HSCT (e.g. day ‐14 to ‐2), then
off while neutropenic because of concern for delayed engraftment (CIII)

Antifungal Prophylaxis
Fungal prophylaxis per Global Guidelines*304
Patients at standard risk of fungal infection (yeast [Candida species] prophylaxis)
Prophylaxis recommended for all starting at the beginning or end of the
Allogeneic
conditioning regimen through at least day +75 (AI)
Consider prophylaxis for patients with certain risk factors: (BIII)
 Underlying hematologic malignancies
 Intense conditioning regimens or graft manipulation leading to
Autologous prolonged neutropenia or mucosal damage
 Recent purine analog therapy
Start with conditioning regimen and continue through engraftment or 7 days
after ANC >1000 cells/mm3 (BIII)
First line preferred regimen: fluconazole 400 mg/day PO/IV (AI)
Allogeneic and
Note: If patient is known to be colonized with Candida krusei or glabrata
autologous
fluconazole is not recommended (DI)
Alternative prophylaxis options:
 Fluconazole 200 mg PO/IV daily (BI)
 Itraconazole 200 mg PO twice daily (CI)
 Micafungin 50 mg IV daily (BI)
 Voriconazole 200 mg PO twice daily (BI)
 Posaconazole 200 mg PO TID (BI) [Delayed release tablet 300 mg PO BID
on day 1, followed by 300 mg daily FDA‐approved post guideline
publication]
Patients at high risk for mold infection (Aspergillus, Fusarium, Mucor species) or
fluconazole‐resistant Candida species
Consider mold prophylaxis for patients at high risk: (BI)
 Prolonged neutropenia (higher risk patients include UCB, BM, and
neutropenia prior to transplant [e.g. aplastic anemia])
 Presence of GVHD and treatment for GVHD
First line preferred regimen for prolonged neutropenia: micafungin 50 mg IV daily
Allogeneic (BI)
First line preferred regimen for GVHD: posaconazole 200 mg PO TID (BI)
[Delayed release tablet 300 mg PO BID on day 1, followed by 300 mg daily FDA‐
approved post global guideline publication]
Alternative prophylaxis option: voriconazole 200 mg PO twice daily (BII)
Fungal prophylaxis per IDSA Guidelines308
Prophylaxis recommended for patients at high risk of invasive Aspergillosis
 Hematologic disorders with dysfunctioning neutrophils
 Acute leukemia with repeated or prolonged neutropenia
 History of invasive Aspergillosis prior to transplant
First line preferred regimen: posaconazole (strong recommendation, high‐quality
Allogeneic
evidence)
Primarily based on evidence in acute leukemia and MDS population
 Voriconazole (strong recommendation; moderate‐quality evidence)309
 Micafungin (weak recommendation; low‐quality evidence)
Prophylaxis recommended throughout duration of immunosuppression in
patients with GVHD (strong recommendation, high‐quality evidence)
Allogeneic with First line preferred regimen: posaconazole (strong recommendation, high‐quality
GVHD evidence)
Alternative prophylaxis option: voriconazole (strong recommendation; moderate‐
quality evidence)

Antiviral Prophylaxis
Viral prophylaxis per Global Guidelines*304
Herpes Simplex Virus (HSV) Prevention
Prophylaxis should be offered to all HSV‐seropositive patients from start of
preparative regimen until engraftment or mucositis resolves, around day 30 (AI)
Allogeneic
Routine prophylaxis is not indicated for HSV‐seronegative recipients, even if donor
is seropositive (DIII)
Prophylaxis may be considered for HSV‐seropositive patients who are likely to
Autologous
experience substantial mucositis from conditioning regimen (CIII)
First line preferred regimen: acyclovir 400 mg – 800 mg PO twice daily or 250
mg/m2/dose IV Q12H (AI)
Alternative prophylaxis option: valacyclovir 500 mg PO daily (CIII) or 500 mg PO
Allogeneic and
twice daily in highly immune suppressed patients (BIII)
autologous
Prophylaxis beyond 30 days is not routinely recommended, but acyclovir 800 mg
PO twice daily could be considered in patients with recurrent infections for one
year after HSCT(BIII)
Varicella Zoster Virus (VZV) Prevention
Prophylaxis recommended for one year after transplant for all allogeneic (BI) and
autologous (CII) patients
May consider longer duration of prophylaxis in allogeneic patients with cGVHD or
who are on systemic immunosuppression (BII), including up to 6 months after
discontinuation of immunosuppression (CIII)
First line preferred regimen: acyclovir 800 mg PO twice daily (BI)
Allogeneic and
Alternative prophylaxis option: valacyclovir 500 mg PO twice daily (BII)
autologous
Post‐exposure prophylaxis: give after exposure if < 24 months post HSCT or > 24
months post HSCT and on immunosuppression or have chronic GVHD
first line preferred regimen: varicella‐zoster immunoglobulin (VZIG) 625 units IM
within 48‐96 hrs after close contact with a person who has chickenpox or shingles
or develops a rash after vaccination for varicella zoster virus (AII)
Alternative option: valacyclovir 1 gm TID for 22 days from exposure (CII)
Influenza A and B Prevention
Life‐long seasonal influenza vaccination with inactivated vaccine for all HSCT
candidates and recipients (AII)
Start before HSCT and restart 6 months after HSCT
Prophylaxis and preemptive treatment among HSCT recipients during community
and nosocomial outbreaks of influenza A for patients < 6 months post HSCT (AII)
First line preferred regimens:
 Oseltamivir 75 mg PO twice daily x 5 days (treatment) or 75 mg PO daily
Allogeneic and (prophylaxis) (paucity of data for “double‐dose” oseltamivir in HSCT
autologous patients and cannot be recommended at this time)
 Rimantadine 100 mg PO twice daily (CIII)
 Zanamivir 10 mg inhaled twice daily x 5 days (treatment) or 5 mg inhaled
twice daily x 10‐28 days (prophylaxis)
Alternative option: amantadine 100 mg PO twice daily (CIII)
Influenza chemoprophylaxis is also recommended for all HSCT patients exposed to
influenza < 24 months post‐HSCT or > 24 months HSCT with chronic GVHD or
receiving immunosuppression (BII)
Cytomegalovirus (CMV) Prevention
Either a prophylaxis strategy or preemptive strategy is recommended (AI)
Prophylaxis strategy in allogeneic recipients has demonstrated reduction in CMV
disease but no improvement in survival in at‐risk allogeneic HSCT patients
First line preferred prophylaxis regimen: ganciclovir 5 mg/kg/dose IV twice daily
x 5‐7 days, and then daily through day 100, starting at time of engraftment (AI)
 Letermovir 480 mg IV/PO once daily beginning between day 0 and day
28 post‐HSCT and continuing through day 100 for CMV prophylaxis in
CMV‐seropositive adult allogeneic HSCT patients (*FDA‐approved in
2017, therefore not included in global guidelines)310
o Spectrum of activity limited to CMV
o Dose adjust to 240 mg daily with concomitant cyclosporine
o Similar rates of adverse effects compared to placebo
o Limited data regarding efficacy for treatment of CMV
 Foscarnet 60 mg/kg IV twice daily x 7 days, followed by 90‐120 mg/kg IV
daily until day 100 after HSCT (CIII)
Allogeneic  Acyclovir 800 mg PO four times daily or valacyclovir 2 gm PO three to four
times daily ‐ both provide some reduction in CMV reactivation but no
difference in CMV disease and monitoring is still required (CI)
Preemptive strategy (see treatment section below) is more commonly used to
minimize toxicity
Randomized trial compared valganciclovir prophylaxis to preemptive valganciclovir
900 mg daily and showed no difference in death, CMV disease, or other invasive
infections311
Patients should be screened for presence of CMV approximately weekly from
engraftment through at least day 100 (AIII)
Preemptive therapy should begin if CMV viremia, antigenemia, or DNA is
detected, and should continue for a minimum of 2 weeks (AI)
Preemptive strategy is preferred over prophylaxis in allogeneic CMV‐
seronegative recipients of seropositive donor cells because of the low attack rate
of CMV replication when screened or filtered blood product support is used (BII)
Other methods of CMV prevention include leukoreduction of blood products or use
of CMV seronegative blood products in CMV negative recipient/donor (AI)
Consider preemptive strategy for certain CMV‐seropositive patients from
engraftment through day 60 (CII)
 Conditioning regimen includes TBI
Autologous  Graft manipulation
 Recent purine analogs
Prophylaxis is not recommended in autologous patients (DII)

Answer: D. Acyclovir, sulfamethoxazole/trimethoprim, posaconazole, and penicillin
Acyclovir to prevent VZV as she remains on immunosuppressive therapy; valacyclovir would be an
acceptable alternative, although it has a lower grade of recommendation. Intravenous ganciclovir could
be used for prophylaxis, but valganciclovir should not be used a prophylaxis given it is not more
effective than as preemptive therapy and is more toxic as prophylaxis.
Sulfamethoxazole/Trimethoprim is recommended to prevent PJP; pentamidine could be considered but
is considered less effective and has a narrower spectrum of activity.
Posaconazole has been shown to be superior to fluconazole in the setting of GVHD requiring
corticosteroids. Voriconazole has not been found to be superior to fluconazole in all patients post
allogeneic HSCT. It is not clear if voriconazole would be better than fluconazole or similar to
posaconazole in patients with GVHD requiring corticosteroids. Voriconazole has been shown to
increase the risk for skin cancers in HSCT patients.
Penicillin is recommended to prevent Streptococcus pneumoniae for allogeneic recipients with chronic
GVHD as long as active chronic GVHD treatment is administered and is generally started after
engraftment when broad spectrum agents are discontinued.

5. Treatment of Selected Infections Post HSCT
a. Cytomegalovirus
1) Pre‐emptive Treatment < 100 days post HSCT304
a) Allogeneic: ganciclovir 5 mg/kg (adjust dose for renal
dysfunction) IV every 12 hours x 7 ‐ 14 days at reactivation
of CMV (via PCR or antigenemia), continue with 5
mg/kg/day once daily until the indicator test is negative for
a minimum total induction and maintenance of 2 weeks if
patient received induction for 2 weeks, or 3 weeks if 7 day
induction course was used (AI), may also be continued
through day 100.
b) Autologous: high risk patients should receive therapy if CMV
antigenemia is > 5 cells per slide; CD34+ selected patients are
treated at any level of antigenemia. Ganciclovir 5 mg/kg IV
every 12 hours x 7 days, continue until indicator test is
negative, but a minimum of 2 weeks (BII)
c) Alternatives: Foscarnet 60 mg/kg IV BID induction, 90 mg/kg
daily maintenance, particularly if there is marrow
suppression from ganciclovir (AI). Valganciclovir 900 mg PO
BID induction, 900 mg PO daily maintenance (BII). Cidofovir
induction: 5 mg/kg per week for 2 doses, maintenance: 5
mg/kg every other week (CII)
2) Pre‐emptive Treatment > 100 days post HSCT304
a) Ganciclovir 5 mg/kg IV every 12 hours x 7 ‐14 days, then
daily x 1‐2 weeks or until indicator test is negative [BIII] OR
b) Valganciclovir 900 mg PO BID x 7‐14 days, then 900 mg PO
daily x 1 – 2 weeks or until indicator test is negative (BIII)
c) Note minimum treatment course is 14 days regardless of
drug used
3) Treatment of CMV pneumonia: ganciclovir 5 mg/kg IV every 12 hours
(assuming normal renal function) plus IVIG 500 mg/kg IV QOD x 21
days, followed by maintenance312
a) CMV‐IVIG 150 mg/kg twice weekly may be used, although no
apparent clinical advantage has been shown313, 314
4) Treatment of CMV disease (esophagitis, bone marrow infection with
secondary cytopenias, colitis): ganciclovir 5 mg/kg IV every 12 hours x
14 ‐21 days or until evidence of resolution of the process.
Maintenance may be given for several weeks or longer until
immunosuppression can be reduced.313 Two studies demonstrated
similar bioavailability in patients with mild to moderate gut GVHD for
oral valganciclovir so experts suggest it can be used for maintenance if
there is no severe gut GVHD, symptoms are improved, there is good
oral intake, and systemic CMV viral load is suppressed.
b. Varicella zoster virus
1) Acyclovir 10 mg/kg IV every 8 hours for 7 ‐ 14 days, or 2 days after
cessation of new lesion formation, whichever is longer
2) Can change to oral valacyclovir 1 g TID (if normal renal function) once
no new vesicles are appearing and all existing lesions have crusted
c. Adenovirus
1) Rapid tapering or withdrawal of immunosuppression (AII) ‐ not
always feasible
2) Cidofovir 5 mg/kg IV once weekly or 1 mg/kg 3 times weekly for 2‐4
weeks or until immune recovery if tolerated and effective (BII) or
ribavirin 15 mg/kg PO TID for 4 days, followed by 8 mg/kg TID for up to
10 days (CIII)304
d. Human herpes virus 6
1) Ganciclovir, foscarnet, and cidofovir have demonstrated in‐vitro
activity with limited clinical data304
e. BK Virus
1) Hyperhydration, reduce immunosuppression if possible
2) Insufficient evidence to support preemptive fluoroquinolone or
cidofovir therapy in asymptomatic patients with BK viruria or viremia
(DIII)304
3) Leflunomide was not addressed by the guideline‐ also insufficient
evidence
4) Cidofovir 1 mg/kg IV 3 times weekly or 5 mg/kg/week with or
without probenecid may be used for patients with BK viruria and
hemorrhagic cystitis (CIII)304
f. Respiratory Syncytial Virus (RSV)
1) Aerosolized ribavirin 6 g over 18 hours per day or intermittent 2 g
over 2 to 3 hours every 8 hours x 7 to 10 days – course may be
prolonged in severe lower respiratory infection (LRI) (CIII)304. Inhaled
ribavirin is now prohibitively expensive.
2) IVIG may decrease rate of progression to LRI and reduce mortality
associated with LRI
3) Limited retrospective data supports the use of oral ribavirin, though
many centers use it because of cost of inhaled ribavirin315‐317
4) There is limited data on the use of palivizumab
g. Influenza
1) Anti‐influenza antiviral agents have not been studied in randomized
trials in patients undergoing HSCT and antiviral susceptibilities of
circulating influenza strains must be continually evaluated
2) Oral or inhaled neuraminidase inhibitors are recommended for
asymptomatic viral shedding and URI depending on susceptibility
patterns. Oseltamivir 75 – 150 mg PO BID x at least 10 days for LRI;
IVIG may be utilized in critically ill patients with LRI and acute lung
injury318
E. Sinusoidal Obstruction Syndrome (SOS) / Veno‐Occlusive Disease (VOD)
1. Risk factors319, 320
a. Patient factors: second myeloablative HSCT, prior liver disease (including
elevated transaminases, hepatitis, or cirrhosis), iron overload in thalassemia
patients, primary diagnosis of osteopetrosis, primary hemophagocytic
lymphocytosis or adrenoleukodystrophy, younger age in pediatric patients,
older age, KPS < 90%, metabolic syndrome, genetic factors (GSTM1
polymorphism, C282Y allele, MTHFR 677CC/1298CC haplotype), norethistrone
use, advanced disease (beyond second CR or relapse/refractory)
b. Conditioning regimen: type and intensity of conditioning regimen is probably
the most important risk factor‐ risk increases with TBI dose and radiation
dose rate. High plasma levels of busulfan, oral busulfan, and
cyclophosphamide metabolites are associated with increased risk as well.
c. Prior therapy: exposure to gemtuzumab ozogamicin, inotuzumab, abdominal
irradiation, or hepatic irradiation
d. GVHD regimen: use of sirolimus for GVHD prevention/treatment

2. Diagnosis
a. Can occur at any time after HSCT, but most commonly occurs during first 3
weeks post‐transplant
b. 2 established diagnostic criteria based primarily on clinical criteria: modified
Seattle and Baltimore (see table below)
Comparison of Diagnostic Criteria for SOS321
Modified Seattle Criteria Baltimore Criteria
2 or more of the following within 20 days of HSCT Bilirubin >2 mg/dL within 21 days of HSCT plus at
(in absence of other identifiable causes): least 2 of the following:
 Serum total bilirubin > 2 mg/dL  Painful hepatomegaly
 Hepatomegaly or right upper quadrant pain  Ascites
 Sudden weight gain due to fluid
 Weight gain >5% from pre‐HSCT weight
accumulation (>2% of basal weight)

3. Prevention321, 322
a. Conditioning regimen modification: reduced intensity conditioning regimen,
targeted dosing of IV busulfan to an AUC below 1500 Mol‐min for
myeloablative conditioning regimens using q 6 hour busulfan dosing,
fractionation of TBI
b. Risk‐adjust preparative regimen intensity according to HCT comorbidity index
c. Identify drug‐drug interactions in preparative regimen and modify as
appropriate
d. Avoid use of hepatotoxins during conditioning (e.g. azoles, acetaminophen)
e. Avoid use of progesterone, estrogen if possible
f. Ursodiol: systematic review of ursodiol to prevent VOD – pooled results of 3
randomized clinical trials demonstrated a reduction in VOD with an RR= 0.34
(CI 0.17 – 0.66); TRM was also reduced RR 0.58 (CI 0.35‐0.95).323 There was no
effect on acute GVHD, relapse, or overall survival. Generally given as 12
mg/kg/day in 2‐3 divided doses through at least day + 30, although some report
benefit through day + 80 to 90. Suggested for use by BCSH/BSBMT
Guideline.319
1) 10 year follow‐up of the largest study shows the overall survival
benefit for ursodiol compared with a control group found at 1 year
was maintained long‐term (1 yr = 71% vs. 55%; 10 yr 48% vs. 38%)324
g. Defibrotide: 4 small, retrospective trials reported VOD in 0 to 11% of patients
receiving defibrotide as prophylaxis. Defibrotide is recommended for use by
BCSH/BSBMT Guideline for prevention in patients with selected risk factors.319
h. Other prevention strategies not suggested for use by BCSH/BSBMT
Guideline319, including: pentoxyfylline, antithrombin, prostaglandin E1, and low
molecular weight heparin and heparin
4. Treatment319, 321
a. Sodium and fluid restriction, diuresis, dialysis if needed
b. Avoid further renal and hepatic insults
c. Pain management
d. Defibrotide325
1) Historically controlled, open label, phase III study of adult and
pediatric patients with severe VOD/SOS and advanced multi‐organ
failure (i.e. renal and/or pulmonary dysfunction by day + 28 post
HSCT) enrolled 101 patients and compared with 32 matched
historical controls
2) Primary endpoint: day 100 OS was 38.2% in the defibrotide group
and 25% in the historical control group (P = 0.01); CR rate was 25.5%
in defibrotide group vs. 12.5% in historical control group (P = 0.16)
3) FDA approved dosing is 6.25 mg/kg IV every 6 hours for at least 21
days and a maximum of 60 days (until resolution or hospital
discharge)
e. Methylprednisolone may be considered with caution regarding infection
f. Transjugular intrahepatic portosystemic shunt (TIPS) or hepatic transplantation
g. Treatment not recommended319
1) Tissue plasminogen activator
2) N‐acetylcysteine
F. Transplant Associated Thrombotic Microangiopathy (TA‐TMA)
1. Treatment326: best supportive care; no controlled trials for any intervention
a. Manipulation of GVHD regimen: reducing trough levels of calcineurin inhibitors
or substituting calcineurin inhibitors and mTOR inhibitors for another agent is a
common first‐line intervention in clinical practice327
b. Therapeutic plasma exchange: response rates range from 0 to 80% with most
recent studies in the 40‐ 60% range. The only prospective study had a response
rate of 64% with cyclosporine withdrawal and plasma exchange. Some experts
consider it to be ineffective and not recommended. 328
c. Rituximab, vincristine, defibrotide, and eculizimab have been reported in case
series as salvage therapy with response rates of 69‐80%.329 A small
retrospective study showed overall survival was significantly higher in subjects
treated with eculizumab compared with untreated patients (56% versus 9%,
P = 0.003).330
G. Pulmonary Complications
1. Types of pulmonary toxicities
a. Interstitial pneumonitis (IP) due to infection, including: bacterial, fungal, CMV,
and Pneumocystis pathogens
b. Idiopathic pneumonia syndrome (IPS)331
1) Treatment
a) Methylprednisolone (or equivalent corticosteroid) 2
mg/kg/day x 7 days, then taper per clinical indication
b) Etanercept 0.4 mg/kg (maximum 25 mg) twice weekly for a
maximum of 8 doses may be considered.332 Study closed early
due to slow enrollment and subsequently showed no
difference in 28 day response. Overall survival was not
statistically significantly different (170 vs. 64 days).
c. Diffuse alveolar hemorrhage (considered a subtype of IPS)331, 333
1) Treatment
a) Prompt initiation of high dose corticosteroids (2 mg/kg/day
to 1 g/m2/day)331; lower doses (<250 mg/day) may be
associated with improved outcomes334
b) Limited evidence to support use of recombinant factor VIIa335
d. Periengraftment respiratory distress syndrome (PERDS) (considered a subtype
of IPS)331, 333
1) Treatment: mild cases are managed with supportive care. Strongly
consider discontinuing filgrastim. Severe cases may be managed with
corticosteroids, often 1 mg/kg/day followed by a rapid taper.
e. Bronchiolitis obliterans organizing pneumonia (BOOP) (AKA cryptogenic
organizing pneumonia [COP])331
1) Treatment: prednisone 1 mg/kg/day, tapered over 3‐6 months
f. Bronchiolitis obliterans syndrome (BOS)‐ note this is considered a diagnostic
feature for chronic GVHD147, 236, 331
1) Screening: baseline PFTs within 2 weeks prior to initiating
conditioning chemotherapy, then every 3 months for the first 2
years, then every 6 months thereafter336
2) Treatment236, 336
a) Prednisone 1‐1.5 mg/kg/day, taper gradually over 6‐12
months
b) Consider additional immunosuppression (e.g. calcineurin
inhibitor, imatinib, mycophenolate, MTOR inhibitors)
c) Consider azithromycin 250 mg PO three times per week as
maintenance anti‐inflammatory337
d) Consider high‐dose inhaled corticosteroids (fluticasone 500‐
940 mcg inhaled BID) +/‐ a bronchodilator (based on
improved FEV1 with budesonide/ formoterol)338
e) Anti‐reflux measures (proton‐pump inhibitor)
f) Consider extracorporeal photopheresis
g) Consider montelukast 10 mg daily
h) Initiate appropriate antimicrobial prophylaxis for chronic
GVHD including vaccinations for influenza and pneumococcus
i) Advanced cases may require oxygen, pulmonary
rehabilitation, and/or lung transplantation
H. Renal Complications339
1. Acute kidney injury (AKI)
a. Etiology: conditioning chemotherapy, TBI, nephrotoxic drugs, infection/sepsis,
dehydration, obstruction, tumor lysis syndrome, hepatorenal syndrome from
VOD, TMA/HUS, GVHD
b. Treatment: depending on the etiology may involve appropriate use of fluids,
antimicrobial therapy, discontinuation of offending agents, and management of
the underlying problem leading to AKI340
2. Chronic Kidney Disease (CKD)
a. Treatment: angiotensin converting enzyme inhibitors and angiotensin
receptor blockers can help reduce inflammation and inflammatory markers
and are the treatment of choice for hypertension and chronic kidney
disease340, 341
Patient Case #2, Continued: JN is a 37‐year‐old female with AML who received cyclophosphamide and
busulfan followed by matched unrelated donor allogeneic HSCT. She received tacrolimus and
methotrexate 15 mg/m2 IV on day +1 and 10 mg/m2 IV on days +3, +6, +11 to prevent GVHD. She was
diagnosed with grade II acute GHVD at day +35 and managed with tacrolimus + methylprednisolone.
She subsequently developed moderate chronic GVHD involving skin and oral mucosa. She is now 1 year
post transplant. She is currently receiving prednisone, extracorporeal photopheresis, acyclovir,
posaconazole, penicillin, omeprazole, and sulfamethoxazole/trimethoprim.

Question # 8: What screening and prevention should JN receive for long‐term complications at this
time?
A. Echocardiogram
B. Mammography
C. Colonoscopy
D. Bone mineral density testing
I. Long‐term complications
1. Late Complications – Screening Recommendations339
a. The Center for International Blood and Marrow Transplant Research, American
Society of Blood and Marrow Transplantation, European Group for Blood and
Marrow Transplantation, Asia‐Pacific Blood and Marrow Transplantation
Group, Bone Marrow Transplant of Australia and New Zealand, East
Mediterranean Blood and Marrow Transplantation, and Sociedade Brasileira de
Transplante de Medula Ossea have developed recommended screening and
preventative practices for long‐term survivors after HSCT
1) Review Table 1 in Majhail et al. for recommended long‐term
monitoring and frequency by organ (one of recommended readings
for module available at:
http://www.ncbi.nlm.nih.gov/pubmed/22178693)


Answer: D. Bone mineral density testing. Based on the 2012 guidelines for recommended screening and
preventative practices for long‐term survivors after HSCT, she should receive bone mineral density
testing. She is not due for a mammogram until age 40 (she did not have radiation to the chest). An
echocardiogram is not routine screening and would only be done if indicated based on clinical
presentation. Colonoscopy screening is per normal guidelines and she is less than 50 years old.

2. Ocular339
a. Sicca syndrome (usually part of GVHD; refer to GVHD section for management)
b. Cataracts
1) Surgical management is recommended even if patients have
sicca syndrome
3. Oral339
a. Salivary gland hypofunction may persist, especially in patients with local
irradiation
1) Discontinue medications that cause oral dryness (antidepressants,
antihistamines, diuretics, muscle relaxants, some analgesics,
anticholinergics/antiemetics)
2) Manage symptomatically with artificial saliva and oral rinses, sugar‐
free candies or gum, sialagogues (pilocarpine or cevimeline),
frequent sips of water, and good oral hygiene
4. Cardiac and vascular complications339
a. No specific screening recommendations
b. Hypertension: manage per national guidelines341, 342
1) Screen with blood pressure assessment at every clinic visit and at least
every year343
2) Choice of antihypertensive agent is based on comorbidities,
medication side effect profile, drug interactions. Nonpharmacological
treatments may be tried for mild hypertension
3) Patients on cyclosporine or tacrolimus respond well to treatment
with a dihydropyridine calcium channel blocker (e.g. amlodipine or
nifedipine)
4) Angiotensin‐receptor blockers and angiotensin‐converting enzyme
inhibitors are generally preferred in CKD and diabetes
c. Hyperlipidemia: manage per national guidelines341, 344, 345
1) Assess lipids at 3 months after HSCT. For patients with ongoing risk
factors (including those on corticosteroids) reassess every 3‐6 months.
For standard risk patients, reassess every 5 years in males above 35
years and females over 45 years.343
2) Primary goal: reduction in LDL via lifestyle modifications and lipid
lowering therapy343
3) Sirolimus, tacrolimus, cyclosporine, and corticosteroids increase risk
4) Chronic liver GVHD, nephrotic syndrome, hypothyroidism, and
hypogonadism may contribute to dyslipidemia
5) Most statins (except for pravastatin, rosuvastatin and pitavastatin)
are substrates of CYP3A4 and patients on inhibitors of CYP3A4 (e.g.
cyclosporine and azole antifungals) are at increased risk for toxicity
(e.g. myopathy, elevated LFTs). Consider using a statin not
metabolized by CYP3A4 in those patients. Note all statins are
substrates of hepatic transporter proteins (OATP1B1) which is
inhibited by cyclosporine (but not tacrolimus).
6) High intensity statin not metabolized by CYP3A4
a) Rosuvastatin 20‐40 mg daily
7) Moderate intensity statins not metabolized by CYP3A4
a) Rosuvastatin 5‐10 mg daily
b) Pravastatin 40‐80 mg daily
c) Pitavastatin 2‐4 mg daily
8) If triglycerides > 500 mg/dL, initiate fibrate or nicotinic acid343
d. Diabetes (no established treatment guidelines in HSCT)
1) Screen with oral plasma glucose, 2 hour plasma glucose during an oral
glucose tolerance test or HBA1c every 3 years in adults > 45 years or
with sustained hypertension in standard risk patients. For high risk
patients (e.g. on corticosteroids) screen every 3‐6 months343
2) Goal: HBA1c <7%
3) Lifestyle modifications include weight reduction and increased
physical activity
4) Insulin recommended for short‐term use or medically unstable
patients
5) Sulfonylureas, metformin, and sitagliptin can be used if there are no
major contraindications or drug interactions341
5. Thyroid dysfunction339
a. Manage with thyroid hormone replacement and reassess approximately 6
weeks after start of therapy341
6. Male hypogonadism
a. If low testosterone confirmed on 2 measurements and men have symptoms
of low libido, erectile dysfunction, fatigue, or bone loss they may be initiated
on testosterone replacement titrated to a testosterone level within normal
range and symptom improvement341
7. Primary ovarian insufficiency or failure297
a. Hormone replacement until the age of normal menopause. Estradiol 100
mcg/day by transdermal patch + cyclic medroxyprogesterone 10 mg/day x 12
days/month in women with an intact uterus or a combination oral
contraceptive may be used341
8. Osteoporosis/osteopenia339
a. Prevention346: calcium 1200 mg daily, vitamin D 800‐2000 IU daily with
titration to 25 hydroxyvitamin D level > 30 ng/mL and normocalcemia.
Weight‐bearing physical activity, smoking cessation, and fall prevention are
also recommended. Prophylactic bisphosphonate therapy in patients
receiving corticosteroids is optional as there is no long‐term data to support
that it prevents fractures in HSCT patients.
b. Treatment346, 347: recommended for patients with T scores < ‐1.5 or fractures
1) Calcium and vitamin D recommended as for prevention
2) Bisphosphonate therapy is recommended although the optimal
agent, dose, route, and duration are undefined
3) Hormone replacement may be considered in deficient states
c. Second‐line therapy346
1) Available alternatives have no data for use is HSCT patients and are
thus considered experimental in this setting
a) Teriparatide: contraindicated in patients who have had bone
radiation (e.g. TBI), renal failure, and bone malignancies
b) Raloxifene
c) Denosumab
9. Avascular necrosis346
a. MRI is best for diagnosis of avascular necrosis348
b. Symptom control with analgesics is recommended. Managed with core
decompression for mild to moderate symptoms and joint replacement surgery
for severe symptoms341
10. Secondary Cancers
a. Standardized incidence ratio (ratio of observed cancer cases in a HSCT cohort
compared to expected cancer cases in the general population of similar age
and gender) for cancers with a statistically significantly increased risk of
cancer349
Standardized Incidence Ratio (SIR) for Secondary Cancers after HSCT349
Site SIR
Any skin 7.2
Melanoma 1.4‐8.3
Thyroid 5.8‐6.6
Mouth/pharynx 7‐16
Lip 19‐27
Tongue 9.3‐20
Oral cavity 7.3‐17
Salivary gland 14‐23
Gum 5.1‐13
Esophagus 8.5‐11
Liver 6.3‐28
Brain/nervous system 3.8‐9.5
Bone 8.5‐13
Connective tissue 6.5‐8

b. Screening Guidelines: follow cancer screening guidelines for the general
population except for the following349:
1) Skin: routine skin exam
2) Thyroid: annual physical exam
3) Oropharyngeal: oral exam every 12 months (6 months if risk factors)
4) Esophagus: upper GI endoscopy for patients with persistent GERD or
dysphagia, especially in those with immunosuppressive therapy > 24
months
5) Breast: for patients with prior chest radiation or TBI, start screening
at age 25 or 8 years after radiation (whichever comes first), but no
later than age 40; annual clinical breast exam, annual mammogram
and annual breast MRI
6) Cervix: annual Pap test and HPV DNA test
J. Vaccination of HSCT recipients350
1. Antibody titers to vaccine‐preventable diseases decline in the 1‐10 years after HSCT
2. Studies demonstrate allogeneic HSCT patients develop immunogenicity to vaccines and
they are safe to use, but there is limited data regarding efficacy against disease
development
3. While there is variability in immunodeficiency, immune recovery, and vaccine
immunogenicity among autologous, allogeneic, umbilical cord blood, reduced intensity
conditioning, patients with T‐cell depleted grafts and chronic GVHD, the same
vaccination schedule (with a few exceptions – see table below) for all HSCT patients is
recommended until additional data are published
4. Patients with active GVHD or ongoing immunosuppression should not receive live
vaccines; it may be prudent to measure vaccine antibody titers after vaccination to
determine level of protection and need for booster immunization
5. Pre‐transplant vaccination351
a. HSCT donor
1) Should be current with vaccines based on CDC annual schedule
2) Avoid administration of live MMR, MMRV, VAR and ZOS vaccines
within 4 weeks of stem cell harvest
3) Vaccination of the donor for the benefit of the recipient is not
recommended
b. HSCT recipient
1) Vaccinate based on CDC annual schedule if they are not already
immunosuppressed and when the interval to the start of the
conditioning regimen is ≥4 weeks for live and ≥2 weeks for inactivated
vaccines. This is based on persistent immunity for several months after
HSCT if titers were adequate.
6. Post‐transplant vaccination350‐352
a. In general, treat a post‐transplant patient as one who has never received
vaccination
b. No difference in autologous and allogeneic HSCT patients except where noted
related to immunosuppression or GVHD
c. Follow post‐transplant vaccination schedule recommendations from the 2009
and 2013 IDSA guidelines and expert opinion when limited data is available
(see table below)

Summary of Post‐transplant Vaccination Schedule Recommendations350‐352
Inactivated Vaccine Recommended Earliest Post‐transplant Comment
Number of Doses Initiation
DTaP, DT, Td, Tdap 3 6 months DTaP preferred for all ages
(although only approved for
age <7 years), with others as
alternatives if dictated by
insurance
Haemophilus influenzae b 3 3 months
conjugate
Hepatitis A 2 6 months
Hepatitis B 3 6 months Consider high dose vaccine
unless ≥ 6 months without
immunosuppression
Human papillomavirus 3 6 months Per 2013 IDSA guidelines, for
patients aged 11 – 26 years
Influenza (inactivated) 1 dose annually 4 months 2 doses one month apart
should be given to children 6
months – 8 years who are
receiving the vaccine for the
first time
Meningococcal conjugate 2 for patients 6 months Consider vaccinating all HSCT
aged 11 – 18 years recipients regardless of age,
as chronic GVHD is a
functionally
immunodeficient state
Pneumococcal conjugate 3 3 months A fourth dose can be given
(PCV13) to patients with chronic
GVHD 12 months after HSCT
instead of PPSV23
Pneumococcal polysaccharide 1 12 months
(PPSV23)
Polio 3 3 months
Zoster (inactivated) Unknown Unknown No current
recommendations
Live Vaccine Recommended Earliest Post‐transplant Comment
Number of Doses Initiation
Influenza (live attenuated) Contraindicated NA
Measles, mumps & rubella 2* 24 months *Administer only if measles
seronegative, ≥24 months
since HSCT, no GVHD, and no
current immunosuppression.
Consider waiting until ≥8
months since last IVIG dose.
Measles, mumps, rubella, Contraindicated NA
varicella
Rabies May be given for Any time
potential
exposure
Rotavirus Contraindicated NA
Varicella 2* 24 months *Administer only if varicella
seronegative, ≥24 months
since HSCT, no GVHD, and no
current immunosuppression.
Consider waiting until ≥8
months since last IVIG dose.
Yellow fever May be used for Unknown Limited safety and efficacy
patients residing data.
or traveling to
endemic areas.
Zoster (live) Contraindicated NA
DTaP = diphtheria toxoid, tetanus toxoid, acellular pertussis; DT = diphtheria toxoid, tetanus toxoid; Td = tetanus
toxoid, reduced diphtheria toxoid; Tdap = tetanus toxoid, reduced diphtheria toxoid, and reduced acellular pertussis

RECOMMENDED READINGS AND RESOURCES

1. https://bethematchclinical.org/Resources‐and‐Education/Education‐Courses‐and‐Events/Curriculum/ [BMT
Curriculum by the National Marrow Donor Program that is free after you register ‐ these are videos that
teach the basics of HSCT designed for physicians to use to teach medical students doing a BMT elective.
They are well done and helpful if you are new to BMT.]
2. Giralt S, Costa L, Schriber J et al. Optimizing Autologous Stem Cell Mobilization Strategies to Improve Patient
Outcomes: Consensus Guidelines and Recommendations. Biol Blood Marrow Transplant. 2014; 20:295‐308.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/24141007
3. Carpenter PA, Kitko CL, Elad S et al. National Institutes of Health Consensus Development Project on Criteria
for Clinical Trials in Chronic Graft‐versus‐Host Disease: V. The 2014 Ancillary Therapy and Supportive Care
Working Group Report. Biol Blood Marrow Transplant 2015; 21:1167‐1187. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25838185
4. Tomblyn M, Chiller T, Einsele H et al. Guidelines for preventing infectious complications among
hematopoietic cell transplant recipients: a global perspective. Bone Marrow Transplant. 2009; 15:1143‐238.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/19861977?dopt=Citation
5. Majhail NS, Rizzo JD, Lee SJ et al. Recommended Screening and Preventive Practices for Long‐Term Survivors
after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2012; 18:348‐71. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22178693
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