1198 CHAPTER 178  Hematopoietic Stem Cell Transplantation

178 
HEMATOPOIETIC STEM CELL
TRANSPLANTATION
ARMAND KEATING AND MICHAEL R. BISHOP

INTRODUCTION
Hematopoietic stem cell transplantation (HSCT) is a procedure by which
hematopoietic stem cells (HSCs) are infused intravenously to restore hema-
topoiesis and immune function after high-dose chemotherapy with or
without radiation therapy. Stem cells used for HSCT are of hematopoietic
origin, in contrast to the more primitive pluripotent stem cells (embryonic
stem cells), which are of growing interest for use in regenerative therapy
because of their ability to differentiate into virtually any somatic cell. The
term HSCT has replaced the term bone marrow transplantation because HSCs
can be derived from a variety of sources, including bone marrow, the periph-
eral blood, and umbilical cord blood. In addition to treating blood cancers
and other malignancies, HSCT can also provide clinically significant enzyme
replacement. HSCs can give rise to all blood elements and may be genetically
modified to enhance their function. Furthermore, HSCs may be manipulated
ex vivo and used in the burgeoning field of regenerative medicine. Taken
together, HSCT is a major component and foundation of the broader field of
cellular therapy, which many believe forms the “third pillar” of medicine,
complementing small molecule drugs and biologic agents.
The clinical development and application of HSCT originated in the
observations of the severe myelosuppressive effects of radiation among sur-
vivors of the Hiroshima and Nagasaki nuclear bombings. There were inten-
sive research efforts over the subsequent decade to develop methods to
protect against and reverse the myelosuppressive effects of radiation, includ-
ing the infusion of bone marrow. These efforts were primarily hindered by
graft rejection. Among animals that did not reject their marrow grafts, a
syndrome of weight loss, alopecia, diarrhea, and eventually death, referred to
as “runting” disease, was commonly observed. This syndrome is now referred
to clinically as graft-versus-host disease (GVHD) and is discussed in more
detail later in this chapter. The subsequent determination and understanding
of the major histocompatibility complex (MHC) and human leukocyte anti-
gens (HLA), the major determinants of graft rejection, and of GVHD,
enabled HSCT to be clinically applied. The first successful reports of clinical
bone marrow transplantation, used for patients with severe combined immu-
nodeficiency disorders, severe aplastic anemia, and advanced acute leuke-
mias, occurred in the late 1960s and early 1970s. Subsequently in the 1980s,
it was demonstrated that the administration of high-dose chemotherapy fol-
lowed by HSCs obtained from the bone marrow or peripheral blood of the
patients themselves improved outcomes and survival of patients with a

Downloaded for IKAD PPDS (ikadppdsfkusu@gmail.com) at Universitas Sumatra Utara from ClinicalKey.com by Elsevier on April 13, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 CHAPTER 178  Hematopoietic Stem Cell Transplantation
variety of hematologic and solid tumors. HSCT is a standard treatment
option for many malignancies, immunodeficiency states, metabolic disorders
(e.g., Hurler syndrome), and defective hematopoietic states (e.g., severe
aplastic anemia, thalassemia).
The three types of HSCT are allogeneic, autologous, and syngeneic. HSCs
obtained from someone other than the patient are referred to as allogeneic,
while HSCs obtained from the patient are referred to as autologous. In syn-
geneic HSCT, patients receive HSCs from an identical twin, a relatively rare
event (<1%). The determination of the type of HSCT that a patient receives
(i.e., allogeneic vs. syngeneic vs. autologous) is based on the disease to be
treated, disease state (e.g., initial treatment vs. treatment of recurrent disease),
the urgency to treat with HSCT, availability of a donor, and urgency in
obtaining a donor.
As previously mentioned, HSCs may be obtained from the bone marrow,
the peripheral blood, and umbilical cord blood. HSCs can be obtained
directly from bone marrow by serial aspirations from the posterior iliac crests
while the patient is under general anesthesia. Alternatively, HSCs can be
obtained from peripheral blood after stimulation of the donor with hemato-
poietic growth factors such as granulocyte colony-stimulating factor (G-CSF)
and plerixafor followed by leukapheresis. HSCs from bone marrow are used
in both autologous and allogeneic HSCT, although less frequently than in the
past. Peripheral blood HSCs are currently used in approximately 90% of
autologous HSCT and in approximately 70% of allogeneic HSCT. The greater
use of peripheral blood HSCs is related to their relative ease of procurement
and moderate advantage in the rate of hematopoietic recovery after infusion
compared with HSCs derived from bone marrow, but the outcomes of the
two approaches are similar. A1  The HSCs may be infused fresh or cryopre-
served. Cryopreservation involves processing the cells in culture medium
containing dimethyl sulfoxide (DMSO), placing them in specialized plastic
bags, and then storing the cells indefinitely in the vapor phase of liquid nitro-
gen until needed. Cord blood HSCs are collected at the time of delivery,
cryopreserved, and stored. For allogeneic donation, HSCs may also be
infused on the day of collection. For autologous donation, HSCs are always
cryopreserved.
ALLOGENEIC HEMATOPOIETIC STEM
CELL TRANSPLANTATION
The distinctive characteristics of allogeneic HSCT are that the stem cell graft
is free of contamination by malignant cells and contains lymphocytes, pri-
marily T and natural killer (NK) cells that are capable of mediating an immu-
nologic reaction against foreign antigens.1 This latter characteristic can be a
major advantage if the immunologic response is directed against malignant
cells, referred to as the graft-versus-leukemia or graft-versus-tumor effect,
which can potentially eradicate disease and reduce the chance of disease
relapse. However, if the immunologic response is directed against antigens
present on normal tissues, the graft-versus-host response, the destruction of
normal organs can result and is described clinically as GVHD. The risk of
both graft rejection (host-versus-graft reaction) and GVHD rises with the
degree of HLA disparity between the donor and the recipient.
The graft-versus-leukemia effect first was recognized in animal models and
subsequently was noted among patients undergoing allogeneic HSCT for
acute and chronic leukemias. The clinical importance of the role that immu-
nocompetent donor T cells play in mediating a graft-versus-leukemia effect
was provided by initial observations of increased rates of relapse in patients
who received allogeneic stem cell grafts from which T cells had been removed
(T-cell depletion), an inverse correlation between relapse and severity of
GVHD, and increased rates of relapse after syngeneic or autologous HSCT
using the same myeloablative conditioning regimen. These data suggested
that T cells within the allograft were involved directly in eradicating leukemia.
Finally, the most compelling evidence for the importance of T cells mediating
the graft-versus-leukemia effect arose from the clinical observation that infu-
sion of allogeneic T cells alone, termed a donor lymphocyte infusion (DLI),
at a time remote from the transplant conditioning regimen, successfully
eradicated leukemia which had persisted or recurred after allogeneic HSCT.
However, there is wide variability in the clinical effectiveness of the graft-
versus-leukemia effect against different malignancies after allogeneic HSCT.
Sources of Donor Hematopoietic Stem Cells
As previously emphasized, HSCs are obtained from a donor other than the
recipient or an identical twin in allogeneic HSCT. Because of the immuno-
logic barriers that can result in graft rejection and GVHD, allogeneic HSCT
requires that the donor and the recipient share key genes. The most important
Downloaded for IKAD PPDS (ikadppdsfkusu@gmail.com) at Universitas Sumatra Utara from ClinicalKey.com by Elsevier on April 13, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
1199
of these are HLA, which are derived from the MHC located on chromosome
6. The most important HLAs include HLA-DR, HLA-DP, and HLA-DQ
loci. A single set of MHC alleles, described as a haplotype, is inherited from
each parent, resulting in HLA pairs. A clinical “match” means that HLA in
the donor match perfectly with those in the patient.
The choice of donor for an allogeneic HSCT takes into account several
factors, including the patient’s disease, disease state, and urgency in obtaining
a donor. A fully HLA-matched sibling is the preferred donor source because
of the sibling’s availability and the observation that the risks of graft rejection
and GVHD are lowest with these allogeneic HSCs. The probability of having
a HLA match from a sibling is approximately 25% and increases with the
number of siblings within a specific family. The probability can be estimated
using the following formula: chance of having an HLA-matched sibling = 1
- (0.75)n, where n is the number of potential sibling donors. There is approxi-
mately a 1% chance of a crossover event (i.e., genetic material switched
between chromosomes during meiosis), primarily between the HLA-A and
the HLA-B loci. The clinical outcomes for allogeneic HSCT using a sibling
with a single HLA mismatch are similar to those with a fully HLA-matched
sibling.
For patients who lack an HLA-identical sibling donor, the alternative
sources for allogeneic HSCs include a fully HLA-matched volunteer unre-
lated donor, a fully or partially HLA-matched cord blood unit, or a partially
HLA-matched first-degree family member. The genes encoding HLAs are
numerous, and the odds that any two unrelated individuals are HLA identical
for main loci are less than one in 10,000. More than 22 million volunteer
donors are available worldwide; a donor can be found for about 50% of
patients for whom a search is initiated. The probability of identifying a suit-
able volunteer is highly dependent upon race because of varying degrees of
HLA diversity. For example, for persons of northern European extraction, the
probability of a match can be as high as 90%. It usually takes about 2 to 4
months to locate an unrelated donor, which may be too long for some patients
with rapidly progressive malignancies. When a suitable volunteer is not avail-
able or a donor is needed more urgently, HSCs from alternative donors can
be considered, including partially HLA-matched (“haploidentical”) relatives
or umbilical cord blood. Haploidentical HSCs are readily available but have
increased risks of graft rejection and GVHD. These risks can be reduced by
T-cell depletion methods but lead to delayed immune reconstitution and
competency posttransplant, leading to increased risks of infection and disease
recurrence. Umbilical cord blood HSCs are taken at the time of delivery,
stored in cord blood banks, and are readily available when needed.2 Because
of the unique immature biology of lymphocytes in umbilical cord blood,
these transplants are associated with less GVHD; consequently, the HLA
matching requirements are less strict, and two or three HLA mismatches may
be acceptable. However, the small volume (50-150 mL) of cord blood that
can be collected results in a limited number of HSCs, which often prohibits
their use in adults because successful engraftment correlates with the number
of HSCs per patient body weight. The limitation of cell dose can be overcome
by the use of more than one cord blood unit. Cord blood HSCs are associated
with delayed times to engraftment and immune reconstitution leading to an
increased rate of infection. The other significant disadvantage is that after the
cord blood unit is used, there is no possibility to obtain additional cells in the
event of graft failure or if a DLI is required.
Conditioning and Preparation of Recipient
After an allogeneic stem cell source has been identified, the recipient patients
then receive regimens with the intent of “conditioning” or “preparing” them
for the infusion of HSCs (Fig. 178-1). These conditioning regimens are
designed to be adequately immunosuppressive to overcome the host-versus-
graft reaction and permit engraftment. They also are designed for tumor
eradication in patients with an underlying malignancy. Most conditioning
regimens use a combination of radiation and chemotherapy. Doses of total
body and total lymphoid irradiation vary between 200 and 1440 cGy. The
most commonly used chemotherapy agents in conditioning regimens are
alkylating agents (e.g., cyclophosphamide). Conditioning regimens also may
contain monoclonal antibodies that target T cells (e.g., alemtuzumab). The
choice of a specific conditioning regimen depends on the disease that is being
treated. The doses of chemotherapy and radiation used in these regimens are
highly variable. When the doses result in a degree of myelosuppression and
immunosuppression that is nearly universally fatal without the infusion of
HSCs as a rescue product, they are referred to as “myeloablative.” Allogeneic
HSCT with myeloablative conditioning regimens has been performed suc-
cessfully in patients older than 60 years of age; however, survival after these
1200 CHAPTER 178  Hematopoietic Stem Cell Transplantation
 

Allogeneic hematopoietic stem cell transplantation

Conditioning
(a.k.a. Preparative
regimen) Stem cell infusion GVHD Prophylaxis
1 2 3

Chemotherapy
Immunosuppressants

Radiation

Donor

FIGURE 178-1.  The process of allogeneic hematopoietic stem cell (HSC) transplantation. (1) The patient receives a conditioning regimen of chemotherapy or radiation therapy
(or both) that is used to both eliminate the underlying malignancy and suppress the immune system to prevent rejection of the allogeneic HSCs. (2) Allogeneic HSCs are then collected
directly from the bone marrow or from the blood of a related or unrelated stem cell donor and infused intravenously into the donor. (3) After the infusion of the HSCs, the patient
receives immunosuppressant drugs to help prevent the development of graft-versus-host disease (GVHD).

transplants declines with increasing age, limiting the application of allogeneic

transplantation to a minority of patients who potentially could benefit from TABLE 178-1  CLASSIFICATION OF PATIENTS WITH ACUTE
this procedure. However, the demonstration that an immune-mediated graft- GRAFT-VERSUS-HOST DISEASE
versus-leukemia effect plays a central role in the therapeutic efficacy of allo-
CLINICAL STAGING
geneic HSCT led to the hypothesis that myeloablative conditioning regimens
were not essential for tumor eradication. This idea subsequently led investiga- STAGE SKIN LIVER GUT
tors to develop less intensive conditioning regimens, which were adequately + Rash <25% BSA Total bilirubin, Diarrhea, 500-1000 mL/day
immunosuppressive to permit the engraftment of donor HSCs but were asso- 2-3 mg/dL
ciated with decreased toxicities compared with myeloablative regimens. ++ Rash 25%-50% BSA Total bilirubin, Diarrhea, 1000-1500 mL/day
These “nonmyeloablative” and “reduced-intensity” conditioning regimens 3-6 mg/dL
increase the potential option of allogeneic HSCT for older patients and +++ Generalized Total bilirubin, Diarrhea >1500 mL/day
patients with preexisting comorbidities. However, the reduced doses in radia- erythroderma 6-15 mg/dL
tion and chemotherapy result in decreased antitumor activity and are associ-
++++ Desquamation and Total bilirubin Pain with or without ileus
ated with higher rates of disease recurrence after transplant. bullae >15 mg/dL
CLINICAL GRADING STAGE
Graft-Versus-Host Disease
After engraftment has occurred, patients are at risk for the development of GRADE SKIN LIVER GUT PS
GVHD, which represents the most important clinical challenge with alloge- 0 (none) 0 0 0 0
neic HSCT. GVHD is described as either acute, generally presenting within I + to ++ 0 0 0
the first 100 days after transplant, or chronic, generally presenting after the
first 100 days after transplant. However, clinical features of both acute and II + to +++ + + +
chronic GVHD may be observed at any time point after allogeneic HSCT. III ++ to +++ ++ to +++ ++ to +++ ++
Current opinion holds that clinical manifestations rather than time after IV ++ to ++++ ++ to ++++ ++ to ++++ +++
transplantation determine whether the clinical GVHD syndrome is consid-
BSA = body surface area; PS = performance status.
ered acute or chronic. The broad category of acute GVHD includes “classic”
acute GVHD, occurring within 100 days after transplantation or DLI and
“persistent,” “recurrent,” or “late” acute GVHD, occurring beyond 100 days
after transplantation or DLI. Risk factors for acute GVHD include HLA firmation can be valuable in excluding other possibilities such as infection.
mismatch, a female donor (particularly a multiparous donor), more advanced Mild GVHD of the skin may demonstrate vacuolar degeneration and infiltra-
age in the patient and the donor, and cytomegalovirus (CMV) seropositivity tion of the basal layer by lymphocytes. With more advanced disease, histo-
of the donor or patient, use of an unrelated donor or the use of a T cell– logic findings of necrotic dyskeratotic cells with acantholysis may progress to
replete versus T cell–depleted graft. frank epidermolysis. In the liver, early GVHD may be difficult to distinguish
Acute GVHD can often be diagnosed on the basis of clinical findings and from hepatitis of other causes. A clinical grading system (Table 178-1) cor-
is manifest by symptoms in several organ systems, but it primarily affects the relates with clinical outcome. Severity is described as grade I (mild) to grade
skin, gastrointestinal tract, and liver. The skin manifestations range from a IV (severe).
maculopapular rash to generalized erythroderma or desquamation. The The best therapy for GVHD is prophylaxis.3 The prophylactic use of a
severity of gastrointestinal GVHD is based on the quantity of diarrhea per calcineurin inhibitor (e.g., cyclosporine, tacrolimus) in combination with
day, and the severity of liver GVHD is scored on the basis of the bilirubin methotrexate is effective in reducing the incidence of acute GVHD as well as
level. Organs may be involved in isolation or simultaneously. Histologic con- improving the survival of transplant patients and is the most commonly used

Downloaded for IKAD PPDS (ikadppdsfkusu@gmail.com) at Universitas Sumatra Utara from ClinicalKey.com by Elsevier on April 13, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 CHAPTER 178  Hematopoietic Stem Cell Transplantation
form of GVHD prophylaxis. Cyclosporine is a cyclic polypeptide that pre-
vents T-cell activation by inhibiting interleukin-2 (IL-2) production and IL-2
receptor expression. Although effective as GVHD prophylaxis, cyclosporine
imparts significant toxicities, including hypertension, nephrotoxicity, hypo-
magnesemia, a risk for seizures, hypertrichosis, gingival hyperplasia, tremors,
and anorexia. Tacrolimus is a macrolide lactone that closely resembles cyclo-
sporine in mechanism of action, spectrum of toxicities, and pharmacologic
interactions. The combination of tacrolimus and methotrexate was demon-
strated to be superior to cyclosporine and methotrexate in reducing grade II
to IV acute GVHD when used as prophylaxis. For allogeneic HSCT, prophy-
lactic immunosuppression is not lifelong; when immunologic tolerance is
established, immunosuppressive agents can be slowly withdrawn and discon-
tinued. The incidence of clinically significant GVHD (grades II-IV) in recipi-
ents of HLA-matched sibling grafts (T-cell replete) using tacrolimus and
methotrexate for GVHD prophylaxis is approximately 30% to 40%. The inci-
dence of grade II to IV GVHD in recipients of HLA-matched unrelated
donor grafts is approximately 50% to 80%. Another strategy to prevent
GVHD is to deplete the donor’s T cells from the graft; the disadvantage of
this approach is its association with increased rates of disease relapse and
infection, and overall survival does not seem to be improved.
Moderate to severe GVHD (grades II-IV) requires treatment; the mainstay
of therapy is corticosteroids. Methylprednisolone at a dose of 1 to 2 mg/kg/
day achieves responses in 40% to 60% of patients. Higher doses of steroids
are not of greater benefit. Steroid-refractory GVHD responds poorly to
second line therapies such as antithymocyte globulin or various monoclonal
antibodies (e.g., daclizumab, infliximab) and are associated with increased
mortality rates. In general, whereas acute GVHD of the skin is most respon-
sive to treatment, GVHD of the liver is least responsive. The fatality rate for
acute GVHD may be as high as 50%.
Chronic GVHD occurs in 20% to 50% of long-term survivors. Chronic
GVHD occurs most commonly between 100 days and 2 years from the
transplant and has polymorphic features similar to a number of autoimmune
diseases. Chronic GVHD is classified as either classic chronic GVHD, which
consists only of manifestations that can be ascribed to chronic GVHD or
acute and chronic GVDH overlap syndrome, in which features of both acute
and chronic GVHD appear together. These distinctions are clinically relevant
as “late-onset” acute GVHD and overlap syndrome subsets have been associ-
ated with poor survival rates in some studies. Chronic GVHD is most likely
to develop in older patients who also had acute GVHD or received peripheral
blood rather than bone marrow grafts. In 20% of cases, there is no history of
prior acute GVHD. Adverse prognostic factors include thrombocytopenia, a
progressive clinical presentation, extensive skin involvement, and an elevated
bilirubin. Common manifestations include the sicca syndrome, lichen
planus–like skin rash, scleroderma-like skin changes, esophageal and intesti-
nal fibrosis, obstructive lung disease with or without pneumonitis, and ele-
vated alkaline phosphatase with or without hyperbilirubinemia. Underlying
immunologic deficiencies, including hypogammaglobulinemia, are common,
placing patients at increased risk for infectious events.
Historically, chronic GVHD has been considered as limited or extensive.
Whereas limited disease implies localized skin involvement with minimal or
no liver involvement, extensive disease suggests generalized skin involvement
with or without other organ involvement. This classification is relatively
poorly reproducible and does not always provide useful prognostic informa-
tion. A new chronic GVHD clinical staging system is now recommended for
scoring of individual organs (scale, 0-3) that describes the severity for each
affected organ or site at any given time and also measures functional impact.
Treatment for chronic GVHD is guided by the extent of disease. Initiation of
therapy before functional impairment is of critical importance. Treatments
for chronic GVHD include corticosteroids, cyclosporine, thalidomide, ultra-
violet light treatments, monoclonal antibodies, or other immunosuppressive
agents. Alternative treatments include azathioprine, psoralen ultraviolet A,
and extracorporeal photopheresis. Given that the most common cause of
death in patients with chronic GVHD remains infection, all patients with
GVHD should receive prophylactic antibiotics with or without intravenous
immunoglobulin depending on levels.
SYNGENEIC HEMATOPOIETIC STEM
CELL TRANSPLANTATION
Syngeneic HSCT uses stem cells from an identical twin. Because the HSCs
are genetically identical with the recipient, the major advantage of a synge-
neic HSCT is that it is not associated with GVHD or graft rejection, resulting
in a relatively low risk of treatment-related morbidity and mortality. Another
Downloaded for IKAD PPDS (ikadppdsfkusu@gmail.com) at Universitas Sumatra Utara from ClinicalKey.com by Elsevier on April 13, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
1201
advantage of syngeneic HSCT, shared with allogeneic HSCT, is a lack of
contamination of the graft by malignant cells. The major disadvantage of
syngeneic HSCT is that it does not provide the graft-versus-leukemia effect
associated with allogeneic HSCT. However, fewer than 1% of patients have
an identical twin, and consequently, this is not an option for most patients.
AUTOLOGOUS HEMATOPOIETIC STEM
CELL TRANSPLANTATION
The major rationale for autologous HSCT, using the patient’s own HSCs, is
that certain malignancies, such as leukemias and lymphomas, have a steep
dose-response curve to chemotherapy and, to a relative degree, radiation.4
However, the major limitation to the administration of higher doses of che-
motherapy or radiation is the myelosuppressive effects of these therapies.
Autologous HSCs (and for that matter, allogeneic and syngeneic HSCs)
permit the administration of high-dose chemotherapy with or without radia-
tion by restoring hematopoiesis. The major advantages of autologous HSCT
compared with allogeneic HSCT are that (1) the patient can serve as his or
her own donor, and (2) it may be performed in older patients with signifi-
cantly lower morbidity and mortality because of the absence of GVHD as a
major complication. However, autologous HSCT can be associated with
more morbidity than conventional doses of chemotherapy. Although patients
undergoing autologous transplantation have higher relapse rates than those
undergoing allogeneic transplantation, the lower rate of other complications
seems to translate into similar long-term outcomes.
INDICATIONS FOR TRANSPLANTATION
An estimated 60,000 HSC transplants are performed annually worldwide.
They are used primarily for the treatment of hematologic malignancies, bone
marrow failure states, and immune and enzyme deficiencies (Fig. 178-2).
Acute Myeloid Leukemia
Acute myeloid leukemia (AML) (Chapter 183) was one of the first malignan-
cies in which all forms of HSCT were demonstrated to be effective. Alloge-
neic HSCT is capable of resulting in the long-term survival of 10% of patients
with refractory AML. Long-term survival and an apparent cure rate of 20%
to 40% have been achieved in patients treated in second or subsequent com-
plete remission, and cure rates of 40% to 70% have been reported in patients
given transplants in first complete remission.5 Randomized controlled trials
comparing autologous and allogeneic HSCT with conventional chemother-
apy in patients with AML in first complete remission have demonstrated
improved leukemia-free survival with both forms of HSCT. However, the
data vary regarding an improvement in overall survival. Several meta-analyses
demonstrate improved overall survival with allogeneic HSCT for AML in
first complete remission, compared with nonallogeneic treatments in patients
with intermediate- and high-risk cytogenetics but not for good-risk AML.6
More recent studies indicate the importance of the presence of molecular
mutations. For example, intermediate-risk AML with a normal karyotype
represents a highly heterogeneous group with respect to prognosis based on
molecular mutation status. Approximately one third of patients with normal
karyotype AML harbor the FLT3-internal tandem mutation, which carries a
poor prognosis, and may benefit from HLA-matched related HSCT trans-
plantation, regardless of the presence of other mutations.
Acute Lymphocytic Leukemia
The results of conventional chemotherapy for acute lymphocytic leukemia
(ALL) in children are excellent, except for ALL associated with the Philadel-
phia chromosome (Ph). In adults, however, although remission is frequently
attained after intensive induction therapy, the probability of relapse is high is
this disease, and some form of consolidation therapy is recommended, includ-
ing allogeneic HSCT. Adverse prognostic factors include the presence of Ph,
high white blood cell count, advancing age, and the presence of minimal
residual disease. Studies suggest that HSCT improves overall survival com-
pared with conventional chemotherapy alone, particularly for those who are
Ph positive. The overall prognosis for both pediatric and adult patients with
relapsed ALL is relatively poor, and the general treatment strategy is to obtain
a second complete remission and then proceed to an allogeneic HSCT.
Myelodysplastic Syndrome
The only known curative treatment for myelodysplastic syndrome (MDS)
(Chapter 182) is allogeneic HSCT. Unfortunately, the vast majority of
patients are not considered candidates for this therapy for many reasons,
including advanced age, comorbidities, donor availability, access to relatively
1202 CHAPTER 178  Hematopoietic Stem Cell Transplantation
 

Indication for Hematopoietic Stem Cell Transplants in the US, 2011

7000 Allogeneic (Total N=7,892)

6000 Autologous (Total N=12,047)

Number of Transplants
5000
4000
3000
2000
1000
0
Multiple NHL AML ALL MDS/ CML Aplastic CLL Other Other HD
Myeloma MPD Anemia Non- Cancer
Malig
Disease
FIGURE 178-2. Indications for hematopoietic stem cell transplantation in the United States as Reported to the Center for International Blood & Marrow Research. AA = aplastic
anemia; ALL = acute lymphocytic leukemia; AML = acute myeloid leukemia; CLL = chronic lymphocytic leukemia; HD = Hodgkin disease; MDS/MPD = myelodysplastic syndrome/
myeloproliferative disorders; MM = multiple myeloma; NHL = non-Hodgkin lymphoma. (From Dunn, R. Current Uses and Outcomes of Hematopoietic Stem Cell Transplantation 2013:
Summary Slides. Center for International Blood & Marrow Transplant Research. http://www.cibmtr.org/referencecenter/slidesreports/summaryslides/documents/2013 summary
slides- final web version v2 4.14.2014.pptx)

well tolerated agents such as azacytidine or lenalidomide, and clinician or
patient preferences. The best results have been obtained in relatively younger
patients, who are earlier in their disease course and have not received any prior
therapy. There is increasing evidence that reduced-intensity allogeneic HSCT
may benefit even considerably older patients with MDS, and this is of impor-
tance given that the median age at diagnosis is in the seventh to eighth decades
of life. The use of autologous HSCT for MDS remains investigational.
Chronic Myeloid Leukemia
Previously, allogeneic HSCT was the treatment of choice for chronic myeloid
leukemia (CML) (Chapter 184); however, currently most CML patients are
successfully treated with a tyrosine kinase inhibitor (TKI), such as imatinib.
Consequently, in most cases, allogeneic HSCT is not performed in patients
with CML in chronic phase, but it is reserved for patients in accelerated phase
(AP) or blast crisis (BC) CML, those who are intolerant of or fail TKIs, and
those with TKI-resistant mutations of BCR-ABL. Although the results of
allogeneic HSCT in AP or BC CML are poor, results of posttransplant treat-
ment with TKIs appear promising. In the TKI era, autologous stem cell col-
lections, even in patients with hematopoiesis shown to be BCR-ABL negative
by reverse transcription polymerase chain reaction, are rarely performed.
Myeloproliferative Neoplasms
Myeloproliferative neoplasms (Chapter 166), such as primary myelofibrosis,
polycythemia vera, and essential thrombocythemia, usually are chronic in
nature but can progress to a “spent” phase and develop myeloid metaplasia,
which is characterized by bone marrow fibrosis and a generally poor progno-
sis with transformation into acute leukemia and a median survival time of less
than 3 years. Conventional treatment options in this disease state are limited,
and an accepted standard of care for myeloid metaplasia/myelofibrosis is
allogeneic HSCT with increasing reports of the efficacy of nonmyeloablative
allogeneic HSCT for these disorders in this older age population.
In the case of mantle cell lymphoma (MCL), further prospective trials are
required, although autologous HSCT appears to improve progression-free
and possibly overall survival in patients when used as part of front-line
therapy. Patients with high-risk MCL are candidates for trials investigating
the role of nonmyeloablative allogeneic HSCT.
Hodgkin Lymphoma
Based on a small prospective randomized trial conducted in the early 1990s,
autologous HSCT has become the standard of care for patients with primary
refractory and relapsed Hodgkin lymphoma (Chapter 186). The usual
approach is to first treat these patients with second-line chemotherapy fol-
lowed by the high-dose therapy and autologous HSCT. Allogeneic HSCT has
had a limited role because of the efficacy of autologous HSCT and the sig-
nificant treatment-related toxicities associated with myeloablative allogeneic
HSCT. Data are accumulating on the efficacy of reduced-intensity allogeneic
HSCT, especially in patients who relapse after autologous HSCT.
Multiple Myeloma
Although the advent of new agents, such as immunomodulatory derivatives
and proteasome inhibitors, for the treatment of multiple myeloma (MM)
(Chapter 187) is leading to a reappraisal of the role of autologous HSCT in
the early treatment of the disease, current opinion indicates that standard of
care remains induction therapy with novel agents followed by autologous
HSCT.7 Prospective comparisons of single versus tandem autologous trans-
plants give conflicting results, although overall survival rates appear similar.
Comparisons of tandem autologous versus autologous followed by allogeneic
HSCT indicate improved complete remission rates and event-free survival
but no increased overall survival and significantly worse nonrelapse mortality
rates with the latter. Consensus appears to be to reserve a second transplant
for patients who relapse after the first autologous HSCT, provided the dura-
tion of response was more than 1 year after the initial transplant.

Non-Hodgkin Lymphoma Solid Tumors

Although allogeneic, syngeneic, and autologous HSCT have all been reported
to yield long-term, disease-free survival and an apparent cure for patients
with advanced non-Hodgkin lymphomas (NHL) (Chapter 185), the current
standard of care for patients with primary refractory or chemotherapy-
sensitive relapsed NHL of specific histologies, including diffuse large B-cell
lymphoma, remains autologous HSCT.
Autologous HSCT also has been used to treat patients with indolent fol-
licular NHL resulting in disease-free survival rates as high as 60%. However,
late relapses and the long overall survival period observed with conventional
therapy make long-term follow-up necessary to document the efficacy of this
approach. The demonstration of a potent graft-versus-leukemia effect against
NHL is less clear. Consensus is currently lacking regarding the most appro-
priate role of HSCT (whether autologous or allogeneic) for patients with
follicular lymphoma. Recent studies, however, suggest the potential value of
nonmyeloablative allogeneic HSCT regimens in the context of clinical trials
that incorporate rituximab or radioimmunoconjugates.
High-dose chemotherapy plus transplantation has had success in the treat-
ment of some chemotherapy-sensitive solid tumors, including germ cell
tumors and childhood cancers such as neuroblastoma and Wilms tumor. In
patients with germ cell tumors for whom platinum-based chemotherapy regi-
mens fail to result in a cure, the use of high-dose chemotherapy and autolo-
gous HSCT has resulted in prolonged disease-free survival time, including
patients with refractory disease. After initial promising results of autologous
HSCT for advanced and metastatic breast cancer, several randomized trials
failed to demonstrate an overall survival benefit, and the procedure is no
longer performed for these indications.
Nonmalignant Conditions
Hematopoietic stem cell transplantation is also effective for treatment of
nonmalignant disorders, including aplastic anemia, thalassemias, sickle cell
disease8, immunodeficiency disorders, and enzyme deficiency states. These
latter indications are primarily for children and young adults. Allogeneic

Downloaded for IKAD PPDS (ikadppdsfkusu@gmail.com) at Universitas Sumatra Utara from ClinicalKey.com by Elsevier on April 13, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 CHAPTER 178  Hematopoietic Stem Cell Transplantation
HSCT can lead to long-term, disease-free survival times in more than 50%
of patients with severe aplastic anemia (Chapter 165). When compared with
standard immunosuppressive therapy, allogeneic transplantation is more
likely to produce a complete and durable reversal of the hematologic abnor-
malities. Patients with aplastic anemia who are less heavily transfused have
better outcomes with allogeneic transplantation. For patients with less severe
aplastic anemia, patients older than 40 years, and those without a matched
sibling donor, a trial of immunosuppression therapy is usually appropriate
before consideration of allogeneic transplantation.
The hemoglobinopathies can be cured only by allogeneic HSCT, and the
most extensive experience is with β-thalassemia (Chapter 162). Best results
are obtained with HLA-identical sibling donor transplantations and in pedi-
atric patients. Adults tend to have more advanced disease with greater iron
overload and more organ dysfunction; hence, they have high treatment-
related mortality rates. Studies with nonmyeloablative regimens are ongoing.
There is considerably less experience with sickle cell disease (Chapter 163),
partly because of reluctance to contemplate allogeneic HSCT in patients with
an unpredictably variable clinical course.
Autologous HSCT has been investigated for almost 20 years for the treat-
ment of severe autoimmune disease, including systemic lupus erythematosus,
rheumatoid arthritis, scleroderma, and multiple sclerosis. Results have been
promising in nonrandomized trials with approximately one third of patients
exhibiting clinically significant responses, including medication-free remis-
sions. The strategy has been to reconstitute the immune system without the
presence of autoreactive T-cell clones. There has been a reluctance to con-
sider allogeneic HSCT, with its attendant morbidity and mortality, because
in general patients with autoimmune diseases have a low probability of death
from their underlying disorder, but HSCT can confer a long-term survival
benefit in patients with diffuse cutaneous systemic sclerosis. A2  complications, patients who are undergoing allogeneic HSCT are at increased
COMPLICATIONS AFTER HEMATOPOIETIC STEM
CELL TRANSPLANTATION
Early complications associated with all forms of HSCT include direct organ
toxicities from the conditioning regimen (e.g., mucositis) and prolonged
cytopenias (7-14 days) resulting in infections and bleeding. As described
earlier in this chapter, allogeneic HSCT can be associated with acute and
chronic GVHD. Long-term complications, particularly secondary malignan-
cies, require that patients continue to be monitored for the remainder of their
lives. Through improved supportive measures, there has been steady improve-
ment in survival after HSCT over time.9 A simple index, based on pretrans-
plant comorbidities, has been developed that reliably predicts nonrelapse
mortality and survival.10 This comorbidity index is useful for patient counsel-
ing before HSCT. The late toxicities of HSCT must always be kept in mind
when considering the option of HSCT for patients.
Graft Rejection
Graft rejection occurs when immunologically competent cells of host origin
destroy the transplanted cells of donor origin. This complication occurs more
commonly in patients who receive transplants from alternative or HLA-
mismatched donors, in T cell–depleted transplants, and in patients with
aplastic anemia. Graft rejection is rarely, if ever, observed in patients undergo-
ing autologous or syngeneic HSCT.
Infections
Infections are a major cause of morbidity and mortality after all forms of
HSCT, but especially after allogeneic transplantation because of prolonged
use of immunosuppression for the prevention or treatment of GVHD. Bac-
terial infections are frequently related to central venous catheters. Prophy­
lactic antibiotics significantly reduce the incidence of infection but not
mortality. A3  Aspergillus infections typically occur in patients receiving pro-
longed high-dose steroids for the treatment of GVHD.11 Viral infections
include reactivation of CMV, human herpes virus 6, and Epstein-Barr virus
(EBV) infections. Brincidofovir, an investigational oral nucleotide analog,
and letermovir, a novel antiviral agent, reduce CMV events in recipients of
HSCT. A4  A5  Post-HSCT patients are also susceptible to seasonal respiratory
,
viruses. Revaccinations for common childhood infections are required after
transplantation.
Cardiac Toxicity
Most transplant centers screen potential patients for underlying cardiac
abnormalities that would place them at a potentially increased risk during
the procedure. Despite this screening, however, a small number of patients
Downloaded for IKAD PPDS (ikadppdsfkusu@gmail.com) at Universitas Sumatra Utara from ClinicalKey.com by Elsevier on April 13, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
1203
experience cardiotoxicity, either acutely during the transplant or at a later
time, manifest as a cardiac arrhythmia, congestive heart failure, or cardiac
ischemia because of the large volumes of fluids administered during the pro-
cedure or from the added physiological stress. Complications associated with
a pericardial effusion can be seen in some patients during or after transplant
and are more common in patients with disease near that area and those
receiving radiation therapy in that field. An idiosyncratic cardiomyopathy,
associated with the administration of high doses of cyclophosphamide, has
been documented in a small number of patients. Viral cardiomyopathies also
can be seen.
Engraftment Syndrome
Engraftment syndrome occurs during neutrophil recovery after both autolo-
gous and allogeneic HSCT. It consists of a constellation of symptoms and
signs that may include fever, erythrodermatous skin rash, and noncardiogenic
pulmonary edema, and, in its most extreme forms, acute renal failure and
diffuse alveolar hemorrhage. These clinical findings reflect the manifestations
of increased capillary permeability and extensive endogenous cytokine. Cor-
ticosteroid therapy is often dramatically effective for engraftment syndrome,
particularly for the treatment of the pulmonary manifestations.
Pulmonary Toxicities
Pulmonary toxicities are common during and after transplantation. Patients
who receive certain chemotherapeutic agents, such as 1,3-bis (2-chloroethyl)-
1-nitrosourea (BCNU; carmustine) have an increased incidence of
chemotherapy-induced lung tissue damage after transplant, which usually
can occur several weeks after transplantation and can be treated successfully
with the prompt initiation of corticosteroid therapy. In addition to these
risk for pneumonitis caused by CMV and fungal infections due to the patient’s
increased immunosuppression, and adult respiratory distress syndrome or
interstitial pneumonia of unknown etiology. Chronic GVHD also can mani-
fest as bronchiolitis obliterans in the lung.
Liver Toxicity
The most common liver complication associated with transplantation is
veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) of
the liver. Symptoms associated with VOD/SOS include jaundice, tender
hepatomegaly, ascites, and weight gain. Progressive hepatic failure and mul-
tiorgan system failure can develop in the most severe cases. Predisposing
factors appear to be previous hepatic injury, use of estrogens, and high-dose
intensity conditioning.
Renal Toxicity
Acute renal failure requiring dialysis during the transplant occurs infre-
quently, although patients with underlying renal dysfunction are at risk for
this complication. An idiopathic or cyclosporine-induced hemolytic-uremic
syndrome can be a serious complication after allogeneic HSCT and poses a
high mortality risk or can result in end-stage renal disease. Recently, nephrotic
syndrome and membranous nephropathy have been described in long-term
survivors; these complications seem to be associated more commonly with
chronic GVHD and nonmyeloablative conditioning.
Secondary Malignancies
One complication of the chemotherapy or radiation therapy (or both) used
to treat malignancy is the development of a secondary malignancy. There
have been several reports of the development of secondary AML or MDS
after autologous transplantation. Some studies have suggested that total-body
irradiation may increase the risk for these complications. After allogeneic
transplantation, the overall incidence of secondary malignancies is 2.2% at
10 years and 6.7% at 15 years after transplantation. Within the first 1 to 2
years, the most common malignancies are EBV-related lymphoproliferative
disorders; solid tumors are more likely to occur more than 3 years after trans-
plantation. Risk factors include the use of antithymocyte globulin to treat
GVHD, the use of a T cell–depleted allogeneic graft, HLA incompatibility,
and perhaps total-body irradiation.
Infertility and Hypogonadism
Many of the preparative regimens used for transplant are associated with a
high incidence of permanent sterility, particularly regimens containing total-
body irradiation. However, successful pregnancies have occurred in some
patients after other regimens, particularly in younger patients. Gynecomastia
1204 CHAPTER 178  Hematopoietic Stem Cell Transplantation
occasionally occurs in males. A reproductive endocrinologist should be
consulted before transplantation in patients for whom future fertility is
important.
Endocrine Dysfunction
Iatrogenic Cushing syndrome and diabetes can occur and are commonly
caused by long-term steroid therapy for chronic GVHD. Particularly dis-
abling are steroid-induced myopathy, avascular necrosis of the hip, and osteo-
porosis. Because many patients take steroids for many months, tapering can
be associated with malaise, nausea, hypotension, and musculoskeletal pains.
In these situations, slower tapering over several months or reintroduction of
physiological replacement doses (e.g., 5 to 7.5 mg/day of prednisone) is
appropriate. Hypothyroidism is typically related to the use of total-body
irradiation or local irradiation of the head and neck for lymphoma or other
cancers. Osteoporosis occurs in 50% to 60% of patients after HSCT. The
major contributing causes include hypogonadism, secondary hyperparathy-
roidism caused by low serum calcium, and posttransplant steroid therapy.
Bone mineral density should be evaluated before and after transplantation;
osteopenia should be treated as appropriate with bisphosphonates, calcium,
vitamin D, estrogen, and testosterone (Chapter 243).
CONCLUSION
There has been much progress in increasing the safety of HSCT and in
expanding the application of this treatment to more patients. Areas currently
under development that may further improve the use and efficacy of trans-
plantation include continuous improvements in supportive care for trans-
Downloaded for IKAD PPDS (ikadppdsfkusu@gmail.com) at Universitas Sumatra Utara from ClinicalKey.com by Elsevier on April 13, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
plant patients and the broadened use of alternative donors. Better treatments
are necessary for the treatment of GVHD, and innovative studies are ongoing.
Future progress depends on the ability to identify safer and better-targeted
antitumor therapies that can be incorporated in transplantation regimens
without increasing toxicity or attenuating graft-versus-tumor responses.
However, novel cellular therapies, including genetic modification of lympho-
cytes to enhance cancer-killing activity, hold considerable promise.
Grade A References
A1. Holtick U, Albrecht M, Chemnitz JM, et al. Bone marrow versus peripheral blood allogeneic hae-
matopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database
Syst Rev. 2014;4:CD010189.
A2. van Laar JM, Farge D, Sont JK, et al. Autologous hematopoietic stem cell transplantation vs intra-
venous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial.
JAMA. 2014;311:2490-2498.
A3. Kimura S, Akahoshi Y, Nakano H, et al. Antibiotic prophylaxis in hematopoietic stem cell transplan-
tation. A meta-analysis of randomized controlled trials. J Infect. 2014;69:13-25.
A4. Marty FM, Winston DJ, Rowley SD, et al. CMX001 to prevent cytomegalovirus disease in hemato-
poietic-cell transplantation. N Engl J Med. 2013;369:1227-1236.
A5. Chemaly RF, Ullmann AJ, Stoelben S, et al. Letermovir for cytomegalovirus prophylaxis in hema-
topoietic-cell transplantation. N Engl J Med. 2014;370:1781-1789.
GENERAL REFERENCES
For the General References and other additional features, please visit Expert Consult
at https://expertconsult.inkling.com.
 CHAPTER 178  Hematopoietic Stem Cell Transplantation
 
1204.e1

GENERAL REFERENCES
1. Gyurkocza B, Rezvani A, Storb R. Allogeneic hematopoietic cell transplantation: the state of the art.
Expert Rev Hematol. 2010;3:285-299.
2. Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years
and beyond. Blood. 2013;122:491-498.
3. Pavletic SZ, Fowler DH. Are we making progress in GVHD prophylaxis and treatment? Hematology
Am Soc Hematol Educ Program. 2012;2012:251-264.
4. Hamadani M. Autologous hematopoietic cell transplantation: An update for clinicians. Ann Med.
2014:1-14.
5. Liu H, Stock W, Bishop MR. Expanded Indications for allogeneic stem cell transplantation in
patients with myeloid malignancies. Curr Opin Hematol. 2013;20:115-122.
6. Thomas X. Current indications of allogeneic stem cell transplant in adults with acute myeloid leu-
kemia. Bull Cancer. 2014;101:856-865.
7. Gahrton G, Krishnan A. Allogeneic transplantation in multiple myeloma. Expert Rev Hematol.
2014;7:79-90.
8. Hsieh MM, Fitzhugh CD, Weitzel RP, et al. Nonmyeloablative HLA-matched sibling allogeneic
hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014;312:48-56.
9. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell
trans- plantation. N Engl J Med. 2010;363:2091-2101.
10. Sorror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood.
2013;121:2854-2863.
11. Girmenia C, Ferretti A, Barberi W. Epidemiology and risk factors for invasive fungal diseases in
hematopoietic stem cell transplantation. Curr Opin Hematol. 2014;21:459-465.

Downloaded for IKAD PPDS (ikadppdsfkusu@gmail.com) at Universitas Sumatra Utara from ClinicalKey.com by Elsevier on April 13, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
1204.e2 CHAPTER 178  Hematopoietic Stem Cell Transplantation
REVIEW QUESTIONS
1. The distinctive characteristic(s) of allogeneic hematopoietic stem cell
transplantation include(s):
A. The stem cell graft is free of contamination by malignant cells
B. Associated with decreased complications compared with autologous
and syngeneic hematopoietic stem cell transplantation
C. Contains lymphocytes that are capable of mediating an immunologic
reaction against foreign antigens
D. Both A and C
E. A, B, and C
Answer: D  Both allogeneic and syngeneic grafts are free of tumor cell con-
tamination. Allogeneic hematopoietic stem cell transplantation (HSCT) is
associated with higher rates of treatment-related morbidity and mortality
because of the potential for the development of graft-versus-host disease and
need for immunosuppressive agents leading to higher risks of infection. Allo-
geneic transplantation contains lymphocytes that can mediate immunologic
reactions against foreign antigens, including those on tumors leading to lower
rates of relapse compared with either autologous or allogeneic HSCT.
2. The cells that contribute most to the graft-versus-tumor effects observed
with allogeneic stem cell transplantation are
A. neutrophils.
B. monocytes.
C. dendritic cells.
D. T lymphocytes.
E. B lymphocytes.
Answer: D  Although neutrophils and monocytes play important roles in
eliminating infections, they contribute little to observed graft-versus-tumor
effect. B lymphocytes and dendritic cells have been demonstrated to play
roles in the graft-versus-tumor effects observed with allogeneic hematopoi-
etic stem cell transplantation ; however, T lymphocytes play the most impor-
tant role. This has been most clearly evident clinically by the observation that
infusion of donor T lymphocytes (i.e., donor lymphocyte infusion) after
recurrence of cancer following allogeneic stem cell transplantation can alone
result in sustained complete remissions.
3. All of the following are disadvantages for the clinical use of cord blood
hematopoietic stem cells (HSCs) except
A. clinical outcomes are in general inferior to fully HLA-matched sibling
and volunteer unrelated donors.
B. because of the unique immature biology of lymphocytes in umbilical
cord blood, these transplants are associated with more GVHD.
C. because of the small volume (50-150 mL) of cord blood, only a limited
number of HSCs can be collected, which often prohibits their use in
adults because successful engraftment correlates with the number of
HSCs per patient body weight.
D. cord blood HSCs are associated with delayed times to engraftment and
immune reconstitution, leading to an increased rate of infection.
E. after a cord blood unit is used, there is no possibility to obtain addi-
tional cells in the event of graft failure or if a donor lymphocyte infu-
sion is required.
Answer: B  Cord blood transplantation is generally associated with less graft-
versus-host disease even when the donor and recipient are human leukocyte
antigen (HLA) disparate. This is the major advantage of cord blood stem cells
and permits the application of hematopoietic stem cell transplantation to a
broader group of patients. Outcomes, however, are generally not as good as
those observed with either fully HLA-matched sibling or volunteer donors
in similar patients. The limited number of HSCs, delayed hematopoietic
recovery and immune reconstitution, and availability of only a single unit for
each patient are major clinical disadvantages.
Downloaded for IKAD PPDS (ikadppdsfkusu@gmail.com) at Universitas Sumatra Utara from ClinicalKey.com by Elsevier on April 13, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
4. Risk factors for the development of acute graft-versus-host disease
(GVHD) include all except which of the following?
A. HLA mismatch
B. Cytomegalovirus seronegativity of the donor or patient
C. More advanced age in the patient and the donor
D. Female donor (particularly a multiparous donor)
E. Use of an unrelated donor
Answer: B  Seropositivity, not negativity, in either the recipient or the donor
is associated with a greater risk of developing acute GVHD. All of the other
factors have also been associated with higher risks of developing acute
GHVD. When a patient has more than one potential human leukocyte
antigen–matched donors, these factors are used in the donor selection.
5. All of the following are considered standard indications for hematopoietic
stem cell transplantation (HSCT) except
A. allogeneic HSCT from HLA-matched donors for patients with inter-
mediate- and high-risk acute myeloid leukemia in first remission.
B. high-dose chemotherapy and autologous HSCT for patients with
primary refractory and relapsed diffuse large B-cell lymphoma that
remains chemotherapy sensitive.
C. allogeneic HSCT from HLA-matched sibling in adult patients with
advanced sickle cell disease.
D. high-dose chemotherapy and autologous HSCT for patients with
newly diagnosed multiple myeloma after induction therapy.
E. allogeneic HSCT for patients with therapy-related acute myeloid
leukemia.
Answer: C  In all of the other clinical scenarios, either allogeneic or autolo-
gous HSCT has been demonstrated to significantly improve progression-free
or overall survival. Several meta-analyses have demonstrated the benefit of
allogeneic HSCT from human leukocyte antigen–matched donors for
patients with intermediate- and high-risk acute myeloid leukemia in first
remission. The benefit in patients with normal cytogenetics is being further
delineated by molecular studies (e.g., FLT3-ITD). In relapsed, chemotherapy-
sensitive diffuse large B-cell lymphoma, autologous HSCT has been demon-
strated to result in improved progression-free and overall survival in
randomized trials compared with conventional therapy. Although the con-
tinuing introduction of novel agents is changing clinical practice, autologous
transplantation remains a standard component in the initial management of
multiple myeloma patients. In the case of therapy-related acute myeloid leu-
kemia, allogeneic stem cell transplantation is the only option that can provide
long-term survival and possibly cure. Although there have been promising
results with allogeneic HSCT in adults with advanced sickle cell disease, it
still is considered investigational because ongoing trials attempt to identify
the most appropriate patients in which to use this treatment.