Download hematopoietic Stem Cell transplant: review Questions

hematology Board Review Manual
Statement of
Editorial Purpose
The Hospital Physician Hematology Board Review
Manual is a study guide for fellows and prac­
ticing physicians preparing for board exami­
nations in hematology. Each manual reviews
a topic essential to the current practice of
hematology.
PUBLISHING STAFF
PRESIDENT, Group PUBLISHER
Bruce M. White
Hematopoietic Stem
Cell Transplant: Review
Questions
Series Editor and Contributor:
Eric D. Jacobsen, MD
Instructor of Medicine, Harvard Medical School, Boston, MA;
Attending Physician, Dana-Farber Cancer Institute, Boston, MA
editorial director
Debra Dreger
Associate EDITOR
Rita E. Gould
assistant EDITOR
Farrawh Charles
executive vice president
Barbara T. White
executive director
of operations
Jean M. Gaul
PRODUCTION Director
Suzanne S. Banish
Table of Contents
PRODUCTION assistant
Nadja V. Frist
ADVERTISING/PROJECT director
Patricia Payne Castle
sales & marketing manager
Deborah D. Chavis
NOTE FROM THE PUBLISHER:
This publication has been developed with­
out involvement of or review by the Amer­
ican Board of Internal Medicine.
Questions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Answers and Explanations . . . . . . . . . . . . . . . . . . . . . 5
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Cover Illustration by Kathryn K. Johnson
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Hematopoietic Stem Cell Transplant:
Review Questions
Eric D. Jacobsen, MD
QUESTIONS
Choose the single best answer for each question.
1.A 29-year-old man presents with a 2-week history of
progressive shortness of breath and dry cough but
no fever. His past medical history is significant for
relapsed Hodgkin lymphoma. Six months ago, the
patient underwent high-dose chemotherapy with
cyclophosphamide, carmustine, and etoposide followed by autologous stem cell transplantation. The
current physical examination is notable for bilateral
basilar crackles, but the jugular venous pressure is
normal. There is no edema and no evidence of a cardiac rub or gallop. The patient’s vital signs are heart
rate of 72 bpm, blood pressure of 114/76 mm Hg,
temperature of 98.6°F, respiratory rate of 22 breaths/
min, and oxygen saturation of 90% on room air. The
patient is receiving trimethoprim/sulfamethoxazole
and acyclovir, both of which were started at the time
of his transplant. A restaging computed tomography (CT) scan of the chest, abdomen, and pelvis
performed 4 weeks prior to this visit showed only a
subtle bilateral interstitial infiltrate but no evidence
of disease recurrence. What is the most likely diagnosis for the patient’s symptoms?
(A)Carmustine-induced lung injury
(B)Congestive heart failure
(C)Pneumocystis jiroveci pneumonia
(D)Pulmonary embolism
(E) Relapsed Hodgkin lymphoma
2. Six days ago, a 42-year-old man with a history of relapsed acute myelogenous leukemia (AML) underwent cyclophosphamide and total body irradiation
(TBI) conditioning followed by allogeneic stem cell
transplantation with a fully matched brother as his
donor. Over the last 2 days, the patient’s weight has
increased by 15 kg. On physical examination, he
now has moderate ascites with 2+ bilateral lower ex-
Hospital Physician Board Review Manual
tremity edema, and his liver is newly enlarged and
tender to palpation. The patient is afebrile. Notable
laboratory studies are listed in Table 1. The patient
had no known liver disease prior to transplantation.
Which is the most likely diagnosis for the patient’s
symptoms?
(A)Acute reactivation of hepatitis B
(B)Cholangitis
(C)Graft-versus-host disease (GVHD) of the liver
(D)Relapsed AML
(E) Veno-occlusive disease of the liver (VOD)
3.A 32-year-old woman who underwent allogeneic
stem cell transplantation for acute lymphoblastic
leukemia (ALL) 40 days ago presents for a followup visit. Over the last 3 visits in the last month,
the platelet count has decreased from 157,000 to
25,000 cells/µL (normal, 150,000–350,000 cells/µL),
and she is mildly anemic. Creatinine levels have risen
from 0.6 to 2.4 mg/dL (normal, 0.6–1.2 mg/dL).
The white blood cell (WBC) count is 4.7 cells/µL
(normal, 4500–11,000 cells/µL), and there are no
circulating blasts. A bone marrow biopsy reveals no
evidence of leukemia but does show increased megakaryocytes and slightly increased red blood cell precursors. Otherwise, the patient reports feeling well
with the exception of fatigue. She is taking sirolimus
and tacrolimus for GVHD prophylaxis. The sirolimus level was low at the last visit, but the tacrolimus
level was within therapeutic range. Which is the most
likely diagnosis for the patient’s symptoms?
(A)Chronic GVHD
(B)Immune thrombocytopenic purpura
(C)Relapsed ALL with a falsely negative bone
marrow biopsy
(D)Tacrolimus toxicity
(E) Thrombotic thrombocytopenic purpura/
hemolytic uremic syndrome (TTP-HUS)
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Table 1. Results of Selected Laboratory Studies for the Patient in Question 2
Study (Unit)
Posttransplant Value
Pretransplant Value
Normal Range
Alanine aminotransferase (U/L)
157
23
10–30
Aspartate aminotransferase (U/L)
142
33
10–40
Creatinine (mg/dL)
2.6
0.9
0.6–1.2
Direct bilirubin (mg/dL)
4.3
0.2
0.1–0.3
Total bilirubin (mg/dL)
5.6
0.9
0.3–1.2
White blood cell count (cells/µL)
0.06
3600
4500–11,000
4.A 50-year-old man who underwent matched unrelated donor (MUD) allogeneic stem cell transplantation for chronic lymphocytic leukemia 8 months ago
presents for evaluation of cervical lymphadenopathy of 2 weeks’ duration. Biopsy of a cervical lymph
node shows a polyclonal infiltrate of Epstein-Barr
virus (EBV) positive B cells consistent with posttransplant lymphoproliferative disorder (PTLD). A
staging CT scan demonstrates non-bulky lymphadenopathy in the neck, mediastinum, and mesentery.
The patient currently takes sirolimus and tacrolimus
for immune suppression. He has a history of acute
grade II skin GVHD (per the Consensus staging and
grading system [Table 2]1), which is currently well
controlled. What is the optimal treatment for the
patient at this time?
(A)Administer chemotherapy
(B)Administer interferon
(C)Donor lymphocyte infusion
(D)Stop immune suppression immediately
(E) Taper immune suppression
5.A 37-year-old woman develops a diffuse rash 30 days
following allogeneic stem cell transplantation for
AML. The results of skin biopsy are consistent
with the diagnosis of acute GVHD. She is currently
taking tacrolimus and sirolimus for GVHD prophylaxis. Levels of both medications are at therapeutic
levels. What is the next step in this patient’s management?
(A)Add denileukin diftitox
(B)Add prednisone
(C)Increase sirolimus dose as sirolimus levels do
not correlate with efficacy
(D)Photopheresis
(E) Switch tacrolimus to mycophenolate mofetil
6.Which of the following viruses requires routine
blood monitoring after allogeneic stem cell transplantation even in asymptomatic patients?
(A)BK virus
(B)Cytomegalovirus (CMV)
(C)EBV
(D)Herpes simplex virus (HSV)
(E) Varicella-zoster virus (VZV)
7.A 30-year-old woman with no significant past medical history who is serving as a stem cell donor for
her brother reports the sudden onset of severe left
upper quadrant abdominal pain. The donor is on
her fourth day of taking high-dose filgrastim. She
denies fevers, nausea, vomiting, dysuria, and hematuria and reports a normal menstrual cycle that
occurred 2 weeks ago. What is the most likely cause
of her abdominal pain?
(A)Ectopic pregnancy
(B)Gastric ulcer
(C)Nephrolithiasis from a uric acid stone induced by stem cell mobilization
(D)Rib pain due to marrow expansion
(E) Splenic rupture
8.Which of the following is the best predictor of
long-term disease-free survival following autologous stem cell transplantation for relapsed diffuse
large B-cell lymphoma?
(A)Addition of rituximab to salvage chemo­
therapy
(B)Antibody purging of the autologous stem cell
graft of lymphoma cells
(C)Disease response following salvage chemotherapy
(D)Type of salvage chemotherapy used
(E) Use of a TBI-based conditioning regimen for
transplant
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Table 2. Consensus Staging and Grading of Acute Graft-Versus-Host Disease
Stage
Skin
Liver
Gut
1
Rash on < 25% of skin*
Bilirubin 2–3 mg/dL†
Diarrhea > 500 mL/day‡ or persistent nausea§
2
Rash on 25%–50% of skin
Bilirubin 3–6 mg/dL
Diarrhea > 1000 mL/day
3
Rash on > 50% of skin
Bilirubin 6–15 mg/dL
Diarrhea > 1500 mL/day
4
Generalized erythroderma with bullous
Bilirubin >15 mg/dL
Severe abdominal pain with or without ileus
formation
Permission to electronically reproduce this table
Overall Grade||
Skin
not granted by copyright holder.
Liver
Gut
I
Stage 1–2
None
None
II
Stage 3 or
Stage 1 or
Stage 1
–
Stage 2–3 or
Stage 2–4
Stage 4 or
Stage 4
–
III
IV¶
Adapted with permission from Macmillan Publishers Ltd. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on acute GVHD
grading. Bone Marrow Transplant 1995;15:826.
*Use “Rule of Nines” or burn chart to determine extent of rash.
†Range given as total bilirubin. Downgrade 1 stage if an additional cause of elevated bilirubin has been documented.
‡Volume of diarrhea applies to adults. For pediatric patients, the volume of diarrhea should be based on body surface area. Gut staging criteria for
pediatric patients was not discussed at the Consensus Conference. Downgrade 1 stage if an additional cause of diarrhea has been documented.
§Persistent nausea with histologic evidence of graft-versus-host disease in the stomach or duodenum.
||Criteria for grading given as a minimum degree of organ involvement required to confer that grade.
¶Grade IV may also include lesser organ involvement but with extreme decrease in performance status.
9.A 50-year-old woman presents for 1-year follow-up
after receiving matched related donor allogeneic
stem cell transplantation for AML. The patient
resides in an endemic area for Lyme disease. Currently, she has no plans for travel outside of the
United States. She does not have chronic GVHD.
At this stage of treatment, which infectious agent
should the patient be vaccinated against?
(A)Borrelia burgdorferi
(B)Haemophilus influenzae type b (Hib)
(C)Human papillomavirus
(D)Measles, mumps, and rubella
(E) VZV
10.A 37-year-old man underwent matched related
donor allogeneic stem cell transplantation for
AML in first complete remission. The patient is
currently 7 days post–stem cell infusion. Through
the course of the day, he has complained of
increasing headache and now appears to be confused. Otherwise, his transplant course to date
has been relatively unremarkable. The patient’s
medications include GVHD prophylaxis consisting
of tacrolimus as well as an antimicrobial regimen
Hospital Physician Board Review Manual
consisting of intravenous ceftazidime and prophylactic acyclovir. In addition, he receives ondansetron and lorazepam for nausea; metoclopramide
was added on hospital day 5 due to persistent nausea. The patient is moderately hypertensive (162/
92 mm Hg), and his maximal temperature over
the last 24 hours was 100.3°F. Laboratory studies
are notable for throm­bocytopenia with a platelet
count of 15,000 cells/µL. On the previous day,
the platelet count was 11,000 cell/µL, and he received a platelet transfusion. The creatinine level
has increased from 0.9 to 1.7 mg/dL over the last
24 hours, and the WBC count is 0.04 cells/µL.
What is the most likely cause of this patient’s headache and confusion?
(A)Central nervous system relapse of AML
(B)HSV encephalitis
(C)Intracranial hemorrhage
(D)Methotrexate toxicity
(E) Tacrolimus toxicity
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11.Which of the following people would be the optimal donor for a 46-year-old woman with progressive chronic myelogenous leukemia who is scheduled to undergo allogeneic stem cell transplant?
(A)A human leukocyte antigen (HLA)-matched
42-year-old sister who has 3 children and no
past medical history
(B)An HLA-matched 44-year-old sister who has
never been pregnant but has mild hypertension
(C)A 20-year-old daughter who has no medical
problems and has never been pregnant
(D)An identical twin who has never been pregnant
12.A 27-year-old woman who is 250 days post–MUD
allogeneic stem cell transplant for ALL presents
for follow-up. The patient’s early transplant course
was complicated by acute GVHD of the skin that is
now much improved after a course of prednisone.
However, she has noted a progressively dry mouth
over the last 2 weeks as well as some difficulty
swallowing and a 2-kg weight loss. On review of
systems, the patient reports a sensation as if she
has sand in her eyes. She denies fevers. Physical
examination is notable for slightly injected, dry
sclerae and a dry mouth with shallow, painless
ulcerations on the palate. The patient has been taking trimethoprim/sulfamethoxazole and acyclovir
since her transplant. She is also receiving sirolimus,
from which she is being weaned. Which of the following is the most likely diagnosis for the patient’s
symptoms?
(A)Chronic GVHD
(B)HSV reactivation
(C)Sirolimus toxicity
(D)Stevens-Johnson syndrome
13.A 36-year-old man is undergoing stem cell mobilization in preparation for autologous stem cell transplantation for recurrent Hodgkin lymphoma. Two
days prior to presentation, he received high-dose
cyclophosphamide with mesna 30 minutes before
cyclophosphamide was administered and then 3, 6,
and 9 hours afterwards to prevent hemorrhagic cystitis. On the day prior to this presentation, subcutaneous filgrastim 10 µg/kg daily was initiated. By the
time of presentation, the patient had also received
that day’s scheduled dose of filgrastim (for a total of
2 doses). The patient’s wife notes that he has been
increasingly confused since the previous night. On
physical examination, the patient’s vital signs are unremarkable and he is afebrile. He seems moderately
confused, but his neurologic examination is nonfocal. The results of the patient’s laboratory studies
are notable for a WBC of 38,000 cell/µL with 90%
neutrophils and 3% neutrophilic bands and a serum
sodium level of 121 mg/dL (normal range, 135–
147 mg/dL). Prior to initiating therapy with filgrastim, the serum sodium level was 137 mg/dL. What
is the most likely cause of this patient’s new-onset
confusion?
(A)Central nervous system recurrence of Hodgkin lymphoma with secondary syndrome of
inappropriate antidiuretic hormone (SIADH)
secretion
(B)Cyclophosphamide-induced SIADH
(C)Filgrastim-induced SIADH
(D)Leukostasis from filgrastim-induced leukocytosis with spurious hyponatremia
(E) Neurologic toxicity from mesna resulting in
hyponatremia and confusion
ANSWERS AND EXPLANATIONS
1. (A) Carmustine-induced lung injury. Cardiac complications such as congestive heart failure are common after chemotherapy, radiation, and stem cell
transplantation. Despite the presence of rales on examination, this patient’s normal jugular venous pressure and lack of edema and cardiac gallop make the
diagnosis of congestive heart failure unlikely. Pneumonia due to P. jiroveci (formerly called P. carinii) is
also a common complication after autologous transplant, but this patient is afebrile and has been taking prophylactic trimethoprim/sulfamethoxazole,
making this possibility much less likely. Pulmonary
embolism does not explain the presence of interstitial infiltrate seen on CT scan and is unlikely
in the absence of tachycardia. Relapsed Hodgkin
lymphoma is also an unlikely cause of the patient’s
dyspnea given a recent CT that showed no relapse,
no evidence of pleural effusion (a complication of
bulky thoracic adenopathy) on examination, and
the low likelihood of Hodgkin lymphoma directly
metastasizing to the lungs. Therefore, carmustineinduced lung injury is the most likely explanation
for this patient’s symptoms. Carmustine-induced
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lung injury may complicate up to 30% of transplants utilizing this agent.2 Patients with carmustineinduced lung injury typically present with dry
cough and shortness of breath in the absence of
fever, which can occur weeks to years after exposure
to carmustine. Pulmonary function testing generally demonstrates a restrictive ventilatory defect with
decreased diffusion capacity of carbon dioxide. A
chest radiograph or CT scan will usually demonstrate a bilateral interstitial infiltrate, although focal
consolidation or nodules can be seen. Patients are
usually treated with steroids, although there is no
clear benefit to this strategy. Death or severe lung
injury can result.3
2. (E) VOD. The patient’s symptoms most closely corresponds with VOD, which typically manifests with
the rapid development of fluid retention resulting
in ascites and peripheral edema, weight gain, and
tender hepatomegaly with a rapid rise in alanine
aminotransferase, asparate aminotransferase, and
bilirubin levels.4–6 VOD results from occlusion of
the terminal hepatic venules and sinusoids, most
likely due to injury to the endothelium of the hepatic venules. The greatest risk for developing VOD
occurs with allogeneic stem cell transplantation,
although VOD can occur in patients undergoing
autologous stem cell transplantation as well. Other
risk factors include preexisting liver disease, exposure to gemtuzumab ozogamicin within 3 months
of transplant, female gender, and TBI delivered as
a single dose rather than in fractions.4,5 The incidence of VOD varies by the definition used to diagnose the condition, but severe cases complicate
approximately 5% to 10% of allogeneic stem cell
transplants.7 Moderate to severe cases of VOD are
often associated with dysfunction of other organs
leading to renal failure, pulmonary edema, cardiac
insufficiency, hemorrhagic complications, and encephalopathy. Most commonly, VOD occurs 3 to
30 days after transplant, although cases occurring
later in the transplant course have been described.6
The diagnosis is established most often on clinical
grounds, with liver biopsy occasionally being necessary to rule out GVHD of the liver. Right upper
quadrant ultrasonography with duplex can demonstrate reversal of flow in the portal venous system,
but the sensitivity of this technique is controversial.8 Treatment of mild to moderate cases is often
with supportive care only and most patients will
Hospital Physician Board Review Manual
recover. Severe cases are almost universally fatal;
however, therapies such as defibrotide and systemic anticoagulation may be effective in some instances.9 Although acute reactivation of hepatitis B
is a possible cause of the patient’s symptoms, both
recipients and donors are screened for viral hepatitis infection prior to transplantation. As such, it is
unlikely that this patient had undetected chronic
viral hepatitis B or that he developed acute hepatitis B from the donor. Acute viral hepatitis can
occur after blood transfusion, and multiple transfusions are common during allogeneic stem cell
transplantation. Again, modern screening of the
blood supply makes transfusion-associated acute
hepatitis B extremely unlikely. Cholangitis is a
possible cause of the patient’s symptoms but is less
likely given that the patient is afebrile. GVHD is an
extremely unlikely diagnosis in this patient because
the donor stem cells have not yet engrafted, as
evidenced by the low WBC count and the fact that
the patient is only day 6 posttransplant. Relapsed
AML would not be expected to manifest primarily
as liver failure.
3. (E) TTP-HUS. Although immune thrombocytopenic purpura can result in a slow decrease in
platelet count with increased megakaryocytes on
bone marrow biopsy, this diagnosis does not explain
the presence of renal insufficiency or the slightly
increased red blood cell precursors. Relapsed ALL
is a much less likely diagnosis given the absence of
increased blasts on the bone marrow biopsy and
that this condition does not explain the increased
megakaryocytes. Chronic GVHD can result in low
platelets but would not explain the other bone
marrow biopsy findings. Likewise, tacrolimus, which
can cause renal injury even at therapeutic levels,
does not explain the bone marrow biopsy findings. TTP-HUS is the correct diagnosis because it
explains the declining platelet count, hemolysis,
and renal insufficiency and is consistent with the
findings of the bone marrow biopsy. TTP-HUS is
well described following allogeneic transplantation
and may be a complication of the transplant itself or
the associated chemotherapy and immunosuppressive medications. Data from 1 study indicated that
the median time to onset is approximately 42 days
following transplant.10 TTP-HUS often presents in
a more insidious fashion in this population than in
the nontransplant population and manifests by a
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subacute decline in platelet count, the development
or worsening of anemia, an increase in creatinine
levels, and a rapid rise in lactate dehydrogenase
levels.11 Other hallmarks of hemolytic microangiopathy such as schistocytes visible on the peripheral
blood smear and a markedly reduced or undetectable serum haptoglobin are also present. Treatment
is generally supportive. Plasma exchange is sometimes used although its benefit is not as clear-cut as
in nontransplant cases of TTP-HUS.11
4. (E) Taper immune suppression. PTLD is a welldescribed complication of allogeneic stem cell
transplantation affecting approximately 1% of patients.12,13 Most patients are EBV positive and have
B-cell lineage. The majority of these cases will occur
within 1 year of transplant. The risk for developing
PTLD is higher with MUD or HLA-mismatched
donors, in patients with a history of GVHD, and
patients whose graft underwent T-cell depletion.13
The polyclonal variety generally behaves in a more
indolent fashion, whereas the monoclonal variety
more often behaves like an aggressive lymphoma.
In an asymptomatic patient with low-bulk polyclonal PTLD, tapering immune suppression is a
reasonable first therapeutic approach, although
some evidence suggests that immediately adding
the anti-CD20 antibody rituximab to this regimen
may also be beneficial.14 Chemotherapy would be
reserved for patients with persistent or progressive
disease despite tapering of immune suppression
(with or without rituximab) or for patients with
monoclonal PTLD. For these patients, adding
interferon alone has been demonstrated to be
inadequate therapy.14 Donor lymphocyte infusion
is a method for controlling relapse of the patient’s
underlying disease (in this case, chronic lymphocytic leukemia) but is not the preferred method
of treating PTLD. Abruptly ceasing immune suppression could trigger a flare of GVHD, which is a
concern for a patient who has already experienced
1 episode of GVHD.
5. (B) Add prednisone. Acute GVHD, which occurs
when the donor’s immune cells react against host
tissue, is a common complication of allogeneic
stem cell transplantation. The incidence of acute
GVHD is higher with MUD or haploidentical donors, increasing parity of the donor (in female donors), and with a female donor donating cells for a
male recipient.15 Cutaneous GVHD tends to affect
the palms, soles, and neck/back, although any skin
area can be affected. In addition to the skin, acute
GVHD often affects the gastrointestinal tract and
the liver, leading to profound diarrhea and hepatic
dysfunction, respectively. The optimal first therapy
for treating acute GVHD is steroids, typically prednisone. Alternatively, intravenous steroids such
as methylprednisolone can be administered to
patients who cannot tolerate oral therapy or have
severe GVHD.15 Although sirolimus levels do not
correlate perfectly with either efficacy or toxicity,
increasing the sirolimus dose in someone with a
therapeutic level who develops GVHD would not
be an acceptable strategy because there is a risk
for significant toxicity with a limited expectation
of benefit. Photopheresis is an effective therapy for
GVHD but is generally reserved for patients who
fail to respond to prednisone therapy.16 Changing
tacrolimus to mycophenolate mofetil or adding denileukin diftitox also would generally be reserved
for patients with more refractory cases of GVHD
who had failed to respond to at least steroids in
addition to front-line GVHD prophylaxis.
6. (B) CMV. CMV is a common cause of morbidity
and mortality following allogeneic stem cell transplantation. The risk of CMV reactivation is highest
when either the donor or recipient is CMV positive.17 De novo CMV infection in the setting of both
donor and recipient being CMV negative is less
common, unless the recipient receives CMV positive blood products.17 Serologic testing for CMV
is not adequate for monitoring CMV reactivation
after transplant as immunosuppressed hosts often
will not mount an antibody response to the reactivated virus. Therefore, direct molecular monitoring for the virus itself is needed.18 Even cases of
asymptomatic reactivation should be treated to
avoid symptomatic end-organ involvement as the
associated morbidity and mortality is high. BK
virus is a polyoma virus that can cause renal infections and hematuria in posttransplant patients, but
testing for the virus is typically performed only in
patients for whom there is a clinical suspicion for
BK virus. Some centers utilize EBV monitoring
as an early marker for the risk of PTLD, but this
practice is not standardized. Reactivation of VZV
and HSV are common after allogeneic transplant,
although less so when prophylactic agents such as
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acyclovir are administered. Blood monitoring for
viral nucleic acids is not generally utilized unless
there is a suspicion for systemic infection.
7. (E) Splenic rupture. Splenic rupture is a very rare
but potentially life-threatening complication of
stem cell mobilization with granulocyte colonystimulating factors (G-CSFs) such as filgrastim. In
this case, the sudden onset of severe left upper
quadrant pain in a patient who has been receiving
a G-CSF for several days should raise suspicion for
splenic ruptures.19 Ectopic pregnancy is unlikely
given that female donors undergo pregnancy testing prior to stem cell mobilization. Additionally, this
patient also had a normal menstrual cycle 2 weeks
ago, which makes an ectopic pregnancy unlikely
to be the cause of her symptoms. G-CSF can cause
bone pain but this usually manifests as the gradual
onset of diffuse bone aches rather than sudden,
severe, focal pain. Gastric ulcer is not a known complication of G-CSF. G-CSF is not known to promote
the formation of uric acid stones, and the absence
of hematuria also makes this diagnosis less likely.
8. (C) Disease response following salvage chemotherapy. Disease response following salvage chemotherapy
remains the best predictor for long-term disease-free
survival following autologous stem cell transplantation.20 Patients who achieve a complete response
or partial response to salvage chemotherapy have a
far superior outcome to patients with stable disease
or progressive disease. There is no evidence that
TBI-based regimens are superior to non-TBI based
regimens, and TBI-based regimens may increase
the risk of secondary malignancies after transplant.21
Currently, there is no evidence demonstrating that
the type of salvage chemotherapy utilized prior to
autologous transplant improves outcome in diffuse
large B-cell lymphoma so long as the patient is responding to chemotherapy. Adding rituximab to
salvage chemotherapy may improve response rates22
but has not conclusively been shown to improve outcome after transplant. A theoretical concern of autologous transplantation is reinfusion of tumor cells
along with the normal marrow or peripheral blood
stem cells. Although various techniques have been
used to purge the stem cell product of malignant
cells, none have conclusively been shown to improve
outcome following transplantation.23
Hospital Physician Board Review Manual
9. (B) Hib. Patients who have undergone autologous
and allogeneic stem cell transplantation have defects in opsonization and are therefore susceptible
to infection with encapsulated organisms. Such
patients are also susceptible to certain viral infections. Hib is a common encapsulated pathogen and
patients undergoing stem cell transplant should
be vaccinated against this organism 12, 14, and
24 months after transplantation. Similarly, patients
should be vaccinated with acellular tetanus and
diphtheria vaccine as well as the hepatitis B vaccine
at similar timepoints. Patients should also be vaccinated against pneumococcal pneumonia 12 and
24 months after transplantation and should be vaccinated against influenza beginning at least 6 months
after transplantation and then seasonally thereafter.
In some instances, patients are also revaccinated
against inactivated polio and meningococcus. The
measles, mumps, and rubella vaccine is the only
live-attenuated vaccine studied in the posttransplant
setting, but it should not be administered until
24 months after transplant. VZV vaccine is also a liveattenuated viral vaccine and at present is contraindicated in post–stem cell transplant patients. Vaccines
for B. burgdorferi and human papillomavirus vaccine
have not been studied in posttransplant patients
and are not recommended.24 Because vaccination
guidelines can change, clinicians should regularly
review the recommendations of the Centers for
Disease Control and Prevention or the American
Society of Blood and Marrow Transplantation to be
sure they are appropriately vaccinating transplant
patients.25
10. (E) Tacrolimus toxicity. Tacrolimus, a macrolide antibiotic isolated from fungi, is a calcineurin inhibitor that reduces the production of several cytokines
including interleukin-2. Tacrolimus is metabolized
through the hepatic cytochrome p450 3A system
and may interact with other drugs metabolized
through this system such as metoclopramide. Such
interactions may lead to increased tacrolimus levels
and signs of toxicity such as headache, confusion,
hypertension, and renal insufficiency.26 Since this
patient developed signs and symptoms of tacrolimus toxicity 2 days after initiating therapy with
metoclopramide, it is likely that his serum tacrolimus levels were elevated by the interaction of the
2 drugs. HSV encephalitis is less likely to be the correct diagnosis given that the patient is on acyclovir
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H e m a t o p o i e t i c S t e m C e l l Tr a n s p l a n t : R e v i e w Q u e s t i o n s
prophylaxis and does not explain the presence of
hypertension and renal insufficiency. Likewise, central nervous system relapse of AML is an unlikely
diagnosis given that the patient was in complete remission entering the transplant, and this condition
does not account for the new renal insufficiency.
Intracranial hemorrhage could cause headache
and confusion but is less likely at a platelet count
exceeding 10,000 cells/µL and does not explain
the new renal insufficiency. Methotrexate toxicity
could account for the increased creatinine but not
the headache, confusion, and hypertension.
11. (B) An HLA-matched 44-year-old sister who has
never been pregnant but has mild hypertension.
Matching of donors is accomplished by testing
HLA class I and class II antigens. Class I antigens
include HLA-A, -B, and -C, which are found on
nearly every cell in the body with the exception
of erythrocytes. Class II antigens include HLA-DR,
-DQ, and -DP and are generally found on cells
of the immune system. Of the class II antigens,
HLA-DR and, to a lesser extent, HLA-DQ are the
most important in donor selection. In the past,
serologic methods were used to match donors
to recipients. However, most centers now use
the more refined molecular methods of typing,
which have led to better donor-recipient matching. Identical twins have identical HLA systems
and therefore recipients of stem cells from an
identical twin almost without exception will not develop GVHD. Unfortunately, the recipient in this
situation also may not benefit from a graft-versusmalignancy effect. This immune response against
the tumor can be the most critical factor in controlling the disease for which the patient was
transplanted, which appears to be especially true
in chronic myelogenous leukemia where relapse
rates are higher if an identical twin is utilized as the
donor.27 Since each individual inherits 50% of their
HLA genes from each parent, a child (in this case,
the patient’s daughter) is unlikely to be a match
unless there is consanguinity. Either HLA-matched
sister would be a potential donor. However, female
donors of increasing parity result in a greater risk
of GVHD for the recipient.28 Therefore, the nulliparous sister would be the ideal choice; in addition,
a history of mild hypertension does not preclude
her from safely donating stem cells. If multiple
donors are available, other factors for donor se-
lection including age (younger is better), CMV
status (CMV negative preferred if recipient is CMV
negative), and medical history should be carefully
considered prior to making a final choice.
12. (A) Chronic GVHD. By definition, chronic GVHD
is defined as starting after day 100 following allogeneic stem cell transplantation. Based on current
definitions, the patient could not have reactivated
acute GVHD. However, it should be noted that this
distinction is arbitrary and may change in the future. Chronic GVHD can affect a variety of organs
including the eyes and mouth where it can result
in sicca syndrome and ulceration. Chronic GVHD
can also affect the skin, causing a scleroderma-like
condition. In the gastrointestinal tract, chronic
GVHD can lead to strictures and malabsorption. In
the lungs, chronic GVHD can cause bronchiolitis
obliterans-like syndrome. Risk factors for chronic
GVHD include a MUD or mismatched donor, history of acute GVHD, and increasing age of the donor
and/or recipient.29 The risk of chronic GVHD may
also be higher with nonmyeloablative allogeneic
transplant.30 In this case, the patient’s immunosuppression was also being weaned, which can trigger
GVHD. HSV reactivation causes keratitis and oral
ulceration, but these ulcers in HSV are painful. In
addition, HSV reactivation would be less likely to
occur in a patient receiving prophylactic acyclovir.
Stevens-Johnson syndrome secondary to sulfa drug
usage is very rare and would be unlikely to develop
in a patient who has been receiving a sulfa drug for
over 200 days. Stevens-Johnson syndrome is also
generally associated with skin rash and/or blistering, which is not seen in this patient.31 Dry eye and
mouth ulcers are not side effects of sirolimus.
13. (B) Cyclophosphamide-induced SIADH. Although
leukostasis can complicate such conditions as
AML, it is not a known complication of filgrastiminduced leukocytosis. Additionally, AML leukostasis
does not generally occur with a WBC count below
100,000 cells/µL. Therefore, the WBC count of
38,000 cells/µL seen in this patient would not
typically be sufficiently high enough to cause
neurologic changes from leukostasis.32 Mesna
(2-mercaptoethane sulfonate sodium) is administered after cyclophosphamide to prevent hemorrhagic cystitis caused by acrolein, a metabolite of
cyclophosphamide and ifosfamide that is excreted
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in the urine and is toxic to the epithelial lining of
the bladder.33 Mesna can cause nausea and vomiting as well as a foul taste but is not associated with
neurologic toxicity.34 Similarly, filgrastim is not
known to cause neurologic toxicity or SIADH.
Finally, Hodgkin lymphoma involving the nervous
system is extremely rare and is an unlikely cause
of this patient’s abnormalities. SIADH, however,
is a known complication of cyclophosphamide
administration, particularly at higher doses (30–
50 mg/kg intravenous) and can be fatal.35,36 In the
setting of stem cell mobilization, SIADH is exacerbated by the use of copious prehydration prior
to cyclophosphamide administration. Treatment
of mild cases involves free water restriction.37 The
treatment of more severe and symptomatic cases
such as this case would involve hospitalization
and the administration of hypertonic saline with
or without the vasopressin receptor antagonist
conivaptan.38 Other therapies include lithium and
demeclocycline.
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test yourself with board-type questions
Questions for self-assessment in selected specialties are available on Hospital Physician’s Web site.
Go to www.turner-white.com, click on Hospital Physician, then click on “Board-Type Questions.”
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