44. A 42-year-old white woman presented 2 months ago with menorrhagia. She was noted to be pancy-topenic on initial laboratory evaluation. After an exhaustive workup, a diagnosis of aplastic anemia was made. The patient is being considered for hematopoietic cell transplantation.
Which of the following statements regarding hematopoietic cell transplantation is false?
❑ A. Hematopoietic stem cells for transplantation may derive from bone marrow, peripheral blood, or umbilical cord blood
❑ B. Syngeneic transplantations come from identical twins; identical twins are the best possible donors of stem cells
❑ C. In allogeneic transplantations, if two persons do not share the same HLA antigens, B cells taken from one person will react vigorously to the mismatched HLA molecules on the surface of the cells from the other person
❑ D. When compared with allogeneic transplantation, autologous trans-plantation has the advantage of avoiding graft versus host disease (GVHD) and associated complications
Key Concept/Objective: To understand the different types of hematopoietic stem cell transplantations Hematopoietic stem cell transplantation can be categorized according to the relation between the donor and the recipient and according to the anatomic source of the stem cell.
Hematopoietic stem cells for transplantation may derive from bone marrow, peripheral blood, or umbilical cord blood and may be harvested from a syngeneic, allogeneic, or
autologous donor. Identical twins are the best possible donors of stem cells. When syn-geneic donors are used, neither graft rejection nor GVHD will develop in the recipient.
Only about one in 100 patients undergoing transplantation will have an identical twin.
Allogeneic transplantation, which involves a related or unrelated donor, is more compli-cated than syngeneic or autologous transplantation because of immunologic differences between donor and host. With allogeneic hematopoietic cell transplantation, in which the immune system of the patient is provided by the graft, the clinical concerns are not only with the prevention of graft rejection by host cells surviving the pretransplant preparative regimen but also with the prevention of donor cells from causing immune-mediated injury to the patient (i.e., GVHD). Immunologic reactivity between donor and host is large-ly mediated by immunocompetent cells that react with HLAs, which are encoded by genes of the major histocompatibility complex. HLA molecules display both exogenous peptides (for example, from an infecting virus) and endogenous peptides, presenting them to T cells, an important step in the initiation of an immune response. If two persons do not share the same HLA antigens, T cells taken from one person will react vigorously to the mismatched HLA molecules on the surface of the cells from the other. These are reactions against so-called major HLA determinants. When compared with allogeneic transplanta-tion, autologous transplantation has the advantage of avoiding GVHD and associated complications; disadvantages are that the autologous cells lack the antitumor effect of an infusion of allogeneic leukocytes (the so-called graft versus tumor effect) and may contain viable tumor cells. (Answer: C—In allogeneic transplantations, if two persons do not share the same HLA antigens, B cells taken from one person will react vigorously to the mismatched HLA molecules on the surface of the cells from the other person)
45. A 20-year-old African-American patient with sickle cell disease was recently evaluated for hematopoiet-ic stem cell transplantation by his hematologist. He comes in to see you and is excited about the possi-bilities of cure but is concerned about possible complications of transplantations.
Which of the following statements regarding transplant complications is true?
❑ A. Late toxicity (occurring weeks to months after transplantation) is usu-ally the result of the preparative regimen and can include nausea, vomiting, skin rash, mucositis, and alopecia
❑ B. Graft failure that occurs after autologous transplantation can result from marrow damage before harvesting, during ex vivo treatment, during storage, after exposure to myelotoxic agents, or as a result of infections with cytomegalovirus (CMV) or human herpesvirus type 6 (HHV-6)
❑ C. Treatment of graft failure requires the use of higher doses of myelosup-pressive agents
❑ D. Veno-occlusive disease of the liver usually occurs after the first year and only rarely occurs in the subacute setting
Key Concept/Objective: To understand the complications of hematopoietic stem cell trans-plantation
Pretransplant preparative regimens are associated with a substantial array of toxicities, which vary considerably depending on the specific regimen used. For example, after the standard cyclophosphamide–total body irradiation regimen, nausea, vomiting, and mild skin erythema develop immediately in almost all patients. Oral mucositis inevitably devel-ops about 5 to 7 days after transplantation and usually requires narcotic analgesia. By 10 days after transplantation, complete alopecia and profound granulocytopenia have devel-oped in most patients. Veno-occlusive disease of the liver (also referred to as sinusoidal obstruction syndrome) is a serious complication of high-dose chemoradiotherapy; it devel-ops in approximately 10% to 20% of patients. Veno-occlusive disease of the liver, charac-terized by the development of ascites, tender hepatomegaly, jaundice, and fluid retention, may occur at any time during the first month after transplantation; the peak incidence occurs at around day 16. Approximately 30% of patients who develop veno-occlusive dis-ease of the liver die as a result of the disdis-ease, with progressive hepatic failure leading to a terminal hepatorenal syndrome. Although complete and sustained engraftment is the
gen-eral rule after transplantation, in some cases marrow function does not return; in other cases, after temporary engraftment, marrow function is lost. Graft failure after autologous transplantation can result from marrow damage before harvesting, during ex vivo treat-ment, during storage, or after exposure to myelotoxic agents after transplantation. Infec-tions with CMV or HHV-6 may also result in poor marrow function. Graft failure after allo-geneic transplantation may be the result of immunologically mediated graft rejection and is more common after conditioning regimens that are less immunosuppressive, in recipi-ents of T cell–depleted marrow, and in recipirecipi-ents of HLA-mismatched marrow. The treat-ment of graft failure begins with removal of all potentially myelosuppressive agents.
(Answer: B—Graft failure that occurs after autologous transplantation can result from marrow damage before harvesting, during ex vivo treatment, during storage, after exposure to myelotoxic agents, or as a result of infections with cytomegalovirus [CMV] or human herpesvirus type 6 [HHV-6])
46. A 49-year-old woman is admitted to the hospital for weight loss, fatigue, and night sweats. A CBC ordered in the emergency department revealed anemia, thrombocytosis, and pronounced leukocytosis with a relatively normal differential consistent with a myeloproliferative disorder. You are concerned that her symptoms may be caused by a hematologic malignancy.
Which of the following statements regarding hematopoietic stem cell transplantation for malignant disease is false?
❑ A. Hematopoietic stem cell transplantation is first-line therapy for chronic lymphocytic leukemia (CLL) and has a cure rate of 80%
❑ B. The best results with allogeneic transplantation for acute myeloid leukemia (AML) are obtained in patients undergoing transplantation in first remission
❑ C. Allogeneic transplantation can cure 15% to 20% of patients with acute lymphocytic leukemia (ALL) who fail induction therapy or in whom chemotherapy-resistant disease develops
❑ D. In CML, the best results from allogeneic transplants are obtained in patients who receive transplants within 1 year of diagnosis
Key Concept/Objective: To know the indications for hematopoietic stem cell transplantation in malignant diseases
Allogeneic marrow transplantation cures 15% to 20% of patients with AML who fail induc-tion therapy; indeed, it is the only form of therapy that can cure such patients. Thus, all patients 55 years of age or younger with newly diagnosed AML should have their HLA type determined, as should their families, soon after diagnosis to enable transplantation for those who fail induction therapy. The best results with allogeneic transplantation for AML are obtained in patients undergoing transplantation in first remission, in whom a cure rate of 40% to 70% is reported. As with AML, allogeneic transplantation can cure 15% to 20% of patients with ALL who fail induction therapy or in whom chemotherapy-resistant disease develops; thus, these patients are candidates for the procedure. Allogeneic and syngeneic marrow transplantations are the only forms of therapy known to cure CML. Time from diagnosis influences the outcome of transplantation during the chronic phase. The best results are obtained in patients who receive transplants within 1 year of diagnosis; progres-sively worse results are seen the longer the procedure is delayed. Use of marrow transplan-tation in CLL has received only limited attention, probably because of the indolent nature of the disease and its propensity to occur in older patients. (Answer: A—Hematopoietic stem cell transplantation is first-line therapy for chronic lymphoctic leukemia [CLL] and has a cure rate of 80%)
47. You are called to see a 26-year-old man in the hematology-oncology service because of fever and a low WBC count. He recently underwent induction chemotherapy for acute myelogenous leukemia. Yesterday, his absolute neutrophil count (ANC) was 500/mm3, and today it is 100/mm3. He has been anemic and thrombocytopenic but has not required transfusion. This morning, he developed a fever of 103.1° F (39.5° F). He has no focal central nervous sytem, respiratory, gastrointestinal, or urinary complaints other than severe stomatitis, caused by the chemotherapy. A careful physical examination fails to reveal any source of infection. Chest x-ray, blood and urine cultures, and a repeat complete blood count are ordered.
Which of the following would you recommend for this patient at this time?
❑ A. No treatment until culture results are known
❑ B. Lumbar puncture
❑ C. Intravenous gentamicin and piperacillin
❑ D. Oral ciprofloxacin
❑ E. Administration of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF)
Key Concept/Objective: To know the indications for empirical treatment of febrile neutropenia and the best antibiotic combination
Febrile neutropenia (ANC < 500/mm3) is an urgent indication for careful history and phys-ical examination, expedient collection of cultures, expedient use of radiography (e.g., chest x-ray), and initiation of empirical antibiotics. In febrile neutropenic patients, the most common sources of infection are the lungs, the genitourinary system, the GI tract, the oropharynx, and the skin. Initially, the infecting organisms are the usual flora or are infect-ing agents commonly found at the anatomic site of infection. However, in patients with recurrent infections or those who require prolonged courses of antibiotics, unusual organ-isms can be responsible for the infection. Frequently, the usual signs and symptoms of infection are attenuated or absent in these patients because of the absence of the inflam-matory responses to infection. In the neutropenic patient, minor infections that might oth-erwise have been well localized can become serious disseminated infections very quickly.
Management includes careful evaluation of the oropharynx, skin, lungs, GI tract, and gen-itourinary tract for subtle signs of infection. Cultures and a chest x-ray are obtained, and empirical antibiotics are started. Clinicians can select traditional combinations of a β-lac-tam antibiotic active against Pseudomonas (e.g., piperacillin) and an aminoglycoside (e.g., gentamicin or tobramycin). Although colony-stimulating factors may be considered for adjunctive use in selected high-risk, severely ill neutropenic patients, they are not indicat-ed in most febrile neutropenic patients. (Answer: C—Intravenous gentamicin and piperacillin)
48. A 23-year-old woman underwent allogeneic bone marrow transplantation for acute myelogenous leukemia. On day 11, she began to complain of right upper quadrant pain, and her weight began to climb. On examination, peripheral edema and tender hepatomegaly were appreciated. Skin examination was unremarkable. Laboratory testing revealed a bilirubin level of 2.4 mg/dl and an alanine amino-transferase level of 146 U/L. Over the next several days, she developed increasing abdominal girth, and her bilirubin level increased to 12 mg/dl.
What is the most likely diagnosis for this patient?
❑ A. Graft versus host disease (GVHD)
❑ B. Acute hepatitis A infection
❑ C. Acute cytomegalovirus infection
❑ D. Graft rejection
❑ E. Veno-occlusive disease of the liver
Key Concept/Objective: To recognize veno-occlusive disease as a potential complication of hematopoietic stem cell transplantation
This patient presents with typical findings of veno-occlusive disease, including ascites, hepatomegaly, jaundice, and fluid retention. Veno-occlusive disease typically occurs in the first few weeks after transplantation. Pathologically, there is cytotoxic injury to the hepat-ic venulae and sinusoidal endothelium, resulting in vascular blockage (the clinhepat-ical phepat-icture is similar to that of Budd-Chiari syndrome). There is a high mortality, and research contin-ues in the fields of treatment and prevention. Other possible causes include GVHD, viral hepatitis, drug reaction, sepsis, heart failure, and tumor invasion. However, acute ascites and fluid retention are more typical of veno-occlusive disease. (Answer: E—Veno-occlusive dis-ease of the liver)
49. A 42-year-old man presents with fatigue and progressive left upper quadrant pain. On examination, the spleen is palpable. CBC reveals a hematocrit of 32% and a WBC count of 97,000/mm3. Bone marrow biopsy reveals hyperplasia of the granulocytic series, and the cytogenetic analysis confirms the presence of the Philadelphia chromosome. A diagnosis of chronic myeloid leukemia (CML) is made.
What is the most appropriate step to take next for this patient?
❑ A. Search for HLA-matched sibling
❑ B. Initiate busulfan therapy
❑ C. Initiate interferon-alfa therapy
❑ D. Initiate hydroxyurea therapy
❑ E. Leukapheresis
Key Concept/Objective: To understand the role of allogeneic transplantation in chronic myeloge-nous leukemia
If an appropriate HLA-matched sibling can be found, most experts would recommend allo-geneic transplantation as initial therapy for a person younger than 50 years who is diag-nosed with CML. In older patients, therapy with interferon alfa or hydroxyurea may be more appropriate. Therefore, the search for potential donors is the critical first step.
Leukapheresis is only infrequently used (primarily in chronic lymphocyte leukemia) when white cell counts are extremely elevated and there are acute CNS symptoms. (Answer: A—
Search for HLA-matched sibling)
50. What is the chance that the sister of the patient in Question 48 will be an HLA match?
❑ A. 0%
❑ B. 10%
❑ C. 25%
❑ D. 50%
❑ E. 75%
Key Concept/Objective: To know the odds of finding an appropriate donor in a transplant candidate
The genes that encode HLA class I and II antigens are tightly linked and are typically inher-ited together. Therefore, there is a one-in-four chance of inheriting the identical haplotype of a sibling. (Answer: C—25%)
51. An 18-year-old woman underwent allogeneic bone marrow transplantation for Hodgkin disease that had failed to respond to first-line chemotherapy. Roughly 6 weeks after transplantation, she is diagnosed with acute GVHD.
Which of the following is not typically associated with GVHD?
❑ A. Abdominal pain
❑ B. Acute renal failure
❑ C. Maculopapular rash
❑ D. Diarrhea
❑ E. Elevation of hepatic transaminase levels
Key Concept/Objective: To understand the clinical presentation of acute GVHD
GVHD is quite common in patients receiving allogeneic transplants. The most common manifestation is that of a maculopapular rash, frequently involving the palms and soles.
The second most common organ affected is the liver. Symptoms of liver involvement typ-ically include an elevation in levels of transaminase, alkaline phosphatase, and conjugat-ed bilirubin; these changes are the result of damage to the small bile ducts. GI symptoms
include diarrhea, anorexia, and crampy abdominal pain. Efforts to prevent GVHD include the use of immunosuppressive agents in the early posttransplantation period. GVHD is most frequently treated with glucocorticoids. (Answer: B—Acute renal failure)
52. A 43-year-old man with CML is being evaluated for allogeneic bone marrow transplantation. On ques-tioning, he states that in the past, he had an allergic rash to trimethoprim-sulfamethoxazole.
What would be the most appropriate regimen for Pneumocystis carinii prophylaxis for this patient?
❑ A. Dapsone
❑ B. Atovaquone
❑ C. Attempted desensitization to sulfa before transplantation
❑ D. Intravenous pentamidine
❑ E. Aerosolized pentamidine
Key Concept/Objective: To appreciate the superiority of sulfa in preventing P. carinii infection in the transplant patient
P. carinii once caused pneumonia in up to 10% of transplant patients. The risk of this com-plication is nearly eliminated through the use of appropriate prophylaxis. Trimethoprim-sulfamethoxazole given 1 week before transplantation and then twice weekly after engraftment is very effective. The other agents listed as choices are all active against Pneumocystis, but trimethoprim-sulfamethoxazole is the most effective. Efforts should be made to desensitize the patient to sulfa. If these efforts are unsuccessful, dapsone is typi-cally used. (Answer: C—Attempted desensitization to sulfa before transplantation)
For more information, see Appelbaum FR: 5 Hematology: XI Hematopoietic Cell
Transplantation. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds. WebMD Inc., New York, April 2004