Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 8)

Hematopoietic Stem Cell Transplantation This is the best therapy for the young patient with a fully histocompatible sibling donor (Chap. 108). Human leukocyte antigen (HLA) typing should be ordered as soon as the diagnosis of aplastic anemia is established in a child or younger adult. In transplant candidates, transfusion of blood from family members should be avoided so as to prevent sensitization to histocompatibility antigens; while transfusions in general should be minimized, limited numbers of blood products probably do not seriously affect outcome.For allogeneic transplant from fully matched siblings, long-term survival rates for children are 80–90%. ...
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Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 8) Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 8) Hematopoietic Stem Cell Transplantation This is the best therapy for the young patient with a fully histocompatiblesibling donor (Chap. 108). Human leukocyte antigen (HLA) typing should beordered as soon as the diagnosis of aplastic anemia is established in a child oryounger adult. In transplant candidates, transfusion of blood from family membersshould be avoided so as to prevent sensitization to histocompatibility antigens;while transfusions in general should be minimized, limited numbers of bloodproducts probably do not seriously affect outcome. For allogeneic transplant from fully matched siblings, long-term survivalrates for children are 80–90%. Transplant morbidity and mortality are increasedamong adults, due mainly to the higher risk of chronic GVHD and seriousinfections. Graft rejection was historically a major determinant of outcome intransplant for aplastic anemia, perhaps related to the underlying pathophysiologyas well as to alloimmunization from transfusions (the latter now much improvedby leukocyte depletion before blood product administration). Most patients do not have a suitable sibling donor. Occasionally, a fullphenotypic match can be found within the family and serve as well. Far moreavailable are other alternative donors, either unrelated but histocompatiblevolunteers or closely but not perfectly matched family members. Survival usingalternative donors is about half that of conventional sibling transplants butimproving with higher-resolution HLA matching and more effective conditioningregimens and GVHD prophylaxis. Patients will be at risk for late complications,especially a higher rate of cancer, if radiation is used as a component ofconditioning. Immunosuppression Used alone, ALG or antithymocyte globulin (ATG) induces hematologicrecovery (independence from transfusion and a leukocyte count adequate toprevent infection) in about 50% of patients. The addition of cyclosporine to eitherALG or ATG has further increased response rates to about 70% and especiallyimproved outcomes for children and for severely neutropenic patients. Suchcombined treatment is now standard for patients with severe disease. An earlyrobust hematologic response strongly correlates with long-term survival.Improvement in granulocyte number is generally apparent within 2 months oftreatment. Most recovered patients continue to have some degree of blood countdepression, the MCV remains elevated, and the bone marrow cellularity returnstoward normal only very slowly, if at all. Relapse (recurrent pancytopenia) isfrequent, often occurring as cyclosporine is discontinued; most, but not all,patients respond to reinstitution of immunosuppression, but some respondersbecome dependent on continued cyclosporine administration. Development ofMDS, with typical marrow morphologic or cytogenetic abnormalities, occurs inabout 15% of treated patients, usually but not invariably associated with a returnof pancytopenia, and some patients develop leukemia. A laboratory diagnosis ofPNH can generally be made at the time of presentation of aplastic anemia by flowcytometry; recovered patients may have frank hemolysis if the PNH cloneexpands. Bone marrow examinations should be performed if there is anunfavorable change in blood counts. Horse ATG is given at 40 mg/kg per day for 4 days; rabbit ALG isadministered at 3.5 mg/kg per day for 5 days. For ATG, anaphylaxis is a rare butoccasionally fatal complication; allergy can be tested by a skin-prick test with anundiluted solution and immediate observation; desensitization is feasible. ATGbinds to peripheral blood cells; therefore, platelet and granulocyte numbers mayfall further during active treatment. Serum sickness, a flu-like illness with acharacteristic cutaneous eruption and arthralgia, often develops about 10 days afterinitiating treatment. Methylprednisolone, 1 mg/kg per day for 2 weeks, canameliorate the immune consequences of heterologous protein infusion. Excessiveor extended glucocorticoid therapy is associated with avascular joint necrosis.Cyclosporine is administered orally at an initial dose of 12 mg/kg per day in adults(15 mg/kg per day in children), with subsequent adjustment according to bloodlevels obtained every 2 weeks. Trough levels should be between 150 and 200ng/mL. The most important side effects of chronic cyclosporine treatment arenephrotoxicity, hypertension, seizures, and opportunistic infections, especiallyPneumocystis carinii (prophylactic treatment with monthly inhaled pentamidine isrecommended). Most patients with aplastic anemia lack a suitable marrow donor, andimmunosuppression is the treatment of choice. Overall survival is equivalent withtransplantation and immunosuppression. However, successful transplant curesmarrow failure, while patients who recover adequate blood counts afterimmunosuppression remain at risk of relapse and malignant evolution. Because ofexcellent results in children and younger adults, allogeneic transplant should beperformed if a suitable sibling donor is available. Increasing age and the severityof neutropenia are the most important factors weighing in the decision betweentransplant and immunosuppression in adults who have a matched family donor:older patients do better with ATG and cyclosporine, whereas transplant ispreferred if granulocytopenia is profound. Some patients may preferimmunosuppression; transplant is used for failure to recover blood counts oroccurrence of late complications.