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

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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) 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%. Transplant morbidity and mortality are increased among adults, due mainly to the higher risk of chronic GVHD and serious infections. Graft rejection was historically a major determinant of outcome in transplant for aplastic anemia, perhaps related to the underlying pathophysiology
as well as to alloimmunization from transfusions (the latter now much improved by leukocyte depletion before blood product administration). Most patients do not have a suitable sibling donor. Occasionally, a full phenotypic match can be found within the family and serve as well. Far more available are other alternative donors, either unrelated but histocompatible volunteers or closely but not perfectly matched family members. Survival using alternative donors is about half that of conventional sibling transplants but improving with higher-resolution HLA matching and more effective conditioning regimens and GVHD prophylaxis. Patients will be at risk for late complications, especially a higher rate of cancer, if radiation is used as a component of conditioning. Immunosuppression Used alone, ALG or antithymocyte globulin (ATG) induces hematologic recovery (independence from transfusion and a leukocyte count adequate to prevent infection) in about 50% of patients. The addition of cyclosporine to either ALG or ATG has further increased response rates to about 70% and especially improved outcomes for children and for severely neutropenic patients. Such combined treatment is now standard for patients with severe disease. An early robust hematologic response strongly correlates with long-term survival. Improvement in granulocyte number is generally apparent within 2 months of
treatment. Most recovered patients continue to have some degree of blood count depression, the MCV remains elevated, and the bone marrow cellularity returns toward normal only very slowly, if at all. Relapse (recurrent pancytopenia) is frequent, often occurring as cyclosporine is discontinued; most, but not all, patients respond to reinstitution of immunosuppression, but some responders become dependent on continued cyclosporine administration. Development of MDS, with typical marrow morphologic or cytogenetic abnormalities, occurs in about 15% of treated patients, usually but not invariably associated with a return of pancytopenia, and some patients develop leukemia. A laboratory diagnosis of PNH can generally be made at the time of presentation of aplastic anemia by flow cytometry; recovered patients may have frank hemolysis if the PNH clone expands. Bone marrow examinations should be performed if there is an unfavorable change in blood counts. Horse ATG is given at 40 mg/kg per day for 4 days; rabbit ALG is administered at 3.5 mg/kg per day for 5 days. For ATG, anaphylaxis is a rare but occasionally fatal complication; allergy can be tested by a skin-prick test with an undiluted solution and immediate observation; desensitization is feasible. ATG binds to peripheral blood cells; therefore, platelet and granulocyte numbers may fall further during active treatment. Serum sickness, a flu-like illness with a characteristic cutaneous eruption and arthralgia, often develops about 10 days after initiating treatment. Methylprednisolone, 1 mg/kg per day for 2 weeks, can
ameliorate the immune consequences of heterologous protein infusion. Excessive or 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 blood levels obtained every 2 weeks. Trough levels should be between 150 and 200 ng/mL. The most important side effects of chronic cyclosporine treatment are nephrotoxicity, hypertension, seizures, and opportunistic infections, especially Pneumocystis carinii (prophylactic treatment with monthly inhaled pentamidine is recommended). Most patients with aplastic anemia lack a suitable marrow donor, and immunosuppression is the treatment of choice. Overall survival is equivalent with transplantation and immunosuppression. However, successful transplant cures marrow failure, while patients who recover adequate blood counts after immunosuppression remain at risk of relapse and malignant evolution. Because of excellent results in children and younger adults, allogeneic transplant should be performed if a suitable sibling donor is available. Increasing age and the severity of neutropenia are the most important factors weighing in the decision between transplant and immunosuppression in adults who have a matched family donor: older patients do better with ATG and cyclosporine, whereas transplant is preferred if granulocytopenia is profound. Some patients may prefer
immunosuppression; transplant is used for failure to recover blood counts or occurrence of late complications.