To determine whether graft-versus-leukemia (GVL) reactions are important in preventing leukemia recurrence after bone marrow transplantation, we studied 2,254 persons receiving HLA-identical sibling bone marrow transplants for acute myelogenous leukemia (AML) in first remission, acute lymphoblastic leukemia (ALL) in first remission, and chronic myelogenous leukemia (CML) in first chronic phase. Four groups were investigated in detail: recipients of non--T-cell depleted allografts without graft-versus-host disease (GVHD), recipients of non-- T-cell depleted allografts with GVHD, recipients of T-cell depleted allografts, and recipients of genetically identical twin transplants. Decreased relapse was observed in recipients of non--T-cell depleted allografts with acute (relative risk 0.68, P = .03), chronic (relative risk 0.43, P = .01), and both acute and chronic GVDH (relative risk 0.33, P = .0001) as compared with recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect of GVHD. AML patients who received identical twin transplants had an increased probability of relapse (relative risk 2.58, P = .008) compared with allograft recipients without GVHD. These data support an antileukemia effect of allogeneic grafts independent of GVHD. CML patients who received T-cell depleted transplants with or without GVHD had higher probabilities of relapse (relative risks 4.45 and 6.91, respectively, P = .0001) than recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect independent of GVHD that is altered by T-cell depletion. These results explain the efficacy of allogeneic bone marrow transplantation in eradicating leukemia, provide evidence for a role of the immune system in controlling human cancers, and suggest future directions to improve leukemia therapy.
To determine whether graft-versus-leukemia (GVL) reactions are important in preventing leukemia recurrence after bone marrow transplantation, we studied 2,254 persons receiving HLA-identical sibling bone marrow transplants for acute myelogenous leukemia (AML) in first remission, acute lymphoblastic leukemia (ALL) in first remission, and chronic myelogenous leukemia (CML) in first chronic phase. Four groups were investigated in detail: recipients of non--T-cell depleted allografts without graft-versus-host disease (GVHD), recipients of non-- T-cell depleted allografts with GVHD, recipients of T-cell depleted allografts, and recipients of genetically identical twin transplants. Decreased relapse was observed in recipients of non--T-cell depleted allografts with acute (relative risk 0.68, P = .03), chronic (relative risk 0.43, P = .01), and both acute and chronic GVDH (relative risk 0.33, P = .0001) as compared with recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect of GVHD. AML patients who received identical twin transplants had an increased probability of relapse (relative risk 2.58, P = .008) compared with allograft recipients without GVHD. These data support an antileukemia effect of allogeneic grafts independent of GVHD. CML patients who received T-cell depleted transplants with or without GVHD had higher probabilities of relapse (relative risks 4.45 and 6.91, respectively, P = .0001) than recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect independent of GVHD that is altered by T-cell depletion. These results explain the efficacy of allogeneic bone marrow transplantation in eradicating leukemia, provide evidence for a role of the immune system in controlling human cancers, and suggest future directions to improve leukemia therapy.
Graft failure was analyzed in 625 patients receiving allogeneic bone marrow transplants from HLA-identical sibling donors as treatment for severe aplastic anemia. Sixty-eight (11%) had no or only transient engraftment. Second bone marrow transplants were successful in achieving extended survival in 16 of 27 patients with transient initial engraftment but in none of ten patients with no sign of engraftment after the first transplant. The major factors associated with a reduced risk of graft failure were use of radiation for pretransplant immunosuppression and use of cyclosporine rather than methotrexate or T- cell depletion of the donor bone marrow for prophylaxis against graft-v- host disease (GVHD). Among 266 patients prepared for transplantation with cyclophosphamide alone, the risk of graft failure was increased in patients who received previous transfusions and reduced in those who received corticosteroids for previous therapy. Neither cell dose nor administration of donor buffy coat cells affected the probability of engraftment. Although use of radiation in conditioning reduced graft failure, survival was not improved. Posttransplant treatment with cyclosporine and avoidance of pretransplant blood transfusions were associated with improved survival.
Chronic graft-versus-host disease (GVHD) is an important complication of bone marrow transplantation. We analyzed risk factors for chronic GVHD in 2,534 recipients of HLA-identical sibling transplants surviving at least 90 days after transplantation. The actuarial probability of developing chronic GVHD within three years posttransplant was 46% +/- 3% (95% confidence interval). The most important risk factor for chronic GVHD was acute GVHD. The 3-year probabilities of chronic GVHD were 28% +/- 3%, 49% +/- 5%, 59% +/- 6%, 80% +/- 9%, and 85% +/- 15% for persons with grades 0, I, II, III, and IV acute GVHD, respectively (P less than .0001). Among patients with no or grade I acute GVHD, recipient age greater than 20 years, use of non-T-cell depleted bone marrow, and alloimmune female donors for male recipients predicted a higher risk of chronic GVHD. When all three adverse risk factors were present, the probability of chronic GVHD was 62% among persons with no prior acute GVHD and 85% among those with grade I acute GVHD. Among patients with grade II through IV acute GVHD, no other risk factor predicted chronic GVHD. These data identify individuals who might benefit from treatment strategies aimed at changing the incidence of chronic GVHD.
About 30% of adults with acute lymphoblastic leukemia (ALL) and 20% to 40% of children and adults with acute myelogenous leukemia (AML) never achieve remission, even with intensive chemotherapy. Most die of resistant leukemia, often within 6 months or less. In this study of 126 patients with resistant ALL or AML, allogeneic bone marrow transplants from HLA-identical siblings produced remissions in 113 of 115 (98%) evaluable patients. The 3-year probability of leukemia-free survival was 21% (95% confidence interval, 15% to 29%). Leukemia-free survival was similar in ALL (23%, 12% to 40%) and AML (21%, 14% to 31%). Only 3 of 27 patients at risk relapsed more than 2 years posttransplant.
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