AUTOLOGOUS BONE MARROW TRANSPLANTATION IN ACUTE LEUKEMIA

For adult patients with acute leukemia in first complete remission (CR), modern dose-intensive consolidation chemotherapy produces a median remission duration of 12 to 18 months, with a 5-year recurrence-free survival rate of only 20% to 44%. 30,44,84,97 The mechanism of relapse is proliferation of leukemia cells that survive induction and consolidation chemotherapy; the effect of low-dose maintenance chemotherapy, debatable in adult acute lymphoblastic leukemia (ALL), is of no benefit in acute myelogenous leukemia (AML). 3,24,47,86,101 To prolong leukemia-free survival (LFS), a variety of dose-intensive postremission strategies have been evaluated, including myelosuppressive maintenance therapy, multiple and prolonged cycles of consolidation chemotherapy, allogeneic bone marrow transplantation (alloBMT), and autologous bone marrow transplantation (ABMT). 51 Because of high treatment-related mortality, the probability of survival after allogeneic transplant is similar to that which can be achieved by dose-intensive consolidation chemotherapy alone, at least for patients with AML. 51,57,104,107,115 Furthermore, allogeneic transplantation from a histocompatible sibling donor is available only to a limited number of younger patients. Autologous bone marrow transplantation allows the use of myeloablative preparative conditioning in a larger, unselected population of patients without the high risk of treatment-related morbidity and mortality of allogeneic transplantation. Autologous transplantation in patients with acute leukemia is done to derive the benefits of myeloablative preparative conditioning without the risk associated with allogeneic grafts. Autologous transplantation is not usually limited on the basis of age or prognostic features. Studies of ABMT were initially conducted in patients with relapsed acute leukemia, but patients receiving ABMT in first remission have demonstrated LFS rates of 30% to more than 50%, with treatment-related mortality rates of 10% to 20%. 2,18,21,22,82,87,90,100,116 An abiding concern in ABMT is the risk of leukemia-cell contamination; techniques such as purging with 4-hydroperoxycyclophosphamide (perfosfamide) may reduce leukemia-cell contamination of the infusate but may also contribute to treatment-related morbidity caused by prolonged myelosuppression. 32,89 Other techniques, such as cell selection or in vivo purging, are the subject of clinical trials. When compared with salvage chemotherapeutic regimens for relapsed and refractory acute leukemia, bone marrow transplantation may offer a survival advantage. Certainly alloBMT is the treatment of choice for eligible patients with resistant disease. 43,51,57,106,107,109 The mechanisms by which allogeneic transplantation cures leukemia are not fully understood. 42 Although leukemia may be treated effectively by the intensive chemoradiotherapy used during pretransplant conditioning, there is also evidence of an immunologic effect of the allogeneic graft. 113 Such evidence is derived from studies that report increased relapse rates following T lymphocyte–depleted transplantation, 27,64 when transplantation from identical twins are compared with transplantation from donors who are major histocompatibility complex (MHC)–matched siblings, 40,113 and an inverse relationship between the rate of graft-versus-host-disease (GvHD) and relapse. 14,78,113,114 In persons with resistant acute leukemia, intensive conditioning followed by alloBMT leads to long-term LFS rates of 20% to 30%, with an actuarial risk of relapse of 40% to 60%. 51,57,104,107,113,114 The major cause of mortality is recurrent leukemia, although other causes include GvHD, interstitial pneumonia, and organ failure. Although the results of alloBMT are superior to those of salvage chemotherapy, the small proportion of younger patients with MHC-matched donors means that this technique is not available to most patients. Autologous transplantation of unmanipulated bone marrow is available to a larger, unselected group of patients. Long-term LFS, however, must result from the myeloablative high-dose preparative regimen rather than from the transplantation itself. Despite studies reporting favorable results for ABMT compared with chemotherapy, the mechanism of action by which ABMT is purported to be effective may not differ from that of conventional chemotherapy.