Adult Acute Lymphoblastic Leukemia in Remission
Current approaches to postremission therapy for adult acute lymphoblastic leukemia (ALL) include short-term, relatively intensive chemotherapy followed by longer-term therapy at lower doses (maintenance), high-dose marrow-ablative chemotherapy or chemoradiation therapy with allogeneic stem cell rescue (alloBMT), and high-dose therapy with autologous stem cell rescue (autoBMT). Several trials, including a Cancer and Leukemia Group B study (CLB-8811), of aggressive postremission chemotherapy for adult ALL have confirmed a long-term, disease-free survival rate of approximately 40%.[1,2,3,4,5] In the latter two series, especially good prognoses were found for patients with T-cell lineage ALL, with disease-free survival rates of 50% to 70% for patients receiving postremission therapy. These series represent a significant improvement in disease-free survival rates over previous, less intensive chemotherapeutic approaches. In contrast, poor cure rates were demonstrated in patients with Philadelphia chromosome (Ph1)-positive ALL, B-cell lineage ALL with an L3 phenotype (surface immunoglobulin positive), and B-cell lineage ALL characterized by t(4;11). Administration of the newer dose-intensive schedules can be difficult and should be performed by physicians experienced in these regimens at centers equipped to deal with potential complications. Studies in which continuation or maintenance chemotherapy were eliminated had outcomes inferior to those with extended treatment durations.[6,7] Imatinib has been incorporated into maintenance regimens in patients with Ph1-postive ALL.[8,9,10]
AlloBMT results in the lowest incidence of leukemic relapse, even when compared with a bone marrow transplant from an identical twin (syngeneic BMT). This finding has led to the concept of an immunologic graft-versus-leukemia effect similar to graft-versus-host disease (GVHD). The improvement in disease-free survival in patients undergoing alloBMT as primary postremission therapy is offset, in part, by the increased morbidity and mortality from GVHD, veno-occlusive disease of the liver, and interstitial pneumonitis.[11]
Despite significant improvements in long-term, disease-free survival in children treated for cancer,[1] cancer remains the second leading disease-related cause of death for children in the United States behind injury, congenital causes, and heart disease.[2] For more than half of children for whom frontline treatment fails, treatment using relapse and disease recurrence clinical trials (phase I and phase II) and unrelated hematopoietic stem cell transplantation is common.[3] For children, this...
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The results of a series of retrospective and prospective studies published between 1987 and 1994 suggest that alloBMT or autoBMT as postremission therapy offer no survival advantage over intensive chemotherapy, except perhaps for patients with high risk or Ph1 positive ALL.[12,13,14,15] The use of alloBMT as primary postremission therapy is limited by both the need for an HLA-matched sibling donor and the increased mortality from alloBMT in patients in their fifth or sixth decades. The mortality from alloBMT using an HLA-matched sibling donor in these studies ranged from 20% to 40%.
Following on the results of these earlier studies, the International ALL Trial (ECOG-2993) was launched as an attempt to examine the role of transplant as postremission therapy for ALL more definitively and accrued patients from 1993 to 2006.[16] Patients with Ph1 negative ALL between the ages of 15 to 59 received identical multiagent induction therapy resembling previously published regimens.[1,2,3] Patients in remission were then eligible for HLA typing; patients with a fully matched sibling donor underwent alloBMT as consolidation. Those patients lacking a donor were randomly assigned to receive either an autoBMT or maintenance chemotherapy. The primary outcome measured was overall survival (OS), with event-free survival, relapse rate, and nonrelapse mortality as secondary endpoints. A total of 1,929 patients were registered and stratified according to age, white blood cell count, and time-to-remission. High-risk patients were defined as those having a high white blood cell count at presentation or those older than age 35. Ninety percent of patients in this study achieved remission after induction therapy. Of these patients, 443 were found to have an HLA-identical sibling, 310 of whom underwent alloBMT. For the 456 patients in remission who were eligible for transplant but lacked a donor, 227 received chemotherapy alone, while 229 underwent an autoBMT. By donor-to-no-donor analysis, standard risk ALL patients with an HLA-identical sibling had a 5-year OS of 53% compared with 45% for patients lacking a donor (P = .01). In subgroup analysis, the advantage for patients with donors remained significant for patients with standard risk ALL (OS = 62% vs. 52%; P = .02). For patients with high-risk disease (age older than 35 or high white blood cell count), the difference in OS was 41% versus 35% (donor vs. no donor), but was not significant (P = .2). Relapse rates were significantly lower (P < .00005) for both standard and high-risk patients with HLA-matched donors. In contrast to alloBMT, autoBMT was less effective than maintenance chemotherapy as postremission treatment (5-year OS = 46% for chemotherapy vs. 37% for autoBMT; P = .03). The results of this trial seem to confirm the existence of a graft versus leukemia effect for adult Ph1 negative ALL and support the use of sibling donor alloBMT as the consolidation therapy providing the greatest chance for long term survival for standard risk adult ALL in first remission.[16][Level of evidence: 2A] The results also suggest that in the absence of a sibling donor, maintenance chemotherapy is preferable to autoBMT as postremission therapy.[16][Level of evidence: 2A]
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