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High-dose systemic methotrexate and IT methotrexate without cranial radiation therapy.
IT chemotherapy alone.
Current approaches to postremission therapy for adult ALL include short-term, relatively intensive chemotherapy followed by any of the following:
Longer-term therapy at lower doses (maintenance therapy).
Allogeneic bone marrow transplant.
Because the optimal postremission therapy for patients with ALL is still unclear, participation in clinical trials should be considered. (Refer to the B-cell (Burkitt) lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
Several trials, including studies from the Cancer and Leukemia Group B (CLB-8811) and the completed European Cooperative Oncology Group (ECOG-2993), of aggressive postremission chemotherapy for adult ALL have confirmed a long-term disease-free survival (DFS) rate of approximately 40%.[1,2,3,4,5,6,7]
In two series,[4,5] especially good prognoses were found for patients with T-cell lineage ALL, with DFS rates of 50% to 70% for patients receiving postremission therapy.
These series represent a significant improvement in DFS 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 was eliminated had outcomes inferior to those with extended treatment durations.[8,9] Imatinib has been incorporated into maintenance regimens in patients with Ph1-positive ALL.[10,11,12]
Evidence (Allogeneic and autologous BMT):
AlloBMT results in the lowest incidence of leukemic relapse, even when compared with a BMT 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 DFS 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.
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.[14,15,16,17] This was confirmed in the ECOG-2993 study.
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 decade.
The mortality from alloBMT using an HLA-matched sibling donor in these studies ranged from 20% to 40%.
Following on the results of 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; patients were accrued from 1993 to 2006. Patients with Ph1-negative ALL between the ages of 15 years and 59 years 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 therapy. Those patients lacking a donor were randomly assigned to receive either an autoBMT or maintenance chemotherapy. The primary outcome measured was overall survival (OS); event-free survival, relapse rate, and nonrelapse mortality were secondary outcomes. A total of 1,929 patients were registered and stratified according to age, white blood cell (WBC) count, and time to remission. High-risk patients were defined as those having a high WBC count at presentation or those older than 35 years.
Ninety percent of patients in this study achieved remission after induction therapy. Of these patients, 443 had an HLA-identical sibling, 310 of whom underwent an 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 a subgroup analysis, the advantage for patients with standard-risk ALL who had donors remained significant (OS = 62% vs. 52%; P = .02).
For patients with high-risk disease (older than 35 years or high WBC 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 suggest 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 patients with standard-risk adult ALL in first remission.[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.[Level of evidence: 2A]