Adult Acute Lymphoblastic Leukemia Treatment (Professional) (cont.)
Treatment for Adult ALL in Remission
Standard Treatment Options for Adult ALL in Remission
Standard treatment options for adult ALL in remission include the following:
- Postremission therapy, including the following:
- Ongoing treatment with a Bcr-abl tyrosine kinase inhibitor such as imatinib, nilotinib, or dasatinib.
- Autologous or allogeneic bone marrow transplant (BMT).
- Central nervous system (CNS) prophylaxis therapy, including the following:
- Cranial radiation therapy plus intrathecal (IT) methotrexate.
- 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]
The use of matched unrelated donors for alloBMT is currently under evaluation but, because of its current high treatment-related morbidity and mortality, it is reserved for patients in second remission or beyond. The dose of total-body radiation therapy administered is associated with the incidence of acute and chronic GVHD and may be an independent predictor of leukemia-free survival.[Level of evidence: 3iiB]
Evidence (B-cell ALL):
Aggressive cyclophosphamide-based regimens similar to those used in aggressive non-Hodgkin lymphoma have shown improved outcome of prolonged DFS for patients with B-cell ALL (L3 morphology, surface immunoglobulin positive).
- Retrospectively reviewing three sequential cooperative group trials from Germany, one group of investigators found the following:
- A marked improvement in survival, from zero survivors in a 1981 study that used standard pediatric therapy and lasted 2.5 years, to a 50% survival rate in two subsequent trials that used rapidly alternating lymphoma-like chemotherapy and were completed within 6 months.
CNS prophylaxis therapy
The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease. Some authors have suggested that there is a subgroup of patients at low risk for CNS relapse for whom CNS prophylaxis may not be necessary. However, this concept has not been tested prospectively.
Aggressive CNS prophylaxis remains a prominent component of treatment. This report, which requires confirmation in other cooperative group settings, is encouraging for patients with L3 ALL. Patients with surface immunoglobulin and L1 or L2 morphology did not benefit from this regimen. Similarly, patients with L3 morphology and immunophenotype, but unusual cytogenetic features, were not cured with this approach. A WBC count of less than 50,000 per microliter predicted improved leukemia-free survival in a univariate analysis.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult acute lymphoblastic leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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- Goldstone AH, Richards SM, Lazarus HM, et al.: In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 111 (4): 1827-33, 2008.
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- Yanada M, Takeuchi J, Sugiura I, et al.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 24 (3): 460-6, 2006.
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- Corv˛ R, Paoli G, Barra S, et al.: Total body irradiation correlates with chronic graft versus host disease and affects prognosis of patients with acute lymphoblastic leukemia receiving an HLA identical allogeneic bone marrow transplant. Int J Radiat Oncol Biol Phys 43 (3): 497-503, 1999.
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- Kantarjian HM, Walters RS, Smith TL, et al.: Identification of risk groups for development of central nervous system leukemia in adults with acute lymphocytic leukemia. Blood 72 (5): 1784-9, 1988.
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