Adult Acute Lymphoblastic Leukemia in Remission
Current Clinical Trials
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 (CALGB-8811), of aggressive postremission chemotherapy for adult ALL now confirm a
long-term disease-free survival rate of approximately 40%.[1-5] 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.[8-10]
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]
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.[12-15] 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.[1-3] 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]
The use of alloBMT as primary postremission therapy is limited
both by the need for an HLA-matched sibling donor and by the increased
mortality from alloBMT in patients in their fifth or sixth decade. The mortality
from alloBMT using an HLA-matched sibling donor ranges from 20% to 40%,
depending on the study. The use of matched unrelated donors for alloBMT is
currently under evaluation but, because of its current high treatment-related
morbidity and mortality, 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.[17][Level of evidence: 3iiB]
Aggressive cyclophosphamide-based regimens similar to those used in aggressive
non-Hodgkin lymphoma have shown improved outcome of prolonged disease-free
status for patients with B-cell ALL (L3 morphology, surface immunoglobulin
positive).[18] Retrospectively reviewing three sequential cooperative group trials
from Germany, Hoelzer and colleagues found 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. 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
but 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 white blood cell count of less than 50,000 per
microliter predicted improved leukemia-free survival in univariate analysis.
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.)
Standard treatment options for central nervous system (CNS) prophylaxis:
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.[19]
- Cranial radiation therapy plus intrathecal (IT) methotrexate.
- High-dose systemic methotrexate and IT methotrexate without cranial
radiation therapy.
- IT chemotherapy alone.
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
References
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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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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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