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 chemoradiotherapy with allogeneic stem cell rescue (alloBMT), and high-dose therapy with autologous stem cell rescue (autoBMT). Several trials of aggressive postremission chemotherapy for adult ALL now confirm a long-term disease-free survival rate of approximately 40%. In the latter 2 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-positive (Ph+) 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.

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. The results of a retrospective study showed a similar outcome to that for intensive chemotherapy for patients receiving alloBMT in first remission in both the International Bone Marrow Transplant Registry and the German chemotherapy trial (Berlin-Frankfurt-Munster). In a prospective French trial, adults with ALL in remission and who were younger than age 40 years received alloBMT if a sibling donor was available or were randomly assigned to either ongoing chemotherapy or autoBMT. There was no advantage to alloBMT for the group of patients with standard-risk ALL.There was, however, significant survival benefit to alloBMT for patients with high-risk ALL (CD10-; B-cell lineage ALL with a white blood cell count >30,000; Ph1+ ALL). This trial confirms the experience of a single institution that suggested the utility of alloBMT for the cure of high-risk ALL. The long-term survival of patients in the French randomized study who received chemotherapy and autoBMT was identical. 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 5th or 6th 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 irradiation administered is associated with the incidence of acute and chronic GVHD and may be an independent predictor of leukemia-free survival.

Aggressive cyclophosphamide-based regimens similar to those used in aggressive non-Hodgkin's lymphoma have shown improved outcome of prolonged disease-free status for patients with B-cell ALL (L3 morphology, surface immunoglobulin positive). Retrospectively reviewing 3 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 2 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.