Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL)

Abstract

The best strategy for incorporating imatinib in front-line treatment of Ph ؉ acute lymphoblastic leukemia (ALL) has not been established. We enrolled 92 patients with newly diagnosed Ph ؉ ALL in a prospective, multicenter study to investigate sequentially 2 treatment schedules with imatinib administered concurrent to or alternating with a uniform induction and consolidation regimen. Coadministration of imatinib and induction cycle 2 (INDII) resulted in a complete remission (CR) rate of 95% and polymerase chain reaction (PCR) negativity for BCR-ABL in 52% of patients, compared with 19% in patients in the alternating treatment cohort (P ‫؍‬ .01). Remarkably, patients with and without a CR after induction cycle 1 (INDI) had similar hematologic and molecular responses after concurrent imatinib and INDII. In the concurrent cohort, grades III and IV cytopenias and transient hepatotoxicity necessitated interruption of induction in 87% and 53% of patients, respectively; however, duration of induction was not prolonged when compared with patients receiving chemotherapy alone. No imatinib-related severe hematologic or nonhematologic toxicities were noted with the alternating schedule. In each cohort, 77% of patients underwent allogeneic stem cell transplantation (SCT) in first CR (CR1). Both schedules of imatinib have acceptable toxicity and facilitate SCT in CR1 in the majority of patients, but concurrent administration of imatinib and chemotherapy has greater antileukemic

Comparable long‐term outcomes after reduced‐intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for adult high‐risk acute lymphoblastic leukemia in complete remission

“…The combination of imatinib with conventional chemotherapy as the first-line treatment has demonstrated an improved CR rate and an increased applicability in allogeneic SCT, thus allowing better outcomes in adults with Ph-positive ALL [33][34][35][36][37]. Previously, we also conducted a prospective, phase II trial of allogeneic SCT following firstline imatinib-based chemotherapy, and our recently updated results continue to show the positive impact of imatinib on long-term outcomes of allogeneic SCT [21][22][23].…”

Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia

“…[1][2][3][4][5][6] However, with an extended follow-up, a substantial proportion of transplant patients and practically almost all non-transplant patients continue to die as a result of relapse. Consequently, patients at the highest risk of relapse are likely to benefit from the identification of new criteria that enable predictable patient outcome.…”

“…[9][10][11] Most published studies in the imatinib era include quantitative MRD findings, [1][2][3][4][5][6] but the longterm outcome in relation to molecular response to any given therapeutic approach remains to be determined. Previously, we conducted a prospective, phase 2 trial of allogeneic SCT following first-line imatinib-based chemotherapy in adults with Ph-positive ALL, and in the trial, BCR-ABL1 transcript levels in the bone marrow (BM) were routinely monitored using real-time quantitative PCR (RQ-PCR).…”

Treatment of Adult Acute Lymphoblastic Leukemia

“…Molecular remission may be defined as a level of minimal residual disease (MRD) after induction therapy below the detection limit of clone-specific PCR, which is generally 10 -4 (i.e., 0.01% blasts or 1 blast in 10,000 normal cells); the frequency of molecular CR in adult ALL certainly depends on the type of induction therapy, and so far few results are available. CR ranges from 50% for Ph + ALL treated with imatinib and chemotherapy 20 to 60% for standard risk ALL 21 and is thereby significantly lower than in pediatric ALL.…”