Administration of imatinib after allogeneic hematopoietic stem cell transplantation may improve disease-free survival for patients with Philadelphia chromosome-positive acute lymphobla stic leukemia

Abstract

BackgroundMaintenance therapy with imatinib during the post-transplant period has been used for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL); however, its efficacy has not been demonstrated. A study was designed to investigate the safety of imatinib and its efficacy in preventing hematological relapse and improving disease-free survival (DFS) when administered after allogeneic hematopoietic stem cell transplantation (allo-HCT).MethodsPatients with Ph + ALL that received allo-HCT were enrolled in the study. Real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to detect BCR-ABL transcript levels. Imatinib therapy was initiated if patient neutrophil counts were > 1.0 × 109/L and platelet counts were > 50.0 × 109/L, or if they displayed either elevated BCR-ABL transcript levels in two consecutive tests, or a BCR-ABL transcript level ≥ 10-2 after initial engraftment. Patients receiving imatinib after relapse were assigned to the non-imatinib group. The imatinib treatment was scheduled for 3–12 months, until BCR-ABL transcript levels were negative at least for three consecutive tests or complete molecular remission was sustained for at least 3 months.ResultsA total of 82 patients were enrolled. Sixty-two patients initiated imatinib therapy post-HCT. Imatinib therapy was initiated at a median time of 70 days post-HCT. Grade 3–4 adverse events (AEs) occurred in 17.7% of patients. Ten patients (16.1%) terminated imatinib therapy owing to AEs. Among the patients in imatinib and non-imatinib groups, the estimated 5-year relapse rate was 10.2% and 33.1% (p = 0.016), and the 5-year probability of DFS was 81.5% and 33.5% (p = 0.000) with the median follow-up of 31 months (range, 2.5-76 months) and 24.5 months (range, 4–72 months), respectively. Multivariate analysis identified imatinib maintenance therapy post-HCT as an independent prognostic factor for DFS (p = 0.000, hazard ratio [HR] =4.8) and OS (p = 0.000, HR = 6.2).ConclusionsThese results indicate that relapse rate can be reduced and DFS may be improved in Ph + ALL patients with imatinib maintenance therapy after HCT. BCR-ABLmonitoring by qRT-PCR can guide maintenance therapy with imatinib including initiation time and treatment duration after allo-HCT.

Haploidentical hematopoietic SCT may be superior to conventional consolidation/maintenance chemotherapy as post-remission therapy for high-risk adult ALL

“…20 In addition, the decreased relapse rate may be owing to some preemptive strategies for preventing relapse, such as risk-stratified DLI 10 or low-dose IL-2, 8 which is administered at our center, and early prophylactic imatinib for Phpositive ALL patients after transplantation. 7,21 The toxicity of transplantation in previous studies may explain why a reduced relapse rate did not translate to improved survival. In the Medical Research Council and Eastern Cooperative Oncology Group study, the 5-year relapse rate was significantly lower in high-risk patients who received transplantations (donor vs no donor, 37% vs 63%, P o0.001).…”

Presence of CD34+CD38−CD58− leukemia-propagating cells at diagnosis identifies patients at high risk of relapse with Ph chromosome-positive ALL after allo-hematopoietic SCT

“…5 Our previous study demonstrated that patients treated with imatinib maintenance therapy guided by BCR-ABL monitoring by RQ-PCR after allo-HSCT have a lower estimated 5-year relapse rate (10.2%) compared with patients not treated with imatinib (33.1%). 3 However, challenges remain in implementing the experimentally validated biomarkers for recurrence prediction for risk-stratification therapy in Ph + ALL after allo-HSCT. In agreement with our previous report for de novoPh + ALL, 13 the novel CD34 + CD38 − CD58 − LPC phenotype has significant power to identify patients at high risk for relapse post HSCT.…”

“…[17][18][19][20] Imatinib treatment was scheduled for 3-12 months post HSCT, after the BCR-ABL transcript levels were negative for at least three consecutive tests or major molecular remission (MMR) was sustained for at least 3 months, as described in our previous report. 3 Minimal residual disease (MRD) assessment BCR/ABL transcript levels in BM samples were monitored at diagnosis; directly before transplantation; 1, 2, 3, 6, 9, 12, 24, 36 and 60 months post HSCT; and at relapse using RQ-PCR as previously described. 20,21 In patients with a 41log rising level of BCR/ABL transcripts, monitoring was performed every 2 weeks.…”

“…Nevertheless, relapse is still the main cause of treatment failure even after allo-HSCT. 1,[3][4][5] Once patients experience a relapse, the outcomes are extremely unfavorable. Therefore, it is imperative to identify novel prognostic factors to predict relapse in Ph + ALL after allo-HSCT.…”

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

“…Both studies argue in favor of a maintenance therapy with imatinib after transplant in patients with a positive MRD evaluation, and this has also been suggested in more recent studies. 46,47 In contrast, Yanada et al 38 observed no association between rapid achievement of BCR-ABL1 negativity and long-term outcome after an initial imatinib/chemotherapy induction regimen, and the GRAAL group also reported that early MRD evaluation did not significantly influence patient outcome, either in terms of OS or DFS. 20 One issue that remains open to discussion concerning the role of MRD is represented by the substantial differences in the way PCR for BCR-ABL1 detection is performed, how results are reported in different laboratories worldwide, and the timing of MRD evaluation.…”