Preemptive interferon-a treatment could protect against relapse and improve long-term survival of ALL patients after allo-HSCT
Scientific reports. 2020;10(1):20148
Relapse was the major cause of treatment failure in patients with acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to identify the efficacy and safety of preemptive interferon-a (IFN-a) treatment in ALL patients who had minimal residual disease (MRD) after allo-HSCT. Multiparameter flow cytometry and polymerase chain reaction assays were applied for MRD monitoring. Recombinant human IFN-a-2b injections were administered subcutaneously twice weekly in every 4 weeks cycle. Twenty-four (35.3%), 5 (7.4%), 6 (8.8%), and 13 (19.1%) patients achieved MRD negativity at 1, 2, 3, and >?3 months, respectively, after treatment. Seven patients showed grade =?3 toxicities after IFN-a treatment. The 4-year cumulative incidence of total acute graft-versus-host disease (aGVHD), severe aGVHD, total chronic GVHD (cGVHD), and severe cGVHD after treatment was 14.7%, 2.9%, 40.0%, and 7.5%, respectively. The 4-year cumulative incidences of relapse and non-relapse mortality after treatment was 31.9% and 6.0%, respectively. The 4-year probabilities of disease-free survival and overall survival after IFN-a treatment were 62.1% and 71.1%, respectively. Thus, preemptive IFN-a treatment could protect against relapse and improve long-term survival for ALL patients who had MRD after allo-HSCT. The study was registered at https://clinicaltrials.gov as #NCT02185261 (09/07/2014).
Effect of Prophylactic Post-transplant Ponatinib Administration on Outcomes in Patients With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia
Clinical lymphoma, myeloma & leukemia. 2020
BACKGROUND The objective of the present retrospective study was to evaluate the effect of ponatinib administration as maintenance therapy on the outcomes after allogeneic hematopoietic stem cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. PATIENTS AND METHODS We retrospectively analyzed the data from 34 consecutive patients treated at our institution from January 2008 to June 2019. We had administered post-transplant tyrosine kinase inhibitors preemptively before December 2017. Thereafter, we had initiated the prophylactic use of post-transplant ponatinib. The initial ponatinib dose was 15 mg/d. Ponatinib plasma trough levels were measured using the liquid chromatography-tandem mass spectrometry method 8 days after the first administration and subsequently. RESULTS Nine patients received ponatinib maintenance. The 2-year overall survival and leukemia-free survival in the ponatinib maintenance group tended to be better than that in the non-ponatinib group (100% vs. 70.5%, P = .10; and 100% vs. 50.8%, P = .02, respectively). In the first 7 of the 9 consecutive patients, the median plasma concentration after ponatinib administration (15 mg/d) was 15.6 ng/mL (range, 4.8-23.3 ng/mL). Although the treatment schedule for 1 patient was altered because of adverse effects (elevation of serum amylase and neutropenia), ponatinib administration was continued for all the patients, except for 1 patient with molecular relapse. One patient developed a transient elevation of serum lipase. No patient presented with any arterial occlusive events. CONCLUSION Our results have indicated that the strategy of ponatinib maintenance after allogeneic hematopoietic stem cell transplantation is safe, efficacious, and promising.
Relapse Prevention with Tyrosine Kinase Inhibitors after Allogeneic Transplantation for Ph+ ALL, A Systematic Review
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
BACKGROUND Relapse after stem cell transplantation for Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL) remains a significant challenge. In this systematic review, we compare survival outcomes of second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib with first generation imatinib when these agents are used after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Ph-positive ALL. In addition, we review the literature on TKI use to prevent relapse in patients who proceed to allo-HSCT beyond first complete response (>CR1). METHODS We performed database searches (inception to Jan 2018) using PubMed, Cochrane Library, and Embase. After exclusions, seventeen articles were included in this analysis. RESULTS Imatinib was used post-transplant either prophylactically or pre-emptively in 12 studies, of which 7 were prospective studies and 5 being retrospective studies. The overall survival (OS) for most prospective studies at 1.5-3 and 5 years ranged between 62-92% and 74.5-86.7%. The disease-free survival (DFS) at 1.5-5 years was 60.4-92%. Additionally, imatinib failed to show survival benefit in patients who were in >CR1 at the time of Allo-HSCT. The cumulative OS for most retrospective studies using Imatinib at 1-2 and 3-5 years was 42-100% and 33-40% respectively. The event free survival (EFS) at 1-2 and 3-5 years was 33.3-67% and 20-31% respectively. Dasatinib was used as maintenance treatment in three retrospective studies (n=34). The OS for patients with Ph+ ALL with utilization of dasatinib as maintenance regimen after Allo-HSCT at 1.4- 3 years was 87-100% and DFS at 1.4-3 years was 89- 100%. 93% of patients with minimal residual disease (MRD) positive status after allo-HSCT became MRD negative. Three prospective studies used Nilotinib. In two studies where investigators studied patients with advanced chronic myeloid leukemia and Ph-positive ALL, the cumulative OS and EFS at 7.5 months- 2 years was 69-84% and 56-84% with nilotinib. In another study (n=5) with Ph+ ALL, nilotinib use resulted in OS at 5 years of 60%. CONCLUSIONS Our review showed utilization of TKI (all generations) post allo-HSCT for patients in CR1 improved OS when given as prophylactic or pre-emptive regimen. Limited data suggests that second generation TKI (Dasatinib) has better OS especially in patients with MRD positive status. Imatinib did not improve OS in patients that were in >CR1 at time of allo-HSCT; for this population, no data was available with newer generation TKI. The evaluation of survival benefit with newer generation TKI and their efficacy in >CR1 patients needs further study in large randomised clinical trials.
Tyrosine kinase inhibitor prophylaxis after transplant for Philadelphia chromosome-positive acute lymphoblastic leukemia
Cancer science. 2019
Tyrosine kinase inhibitor (TKI) administration after allogeneic hematopoietic stem cell transplantation (HSCT) may carry a survival benefit in Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Therefore, we investigated whether TKI prophylaxis for negative-minimal residual disease (MRD) after HSCT would improve their outcomes in this nationwide retrospective cohort study. We included patients with Ph+ ALL who underwent their first allogeneic HSCT between 2001 and 2016, received TKI before HSCT, and achieved negative-MRD status within 180 days after HSCT. Of 850 patients for inclusion, 50 patients received TKI prophylaxis, mostly imatinib or dasatinib (median dose: 400 mg with imatinib and 40 mg with dasatinib). In a multivariate analysis, disease status at HSCT was the sole risk factor for relapse (hazard ratio, 3.58; P < 0.001 for positive-MRD with CR, and hazard ratio, 6.13; P < 0.001 for active disease). TKI prophylaxis was not associated with a decreased risk of relapse or superior overall survival in either the whole cohort or in the analysis limited to negative-MRD or positive-MRD with CR1 at HSCT. Meanwhile, TKI prophylaxis limited to dasatinib might be associated with a decreased risk of relapse (hazard ratio, 0.34; P = 0.140), unlike imatinib. Alternative strategies using new generation TKIs for high-risk patients are warranted to improve the outcomes after allogeneic HSCT. This article is protected by copyright. All rights reserved.
Administration of imatinib after allogeneic hematopoietic stem cell transplantation may improve disease-free survival for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia
J Hematol Oncol. 2012;5:29
BACKGROUND Maintenance 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). METHODS Patients 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 x 10(9)/L and platelet counts were > 50.0 x 10(9)/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. RESULTS A 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). CONCLUSIONS These 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.