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1.
Safety and efficacy of post-haematopoietic cell transplantation maintenance therapy with blinatumomab for relapsed/refractory CD19-positive B-cell acute lymphoblastic leukaemia: protocol for a phase I-II, multicentre, non-blinded, non-controlled trial (JPLSG SCT-ALL-BLIN21)
Sakaguchi, H., Umeda, K., Kato, I., Sakaguchi, K., Hiramatsu, H., Ishida, H., Yabe, H., Goto, H., Kawahara, Y., Yamashita, Y. I., et al
BMJ open. 2023;13(4):e070051
Abstract
INTRODUCTION Relapsed and refractory B-cell acute lymphoblastic leukaemia (R/R-B-ALL) is linked to a significant relapse rate after allogeneic haematopoietic cell transplantation (allo-HCT) in children, adolescents and young adults (CAYA). No standard treatment has been established to prevent relapse after allo-HCT for R/R-B-ALL, which is an unmet medical need. The administration of blinatumomab after allo-HCT is expected to enhance the antileukaemic effect on residual CD19-positive blasts by donor-derived CD3-positive T-cells. METHODS AND ANALYSIS The goal of this multicentre, open-label, uncontrolled, phase I-II clinical trial is to assess the safety and effectiveness of post-transplant maintenance therapy with blinatumomab for CAYA patients (25 years old or younger) with CD19-positive R/R-B-ALL who have received allo-HCT beyond first complete remission (CR) and have CR with haematological recovery between 30 and 100 days after allo-HCT. Eighty-five paediatric institutions in Japan are participating in this study. Forty-one patients will enrol within 2.25-year enrolment period and follow-up period is 1 year. The primary endpoints are the treatment completion rate for phase I study and the 1-year graft-versus-host disease-free/relapse-free survival rate for phase II study, respectively. ETHICS AND DISSEMINATION This research was approved by the Central Review Board at National Hospital Organization Nagoya Medical Center (Nagoya, Japan) on 21 January 2022 and was registered at the Japan Registry of Clinical Trials (jRCT) on 3 March 2022. Written informed consent is obtained from all patients and/or their guardians. The results of this study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER jRCTs041210154.
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2.
Maintenance Treatment With Low-Dose Decitabine After Allogeneic Hematopoietic Cell Transplantation in Patients With Adult Acute Lymphoblastic Leukemia
Liu, J., Jiang, Z. X., Xie, X. S., Wan, D. M., Cao, W. J., Wang, M., Liu, Z. Z., Dong, Z. K., Wang, H. Q., Lu, R. Q., et al
Frontiers in oncology. 2021;11:710545
Abstract
BACKGROUND Post-transplant relapse remains a principal leading cause of failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with adult acute lymphoblastic leukemia (ALL). The aim of this study was to investigate the efficacy and safety of low-dose decitabine on the prevention of adult ALL relapse after allo-HSCT. METHODS In this prospective study, we enrolled 34 patients with ALL who underwent allo-HSCT from August 2016 to April 2020 and received low-dose decitabine maintenance treatment after transplantation. The primary objectives were cumulative incidence of relapse rate (CIR), overall survival (OS), and disease-free survival (DFS). The secondary objectives were graft-versus-host disease (GVHD) and safety. RESULTS Among the enrolled 34 patients, 6 patients relapsed and 6 patients died. The 2-year CIR, OS, and DFS were 20.2, 77.5, and 73.6%, respectively. Subgroup analysis revealed the 2-year CIR, OS, and DFS rates of 12 patients with T-ALL/lymphoblastic lymphoma (LBL) were 8.3, 90, and 81.5%, respectively. None of the seven patients with T-ALL relapsed. During maintenance treatment, only one patient (2.9%) developed grade IV acute GVHD and four (11.8%) patients had severe chronic GVHD. Thirty-two patients (94.1%) developed only grade I to II myelosuppression, and two patients (5.8%) developed grade III to IV granulocytopenia. CONCLUSIONS Maintenance treatment with low-dose decitabine after allo-HSCT may be used as a therapeutic option to reduce relapse in patients with adult ALL, especially in patients with T-ALL. Our findings require confirmation in larger-scale controlled trials. CLINICAL TRIAL REGISTRATION Chinese Clinical Trials Registry, identifier ChiCTR1800014888.
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Blinatumomab Maintenance After Allogeneic Hematopoietic Cell Transplantation for B-lineage Acute Lymphoblastic Leukemia
Gaballa, M. R., Banerjee, P. P., Milton, D. R., Jiang, X., Ganesh, C., Khazal, S. J., Nandivada, V., Islam, S., Kaplan, M., Daher, M., et al
Blood. 2021
Abstract
Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single center phase II study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least one cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44-105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute GVHD grades 2-4 and 3-4 were 33% and 5%, respectively; two cases of mild (10%) and one case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival, progression-free survival, and non-relapse mortality rates were 85%, 71%, and 0%, respectively. In a matched-analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab's efficacy. Correlative studies of baseline and post-treatment samples identified patients with specific T-cell profiles as "responders" or "non-responders" to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Non-responders were T-cell deficient and expressed more inhibitory checkpoint molecules, including TIM3. We found that blinatumomab post-allogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment.
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4.
Post-transplantation Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography in Patients with Lymphoblastic Lymphoma is an Independent Prognostic Factor with an Impact on Progression-Free Survival but not Overall Survival
Dai, N., Liu, H., Deng, S., Sang, S., Wu, Y.
Technology in cancer research & treatment. 2021;20:15330338211056478
Abstract
Purpose: In the present study, we mainly aimed to evaluate the prognostic value of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]F-FDG) positron emission tomography (PET)/computed tomography (CT) after allogeneic stem cell transplantation (allo-SCT) in lymphoblastic lymphoma (LBL) patients using Deauville Scores (DS). Materials and Methods: A total of 63 LBL patients who benefited from (18)F-FDG PET-CT after allo-SCT in our institution between April 2010 and August 2020 were enrolled in this retrospective study. These above-mentioned patients were divided into two groups based on the Deauville criteria. Diagnostic efficiency of (18)F-FDG PET/CT and integrated CT in detecting lymphoma were calculated. Consistencies were evaluated by comparing 18F-FDG PET/CT and integrated CT results through kappa coefficient. Kaplan-Meier method was used in survival analysis, and the log-rank method was adopted in comparisons. Prognostic factor analysis was performed by the Cox regression model. Results: The sensitivity, specificity, positive predictive value, negative predictive value, accuracy of post-SCT (18)F-FDG PET-CT were 100%(12/12), 92.2%(47/51), 75.0%(12/16), 100%(47/47) and 93.7%(59/63). The consistency of 18F-FDG PET-CT and integrated CT was moderate(Kappa?=?.702,P?.001). Positive post-SCT 18F-FDG PET-CT was associated with lower progression-free survival (PFS) but not overall survival (OS) (p?=?.000 and p?=?.056, respectively). The 3-year PFS of the PET-positive group and PET-negative group was 18.8% and 70.2%, respectively. Multivariate analysis showed that post-SCT PET-CT findings was an independent prognostic factor for PFS (p?=?.000; HR, 3.957; 95%CI, 1.839-8.514). Other factors independently affecting PFS were sex (p?=?.018; HR, 2.588; 95% CI, 1.181?-?5.670) and lactate dehydrogenase (LDH) (p?=?.005; HR, 3.246; 95% CI, 1.419?-?7.426). However, none of the above-mentioned factors were associated with OS. Conclusions: Collectively, we found that 18F-FDG PET-CT after allo-SCT was a strong indicator for PFS, but not OS, which might provide important evidence for the selection of subsequent treatment regimen for LBL patients. Trial registration number: ChiCTR2100046709.
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5.
Preemptive interferon-a treatment could protect against relapse and improve long-term survival of ALL patients after allo-HSCT
Liu, S., Luo, X., Zhang, X., Xu, L., Wang, Y., Yan, C., Chen, H., Chen, Y., Han, W., Wang, F., et al
Scientific reports. 2020;10(1):20148
Abstract
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).
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6.
Tyrosine kinase inhibitor prophylaxis after transplant for Philadelphia chromosome-positive acute lymphoblastic leukemia
Akahoshi, Y., Nishiwaki, S., Mizuta, S., Ohashi, K., Uchida, N., Tanaka, M., Fukuda, T., Ozawa, Y., Takahashi, S., Onizuka, M., et al
Cancer science. 2019
Abstract
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.
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Relapse Prevention with Tyrosine Kinase Inhibitors after Allogeneic Transplantation for Ph+ ALL, A Systematic Review
Warraich, Z., Tenneti, P., Thai, T., Hubben, A., Amin, H., McBride, A., Warraich, S., Hannan, A., Warraich, F., Majhail, N., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
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.
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8.
Administration of imatinib after allogeneic hematopoietic stem cell transplantation may improve disease-free survival for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia
Chen, Huan, Liu, Kai-yan, Xu, Lan-ping, Liu, Dai-hong, Chen, Yu-hong, Zhao, Xiang-yu, Han, Wei, Zhang, Xiao-hui, Wang, Yu, Zhang, Yuan-yuan, et al
J Hematol Oncol. 2012;5:29
Abstract
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.