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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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Preemptive Interferon-α Therapy Could Protect Against Relapse and Improve Survival of Acute Myeloid Leukemia Patients After Allogeneic Hematopoietic Stem Cell Transplantation: Long-Term Results of Two Registry Studies
Shen, M. Z., Zhang, X. H., Xu, L. P., Wang, Y., Yan, C. H., Chen, H., Chen, Y. H., Han, W., Wang, F. R., Wang, J. Z., et al
Frontiers in immunology. 2022;13:757002
Abstract
For allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, preemptive interferon-α (IFN-α) therapy is considered as a useful method to eliminate the minimal residual disease (MRD). Our purpose is to assess the long-term efficacy of preemptive IFN-α therapy in acute myeloid leukemia (AML) patients following allo-HSCT based on two registry studies (#NCT02185261 and #NCT02027064). We would present the final data and unpublished results of long-term clinical outcomes with extended follow-up. We adopted polymerase chain reaction (PCR) and multiparameter flow cytometry (MFC) to monitor MRD, and a positive result of bone marrow specimen examined by either of them would be identified as the MRD-positive status. Subcutaneous injections of recombinant human IFN-α-2b were performed for 6 cycles, and prolonged IFN-α therapy could be permitted at the request of patients. The median cycles were 3.5 (range, 0.5-30.5) cycles. A total of 9 patients suffered from grade ≥3 toxicities (i.e., infectious: n = 6; hematologic: n = 3). The 6-year cumulative incidences of relapse and non-relapse mortality following IFN-α therapy were 13.0% (95% confidence interval [CI], 5.4-20.6%) and 3.9% (95%CI, 0.0-17.6%), respectively. The probability of disease-free survival at 6 years following IFN-α therapy was 83.1% (95%CI, 75.2-91.9%). The probability of overall survival at 6 years following IFN-α therapy was 88.3% (95%CI, 81.4-95.8%). The cumulative incidences of total chronic graft-versus-host disease (cGVHD) and severe cGVHD at 6 years following IFN-α therapy were 66.2% (95%CI, 55.5-77.0%) and 10.4% (95%CI, 3.6-17.2%), respectively. Multivariable analysis showed that an alternative donor was associated with a lower risk of relapse and the better disease-free survival. Thus, preemptive IFN-α therapy could clear MRD persistently, prevent relapse truly, and improve long-term survival in AML patients following allo-HSCT.
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Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: A retrospective analysis by the chronic malignancies working party on behalf of European Society for Blood and Marrow Transplantation (EBMT)
Polverelli, N., Mauff, K., Kröger, N., Robin, M., Beelen, D., Beauvais, D., Chevallier, P., Mohty, M., Passweg, J., Rubio, M. T., et al
American Journal of Hematology. 2021;96(1):69-79
Abstract
The role of spleen size and splenectomy for the prediction of post-allogeneic hematopoietic stem cell transplant (allo-HCT) outcome in myelofibrosis remains under debate. In EBMT registry, we identified a cohort of 1195 myelofibrosis patients transplanted between 2000-2017 after either fludarabine-busulfan or fludarabine-melphalan regimens. Overall, splenectomy was performed in 202 (16.9%) patients and its use decreased over time (28.3% in 2000-2009 vs 14.1% in 2010-2017 period). By multivariate analysis, splenectomy was associated with less NRM (HR 0.64, 95% CI 0.44-0.93, P = .018) but increased risk of relapse (HR 1.43, 95% CI 1.01-2.02, P = .042), with no significant impact on OS (HR 0.86, 95% CI 0.67-1.12, P = .274). However, in subset analysis comparing the impact of splenectomy vs specific spleen sizes, for patients with progressive disease, an improved survival was seen in splenectomised subjects compared to those patients with a palpable spleen length ≥ 15 cm (HR 0.44, 95% CI 0.28-0.69, P < .001), caused by a significant reduction in NRM (HR 0.26, 95% CI 0.14-0.49, P < .001), without significantly increased relapse risk (HR 1.47, 95% CI 0.87-2.49, P = .147). Overall, despite the possible biases typical of retrospective cohorts, this study highlights the potential detrimental effect of massive splenomegaly in transplant outcome and supports the role of splenectomy for myelofibrosis patients with progressive disease and large splenomegaly.
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Maintenance tyrosine kinase inhibitors following allo-HCT for chronic myeloid leukemia: A CIBMTR Study
DeFilipp, Z., Ancheta, R., Liu, Y., Hu, Z. H., Gale, R. P., Snyder, D., Schouten, H. C., Kalaycio, M., Hildebrandt, G. C., Ustun, C., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myeloid leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML transplanted from 2007-2014 who received maintenance TKI following HCT (n=89) as compared to no TKI maintenance (n=301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy prior to HCT. The majority of patients had disease beyond CP1 at HCT (n=240, 62%). The study was conducted as a landmark analysis, excluding patients that died, relapsed, had chronic graft-versus-host disease or were censored prior to Day 100 following HCT. Of the 89 patients receiving TKI maintenance, 77 (87%) received a single TKI while 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n=50), imatinib (n=27) and nilotinib (n=27). As measured from Day 100, the adjusted estimates for 5-year relapse (maintenance, 35% vs. no maintenance, 26%; p=0.11), leukemia-free survival (LFS, maintenance, 42% vs. no maintenance, 44%; p=0.65) or overall survival (OS, maintenance, 61% vs. no maintenance, 57%; p=0.61) did not significantly differ between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by the status of disease prior to transplant. In conclusion, our data did not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes in a Day 100 landmark analysis. The optimal approach to TKI administration in the post-transplant setting in CML remains undetermined.
PICO Summary
Population
Adult patients with CML transplanted from 2007-2014 (n=390)
Intervention
Maintenance TKI following HCT (n=89)
Comparison
no TKI maintenance (n=301)
Outcome
As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; ) or overall survival (maintenance, 61% versus no maintenance, 57%; ) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation.
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Interferon-alpha Is Effective for Treatment of Minimal Residual Disease in Patients with t(8;21) Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation: Results of a Prospective Registry Study
Mo, X. D., Wang, Y., Zhang, X. H., Xu, L. P., Yan, C. H., Chen, H., Chen, Y. H., Qin, Y. Z., Liu, K. Y., Huang, X. J.
The oncologist. 2018
Abstract
BACKGROUND RUNX1-RUNX1T1 transcript levels were established as a powerful marker for predicting relapse in patients with t(8;21) acute myeloid leukemia (AML). We aimed to identify the efficacy of minimal residual disease (MRD)-directed interferon-alpha (IFN-alpha) treatment in patients with t(8;21) AML who were positive for MRD after allogeneic hematopoietic stem cell transplantation (allo-HSCT; n=42). SUBJECTS, MATERIALS, AND METHODS MRD-positive status was defined as a <4.5-log reduction from diagnosis in RUNX1-RUNX1T1 transcripts and/or the loss of a ≥4.5-log reduction after 3 months after HSCT. Patients with positive MRD received six cycles of IFN-alpha treatment (twice or thrice weekly of every 4 weeks cycle). RESULTS The 1-year cumulative incidence of severe acute and chronic graft-versus-host disease after MRD-directed IFN-alpha treatment was 7.1% and 4.8%, respectively. After the treatment, 15 (35.7%), 5 (11.9%), 3 (7.1%), and 9 (21.5%) patients achieved MRD negativity at 1, 2, 3, and >3 months, respectively. Three patients relapsed after the IFN-alpha treatment, in which the 1-year cumulative incidence of relapse was 7.2%. One patient died of severe infection at 460 days after treatment. The 1-year probabilities of event-free survival, disease-free survival, and overall survival after treatment were 76.0%, 92.4%, and 92.5%, respectively. The clinical outcomes in patients who received MRD-directed IFN-alpha treatment were significantly better than those of the MRD-positive patients without any interventions in the historical cohort. CONCLUSION MRD-directed IFN-alpha treatment is effective for patients with t(8;21) AML who were MRD-positive after allo-HSCT. The study was registered at http://clinicaltrials.gov as NCT02027064. IMPLICATIONS FOR PRACTICE In patients with t(8;21) acute myeloid leukemia (AML), the presence of post-allogeneic hematopoietic stem cell transplantation (allo-HSCT) minimal residual disease (MRD), measured by RUNX1-RUNX1T1 transcript levels, has been established as a powerful marker for predicting relapse. Interferon-alpha (IFN-alpha) could exert a relatively strong graft-versus-leukemia effect, and MRD-directed IFN-alpha treatment is effective for patients with t(8;21) AML who were MRD-positive after allo-HSCT.
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Impact of post-transplantation maintenance therapy on health-related quality of life in patients with multiple myeloma: data from the Connect(R) MM Registry
Abonour, R., Wagner, L., Durie, B. G. M., Jagannath, S., Narang, M., Terebelo, H. R., Gasparetto, C. J., Toomey, K., Hardin, J. W., Kitali, A., et al
Annals of hematology. 2018
Abstract
Maintenance therapy after autologous stem cell transplantation (ASCT) is recommended for use in multiple myeloma (MM); however, more data are needed on its impact on health-related quality of life (HRQoL). Presented here is an analysis of HRQoL in a Connect MM registry cohort of patients who received ASCT +/- maintenance therapy. The Connect MM Registry is one of the earliest and largest, active, observational, prospective US registry of patients with symptomatic newly diagnosed MM. Patients completed the Functional Assessment of Cancer Therapy-MM (FACT-MM) version 4, EuroQol-5D (EQ-5D) questionnaire, and Brief Pain Inventory (BPI) at study entry and quarterly thereafter until death or study discontinuation. Patients in three groups were analyzed: any maintenance therapy (n = 244), lenalidomide-only maintenance therapy (n = 169), and no maintenance therapy (n = 137); any maintenance and lenalidomide-only maintenance groups were not mutually exclusive. There were no significant differences in change from pre-ASCT baseline between any maintenance (P = 0.60) and lenalidomide-only maintenance (P = 0.72) versus no maintenance for the FACT-MM total score. There were also no significant differences in change from pre-ASCT baseline between any maintenance and lenalidomide-only maintenance versus no maintenance for EQ-5D overall index, BPI, FACT-MM Trial Outcomes Index, and myeloma subscale scores. In all three groups, FACT-MM, EQ-5D Index, and BPI scores improved after ASCT; FACT-MM and BPI scores deteriorated at disease progression. These data suggest that post-ASCT any maintenance or lenalidomide-only maintenance does not negatively impact patients' HRQoL. Additional research is needed to verify these findings.
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IFN-alpha Is Effective for Treatment of Minimal Residual Disease in Patients with Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: Results of a Registry Study
Mo, X. D., Zhang, X. H., Xu, L. P., Wang, Y., Yan, C. H., Chen, H., Chen, Y. H., Han, W., Wang, F. R., Wang, J. Z., et al
Biology of Blood & Marrow Transplantation. 2017;23(8):1303-1310
Abstract
The efficacy of minimal residual disease (MRD)-directed IFN-alpha treatment was investigated in acute leukemia patients who were positive for MRD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n=107). MRD-positive status was defined as positivity for leukemia-associated aberrant immune phenotypes or positivity for Wilms' tumor gene 1 in a single bone marrow sample. Recombinant human IFN-alpha-2b injections were administered subcutaneously 2 to 3 times per week for 6 months. The 2-year cumulative incidence of severe acute and chronic graft-versus-host disease after IFN-alpha treatment was 5.7% and 6.6%, respectively. Eighty-one patients (75.7%) turned MRD-negative after IFN-alpha treatment 1 month (42; 39.3%), 2 months (6; 5.6%), 3 months (7; 6.5%), and >3 months (26; 24.3%) after MRD-directed IFN-alpha treatment. Twelve patients showed relapse after IFN-alpha treatment, and 7 died of relapse. Four patients died of nonrelapse mortality (NRM). The 2-year cumulative incidence of relapse, relapse mortality, and NRM after IFN-alpha treatment was 11.5%, 6.8%, and 4.3%, respectively. The 2-year probabilities of event-free survival, disease-free survival, and overall survival after IFN-alpha treatment were 66.5%, 82.4%, and 87.4%, respectively. Persistent MRD after IFN-alpha treatment was significantly associated with higher relapse risk and poorer survival. Thus, MRD-directed IFN-alpha treatment is effective for patients who were MRD-positive after allo-HSCT. The study was registered at http://clinicaltrials.gov as NCT02185261.Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.