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1.
Prophylactic maintenance with venetoclax/azacitidine after reduced intensity conditioning allo-transplant for high risk MDS and AML
Garcia, J. S., Kim, H. T., Murdock, H. M., Ansuinelli, M., Brock, J., Cutler, C. S., Gooptu, M., Ho, V. T., Koreth, J., Nikiforow, S., et al
Blood advances. 2024
Abstract
We conducted a phase 1 trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) in patients with high risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) undergoing reduced intensity allogeneic hematopoietic stem cell transplantation following venetoclax and FluBu2-conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT (55.6% prior venetoclax exposure and 96% molecular measurable residual disease (MRD)-positive), 22 received maintenance therapy with azacitidine 36 mg/m2 intravenously on days 1-5 and venetoclax 400 mg by mouth on days 1-14 on one of two schedules (42-day cycles x 8 or 28-day cycles x 12). During maintenance, the most common grade 3/4 adverse events were leukopenia, neutropenia and thrombocytopenia, which were transient and manageable. Infections were uncommon (n=4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% CI, 0.3-18%) and 22% (95% CI, 9-40%). After a median follow-up of 25-months among survivors, median overall survival (OS) was not reached. In the 22 patients who received Ven/Aza maintenance, the 2-year OS, progression-free survival, non-relapse mortality, and cumulative incidence of relapse rates were 67% (95% CI, 43-83%), 59% (95% CI, 36-76%), 0%, and 41% (95% CI, 20-61%), respectively. Immune monitoring demonstrated no significant impact on T cell expansion, but identified reduced B cell expansion compared to controls. This study demonstrates prophylactic Ven/Aza maintenance can be safely administered in high risk MDS/AML patients, but a randomized study is required to properly assess any potential benefit. (NCT03613532).
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2.
Comparison of long-term outcomes between imatinib and dasatinib prophylaxis after allogeneic stem cell transplantation in patients with Philadelphia-positive acute lymphoblastic leukemia: A multicenter retrospective study
Guan, F., Yang, L., Chen, Y., Shi, J., Song, X., Lai, X., Lu, Y., Liu, L., Ouyang, G., Zhao, Y., et al
Cancer. 2024
Abstract
BACKGROUND Although the prognosis of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) has improved with the introduction of tyrosine kinase inhibitors (TKIs) and stem cell transplantation, prevention of relapse after transplantation remains a concern. The aim of this study was to compare the impact of TKI prophylaxis with imatinib and dasatinib on long-term outcomes after transplantation. METHODS Patients with Ph+ ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) and received TKI prophylaxis after allo-HSCT were included in this retrospective analysis. Two cohorts were established based on the choice of TKI prophylaxis: the imatinib (Ima) and dasatinib (Das) cohorts. The survival and safety outcomes of these cohorts were compared. RESULTS Ninety-one patients in the Ima cohort and 50 in the Das cohort were included. After a median follow-up of 50.6 months, the 5-year cumulative incidence of relapse, nonrelapse mortality rate, and overall survival in the Ima and Das cohorts were 16.1% and 12.5%, 5.2% and 9.8%, and 86.5% and 77.6%, respectively, with no statistical differences. The cumulative incidence of mild chronic graft-versus-host disease was higher in the Das cohort. The most common adverse event was neutropenia (64.7% vs. 69.5%). The Das cohort had a higher incidence of gastrointestinal bleeding (25.5% vs. 2.3%) and gastrointestinal reaction (48.9% vs. 31.4%) than the Ima cohort. The proportion of patients treated on schedule was significantly lower in the Das cohort than in the Ima cohort, and drug intolerance was the main reason for protocol violation. CONCLUSIONS For patients with Ph+ ALL undergoing allo-HSCT in CR1, imatinib prophylaxis achieved long-term outcomes similar to those of dasatinib.
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3.
Effects of post-transplant maintenance therapy with decitabine prophylaxis on the relapse for acute lymphoblastic leukemia
Fan, J., Lu, R., Zhu, J., Guo, X., Wan, D., Xie, X., Cao, W., Zhang, Y., Zhao, H., Li, Y., et al
Bone marrow transplantation. 2023
Abstract
In adults with acute lymphoblastic leukemia (ALL), post-transplant relapse is a major risk factor for mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our study investigated the efficacy and safety of decitabine (dec) with ALL patients post-transplantation. We performed a retrospective cohort study to assess the efficacy of decitabine (dec) with post-transplant ALL at the First Affiliated Hospital of Zhengzhou University from February 2016 to September 2021. A total of 141 consecutive ALL patients were analyzed and divided into decitabine (dec, n = 65) and control (ctrl, n = 76) groups based on whether they were treated with decitabine after allo-HSCT. The 3-year cumulative incidence of relapse (CIR) rate in the dec group was lower than that in the ctrl group (19.6 vs. 36.1%, p = 0.031), with a hazard ratio of 0.491 (95% confidence interval [CI], 0.257-0.936). Additionally, subgroup analyses revealed that the 3-year CIR rate of T-ALL and Ph-negative B-ALL patients in the dec and ctrl groups was 11.7 vs. 35.9% and 19.5 vs. 42.2% (p = 0.035, p = 0.068) respectively. In summary, ALL patients, especially those with T-ALL and Ph-negative B-ALL, may benefit from decitabine as maintenance therapy following allo-HSCT.
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4.
Preemptive interferon-α therapy could prevent relapse of acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation: A real-world analysis
Fan, S., Pan, T. Z., Dou, L. P., Zhao, Y. M., Zhang, X. H., Xu, L. P., Wang, Y., Huang, X. J., Mo, X. D.
Frontiers in immunology. 2023;14:1091014
Abstract
INTRODUCTION Measurable residual disease (MRD)-directed interferon-a treatment (i.e. preemptive IFN-α treatment) can eliminate the MRD in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, this study aimed to further assess its efficacy in a multicenter retrospective study in a real-world setting. METHODS A total of 247 patientswho received preemptive IFN-α treatment were recruited from 4 hospitals in China. The protocols for MRD monitoring mainly based on quantitative polymerase chain reaction [qPCR] and multiparameter flow cytometry [MFC]. RESULTS The median duration of IFN-α treatment was 56 days (range, 1-1211 days). The cumulative incidences of all grades acute graft-versus-host disease (aGVHD), all grades chronic graft-versus-host disease (cGVHD), and severe cGVHD at 3 years after IFN-α therapy were 2.0% (95% confidence interval [CI], 0.3-3.8%), 53.2% (95% CI, 46.8-59.7%), and 6.2% (95% CI, 3.1-9.2%), respectively. The cumulative incidence of achieving MRD negative state at 2 years after IFN-α treatment was 78.2% (95% CI, 72.6-83.7%). The 3-year cumulative incidences of relapse and non-relapse mortality following IFN-α therapy were 20.9% (95% CI, 15.5-26.3%) and 4.9% (95%CI, 2.0-7.7%), respectively. The probabilities of leukemia-free survival and overall survival at 3 years following IFN-α therapy were 76.9% (95% CI, 71.5-82.7%) and 84.2% (95% CI, 78.7-90.1%), respectively. Multivariable analysis showed that MRD positive state by qPCR and MFC before IFN-α treatment, high-risk disease risk index before allo-HSCT, and receiving identical sibling donor HSCT were associated with a higher risk of relapse and a poorer leukemia-free survival. Severe cGVHD was associated with an increased risk of non-relapse mortality. DISCUSSION Thus, real-world data suggest that preemptive IFN-α is effective for treating patients with AML with MRD after allo-HSCT.
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5.
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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6.
Chidamide maintenance therapy in high-risk T-ALL/T-LBL after allo-HSCT: a prospective, single-center, single-arm study
Guo, W., Cao, Y., Liu, J., Zheng, X., Wang, M., Zheng, Y., Zhang, X., Zhai, W., Chen, X., Zhang, R., et al
Bone marrow transplantation. 2023
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7.
Application of prophylactic or pre-emptive therapy after allogeneic transplantation for high-risk patients with t(8;21) acute myeloid leukemia
Guo, W., Liu, X., Wang, M., Liu, J., Cao, Y., Zheng, Y., Zhai, W., Chen, X., Zhang, R., Ma, Q., et al
Hematology (Amsterdam, Netherlands). 2023;28(1):2205739
Abstract
OBJECTIVES To determine the impact of pretransplant measurable residual disease (pre-MRD) and the efficacy of maintenance therapy in t(8;21) acute myeloid leukemia (AML) patients after allogeneic hematopoietic cell transplantation (allo-HCT). METHODS We retrospectively analyzed 100 t(8;21) AML patients who underwent allo-HCT between 2013 and 2022. 40 patients received pre-emptive therapy including immunosuppressant adjustment, azacitidine, and donor lymphocyte infusion (DLI) combined with chemotherapy. 23 patients received prophylactic therapy, including azacitidine or chidamide. RESULTS Patients with a positive pre-MRD (pre-MRDpos) had a higher 3-year cumulative incidence of relapse (CIR) (25.90% [95% CI, 13.87%-39.70%] vs 5.00% [95% CI, 0.88%-15.01%]; P = 0.008). Pre-MRDpos patients were less likely to have a superior 3-year disease-free survival (DFS) (40.83% [95% CI, 20.80%-80.16%]) if their MRD was still positive at 28 days after transplantation (post-MRD(28)pos). The 3-year DFS and CIR were 53.17% (95% CI, 38.31% - 73.80%) and 34.87% (95% CI, 18.84% - 51.44%), respectively, for patients receiving pre-emptive interventions after molecular relapse. The 3-year DFS and CIR were 90.00% (95%CI, 77.77% - 100%) and 5.00% (95%CI, 0.31% - 21.10%), respectively, for high-risk patients receiving prophylactic therapy. In most patients, epigenetic-drug-induced adverse events were reversible with dose adjustment or temporary discontinuation. CONCLUSION Patients with pre-MRDpos and post-MRD(28)pos were more likely to have higher rates of relapse and inferior DFS, even after receiving pre-emptive interventions. Prophylactic therapy may be a better option for high-risk t(8;21) AML patients; however, this warrants further investigation.
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8.
Efficacy and safety of venetoclax combined with hypomethylating agents for relapse of acute myeloid leukemia and myelodysplastic syndrome post allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis
Du, Y., Li, C., Zhao, Z., Liu, Y., Zhang, C., Yan, J.
BMC cancer. 2023;23(1):764
Abstract
BACKGROUND Currently, there is no standard treatment for managing relapse in patients with acute myeloid leukemia and myelodysplastic syndrome (AML/MDS) after allogeneic hematopoietic cell transplantation. Venetoclax-based therapies have been increasingly used for treating post-transplantation relapse of AML. The aim of this systematic review and meta-analysis was to evaluate the efficacy and adverse events of Venetoclax combined with hypomethylating agents (HMAs) for AML/MDS relapse post-transplantation. METHODS We searched PubMed, Web of Science, Excerpta Medica Database, Cochrane Library, and Clinical. gov for eligible studies from the inception to February 2022. The Methodological Index for Non-Randomized Studies was used to evaluate the quality of the included literatures. The inverse variance method calculated the pooled proportion and 95% confidence interval (CI). RESULTS This meta-analysis included 10 studies involving a total of 243 patients. The pooled complete response and complete response with incomplete blood count recovery rate of Venetoclax combined with HMAs for post-transplantation relapse in AML/MDS was 32% (95% CI, 26-39%, I(2) = 0%), with an overall response rate of 48% (95% CI, 39-56%, I(2) = 37%). The 6-month survival rate was 42% (95% CI, 29-55%, I(2) = 62%) and the 1-year survival rate was 23% (95% CI, 11-38%, I(2) = 78%). CONCLUSION This study demonstrated a moderate benefit of Venetoclax in combination with HMAs for patients with relapsed AML/MDS post-transplantation (including those who have received prior HMAs therapy), and may become one of treatment options in the future. Large-scale prospective studies are needed to confirm the potential benefit from venetoclax combined with HMAs.
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9.
Real-world experience of sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for FLT3-ITD AML reveals high rates of toxicity-related treatment interruption
Morin, S., Giannotti, F., Mamez, A. C., Pradier, A., Masouridi-Levrat, S., Simonetta, F., Chalandon, Y.
Frontiers in oncology. 2023;13:1095870
Abstract
Sorafenib significantly improves survival of FLT3-ITD mutated AML patients when used as a post-allogeneic HSCT maintenance. Importantly, clinical trials reported a low rate of toxicities requiring sorafenib discontinuation. The aim of our analysis was to evaluate the real-world experience in patients treated with post-allogeneic HSCT sorafenib maintenance therapy for FLT3-ITD AML with a particular focus on tolerability and toxicity-related treatment interruption. We conducted a single-center retrospective study on 30 FLT3-ITD AML patients undergoing allogeneic HSCT in complete remission between 2017 and 2020 and who received sorafenib maintenance. 26 patients (87%) experienced toxicities leading to dose reduction (n=9) or direct interruption (n=17). Average time on sorafenib was 125 days (range 1-765). Most common toxicities were skin, gastrointestinal, and hematologic. Among patients who had a dose reduction, 4 eventually interrupted the drug and 5 were able to continue. Among patients who interrupted sorafenib because of toxicities, 7 were re-challenged with good tolerance in 3 cases. Overall, 18 patients (60% of the entire cohort) definitively discontinued sorafenib because of toxicities. 14 patients were thereafter switched to midostaurin. Importantly, with a median follow-up of 12 months, the median overall survival was not reached suggesting a positive impact of sorafenib maintenance despite the high rates of treatment interruption. In conclusion, our real-world analysis reveals high rates of toxicity-related interruption of sorafenib maintenance after allogeneic HSCT. Interestingly, our results suggest the feasibility of re-challenging with sorafenib and/or of switching to other maintenance approaches in case of intolerance.
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10.
Efficacy and Safety of Recombinant Thrombomodulin for the Prophylaxis of Veno-Occlusive Complication in Allogeneiccit Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis
Kashyap, R., Anwer, F., Iqbal, M. A., Khalid, F., Khan, A., Ali, M. A., Anwar, M. Y., Chaudhary, A., Jaan, A.
Hematology/Oncology and Stem Cell Therapy. 2023;16(2):93-101
Abstract
BACKGROUND Hepatic veno-occlusive disease (VOD), also termed as sinusoidal obstruction syndrome (SOS), is a lethal complication after hematopoietic stem cell transplantation (HSCT). Various factors put patients undergoing allogeneic HSCT at an increased risk for VOD. Thrombomodulin (TM) is an important factor which has a wide range of effects, including anticoagulant, anti-inflammatory, angiogenic, and protective effect, on endothelial cells. It plays a role in preventing excessive coagulation and thrombosis by binding with thrombin and inhibiting the coagulation cascade. There are a limited number of options for the prevention of this fatal complication. Recombinant thrombomodulin (rTM), an endothelial anticoagulant co-factor, as prophylactic therapy might be able to prevent veno-occlusive complications after stem cell transplantation. METHODS A literature search was performed on PubMed, Embase, and Web of Science. We used the following Mesh terms and Emtree terms, "Hepatic Veno-Occlusive Diseases" OR "Sinusoidal Obstruction" OR "Stem Cell Transplantations " AND "Thrombomodulin" from the inception of data up to April 1, 2021. The PICO (Patient/Population, Intervention, Comparison and Outcomes) framework was used for the literature search. RESULTS For the VOD incidence after HSCTstem cell transplantation, the result was in favor of rTM with a risk ratio (RR) of 0.53 (I(2) = 0%, 95% confidence interval [CI] = 0.32-0.89). The incidence of transplant-associated thrombotic microangiopathy (TA-TMA) after HSCT was reduced in rTM group. The RR for incidence of TA-TMA was 0.48 (I(2) = 62%, 95% CI = 0.20-1.17) favoring rTM. The RR for incidence of graft-versus-host disease (GvHD) was also lower in rTM group, 0.48 (I(2) = 64%, 95% CI = 0.32-0.72). CONCLUSION In our meta-analysis, we evaluate the efficacy and safety of rTM in the prevention of SOS after HSCT. According to our results, rTM use led to a significant reduction in SOS episodes, TA-TMA, and GvHD after HSCT.