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Phase I study of zoledronic acid combined with escalated doses of interleukine-2 for early in vivo generation of Vγ9Vδ2 T-cells after haploidentical stem cell transplant with posttransplant cyclophosphamide
Jullien, M., Guillaume, T., Le Bourgeois, A., Peterlin, P., Garnier, A., Eveillard, M., Le Bris, Y., Bouzy, S., Tessoulin, B., Gastinne, T., et al
American journal of hematology. 2024
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Editor's Choice
Abstract
The presence of donor Vγ9Vδ2 T-cells after haploidentical hematopoietic stem cell transplant (h-HSCT) has been associated with improved disease-free survival. These cells kill tumor cells in a non-MHC restricted manner, do not induce graft-versus-host disease (GVHD), and can be generated by stimulation with zoledronic acid (ZA) in combination with interleukin-2 (IL-2). This monocentric phase I, open-label, dose-escalating study (ClinicalTrials.gov: NCT03862833) aimed at evaluating the safety and possibility to generate Vγ9Vδ2 T-cells early after h-HSCT. It applied a standard 3 + 3 protocol to determine the maximum tolerated dose (MTD) of increasing low-doses of IL-2 (5 days [d] per week, 4 weeks) in combination with a single dose of ZA, starting both the first Monday after d + 15 posttransplant. Vγ9Vδ2 T-cell monitoring was performed by multiparameter flow cytometry on blood samples and compared with a control cohort of h-HSCT recipients. Twenty-six patients were included between April 2019 and September 2022, 16 of whom being ultimately treated and seven being controls who received h-HSCT only. At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. MTD was not reached. A significantly higher number of Vγ9Vδ2 T-cells was observed during IL-2 treatment compared with controls. In conclusion, early in vivo generation of Vγ9Vδ2 T-cells is feasible after h-HSCT by using a combination of ZA and repeated IL-2 infusions. This study paves the way to a future phase 2 study, with the hope to document lesser posttransplant relapse with this particular adaptive immunotherapy.
PICO Summary
Population
Adults with haematological malignancy, eligible for haploidentical transplant from a single centre in France (n=26)
Intervention
Increasing low-doses of IL-2 (5 days per week, 4 weeks) in combination with a single dose of zoledronic acid (ZA) to generate Vγ9Vδ2 T-cells early after h-HSCT (n=16)
Comparison
Haploidentical HSCT only (n=7)
Outcome
At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. Maximum tolerated dose was not reached.
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On behalf of the SFGM-TC: prophylactic donor lymphocyte infusion in patients treated with allogeneic stem-cell transplantation for high-risk myelodysplastic syndrome and acute myeloid leukemia
Guisnel, C., Schirmer, L., Morisset, S., Robin, M., Labussière-Wallet, H., Duléry, R., Ceballos, P., Forcade, E., Nguyen, S., Poiré, X., et al
Acta haematologica. 2023
Abstract
INTRODUCTION Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the best curative option for high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Unfortunately, it is still associated with a significant risk of relapse due to mechanisms of escape from the control of alloreactive T cells. Repetitive adjuvant donor lymphocyte infusions (DLI), termed prophylactic DLI (proDLI), as an effective strategy in preventing relapse is still debated. METHODS We performed a retrospective multicenter study to evaluate the efficacy of proDLI in allografted AML and MDS. We identified 56 patients treated with proDLI (DLI planned in full chimeras without any sign of disease relapse) and matched them to 167 patients in control group, (DLI performed for mixed chimerism or positive minimal residual disease) based on similar age, initial disease, cytogenetic prognosis, and conditioning intensity. RESULTS In univariate analysis, the incidence of severe aGVHD at 100 days and incidence of all grades of chronic GVHD 1 year after allo-HSCT were similar in the two groups. We also observed a trend of higher 3-year RI (52.61% [95% confidence interval 25.99-79.23]) in the proDLI group versus the control group (29.31% [20.28-38.34], p=0.067). However, 3-year overall survival (p=0.892), progression-free survival (p=0.239), and non-relapse mortality (p=0.343) were similar between the two groups. In multivariate analysis, the only factor influencing overall and progression-free survival was anti-thymocyte globulin administration during the conditioning regimen. DISCUSSION/CONCLUSION The proDLI strategy had an acceptable toxicity profile but did not improve patient outcomes compared to the pre-emptive strategy.
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Prophylactic or preemptive low-dose azacitidine and donor lymphocyte infusion to prevent disease relapse following allogeneic transplantation in patients with high risk acute myeloid leukemia or myelodysplastic syndrome
Guillaume, T., Thépot, S., Peterlin, P., Ceballos, P., Bourgeois, A. L., Garnier, A., Orvain, C., Giltat, A., François, S., Bris, Y. L., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Because of the persistently high rates of relapse of patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) following allogeneic stem cell transplantation, maintenance post-transplant therapy has been proposed. We previously initiated a Phase II trial in which epigenetic therapy was combined with immunotherapy in an attempt to reduce disease relapse. In that study, low dose azacitidine (AZA) and escalating dose of donor lymphocyte infusion (DLI) were given as maintenance treatment. In the present study, we retrospectively analyze a larger cohort of patients receiving post-transplantation maintenance therapy plus an update of some patients of the earlier study. OBJECTIVES To analyze the cumulative incidence of relapse (CIR), overall survival (OS), progression-free survival (PFS), incidence of acute and chronic graft-versus-host disease (GVHD) of patients with high-risk AML or MDS receiving a post-transplant maintenance treatment with AZA with or without DLI. STUDY DESIGN We retrospectively analyzed 77 patients (54 AML, 23 MDS) considered to be at high-risk based on either their genomic or clinical status at transplant. Following allogeneic transplantation, they received at least one cycle of prophylactic or preemptive low-dose AZA with or without escalating doses of DLI to prevent disease relapse. RESULTS Almost half of the patients (47%) were able to receive the full 12 cycles of scheduled AZA and a majority of patients (79%) received at least one DLI. With a median follow-up of 24 months, 19 patients (25%, 16 AML, 3 MDS) relapsed with a median time of 9.8 months (range 4-58.6 months), giving a 22% CIR at 24 months. OS and PFS at 24 months were 70.8% and 68.3% respectively. The cumulative incidence of acute GvHD Grade II-IV and chronic GvHD was 27.4% and 45%, respectively. Only a minority of patients (11%) requiring delayed administration of AZA. CONCLUSIONS These findings confirm that AZA-DLI maintenance is both tolerable and effective in reducing post-transplantation relapse risk.
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Prospective phase II study of prophylactic low-dose azacitidine and donor lymphocyte infusions following allogeneic hematopoietic stem cell transplantation for high-risk acute myeloid leukemia and myelodysplastic syndrome
Guillaume, T., Malard, F., Magro, L., Labopin, M., Tabrizi, R., Borel, C., Chevallier, P., Vigouroux, S., Peterlin, P., Garnier, A., et al
Bone marrow transplantation. 2019
Abstract
Thirty patients, with high-risk acute myeloid leukemia (AML, n = 20) or myelodysplastic syndrome (MDS, n = 10), were enrolled in a phase II trial entailing prophylactic post-transplant azacitidine (AZA) plus escalated doses of donor lymphocyte infusion (DLI). The median number of AZA cycles was 5 (1-12) with 10 patients (33%) completing the 12 projected cycles. DLI were performed in 17 patients: 5 received one DLI, 2 received 2 DLI and 8 received 3 infusions. AZA was well tolerated, but discontinued in 20 patients primarily due to graft-versus-host disease (GvHD) and relapse. The cumulative incidence (CI) of grade 1-3 acute GvHD was 31.5% and the chronic GvHD CI was 53% at 2 years. At a median follow-up of 49 months (27-63), 18 patients are alive. The overall and disease-free survivals are 65.5% (CI 95% = 48.2-82.8) at 2 years. Cause of death was mainly relapse for 9 patients. The median time to relapse was 7 months (2.5-58) and the cumulative incidence of relapse at 2 years was 27.6% (CI 95% = 12.8-44.6). These results confirm that AZA is well tolerated as a prophylactic treatment to reduce the risk of post-transplantation relapse and compared favorably to those of patients who receive no post-transplant maintenance.
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Management of Myelodysplastic Syndrome Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation: A Study by the French Society of Bone Marrow Transplantation and Cell Therapies
Guieze, R., Damaj, G., Pereira, B., Robin, M., Chevallier, P., Michallet, M., Vigouroux, S., Beguin, Y., Blaise, D., El Cheikh, J., et al
Biology of Blood & Marrow Transplantation. 2016;22(2):240-7
Abstract
To find out prognostic factors and to investigate different therapeutic approaches, we report on 147 consecutive patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS). Sixty-two patients underwent immunotherapy (IT group, second allo-HSCT or donor lymphocyte infusion), 39 received cytoreductive treatment alone (CRT group) and 46 were managed with palliative/supportive cares (PSC group). Two-year rates of overall survival (OS) were 32%, 6%, and 2% in the IT, CRT, and PSC groups, respectively (P < .001). In multivariate analysis, 4 factors adversely influenced 2-year rates of OS: history of acute graft-versus-host disease (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.26 to 2.67; P = .002), relapse within 6 months (HR, 2.69; 95% CI, .82 to 3.98; P < .001), progression to acute myeloid leukemia (HR, 2.59; 95% CI, 1.75 to 3.83; P < .001), and platelet count < 50 G/L at relapse (HR, 1.68; 95% CI, 1.15 to 2.44; P = .007). A prognostic score based on those factors discriminated 2 risk groups with median OSs of 13.2 versus 2.4 months, respectively (P < .001). When propensity score, prognostic score, and treatment strategy were included in Cox model, immunotherapy was found to be an independent factor that favorably impacts OS (HR, .40; 95% CI, .26 to .63; P < .001). In conclusion, immunotherapy should be considered when possible for MDS patients relapsing after allo-HSCT. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Effect of immune modulation in relapsed peripheral T-cell lymphomas after post-allogeneic stem cell transplantation: a study by the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC)
Mamez, A. C., Levy, V., Chevallier, P., Blaise, D., Vigouroux, S., Xhaard, A., Fegueux, N., Contentin, N., Beguin, Y., Ifrah, N., et al
Bone Marrow Transplantation. 2016;51(3):358-64
Abstract
Peripheral T-cell lymphoma carries a poor prognosis. To document a possible graft-versus-lymphoma effect in this setting, we evaluated the impact of immunomodulation in 63 patients with peripheral T-cell lymphoma who relapsed after allogeneic transplant in 27 SFGM-TC centers. Relapse occurred after a median of 2.8 months. Patients were then treated with non-immunologic strategies (chemotherapy, radiotherapy) and/or immune modulation (donor lymphocyte infusions (DLI) and/or discontinuation of immunosuppressive therapy). Median overall survival (OS) after relapse was 6.1 months (DLI group: 23.6 months, non-DLI group: 3.6 months). Among the 14 patients who received DLI, 9 responded and 2 had stable disease. Among the remaining 49 patients, a complete response accompanied by extensive chronic GvHD was achieved in two patients after tapering of immunosuppressive drugs. Thirty patients received radio-chemotherapy, with an overall response rate of 50%. In multivariate analysis, chronic GvHD (odds ratio: 11.25 (2.68-48.21), P=0.0009) and skin relapse (odds ratio: 4.15 (1.04-16.50), P=0.043) were associated with a better response to treatment at relapse. In a time-dependent analysis, the only factor predictive of OS was the time from transplantation to relapse (hazards ratio: 0.33 (0.17-0.640), P=0.0009). This large series provides encouraging evidence of a true GvL effect in this disease.