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Post-transplant cyclophosphamide versus anti-thymocyte globulin after reduced intensity peripheral blood allogeneic cell transplantation in recipients of matched sibling or 10/10 HLA matched unrelated donors: final analysis of a randomized, open-label, multicenter, phase 2 trial
Brissot, E., Labopin, M., Labussière, H., Fossard, G., Chevallier, P., Guillaume, T., Yakoub-Agha, I., Srour, M., Bulabois, C. E., Huynh, A., et al
Blood cancer journal. 2024;14(1):31
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Editor's Choice
Abstract
The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is not established after reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) from fully matched donors. This was a randomized, open-label, multicenter, phase 2 trial. All patients received a RIC regimen with fludarabine, intravenous busulfan for 2 days (Flu-Bu2), and a peripheral blood stem cell (PBSC) graft from a matched related or 10/10 HLA-matched unrelated donor. Patients were randomly assigned to receive anti-thymocyte globulin (ATG) 5 mg/kg plus standard GVHD prophylaxis or PTCy 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis. The primary endpoint was the composite endpoint of GVHD- and relapse-free survival (GRFS) at 12 months after HSCT. Eighty-nine patients were randomly assigned to receive either PTCy or control prophylaxis with ATG. At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group (P = 0.99). Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group (P = 0.27). The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups. Although the primary objective was not met, PTCy is effective for GVHD prophylaxis in patients receiving Flu-Bu2 conditioning with a PBSC graft from a fully matched donor and was well tolerated in term of adverse events and quality of life. This trial was registered at clinicaltrials.gov: NCT02876679.
PICO Summary
Population
Adults with haematological malignancies undergoing transplant from a matched related or 10/10 HLA-matched unrelated donor with reduced intensity conditioning, recruited from eleven centres in France (n=89)
Intervention
Post-transplantation cyclophosphamide 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis (PTCy, n=44)
Comparison
Anti-thymocyte globulin 5 mg/kg plus standard GVHD prophylaxis (ATG, n=45)
Outcome
At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group. Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group. The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups.
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Post-transplantation cyclophosphamide combined with tacrolimus and low-dose post-engraftment anti-thymoglobulin as GVHD prophylaxis for patients undergoing peripheral blood stem cell transplantation from haploidentical family donor: A single center analysis
Gao, W. H., Zhu, J. Y., Wang, L. N., Wan, M., Wang, L., Devillier, R., Jiang, J. L., Blaise, D., Hu, J.
Frontiers in medicine. 2023;10:1140217
Abstract
INTRODUCTION Post-transplantation cyclophosphamide (PT-Cy) use is a recent graft-versus-host disease (GVHD) prophylaxis strategy for patients undergoing allogeneic stem cell transplantation (allo-HSCT). PT-Cy combined with two immunosuppressants is now widely used after haplo-identical (haplo) and HLA-matched peripheral blood stem cell (PBSC) transplantations with promising GVHD and relapsefree survival (GRFS) probabilities. Although appealing, these results may benefit from improvement notably outside matched sibling donor transplantation, and should be investigated in various ethnic populations. METHODS Therefore, we report our experience of GVHD prophylaxis regimen combining PT-Cy and tacrolimus with addition of post-engraftment low-dose anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation from haplo-identical donors (Haplo). Sixtyseven patients were included in the analysis. All patients received myeloablative or intensified sequential conditioning regimen. RESULTS The median follow-up was 521 (range, 10~991) days. The cumulative incidences of 100-day grade II-IV acute GVHD was 14.9±4.4%, and no case of grade III-IV acute GVHD was documented. The cumulative incidences of 2-yearchronic GVHD and moderate-to-severe chronic GVHD were 25.4±5.4% and 11.9±4%, respectively. The non-relapse mortality at day+100 and 2year were 7.5±3.2% and 9.0±3.5%, respectively. The cumulative incidence of relapse at 2year was 16±6.4%. The 2-year probability of DFS and OS were 73.8% (95%CI, 61.5~88.4%) and 72.5% (95% CI, 57.1~92.1%), respectively. The 2-year GRFS was estimated as 63.6% (95%CI, 50.6~80%). DISCUSSION Our results suggested that a combination of PT-Cy, tacrolimus, and low-dose post-engraftment ATG was a promising GVHD prophylaxis with low incidence of acute GVHD in the haplo-transplantation setting.
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Graft-versus-Host Disease Prophylaxis with Post Transplant Cyclophosphamide in Chronic Myeloid Leukemia patients undergoing Allogeneic Hematopoietic Cell Transplant from either an Unrelated or Mismatched Related Donor: a comparative study from the Chr
Ortí, G., Gras, L., Koster, L., Kulagin, A., Byrne, J., Apperley, J. F., Halaburda, K., Blau, I. W., Clark, A., Kröger, N., et al
Transplantation and cellular therapy. 2023
Abstract
Outcomes following allogeneic hematopoietic cell transplant (allo-HCT) for Chronic Myeloid Leukemia (CML) with post-transplant cyclophosphamide (PTCy) utilising an unrelated donor (UD) or mismatched related donor (MMRD) remain unknown. We report on a retrospective comparison of PTCy based allo-HCT from an UD, non-PTCy allo-HCT from an UD and PTCy allo-HCT from a MMRD. Inclusion criteria were adult patients with CML undergoing first allo-HCT between 2012 to 2019 from an UD with either PTCy or non-PTCy GvHD prophylaxis and MMRD using PTCy. Primary endpoint was GvHD relapse-free survival (GRFS). A total of 1341 patients were included (82% in the non-PTCy UD cohort). With a median follow-up of 34.9 months, the 3-year GRFS was 43%, 37% and 39% in the non-PTCy UD, PTCy-UD and PTCy MMRD cohorts, respectively (p=0.15). In multivariable analyses, there were no significant differences between the three cohorts regarding OS, PFS, RI and NRM. Factors independently associated with worse OS in the overall cohort were KPS<90 (HR 1.86, 95%CI, 1.41-2.45; p<0.001), older age (HR 1.24, 95%CI, 1.11-1.38; p<0.001) and disease stage (compared to CP1) blast phase HR 2.25, 95% CI, 1.60-3.16; p<0.001, accelerated phase HR 1.63, 95% CI, 1.05-2.54; p=0.03 and CP>2 HR 1.58, 95% CI, 1.15-2.17; p=0.005. These results suggest that allo-HCT in CML utilizing either an UD or MMRD with a PTCy GvHD-based prophylaxis are feasible transplant platforms and that the disease stage at allo-HCT remains a major prognostic factor, highlighting the importance to closely monitor CML patients and propose transplantation when indicated, when still in CP1.
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Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis in HLA-matched and haploidentical donor transplants for patients with Hodgkin lymphoma: a comparative study of the LWP EBMT.: GVHD prophylaxis for patients with Hodgkin lymphoma
Montoro, J., Boumendil, A., Finel, H., Bramanti, S., Castagna, L., Blaise, D., Dominietto, A., Kulagin, A., Yakoub-Agha, I., Tbakhi, A., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Post-transplant cyclophosphamide (PTCy) has emerged as a promising approach for preventing graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is a lack of studies examining the impact of this GVHD prophylaxis when different donor types are used in patients with Hodgkin lymphoma (HL). OBJECTIVE To compare the outcomes of patients with HL undergoing HSCT from both HLA-matched donors, which include matched sibling donors (MSD) and matched unrelated donors (MUD), and haploidentical donors, using PTCy as GVHD prophylaxis approach in all cohorts. STUDY DESIGN We retrospectively compared transplant outcomes of allo-HSCT from 166 HLA-matched donors (96 siblings and 70 unrelated) and 694 haploidentical donors using PTCy-based GVHD prophylaxis in patients with HL registered in the EBMT database from 2010 to 2020. RESULTS Haploidentical transplantation showed significantly lower platelet engraftment (86% vs 94%, p<0.001) and higher rates of grades II-IV acute GVHD (24% vs 34%, p=0.01) compared to HLA-matched transplantation. The 2-year cumulative incidence of non-relapse mortality (NRM) was significantly lower in the HLA-matched cohort compared to haploidentical cohort (10% vs 18%, p=0.02), resulting in a higher overall survival (OS) rate (82% vs 70%, p=0.002). There were no significant differences observed in terms of relapse, progression-free survival, or GVHD-free relapse-free survival between the groups. In multivariable analysis, haploidentical transplantation was associated with an increased risk of grades II-IV acute GVHD, NRM, and worse OS compared to HLA-matched transplantation. CONCLUSIONS Our findings suggest that, in the context of PTCy-based GVHD prophylaxis, transplantation from HLA-matched donors appears to be a more favorable option compared to haploidentical transplantation.
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Posttransplant cyclophosphamide versus antithymocyte globulin in patients with acute lymphoblastic leukemia treated with allogeneic hematopoietic cell transplantation from matched unrelated donors. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Giebel, S., Labopin, M., Salmenniemi, U., Socié, G., Bondarenko, S., Blaise, D., Kröger, N., Vydra, J., Grassi, A., Bonifazi, F., et al
Cancer. 2023
Abstract
BACKGROUND The aim of this study was to compare two immunosuppressive strategies, based on the use of either rabbit antithymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCY), as a prophylaxis of graft-versus-host disease (GVHD) for patients with acute lymphoblastic leukemia (ALL) in first complete remission who underwent hematopoietic cells transplantation from matched unrelated donors. METHODS Overall, 117 and 779 adult patients who received PTCY and ATG, respectively, between the years 2015 and 2020 were included in this retrospective study. The median patient age was 40 and 43 years in the PTCY and ATG groups, respectively, and 37% and 35% of patients, respectively, had Philadelphia chromosome-positive ALL. RESULTS In univariate analysis, the cumulative incidence of acute and chronic GVHD did not differ significantly between the study groups. The cumulative incidence of relapse at 2 years was reduced in the PTCY group (18% vs. 25%; p = .046) without a significant impact on nonrelapse mortality (11% vs. 16% in the ATG group; p = .29). The rates of leukemia-free survival (LFS) and overall survival were 71% versus 59%, respectively (p = .01), and 82% versus 74%, respectively (p = .08). In multivariate analysis, the receipt of ATG compared with PTCY was associated with a reduced risk of extensive chronic GVHD (hazard ratio, 0.54; 95% confidence interval, 0.3-0.98; p = .04) and an increased risk of low LFS (hazard ratio, 1.57; 95% confidence interval, 1.01-2.45; p = .045). CONCLUSIONS The receipt of ATG compared with PTCY, despite the reduced risk of extensive chronic GVHD, is associated with inferior LFS in adults with ALL who undergo hematopoietic cell transplantation from 10/10 human leukocyte antigen-matched unrelated donors. These findings warrant verification in prospective trials.
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GVHD occurrence does not reduce AML relapse following PTCy-based haploidentical transplantation: a study from the ALWP of the EBMT
Baron, F., Labopin, M., Tischer, J., Raiola, A. M., Vydra, J., Blaise, D., Chiusolo, P., Stölzel, F., Fanin, R., Chevallier, P., et al
Journal of hematology & oncology. 2023;16(1):10
Abstract
The association between graft-versus-host disease (GVHD) occurrence and acute myeloid leukemia (AML) relapse in patients treated with HLA-haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) with post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis has remained debated. Here, we addressed this issue in patients with active AML at transplantation. 2-year cumulative incidences of relapse and leukemia-free survival (LFS) were 49% and 32.3%, respectively. There were no associations between acute nor chronic GVHD of any grade and lower relapse incidence. However, grade I acute GVHD was associated with better LFS (HR = 0.71, 95% CI 0.51-0.99, P = 0.04). In contrast, grade III-IV acute (HR = 3.09, 95% CI 1.87-5.12, P < 0.0001) as well as extensive chronic (HR = 3.3, 95% CI 1.81-6.04, P = 0.0001) GVHD correlated with higher nonrelapse mortality leading to lower LFS (HR = 1.36, 95% CI 0.99-1.86, P = 0.056 and HR = 1.97, 95% CI 1.35-2.89, P = 0.0004, respectively). In conclusion, these data suggest a dissociation of graft-versus-leukemia effects from GVHD in patients with active AML treated with PTCy-based Haplo-HCT.
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GVHD prophylaxis with post-transplant cyclophosphamide results in lower incidence of GVHD and allows faster immunosuppressive treatment reduction compared to antithymocyte globulin in 10/10 HLA-matched unrelated allogeneic hematopoietic cell transplantation
Dachy, F., Furst, S., Calmels, B., Pagliardini, T., Harbi, S., Bouchacourt, B., Calleja, A., Lemarie, C., Collignon, A., Morel, G., et al
Bone marrow transplantation. 2023;58(11):1179-1181
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Feasibility of cyclosporine prophylaxis withdrawal in critically ill allogenic hematopoietic stem cell transplant patients admitted to the Intensive Care Unit with no GVHD
Saillard, C., Legal, P. H., Furst, S., Bisbal, M., Servan, L., Sannini, A., Gonzalez, F., Faucher, M., Vey, N., Blaise, D., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Twenty percent of allogenic hematopoietic stem cell transplantation (allo-HSCT) patients require intensive care unit (ICU) admission. Feasibility and long-term consequences of cyclosporine graft-versus-host disease (GVHD) prophylaxis withdrawal in the ICU are unknown. OBJECTIVES To assess the impact of cyclosporine prophylaxis withdrawal in critically ill allo-HSCT patients admitted to the ICU on GVHD incidence and to evaluate 6-months overall survival according to cyclosporine withdrawal and GVHD occurrence. STUDY DESIGN From 2010 to 2020, 101 critically ill allo-HSCT patients admitted to the ICU in our institution were included. All received cyclosporine as GVHD prophylaxis. None of them had GVHD at ICU admission. RESULTS Patients were admitted in the ICU after a median time of 11 days [5.5-18] after allo-HSCT. ICU, hospital mortality and 6-months mortality were 43.6%, 56.4% and 59.4% respectively. Cyclosporine was withdrawn for 52 and continued for 49 patients in the ICU. 38.6% (n=39) developed secondarily acute GVHD (aGVHD) after a median of 28 days (15-40) after cyclosporine stop. In 74.4% (n=29) of cases, patients developed aGVHD after ICU discharge, in hematology ward. Cyclosporine dosages were similar in both groups. Factors independently associated with aGVHD occurrence in multivariate analysis were cyclosporine withdrawal in the ICU (sHR=2.04, 95%CI=1.02-4.1, p=0.044), renal replacement therapy (RRT) (sHR=0.43, 95%CI=0.19-0.9, p=0.03) and fungal prophylaxis (sHR=2.62, 95%CI=1.35-5.07, p=0.004). Cyclosporine withdrawal in the ICU was associated with poorer 6-months overall survival (OS) (HR=1.96, 95%CI=1.16-3.33, p=0.012), but after adjusting on severity (SAPSII, vasopressors, mechanical ventilation and RRT requirement), 6-months OS did not differ (HR=1.35, 95%CI=0.76-2.42, p=0.3). GVHD occurrence after ICU stay was significantly associated with better 6-months OS in unadjusted (HR=0.53, 95%CI= 0.31-0.90, p= 0.02) and severity-adjusted analysis (HR=0.54, 95%CI=0.31-0.93, p=0.028). CONCLUSION Cyclosporine prophylaxis withdrawal in critically ill allo-HSCT patients in the ICU appears as feasible and did not impair long-term outcome.
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Posttransplant cyclophosphamide-based anti-graft-vs-host disease prophylaxis in patients with acute lymphoblastic leukemia treated in complete remission with allogeneic hematopoietic cell transplantation from human leukocyte antigen-mismatched unrelated donors versus haploidentical donors: A study on behalf of the ALWP of the EBMT
Nagler, A., Labopin, M., Arat, M., Reményi, P., Koc, Y., Blaise, D., Angelucci, E., Vydra, J., Kulagin, A., Socié, G., et al
Cancer. 2022
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Editor's Choice
Abstract
BACKGROUND Both mismatched unrelated donor (MMUD) and haploidentical (haplo) transplantation are valid options in patients with high-risk acute lymphoblastic leukemia (ALL) lacking a matched donor. METHODS The study compared the outcomes of adult patients with ALL in complete remission (CR) who underwent 9/10 MMUD versus haplo transplantation with posttransplant cyclophosphamide (PTCy) as graft-vs-host disease (GVHD) prophylaxis in 2010-2020. RESULTS The study included 781 patients (MMUD, 103; haplo, 678). The median age was 40 (19-73) and 38 (18-75) years, respectively (p = .51). The most frequent immunosuppression agents added to PTCy were mycophenolate mofetil (MMF)/cyclosporine A and MMF/tacrolimus. In vivo T-cell depletion (anti-thymocyte globulin) was administered to 21% and 8% of the transplants, respectively (p < .0001). Neutrophil (absolute neutrophil count >0.5 × 10(9) /L) recovery was achieved in 97.1% versus 96.7% versus (p = 1) in MMUD and haplo, respectively. Nonrelapse mortality and relapse incidence were not significantly different between MMUD and haplo, hazard ratio (HR) = 1.45 (95% confidence interval [CI], 0.81-2.62; p = .21) and HR = 0.81 (95% CI, 0.52-1.28, p = .38), respectively. HRs for leukemia-free survival, overall survival, and GVHD-free, relapse-free survival were respectively, HR = 1.05 (95% CI, 0.73-1.50, p = .8), HR = 1.17 (95% CI, 0.77-1.76, p = .46), and HR = 1.07 (95% CI, 0.78-1.46, p = .7) for haplo compared to MMUD. Acute (a)GVHD grade 2-4 was significantly higher with haplo, HR = 1.73 (95% CI, 1.08-2.76, p = .023), whereas aGVHD grade 3-4 and chronic GVHD did not differ significantly between the two transplant groups. CONCLUSION Outcomes of MMUD and haplo transplants with PTCy-based GVHD prophylaxis for ALL patients in CR are similar, apart from a higher incidence of aGVHD with haplo transplants.
PICO Summary
Population
Adults with high-risk acute lymphoblastic leukemia (ALL) in complete remission, lacking a matched donor (n=781)
Intervention
9/10 mismatched unrelated donor transplantation (MMUD, n=103)
Comparison
Haploidentical transplantation (haplo, n=678)
Outcome
Neutrophil (absolute neutrophil count >0.5 × 10(9) /L) recovery was achieved in 97.1% versus 96.7% versus in MMUD and haplo, respectively. Nonrelapse mortality and relapse incidence were not significantly different between MMUD and haplo, hazard ratio (HR) = 1.45 (95% confidence interval [CI], 0.81-2.62) and HR = 0.81 (95% CI, 0.52-1.28), respectively. HRs for leukemia-free survival, overall survival, and GVHD-free, relapse-free survival were respectively, HR = 1.05 (95% CI, 0.73-1.50), HR = 1.17 (95% CI, 0.77-1.76), and HR = 1.07 (95% CI, 0.78-1.46) for haplo compared to MMUD. Acute (a)GVHD grade 2-4 was significantly higher with haplo, HR = 1.73 (95% CI, 1.08-2.76), whereas aGVHD grade 3-4 and chronic GVHD did not differ significantly between the two transplant groups.
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Reduced post-transplant cyclophosphamide doses in haploidentical hematopoietic cell transplantation for elderly patients with hematological malignancies
Duléry, R., Goudet, C., Mannina, D., Bianchessi, A., Granata, A., Harbi, S., Maisano, V., Chabannon, C., Malard, F., Brissot, E., et al
Bone marrow transplantation. 2022
Abstract
Although post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, it is associated with toxicities, which might be dose-dependent. We compared the outcomes with PT-Cy at 80 mg/kg to those with PT-Cy at 100 mg/kg in elderly patients undergoing haploidentical hematopoietic cell transplantation (HCT). Inclusion criteria included peripheral blood stem cells, hematological malignancy, and age>65 years (or age>60 years if cardiac event history). Thirty-eight patients received PT-Cy at 80 mg/kg and 55 100 mg/kg, divided in two doses. The cumulative incidences (CI) of acute grade II-IV, acute grade III-IV, and moderate/severe chronic GVHD were 32%, 16%, and 13% with PT-Cy at 80 mg/kg compared to 33%, 13%, and 16% with 100 mg/kg, respectively. In multivariable analysis, reducing PT-Cy dose had no significant impact on GVHD. Neutrophil and platelet engraftments were significantly improved, and CI of BK virus-associated hemorrhagic cystitis was reduced with 80 mg/kg of PT-Cy compared to 100 mg/kg. At 2 years, non-relapse mortality was 16% and 31%, progression-free survival 65% and 49%, overall survival 70% and 56%, and GVHD-free, relapse-free survival 52% and 36% with 80 mg/kg and 100 mg/kg, respectively. Reducing PT-Cy dose to 80 mg/kg is safe and associated with improved hematological recovery and lower CI of hemorrhagic cystitis in elderly patients undergoing haploidentical HCT.