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Impact of early cyclosporine A levels on acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation using in vivo T-cell depletion
Nikoloudis, A., Buxhofer-Ausch, V., Aichinger, C., Binder, M., Hasengruber, P., Kaynak, E., Wipplinger, D., Milanov, R., Strassl, I., Stiefel, O., et al
Cytotherapy. 2024
Abstract
BACKGROUND AIMS Cyclosporin A (CsA) remains a major component of immunosuppressive regimens applied in allogeneic hematopoietic stem cell transplantation (HSCT). The impact of CsA trough levels during the first weeks after HSCT has not yet been investigated specifically in anti-T-lymphocyte globulin (ATLG)-based HSCT from matched related and unrelated donors. METHODS To address this issue, we have retrospectively examined 307 consecutive matched related (n = 145) and unrelated (n = 162) HSCTs, using peripheral blood stem cells or bone marrow. HSCTs for active, uncontrolled malignancies were excluded. The initial three weeks' average mean CsA trough levels were analyzed in landmark and multi-state models, using a cut-off of 200 ng/mL. RESULTS CsA levels >200 ng/mL were associated with a reduced risk of acute graft-versus-host disease (GVHD) grade 3-4 at the first-week landmark (subdistribution hazard ratio [SHR] 0.59, P = 0.03) and the second-week landmark (SHR 0.48, P = 0.004), whereas there was no impact at the third-week landmark (HR 0.87, P = 0.69). This was supported by a multi-state model, in which week 1 (hazard ratio [HR] 0.53, P = 0.006) and week 2 (HR 0.48, P = 0.003), but not week 3 (HR 0.80, P = 0.44) CsA levels >200 ng/mL were associated with a reduced acute GVHD 3-4 risk. Relapse incidence was not significantly affected by week 1 through 3 CsA levels. Despite ATLG's inherent GVHD-preventive properties, week 1 CsA trough levels >200 ng/mL following ATLG-based HSCT (n = 220) were associated with a significantly reduced risk of non-relapse mortality (SHR 0.52, P = 0.02) and improved overall survival (HR 0.61, P = 0.02). CONCLUSIONS Our findings emphasize the continuing importance of ensuring CsA levels ≥200 ng/mL immediately post-transplant in the setting of ATLG-based HSCT.
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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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Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis
Bolaños-Meade, J., Hamadani, M., Wu, J., Al Malki, M. M., Martens, M. J., Runaas, L., Elmariah, H., Rezvani, A. R., Gooptu, M., Larkin, K. T., et al
The New England journal of medicine. 2023;388(25):2338-2348
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Editor's Choice
Abstract
BACKGROUND In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil. METHODS In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis) or tacrolimus-methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause. RESULTS In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P = 0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups. CONCLUSIONS Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. (Funded by the National Heart, Lung, and Blood Institute and others; BMT CTN 1703 ClinicalTrials.gov number, NCT03959241.).
PICO Summary
Population
Adults with hematologic cancers undergoing HLA-matched related donor or a matched or 7/8 mismatched unrelated donor transplant, enrolled in an RCT in multiple centres in USA (n=431)
Intervention
Cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis, n=214)
Comparison
Tacrolimus-methotrexate (standard prophylaxis (standard prophylaxis, n=217)
Outcome
GVHD-free, relapse-free survival was significantly more common among patients in the experimental-prophylaxis group than among the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups.
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Post-transplant cyclophosphamide as sole GHVD prophylaxis after matched reduced-intensity conditioning allotransplant
Bourgeois, A. L., Jullien, M., Garnier, A., Peterlin, P., Béné, M. C., Guillaume, T., Chevallier, P.
Clinical and translational medicine. 2023;13(4):e1242
Abstract
BACKGROUND Post-transplant cyclophosphamide (PTCY) alone as graft-versus-host disease (GVHD) prophylaxis may avoid/reduce short- and mid-term toxicities of drugs commonly used for GVHD prophylaxis, accelerate immune reconstitution after the graft to decrease infections and facilitate the early integration of adjunct maintenance therapies to prevent relapse. OBJECTIVE A prospective phase 2 study was designed in order to assess the feasibility and safety of PTCY as a sole GVHD prophylaxis in adult patients receiving a Baltimore-based reduced-intensity conditioning (RIC) peripheral blood (PB) allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with a matched donor. STUDY DESIGN Patients were planned to be included stepwise up to 59 evaluable PTCY recipients, in order to be able to stop the protocol in case of excessive corticosteroid resistant grade 3-4 severe acute GVHD (aGVHD). Because a high incidence of grade 2-4 aGVHD was observed after analysis of the first 27 patients, the protocol was amended to test the addition of 1 day of anti-thymoglobulin to PTCY. In spite of this, the trial had to be stopped after 38 treated patients, because of an unacceptable rate of grade 3-4 aGVHD. Donors were matched related to 12 patients and unrelated to 26. RESULTS With a median follow-up of 29.6 months, 2-year overall, disease-free and GVHD-free relapse-free (GRFS) survivals were respectively 65.4%, 62.1% and 46.9%. Cumulative incidences of grade 2-4 and 3-4 aGVHD at day 100 were 52.6% and 21.1%, respectively, while that of moderate/severe chronic(c) GVHD was 15.7% at 2 years. Addition of ATG to PTCY did influence neither aGVHD, cGVHD nor GRFS. CONCLUSION Despite paradoxically good survivals, especially GRFS, this study failed to demonstrate that PTCY (± ATG) alone can be used for Baltimore-based RIC PB Allo-HSCT with matched donors. Other combinations should be tested to try and avoid long-term use of immunosuppressive drugs following Allo-HSCT in this setting.
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Abatacept for the prevention of graft versus host disease in pediatric patients receiving 7/8 HLA-mismatched unrelated transplant for hematologic malignancies: a real-world analysis
Raghunandan, S., Gorfinkel, L., Bratrude, B., Suessmuth, Y., Hebert, K., Neuberg, D., Williams, K. M., Schoettler, M. L., Langston, A. A., Kean, L. S., et al
Bone marrow transplantation. 2023
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Abatacept for The Prevention of GVHD in Patients Receiving Mismatched Unrelated Transplants: A Real-World Analysis
Raghunandan, S., Gorfinkel, L., Graiser, M., Bratrude, B., Suessmuth, Y., Gillespie, S., Westbrook, A. L., Williams, K. M., Schoettler, M. L., Kean, L. S., et al
Blood advances. 2023
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Abatacept for graft versus host disease prophylaxis in patients 60 years and older receiving mismatched unrelated donor transplantation for hematologic malignancies
Raghunandan, S., Qayed, M., Watkins, B. K., Graiser, M., Gorfinkel, L., Westbrook, A., Gillespie, S., Bratrude, B., Petrovic, A., Suessmuth, Y., et al
Bone marrow transplantation. 2023
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Immune reconstitution profile after allogeneic hematopoietic stem cell transplantation with post-transplant cyclophosphamide
Espinoza-Gutarra, M., Saad, A., Jamy, O.
Stem cell investigation. 2023;10:8
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Low-dose PTCy plus low-dose ATG as GVHD prophylaxis after UD-PBSCT for hematologic malignancies: a prospective, multicenter, randomized controlled trial
Zu, Y., Gui, R., Li, Z., Wang, J., Zhang, Y., Yu, F., Zhao, H., Zhan, X., Wang, Z., Xing, P., et al
Blood Cancer Journal. 2023;13(1):10