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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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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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Higher cyclosporine-A concentration increases the risk of relapse in AML following allogeneic stem cell transplantation from unrelated donors using anti-thymocyte globulin
Lisak, M., Nicklasson, M., Palmason, R., Wichert, S., Isaksson, C., Andersson, P. O., Johansson, J. E., Lenhoff, S., Brune, M., Hansson, M.
Scientific reports. 2023;13(1):22777
Abstract
Cyclosporine-A (CsA) is used to prevent acute graft-versus-host disease (aGvHD). European Society for Blood and Marrow transplantation (EBMT) recommends a CsA target serum concentration of 200-300 µg/L during the first month after allogeneic hematopoietic stem cell transplantation (HSCT). With this study, we investigated whether a median CsA concentration > 200 µg/L (CsA(high)) the first month after HSCT, compared to ≤ 200 µg/L (CsA(low)), increased the relapse risk of acute myloid leukemia (AML), using unrelated donors (URD) and antithymocyte globulin (ATG). Data was collected from 157 patients with AML, transplanted 2010-2016. The cumulative incidence of relapse (CIR) at 60 months was 50% in the CsA(high) versus 32% in the CsA(low) group (p = 0.016). In univariate analysis, CsA(high) versus CsA(low) (p = 0.028), 10-unit increase of CsA as a continuous variable (p = 0.017) and high risk disease (p = 0.003) were associated with higher CIR. The results remained after adjusting for disease risk. Death following relapse occurred more frequently in the CsA(high) group (p = 0.0076). There were no significant differences in rates of aGvHD, chronic GvHD (cGvHD), EBV/CMV-infections or overall survival (OS) between the two groups. In conclusion, we found that a median CsA concentration > 200 µg/L, the first month after HSCT, results in higher CIR of AML when combined with ATG.
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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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Low-dose anti-thymocyte globulin plus low-dose post-transplant cyclophosphamide-based regimen for prevention of graft-versus-host disease after haploidentical peripheral blood stem cell transplants: a large sample, long-term follow-up retrospective study
Li, X., Yang, J., Cai, Y., Huang, C., Xu, X., Qiu, H., Niu, J., Zhou, K., Zhang, Y., Xia, X., et al
Frontiers in immunology. 2023;14:1252879
Abstract
INTRODUCTION The novel low-dose anti-thymocyte (ATG, 5 mg/kg) plus low-dose post-transplant cyclophosphamide (PTCy, 50 mg/kg) (low-dose ATG/PTCy)-based regimen had promising activity for prevention of graft-versus-host disease (GVHD) in haploidentical-peripheral blood stem cell transplantation (haplo-PBSCT), but its impacts on long-term outcomes remain to be defined. METHODS We performed a large sample, long-term follow-up retrospective study to evaluate its efficacy for GVHD prophylaxis. RESULTS The study enrolled 260 patients, including 162 with myeloid malignancies and 98 with lymphoid malignancies. The median follow-up time was 27.0 months. For the entire cohort, the cumulative incidences (CIs) of grade II-IV and III-IV acute GVHD (aGVHD) by 180 days were 13.46% (95% CI, 9.64%-17.92%) and 5.77% (95% CI, 3.37%-9.07%); while total and moderate/severe chronic GVHD (cGVHD) by 2 years were 30.97% (95% CI, 25.43%-36.66%) and 18.08% (95% CI, 13.68%-22.98%), respectively. The 2-year overall survival (OS), relapse-free survival (RFS), GVHD-free, relapse-free survival (GRFS), non-relapse mortality (NRM), and CIs of relapse were 60.7% (95% CI, 54.8%-67.10%), 58.1% (95% CI, 52.2%-64.5%), 50.6% (95% CI, 44.8-57.1%), 23.04% (95% CI, 18.06%-28.40%), and 18.09% (95% CI, 14.33%-23.97%, respectively. The 1-year CIs of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation were 43.46% (95% CI, 37.39%-49.37%) and 18.08% (95% CI, 13.68%-22.98%), respectively. In multivariate analysis, the disease status at transplantation was associated with inferior survivor outcomes for all patients and myeloid and lymphoid malignancies, while cGVHD had superior outcomes for all patients and myeloid malignancies, but not for lymphoid malignancies. DISCUSSION The results demonstrated that the novel regimen could effectively prevent the occurrence of aGVHD in haplo-PBSCT.
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6.
Outcomes of patients with hematological malignancies who undergo unrelated donor hematopoietic stem cell transplantation with ATG-Fresenius versus ATG-Genzyme
Wang, L., Kong, P., Zhang, C., Gao, L., Zhu, L., Liu, J., Gao, S., Chen, T., Liu, H., Yao, H., et al
Annals of hematology. 2023
Abstract
To compare the outcomes of patients with hematological malignancies who received ATG-Fresenius (ATG-F) 20 mg/kg versus those who received ATG-Genzyme (ATG-G) 10 mg/kg in an unrelated donor hematopoietic stem cell transplantation (HSCT) procedure, a total of 186 patients who underwent their first allogeneic HSCT with an unrelated donor were retrospectively analyzed. One hundred and seven patients received ATG-F, and seventy-nine patients received ATG-G. Multivariate analysis showed that the type of ATG preparation had no effect on neutrophil engraftment (P = 0.61), cumulative incidence of relapse (P = 0.092), nonrelapse mortality (P = 0.44), grade II-IV acute graft-versus-host disease (GVHD) (P = 0.47), chronic GVHD (P = 0.29), overall survival (P = 0.795), recurrence-free survival (P = 0.945) or GVHD-free relapse-free survival (P = 0.082). ATG-G was associated with a lower risk of extensive chronic GVHD and a higher risk of cytomegaloviremia (P = 0.01 and HR = 0.41, P < 0.001 and HR = 4.244, respectively). The results of this study suggest that the preparation of rabbit ATG used for unrelated HSCT should be selected based on the incidence of extensive chronic GVHD of each center, and the posttransplant management strategy should be adjusted according to the ATG preparation.
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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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Post-transplant Cyclophosphamide in Acute Leukemia Patients Receiving more than 5/10 HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation from Related Donors: a Study on behalf of the ALWP of the EBMT
Wieczorek, M., Labopin, M., Castagna, L., Brissot, E., Socié, G., Raiola, A. M., Angelucci, E., Bermúdez Rodríguez, A., Yakoub-Agha, I., Aljurf, M., et al
American journal of hematology. 2022
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Low-dose post-transplant cyclophosphamide with low-dose antithymocyte globulin for prevention of graft-versus-host disease in first complete remission undergoing 10/10 HLA-matched unrelated donor peripheral blood stem cell transplants: a multicentre, randomized controlled trial
Zu, Y., Li, Z., Gui, R., Liu, Y., Zhang, Y., Yu, F., Zhao, H., Fu, Y., Zhan, X., Wang, Z., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
The most widely used regimens of graft-versus-host disease (GVHD) prophylaxis in HLA-matched unrelated donor peripheral blood stem cell transplantation (MUD-PBSCT) are based on anti-thymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). To improve the efficiency of GVHD prophylaxis, a novel regimen, composed of low-dose PTCy (20 mg/kg on day +3 and +4) and low-dose ATG (6 mg/kg), was evaluted in patients with hematological malignancies ungoing 10/10 HLA MUD-PBSCT in first remission (CR1). In our prospective, multicenter study, 104 patients were randomly assigned one-to-one to low-dose PTCy-ATG (n = 53) or standard-dose ATG (10 mg/kg, n = 51). Both the cumulative incidences (CIs) of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at 2 years in low-dose PTCy-ATG cohort were significantly reduced (24.5% vs. 47.1%; P = 0.017; 14.1% vs. 33.3%; P = 0.013). The CI of non-relapse-mortality (NRM) was much lower (13.2% vs. 34.5%; P = 0.049) and GVHD-free, relapse-free survival (GRFS) was significantly improved at 2 years in low-dose PTCy-ATG arm (67.3% vs 42.3%; P = 0.032). The low-dose PTCy-ATG based GVHD prophylaxis is a promising strategy for patients in CR1 after 10/10 HLA MUD-PBSCT.
PICO Summary
Population
Participants aged 12-69 years with haematological malignancies receiving 10/10 matched unrelated donor (MUD) transplantation in three transplant centres in China (n=104)
Intervention
Post-transplant cyclophosphamide, 20 mg/kg on day +3 and +4 and low-dose (6mg/kg) antithymocyte globulin (low-dose PTCy-ATG, n=53)
Comparison
ATG 2.0 mg/kg/day on days −5 through -1 (standard-dose ATG, n=51)
Outcome
Both the cumulative incidences (CIs) of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at 2 years in low-dose PTCy-ATG cohort were significantly reduced (24.5% vs. 47.1%; 14.1% vs. 33.3%). The CI of non-relapse-mortality (NRM) was much lower (13.2% vs. 34.5%) and GVHD-free, relapse-free survival (GRFS) was significantly improved at 2 years in low-dose PTCy-ATG arm (67.3% vs 42.3%).
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ATG in HLA-matched, peripheral blood, hematopoietic cell transplantation in acute myeloid leukemia and myelodysplastic syndrome: a secondary analysis of a CIBMTR database
Arcuri, L. J., Kerbauy, M. N., Kerbauy, L. N., Santos, F. P. S., Ribeiro, A. A. F., Hamerschlak, N.
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND Peripheral blood stem cells (PBSC) are the preferred grafts for hematopoietic cell transplantation (HCT), according to the CIBMTR. Donor recovery is faster with PBSC harvest, but PBSC is associated with higher chronic graft-versus-host disease (GVHD) and poorer quality of life. Anti-T cell globulin (ATG) is polyclonal IgG from rabbits or horses immunized with human thymocytes or a human T-cell line which may reduce graft-versus-host disease in HCT and improve outcomes. OBJECTIVE The objective of this study was to analyze the impact of ATG in HLA-matched Related (MRD) and matched (HLA 8/8) unrelated donor (MUD) HCT. STUDY DESIGN We used a freely available CIBMTR database published online for secondary analyses. The database included patients ≥ 40 y/o who have undergone their first PBSC MRD or MUD HCT for acute myeloid leukemia or myelodysplastic syndrome with or without ATG between 2008 and 2017. Patients who received posttransplant cyclophosphamide or alemtuzumab were excluded. RESULTS Overall survival was not different with ATG (HR = 1.09, 95CI 1.00-1.19, p = 0.06) compared with no ATG. Relapse rate was higher with ATG (HR = 1.29, 95CI 1.17-1.43, p < 0.001) and NRM was lower with ATG (HR = 0.84, 95CI 0.72-0.98, p = 0.03). Grades II-IV acute GVHD was significantly lower with ATG (HR = 0.77, 95CI 0.69-0.87, p < 0.001) but not grades III-IV acute GVHD (HR = 0.85, 95CI 0.69-1.04, p = 0.11). Both chronic GVHD (HR = 0.54, 95CI 0.48-0.60, p < 0.001) and moderate/severe chronic GVHD (HR = 0.45, 95CI 0.38-0.52, p < 0.001) were lower with ATG. There was an interaction between ATG and conditioning regimen for relapse rate and overall survival. Relapse rate was higher in those who received reduced-intensity (RIC) or non-myeloablative (NMA) conditioning regimens and ATG, compared with MAC ± ATG or RIC without ATG (interaction test, p = 0.003). Overall survival was also poorer with ATG and RIC or NMA conditioning regimens (interaction test, p = 0.03). CONCLUSION Our results show that ATG can mitigate the more severe forms of chronic GVHD without impairing overall survival in HLA-matched HCT with PBSC grafts and myeloablative conditioning regimen. ATG should be standard in this population.
PICO Summary
Population
Adults over 40 years drawn from the CIBMTR database, undergoing first peripheral blood stem cell transplant from matched related donor or matched unrelated donor for acute myeloid leukemia or myelodysplastic syndrome with or without ATG (n=4320)
Intervention
Received Anti-T cell globulin (ATG) prophylaxis (n=1007)
Comparison
Received no ATG prophylaxis (n=3313)
Outcome
Overall survival was not different with ATG (HR = 1.09, 95CI 1.00-1.19) compared with no ATG. Relapse rate was higher with ATG (HR = 1.29, 95CI 1.17-1.43) and non-relapse mortality was lower with ATG (HR = 0.84, 95CI 0.72-0.98). Grades II-IV acute GVHD was significantly lower with ATG (HR = 0.77, 95CI 0.69-0.87) but not grades III-IV acute GVHD (HR = 0.85, 95CI 0.69-1.04). Both chronic GVHD (HR = 0.54, 95CI 0.48-0.60) and moderate/severe chronic GVHD (HR = 0.45, 95CI 0.38-0.52) were lower with ATG. Relapse rate was higher in those who received reduced-intensity (RIC) or non-myeloablative (NMA) conditioning regimens and ATG, compared with myeloablative conditioning with or without ATG or RIC without ATG. Overall survival was also poorer with ATG and RIC or NMA conditioning regimens.