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1.
Timing of cyclosporine administration for GvHD prophylaxis in haploidentical stem cell transplantation setting: Single center experience
El Cheikh, J., Sharrouf, L., Hamade, M., Terro, K., Bidaoui, G., Charafeddine, M., Ismail, F., Zahreddine, A., Moukalled, N., Abou Dalle, I., et al
Current research in translational medicine. 2023;71(2):103387
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2.
Triple post transplant cyclophosphamide (PTCY) based GVHD prophylaxis: HLA matched versus HLA haploidentical transplants
Galli, E., Metafuni, E., Giammarco, S., Limongiello, M. A., Innocenti, I., Autore, F., Laurenti, L., Sorà, F., Chiusolo, P., Teofili, L., et al
Bone marrow transplantation. 2022
Abstract
We report a retrospective analysis of 198 allogeneic hematopoietic stem cell transplant (HSCT) recipients with post-transplant cyclophosphamide (PTCY), cyclosporine and mycophenolate mophetil as graft-versus-host-disease (GVHD) prophylaxis: the donors were HLA-matched (n = 78), or haploidentical relatives (HAPLO) (n = 120). The two groups were comparable except for older age in the HAPLO group. The main diagnosis were acute leukemia (57%) and myelofibrosis (21%). In the HLA-matched and HAPLO group the outcomes were as follows: aGVHD grade II-IV, 10% vs 27% (p = 0.005); moderate-severe cGVHD, 4% vs 19% (p = 0.004); transplant related mortality (TRM) at 1 year 10% vs 21% (p = 0.04); relapse at 1 year 24% vs 10% (p = 0.051) respectively. Disease free survival (DFS) at 1 year was 65% for matched and 68% for HAPLOs (p = 0.85). DFS and OS were independently predicted by age over 60 and higher DRI, whether the only independent predictive variable for GVHD and relapse free survival (GRFS) was age over 60. In conclusion: given the same PTCY based, GVHD prophylaxis, HLA-mismatched grafts are exposed to a higher risk of acute and chronic GVHD. This translates in increased TRM. DFS is comparable for HLA matched and HAPLO grafts.
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3.
Characteristics of Graft-versus-Host Disease (GvHD) after Post-transplant Cyclophosphamide versus Conventional GvHD Prophylaxis
Saliba, R. M., Majid, A. A., Pidala, J., Arora, M., Spellman, S. R., Hemmer, M. T., Wang, T., Abboud, C., Ahmed, S., Antin, J. H., et al
Transplantation and cellular therapy. 2022
Abstract
Post-transplantation cyclophosphamide (PTCy) has been shown to effectively control GvHD in haploidentical (Haplo) transplants. In this retrospective registry study, we compared GvHD organ distribution, severity, and outcomes in patients with GvHD occurring after Haplo transplantation with PTCy GvHD prophylaxis (Haplo/PTCy) versus HLA-matched unrelated donor transplantation with conventional prophylaxis (MUD/conventional). We evaluated two cohorts: patients with grade 2-4 acute GvHD (aGvHD) including 264 and 1,163 recipients of Haplo and MUD transplants; and patients with any chronic GvHD (cGvHD) including 206 and 1,018 recipients of Haplo and MUD transplants, respectively. In comparison with MUD/conventional transplantation +/- antithymocyte globulin (ATG), grade 3-4 aGvHD (28% vs. 39%, P=.001), stage 3-4 lower gastrointestinal (GI) tract aGvHD (14% vs 21%, P=.01), and chronic GI GvHD (21% vs. 31%, P=.006) were less common after Haplo/PTCy transplantation. In patients with grade 2-4 aGvHD, cGcHD rate after Haplo/PTCY was also lower (HR =.4, P<.001) in comparison with MUD/conventional transplantation without ATG in the non-myeloablative conditioning setting. Irrespective of the use of ATG, non-relapse mortality rate was lower (HR=.6, P =.01) after Haplo/PTCy transplantation, except for transplants that were from a female donor into a male recipient. In patients with cGvHD, irrespective of ATG use, Haplo/PTCy transplantation had lower non-relapse mortality rate (HR=.6, P=.04). Mortality rate was higher (HR=1.6, P=.03) within, but not after (HR=.9, P=.6) the first six months subsequent to cGvHD diagnosis. Our results suggest that PTCy-based GvHD prophylaxis mitigates the development of GI GvHD and may translate into lower GvHD-related non-relapse mortality rate.
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4.
Optimal Active Anti-Thymocyte Globulin Exposure Associated with Minimum Risk of Virus Reactivation and Comparable Acute Graft-Versus-Host Disease under Adult Myeloablative Haploidentical Peripheral Blood Stem Cell Transplantation
Wang, H., Zhao, Y., Fang, S., Wang, L., Peng, B., Yang, J., Wang, N., Du, J., Li, F., Jin, X., et al
Transplantation and cellular therapy. 2022
Abstract
Anti-thymocyte globulin (ATG) is often included in the conditioning regimen to prevent graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HCT). Meanwhile, the risk of virus reactivation increased significantly. We conducted a single-center prospective study to identify the optimal ATG exposure that ensures engraftment, effectively prevent aGVHD, and reduces the risk of virus reactivation without increasing relapse of malignant diseases in haplo-PBSCT. From September 2018 to June 2020, 106 patients (median age: 32 years) with malignant hematological diseases who received haplo-PBSCT for the first time were enrolled. All patients received 10 mg/kg rabbit-ATG (thymoglobulin) divided for 4 days (Day -5 to -2). Pre-transplant, post-transplant, and total areas under the concentration-time curve (AUCs) of active ATG were calculated. Total AUC of active ATG was shown to be the best predictor for virus reactivation and aGVHD of grades II-IV or III-IV. The optimal total AUC range of active ATG was 100-148.5 UE/mL•day. The median time was 14 versus 13 days (P = .184) for myeloid engraftment and 13 versus 13 days (P = .263) for platelet engraftment in the optimal and non-optimal AUC group, respectively. The optimal AUC group showed a lower CI of CMV reactivation and persistent CMV viremia than the non-optimal AUC group [60.6% (95%CI, 48.3%-73.1%) versus 77.1% (95%CI, 64.5%-87.7%), P = .016, and 31.5% (95%CI, 21.2%-45.3%), versus 56.3% (95%CI, 42.9%-70.4%), P = .007, respectively]. The CI of persistent EBV viremia in the optimal AUC group was significantly lower than the non-optimal total AUC group [33.1% (95%CI, 22.5%-46.8%) versus 52.6% (95%CI, 39.3%-67.2%), P=0.048], but there was no difference in EBV reactivation (P=0.752). Similar outcomes were observed for Grade II-IV and grade III-IV aGVHD between the two groups (48.6% (95%CI, 36.8%-62.0%) versus 37.0% (95%CI, 24.8%-52.5%), P = 0.113, and 10.4% (95%CI, 4.8%-21.7%) versus 4.2% (95%CI, 1.0%-15.6%), P = 0.234, respectively). Relapse, non-relapse mortality, and disease-free survival had no significant differences between the two groups. But overall survival at 2years tended to increase in optimal AUC group (75.7% [95%CI, 62.4%-84.8%] vs. 57.8% [95%CI, 42.4%-70.4%], P=0.061). These data support an optimal active ATG exposure of 110-148.5 UE/mL•day in haplo-PBSCT. Individualized dosing of ATG in allo-HCT might reduce the risk of virus reactivation and effectively prevent aGVHD simultaneously.
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5.
A phase 2 trial of GVHD prophylaxis with PTCy, sirolimus, and MMF after peripheral blood haploidentical transplantation
Bejanyan, N., Pidala, J. A., Wang, X., Thapa, R., Nishihori, T., Elmariah, H., Lazaryan, A., Khimani, F., Davila, M. L., Mishra, A., et al
Blood advances. 2021;5(5):1154-1163
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Editor's Choice
Abstract
The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype-incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (=18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223.
PICO Summary
Population
Adult patients who received a haploidentical stem cell transplant (n=32)
Intervention
Post-transplant cyclophosphamide (PTCy) and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis
Comparison
None
Outcome
At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8%. There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8%, nonrelapse mortality was 18.8%, relapse was 22.2% , disease-free survival was 59.0%, GVHD-free relapse-free survival was 49.6% and overall survival was 71.7% for the entire cohort.
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6.
Comparison of 2 Different Doses of Antithymocyte Globulin in Conditioning Regimens for Haploidentical Hematopoietic Stem Cell Transplantation
Wang, M., Fang, X., Jiang, Y., Sui, X., Li, Y., Liu, X., Wang, X., Li, P., Xu, H., Wang, X.
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 2021
Abstract
OBJECTIVES Antithymocyte globulin is extensively used for prophylaxis of graft-versus-host disease in patients undergoing haploidentical hematopoietic stem cell transplantation. However, different doses of antithymocyte globulin are administered in clinical practice. This study aimed to identify the optimal dose of antithymocyte globulin (thymoglobulin) in haploidentical hematopoietic stem cell transplantation. MATERIALS AND METHODS We retrospectively analyzed the effects of 10 mg/kg (2.5 mg/kg on days -5 to -2) versus 7.5 mg/kg thymoglobulin (2.5 mg/kg on days -4 to -2) on patients receiving haploidentical hematopoietic stem cell transplantation with myeloablative conditioning. RESULTS We observed significant differences between the 2 treatment groups with regard to cumulative incidence of grade II to IV acute graft-versus-host disease (15.3% vs 14.6%; P = .93) and 3-year chronic graft-versus-host disease (12.1% vs 14.3%; P = .77). The probabilities of 3-year overall survival (68.9% vs 73.5%; P = .98) and graft-versus-host disease-free/relapse-free survival (66.7% vs 53.1%; P = .14) were comparable between the 2 groups. However, there was a trend for lower cumulative incidence of hemorrhagic cystitis in the 7.5 mg/kg treatment group compared with the 10 mg/kg treatment group (40.7% vs 24.4%; P = .07). CONCLUSIONS For patients who received a reduced dose of antithymocyte globulin (7.5 vs 10 mg/kg), there was no impaired effect on prophylaxis of graft-versus-host disease, with a trend of reduced incidence of hemorrhagic cystitis. Further studies of the 7.5 mg/kg dose of antithymocyte globulin are warranted for patients receiving haploidentical hematopoietic stem cell transplantation.
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7.
Optimizing antithymocyte globulin dosing in haploidentical hematopoietic cell transplantation: long-term follow-up of a multicenter, randomized controlled trial
Wang, Y., Liu, Q. F., Lin, R., Yang, T., Xu, Y. J., Mo, X. D., Huang, X. J.
Science Bulletin. 2021;66(24):2498-2505
Abstract
Given that randomized studies testing the long-term impact of antithymocyte globulin (ATG) dosing are scarce, we report the results of an extended follow-up from the original trial. In our prospective, multicenter, randomized trial, 408 leukemia patients 14-65 years of age who underwent haploidentical hematopoietic cell transplantation (haplo-HCT) under our original "Beijing Protocol" were randomly assigned one-to-one to ATG doses of 7.5 mg/kg (n = 203, ATG-7.5) or 10 mg/kg (n = 205, ATG-10.0) at four sites. Extended follow-up (median 1968 d (range: 1300-2710 d) indicated comparable 5-year probabilities of moderate-to-severe chronic graft-versus-host disease (GVHD) (hazard ratio (HR): 1.384, 95% confidence interval (CI): 0.876-2.189, P = 0.164), nonrelapse mortality (HR: 0.814, 95% CI: 0.526-1.261, P = 0.357), relapse (HR: 1.521, 95% CI: 0.919-2.518, P = 0.103), disease-free survival (HR: 1.074, 95% CI: 0.783-1.473, P = 0.658), and GVHD-free/relapse-free survival (HR: 1.186, 95% CI: 0.904-1.555, P = 0.219) between groups (ATG-7.5 vs. ATG-10.0). The 5-year rate of late effects did not differ significantly. However, the cytomegalovirus/Epstein-Barr virus-related death rate was much higher in the ATG-10.0 cohort than in the ATG-7.5 cohort (9.8% vs. 1.5%; P = 0.003). In summary, patients undergoing haplo-HCT benefit from 7.5 mg/kg ATG compared to 10.0 mg/kg ATG based on a balance between GVHD and infection control. ATG (7.5 mg/kg) is potentially regarded as the standard regimen in the platform. These results support the optimization of ATG use in the "Beijing Protocol", especially considering the potential economic advantage in developing countries.
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8.
Post-transplant cyclophosphamide versus anti-thymocyte globulin for graft-versus-host disease prevention in haploidentical transplantation for adult acute lymphoblastic leukemia
Nagler, A., Kanate, A. S., Labopin, M., Ciceri, F., Angelucci, E., Koc, Y., Gulbas, Z., Arcese, W., Tischer, J., Pioltelli, P., et al
Haematologica. 2020
Abstract
Graft-versus-host disease (GVHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation (haplo-HCT) include post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing EBMT registry, we compared ATG versus PTCy based GVHD prophylaxis in adult acute lymphoblastic leukemia (ALL) patients undergoing haplo-HCT. Included were 434 patients; ATG (n=98) and PTCy (n=336). Median follow-up was ~2 years. Baseline characteristics were similar between the groups except that the ATG-group was more likely to have relapsed/refractory ALL (P=0.008), non-TBI conditioning (P<0.001), peripheral blood graft source (P=<0.001) and transplanted at an earlier time-period (median year of HCT 2011 vs. 2015). The 100-day grade II-IV and III-IV acute-GVHD was similar between ATG and PTCy, as was 2-year chronic-GVHD. On multivariate analysis (MVA), leukemia-free survival (LFS) and overall survival (OS) was better with PTCy compared to ATG prophylaxis. Relapse incidence (RI) was lower in the PTCy group (P=0.03), while non-relapse mortality (NRM) was not different. Advanced disease and lower performance score were associated with poorer LFS and OS and advanced disease with inferior GVHD-free/relapse-free survival (GRFS). Peripheral grafts were associated with higher GVHD compared to bone marrow grafts. In ALL patients undergoing unmanipulated haplo-HCT, PTCy for GVHD prevention resulted in lower RI and improved LFS and OS compared to ATG.
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9.
Comparison of ATG-thymoglobulin with ATG-Fresenius for Epstein-Barr virus infections and graft-versus-host-disease in patients with hematological malignances after haploidentical hematopoietic stem cell transplantation: a single-center experience
Zhou, L., Gao, Z. Y., Lu, D. P.
Annals of hematology. 2020
Abstract
Two anti-thymocyte globulin (ATG) forms are used in graft-versus-host disease (GVHD) prophylaxis during haploidentical hematopoietic stem cell transplantations (haplo-HSCTs): ATG-thymoglobulin (ATG-T) and ATG-fresenious (ATG-F). However, comparable dosages for haplo-HSCT remain unclear. We compared and evaluated the effects of ATG-T (7.5 mg/kg) or ATG-F (20 mg/kg) dosages in a relatively homogenous population in haplotype HSCT settings. Patients administered ATG-T 7.5 mg/kg (n = 81) or ATG-F 20 mg/kg (n = 35) as part of GVHD prophylaxis during haplo-HSCT were enrolled. Incidence and severity of GVHD, Epstein-Barr virus (EBV) infection, and immune cell recovery were compared using the Mann-Whitney U rank test and chi-square test. Cumulative incidences of GVHD, EBV infection and its subgroups, and relapse mortality were computed; overall survival (OS) was analyzed using the Kaplan-Meier method, with the log-rank test used for univariate comparison. Risk factors for OS were analyzed by the Cox proportional hazards model. Incidence and cumulative incidence of all grades of acute GVHD and subgroups were comparable in both groups (all p > 0.05); however, cumulative incidence of any grade and limited chronic GVHD was significantly higher in the ATG-T group (p = 0.002, p = 0.007, respectively). Cumulative incidences of EBV infections, EBV-DNAemia, and EBV-related diseases were similar; relapse mortality and OS rates were comparable between both groups (all p > 0.05). ATG-T dosage (7.5 mg/kg) appeared comparable to ATG-F dosage (20 mg/kg) for haplo-HSCT. Currently approved ATG-T and ATG-F doses appear efficient to balance the risk-benefit ratio of GVHD, OS, relapse mortality, and EBV infection in haplo-HSCT.
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10.
Posttransplant Cyclophosphamide and Antithymocyte Globulin versus Posttransplant Cyclophosphamide as Graft-versus-Host Disease Prophylaxis for Peripheral Blood Stem Cell Haploidentical Transplants: Comparison of T Cell and NK Effector Reconstitution
Makanga, D. R., Guillaume, T., Willem, C., Legrand, N., Gagne, K., Cesbron, A., Gendzekhadze, K., Peterlin, P., Garnier, A., Le Bourgeois, A., et al
Journal of immunology (Baltimore, Md. : 1950). 2020
Abstract
A higher incidence of graft-versus-host disease (GVHD) has been observed after haploidentical hematopoietic stem cell transplantation (h-HSCT) with posttransplant cyclophosphamide (PTCY) using peripheral blood stem cells (PBSC) as a source of graft. Moreover, combining PTCY with antithymocyte globulin (ATG) may help to reduce GVHD incidence. In this study, early immune reconstitution, especially of T and NK cell compartments, was compared after both types of transplant (PTCY versus PTCY + ATG) investigate their influence on patient outcomes. This retrospective study included 58 adults who received a reduced intensity conditioning to PBSC h-HSCT with cyclosporine and mycophenolate mofetyl + PTCY (n = 32) or PTCY + ATG (n = 26) as GVHD prophylaxis. Both groups shared similar characteristics except for the median number of CD3(+) T cells infused, significantly higher for PTCY + ATG patients. Blood samples from all patients were collected three times a week from day 0 until day 30 then at day 60 and day 90/100 to evaluate T and NK cells reconstitution by flow cytometry. The results show that PTCY + ATG versus PTCY alone significantly limits the occurrence of acute grade 2-4 GVHD after reduced intensity conditioning PBSC h-HSCT, perhaps because of the combined effect of T and NK cell reconstitution. Indeed, although a slower T cell reconstitution with PTCY + ATG may limit GVHD occurrence, the quicker reconstitution of some NK cell subtypes may help with avoiding relapse. Larger prospective studies are needed to better determine which NK cell subsets may influence the incidence of relapse after h-HSCT and optimize donor selection.