Choice of calcineurin inhibitor may impact the outcome of patients undergoing T-cell replete hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PT-Cy) and mycophenolate mofetil (MMF) for prophylaxis of graft-versus-host disease (GVHD). We retrospectively analyzed 2427 patients with acute myeloid leukemia (AML) in first remission transplanted from a haploidentical (n = 1844) or unrelated donor (UD, n = 583) using cyclosporine A (CSA, 63%) or tacrolimus (TAC, 37%) and PT-Cy/MMF. In univariate analysis, CSA and TAC groups did not differ in 2-year leukemia-free or overall survival, cumulative incidence (CI) of relapse or non-relapse mortality. CI of severe grade III-IV acute GVHD was lower with TAC (6.6% vs. 9.1%, p = 0.02), without difference in grade II-IV acute GVHD or grade III-IV acute GVHD/severe chronic GVHD, relapse-free survival (GRFS). In multivariate analysis, TAC was associated with a lower risk of severe grade III-IV acute GVHD solely with haploidentical donors (HR 0.64 [95% CI, 0.42-0.98], p = 0.04), but not UD (HR 0.49 [95% CI, 0.2-1.21], p = 0.12). There was no significant difference for chronic GVHD. In conclusion, PT-Cy/MMF-based GVHD prophylaxis resulted in favorable OS and GRFS, irrespective of the CNI added. In haploidentical HCT, TAC seemed to prevent severe acute GVHD more effectively than CSA without impact on other outcome parameters.

• MeSH
• akutní myeloidní leukemie * terapie   mortalita   MeSH
• cyklofosfamid * terapeutické užití   MeSH
• cyklosporin * terapeutické užití   MeSH
• dítě MeSH
• dospělí MeSH
• imunosupresiva terapeutické užití   MeSH
• indukce remise MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoc štěpu proti hostiteli * prevence a kontrola   mortalita   etiologie   MeSH
• předškolní dítě MeSH
• retrospektivní studie MeSH
• senioři MeSH
• takrolimus * terapeutické užití   MeSH
• transplantace hematopoetických kmenových buněk * metody   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• srovnávací studie MeSH
• Názvy látek
• cyklofosfamid * MeSH
• cyklosporin * MeSH
• imunosupresiva MeSH
• takrolimus * MeSH

In children with acute myeloid leukemia (AML) who lack a human leukocyte antigen (HLA) identical sibling, the donor can be replaced with an HLA-matched unrelated donor (MUD) or a haploidentical donor (haplo). We compared outcomes of patients <18 years with AML in first and second complete remission (CR1 and CR2) undergoing a hematopoietic stem cell transplantation (HCT) either with a MUD with anti-thymocyte globulin (ATG) (N=420) or a haplo HCT with post-transplant cyclophosphamide (PT-CY) (N=96) after a myeloablative conditioning regimen (MAC) between 2011 and 2021, reported to the European Society for Blood and Marrow Transplantation. A matched pair analysis was performed to adjust for differences among groups. The final analysis was performed on 253 MUD and 95 haplo-HCT. In the matched cohort, median age at HCT was 11.2 and 10 years and median year of HCT was 2017 and 2018, in MUD and haplo-HCT recipients, respectively. The risk of grade III-IV acute graft-versus-host disease (aGVHD) was significantly higher in the haplo group (hazard ratio [HR]=2.33, 95% confidence interval [CI]: 1.18-4.58; P=0.01). No significant differences were found in 2 years overall survival (OS; 78.4% vs. 71.5%; HR=1.39, 95% CI: 0.84-2.31; P=0.19), leukemia-free survival (LFS; 72.7% vs. 69.5%; HR=1.22, 95% CI: 0.76-1.95; P=0.41), CI of relapse (RI; 19.3% vs. 19.5%; HR=1.14, 95% CI: 0.62-2.08; P=0.68) non-relapse-mortality (NRM; 8% vs. 11%; HR=1.39, 95% CI: 0.66-2.93; P=0.39) and graft-versus-host free relapse-free survival (GRFS; 60.7% vs. 54.5%, HR=1.38, 95% CI: 0.95-2.02; P=0.09) after MUD and haplo-HCT respectively. Our study suggests that haplo-HCT with PT-CY is a suitable option to transplant children with AML lacking a matched related donor.

• MeSH
• akutní myeloidní leukemie * terapie   mortalita   MeSH
• cyklofosfamid * terapeutické užití   aplikace a dávkování   MeSH
• dítě MeSH
• haploidentická transplantace * metody   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• nemoc štěpu proti hostiteli * etiologie   prevence a kontrola   MeSH
• nepříbuzný dárce * MeSH
• předškolní dítě MeSH
• příprava pacienta k transplantaci * metody   MeSH
• testování histokompatibility MeSH
• transplantace hematopoetických kmenových buněk * metody   škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• cyklofosfamid * MeSH

Availability of haploidentical donors has broadened utilization of allogeneic hematopoietic cell transplantation (allo-HCT). Peripheral blood stem cells (PBSC) are being used with increased frequency in haploidentical allo-HCT. We evaluated extent of HLA disparity (2-3/8 versus 4/8 HLA antigen mismatches) on post-allograft outcomes when using T-cell replete PBSC from haploidentical donors for acute myeloid leukemia in first complete remission. Primary objectives entailed assessing cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD (any grade). A total of 645 patients received a haploidentical allo-HCT from a donor with either 2-3 of 8 HLA antigen mismatches (n = 180) or with 4 of 8 HLA antigen mismatches (n = 465). Presence of 2-3 of 8 versus 4 of 8 HLA mismatches did not affect the incidence of acute GVHD (grade 2-4) and chronic GVHD (any grade). Overall survival (OS), leukemia-free survival (LFS) relapse incidence (RI), nonrelapse mortality and the composite endpoint of GVHD-free relapse-free survival were also similar among the groups. Pertaining to HLA-B leader matching effect, our analysis did not discern any difference in aforementioned post-allograft outcomes for this variable. However, in univariate analysis, absence of an antigen mismatch in HLA-DPB1 showed a trend for better OS. Notwithstanding inherent limitations associated with registry data, our results did not show an advantage of selecting a haploidentical donor with 2-3 of 8 HLA antigen mismatches over one with 4 of 8 HLA antigen mismatches when using PBSC as the cell source. Adverse cytogenetics remains a major adverse determinant of inferior OS and LFS and a higher RI. Using reduced-intensity conditioning yielded worse OS and LFS.

• Publikační typ
• časopisecké články MeSH

Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM-risk scores in patients receiving PTCY-based GVHD prophylaxis, and subsequently developed and validated a novel PTCY-specific NRM-risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY-based GVHD prophylaxis were included. The PTCY-risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation-comorbidity index (HCT-CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2-year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT-CI, and integrated EBMT score was relatively poor for discriminating 2-year NRM (c-statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY-risk score included 10 variables which were collapsed in 3 risk groups estimating 2-year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c-statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c-statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM-risk score for acute leukemia patients receiving PTCY that better predicted 2-year NRM compared with existing models, which might be applicable to the specific toxicities of high-dose cyclophosphamide.

• Publikační typ
• časopisecké články MeSH

IMPORTANCE: Use of haploidentical (HAPLO) stem cell transplantation with posttransplant cyclophosphamide is rapidly increasing in adults with hematologic cancers. However, its specific role compared with other transplant strategies has yet to be identified. OBJECTIVE: To synthesize the existing evidence regarding outcomes of stem cell transplantations comparing HAPLO stem cell transplantation and posttransplant cyclophosphamide therapy with transplantations from matched related donors (MRDs), matched unrelated donors (MUDs), or mismatched unrelated donors (MMUDs). DATA SOURCES: PubMed, Cochrane Library, ClinicalTrials.gov, and meeting abstracts were searched for the key words haploidentical and cyclophosphamide from inception through March 1, 2019. STUDY SELECTION: Studies comparing HAPLO stem cell transplantation and posttransplant cyclophosphamide therapy with transplantations from other donors in adults with hematologic cancers were eligible for meta-analysis. DATA EXTRACTION AND SYNTHESIS: Pooled odds ratios (ORs) and 95% CIs were calculated using a random-effects model. MAIN OUTCOMES AND MEASURES: Main outcomes were all-cause mortality, nonrelapse mortality, and relapse. RESULTS: A total of 30 studies including 22 974 participants were analyzed. HAPLO stem cell transplantation with posttransplant cyclophosphamide therapy was associated with increased all-cause mortality compared with MRDs (OR, 1.17; 95% CI, 1.05-1.30), similar all-cause mortality compared with MUDs (OR, 1.06; 95% CI, 0.96-1.18), and reduced all-cause mortality compared with MMUDs (OR, 0.75; 95% CI, 0.61-0.92). Regarding nonrelapse mortality, HAPLO stem cell transplantation with posttransplant cyclophosphamide was associated with worse outcomes compared with MRDs (OR, 1.20; 95% CI, 1.04-1.40) but better outcomes compared with MUDs (OR, 0.75; 95% CI, 0.61-0.92) and MMUDs (OR, 0.51; 95% CI, 0.25-1.02). In terms of relapse, HAPLO stem cell transplantation with posttransplant cyclophosphamide was associated with similar outcome compared with MRDs (OR, 1.01; 95% CI, 0.86-1.17) and MMUDs (OR, 1.06; 95% CI, 0.77-1.47) but showed increased relapse compared with MUDs (OR, 1.20; 95% CI, 1.03-1.40). CONCLUSIONS AND RELEVANCE: Results of this meta-analysis suggest that MRDs, if available, remain the optimal donors regarding mortality and HAPLO stem cell transplantation with posttransplant cyclophosphamide may be preferred over MMUDs. Prospective comparisons with MUDs are needed.

• MeSH
• cyklofosfamid terapeutické užití   MeSH
• dospělí MeSH
• haploidentická transplantace MeSH
• hematologické nádory terapie   MeSH
• lidé MeSH
• nepříbuzný dárce MeSH
• přežití po terapii bez příznaků nemoci MeSH
• transplantace hematopoetických kmenových buněk metody   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• srovnávací studie MeSH
• systematický přehled MeSH
• Názvy látek
• cyklofosfamid MeSH

BACKGROUND: Data comparing fully matched and mismatched-unrelated-donor (M- and mM-URD) allogeneic hematopoietic stem cell transplant (allo-SCT) following reduced intensity conditioning regimens for acute myeloid leukemia are limited. METHODS: We retrospectively compared the outcome of 3398 patients above the age of 50 years who underwent 10/10 M-URD (n = 2567), 9/10 (n = 723), or 8/10 (n = 108) mM-URD allo-SCT for acute myeloid leukemia after reduced intensity conditioning regimen between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. RESULTS: HLA matching had no impact on engraftment (p = 0.31). In univariate analysis, in comparison to 10/10 M-URD, mM-URD was associated with higher incidence of grade II-IV acute graft-versus-host disease (GVHD) (p = 0.0002), similar rates of chronic GVHD (p = 0.138) but increased incidence of its extensive form (p = 0.047). Compared to 10/10 M-URD, patients transplanted in the first complete remission (CR1) with a 9 or an 8/10 mM-URD had decreased 2-year leukemia free (LFS) (p = 0.005) and overall survivals (OS) (56.7, 46.1, and 50.2 %, respectively, p = 0.005), while outcomes were comparable between all groups for patients transplanted beyond CR1. In multivariate analysis, 9/10 versus 10/10 URD was associated with higher non-relapse mortality (HR 1.34, p = 0.001), similar risk of relapse and chronic GVHD and inferior LFS (HR 1.25, p = 0.0001), and OS (HR 1.27, p = 0.0001). There was no difference in adjusted transplant outcomes between 9/10 and 8/10 mM-URD. CONCLUSIONS: Reduced intensity conditioned allo-SCT with a 10/10 M-URD remains the preferable option for AML patients above the age of 50 years. The use of a 9/10 or an 8/10 mM-URD in patients not having a fully matched donor represents an alternative therapeutic option that should be compared to other alternative donor transplant strategies.

• Klíčová slova
• Acute leukemia, Allogeneic stem cell transplantation, Anti-leukemic effect, HLA matching, Older patients, Toxicity, Unrelated donor,
• MeSH
• akutní myeloidní leukemie komplikace   mortalita   terapie   MeSH
• analýza přežití MeSH
• indukce remise MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoc štěpu proti hostiteli etiologie   imunologie   MeSH
• nepříbuzný dárce * MeSH
• přežívání štěpu MeSH
• příprava pacienta k transplantaci metody   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• testování histokompatibility * MeSH
• transplantace hematopoetických kmenových buněk škodlivé účinky   metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH