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

IntroductionPost-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.MethodsTherefore, 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.ResultsThe 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%).DiscussionOur 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

Peripheral Blood Stem Cells versus Bone Marrow for T Cell-Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide in Hodgkin Lymphoma.

Abstract Haploidentical stem cell transplantation (haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) represents a potential curative strategy for patients with Hodgkin lymphoma (HL) when a matched related or unrelated donor is not available. The role of graft source, either bone marrow (BM) or peripheral blood stem cells (PBSCs), in this setting has not been fully elucidated. We performed a retrospective study on 91 patients with HL to compare the outcome after BM (n = 53) or PBSC (n = 38) transplant. Eighty-nine patients engrafted with no difference between BM and PBSCs in terms of median time for neutrophil (20 versus 20 days, P = .405) and platelet (26 versus 26.5 days, P = .994) engraftment. With a median follow-up of 40.2 months, 100-day cumulative incidences of grades II to IV acute graft-versus host disease (GVHD) and grades II to IV acute GVHD were 24% and 4%, respectively. Graft source was not associated with a different risk of acute GVHD both by univariate and multivariate analyses. Consistently, 1-year cumulative incidence of chronic GVHD was 7% with no differences between the 2 graft types (P = .761). Two-year rates of overall survival (OS), progression-free survival (PFS), nonrelapse mortality, and GVHD/relapse-free survival (GRFS) were 67%, 58%, 20%, and 52%, respectively. By univariate analysis, pretransplant disease status was the main variable affecting all outcomes. By multivariate analysis, PBSCs resulted in a protective factor for OS (hazard ratio [HR], .29; P = .006), PFS (HR, .38; P = .001), and GRFS (HR, .44; P = .020). The other independent variables affecting the final outcome were pretransplant disease status and hematopoietic cell transplant–specific comorbidity index. In conclusion, when planning a haplo-SCT with PT-Cy for patients with poor-risk HL, graft type is an important variable to take into account when selecting the best available donor

Antithymocyte Globulin in Reduced-Intensity Conditioning Regimen Allows a High Disease-Free Survival Exempt of Long-Term Chronic Graft-versus-Host Disease

AbstractNonmyeloablative (NMA) regimens allow the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients considered unfit for standard myeloablative conditioning (MAC) regimens using high-dose alkylating agents with or without total body irradiation (TBI). Reduced-intensity conditioning (RIC) regimens, based on fludarabine (Flu), busulfan (Bu), and rabbit antithymocyte globulin (r-ATG), represent an intermediate alternative between NMA and MAC regimens. This platform was subsequently optimized by the introduction of i.v. Bu and the use of 5 mg/kg r-ATG, based on the hypothesis that these modifications would improve the safety of RIC allo-HSCT. Here we report a study conducted at our institution on 206 patients, median age 59 years, who underwent allo-HSCT after conditioning with Flu, 2 days of i.v. Bu, and 5 mg/kg r-ATG (FBx-ATG) between 2005 and 2012. The prevalence of grade III-IV acute graft-versus-host disease (GVHD) was 9%, and that of extensive chronic GVHD was 22%. Four-year nonrelapse mortality (NRM), relapse, and overall survival (OS) rates were 22%, 36%, and 54%, respectively. NRM tended to be influenced by comorbidities (hematopoietic cell transplantation–specific comorbidity index [HCT-CI] <3 versus HCT-CI ≥3: 18% versus 27%; P = .075), but not by age (<60 years, 20% versus ≥60 years, 25%; P = .142). Disease risk significantly influenced relapse (2 years: low, 8%, intermediate, 28%, high, 34%; very high, 63%; P = .017). Both disease risk (hazard ratio [95% confidence interval]: intermediate, 2.1 [0.8 to 5.2], P = .127; high, 3.4 [1.3 to 9.1], P = .013; very high, 4.0 [1.1 to 14], P = .029) and HCT-CI (hazard ratio [95% confidence interval]: HCT-CI ≥3, 1.7 (1.1 to 2.8), P = .018) influenced OS, but age and donor type did not. The FBx-ATG RIC regimen reported here is associated with low mortality and high long-term disease-free survival without persistent GVHD in both young and old patients. It represents a valuable platform for developing further post-transplantation strategies aimed at reducing the incidence of relapse, particularly in the setting of high-risk disease

Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases

The ASXL1 gene is one of the most frequently mutated genes in malignant myeloid diseases. The ASXL1 protein belongs to protein complexes involved in the epigenetic regulation of gene expression. ASXL1 mutations are found in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). They are generally associated with signs of aggressiveness and poor clinical outcome. Because of this, a systematic determination of ASXL1 mutational status in myeloid malignancies should help in prognosis assessment

Molecular characterization of acute myeloid leukemia with myelodysplasia related changes

Les leucémies aiguës myéloïdes (LAM) avec dysplasie, identifiées par la classification OMS 2008 sous le nom de LAM-MRC (« AML with myelodysplasia-related changes »), sont actuellement définies par la présence de critères cliniques, cytologiques et cytogénétiques. Elles forment un groupe hétérogène tant sur le plan biologique que pronostique. Nous avons fait l'hypothèse que la caractérisation moléculaire des LAM-MRC pourrait permettre d'identifier des marqueurs spécifiques associés à ces pathologies et d'en distinguer différents sous-groupes. Nous avons mis en évidence que les LAM-MRC de risque cytogénétique intermédiaire présentent un profil mutationnel spécifique caractérisé par un taux élevé de mutation d'ASXL1 et une faible proportion de mutations de DNMT3A, NPM1 et FLT3. Les LAM-MRC de risque cytogénétique défavorable, essentiellement complexes et/ou monosomales, sont quant à elle associées aux mutations de TP53. Alors que les critères actuels des LAM-MRC ne permettent pas d'en stratifier le pronostic, nous avons montré que les mutations d'ASXL1 ou de TP53 sont des facteurs pronostics péjoratifs majeurs. Ainsi, une reclassification basée sur la présence de ces altérations moléculaires exclusives entre elles permettrait d'affiner le diagnostic et la stratification pronostique de ces maladies. Enfin, dans une stratégie de médecine personnalisée combinant le séquençage à haut débit à des tests de sensibilité thérapeutique in vitro, l'identification de tels marqueurs moléculaires permettraient de prédire la réponse aux traitements, de guider les choix thérapeutiques et d'orienter le développement de nouvelles drogues.Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) as reported in the WHO 2008 classification are defined by the presence of clinical, morphological and cytogenetic criteria. AML-MRCs are heterogeneous diseases with prognostic heterogeneity. We hypothesized that molecular characterization of AML-MRC could identify specific molecular markers and disease subgroups. We showed that AML-MRCs with intermediate cytogenetic risk harbor a specific mutational profile characterized by a high frequency of ASXL1 mutations and a low incidence of DNMT3A, NPM1 and FLT3 mutations. Unfavorable cytogenetic risk AML-MRCs, especially due to complex and/or monosomal karyotypes, are associated with TP53 mutations. While WHO criteria do not stratify the prognosis of AML-MRC patients, we showed that the mutations of ASXL1 or TP53 are major poor prognostic factors. The criteria defining AML-MRC do not identify distinct clinical and biological subgroups and do not predict outcome of patients with AML-MRC. In contrast, ASXL1 and TP53-mutated AML identify two distinct biological subgroups of AML-MRC with very poor outcome. This molecular characterization could be useful to redefine AML-MRC in a future classification aiming at merging biological characterization and specific prognostic value. Finally, we showed that a personalized treatment approach combining next generation sequencing and in vitro drug screening could be useful to predict therapeutic response and to guide both treatment choices and new targeted drug developments

T-cell-replete haploidentical transplantation in acute myeloid leukemia

In the last decade, the number of haploidentical stem cell transplantation has increased because of the widespread use of T-cell-replete platforms developed worldwide. Acute myeloid leukemia (AML) is the main indication to perform allogeneic stem cell transplantation. Here, we reviewed the clinical results obtained using T-cell-replete platforms in different clinical situations such as first or further complete remission, refractory disease, and in the elderly population. Overall, the toxic profile of T-cell-replete haploidentical transplantation is similar to transplantation from other donors, with positive aspects such as a reduced incidence of chronic graft versus-host disease. Leukemia-free survival and overall survival are also similar. In conclusion, T-cell-replete haploidentical transplantation represents a new frontier in the treatment landscape of AML, lessening problems linked to donor search and ensuring that a donor can be found for all patients in a timely manner. (C) 2018 ISEH Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved

Maitrise de l'exposition au Busulfan à travers le développement d'un modèle prédictif de la survie

Book of abstractsInternational audienceEtude monocentrique rétro-spective, de patients ayant eu une greffe CSH conditionnée par Busulfan, avec un suivi des concentrations plasmatiques

Développement d'un modèle d'intelligence artificielle pour la prédiction de l'exposition au Busulfan et l'individualisation des posologies

Book of abstractsInternational audienc

Utilisation de l'IA pour une meilleur compréhension des mécanismes de rechute dans les greffes CSH conditionnées par Busulfan haute dose

Book of abstractsInternational audienc

Les glycosylations de PD-L1 sous les feux de la rampe

International audienceNo abstract availabl