Venetoclax-based non-intensive induction followed by allogenic stem-cell transplantation in elderly acute myeloid leukemia patients with adverse cytogenetics.

INTRODUCTION: Elderly acute myeloid leukemia (AML) patients with poor-risk cytogenetics have a poor outcome with intensive chemotherapy (IC). While Venetoclax (VEN) has changed the outcomes of elderly unfit patients treatment, it is unknown whether it could be effective in poor-risk cytogenetics 60-75 years old patients. MATERIALS AND METHODS: We included 60-75-year-old AML patients eligible to allogenic stem cell transplantation (allo-SCT) treated with VEN (combined with azacitidine or with Cladribin and Aracytine) at Institut Paoli Calmettes, between 2020 and 2023 and compared this cohort with patients treated by IC between 2010 and 2019. RESULTS: Twenty six patients were treated with VEN (17 in combination with azacitidine and 9 with Cladribin and Aracytine) and 90 were treated with IC. Thirteen patients (50%) had a TP53 mutation. The median time for leucocyte and platelet counts recovery was 26 days (range 0-103) and 26 days (range, 0-63). The median duration of the first hospitalization was 32 days (ranges, 7-79). The composite response rate was 69% (CR = 50%, CRi = 4%, MLFS = 15%). Allo-SCT could be performed in 42% of cases. Median overall survival (OS) was 7.9 months (20.9 months in the group of patients who transitioned to allo-SCT). We found no difference with the historical cohort of patients treated with IC except a trend toward less lower and upper tract gastro-intestinal (GI) tract infections in the VEN group (respectively 8% vs 26%, p = .06; and 0% vs. 13% p = .06). CONCLUSION: VEN-based treatment was found to be effective in high risk AML can be considered as an alternative to IC in patients aged 60-75 with adverse cytogenetics.

Poor prognosis of SRSF2 gene mutations in patients treated with VEN-AZA for newly diagnosed acute myeloid leukemia.

Mutations in spliceosome genes (SRSF2, SF3B1, U2AF1, ZRSR2) correlate with inferior outcomes in patients treated with intensive chemotherapy for Acute Myeloid Leukemia. However, their prognostic impact in patients treated with less intensive protocols is not well known. This study aimed to evaluate the impact of Spliceosome mutations in patients treated with Venetoclax and Azacitidine for newly diagnosed AML. 117 patients treated in 3 different hospitals were included in the analysis. 34 harbored a mutation in at least one of the spliceosome genes (splice-mut cohort). K/NRAS mutations were more frequent in the splice-mut cohort (47% vs 19%, p=0.0022). Response rates did not differ between splice-mut and splice-wt cohorts. With a median follow-up of 15 months, splice mutations were associated with a lower 18-month LFS (p=0.0045). When analyzing splice mutations separately, we found SRSF2 mutations to be associated with poorer outcomes (p=0.034 and p=0.037 for OS and LFS respectively). This negative prognostic impact remained true in our multivariate analysis. We believe this finding should warrant further studies aimed at overcoming this negative impact.

Post-remission outcomes in AML patients with high hyperleukocytosis and inaugural life-threatening complications.

INTRODUCTION: Patients with hyperleukocytic (HL) acute myeloid leukemia (AML) are at higher risk of early death. Initial management of these patients is challenging, not fully codified and heterogenous. Retrospective studies showed that several symptomatic measures might decrease early death rate but long-term data are scarce. We aimed to analyze whether the therapeutic measures carried out urgently at diagnosis may influence the outcome among HL AML patients having achieved who survived inaugural complications. METHODS: We retrospectively reviewed all medical charts from patients admitted to Saint-Louis Hospital between January, 1st 1997 and December, 31st 2018 with newly diagnosed AML and white blood cell (WBC) count above 50x109/L. Outcome measures were cumulative incidence of relapse (CIR), treatment-related mortality (TRM) defined as relapse-free death, and overall survival. Univariate and multivariate analyses were performed using Cox proportional hazards models. RESULTS: A total of 184 patients with HL AML in complete remission (CR) were included in this study. At 2 years after CR. 62.5% of patients were alive, at 5 years, cumulated incidence of relapse was 55.8%. We found that every therapeutic measure, including life-sustaining therapies carried out in the initial phase of the disease, did not increase the relapse risk. The use of hydroxyurea for more than 4 days was associated with a higher risk of relapse. At the end of the study, 94 patients (51.1%) were still alive including 23 patients out of 44 aged less than 60 yo that were able to return to work. CONCLUSION: We show that the use of emergency measures including life sustaining therapies does not come at the expense of a higher risk of relapse or mortality, except in the case of prolonged use of hydroxyurea. Patients with HL AML should be able to benefit from all available techniques, regardless of their initial severity.

Replica moulded poly(dimethylsiloxane) microwell arrays induce localized endothelial cell immobilization for coculture with pancreatic islets.

PolyJet three-dimensional (3D) printing allows for the rapid manufacturing of 3D moulds for the fabrication of cross-linked poly(dimethylsiloxane) microwell arrays (PMAs). As this 3D printing technique has a resolution on the micrometer scale, the moulds exhibit a distinct surface roughness. In this study, the authors demonstrate by optical profilometry that the topography of the 3D printed moulds can be transferred to the PMAs and that this roughness induced cell adhesive properties to the material. In particular, the topography facilitated immobilization of endothelial cells on the internal walls of the microwells. The authors also demonstrate that upon immobilization of endothelial cells to the microwells, a second population of cells, namely, pancreatic islets could be introduced, thus producing a 3D coculture platform.