Haematologica最新文献

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We evaluated response to venetoclax/hypomethylating agents (HMA) in 46 patients with acute myeloid leukemia (AML) characterized by extramedullary disease. The median age of these patients was 65 years (range, 19-81). The patients had a median of two sites of extramedullary disease (range, 1-5) and 35 (76%) had concurrent bone marrow involvement. Twenty (43%) patients had high-risk genetic features according to the European LeukemiaNet 2022 classification. Twenty-nine (63%) had relapsed or were refractory after intensive chemotherapy, including 13 (28%) who had undergone prior allogeneic hematopoietic cell transplantation. Patients received a median of two cycles of venetoclax/HMA (range, 1-31). Twenty (43%) patients achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) after venetoclax/HMA and five (11%) achieved a partial remission (PR). Six patients were subsequently consolidated with allogeneic hematopoietic cell transplantation (CR/CRi, N=4; PR, N=2). The median follow-up was 49.1 months (95% confidence interval [95% CI]: 26.1 months - not reached) and the median overall survival was 6.4 months (95% CI: 5.1-11 months). One-year and 2-year overall survival rates were 29.3% (95% CI: 18.6-46.2%) and 12.3% (95% CI: 5.5-27.6%), respectively. Age, with a cutoff of 60 years, did not have an impact on overall survival (P=0.90). Relapse occurred in 12 of 20 (60%) patients who achieved CR/CRi after venetoclax/ HMA treatment. Of those, all except one succumbed to their disease. Six (30%) patients were in CR/CRi at last follow-up and two (10%) died in CR. In our cohort of patients with AML with extramedullary disease with high-risk features, treatment with venetoclax/HMA resulted in an encouraging overall response rate of 54% with a CR/CRi rate of 43.5%. However, venetoclax/ HMA alone may not be effective in maintaining disease control.

Intensified chemoimmunotherapy regimens are often used in young patients with double-hit and triple-hit lymphoma (DHL/ THL) despite no survival benefit compared to R-CHOP. Favorable retrospective reports on the application of CODOX-M/IVAC-R are subject to selection bias as only young fit patients can tolerate this treatment. We conducted a retrospective analysis to investigate outcome differences between CODOX-M/IVAC-R and DA-EPOCH-R in DHL/THL patients aged 60 years or younger. One hundred and thirteen patients were identified; CODOX-M/IVAC-R (N=49) and DA-EPOCH-R (N=64). Eighty percent (39/49) achieved complete (CR) after completing CODOX-M/IVAC-R compared to 58% (37/64) with DA-EPOCH-R. The median follow-up was 5.3 years and 3.3 years for the CODOX-M/IVAC-R and DA-EPOCH-R group respectively. CODOX-M/IVAC-R demonstrated superior event-free survival (EFS) on univariate (hazard ratio [HR]=0.54, 95% confidence interval [CI]: 0.31-0.97) and multivariable analysis adjusted for age, BCL translocation (BCL2 vs. BCL6 vs. both), International Prognostic Index score and receipt of autologous stem cell transplant (adjusted HR [aHR]=0.52, 95% CI: 0.29-0.93); however there was no significant influence on OS (aHR=0.92, 95% CI: 0.46-1.84). The 1, 2 and 5 years EFS in the CODOX-M/IVAC-R group was 68.3%, 64.1% and 61.5%, respectively compared to 52.4%, 48.9% and 39.5%, respectively in the DA-EPOCH-R group. Primary refractory disease or relapse (R/R) occurred in 33% (16/49) of CODOX-M/IVAC-R and 54% (35/64) of DA-EPOCH-R recipients, and produced median OS of 10.3 months and 33.7 months, respectively, indicating poor outcomes in the CODOX-M/IVAC-R subgroup with R/R disease. More patients were able to receive subsequent salvage therapies in the DA-EPOCH-R group. No patients died of regimen toxicity and the rates of central nervous system relapse and therapy related hematologic neoplasms were similar in both groups.

High levels of branched-chain amino acid (BCAA) transaminase 1 (BCAT1) have been associated with tumor aggressiveness and drug resistance in several cancer types. Nevertheless, the mechanistic role of BCAT1 in T-cell acute lymphoblastic leukemia (T-ALL) remains uncertain. We provide evidence that Bcat1 was over-expressed following NOTCH1-induced transformation of leukemic progenitors and that NOTCH1 directly controlled BCAT1 expression by binding to a BCAT1 promoter. Further, using a NOTCH1 gain-of-function retroviral model of T-ALL, mouse cells genetically deficient for Bcat1 showed defects in developing leukemia. In murine T-ALL cells, Bcat1 depletion or inhibition redirected leucine metabolism towards production of 3-hydroxy butyrate (3-HB), an endogenous histone deacetylase inhibitor. Consistently, BCAT1-depleted cells showed altered protein acetylation levels which correlated with a pronounced sensitivity to DNA damaging agents. In human NOTCH1-dependent leukemias, high expression levels of BCAT1 may predispose to worse prognosis. Therapeutically, BCAT1 inhibition specifically synergized with etoposide to eliminate tumors in patient-derived xenograft models suggesting that BCAT1 inhibitors may have a part to play in salvage protocols for refractory T-ALL.