Venetoclax with azacitidine targets refractory MDS but spares healthy hematopoiesis at tailored dose

Abstract

Patients with Myelodysplastic Syndromes (MDS) and secondary Acute Myeloid Leukemia (sAML) have a very poor prognosis after failure of hypomethylating agents (HMA). Stem cell transplantation is the only effective salvage therapy, for which only a limited number of patients are eligible due to age and comorbidity. Combination therapy of venetoclax and azacitidine (5-AZA) seems to be a promising approach in myeloid malignancies, but data from patients with HMA failure are lacking. Furthermore, a considerable concern of combination regimens in elderly AML and MDS patients is the toxicity on the remaining healthy hematopoiesis. Here, we report in vitro data showing the impact of venetoclax and 5-AZA, alone or in combination, in a larger cohort of MDS/sAML patients (n = 21), even after HMA failure (n = 13). We especially focused on the effects on healthy hematopoiesis and the impact on colony forming capacity as a parameter for long-term effects. To the best of our knowledge, we show for the first time that venetoclax in combination with capped dose of 5-AZA targets cell malignancies, while sparing healthy hematopoiesis. Electronic supplementary material The online version of this article (10.1186/s40164-019-0133-1) contains supplementary material, which is available to authorized users.

Targeting Chronic Myeloid Leukemia Stem/Progenitor Cells Using Venetoclax-Loaded Immunoliposome

“…In different clinical trials administration of venetoclax led to neutropenia, thrombocytopenia, tumor lysis syndrome, and neutropenic fever [ 33 , 34 ]. Meanwhile, treatment of healthy bone marrow mononuclear cells with venetoclax reduced their cell viability and this toxic effect further increased by the addition of 5-azacitidine [ 35 ]. Furthermore, Ko et al claimed the higher sensitivity of healthy CD34+ cord blood stem cells to venetoclax compared to CML cells [ 36 ].…”

The lncRNA LAMP5-AS1 drives leukemia cell stemness by directly modulating DOT1L methyltransferase activity in MLL leukemia

“…Recently, the MLL gene can recombine with more than 60 partners to acquire abnormal gain-of-function effects on aberrant epigenetic modification and proto-oncogene activation, as a result triggering dysregulated increased expression of the clustered homeobox A (HOXA) genes, which results in limitless self-renewal capacity necessary for leukemia initiation and propagation [3]. Hematopoietic malignancy caused by MLL translocation, especially MLL-AF9, has been reported to have an apex self-renewal to generate more distinct self-renewing progenitor-like leukemia cells that are resistant to chemotherapy and are responsible for relapse [6,[8][9][10]. Persistence of MLL leukemia clones after treatment including available cell cycle-based or signaling protein-targeted therapies is the critical factor for unsatisfactory treatment outcome [11,12].…”

Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma

“…Western blot analysis furthermore confirmed the reduction in Mcl1 protein levels in both OTSSP167 and combo treated cells and the further increase in cleaved caspase-3 levels in the combo treated cells. Importantly, it has been reported that a concentration of 1 μM venetoclax corresponds to the clinically recommended dose of 400 mg per day in patients 57,58 . For our in vitro combination experiments, we used sub-optimal concentrations of venetoclax well below 1 μM.…”