The myelodysplastic syndromes (MDS) are a group of clonal bone marrow (BM) stem cell disorders, characterized by ineffective hematopoiesis, peripheral cytopenias, and hematologic cellular dysfunction, as well as potential transformation to acute leukemia.Thrombocytopenia is common in MDS and is associated with bleeding complications, occasionally life-threatening. Low platelet count (PLT), as well declining PLT also serves as a prognostic marker. Understanding thrombopoiesis led to the cloning of thrombopoietin, resulting in the development of platelet stimulating agents, thrombomimetics, romiplostim and eltrombopag.Both agents have been shown to increase PLT, decrease the need for platelet transfusions and reduce the number of bleeding episodes, with a reasonable tolerance. They are already approved for immune thrombocytopenia and thrombocytopenia related to liver disease.Romiplostim and eltrombopag have proven efficacy in lower- and higher-risk MDS with thrombocytopenia, as monotherapy, as well as a part of a combination, either with lenalidomide, and mainly combined with hypomethylating agents. However, safety concerns have been raised: while several trials have been completed with no evidence of disease progression, others have been early terminated due to an increased number of BM blasts and possible leukemic transformation in treated-patients. The jury is still out regarding this safety concern, although recent publications are more encouraging.

Combinations of the BCL‐2 inhibitor, venetoclax, with either hypomethylating agents (HMA) or low dose cytarabine (LDAC), have shown promising results in clinical trials of AML patients unfit for intensive therapy. We report on the efficacy and safety of venetoclax combinations in AML patients treated outside of clinical trials. Complete remission (CR) + CR with incomplete count recovery (CRi) were achieved in 61% of patients, with similar CR+CRi rates in with secondary AML, and in patients who were previously treated with HMA (61% and 43%, respectively). Relapse occurred in 25% of patients, with a median event‐free survival (EFS) of 11.7 months (95% CI, 10.09–13.35) in responding patients. At a median follow up of 8.7 months, the median overall survival (OS) was 9.8 months (95% CI 6.42–13.3) in the entire cohort. In multivariate analysis adverse karyotype was the only negative predictor of CR/CRi (p = .03), while both ECOG performance status (PS) and adverse karyotype were significantly associated with shorter OS (p = .023 and .038, respectively). Median OS was higher in patients achieving CR/CRi and in patients proceeding to allogeneic stem cell transplantation (allo‐SCT). Treatment was well tolerated, with side effects similar to those described in the randomized clinical trials. Tumor lysis syndrome (TLS) occurred in 12% of patients. Our data support the efficacy and safety of venetoclax combinations in newly diagnosed AML patients not eligible for intensive therapy. According to our data, secondary AML patients could benefit from venetoclax combinations similarly to de‐novo AML patients, and allo‐SCT could be offered to selected patients achieving CR/CRi.

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Results: Narazaciclib exhibited the highest antitumor activity among MCL cell lines (mean IC 50 : 3.61 � 2.1 µM), regardless of their sensitivity to ibrutinib. Although there was no correlation between CDKi sensitivity and activation of the CDK4/CDK6-pRb pathway in MCL, transcriptomic and phenotypic analyses revealed a predominant downregulation of E2F target genes and G2/M checkpoint response (NES > 2.5) upon narazaciclib treatment. This feature was associated to intracellular accumulation of p21, p16, and phospho-p27, decreased mitotic index, G1 cell cycle blockade, and apoptosis onset. When combined with ibrutinib, but not with the second generation therapeutic acalabrutinib, narazaciclib achieved significant synergistic antitumor activity in both BTK-sensitive and BTKresistant cells. The combination was not associated with improved apoptosis, but rather with a slight but constant (+10%-15%) augmentation in G1 phase blockade and the down-modulation of cell cycle-associated transcriptome. Both the downregulation of phospho-histone H3 and the upregulation of p-p27/p27 and p16, also underwent a 10%-15% improvement in combination-treated cells. In vivo, while narazaciclib single agent achieved a 28% TGI in the CAM model, the narazaciclib-ibrutinib combination reduced tumor spreading by 65% and allowed a 50% reduction in malignant B cell infiltration into the bone marrow, with no detectable toxicity.Conclusions: Narazaciclib, due to its completely distinct MoA from BTKi involving the direct modulation of the cell cycle, can achieve significant synergistic activity with ibrutinib in vitro and in vivo, especially in BTKi-resistant models of MCL. Ongoing phosphoproteomics and genetic edition assays will help deciphering the molecular bases of this unique drug cooperation at the cell cycle level.