Background: Patients (pts) with acute myeloid leukemia (AML) over the age of 75 are commonly considered unfit for intensive chemotherapy. Several population based studies have shown that many of these pts are managed with supportive care only. Until recently, effective non-intensive treatments for AML were lacking. In Jan 2019 venetoclax (ven) based low intensity regimens were approved in Israel on the basis of their efficacy and safety in clinical trials. Aims: We examined the impact of the approval of venetoclax on the management and outcomes of AML pts over the age of 75 in a real world, single center setting. Methods: We retrospectively analyzed all pts older than 75 years of age diagnosed with AML at Tel Aviv Sourasky Medical Center from Jan 2016 to Dec 2021. We compared pts characteristics and outcomes in 2019-21 to 2016-18 (ven era and pre-ven era, respectively). We compared categorical and continuous variables as appropriate, and examined overall survival (OS), event free survival (defined as time to non-response, relapse or death, EFS) and relapse free survival (RFS) using a Kaplan Meier estimator and Log-Rank test. IBM SPSS version 29 was applied for the statistical analyses. Results: 83 AML pts over the age of 75 were identified (median age 81.9, range 75.3-95.2); 47 diagnosed in the ven era and 36 in the pre-ven era. In this pt population, 55% had secondary AML and 56.1% had ELN adverse risk AML. These and other baseline characteristics - age, sex, bone marrow blast count, peripheral blood cell counts and kidney function - were similar between pts diagnosed before and after 2019. In 2016-18 only 20 (55.6%) pts received any anti-leukemia treatment, including 4 pts who received intensive chemotherapy. In 2019-21, 41 (87.2%) pts received anti-leukemia treatment, all of whom were treated with ven-HMA combinations (p=0.001). There were no significant differences in baseline characteristics of pts selected for anti-leukemia treatment before and after 2019. Overall, CR/CRi rates were significantly higher in the ven era compared to the pre ven era, 44.7% vs. 19.4% respectively (p=0.016). 30 day mortality in 2019-21 was lower than in 2016-18 (12.8% vs 38.9%, p=0.012). EFS was significantly longer during 2019-2021 (median EFS 2.5 months, 95% CI 1.8-3.2; 1y-EFS 25.5%, 2y-EFS 17.0%) than 2016-2018 (median 1.2 months, 95% CI 0.6-1.8; 1y-EFS 2.8%, 2y-EFS 0.0%) (Figure 1C, P<0.001). RFS was significantly longer after 2019 (median RFS: 16.6 months, 95% CI 5.1-2.8, 1y RFS 57.1%, 2y RFS 38.1%), than prior to 2019 (median RFS 6.7 months, 95% CI 4.9-8.5, 1y-RFS 14.3%, 2y-RFS 0.0%) (Figure 1B, p=0.028). Finally, OS was significantly longer in the ven era vs. pre ven (median OS 4.6 months (95% CI 2.4-6.8), 1-year OS 29.8%, 2-year OS 18.7%. vs. median OS 1.7 months (95% CI 0.3-3.2), 1-year OS 11.1%, and 2-year OS 0.0%. (Figure 1A, p=0.004). When the analysis was restricted only to pts who received any anti-leukemia treatment, CR and 30 day mortality rates were 51.2% and 4.95% after 2019 and 35% and 20% before 2019 respectively. 1 year OS was 34% vs 20%. These differences were not statistically significant, presumably due to the small number of pts treated in 2016-2018 (20 pts). EFS was significantly longer in AML patients treated in the ven era vs pre-ven (Figure 1D, p=0.013). Summary/Conclusion: In the era following the approval of ven for unfit AML patients, more elderly pts are selected for anti-leukemic treatment, with higher remission rates, lower early mortality, prolonged remissions and prolonged event free and overall survival for this patient population.Keywords: Venetoclax, Acute myeloid leukemia, Real world data, Elderly

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.

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.