Association of Hypometilating Agents + Venetoclax in the Treatment of Secondary Acute Myeloid Leukemias Evolved from Chronic Myelomonocytic Leukemia
Authors: Onida Francesco , Bruzzese Antonella , Cavalca Fabrizio , Cambò Benedetta , Piccioni Anna Lina , Rizzo Lorenzo , Niscola Pasquale , Strazimiri Alda , Poloni Antonella , Binotto Gianni , Defina Marzia , Piedimonte Monica , De Luca Giulia , Bucelli Cristina , Fenu Susanna , Salutari Prassede , Bonifacio Massimiliano , Riva Marta , Crugnola Monica , Iurlo Alessandra , Vigna Ernesto , Elli Elena Maria , Latagliata Roberto 
Published: December 2024

Background: Prognosis of patients (pts) with secondary acute myelogenous leukemia (sAML) evolved from Chronic Myelomonocytic Leukemia (CMML) is still very poor, with an overall survival (OS) generally not exceeding 3 months. While the association of hypomethylating agents (HMA) and venetoclax (VEN) is widely used in de novo AML not eligible for intensive chemotherapy, very few data are available in pts affected by sAML from CMML. Methods: Data of 23 pts with sAML from CMML treated frontline with HMA+VEN in 14 hematologic Centres in Italy outside clinical trials from 12/2020 to 04/2024 were retrospectively collected and analysed. Composite overall response rate [ORR; complete remission (CR) + CR with incomplete hematologic recovery (iCR) + partial remission (PR) + hematologic improvement (HI)], duration of response and overall survival (OS) were assessed. Results: At initial diagnosis, 13 pts had a proliferative-CMML and 10 a dysplastic-CMML. Median interval from initial CMML diagnosis to sAML evolution was 24.4 months [interquartile range (IQR) 7.9-46.1]. Baseline characteristics at evolution in sAML were as follows: M/F 21/2 (91.3/8.7), median age 73.1 years (IQR 70.9 - 75.4), median WBC count 13.0 x 109/l (IQR 4.0 - 26.9), median marrow blasts 30% (IQR 21 - 66). 7/10 pts (70%) with an evaluable NGS had ASXL1 mutations. Pts were treated for a median of 3 courses (range 1 - 18): HMA were administered at standard dosage, VEN daily doses in the 1st cycle were &lt; 400 mg in 19 pts (most of them due to prophylaxis with azoles) and 400 mg in 4 pts. Twenty pts (86.9%) had at least one hematologic toxicity of grade 3-4: in particular, severe neutropenia (PMN &lt; 0.5 x 109/l) was reported in 18 pts (78.2%). Thirteen pts (56.5%) had at least one infective episode during the treatment: pulmonary infections were reported in 6 pts (26.0%). All patients were evaluable for response: the ORR was 74.0% [9 CR/iCR (39.2%) + 7 PR (30.5%) + 1 HI (4.3%)], with a median response duration of 12.6 months (95%CI 8.3-16.8). At the last follow-up, 15 pts (65.2%) died and 8 (34.8%) were alive. Median OS from AML evolution of the whole cohort was 11.2 months (95%CI 7.6-14.7): pts with any type of response to HMA+VEN had a longer OS compared to pts with progressive/stable disease [11.5 (95%CI 6.5-16.6) versus 3.7 (95%CI 0.5-7.4) months, respectively (p=0.005)]. Conclusions: Present data on our small real-life cohort of pts with sAML from CMML suggest that HMA+ VEN combination could offer a relatively high chance of response also in this rare and dismal condition, with an ORR exceeding 70%: however, toxicities were severe and response duration still short. Further studies to analyse factors predicting better response as well as new approaches are thus warranted.