Outcome with Hypomethylating Agent and Venetoclax Combination in Patients with Chronic Myelomonocytic Leukemia
Authors: Ball Somedeb , Jain Akriti G , Aguirre Luis E. E. , Ali Najla Al , Zhang Yumeng , Chan Onyee , Kuykendall Andrew T. , Sweet Kendra , Lancet Jeffrey E. , Padron Eric , Swoboda David , Komrokji Rami S. , Sallman David A. 
Published: November 2021

Abstract
Introduction: Hypomethylating agents (HMA) are commonly used in treatment of high risk chronic myelomonocytic leukemia (CMML), although only 40% patients (pts) respond. Decitabine failed to improve overall survival (OS) in comparison with hydroxyurea in proliferative CMML (Itzykson et al. 2020). Preliminary results have suggested safety and clinical activity of HMA and venetoclax combination (HMA-Ven) in a small CMML cohort (n=9; Morita et al. 2020). However, real world evidence lacks on efficacy of HMA-Ven and its impact on outcome in pts with CMML and post-CMML secondary acute myeloid leukemia (sAML).

Methods: In this single center retrospective study, clinical and genomic data were collected from medical records of CMML pts treated with HMA-Ven at Moffitt Cancer Center. Treatment response was assessed with International Working Group criteria for CMML and European Leukemia Network 2017 criteria for post-CMML sAML. Survival estimates using Kaplan-Meier statistics and multivariate analysis (MVA) with Cox regression were performed in SPSS.

Results: Our study included 26 pts with CMML. At time of HMA-Ven initiation, 13 (50%) pts had CMML and rest 13 (50%) had sAML from antecedent CMML [Table 1]. Median age at HMA-Ven initiation was 74 years. Majority (84%) of pts were Caucasian, and gender distribution was even. There were no significant differences in cytopenias or monocytosis between groups. About half the pts (n=7) in CMML group had proliferative CMML at HMA-Ven initiation. Overall, 58% pts received HMA-Ven in relapsed/ refractory setting and 50% had prior HMA failure, with no significant difference in CMML and sAML cohorts. On assessment of recurrent mutations present at HMA-Ven initiation, ASXL1 was the most frequent (61%), followed by TET2 (35%) and SRSF2 (35%). There was no significant difference in incidence of mutations between CMML and post-CMML sAML.
In pts receiving HMA-Ven for CMML, overall response rate (ORR) was 62%, with one (8%) pt experiencing complete remission (CR) [Table 2]. Marrow CR was noted in half the pts with CMML. In post-CMML sAML pts, ORR was 54%, including one (8%) CR and three (23%) CRi. Both pts achieving CR in our study were HMA-naïve. Treatment with HMA-Ven induced response in 5 out of 7 (71%) HMA refractory pts with CMML. A total of 5 sAML pts (19% overall; 38% of sAML) died within 60 days of HMA-Ven initiation, with one death within 30 days. Three pts with CMML and two with post-CMML sAML were bridged to allogeneic stem cell transplant (allo-SCT). Median duration of HMA-Ven treatment was 2.3 months (mo) overall (CMML- 5.5 mo, sAML-2 mo), 4.3 mo in responding pts, 2.7 mo in those bridged to allo-SCT, and 5.5 mo in responding pts not proceeding to allo-SCT. Median number of HMA-Ven cycles was 3 (1-16), with no difference between groups. Two (15%) CMML pts progressed to AML while on HMA-Ven treatment. Median event free survival (EFS) was 4.3 (95% CI: 1.6-7.0) mo (CMML vs. post-CMML sAML- 5.7 vs. 2.5 mo, p= 0.194). Most common reasons for treatment discontinuation were refractory cytopenias (n=8, 31%) and progressive disease (n=8, 31%).
Median OS (mOS) of entire cohort was 8.1 mo (95% CI: 3.6-12.6) since HMA-Ven initiation, with a median duration of follow up of 17.4 mo. Patients receiving HMA-Ven for CMML had significantly prolonged mOS compared to post-CMML sAML (15.6 vs. 4.1 mo, p= 0.007) [Figure 1]. Disease status at HMA-Ven initiation remained an independent prognostic factor (p= 0.045) for OS after adjusting for ASXL1 mutation and allo-SCT status on MVA. Overall, no significant difference in mOS was observed between pts receiving HMA-Ven as 1 st line vs. later lines of therapy (9.7 vs. 8.1 mo, p= 0.586), and between HMA-naïve and refractory pts (9.7 mo vs. 8.1 mo, p= 0.707). Presence of RAS pathway mutations was not predictive of OS. In treatment-naïve pts (n=11), mOS was 9.7 mo (CMML vs. sAML- not reached vs. 2.5 mo, p= 0.280). Among pts with an objective response to HMA-Ven, mOS was 9.7 mo [CMML vs. s-AML- not reached vs. 4.9 mo (95% CI: 0-11.3); p= 0.96]. Median OS in pts bridged to allo-SCT (n=5) was similar (8.1 mo) to overall study population.
Conclusions: Treatment with HMA-Ven led to an ORR of 58% (54% in HMA refractory cohort) in pts with CMML and post-CMML sAML. However, achievement of CR was rare, with a short duration of treatment. Notably, EFS and OS were poor, particularly in the setting of transformed CMML, supporting urgent need for novel therapeutic strategies in this rare patient population.
Figure 1 Figure 1.

Disclosures
Kuykendall: Prelude: Research Funding; PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet: Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: Millenium Pharma/Takeda: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jazz: Consultancy; AbbVie: Consultancy. Padron: Stemline: Honoraria; Taiho: Honoraria; Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding. Komrokji: Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Acceleron: Consultancy; AbbVie: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees. Sallman: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau.