Metronomic Low-Dose Regimen of Decitabine and Venetoclax Is Safe and Efficacious for Chronic Myelomonocytic Leukemia
Authors: Rockwell Bradley , Mantzaris Ioannis , Shastri Aditi , Gritsman Kira , Sica R. Alejandro , Kornblum Noah , Shah Nishi , Levitz David , Shapiro Lauren , Gupta Ridhi , Munoz Annemarie , Dhawan Aradhika , Fehn Karen , Comas Monica , Verceles Jhannine , Cooper Dennis L , Konopleva Marina , Feldman Eric J. , Verma Amit , Goldfinger Mendel 
Published: December 2024

Introduction: Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm, sharing features with both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), that has a high propensity to transform into acute myeloid leukemia (AML). Hypomethylating agents (HMA) and hydroxyurea are the only approved agents and allogeneic stem cell transplant (alloSCT) is reserved for fit patients with advanced disease.

Venetoclax (Ven) is a BCL-2 inhibitor that, when combined with HMAs, decitabine or azacitidine, has been shown to be beneficial in elderly or frail patients with AML who are not fit to undergo “intensive chemotherapy” and is being actively investigated in high-risk MDS. While data are still immature, it is emerging as a potential therapeutic option, but myelosuppression remains a significant concern. In a small retrospective study by Levitz et. al. (Clinical Cancer Research 2023), we have previously shown that metronomic administration of low-dose decitabine with Ven was effective and well tolerated in elderly and frail patients with AML causing minimal myelosuppression. Here we report the results of a retrospective cohort study of newly diagnosed CMML patients treated with metronomic decitabine and Ven at Montefiore Einstein Comprehensive Cancer Center.

Methods: Eligible patients had histologically confirmed CMML according to World Health Organization (WHO) criteria. Patients received decitabine 0.2 mg/kg subcutaneous injection and Ven 400 mg by mouth on days 1, 8, 15 and 22 of a 28-day cycle. Primary objective was to assess CMML response criteria, defined by Savona et. al. (Blood 2015). Secondarily, we assess changes in cytopenias over time. Mortality and length of therapy are also reported. Hospitalizations and cytopenias are reported to assess safety and adverse events.

Results: Between May 2020 and July 2024, 8 patients were diagnosed with CMML and began treatment with metronomic decitabine and Ven. Seven were male. Median age at diagnosis was 73 years. At time of diagnosis, median white blood cell count (WBC) was 14 k/uL (range 5-57 k/uL), absolute neutrophil count (ANC) was 6,650 /uL (range 600-22,300 /uL), monocytes were 6150 /uL (range 1,800-15,100 /uL), hemoglobin (Hb) was 11.2 g/dL (range 8.2-14.9 g/dL), and platelets were 80 k/uL (range 5-487 k/uL). Two patients were low-risk, 4 were moderate-risk, and 2 were high-risk, by International Prognostic Scoring System-Molecular criteria. Three patients were low-risk, 4 were moderate-risk, and 1 was high-risk by CMML-specific prognostic scoring system-Molecular. By WHO criteria, 5 patients were CMML-0 and 3 were CMML-1. Five were proliferative type and 3 were dysplastic type. The most common mutations seen were SRSF2, TET2 and NRAS (4 patients each), followed by CBL (3 patients). ASXL1 was seen in 1 patient.

After 3 months of treatment, median WBC decreased to 5.6 k/uL (p=0.039), ANC to 2,625 /uL (p=0.049) and monocytes to 625 /uL (p=0.012). Hb was 11.4 g/dL (p=0.34) and platelets were 113 k/uL (p=0.71). Five patients achieved complete remission, one achieved a partial remission, and 2 had a clinical benefit. Three patients died during the study: 2 from progression to AML and the third from cardiac tamponade deemed not related to CMML. All 3 patients who died had a bone marrow blast count greater than 5% at the time of diagnosis and were considered CMML-1. Of the 3 patients who died, the median length of therapy was 512 days. For all patients, the median length of therapy is 574 days, with 3 of the 5 alive patients still on therapy at the time of writing (1 lost to follow up and 1 having received successful alloSCT). Three patients required hospitalization during the first 6 months of initiation: 1 for progression to AML, 1 for cytopenias after missing a dose of therapy, and 1 for syncope deemed unrelated to CMML.

Discussion: Approved treatments for CMML (HMA, hydoxyurea) are often dose limiting due to cytopenias. Here we show that metronomic low-dose decitabine with Ven appears to be a safe, non-myelosuppressive treatment for CMML, with a promising signal of efficacy. This regimen is currently being prospectively studied in a trial with patients with AML, MDS, MDS/MPN, and CMML.