Metronomic low-dose regimen of decitabine and venetoclax is safe and reduces monocyte burden in chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm with features both of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), that has a high propensity to transform into acute myeloid leukemia (AML). Allogeneic stem cell transplant (alloSCT) is the only available cure but is reserved for younger fit patients. Hypomethylating agents (HMA) are currently the only Food and Drug Administration (FDA)-approved therapies for CMML based on trials that predominantly enrolled patients with MDS and only a fraction with CMML. In fact, the only phase III trial that exclusively enrolled CMML patients and compared HMA to hydroxyurea did not show an event-free or overall survival (OS) benefit for HMA over hydroxyurea.^1,2 This was despite the higher response rate in the HMA arm, as this was offset by increased toxicity related to infections from myelosuppression. Optimizing the dosing schedule of HMA therapy in CMML may overcome toxicity, thereby enhancing the efficacy and survival benefits.

Venetoclax (Ven) is a BCL-2 inhibitor that, when combined with HMA, is the current standard of care for elderly or frail patients with AML³ unfit for “intensive chemotherapy.” Similar to AML, the addition of Ven to HMA in MDS⁴ has been challenging due to myelosuppression with the current practice of prolonged and continuous Ven exposure. In two previous studies decitabine, administered by a minimum biologically effective dose (MBD) to produce HMA effects (“low-dose decitabine”) administered once a week (“metronomic”) combined with Ven, also given weekly, was shown to be effective and well tolerated in elderly and frail patients with AML and MDS, including heavily pre-treated patients with poor bone marrow (BM) reserves.^5,6 The addition of Ven to HMA therapy has been tried in CMML but is limited to retrospective experiences. Using continuous Ven, per the current FDA label in AML, has resulted in 100% of patients having grade 3-4 cytopenic adverse events.⁷ In addition, outcomes do not appear improved over single agent HMA despite decreases in dosing schedules to mitigate toxicities.⁸ Here, in an effort to rationalize the HMA/Ven combination towards decreasing toxicities and risks while maintaining potential efficacy benefits, we report the results of a retrospective cohort study of newly diagnosed CMML patients treated with metronomic weekly low-dose decitabine and Ven at Montefiore Einstein Comprehensive Cancer Center.

Eligible patients had histologically confirmed CMML by 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. Full methods have previously been reported.⁶ The study was designed according to Good Clinical Practice Guidelines and the Declaration of Helsinki.

The primary objective was to assess CMML response criteria, defined by the 2015 MDS/MPN International Working Group.⁹ Secondarily, we assessed changes in cytopenias over time. Mortality and length of therapy are also reported. Hospitalizations are reported to assess safety and adverse events. Statistical analysis was performed using a repeated-measures ANOVA to compare values of monocytes. The significance value was preset at a P valueof 0.05.

Table 1.Baseline characteristics.

Between May 2020 and March 2025, eight patients were diagnosed with CMML and began treatment with metronomic decitabine and Ven. Seven were male. Median age at diagnosis was 73 years. At diagnosis, median white blood cell count (WBC) was 14x10⁹/L (range, 5-57x10⁹/L), absolute neutrophil count (ANC) was 0.66x10⁹/L (range, 0.66-2.23x10⁹/L), monocytes were 6.15x10⁹/L, 1.8-15.1x109/L, hemoglobin (Hb) was 11.2 g/dL (range, 8.2-14.9 g/dL), and platelets were 80x10⁹/L (range, 5-487x10⁹/L). Half of the patient were transfusion dependent at baseline. By International Prognostic Scoring System-Molecular criteria, two patients were low-risk, four were moderate-risk, and two were high-risk and by CMML-specific prognostic scoring system-Molecular, three patients were low-risk, four were moderate-risk, and one was high-risk. All eight patients were CMML-1 per WHO 2022 criteria, five were proliferative type and three were dysplastic type. The most common mutations were SRSF2, TET2 and NRAS (4 patients each), followed by CBL (3 patients). ASXL1 was seen in 1 patient. Baseline characteristics are displayed in Table 1.

After 3 months of treatment, median WBC decreased to 5.6x10⁹/L, ANC to 2.63x10⁹/L and monocytes to 0.625x10⁹/L, while Hb was 11.4 g/dL and platelets were 113x10⁹/L. After 6 months of treatment, median WBC continued to decrease to 0.475x10⁹/L, ANC 2.85x10⁹/L and monocytes to 0.5x10⁹/L, while Hb increased to 12.4 g/dL and platelets to 141x10⁹/L. After 12 months of treatment, median WBC was 6.15x10⁹/L, ANC 4.0x10⁹/L, and monocytes 0.7x10⁹/L, while Hb was 11.9 g/dL and platelets were 75x10⁹/L. Monocytes decreased significantly over time (P=0.00158). Changes in cytopenias are shown in Figure 1. Of the four patients transfusion-dependent at diagnosis, three (75%) became transfusion independent. According to the 2015 MDS/MPN International Working Group criteria, five patients achieved a complete response, one achieved a partial response, and two had clinical benefit at 3 months. At 6 months, three patients remained in a complete response and one had progression of disease. At 12 months, two patients remained in a complete response. For the three patients with BM blasts >5% at baseline, only two had BM biopsies to assess their response and both had BM blasts <5% at 3 months. One continued with BM blasts <5% for 12 months and the other did not have an evaluable BM biopsy after 3 months. Individual responses are shown in Figure 2.

Figure 1.Changes in cytopenias. (A) Monocyte count, (B) hemoglobin, (C) platelet count. (B) Monocyte count significantly decreases (P=0.00158) over time, while (A) hemoglobin and (C) platelet count do not decrease and in fact slightly increase, although not significantly. Individual patients 1-8 represented by different colors. Black line indicates the median count.

Figure 2.Individual patient responses. Patient went onto allogeneic stem cell transplant.

Three patients died during the study: two from progression to AML and the third from cardiac tamponade possibly related to CMML (thought to be progressing but died before BM assessment). All three patients who died had a BM blast count >5% at the time of diagnosis. Of the patients who died, the median length of therapy was 16.8 months. For all patients, the median length of therapy was 18.9 months, with three of the five alive patients still on therapy at time of writing (1 lost to follow-up and 1 received successful alloSCT). Median event-free survival was 20.9 months. Three patients required hospitalization during the first 6 months: one for progression to AML, one for symptomatic anemia, and one for syncope due to hypotension/dehydration. Throughout the entire treatment period, there were seven hospitalizations among three (38%) patients and there were no hospitalizations for febrile neutropenia. Five (63%) patients experienced ≥3 neutropenia (ANC <1.0x10⁹/L). Three patients (38%) experienced grade 4 neutropenia (ANC <0.5x10⁹/L); one for 2 days, one for 7 days, and one for 1 month. Grade ≥3 thrombocytopenia occurred in five (63%) patients.

Despite recent improvements in novel therapies for MDS and AML, there has been limited progress in CMML. The addition of Ven to HMA therapy has not to date, been shown to improve OS in CMML. This may be a result of toxicity with single-agent HMA, leaving no room for toxicity of an additional agent. To address this an expert panel recently recommended that it will be prudent to identify drug dosages that maximize not only efficacy but also safety and tolerability.¹⁰ In other words finding an “optimal dosage” as opposed to the “maximum tolerated dose” using the totality of pharmacokinetic, pharmacodynamic, safety, and exposure-response data.¹⁰ Currently approved doses of HMA in CMML, despite showing efficacy, have been limited by myelotoxicity, abrogating any long-term benefit without showing an improvement in OS. An additional challenge is that the toxicity with currently approved HMA backbones has hampered the ability to safely add a doublet such as Ven which also causes marrow suppression and cytopenias. Here we show a proof of concept that metronomic once weekly low-dose decitabine with Ven is a safe, non-myelosuppressive treatment for CMML, with a promising signal of efficacy. Most importantly we show that low-dose decitabine with Ven significantly lowers monocytes count (on-target effect) with minimal toxicity is other cell lines by preserving functioning hematopoietic cells. Responses were seen in all patients, including 5 patients achieving a complete response. The main reason for the others not achieving a complete response was the high threshold of 100x10⁹/L for a platelet response. The patients who achieved a partial response and had clinical benefit, all had a drop in monocyte count which demonstrates a benefit of this regimen.

We also show that patients remain on therapy for a significant time. The median time on treatment was 26.0 months, including 16.8 months for those who progressed. While much of this may be limited to patients with low-risk and intermediate-risk disease, the long participation for patients who eventually progressed shows significant value in low-dose as a therapeutic option. Additionally, determining when to initiate treatment versus adopting a “watch and wait” approach is often challenging in CMML, due to variability in clinical practice regarding the optimal timing to start therapy. Therefore, the availability of well-tolerated treatments may lower the threshold for initiating therapy.

Limitations of our study include: small sample size and retrospective single center experience with a lack of a comparative cohort in a heterogeneous disease. Future prospective trials will be needed to fully assess the safety and efficacy of low-dose decitabine with Ven in CMML. Expanding to include quality of life metrics, like fatigue scores which have been validated in non-malignant hematologic diseases such as immune thrombocytopenia¹¹ and suggested in CMML and MDS,¹² would help assess if the decrease in monocytes correlates to a change in quality of life.

Footnotes

• Received December 23, 2024
• Accepted July 8, 2025

Correspondence

M. GOLDFINGER - mgoldfin@montefiore.org

Disclosures

AS received research funding from Kymera Therapeutics; advisory board fees from Gilead Sciences, Rigel Pharmaceuticals, and Kymera Therapeutics; consultancy fees from Janssen Pharmaceuticals; and honoraria from National Association of Continuing Education and PeerView. YS holds equity and board positions in EpiDestiny and Treebough Therapies and has patents: “Compositions comprising decitabine and tetrahydrouridine and uses thereof” (US-9259469-B2; US-9265785-B2; US-9895391-B2) and “Compositions containing decitabine, 5-azacitidine and tetrahydrouridine and uses thereof” (US-11376270-B2) and “Antitumor derivatives for differentiation therapy” (US-9926316-B2). KG receives research funding from iOnctura SA and ADC Therapeutics. MK has received research funding from AbbVie, Allogene, AstraZeneca, Genentech, Gilead, ImmunoGen, MEI Pharma, Precision, Rafael, Sanofi and Stemline; discloses advisory/ consulting fees from AbbVie, AstraZeneca, Auxenion, Bakx, Boehringer, Dark Blue Therapeutics, F. Hoffman La-Roche, Genentech, Gilead, Janssen, Legend, MEI Pharma, Redona, Sanofi, Sellas, Stemline and Vincerx; discloses stock options or royalties from Reata Pharmaceutical; discloses patents at Novartis, Eli Lilly and Reata Pharmaceutica. AV received research funding from Prelude, Bristol Myers Squibb, GlaxoSmithKline, Incyte, Medpacto, Curis, and Eli Lilly; is a scientific advisor for Stelexis, Novartis, Acceleron, and Celgene; receives honoraria from Stelexis and Janssen; and holds equity in Stelexis and Throws Exception. The remaining authors have no conflicts of interest to disclose.

Contributions

Funding

We thank the Leukemia and Lymphoma Society for CMML grant initiative.

Acknowledgments

We thank Kith Pradhan for assistance with statistical analysis and figure creation.