Exploring Venetoclax Plus Azacitidine in CMML and MPNs

The combination of the BCL2 inhibitor venetoclax and the hypomethylating agent azacitidine has been established as a standard of care for patients with acute myeloid leukemia (AML), but its role in the treatment of patients with other myeloid malignancies has not been fully explored. Results from two recently published studies investigated the treatment combination in patients with chronic myelomonocytic leukemia (CMML) and myeloproliferative neoplasms (MPNs), finding that venetoclax plus azacitidine led to high response rates in these disease settings.

In the first study, which was published as a research letter in Leukemia, approximately two-thirds of patients with CMML responded to treatment with the venetoclax-azacitidine combination. Researchers led by Guillermo Montalban-Bravo, MD, evaluated outcomes for patients who received venetoclax-based regimens as any line of therapy for CMML and as frontline therapy for AML with myelodysplasia related changes (AML-MRC) after CMML at the University of Texas MD Anderson Cancer from 2016 to 2020. A total of 53 patients were included in the analysis: 27 with CMML and 26 with AML-MRC with anteceding CMML.

After a median of one cycle of therapy (range = 1-6), the overall response rate (ORR) among patients with CMML was 67%, including a complete response (CR) rate of 4%, a marrow complete remission (mCR) with hematologic improvement rate of 11%, and an mCR rate of 48%. The median response duration was four months (range = 1-14).

Dr. Montalban-Bravo and colleagues found that all treatment-naïve patients achieved a response, with a median response duration of six months (range = 0-13). Two of these patients (28%) proceeded to allogeneic hematopoietic cell transplantation (alloHCT) at best response.

Among patients with AML-MRC, the median number of cycles was three (range = 1-37) and the ORR was 81%, which included a CR rate of 23% and a composite CR rate of 62% [including CR, CR with incomplete hematologic recovery (CRi), and CR with incomplete platelet counts (CRp)]. The median duration of response was four months (range = 1-24). Approximately 19% of patients proceeded to alloHCT.

The investigators also found that patients with isocitrate dehydrogenase (IDH) mutations achieved a CR/CRi. However, after a median follow-up of 10.86 months, nine patients with CMML (33%) had leukemic transformation during therapy with venetoclax.

“Of note, venetoclax-based therapy resulted in a relatively higher response rate in AML-MRC, with almost half of the observed responders achieving [measurable residual disease] negativity by flow cytometry,” the authors noted. “Overall, our data suggests hypomethylating agent (HMA)-venetoclax therapy may be considered an adequate option for CMML and both post-CMML and post-MDS AML-MRC as a bridge to [alloHCT].”

In the second study, Naseema Gangat, MBBS, of Mayo Clinic in Rochester, Minnesota, and researchers evaluated the combination of venetoclax and an HMA (azacitidine or decitabine) in patients with blast-phase MPNs (MPN-BP). They retrospectively reviewed data from 32 patients (median age = 69 years). The pre-leukemic phenotypes in this group included essential thrombocythemia (ET)/post-ET myelofibrosis (34%), polycythemia vera (PV)/post-PV myelofibrosis (38%), and primary myelofibrosis (28%).

Twenty-nine of the 32 patients had complete molecular and cytogenetic results available for analysis. Of this group, two-thirds harbored complex karyotype and/or mutations, including TP53 (41%), IDH1/2 (21%), ASXL1 (21%), N/KRAS (14%), SRSF2 (10%), EZH2 (10%), and U2AF1 (7%).

The researchers noted that 12 patients received venetoclax combined with azacitidine (n=12) and 20 patients received venetoclax with decitabine. Most patients (n=20) had previously untreated disease, while nine had disease that failed to respond to a previous induction therapy.

A total of 14 patients experienced a CR or CRi (44%). The authors observed that patients without the pre-leukemic PV/post-PV myelofibrosis phenotype were more likely to achieve a CR/CRi (p<0.01). Presence of a complex karyotype or K/NRAS mutation also was associated with achieving CR/CRi: Seven of the eight patients (88%) without either of these factors achieved CR/CRi, compared with four of the 21 patients (19%) with complex karyotype or K/NRAS mutations (p<0.01 and 0.03). The researchers reported that all 11 patients with pre-leukemic PV/post-PV myelofibrosis phenotype who had cytogenetic results available had a complex karyotype. In contrast, neither TP53 or IDH1/2 mutations affected response.

Six patients who achieved CR/CRi were able to proceed to alloHCT.

The findings of this study are limited by the small patient population and retrospective nature of the analysis, but, given the “robust” CR/CRi rates achieved with venetoclax plus an HMA in this setting, the authors concluded that this combination could be valuable in MPN-BP as a bridge to alloHCT.

Authors of each article report relationships with AbbVie.


  1. Montalban-Bravo G, Hammond D, DiNardo CD, et al. Activity of venetoclax-based therapy in chronic myelomonocytic leukemia. Leukemia. 2021;35:1494-1499.
  2. Gangat N, Guglielmelli P, Szuber N, et al. Venetoclax with azacitidine or decitabine in blast-phase myeloproliferative neoplasm: A multicenter series of 32 consecutive cases. Am J Hematol. 2021;96(7):781-789.