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Phase I results of venetoclax combined with azacitidine in high-risk MDS or CMML

Feb 10, 2022

During the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, Alexandre Bazinet1 presented phase I results of the combination of venetoclax and 5-azacitidine in treatment-naïve or relapsed/refractory (R/R) high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML).1

Hypomethylating agents (HMAs), such as azacitidine, have produced modest response rates (6–34%) with limited duration of response (median, 8–10 months) in high-risk MDS, and failure on hypomethylating agents is associated with poor prognosis (overall survival, 4.3–5.6 months). Therapeutic options are limited. Pre-clinical data have shown that high-risk MDS cells survive through the action of anti-apoptotic proteins B-cell lymphoma-2 (BCL-2) and myeloid-cell leukemia-1 (MCL-1). Exposure to azacitidine shifts the balance towards BCL-2 action, making MDS cells more sensitive to BCL-2 inhibition, suggesting a synergy between venetoclax and azacitidine.

Study design

  • Single center, phase I/II study (NCT04160052)
  • Primary objectives include safety tolerability (phase I) and recommended phase II dose
  • Eligibility criteria:
    • HMA-naïve, high-risk MDS defined as intermediate-2 or high risk by International Prognostic Scoring System (IPSS) (Cohort A: HMA naïve)
    • R/R MDS following ≥4 cycles of HMA (Cohort B: HMA failure)
    • CMML
    • ≥18 years of age
    • Bone marrow blasts of 5–19%
  • Exclusion criteria:
    • Low-risk MDS
    • Prior exposure to BCL-2 inhibitors

Figure 1 depicts the phase I dose escalation design.

Figure 1. Phase I dose escalation (3 + 3 design)*

D, Day; DL, dose level.
*Adapted from Bazinet, et al.1


Twenty patients were enrolled in the phase I study. The median age was 68.5 years (range, 58–84). Cohort A included 14 patients, and cohort B included six patients. Patient characteristics are summarized in Table 1.

Table 1. Baseline characteristics by cohort*

Characteristic, % unless stated otherwise

Cohort A:
 = 14)

Cohort B:
HMA failure
 = 6)

Median age, years (range)

68.5 (58–83)

67 (59–84)













Karyotype by IPSS












IPSS risk category









Therapy-related MDS



BM blasts (range)

12 (6–19)

10.5 (7–17)

BM, bone marrow; CMML, chronic myelomonocytic leukemia; EB, excess blast; HMA, hypomethylating agent; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; R/R, relapsed/refractory.
*Adapted from Bazinet, et al.1
MDS-EB1 is defined as blasts that make up 5–9% of the cells in the BM or 2–4% of the cells in the blood.2
MDS-EB2 is defined as blasts that make up 10–19% of the cells in the BM or 5–19% of the cells in the blood.2

The most common mutations identified in the baseline mutational profile by next-generation sequencing were TET2, ASXL1, SRSF2, and TP53 mutations. Six patients had TP53 mutations with a median variant allele frequency (VAF) of 52.3% (range, 2.4–84.4), and all had complex karyotypes.


The most common Grade 3–4 adverse events included infection (n = 9; mainly in the lungs), thrombocytopenia (n = 6), neutropenia (n = 5), and neutropenic fever (n = 2), which were expected with this combination. Three patients died due to sepsis; 4-week and 8-week mortality was 5% and 10%, respectively.

Median days to Cycle 2 was 35.5 days (range, 28–76), indicating a long time to count recovery. There was one dose-limiting toxicity, namely BM aplasia, in DL2 (400 mg, Days 1–7).

In terms of hematologic recovery, neutrophil, platelet, and hemoglobin recovery were found to be delayed or suboptimal for a large proportion of patients, suggesting continuous myelosuppression by venetoclax.


Seventeen patients were eligible for this analysis, and overall response rates were high, as shown in Figure 2. Responses were mainly marrow complete remission and were observed across different dose levels. Patients achieved a response after the first cycle of treatment, with a median duration of response of about 6 months (5.9 months in Cohort A; 5.8 months in Cohort B). In patients with baseline genetic abnormality, cytogenetic response rate was 22.2%.

Figure 2. Response rates*

*Adapted from Bazinet, et al.1

CR, complete remission; HMA, hypomethylating agent, mCR, marrow CR; ORR, overall response rate.

Median duration of follow-up was 14.8 months.

  • Median overall survival was not reached in cohort A versus 10.5 months in cohort B (p = 0.17).
  • Median progression-free survival was 5.7 months and 6.8 months in cohort A and B, respectively (p = 0.56).

Reasons for study withdraws were progression to acute myeloid leukemia, recurrence of MDS/CMML, need for stem cell transplantation, and death.


This study indicates that the combination of azacitidine and venetoclax is tolerable in older patients with high-risk MDS/CMML; however, the occurrence of myelosuppression and infections as well as delayed count recovery were high. Dose escalation is currently ongoing to determine recommended phase II dose. In terms of preliminary efficacy, overall response rates were high, regardless of exposure to HMA; responses were mostly marrow complete remission and achieved after a median of one cycle. Median overall survival was not reached in Cohort A versus 10.5 months in cohort B, which compares favorably to previous experience. A dose expansion phase is planned to include 80 patients (n = 40 in each cohort).

  1. Bazinet A, Jabbour EJ, Kantarjian H, et al. A phase I/II study of venetoclax in combination with 5-azacytidine in treatment-naïve and relapsed/refractory high-risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML). Oral abstract #535. 63rd American Society of Hematology Annual Meeting and Exposition; Dec 12, 2021; Atlanta, US.
  2. Types of myelodysplastic syndromes. Accessed Jan 14, 2022.