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The real-world experience of venetoclax and hypomethylating agent therapy in high-risk myelodysplastic syndromes

Aug 31, 2020

The current standard of care for patients with high-risk myelodysplastic syndromes (MDS) is treatment with the hypomethylating agents (HMAs) azacitidine or decitabine. However, this is associated with low rates of response. If venetoclax, an inhibitor of the BCL-2 protein, is combined with an HMA, high response rates are seen in unfit and previously untreated acute myeloid leukemia.1

Armon Azizia et al.1 performed a retrospective study of patients with high risk-MDS receiving the combination of HMA plus venetoclax to assess its effectiveness in this setting. The study was published in Leukemia & Lymphoma, and concluded that the combination of venetoclax and an HMA results in high response rates in patients with high-risk MDS, but at the cost of high frequency of myelosuppression, warranting further prospective evaluation in clinical trials.

Study design

This was a retrospective analysis of 20 patients with high-risk MDS who received an HMA plus venetoclax. Researchers retrospectively reviewed patients with MDS who were assessed and/or received treatment at Stanford Cancer Institute (Stanford, CA) between June 2017 and September 2019 or the University of Massachusetts Memorial Medical Center (Worcester, MA) between July 2019 and December 2019. A total of 20 patients (18 patients from Stanford Cancer Institute and 2 patients from the University of Massachusetts Memorial Medical Center) were included in the final analysis.

Overall response rate (ORR) was defined as the percentage of patients achieving complete response (CR), maintained complete response (mCR), or partial response (PR). Duration of response (DOR) was defined as the time from when a patient achieved a CR/mCR until disease progression, relapse, or death. HMA failure was defined as having received at least four cycles of decitabine or six cycles of azacitidine prior to starting venetoclax. Log-rank tests were performed on censored OS using response to therapy as the sole predictor to compare the OS of responders and non-responders.


  • The cohort had a median age of 66 years (range, 45–78) and was predominantly male (n = 14; 70%)
  • 30% of patients were intermediate risk, 25% were high risk, and 45% were very high risk
  • All patients had a Revised International Prognostic Scoring System (IPSS-R) score > 3.5
  • The median blast percentages at the time of diagnosis and initiation of combination therapy were similar: 9.25% (range, 4–18%) and 10.00% (range, 4–19%), respectively
  • 20% of cases were therapy related, 40% were classified as MDS-EB1 (containing excess  blasts in 5% to 9% of the bone marrow, or 2% to 4% of the blood), and 50% were classified as MDS-EB2 (containing excess blasts in 10% to 19% of the bone marrow, or 5% to 19% of the blood)
  • The duration of each HMA cycle for all patients was 28 days
    • For all but one patient, venetoclax was administered continuously during each cycle
  • 40% (n = 8) of cases received azacitidine + venetoclax and 60% (n = 12) of cases received decitabine + venetoclax
    • 35% (n = 7) of patients failed either azacitidine or decitabine before starting venetoclax
  • The median number of cycles from initiation of combination therapy to response evaluation was 1.89 (range, 0.71–4.32)
    • For patients receiving azacitidine, the median number of cycles was 2.18 (range, 1.89–2.71)
    • For patients receiving decitabine, the median number of cycles was 1.79 (range, 0.71–4.32)
  • Due to early death (21 days after starting combination therapy), one patient was not formally evaluated for a response to therapy and was categorized as a nonresponder
  • Next-generation sequencing (NGS) was performed on 19 patients
    • The most frequently mutated genes were TET2, RUNX1, ASXL1, and TP53
  • The ORR for the cohort was 75% (n = 15)
    • One patient achieved a CR, 60% (n = 12) of patients achieved mCR, and 10% (n = 2) of patients achieved a PR
  • 35% (n = 7) of patients had at least one occurrence of neutropenic fever, 20% (n = 4) of patients had treatment cessation for a period of time to allow count recovery, 5% (n = 1) of patients had a dose reduction of venetoclax, and 35% (n = 7) of patients were hospitalized as a result of the myelosuppression related to HMA + venetoclax


In conclusion, this retrospective analysis of 20 patients with high-risk MDS, who received an HMA plus venetoclax, reports an ORR of 75%. Venetoclax plus HMA results in high response rates in patients with high-risk MDS but is associated with toxicities and myelosuppression, which necessitate extra investigation of this combination therapy in clinical trials.

  1. Azizi A, Ediriwickrema A, Dutta R, et al. Venetoclax and hypomethylating agent therapy in high risk myelodysplastic syndromes: a retrospective evaluation of a real-world experience. Leukemia & Lymphoma. 2020. Online ahead of print. DOI: 1080/10428194.2020.1775214