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Venetoclax and Azacitidine Combination Associated With Durable Responses in Higher-Risk MDS

December 30, 2021

More than three-quarters of patients with higher-risk, treatment-naïve myelodysplastic syndromes (MDS) responded to the combination of venetoclax plus azacitidine, according to study results presented during the 2020 ASH Annual Meeting by Jacqueline Garcia, MD, of the Dana-Farber Cancer Institute. The combination also led to improvements in patient-reported outcomes, such as dyspnea and fatigue.

"The majority of patients with MDS are elderly and have largely incurable disease, and these patients are commonly symptomatic and transfusion dependent," Dr. Garcia said. Hypomethylating agents are the mainstay of treatment in this setting, but response and survival rates are low, she explained. The azacitidine and venetoclax combination has demonstrated clinical activity and synergy in acute myeloid leukemia (where it is approved as frontline treatment), which prompted researchers to evaluate the combination in patients with high-risk MDS.

The phase Ib study enrolled 78 adults with treatment-naïve disease who were not candidates for hematopoietic cell transplantation or intensive chemotherapy. Per study protocol, participants received azacitidine 75 mg/m2 on days one through seven of each 28-day cycle. Venetoclax was initially given at doses of 400 mg or 800 mg for 28 days of each cycle, but treatment intolerance led researchers to amend dosing to an escalating dose of 100, 200, and 400 mg for 14 days per treatment cycle.

Participants' median age was 70 years, and 91% of patients had an Eastern Cooperative Oncology Group score of 0 to 1.

Most participants (96%) experienced a grade 3/4 adverse event (AE). The most commonly reported grade 3/4 AEs included neutropenia (n=64; 82%), thrombocytopenia (n=33; 42%), leukopenia (n=30; 38%), and anemia (n=18; 23%).

Serious AEs were reported in 73% of patients. These included neutropenia (49%), pneumonia (6%), and diverticulitis (5%).

Overall, three-quarters of patients required a cycle delay for a median of 15 days. More than half (55%) experienced at least two venetoclax dose interruptions, most of which were due to AEs (80%) or hematologic toxicity (37%). The researchers also reported that one-third of patients required at least one azacitidine dose reduction.

The mortality rate at 30 days was 1%. The overall response rate (ORR) was 79.4%, which included a complete remission (CR) rate of 39.7% and a marrow CR rate of 39.7%. CR was achieved at a median of 2.6 months, and the median duration of response was 12.9 months. Among the 51 patients who received venetoclax 400 mg (the recommended phase II dose), the ORR was 84%, with a CR rate of 35%.

Dr. Garcia also noted that 65% of patients who were dependent on red blood cell or platelet transfusions were able to achieve independence.

"At a median follow-up of 16.4 months, the estimated overall survival (OS) was impressive, especially compared to historical controls for azacitidine alone," Dr. Garcia reported. The median OS was 27.5 months among all patients and was not reached among those who received venetoclax 400 mg. OS rates were 76.8% at one year and 59.6% at two years.

The investigators also assessed the effects of azacitidine plus venetoclax on patient-reported outcomes and found that participants experienced clinically meaningful improvements in dyspnea, fatigue, and quality of life. These improvements began in cycle three and continued through cycle 13. Improvements were graded as moderate or large in patients who achieved a CR, the authors added.

Limitations of the study were the nonrandomized design, lack of a control group, and the small sample size. The findings of this phase Ib study supported the phase III, placebo-controlled VERONA trial, which is currently enrolling patients with higher-risk MDS.

Study authors report relationships with AbbVie, which sponsored this trial.


Garcia JS, Wei AH, Borate U, et al. Safety, efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: A phase 1b study. Abstract #656. Presented at the 2020 ASH Annual Meeting, December 7, 2020.


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