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Patients who received venetoclax with azacytidine for the treatment of higher-risk myelodysplastic syndrome (HR-MDS) had high overall survival rates and clinically meaningful improvements of dyspnea and fatigue through 48 weeks. These findings were presented during the American Society of Hematology (ASH) 62nd Annual Meeting and Exposition.

Jacqueline S. Garcia, MD, coauthor of this study, explained the mechanism of this therapy. “Apoptosis is normally under tight control by the interaction between pro-survival and pro-biotic proteins. In HR-MDS, myeloblasts overexpress BCL-2 and blasts are generally highly prone to pro-apoptotic proteins. Azacytidine indirectly decreases other apoptotic proteins, which sensitizes cells to venetoclax. Venetoclax is a BCL-2 inhibitor, which induces death.… Thus, these drugs have the potential to irreversibly commit the cell to death.”

Patients (N=78) with HR-MDS who were not candidates for intensive chemotherapy were recruited for this ongoing, open-label, dose-escalation, phase 1b study. Study participants received venetoclax 400 or 800 mg for 28 days followed by an escalating dose (100, 200, and 400 mg) for 14 days in a 28-day cycle with azacitidine 75 mg/m2 subcutaneously or intravenously administered on the first 7 days of each cycle. Participants were assessed for adverse events and efficacy.

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Patient group was 75% men, median age 71 years (range, 26 to 85) and 56% had very high-risk disease.

Of the 31 patients with baseline marrow data, the most frequent mutations were located in tumor protein p53 (TP53; 35.5%), additional sex combs like 1 (ASXL1; 19.4%), and stromal antigen 2 (STAG2; 16.1%).

All participants experienced at least 1 adverse event during the study. The most commonly observed events were constipation (54%), nausea (55%), and neutropenia (83%). Adverse events grade 3 or higher were experienced by 96% of patients and included febrile neutropenia (49%) and thrombocytopenia (42%). Few infections were observed, likely due to the antibiotic prophylaxis.

At 30 days, the mortality rate was 1% and 1.3% experienced disease progression. A total of 16 patients received post-study transplants (bone marrow, 7 patients; stem cell, 9 patients).

The objective response rate was 79%; in which 39.7% entered into complete remission, 39.7% into marrow complete remission, and 14.1% had stable disease.

The median duration of response was 12.9 months (range, 12.1 to 16.8), and among those who achieved complete remission, the median duration of response after remission was 13.8 months (range, 6.5 to 20.9). The median time to complete remission was 2.6 months (range, 1.2 to 19.6).

Physical function through 48 weeks was generally maintained and fatigue, dyspnea, and global health quality of life were improved among patients who received 400 mg of venetoclax for 14 days.

This study was limited by its small sample size and short duration; however, this study was still on-going, and a phase 3 trial has begun.

These results indicated venetoclax with azacitidine was efficacious, allowing for maintenance of physical functioning for up to 48 weeks among patients with HR-MDS who were not candidates for intensive chemotherapy.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


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. Presented at: American Society of Hematology (ASH) 62nd Annual Meeting and Exposition; December 5-8, 2020. Abstr 656.