ASH 2020: Role of Venetoclax in High-Risk Myeloid Malignancies

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The BCL2 inhibitor venetoclax can be safely added to standard therapies for some high-risk myeloid blood cancers, and in early studies, the combination showed improved outcomes, according to two reports presented by Jacqueline S. Garcia, MD, and colleagues at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.

Dr. Garcia, of Dana-Farber Cancer Institute, reported on two studies examining the safety and efficacy of combining venetoclax with standard treatments for high-risk patients with myeloid blood cancers such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

Jacqueline S. Garcia, MD

Jacqueline S. Garcia, MD

Treatment With Venetoclax Before Stem Cell Transplant

In one study (Abstract 190), venetoclax was added to the standard chemotherapy administered to patients with AML or MDS prior to receiving reduced-intensity conditioning stem cell transplantation. Older patients or those with comorbidities are commonly recommended for reduced-intensity conditioning transplants because they are less toxic to patients. Reduced-intensity conditioning chemotherapy is given to deplete the immune system of the recipient to prevent rejection of the donor stem cells. However, reduced-intensity conditioning chemotherapy approaches are associated with a high risk of disease recurrence.

Because outcomes are poor in patients with myeloid blood cancers who relapse following transplantation, the investigators proposed adding venetoclax to chemotherapy before the patient receives a transplant to restore the blood-forming and immune systems. The hope was that venetoclax would make the pretransplant chemotherapy, consisting of fludarabine and busulfan, more effective, lessening the risk of disease relapse.

To test this strategy for efficacy and safety, the combination was given to 22 patients ranging in age from 25 to 71, who had AML, MDS, or MDS/myeloproliferative neoplasms. Of these patients, 35% had intermediate-risk disease and 65% had adverse-risk disease.

Dr. Garcia and colleagues reported that all 22 patients engrafted donor cells (ie, had restoration of count recovery after transplant) and no serious additional toxicities were observed with the addition of venetoclax. Further, graft-vs-host disease rates were not increased with the addition of venetoclax. At the time of this analysis, 7 of the 22 patients relapsed and 5 of them died. Median survival has not been reached, but the 6-month overall survival for the cohort is 84% and progression-free survival is 76%.

Dr. Garcia noted that the addition of venetoclax did not result in any increased toxicity. The combination of venetoclax, fludarabine, and busulfan “demonstrates promising clinical activity supporting further evaluation for high-risk disease features,” she said.

Venetoclax Plus Azacitidine for High-Risk MDS

In a second study reported by Dr. Garcia (Abstract 656), venetoclax was combined with azacitidine for patients with higher-risk MDS requiring treatment and not immediately undergoing transplantation at the time the study started. Azacitidine is a hypomethylating agent, a drug that increases the expression of tumor-suppressor genes to slow the growth of cancer cells. However, azacitidine alone has produced a low overall response rate in patients with MDS, and median overall survival is around 15 months.

The researchers noted that venetoclax has shown synergistic activity with hypomethylating agents in laboratory studies. This combination was recently approved by the U.S. Food and Drug Administration for previously untreated patients with AML ineligible for intensive chemotherapy.

To test the safety and efficacy of this combination, investigators administered it to 57 patients with high-risk MDS who had not previously been treated. The patients ranged in age from 26 to 85, with a median age of 71.

Results showed an overall response rate of 77%, including complete remission in 42% of patients and marrow complete response rate of 42%. Median overall survival was not reached; median duration of response was 14.8 months. Median progression-free survival was 17.5 months.

Patients with MDS commonly report fatigue and poor quality of life due to underlying disease, so the study also evaluated patient-reported outcomes of the population while on treatment. The researchers said physical functioning was maintained through 48 weeks of treatment, confirming tolerability of therapy. In addition, clinically meaningful improvement in fatigue and shortness of breath was achieved by the beginning of cycle 5 and was maintained through week 48.

The most commonly reported adverse events were constipation, neutropenia, and nausea. The most common serious adverse event was neutropenia with fever, at 42%. Prophylactic antibiotics were required to help reduce complications.

Dr. Garcia and colleagues concluded that the combination of venetoclax and azacitidine “demonstrates promising efficacy, including response durability, and an acceptable safety profile for patients with high-risk MDS.” A phase III clinical trial (VERONA) was launched comparing azacitidine plus venetoclax to azacitidine plus placebo for the treatment of higher-risk MDS based on these data.

Disclosure: For full disclosures of the study authors, visit (Abstract 190 and Abstract 656).

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.