Venetoclax Combination Earns FDA Breakthrough Therapy Designation for Higher-Risk MDS


The combination of venetoclax and azacitidine will be considered as a treatment for patients with newly diagnosed, higher-risk myelodysplastic syndrome.

The FDA has granted breakthrough therapy designation to the combination of venetoclax (Venclexta) plus azacitidine as a potential systemic therapy for patients with treatment-naïve myelodysplastic syndrome (MDS) whose disease is considered to be intermediate-, high-, or very high–risk per the revised International Prognostic Scoring systemic (IPSS-R), according to 2 companies that are jointly responsible for developing the BCL2 inhibitor, AbbVie and Genentech, a member of the Roche Group.1,2

The designation will expediate the development and review process for venetoclax in this indication and is the sixth of its kind for the agent. Currently, venetoclax is approved to treat adults with chronic lymphocytic leukemia or small lymphocytic lymphoma and adults with newly diagnosed acute myeloid leukemia who are 75 years of age or older and cannot be treated with intensive induction chemotherapy when given in combination with azacitidine, decitabine, or low-dose cytarabine.3

“Higher-risk MDS is associated with poor prognosis, reduced quality of life, and limited treatment options,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, said in a press release. “We are pleased that the FDA has granted Venclexta its sixth Breakthrough Therapy Designation in recognition of its potential to improve outcomes for people with MDS in combination with azacitidine.”

The decision by the FDA is supported by data from the phase 1b M15-531 trial (NCT02942290) of venetoclax plus azacitidine in the treatment of patients with previously untreated higher-risk MDS. The dose-escalation study evaluated safety and pharmacokinetics of the combination with secondary efficacy end points including duration of response, progression-free survival, overall survival (OS), hematologic improvement, rate of plasma transfusion independence, and event-free survival.

Additional ongoing studies of the agents include the phase 1b M15-522 trial (NCT02966782) of venetoclax either alone or in combination with azacitidine for the treatment of patients with relapsed or refractory MDS and the phase 3 Verona trial (NCT04401748) of venetoclax with intravenous or subcutaneous azacitidine in newly diagnosed higher-risk MDS.

Verona has an enrollment goal of 500 participants and compares the experimental venetoclax combination vs control therapy of placebo plus azacitidine. The dual primary end points are the rate of complete remission and OS. Secondary end points include the rate of transfusion independence in those who were dependent at baseline, change in patient-reported outcomes, time to deterioration in physical functioning, overall response rate, and modified overall response.

To be eligible for enrollment, patients must have confirmed MDS per the 2016 World Health Organization (WHO) classification and have fewer than 20% bone marrow blasts per marrow biopsy/aspirate, and overall IPSS-R score of greater than 3, an ECOG performance score of 2 or less, and have not scheduled hematopoietic stem cell transplantation. Patients who have had prior therapy for MDS or a prior diagnosis of therapy-related MDS evolving from myeloproliferative neoplasms (MPNs), chronic myelomonocytic leukemia, atypical myeloid leukemia, juvenile myelomonocytic leukemia, or unclassifiable MDS/MPN are not eligible for enrollment.

“MDS is a devastating diagnosis—not only does it have the potential to greatly impact patients’ quality of life, but 30 percent of patients will also progress to AML,” Jalaja Potluri, MD, executive medical director of Oncology at AbbVie, said in a press release. “This Breakthrough Therapy Designation underscores the need for more treatment options for these patients and the utility of venetoclax to potentially treat different forms of blood cancer.”


1. Venetoclax (VENCLEXTA) granted US FDA breakthrough therapy designation (BTD) in higher risk myelodysplastic syndrome (MDS). News release. Abbvie. July 21, 2021. Accessed July 21, 2021.

2. FDA grants breakthrough therapy designation for Venclexta in combination With azacitidine for the treatment of patients with myelodysplastic syndromes. News release. Genetech, a member of the Roche group. July 21, 2021. Accessed July 21, 2021.

3. Venclexta [package insert]. 2016. Genentech USA, Inc; AbbVie, Inc. Accessed July 21, 2021.

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