New combination therapy for AML approved by FDA

A combination of a standard drug and the novel agent venetoclax – has been granted accelerated approval by the FDA for patients after a large, multicenter phase 1 clinical trial showed the combination had “promising efficacy” and was well tolerated in older AML patients.

“I think it’s likely to become a standard for patients in this situation who have AML but can’t tolerate induction therapy” with harsher chemotherapy regimens” said Anthony Letai, MD, PhD, a medical oncologist at Dana-Farber Cancer Institute. Letai, who has carried out key research on inhibition of the BCL-2 pathway, leading to drugs like venetoclax, is corresponding author of a recent report in Blood on the results of an industry-sponsored phase 1 clinical trial.

The FDA approval is for use of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine for treatment of patients with newly diagnosed AML who are 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

The median age of people diagnosed with AML is 67. Patients who are considered fit enough are treated with “induction” therapy aimed at putting the disease in remission, followed by “consolidation” therapy with additional chemotherapy or a stem cell transplant. If successful, that two-step process can cure up to 40 percent of patients, said Letai. “But only a minority of patients are eligible to begin with” because of advanced age or because they have other conditions, such as heart disease, that increases their risk of death.

As a compromise, these patients may be treated with lower-intensity drugs called hypomethylating agents, such as azacitidine and decitabine. Letai said these drugs are “relatively nontoxic, but not that effective.” They induce remissions only in about 20 percent of patients, and often require several months of treatment to achieve remission, he said. They are rarely curative, with patients having a median survival of less than a year.

In an effort to improve this situation, the clinical trial paired hypomethylating agents with venetoclax, the first of a new class of targeted drugs called BCL-2 inhibitors that destroy cancer cells by attacking BCL-2, a “survival protein” they rely on to survive and multiply. Important advances in understanding BCL-2’s role in cancer and how it could be blocked to kill cancer cells was conducted in Letai’s Dana-Farber laboratory. Venetoclax, sold under the name Venclexta, was first approved in 2016 to treat certain patients with chronic lymphocytic leukemia (CLL) and its use has been expanded in those patients more recently.

Letai and Marina Konopleva, MD, PhD, of MD Anderson Cancer Center, in collaboration with researchers at the pharmaceutical company AbbVie, focused on how inhibiting BCL-2 in AML might be a new approach to treating the disease. Initial human trials with a BCL-2 inhibitor showed that as a single agent it had activity in patients with AML, but the effects weren’t robust.

The FDA approval “marks a significant advance for people with acute myeloid leukemia, a highly aggressive and difficult-to-treat blood cancer,” said Sandra Horning, MD, chief medical officer at Genentech.

Source: News Medical Net

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