Venetoclax approved combination for LMA seniors

BOSTON – Older patients with acute myeloid leukemia (AML) are often not healthy enough to receive intensive chemotherapy, and milder treatments are not very effective in treating this aggressive blood cancer.

But a new option – a combination of a standard drug and the new venetoclax agent – has been expedited approval by the Food and Drug Administration for these patients after a large, multi-center, phase 1 clinical trial showed that the combination was "promising effective" and well tolerated in elderly patients with AML.

"I think this will likely become a standard for patients in this situation who are suffering from AML but can not tolerate induction therapy" with more severe chemotherapy regimens, said Anthony Letai, MD, PhD, a Medical oncologist of the Dana-Farber Cancer Institute. Letai, who has conducted key research on the inhibition of the BCL-2 pathway, leading to drugs such as venetoclax (Venclexta), is the corresponding author of a recent report published in Some blood on the results of an industry-sponsored phase 1 clinical trial.

The FDA's approval concerns the use of venetoclax in combination with azacitidine, decitabine or low-dose cytarabine for the treatment of patients with newly diagnosed AML aged 75 years or older or who have comorbidities preventing the use of intensive intensive chemotherapy.

The median age of people diagnosed with AML is 67 years. Patients deemed sufficiently fit are treated with an "induction" treatment aimed at remitting the disease into remission, followed by a "consolidation" treatment with complementary chemotherapy or stem cell transplantation. If successful, this two-step process can cure up to 40% of patients, said Letai. "But only a minority of patients are eligible at the start" because of their advanced age or other conditions, such as heart disease, which increases their risk of death.

As a compromise, these patients can be treated with lower-intensity drugs called hypomethylating agents, such as azacitidine and decitabine. Letai said that these drugs are "relatively non-toxic, but not as effective". They only cause remissions in about 20% of patients and often require several months of treatment to achieve remission, he said. They are rarely curative, patients with median survival less than one year.

In an attempt to improve this situation, the clinical trial badociates hypomethylating agents with venetoclax, the first of a new clbad of targeted drugs called BCL-2 inhibitors, which destroy cancer cells by attacking BCL-2, a "survival protein" on which they rely. survive and multiply. Significant progress has been made in understanding the role of BCL-2 in cancer and how it could be blocked to kill cancer cells in Letai's Dana-Farber laboratory. Venetoclax, sold as Venclexta, was first approved in 2016 to treat certain patients with chronic lymphocytic leukemia (CLL) and has been expanded in these patients more recently.

Letai and Marina Konopleva, MD, PhD, of MD Anderson Cancer Center, in collaboration with researchers at AbbVie Pharmaceuticals, have explained how the inhibition of BCL-2 in AML could constitute a new approach to the treatment of cancer. disease. The first human trials with a BCL-2 inhibitor showed that as a sole agent, it had activity in patients with AML, but the effects were not robust.

Nevertheless, the reasoning was promising. AbbVie researchers and scientists have therefore created a clinical trial combining venetoclax at varying doses with a hypomethylating drug, azacitidine or decitabine. The report Some blood demonstrates that the combination of the two drugs is safe and relatively tolerable in patients with AML who are not healthy enough for standard induction chemotherapy.

The trial included 145 patients aged 65 years and older who received venetoclax and decitabine or azacytidine as initial therapy. The overall response rate – complete responses plus complete responses with incomplete recovery of blood counts – was 67%. Elderly patients (75 years of age or older) with low-risk pathological features in their cancer cells had a 60% CR and a CR plus CRi of 65%.

Median overall survival was not achieved in patients receiving 400 mg of venetoclax. For patients receiving all doses, the median overall survival was 17.5 months.

According to Letai, it is also encouraging to note that reactions badociated with combination therapy are faster than they usually are with hypomethylating agents alone.

An ongoing phase 3 trial compares venetoclax and azacytidine with azacytidine monotherapy.

This trial was supported by AbbVie and Genentech, who jointly develop venetoclax.

The FDA's approval "marks a significant advance for people with acute myeloid leukemia, an extremely aggressive and hard-to-treat blood cancer," said Sandra Horning, MD, Chief Medical Officer at Genentech.

###

Warning: AAAS and EurekAlert! are not responsible for the accuracy of the news releases published on EurekAlert! contributing institutions or for the use of any information via the EurekAlert system.