Standard-of-care treatment comprising venetoclax plus hypomethylating agents was found to be safe and effective in some patients aged 80 years and older with acute myeloid leukemia (AML), according to a recent study published by Madarang et al in Blood Neoplasia.
Background
Older adult patients with AML are conventionally treated with a combination of venetoclax and a hypomethylating agent. Some of these patients—especially those of advanced older age—may be ineligible to receive treatment, given its intensity, immune system suppression, and increased risks of other health complications. These patients may instead be recommended to pursue palliative care.
Study Methods
In the recent study, investigators used electronic medical records to examine the overall survival and remission rates of 154 patients aged 80 years and older with AML who were treated with venetoclax plus hypomethylating agents between March 2015 and April 2022 in medical institutions across the United States and Italy. The patients had a median age of 82 years, 69% of them identified as male, 77% of them had newly diagnosed AML, 10% had relapsed or refractory AML, and 14% of them had unknown disease status.
The investigators noted that 67% of the patients started with the standard dose and treatment schedule of venetoclax plus hypomethylating agents, and 72% of them had subsequent modifications to their venetoclax dose or treatment schedule following the first cycle. The patients were administered a final median venetoclax dose of 400 mg for 21 days in 35-day cycles. Those who responded to treatment received a final median venetoclax dose of 200 mg for 21 days in 35-day cycles.
Key Findings
The investigators reported that 20% to 25% of the patients involved in the study experienced prolonged survival—encompassing about 40% of the patients who responded to treatment. The median overall survival was 8.2 months among all of the patients and 13.2 months among those who responded to treatment. After a follow-up of just under 8 months, 23% of the patients remained in remission and 20% of them were still receiving treatment. The 30-day and 60-day mortality rates were 8.5% and 17%, respectively.
Additionally, 73% of the patients with newly diagnosed AML without a prior myelodysplastic syndrome achieved complete remission or complete remission with incomplete count recovery. In this group of patients, those who received a final venetoclax duration of 14 days or less per cycle had an increased average survival time with a median survival of 24.0 months.
The patients whose cancer cells exhibited TP53 mutations had poorer overall survival, whereas those with NPM1 mutations had very favorable survival and those with KRAS/NRAS or FLT3-ITD mutations did not have inferior survival compared with those who didn’t have the mutations.
The venetoclax plus hypomethylating agent treatment regimen may lead to myelosuppression, reducing the bone marrow’s ability to produce healthy blood cells and weakening the immune system. Because older patients—especially those older than 80 years—may be more susceptible to experiencing myelosuppression, the investigators suggested reducing the dose and duration of treatment for those at increased risk.
“A second major theme here is that treating this patient population requires adjusting the dosage and duration of [venetoclax plus hypomethylating agents]," explained senior study author Justin Watts, MD, a hematologist at the University of Miami Sylvester Comprehensive Cancer Center. "Unlike typical adult AML cases, these patients exhibit lower tolerance to venetoclax, suggesting that they may benefit from a reduced dosage,” he added.
Conclusions
“Our study reveals that a significant portion of these patients at the extremes of older age still derive benefit from the [venetoclax plus hypomethylating agent] regimen—which is the standard of care for older patients [with AML] and those who are ineligible to receive intensive chemotherapy. While acknowledging it certainly isn’t for [all patients], we hope our findings encourage health-care providers to thoughtfully explore all treatment avenues for [older] patients with AML rather than prematurely resorting to [hypomethylating agents] alone, best supportive care, or hospice care,” emphasized Dr. Watts.
This research was limited by its retrospective format. Further, the median follow-up duration was approximately 7.7 months, indicating that the data may have been stronger if the study period was extended.
In future studies, the investigators plan to examine the optimal dose and treatment schedule of venetoclax plus hypomethylating agents, explore the relationship between minimal residual disease and molecular subtype on venetoclax exposure and ultimately stopping venetoclax in patients who achieve durable responses, develop a better understanding of the impact of treatment on quality of life, and uncover strategies to further enhance health outcomes in this patient population.
Disclosure: For full disclosures of the study authors, visit sciencedirect.com.
