Acute myeloid leukemia (AML)
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The standard-of-care treatment for older adults with acute myeloid leukemia (AML) of venetoclax combined with a hypomethylating agent (HMA)—referred to as VEN-HMA— prolonged patient survival of roughly one-quarter of patients aged 80 to 90. The findings, published in the journal Blood Neoplasia, show the potential for oncologists to consider using venetoclax as opposed to ruling it out completely, for a portion of their patients.

Still, the research team from the University of Miami Miller School of Medicine, notes that treatment of AML is quite intensive and often suppresses the immune system significantly, while also presenting other potential health complications, which will rule out many patients. The study sought to find whether broadly ruling out these treatments for this vulnerable population was the best option.

“Our study reveals that a significant portion of these patients at the extremes of older age still derive benefit from the VEN-HMA regimen—which is the standard of care for older AML patients and those who are ineligible to receive intensive chemotherapy,” said Justin Watts, MD, chief of the leukemia section at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine. “While acknowledging it certainly isn’t for everyone, we hope our findings encourage health care providers to thoughtfully explore all treatment avenues for elderly patients with AML, rather than prematurely resorting to HMA alone, best supportive care, or hospice care.”

To better understand overall survival of patients 80 to 90 who received VEN-HMA treatments, the investigators analyzed medical records of 154 who received VEN-HMA treatments for the first between March 2015 and April 2022. Six medical systems in both the U.S. and Italy provided data for these patients who had a median age of 82—ranging from 80 to 92 years old—with 69 percent of the patients male. Of those included, 77 percent of patients were newly diagnosed, 10 percent had relapsed or refractory AML, and the remaining 14 percent had an unknown disease status.

More than three-quarter of the patients started the standard-of-care VEN-HMA treatment and 72 percent of them had modifications made to their venetoclax dosing or schedule after the first cycle of treatment. Across the cohort, patients were administered a final median venetoclax dose of 400 mg for 21 days, repeated every 35 days. Patients who demonstrated a response to treatment received a final median venetoclax dose of 200mg of Venetoclax for 21 days, in 35-day cycles.

Analysis of the medical records showed that between 20 and 25 percent of all the patients in the study group showed increased median survival of 13.2 months of those who responded to VEN-HMA versus 8.1 month for all in the study group. Further, at follow-up of just under eight months, 23 percent of patients remained in remission, while 20 percent were still receiving treatment.

The team also found biomarkers that could both predict which patients would respond well to this therapy regimen versus those who wouldn’t. Patients who showed poor survival on the VEN-HMA treatment had a mutation in TP53, which is a protein that plays a key role in preventing abnormal cell growth. Patients with a mutation in the NPM1 protein showed improved survival, while patients with K/NRAS or FLT3-ITD mutations did not have inferior survival compared to those without.

Because patients over the age of 80 are more prone to myelosuppression, a reduced ability of the bone marrow to produce health blood cells, thus weakening immune response, the investigators noted the need for a flexible treatment regimen.

“A second major theme here is that treating this patient population requires adjusting the dosage and duration of VEN-HMA,” Watts noted. “Unlike typical adult AML cases, these patients exhibit lower tolerance to Venetoclax, suggesting that they may benefit from a reduced dosage.”

With this in mind, the investigators’ next path is to conduct research that can determine the optimal dose and duration for this population to improve outcomes. A focus of this continued research will be to find any relationship between minimal residual disease and molecular subtype of AML on venetoclax exposure and whether stopping venetoclax is feasible among those patients exhibiting a durable response.

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