Venetoclax Combo Safe, Effective in AML Patients Age 80 and Up, Real-World Data Show

Venetoclax (Venclexta) combined with a hypomethylating agent (HMA) -- the standard of care for older patients with acute myeloid leukemia (AML) -- appeared to be safe and effective in patients in their 80s and 90s, a retrospective analysis showed.

Median overall survival (OS) was 8.1 months among a total of 154 patients with a median age of 82 years (range 80-92), and was 13.2 months among the 87 patients who achieved a response, reported Justin Watts, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami, and colleagues in Blood Neoplasia.

With a median follow-up of 7.7 months, 23% of patients remained in remission, with 20% still on treatment.

"There is certainly a subset of these patients who can be treated," Watts told MedPage Today. "The response rates themselves -- even in a high-risk population, and especially in newly diagnosed AML or de novo AML patients -- did just as well as younger patients did in VIALE-A. They still respond to treatment."

"The question is how long they will respond to treatment, and what is their survival," he continued. "And about one-quarter of patients had prolonged survival, and those patients in whom there was a response could have quite long survival."

The FDA approved the combination of venetoclax with azacitidine, decitabine, or low-dose cytarabine in 2020 for the treatment of newly diagnosed AML in adults ages 75 and older or those unfit to receive intensive chemotherapy. Approval was based on results from the VIALE-A trial, in which median OS increased from 9.6 months with azacitidine plus placebo to 14.7 months with the addition of venetoclax. Patients had a median age of 76 years, and about 60% were 75 or older.

In explaining the rationale behind the current study, Watts and colleagues noted that while the use of HMAs led to improved outcomes, venetoclax combined with HMAs provide even more of an opportunity for these older patients to increase survival -- "if they can tolerate it."

While better tolerated than intensive chemotherapy, venetoclax plus HMAs can cause significant myelosuppression, as well as infectious and other non-infectious complications.

"The extent to which this may limit its use in a population of extreme advanced age (>80 years) is not known," the authors wrote, adding that their study is the first to assess the tolerability and efficacy of the combination in an exclusively octogenarian and nonagenarian population.

Watts and colleagues analyzed electronic medical records for 154 patients with AML treated with venetoclax plus HMAs for the first time from March 2015 to April 2022 across six medical institutions in the U.S. and Italy.

Of the patients included in the study, 77% were newly diagnosed, 10% had relapsed or refractory AML, and disease status was unknown in the remaining 14%. More than half (53%) of patients had European LeukemiaNet 2017 adverse risk AML, 33% had intermediate risk, 8% had favorable risk, and 6% were unknown.

Among newly diagnosed patients, 56% had newly diagnosed AML without prior myelodysplastic syndrome (MDS) or other myeloid neoplasm, and 44% had newly diagnosed AML with a history of prior MDS or other myeloid neoplasm.

In terms of how to dose these patients, "it does seem a lower dose is OK, even if they receive less venetoclax," Watts said. "You can give them less therapy, because the therapy is very effective, even when we give it in shorter durations."

Two-thirds of patients started treatment with the standard dose and treatment schedule, with 72% subsequently modifying their venetoclax dose or schedule after cycle 1.

Across the cohort, patients were administered a final median venetoclax dose of 400 mg for 21 days, repeated every 35 days, and those patients who demonstrated a treatment response received a final median venetoclax dose of 200 mg for 21 days in 35-day cycles.

A shorter final venetoclax duration (≤14 days vs >14 days) was associated with improved OS.

The median follow-up of 7.7 months was a limitation of the study, the authors acknowledged. However, they also pointed out that the median follow-up was 18.6 months for those still alive at data cutoff, "which underscores the notable response durability in a subset of patients."

In the entire patient population, the complete remission with incomplete count recovery (CRc) rate was 57%, and the complete response (CR) rate was 41%. In patients who had a response assessment, the CRc rate was 63% and the CR rate was 46%.

For patients with newly diagnosed AML without prior MDS, 73% achieved CR or CRc.

Favorable risk AML, as well as NPM1 and FLT3 mutations were associated with improved response rates, while patients with relapsed/refractory AML, prior MDS, prior HMA use, TP53 mutations, and complex karyotype had lower response rates.

"And the safety, even in this older patient group who are going to be more frail and have more comorbidity, was quite similar to VIALE-A in terms of 30- and 60-day mortality rates (8.5% and 17%, respectively)," Watts pointed out. "So, it is tolerable in most of these patients."

Treatment-emergent grade 3-4 anemia occurred in 50% of patients, thrombocytopenia in 48%, neutropenia in 53%, and neutropenic fever in 46%. Mortality was attributed to progression/relapse in 60% of cases.

Watts and colleagues said further research is needed to define subsets of patients more likely to durably respond (such as those with NPM1, IDH1/2, and RUNX1 mutations) versus those who might benefit from less venetoclax exposure (those with TP53 mutations and prior MDS), in order to better determine how intensively to treat octogenarians and nonagenarians with venetoclax and HMAs.

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