VEN-HMA May Prolong Survival in Elderly Acute Myeloid Leukemia Population

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A reduced dosing duration of venetoclax plus hypomethylating agents may be appropriate for elderly patients with acute myeloid leukemia.

"Our work demonstrates that [patients with] AML at the extremes of older age can be treated successfully with VEN-HMA, and a subset of these patients have prolonged survival," according to the study authors.

"Our work demonstrates that [patients with] AML at the extremes of older age can be treated successfully with VEN-HMA, and a subset of these patients have prolonged survival," according to the study authors.

Combining venetoclax (Venclexta) with hypomethylating agents (VEN-HMA) may boost survival in a subset of octo- and nonagenarian patients with acute myeloid leukemia (AML), according to findings from a retrospective study published in Blood Neoplasia.

Among all patients, the median overall survival (OS) was 8.1 months (95% CI, 6.7-10.2). Additionally, the median OS was 13.2 months (95% CI, 9.4-16.4) in those who had a response vs 4.1 months (95% CI, 2.5-6.3) in those without a response (P <.001); the median OS for those with a complete response (CR) was 13.8 months (95% CI, 9.4-21.1; P <.001). Investigators reported a median OS of 10.2 months for patients with newly diagnosed AML without prior myelodysplastic syndrome (MDS), 6.4 months in those with newly diagnosed disease and prior MDS, and 9.2 months in patients with relapsed/refractory AML (P = .13).

The median OS for patients with any TP53 mutation (n = 31) was 6.4 months, which investigators highlighted as worse compared with all other groups (P = .0048). The median OS was 9.1 months in those with any RAS pathway mutation (n = 20) compared with 7.8 months in those without a RAS mutation (P = .96).

The median OS for patients with a FLT3-ITD mutation (n = 12) was 12.2 months vs 7.8 months in those with FLT3-ITD wild-type disease (P = .44). For those with a FLT3-ITD mutation but not a TP53 mutation (n = 10), the median OS was 19.5 months (P = .55). Treatment yielded a median OS of 6.3 months in patients with complex karyotype (P = .0004).

“Our work demonstrates that [patients with] AML at the extremes of older age can be treated successfully with VEN-HMA, and a subset of these patients have prolonged survival,” Ellen Madarang, a clinical pharmacist in the Department of Pharmacy at the University of Miami Sylvester Comprehensive Cancer Center, and coauthors wrote.

“Elderly patients may benefit from significant dose reductions, particularly after achieving response. In patients who achieved a composite complete remission [CRc], the median final dose and duration of venetoclax was 200 mg daily for 21 days every 35 days,” they added.

Investigators of this multi-center study assessed patients across 6 institutions in the United States and Italy. Patients received venetoclax at 200 mg plus moderate CYP3A4 inhibitors or at 100 mg in combination with strong CYP3A4 inhibitors at a target dose of 400 mg.

The study’s primary end point was OS. Secondary end points included the CRc rate, median venetoclax dose and duration at cycle 1 and last follow-up, VEN-HMA cycle length, and dose reductions. Safety end points included grade 3 or higher treatment-emergent adverse effects (TEAEs) such as anemia, thrombocytopenia, neutropenia, and febrile neutropenia.

Among 154 patients who were 80 years and older with AML, 77% had newly diagnosed disease, 10% had relapsed/refractory disease, and 14% had unknown disease type. Of those with newly diagnosed disease, most had newly diagnosed AML without prior MDS (56%).

The median age was 82 years (range, 80-92), and most patients were male (69%). Among 140 patients with evaluable molecular data, common mutations included TP53 mutations (22%), IDH1/2 mutations (19%), NPM1 mutations (12%), and FLT3-ITD mutations (8%).

According to multivariate analysis, factors that correlated with worse OS included an ECOG performance status of 3 or higher (HR, 3.57; 95% CI, 1.35-9.45; P = .010), intermediate-risk disease (HR, 3.56; 95% CI, 1.07-11.87; P = .039), adverse risk (HR, 3.31; 95% CI, 0.99-11.05; P = .052), TP53 mutations (HR, 1.96; 95% CI, 1.14-3.36; P = .015), and prior MDS (HR, 1.72; 95% CI, 1.08-2.73; P = .022). Patients who received a shorter duration of venetoclax treatment at 14 or fewer days experienced improvements in OS compared with those who received treatment for more than 14 days (HR, 2.47; 95% CI, 1.52-4.02; P <.001).

Data highlighted a CRc rate of 57% (n = 87/154) and a CR rate of 41% (n = 63/154) across the intent-to-treat population. Lower response rates were reported in those with relapsed/refractory or newly diagnosed AML with prior MDS and patients with prior treatment with HMAs for MDS or AML.

Overall, 36 (23%) patients were still in remission at the time of the final data cutoff, and 31 (20%) were still receiving treatment with VEN-HMA. The mortality rates were 8.5% at 30 days and 17% at 60 days.

Grade 3/4 TEAEs included neutropenia (53%), anemia (50%), thrombocytopenia (48%), and neutropenic fever (46%). Of the known causes, most patients died due to disease progression or relapse (60%), sepsis (8%), and factors unrelated to AML (8%).

Reference

Madarang E, Lykon J, Zhao W, et al. Venetoclax and hypomethylating agents in octo- and nonagenarians with acute myeloid leukemia. Blood Neoplasia. 2024;100016. doi:10.1016/j.bneo.2024.100016

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