Reducing 1L venetoclax to 7 days feasible in elderly AML patients ineligible for intensive chemo

In treatment-naïve elderly patients with acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy (IC), reducing venetoclax (VEN) exposure to 7 days concurrently with azacitidine (AZA) (7+7 scheme) led to similar response rates as the recommended protocol of 28 days of VEN plus 7 days of AZA (28+7 scheme), a retrospective study has shown.

“Based on results of the phase III VIALE-A study, the 28+7 scheme of VEN plus AZA has become standard of care for patients with previously untreated AML who are ineligible for IC, including those with comorbidities or those aged ≥75 years,” said Dr Christophe Willekens of Gustave Roussy, University of Paris-Saclay, Villejuif, France. [N Engl J Med 2020;383:617-629] “However, toxicity remains problematic in this old and frail population, often leading to modifications of the recommended treatment scheme.”

The retrospective study included 82 patients with previously untreated AML considered ineligible for IC (median age, 75.2 years; age ≥75 years, 56.1 percent; ≥1 VIALE-A protocol exclusion criteria, 29.3 percent), who received the 7+7 scheme of VEN plus AZA given in 28-day cycles. [Willekens C, et al, ASH 2022, abstract 222]

VIALE-A protocol exclusion criteria in the cohort included active solid/lymphoid neoplasia at AML diagnosis (45.8 percent), altered Eastern Cooperative Oncology Group performance status (ECOG PS; ≥3 if age ≥75 years; ≥4 if age <75 years) (25.0 percent), chronic renal failure (creatinine clearance <30 mL/min) (16.7 percent), and prior myeloproliferative neoplasm (12.5 percent).

The patients received a median of four cycles of treatment. Overall response rate (ORR; ie, complete remission [CR] and CR with incomplete haematologic recovery [CRi]) was 41.5 percent after cycle 1, 53.9 percent after cycle 2, and 68.3 percent after all cycles.

“In univariate analysis, complex karyotype [≥3 abnormalities], TP53 mutations and adverse risk based on the European LeukemiaNet [ELN] 2022 classification criteria were correlated with worse ORR,” said Willekens.

“After a median follow-up of 4.8 months, estimated event-free survival [EFS] and overall survival [OS] were 7.5 months and 12.8 months, respectively,” he reported. “Univariate analysis showed that EFS and OS were significantly improved in patients without VIALE-A protocol exclusion criteria, those aged ≥75 years, those with ECOG PS 0–1 or normal karyotype, and those without TP53 mutations. Estimated median EFS and OS in patients without VIALE-A exclusion criteria were 11.4 months and 13.8 months, respectively.”

In the VIALE-A study (n=431; median age, 76 years), CR or CRi was achieved in 66.4 percent of patients treated with the 28+7 scheme of VEN plus AZA overall, and in 43.4 percent of patients before cycle 2. Median OS and EFS in the VEN plus AZA group were 14.7 months and 9.8 months, respectively, after a median follow-up of 20.5 months. [N Engl J Med 2020;383:617-629]

“Significant toxicity occurred even with reduced VEN exposure,” noted the researchers. “After the first cycle, 49 percent of patients experienced grade 3/4 febrile neutropenia, and 88 percent required ≥1 transfusion. Early death rate at 60 days was 6.1 percent. Recovery of neutrophils [>1 G/L] and platelets [>100 G/L] was observed after a median of 36 days and 31 days, respectively.”

Among 56 patients with CR/CRi, 61 percent had dose reduction mainly due to grade 3/4 cytopenia (treatment duration reduced to 5 days, 97 percent; VEN dose reduced to 200 mg/day, 50 percent; 5-week intervals between treatment cycles, 29 percent). Estimated median OS was 25.8 months in patients with dose reduction.

“The 7+7 scheme, applied to the same population as the VIALE-A trial, compared favourably to the 28+7 usual dose,” noted the researchers. “In responders, subsequent VEN dose reduction appeared to be associated with favourable outcome.”

“Our findings could extend the use of the VEN/AZA combination, particularly in frail AML patients with significant comorbidities defined as exclusion criteria in VIALE-A,” suggested Willekens. “The study’s cost-effective scheme may help patients from low-income countries access the combination therapy.”