Venetoclax Plus Hypomethylating Agents Elicit Encouraging Responses in MDS

Minimal tumor lysis syndrome was observed with venetoclax combined with hypomethylating agents in patients with myelodysplastic syndrome.

Investigators found that venetoclax (Venclexta) plus hypomethylating agents (HMAs) attained favorable responses compared with HMAs alone in adult patients with myelodysplastic syndrome (MDS), according to findings from a poster presented at the 2024 American Society of Hematology Annual Meeting & Exposition (ASH).¹

Results from the retrospective study show that venetoclax plus HMAs achieved a complete response (CR) rate of 33% vs 12% with HMAs alone. Additionally, the marrow CR rate was 40% vs 27% in each respective group (P < .001).

Additional data reveal that treatment with the venetoclax combination therapy achieved a statistically significant improvement in event-free survival (EFS) over HMAs alone (HR, 0.59; 95% CI, 0.44-0.78; P < .001) after adjusting for covariates in analysis, as well as a numerical overall survival (OS) benefit (HR, 0.77; 95% CI, 0.57-1.04; P = .08). Furthermore, venetoclax achieved encouraging response rates when given post-HMA failure, with a CR and marrow CR rate of 10% and 32%, respectively.

The retrospective multicenter center included 13 academic medical centers and included patients of at least 18 years with MDS (n = 454). In total, 258 patients received venetoclax in combination with HMAs—as either upfront combination therapy (n = 175) or venetoclax added after HMA failure (n = 83)—and 196 received HMA monotherapy.

The average age of patients on study was 69 (range, 59-77) years, with a majority of patients having MDS with excess blasts (75%). Additionally, most patients had either high-risk (31.9%) or very high-risk disease (41.8%) by IPSS-R criteria. Furthermore, 23.7% had therapy-related disease, 33% had either a 17p deletion or TP53 mutation, and 40.9% underwent allogenic stem cell transplantation.

Venetoclax was administered in the outpatient setting for 78.6% of patients, and tumor lysis syndrome (TLS) prophylaxis and venetoclax doses ranged from 70 to 400 mg, depending on concomitant antifungal drug use.

Study end points included clinical response, adverse events (AEs), and survival, with determinants of outcomes analyzed using multivariable regression models.

Additional factors that significantly correlated with EFS and OS outcomes included having very high-risk disease per IPSS-R guidelines (EFS HR, 2.33; 95% CI, 1.62-3.37; P <.001; OS HR, 1.94; 95% CI, 1.32-2.85; P <.001) and having 17p deletions or TP53 mutations (EFS HR,1.70; 95% CI, 1.28-2.27; P <.001; OS HR, 1.77; 95% CI, 1.30-2.41; P <.001).

In total, only 1 patient was observed to have clinical TLS, with 6.2% of patients reported to have lab-only TLS; the remaining 92.9% were TLS-free. Of note, neutropenic fever was the main AE observed, with a 34.2% incidence in the upfront venetoclax arm, 22.5% incidence in the HMA monotherapy arm, and 44.5% in the post-HMA venetoclax arm.

According to the poster, a previous study published in the American Journal of Hematology evaluating venetoclax in combination with azacitidine (Vidaza) in relapsed or refractory MDS showed similar efficacy when treating patients whose disease progressed following HMA therapy.² Of note, modified objective response rate for this patient population (n = 44) was 39%, with 7% of patients achieving a CR and 32% of patients achieving a marrow CR.

Additionally, the median OS was 12.6 months (95%, 9.1-17.2), including 14.8 months (95% CI, 11.3-not evaluable [NE]) in patients with marrow CR (n = 14). Furthermore, the median progression-free survival was 8.6 months (95% CI, 5.4-14.3), with a median EFS of 6.9 months (95% CI, 5.1-8.8).

Median duration of response (DOR) among patients who attained a response was 8.6 months (95% CI, 6.0-13.3), with a median time to response (TTR) of 1.2 months (95% CI, 0.7-6.3). Among patients who achieved a marrow CR, TTR and DOR were 1.4 months (95% CI, 0.7-6.3) and 8.6 months (95% CI, 6.0-23.8), respectively.

Across dose levels, grade 3 or higher adverse events occurred in 91.4% of patients, the most common of which included febrile neutropenia (30.0%), thrombocytopenia (25.7%), and neutropenia (24.3%).

References

1. Murthy GSG, Ball S, Feld J, et al. Clinical utilization and outcomes of hypomethylating agents and venetoclax in patients with myelodysplastic syndrome- a multicenter retrospective analysis. Blood. 2024;144(suppl 1):3206.doi:10.1182/blood-2024-211623
2. Zeidan AM, Borate U, Pollyea DA, et al. A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Am J Hematol. 2023;98(2):272-281. doi:10.1002/ajh.26771