The addition of venetoclax to FLAG IDA or FCE in relapsed or refractory (R/R) acute myeloid leukemia (AML)

Abstract

Abstract Background The addition of venetoclax (ven) to intensive chemotherapy (IC) has shown high remission rates in both newly diagnosed and R/R AML. Landmark trials combining ven with IC (ICV) excluded patients with previous ven exposure, limiting guidance on how to integrate ven in the R/R setting. FLAG-IDA-Ven is a commonly used ICV regimen, however the chemotherapy backbone may require modification in patients (pts) unable to tolerate an anthracycline, and etoposide (FCE) may be considered (Aldoss et al. Acta Haematol. 2014). Herein, we describe our experience comparing IC regimens (FLAG-IDA or FCE) with/without (w/wo) ven. Methods We conducted a retrospective analysis of adult R/R AML pts treated with IC (FCE or FLAG-IDA) w/wo ven at City of Hope (COH) between October 2017 to July 2023. Study endpoints were the complete response, complete response with incomplete count recovery or morphologic leukemia free state (CR/CRi/MLFS) rate and overall survival (OS) from start of treatment. Secondary endpoints included allogeneic transplant (HCT) rate, OS, cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) from HCT. Continuous variables (e.g. age) were compared between two groups by Wilcoxon rank-sum test. Fisher exact test was used to assess the association between two categorical variables. Kaplan-Meier method and log-rank test were used to assess time-to-event (e.g. OS) data between two groups. Response criteria were defined per standard International Working Group (IWG) criteria within six weeks from start of treatment. Measurable residual disease (MRD) by flow cytometry was performed at the University of Washington. Results Of 116 eligible pts, 63 (54%) received IC and 53 (46%) received ICV. The median (range) age for the entire cohort was 55 (20-78), which was similar between groups. Almost half (48%) of the pts had prior ven exposure, with more in the ICV group (38% vs 60%, p=0.025). The ICV group also had more prior lines of therapy (2 vs 1, p=0.037) compared to the IC cohort. Among 112 pts with response assessment, rates of CR/CRi/MLFS were 69% (41/59) vs 79% (42/53) for IC vs ICV (p=0.28), and there was no significant difference in OS between IC and ICV (median: 8.6 vs 12.0 months; p=0.17). Of all pts who responded, 75 (90%) had MRD data, and there was a trend toward higher MRD negativity in the ICV group (21/35 vs 32/40 or 60% vs 80%, p=0.08). Febrile neutropenia was common amongst the entire cohort (89%) with no difference between IC vs ICV (84% vs 94%, p=0.14). The median neutrophil and platelet recovery were not different between IC and ICV (31 vs 35 days, p=0.65 and 31 vs 35 days, p=0.17, respectively). When stratified by prior ven exposure, rates of CR/CRi/MLFS in IC vs ICV were not significantly different in both ven naïve pts (29/37=81% vs 19/21=90%, p=0.30) and ven exposed pts (12/22=55% vs 23/32=72% p=0.37). In ven exposed pts, MRD negative rates among responders were 45% (5/11) and 71% (15/21) for IC vs ICV, and in ven naïve were 70% (16/24) vs 89% (17/19) for IC vs ICV. The OS was not significantly different between IC vs ICV in ven naïve pts (median: 12.7 vs 17 months, p=0.34), while was significantly longer for ICV in ven exposed pts (median: 4.6 vs 8.3 months, p=0.032). Following salvage treatment, 54% (32/59) of IC and 66% (35/53) of ICV pts underwent HCT with a median of 85 days (range: 21-305). In the ICV group, the 12-month OS rate was 68% vs 17% (p<0.001) for pts undergoing HCT vs non-HCT. In the IC group, the rate was 71% vs 11% (p<0.001) for HCT vs non-HCT. The post-HCT OS at 12 months in ICV (ven naive), IC (ven naive), ICV (ven exposed), and IC (ven exposed) was 64.7%, 69.6%, 55%, 33.3% (p=0.03) and CIR was 17.6%, 17.4% 33.3%, and 55.6% (p=0.003), respectively.There was no significant difference in response rates or OS with the substitution of etoposide (44.8%) for anthracycline in both IC and ICV. Conclusions While overall response was similar with ICV vs IC, there was a trend toward more MRD negative responses (p=0.08) in the ICV group compared to IC. In subgroup analysis, pts with prior ven exposure showed longer OS with ICV than with IC. There were more MRD negative responses in ven exposed pts in the ICV group compared to IC, while small numbers limit statistical analysis. More pts treated with ICV were able to proceed to HCT, which was significantly associated with improved OS. Substitution of etoposide for anthracycline did not impact response rates or survival.