Comparison of Patients with Newly Diagnosed (ND) Acute Myeloid Leukemia (AML) Treated with Venetoclax and Hypomethylating Agents Vs Other Therapies By TP53 and IDH1/2 Mutation: Results from the AML Real World Evidence (ARC) Initiative

Introduction: Venetoclax (VEN; a BCL-2 inhibitor) is approved in combination with hypomethylating agents (HMA) or low dose cytarabine for ND adults with AML ineligible for intensive chemotherapy (IC) (i.e., ≥75 years old or comorbidities that preclude use of IC). This study describes the real-world characteristics and clinical outcomes of patients (pts) treated with VEN-HMA vs. non-VEN-based regimens in the ARC Initiative, overall and specifically among pts ≥75 years old or with comorbidities.

Methods: A multicenter chart review study including randomly selected adult pts with ND AML treated with VEN (VEN cohort) after April 2016 from 14 academic sites (US: 10; Israel: 4) matched 1:1 to control pts who received non-VEN-based regimens after May 2015 (CON cohort) based on age (<60, 60-74, ≥75) and ELN risk. Interim descriptive results from May 2022 are presented; data collection is ongoing. Clinical outcomes, including composite complete remission (CRc; i.e., CR, CRh, or CRi), minimal residual disease (MRD; assessed by flow cytometry or molecular monitoring), overall survival (OS), hematopoietic cell transplantation (HCT), and transfusion independence (TI), were compared between the VEN cohort and matched CON cohort. A subset of VEN pts ≥75 years old or with ≥1 comorbidity of interest (based on the Ferrara criteria) and their matched CON pts were analyzed separately (unfit subgroup) and results among pts with TP53 and IDH1/2 mutation were also reported.

Results: Results are described in Table 1. A total of 176 VEN pts and 176 CON pts were included, including 116 unfit VEN with their matched CON pts. Overall, VEN pts received VEN-azacitidine (AZA; 76.1%) or VEN-decitabine (DEC; 23.9%) and 65.3% of CON pts received high intensity regimens. In the unfit subgroup, VEN pts received VEN-AZA (77.6%) or VEN-DEC (22.4%) and 55.2% of CON pts received high intensity regimens. The proportion of pts who were ≥75 years old was 34.1% and 50.9% in the unfit subgroup. A total of 64.8% of all pts were classified as ELN adverse risk, which was 67.2% in the unfit subgroup. Among pts with genetic mutations tested, 22.2% of VEN pts and 13.5% of CON pts had TP53 mutations and 19.9% and 14.6% had IDH1/2 mutations, respectively, which was similar in the unfit subgroup of each cohort.

Among pts with a response assessment, 65.7% of VEN pts and 53.5% of CON pts achieved CRc (p<0.05) and 39.6% of VEN pts and 43.4% of CON pts achieved CR (p=0.53). In the unfit subgroup with a response assessment, 66.1% of pts in the VEN cohort and 44.6% of pts in the CON cohort achieved CRc (p<0.01) and 37.5% of VEN pts and 36.0% of CON pts achieved CR (p=0.91). Among pts with TP53 mutations, response was not statistically different for the overall and unfit subgroup. Among pts with IDH1/2 mutations, CRc was significantly higher in overall VEN versus CON (87.9% vs. 54.2%; p<0.01) and in the unfit subgroup (85.7% vs. 52.9%; p<0.05). The duration of CRc was not statistically different between the VEN and CON cohorts, overall or in the unfit subgroup.

For pts who achieved CRc and had MRD assessed, 74.0% of VEN pts and 66.7% of CON pts had negative MRD. Similar proportions were observed overall and for IDH1/2 in the unfit subgroup although statistical significance was not met.

HCT rate was 6.8% and 14.2% in the VEN and CON cohorts (p<0.05) and 6.9% and 12.1% in the unfit subgroup, respectively (p=0.26). The median OS was 15.8 and 13.9 months in the VEN and CON cohorts, respectively (p=0.20) and 17.1 and 12.4 months in the unfit subgroup (p=0.30). The 6-month OS rate was 74.3% and 70.1% in the VEN and CON cohorts (p=0.30) and 75.6% and 66.2% in the unfit subgroup (p=0.10). Among the pts with ≥56 days of follow-up, 61.9% and 54.8% in the VEN and CON cohorts (p=0.29) and 67.0% and 51.1% in the unfit subgroup (p=0.05), respectively, achieved TI.

Conclusions: Pts with ND AML receiving VEN-HMA had significantly higher rates of CRc than matched pts on non-VEN-based regimens in the overall population, those unfit for IC, and with IDH1/2 mutations. OS and durability of response were similar in VEN and CON pts, despite 65% of pts in the overall CON cohort receiving IC and 55% in the unfit subgroup. VEN pts who were considered as unfit had similar clinical outcomes to the overall VEN pts. Although VEN pts with TP53 mutation had non-significantly higher CRc rates compared with CON pts, median OS was poor in both groups highlighting the need for novel approaches in this high-risk molecular subset.