Purine-Analog Based Intensive Chemotherapy (IC) Combined with Venetoclax (VEN) Is Highly Active in Newly Diagnosed (ND) and Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)
Authors: Lachowiez Curtis A , Cohen-Nowak Adam Julian , Khan Talha , Cwykiel Joanna , Tabiti Bukky Florence , Khan Irum , Dinner Shira N. , Grenet Justin , Agha Aya , Saultz Jennifer N. , Gandhi Arpita , Meyers Gabrielle , Newell Laura F. , Leonard Jessica T. , Hayes-Lattin Brandon , Traer Elie , Maziarz Richard T. , Cook Rachel J. , Swords Ronan T. , Altman Jessica Kaplan , Abaza Yasmin 
Published: December 2024

Background:

Purine-analog based IC plus VEN are effective regimens inducing deep remissions with impressive survival in single center non-randomized trials including patients (pts) with ND and R/R AML (DiNardo et. al. JCO 2021; Kadia et. al. Lancet Haem. 2021). Whether these results are more broadly extrapolatable is largely unknown. We report outcomes of a large cohort of pts treated with IC + VEN outside the context of a clinical trial.

Methods:

Pts with ND or R/R-AML treated with either fludarabine, cytarabine, idarubicin and G-CSF (FLAG-IDA; N=74) or cladribine, cytarabine, idarubicin (CLIA; N=9) plus VEN at two academic medical centers with baseline clinical, molecular and treatment characteristics, and survival outcomes were included.

Comparisons of categorical and continuous variables utilized the Fisher exact test and Wilcoxon rank-sum or Kruskal-Wallis test as appropriate. Time to event endpoints were evaluated using the Kaplan-Meier method with Cox proportional hazards modeling for multivariable analysis (MVA). Allogeneic hematopoietic cell transplant (HCT) was considered as a time-dependent covariate.

Results:

52 (63%) pts had ND and 31 (37%) had R/R-AML. Median age was 48 years (range: 20-70). ELN 2022 risk was favorable, intermediate, and adverse risk in 25% (N=21), 23% (N=19), and 52% (N=43) of the pts, respectively. Ten pts (12%; ND: 6, R/R: 4) had mutated TP53 or deletion/abnormal 17p (TP53+/17p). During induction, 81% (N=66) and 19% (N=14) of pts received VEN for 7 vs. 8-14 days, respectively. In the R/R cohort, median number of prior therapies was 1 (range: 1-5). Thirty-two percent (N=10) of pts received prior VEN and 23% (N=7) had prior HCT.

In ND-AML, the CR/CRi rate was 85% (N=44; CR: 81%, CRi: 4%). CR/CRi was attained in 100% (N=12), 100% (N=14), and 69% (N=18) of pts with ELN favorable, intermediate, and adverse risk, respectively. Pts receiving 7 (N=45) vs. 8-14 days of VEN (N=7) had higher CR/CRi rates (91% vs. 43%, p: 0.007); the latter group being enriched for TP53+/17p (7% vs. 43%, p: 0.02). Accordingly, pts without TP53+/17p were more likely to attain CR/CRi (89% [N=41/46] vs. 50% [N=3/6]). Median time to count recovery (ANC ≥ 500 and/or ≥ platelets 50 x 109/L) was 23 days (range: 17-42). 30 and 60-day mortality was 1.9 and 3.8%.

In R/R-AML (refractory N= 23; relapsed N=8), the overall response rate was 71% (N=22; CR: 53%, CRi: 9.6%, MLFS: 9.6%). CR/CRi rates were 89% (N=8), 80% (N=4), and 41% (N=7) in pts with ELN favorable, intermediate, or adverse-risk AML, respectively. Pts without prior VEN exposure (81% vs. 20%, p=0.002) or pts without TP53+/17p (70% vs. 0%, p= 0.015) were more likely to attain CR/CRi . Median time to count recovery was 31 days (range: 18-71). 30 and 60-day mortality was 3.2 and 6.5%.

Median follow up was 15 and 14 months (mos) in ND and R/R-AML, respectively (range: 1-39 mos). In ND-AML, median EFS and OS was not reached (NR; 12-month EFS: 69%; 12-month OS: 76%). Median EFS and OS were NR in ELN favorable (12-month EFS/OS: 91%/100%) and intermediate risk AML (12-month EFS/OS:100%/100%). In ELN adverse risk, median EFS and OS were 6.8 and 13 mos, respectively, largely driven by pts with vs. without TP53+/17p (median OS: 5.5 mos vs. NR, p=0.018; 12-month OS: 17% vs. 66%).

In R/R-AML, median EFS and OS were 6 and 15.4 mos, respectively. No significant difference in OS was observed based on ELN risk group (p=0.15). Pts with TP53+/17p experienced shorter OS (median 5 vs. 33 mos, p: 0.057), as did pts who received prior VEN (5 vs. 33 mos, p: 0.005).

Forty-eight-percent (N=25) of ND and 57% (N=16) of R/R-AML pts received HCT in CR after a median of 4.1 mos. In ND-AML, receipt of HCT corresponded with a 12-month EFS and OS rate of 91% and 90%, respectively. In pts with ELN intermediate/adverse-risk AML (N=40), median OS with HCT was NR (12-month OS: 89%). In R/R-AML, median OS with HCT was 33 mos.

In MVA, prior VEN use in R/R-AML (HR: 3.6, 95% CI: 1.13-11.3, p: 0.03), and TP53+/17p status in ND or R/R-AML (HR: 5.87, 95% CI: 2.45-14.10, p &lt; 0.0001) correlated with an increased risk of death.

Conclusions:

This study confirms the favorable outcomes observed in pts with ND and R/R-AML treated with CLIA or FLAG-IDA+VEN. Receipt of prior VEN therapy or the presence of TP53+/17p AML predict for inferior response. Given the high efficacy observed in the frontline and salvage setting when combined with HCT in all other patient subgroups, a randomized comparison to standard anthracycline and cytarabine based IC is planned.