Treatment of Adverse-Risk and Refractory/Relapsed Acute Myeloid Leukemia (AML) Patients with FLAG-IDA ± Venetoclax and CLAG-M: A Monocentric Experience
Authors: Rahmé Ramy , Vidal Valérie , Hueso Thomas , Le Meur Lucie , Rigal Marthe , Ivanoff Sarah , Brechignac Sabine , Peffault De Latour Regis , Gardin Claude , Braun Thorsten 
Published: December 2023

Background: ELN 2022 risk classification of AML includes three risk categories and guides treatment choice. Adverse-risk patients, encompassing secondary (sAML) and therapy-related AML (tAML), show lower response rates to upfront traditional intensive chemotherapy (IC) combining anthracycline and cytarabine (3+7 regimen). In refractory/relapsed (R/R) cases, no standard IC approach is established, in particular as a bridging therapy to allogeneic stem cell transplantation (ASCT) that, whenever feasible, remains the only curative strategy. Recently, alternative IC such as CLAG-M (cladribine, cytarabine, G-CSF and mitoxantrone) and FLAG-IDA (fludarabine, cytarabine, G-CSF and idarubicin) were considered for adverse-risk and R/R patients, and were associated with encouraging results including our recent experience with CLAG-M. Specifically, the addition of the bcl2 inhibitor venetoclax (VEN) to FLAG-IDA was associated with deep remissions and a high rate of transition to transplantation (56%). As publications on intensive approaches in these high-risk patients remain sparse in the literature, we report our single-center experience with FLAG-IDA ± VEN compared to our updated experience with CLAG-M in this setting.

Methods: We retrospectively collected data on patients with adverse and R/R AML who were treated with either CLAG-M or FLAG-IDA ± VEN at our center from January 2015 to July 2023. We assessed data for baseline characteristics, response to administered treatment as well as univariate and multivariate analyses for specific hazard of survival.

Results: Fifty-two patients were enrolled. Thirty patients were treated with CLAG-M (median age 64.0 y [33, 79] and 22 with FLAG-IDA ± VEN (median age 55.5 y [26, 79], p 0.008), 55% of whom received VEN. The distribution of AML types as de novo, sAML and tAML was as follows: 50%, 30% and 20% in CLAG-M; 81.8%, 13.6% and 4.5% in FLAG-IDA ± VEN (ANOVA, p 0.04). Overall, 15 (28.8%) and 37 (71.2%) were newly diagnosed (ND-AML) and R/R cases, respectively: 11 (36.7%) and 19 (63.3%) in CLAG-M; 4 (18.2%) and 18 (81.8%) in FLAG-IDA ± VEN (p 0.115). In R/R, median time to relapse (in months) after first remission was 22 [6, 97] in CLAG-M and 15.0 [4, 36] in FLAG-IDA ± VEN, and median number of prior lines was 1 [0, 4] and 1 [0, 2], respectively. As for ELN 2022 risk groups, 14 (46.7%) and 12 (54.4%) were classified as adverse in CLAG-M and FLAG-IDA ± VEN , respectively (p 0.811). Gene mutations comprised, respectively, the following high-risk defining alterations: 2 (6.7%) and 2 (9.1%) RUNX1; 3 (10%) and 6 (27.3%) ASXL1; 7 (23.3%) and 3 (13.6%) TP53. After induction course, 19 (63.3%) patients in CLAG-M and 19 (86.3%) in FLAG-IDA ± VEN obtained a complete remission (CR). Early deaths (0-30 days) were observed in 4 (13.3%) and 1 (4.5%) patients, respectively. Overall, observed treatment-related toxicities were mild: no unusual infections were seen; median duration of neutropenia (&lt; 0.5 G/L) in days was 30.0 [12, 212] in CLAG-M and 25 [20, 85] in FLAG-IDA ± VEN (p 0.34); median duration of thrombocytopenia (&lt; 100 G/L) was 33.0 [22.0, 212] and 27.5 [22.0, 187] (p 0.38), respectively. Thirteen patients in each group (CLAG-M 43.3%, FLAG-IDA/VEN 59.1%; p 0.086) proceeded to ASCT with a median time in days to transplantation of 100 [31, 212] and 103 [36, 124], respectively. After median follow-up of 365 days [11, 2640] in CLAG-M and 410 [26, 3100] in FLAG-IDA/VEN, 8 (26.7%) and 13 (59.1%) patients were alive (p 0.066). We then performed hazard-risk analyses. In the univariate analysis, these variables were associated with survival: female gender (HR 0.4 [0.17, 0.94], p 0.03); complex karyotype (HR 2.78 [1.07-7.17], p 0.03); ELN 2022 adverse/intermediate (HR 3.82 [0.90-16.21], p 0.05); TP53 mutation (HR 2.84 [1.20-6.71], p 0.013) and ASCT (HR 0.34 [0.16-0.71], p 0.003). In the multivariate analysis, the following variables remained independently associated with survival: ASCT (HR 0.27 [0.12-0.60], p 0.001) and TP53 mutation (HR 3.15 [1.24-8.0], p 0.01).

Conclusion: In this cohort of high-risk patients, FLAG-IDA ± VEN and CLAG-M induced high remission rates than prevoiusly reported. These regimens were associated with limited toxicity and bridged to transplant 50% of patients. In addition, ASCT offered a survival benefit, specifically in the FLAG-IDA ± VEN group, although numbers were limited. The presence of a TP53 mutation was associated with inferior outcomes.