The Well Tolerated VA-Based Regimen Bringing to High Quality of Life Did Not Absolutely Inferior to Intensive Chemotherapy in AML Patients with NPM1 Mutation
Authors: Duan Wenbing , Chen Qi , Yu WenJing , Jia Jinsong , Wang Jing , Zhu Xiaolu , Zhao Ting , Jiang Qian , Ruan Guorui , Zhao Xiaosu , Shi Hongxia , Chang Ying-Jun , Wang Yu , Xu Lanping , Zhang Xiaohui , Huang Xiaojun , Jiang Hao 
Published: December 2024

Background The B-cell lymphoma 2 (BCL2) plays an important role in the survival and persistence of acute myeloid leukemia (AML) blasts. Venetoclax, an oral BCL2 inhibitor, combined with hypomethylating agents or low dosage of cytarabine makes newly diagnosed AML patients with NPM1 mutation who are ineligible for intensive chemotherapy achieve high rate of complete remission (CR)/CR with incomplete hematological recovery (CRi). However, whether this kind of induction regimen is comparable to intensive chemotherapy? We did the retrospective study.

Method Newly diagnosed AML patients with NPM1 mutation in our single center from April 2013 to January 2024 were retrospected. Propensity score matching (PSM) in a 1:2 ratio was performed to adjust for differences in baseline covariates between patients ineligible for intensive chemotherapy who received venetoclax+ azacitidine (VA)-based regimen or intensive chemotherapy (IC)-based regimen as induction therapy. IC regimens included IA, HAA, or CAG regimen. Covariates were matched for FLT3-ITD mutation and DNMT3A mutation. Rate of CR/CRi, log reduction of NPM1, event free survival (EFS) and overall survival (OS) between VA-based and IC-based group were compared. The survival excluded the patients who underwent hematopoietic stem cell transplantation (HSCT), but patients relapsed before HSCT were included, and data of the survival analysis were censored at the time of HSCT.

Results A total of 49 patients induced by VA-based regimen. In the PSM cohort of 141 patients, 47 and 94 patients were in the VA-based and IC-based group, respectively. Median age was 51(IQR 38-61) years old, and median follow-up time were 19.5 (IQR 11.35-32.4) months. FLT3-ITD mutation and DNMT3A mutation occurred in 40.4% (57/141), 56.0% (79/141) patients respectively, and 66.6% (38/57) patients with FLT3-ITD mutation received FLT3 inhibitor (FLT3i). A total of 21.3%（30/141）patients underwent HSCT. The median age was different between two groups (60 vs. 48, p＜0.001). In patients without FLT3-ITD mutation, the CR/CRi rate after one induction cycle was 93% (26/28) in VA group and 89% (50/56) in IC group (p=0.713), and it was both 96% in the two groups (27/28 vs.54/56) after two induction cycle (p=1.000). The median log reduction of NPM1 was 2.6 (IQR 1.7-3.2) and 2.7(IQR 2.1-3.4) in the two groups respectively (p=0.326). In patients with FLT3-ITD mutation, 79% (15/19) patients used FLT3i in VA group and 61% (23/38) patients in IC group (p=0.387), and 37% (14/38) in IC group used FLT3i during induction. The CR/CRi rate was 84% (16/19), 95% (18/19) after one, and two induction cycle respectively in VA group. In IC group, 87% (33/38) and 92% (35/38) patients achieved CR/CRi after one, and two induction cycles. The CR/CRi rate between two groups did not differ (both p=1.000 for one and two induction cycles). In IC group, 100% (14/14) patients achieved CR/CRi after one induction cycle who used IC+sorafenib, while that was 79.2% (19/24) in patients used IC only during induction. The log reduction of NPM1 also had no difference between two groups [3.2 (IQR 1.4-3.8) vs. 2.5 (IQR 1.4-2.9), p=0.276]. According to the consolidation regimen patients received after achieving CR/CRi，long term of VA-based group (n=19), VA-based regimen followed by intensive consolidation chemotherapy group（n=17），IC-based group (n=79) were divided into. After 2 cycles of consolidation, 79%(15/19), 80% (12/15) and 82% (61/74) of NPM1 in each group decreased ≥3log（p=0.935）. The 2-year EFS rate (40.1% vs. 60.9% vs. 60.6%, p=0.199), and 2-year OS rate were not different (88.9% vs. 90.0% vs. 70.9%, p=0.199). In multivariate analysis, FLT3-ITD mutation [EFS, hazard ratio (HR)=2.4, p=0.008; OS, HR=2.6, p=0.027] and log reduction of NPM1 after 2 cycle of consolidation ≥3log[EFS, HR=0.3; OS, HR=0.2, both p＜0.001] were independent prognostic factors for survival.

Conclusion The well tolerated VA-based regimen, which not only brought to high quality of life, but also had high rate of CR/CRi, did not be absolutely inferior to IC in AML patients with NPM1 mutation who were ineligible for IC. However, the survival needs to be verified by longer follow-up time and more patients.