AUTHORS
Leora Boussi, MD, Baher Krayem2, Kuo-Kai Chin, MD3, Xin Wang, MD, MSCE4, Ali Kamali, PhD5, Richard Shin, PharmD6, Sean Hwang7, Eytan M Stein I, MD8
AFFILIATIONS
1 Memorial Sloan Kettering Cancer Center, New York, United States
2 Rambam Health Care Campus, Haifa, Israel
3 Memorial Sloan Kettering Cancer Center, New York, United States
4 Memorial Sloan Kettering Cancer Center, New York, United States
5 Memorial Sloan Kettering Cancer Center, New York, United States
6 Memorial Sloan Kettering Cancer Center, New York, United States
7 Memorial Sloan Kettering Cancer Center, New York, United States
8 Memorial Sloan Kettering Cancer Center, New York, United States
ABSTRACT
Background: Patients (pts) with initial response to hypomethylating agent+venetoclax (HMA+ven-1) with subsequent relapse have limited treatment options, especially those without a targetable mutation, ineligible for intensive chemotherapy, and without access to clinical trials. HMA+ven is a widely used treatment for relapsed and refractory (RR) AML. However, clinical outcomes with HMA+ven retreatment (HMA+ven-2) after initial response to HMA+ven-1 are unknown. We performed a retrospective analysis of outcomes in pts who responded to HMA+ven-1 and were retreated with HMA+ven-2 in a subsequent line of therapy.
Methods: We reviewed pts with AML at our center who responded to HMA+ven-1, relapsed (either on HMA+ven-1, during treatment interruption, or after allogeneic stem cell transplant [alloHSCT]), and were rechallenged with HMA+ven-2. Initial response to HMA+ven-1 was defined as complete remission (CR), CR with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), or partial response (PR). Predictors of response were assessed by logistic regression and for survival by a Cox proportional hazards model. Kaplan-Meier method was used to estimate overall survival (OS).
Results: 67 pts retreated with HMA+ven were identified, 77% and 12% of whom were adverse risk by ELN 2022 and 2024, respectively. HMA+ven-1 was given in first line (57%) or the RR setting (43%) for a median of 2 cycles (range 1-20). Responses to HMA+ven-1 included CR/CRi in 55 (82%), MLFS in 11 (16%), and PR in 1 (2%), and 21 (32%) pts with available testing achieved minimal residual disease (MRD) negativity by multiparameter flow cytometry (mFC). Reasons for discontinuation of HMA+ven-1 included alloHSCT (n=41, 61%), relapse (11, 16%), patient preference (8, 12%), unrelated health complications (3, 4%), cytopenias (2, 3%), donor lymphocyte infusion (1, 1%), and loss to follow-up (1, 1%). Median time from HMA+ven-1 start to relapse was 9 months. Median age at HMA+ven-2 was 65 (range 22-85) and 93% with scores available had ECOG 0-1. Cytomolecular characteristics at HMA+ven-2 included complex karyotype (CK) in 22 (34%), SRSF2 in 7 (11%), NRAS/KRAS in 9 (14%), TP53 in 11 (17%), ASXL1 in 11 (17%), TET2 in 14 (22%), DNMT3A in 18 (28%), and RUNX1 in 19 (29%). HMA+ven-2 consisted of azacitidine in 59 (89%) and decitabine in 7 (11%) given for a median of 2 cycles (range 1-10).
Responses to HMA+ven-2 occurred in 25 pts (37%), with CR/CRi in 18 (26%), MLFS in 5 (8%), and PR in 2 (3%). MRD negativity was confirmed in 7/19 (37%) responders by mFC, and 5 responders proceeded to alloHSCT. Median time to best response was 1.7 mos (range 0.7-5.2), and median OS of responders was 23 months (95% CI 14-NR).
We next evaluated features associated with response and OS after HMA+ven-2. CK was present in a higher proportion of non-responders (35% vs 29%) and was associated with inferior OS (HR 2.84, 95% CI 1.21-6.64, p=0.016). TP53 mutation was associated with decreased response to HMA+ven-2 (OR 0.16, 95% CI 0.01-0.91, p=0.04) and shorter OS (HR 3.72, 95% CI 1.72-8.06, p=0.0009). Pts with greater than the median of 9 mos between HMA+ven-1 start and relapse were significantly more likely to respond to HMA+ven-2 (OR 3.10, 95% CI 1.09-9.22, p=0.03) with improved OS (HR 0.52, 95% CI 0.28-0.97, p=0.04). Additionally, response rate to HMA+ven-2 varied by the reason for HMA+ven-1 discontinuation, with responses observed in 16 (39%) who discontinued for alloHSCT, 1 (9%) who discontinued because of relapse, and 6 (40%) who discontinued for other reasons. Pts who relapsed on HMA+ven-1 had significantly lower response rate to HMA+ven-2 (9% vs 39%; OR 0.16, 95% CI 0.01-0.89, p=0.035) and inferior OS (median OS 8 vs 11 mos; HR 2.36, 95% CI 1.13-4.95, p=0.02) compared to those who discontinued for any other reason. Outcomes with HMA+ven-1 including CR/CRi vs MLFS/PR, MRD status, time to best response, alloHSCT, and administration in first line vs RR were not significantly associated with response and OS outcomes after HMA+ven-2, nor were age and RAS mutation at HMA+ven-2.
Conclusions: HMA+ven retreatment after initial sensitivity had an ORR of 37%, including 26% CR/CRi. CK, TP53 mutation, and relapse on HMA+ven-1 were associated with inferior response and OS following HMA+ven retreatment, and pts with >9 mos between first HMA exposure and relapse were more likely to respond to HMA+ven-2. HMA+ven rechallenge may be an appropriate option for selected pts.
DISCLOSURES
Leora Boussi, MD: No relevant conflicts of interest to declare.