Venetoclax Plus Azacitidine for Newly Diagnosed Younger Acute Myeloid Leukemia Patients Independent of Fitness for Intensive Chemotherapy
Authors: Watts Justin M. , Sohalski Connor , Zoso Alessia , Dell-Martin Jessica , Belachew Ayele , Abbott Diana , Amaya Maria L , Kent Andrew , McMahon Christine M. , Schwartz Marc , Sekeres Mikkael A. , Smith Clayton , Venugopal Sangeetha , Jordan Craig T , Berg Mary , Haag Mary , Willard Nicholas , Aisner Dara , Schowinsky Jeffrey , Pan Zenggang , Zhang Jingjing , Gutman Jonathan , Pollyea Daniel A 
Published: December 2024

Background
Venetoclax (ven) with azacitidine (aza) is the standard of care for newly diagnosed acute myeloid leukemia (AML) patients unfit for intensive chemotherapy (IC) due to age or comorbidities. However, fit patients with poor-risk disease biology may not benefit from IC. Furthermore, adverse risk factors for IC are not necessarily adverse risk factors for ven/aza. Therefore, we designed a pilot study of ven/aza for newly diagnosed younger AML patients with non-favorable risk disease.
Methods
This is a prospective, single-arm, multi-institutional investigator-initiated trial (NCT03573024). Newly diagnosed AML patients aged 18-59 with ELN 2017 non-favorable risk disease were enrolled (initially only adverse risk patients were permitted; after five years intermediate risk patients were allowed). Of 36 subjects planned, 32 have enrolled. Stopping rules for futility based on responses were planned. Subjects were matched 1:1 to historical controls who received IC based on age and ELN risk for this analysis. Subjects received aza 75mg/m2 IV d1-7 of a 28-day cycle. Ven was escalated to 600mg on days 1-4 and continued x 28 days. Interruptions to allow count recovery between cycles, with growth factor as needed, occured. Subjects had to achieve complete remission (CR), CRi or morphologic leukemia free state (MLFS) by cycle 2 to continue on study. After at least MLFS, subjects could receive up to 3 additional cycles. Once subjects achieved MRD negativity, they could receive MRD-negative maintenance (5 days of aza and 28 days of ven at 400mg). Subjects with MRD after 4 cycles remained on 7 days of aza and 600mg ven. All subjects were encouraged to proceed to allogeneic stem cell transplantation (ASCT) as soon as they achieved response.
Results
Among the first 28 subjects, median follow up was 35.3 months. Median age was 48.5 years (22-59); 16/28 (57%) were female. Two of 28 (7%) had treatment related disease; 8/28 (29%) had monocytic disease. Most (23/28, 82%) had adverse risk; 5/28 (18%) had intermediate risk disease. The median number of cycles was 1 (0-4). Overall response rate (ORR: CR+CRi+MLFS), was 17/28 (61%), with 14 CR, 0 CRi and 3 MLFS. After the 27th subject the ORR did not meet the futility threshold (70%) for continuation. However, 4/8 (50%) with monocytic features were non responders compared with 7/20 (35%) without monocytic features. We therefore received approval to continue accrual to 36 subjects after subsequent subjects with monocytic disease were excluded; this was defined by clinical pathologists based on morphologic and/or immunophenotypic disease features.
Most (18/28, 75%) ultimately received ASCT; 13/28 (46%) were transplanted in first remission following the study treatment. Eleven of 28 (39%) were refractory to treatment; of these 9 were salvaged with IC and 7/9 responded. Four of 18 responders relapsed prior to ASCT. Only 1/28 (4%) died within 30 days. Median duration of response and OS have not been reached.
For the 28 IC matched-control patients, median follow up was 82.3 months. Their ORR was 14/28 (50%) with 8 CR, 4 CRi and 2 MLFS. Twenty received ASCT but only 9 were transplanted in first remission following initial IC therapy. Fourteen were refractory to IC; of these 12 were salvaged, with IC (N=9), ven/aza (n=1) or hypomethylating agent (N=1). Only 1/14 (7%) relapsed prior to transplant; 3/28 (11%) died within 30 days. Median duration of response was not reached and OS was 60.8 months. When comparing study subjects vs controls during the 30 day post treatment period, median days in the hospital were 7.5 (4-30) vs 30 (9-30) (p&lt;0.0001), median units of platelets transfused were 4 versus 11 (p=0.0076), median red blood cell transfusions were 3.5 vs 9 (p=0.0068) and infectious complications occurred in 11/28 (39%) versus 26/28 (93%) (p=0.0071), respectively.
Conclusions
Ven/aza for younger newly diagnosed AML patients given regardless of fitness for IC in a mostly adverse risk population resulted in an ORR of 61%, with most bridging to ASCT and these subjects having generally good outcomes. Those with monocytic disease features were ultimately excluded because of low response rates; the ORR in the non-monocytic population was 65%. Efficacy and ASCT rates appear similar to matched controls who received IC, with significant decreases in hospitalization, transfusion needs and infectious complications. Molecular sub-classification and propensity score-matched analysis will be presented.