Phase 1b/2 Study of Magrolimab (Magro), Azacitidine (AZA) and Venetoclax (VEN) in Patients (pts) with Newly Diagnosed (ND) Older/Unfit or High Risk Acute Myeloid Leukemia (AML) and Relapsed Refractory (R/R) AML: Final Clinical Data and Genomic Markers of Resistance/Relapse
Authors: Arora Sankalp , Senapati Jayastu , Loghavi Sanam , Reville Patrick K. , Wang Bofei , Kadia Tapan M. , DiNardo Courtney D. , Pemmaraju Naveen , Yilmaz Musa , Jabbour Joseph E. , Short Nicholas J. , Montalban-Bravo Guillermo , Maiti Abhishek , Tang Guilin , Sasaki Koji , Borthakur Gautam , Alvarez Joie , Pierce Sherry , González Graciela M. Nogueras , Ning Jing , Issa Ghayas C. , Andreeff Michael , Ravandi Farhad , Garcia-Manero Guillermo , Abbas Hussein A. , Daver Naval 
Published: December 2024

Introduction:
Induction therapy with AZA-VEN has become the standard of care for older/unfit pts with ND AML. However, outcomes of AML pts with adverse risk (AR) genomics, and post relapse after AZA-VEN based therapy remain dismal warranting evaluation of novel agents/combinations. We conducted a phase 1b/2 clinical trial evaluating the addition of the CD47 antibody magrolimab to the AZA/VEN backbone in ND older/unfit or high-risk AML and R/R AML patients. Herein, we report final clinical data for the full cohort of pts enrolled in the study and additionally include previously undescribed genomic mechanisms of resistance to study treatment.
Methods:
Single center open label phase 1b/2 study conducted at MDACC. Phase 1b included pts ≥ 18 yrs with R/R AML. The phase 2 portion included adult pts with both ND and R/R AML. Frontline cohort included pts ineligible for intensive treatment (age ≥ 75 yrs or documented comorbidities precluding intensive chemotherapy), or high-risk disease (adverse karyotype per ELN 2017 or TP53m) irrespective of age/comorbidities. The R/R cohort in phase 2 was further divided based on prior VEN exposure. The treatment regimen has been previously described (N Daver et al, ASH 2022). Primary objectives included safety and rate of composite complete remission (CRc= CR + CRi) per ELN 2017.
Results:
From 8/2020 - 6/2023, 110 pts were treated on protocol, 54 (49%) in frontline, 52 (47%) in R/R cohort, and 4 with post MPN AML. For frontline cohort, median (med) age was 70 yrs (33-86), 35 pts (65%) had TP53 mutation (TP53mut), 19 (35%) were TP53 wild type (TP53wt). In frontline TP53mut cohort, med age was 67 yrs (38-86) with AR cytogenetics noted in 91% as anticipated. In frontline TP53wt cohort, med age was 75 yrs (33-83), 5 (26%) had secondary untreated AML, with AR cytogenetics in 6 pts (32%).
For the full frontline cohort, CRc was attained in 34 pts (63%). CRc was attained in 17 pts (49%) with TP53mut, and 17 (89%) pts with TP53wt AML. At med follow-up of 28 mos, med EFS and med OS for full frontline cohort was 6.6 mos (95% CI 5-10) and 9.8 mos (95% CI 7-13) respectively. For the TP53mut cohort, med EFS and med OS were 5.9 mos and 7.6 mos respectively. For the TP53wt cohort, med EFS and med OS were 9.6 mos and 13 mos respectively. Med duration of response (DOR) for CRc in frontline was 9.1 mos (9.2 mos in TP53mut and 9 mos in TP53wt). A total of 17 pts (32%) underwent alloSCT in 1st remission: 12 (34%) of TP53mut group, 5 (26%) of TP53wt group. For these pts, the med EFS and med OS was 11 mos (95% CI 6-NR) (12.1 mos in TP53mut and 5.9 mos in TP53wt) and 16.7 mos (95% CI 9-NR) (NR in TP53mut and 8.5 mos in TP53wt), respectively.
For R/R cohort, med age was 61 yrs (28-80), 39 pts (75%) had R/R AML and 13 (25%) had treated secondary AML. In the full cohort, 28 pts (54%) were Ven naïve, and 24 pts (46%) were Ven exposed. CRc was attained in 11 (39%) Ven naïve pts and 4 (17%) Ven exposed pts. At med follow up of 16 mos, med EFS and med OS for full R/R cohort was 2.3 mos (95% CI 2-3) and 3.9 mos (95% CI 3-6). Med OS for VEN-naïve and VEN-exposed was 4.1 mos and 3.5 mos respectively. Med DoR for CRc pts in full cohort was 13.1 mos. 7 pts (13.5%), all from the Ven naïve group underwent an alloSCT.
Most common grade 3-5 treatment emergent AEs were infectious complications, seen in 83 pts (75%), most prevalent being febrile neutropenia (44%). In the frontline cohort, the mean hemoglobin (Hb) dropped from 8.5g/dL at baseline to 7.8 g/dL post 1st Magro infusion (p=0.002), with the med units of pRBC transfused being 6 (2-13) in the first 2 weeks. No grade ≥3 AEs related to anemia were noted.
Single cell RNA seq was performed on 27 samples from 11 TP53mut pts (including 8 treatment responders). On gene set enrichment analysis pre-therapy, non-responders (NR) had upregulated IFNγ and TNFα signaling. Post-therapy, NRs had increased erythroid differentiation. Pts at relapse had upregulated CD47 expression, enrichment of regeneration enriched cells, and increased erythroid differentiation.
Conclusion
Addition of magrolimab to AZA/Ven was safe with manageable anemia, but med OS in frontline TP53mut AML remained poor at 7.6 mos in spite of encouraging response rates. Interestingly, pts with TP53mut AML who underwent alloSCT had med EFS 12 mos and med OS NR. Potential mechanisms of resistance/relapse included erythroid differentiation, inflammatory tumor microenvironment, and CD47 upregulation.