Outcomes of Patients (pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) and TP53 mutation/Loss Treated on the Phase 2 Study of Venetoclax (Ven) Added to Alternating Cladribine (Clad) Plus Low-Dose Cytarabine (LDAC) and Azacitidine (Aza): A Subgroup Analysis
Authors: Senapati Jayastu , Loghavi Sanam , Reville Patrick K , Daver Naval , Borthakur Gautam , DiNardo Courtney D. , Jabbour Elias , Short Nicholas J. , Pemmaraju Naveen , Maiti Abhishek , Issa Ghayas C. , Popat Uday R. , Alousi Amin , Shpall Elizabeth J. , Sasaki Koji , Garcia-Manero Guillermo , Ravandi Farhad , Kadia Tapan M. 
Published: December 2023

Background:
Despite the introduction of newer drugs and combination therapies, outcomes of patients with AML and TP53mutation (mut) and/or loss continue to remain poor, with a median survival of 6-12 months. The phase 2 study of venetoclax (Ven) added to Clad+ LDAC alternating with azacitidine (Aza) in pts with newly diagnosed (ND) AML demonstrated a composite complete remission (CRc) rate of 93% and median overall survival (OS) not reached (NR) at 22 months (mos) (Kadia et al, JCO, 2022) (NCT03586609) . The trial was amended to increase enrollment, including a prespecified cohort of pts with AML with TP53mut/loss.
Methods:
This is a subgroup analysis of pts with TP53mut/loss on the phase 2 clinical trial. The treatment protocol has been previously published. Pts with AML with TP53 mut (next generation sequencing, lower limit of detection: 2% variant allele frequency [VAF]) or loss by conventional cytogenetics/fluorescent in situ hybridization and/or array comparative genomic hybridization at AML diagnosis were included. CRc was defined as complete remission (CR) plus CR with incomplete count recovery (CRi). Relapse free survival (RFS) was calculated from response to relapse/death and OS from treatment initiation to death; neither censored for allogeneic hematopoietic stem cell transplantation (HSCT).
Results:
From Nov 2018-Apr 2023, 124 pts with ND AML were treated on this trial, 14 (11%) of whom had TP53mut/loss. The median age in this subgroup was 66 years (yrs) (range 48-75 yrs) and 8 pts (57%) were male. Two pts (14%) had secondary AML (one treated secondary, post HSCT) and another 2 pts (14%) had therapy-related AML. Twelve pts (86%) had a TP53 mut, 8 of whom had bi-allelic loss (two mut, 1 mut with chromosome 17 loss or 1 mut with VAF≥50%). Two pts (14%) had only TP53 deletion (ie. -17/del17p). CRc was attained in 8 pts (57%) [7 CR (50%) and 1 CRi (7%)] and another pt attained partial remission (PR) with 5% bone marrow blasts as best response. 5/8 pts (63%) pts with CRc attained measurable residual disease (MRD) negativity and 4/8 (50%) also had normalization of their TP53 abnormality . The median therapy cycle to best response was 1. Notably 3 pts (21%) had erythroid leukemia, one of whom attained an MRD+ CR. Nine pts had a complex karyotype, 4 (44%) of whom attained a CRc. 4/8 pts (50%) with bi-allelic TP53 loss attained a CRc (2 became MRD negative by flow cytometry and one cleared both TP53 mutations).
Pts received a median of 1 cycle (range, 1-5) of therapy. At a median follow-up of 9 mos from study initiation, the median RFS in the responders was not reached (NR) and 1-yr RFS was 56%; median OS for the entire cohort was NR and 1-yr OS was 56%. The 1 yr-OS in responders was 75%. 4/8 pts with CRc and the pt with PR underwent HSCT at a median of 4.5 mos (range 3.9-5.9 mos) from study therapy initiation; all are alive and in remission at a median of 6 mos (range 1-12.3 mos) from HSCT.
Conclusion:
The phase 2 trial of Ven added to alternating Clad+LDAC and Aza showed promising remission rates of 57% in pts with ND AML having TP53 mut/loss and high rates of MRD negativity in responders; median RFS and OS was not reached at 9 mos follow-up. Five pts (36% overall, and 50% of the responders) could be consolidated with HSCT, with none of them relapsing after HSCT. The trial continues to accrue pts.