Outcomes of TP53-Mutant Acute Myeloid Leukemia with Venetoclax and Decitabine
Authors: Kim Kunhwa , Maiti Abhishek , Kadia Tapan M. , Ravandi Farhad , Daver Naval , Pemmaraju Naveen , Borthakur Gautam , Bose Prithviraj , Issa Ghayas C. , Short Nicholas J. , Yilmaz Musa , Alvarado Yesid , Ferrajoli Alessandra , Jabbour Elias , Jain Nitin , Ohanian Maro , Takahashi Koichi , Thompson Philip A. , Rausch Caitlin R. , Montalbano Kathryn , Pierce Sherry A. , Patel Keyur P. , Garcia-Manero Guillermo , Kantarjian Hagop M. , DiNardo Courtney D. , Konopleva Marina 
Published: February 2021

Background: TP53 mutation (TP53mut) confers adverse prognosis in acute myeloid leukemia (AML) with limited response to chemotherapy. 10-day decitabine (DEC) regimen has shown high efficacy in TP53mut AML (Welch et al. NEJM 2016). We hypothesized that adding venetoclax (VEN) to 10-day DEC may further improve outcomes in high-risk AML (NCT03404193). However, preclinical data suggests that TP53mut confers resistance to VEN in AML (Nechiporuk et al. Cancer Discov. 2019). Herein, we investigated outcomes of patients (pt) with TP53mut AML who received frontline therapy on this prospective trial of 10-day DEC and VEN (DEC10-VEN).
Methods: Patients 60 years of age and older with newly diagnosed previously untreated AML were treated with DEC 20 mg/m2 for 10 days every 4 to 6 weeks for induction followed by DEC for 5 days after CR/CRi. VEN dose was 400 mg daily or equivalent. Reduction of VEN duration was allowed in cases of cytopenias and/or myelosuppression. TP53mut was assessed in bone marrow samples using a PCR-based 81-gene Next Generation Sequencing panel targeting the entire coding regions. A MiSeq platform (Illumina, San Diego, CA, USA) was used with an analytical sensitivity established at 5% mutant reads in a background of wild type reads. Full protocol of the study has been published previously (DiNardo et al. Lancet Haematol. 2020. In press).
Results: Between January 2018 and April 2020, 121 pts received frontline therapy with DEC10-VEN on this trial. The median age of the cohort was 72 yrs (range 49-89), 34 (28%) pts had ECOG performance status ≥2 and 81 (67%) pts had ELN adverse risk AML. 37 (31%) pts had TP53mut. Pts with TP53mut were more likely to have therapy-related AML (t-AML) in 43% pts compared to 11% in pts with TP53 wild type (TP53WT, p&lt;.001), adverse ELN cytogenetic risk in 92% compared to 27% in pts with TP53WT (p&lt;.001), and less frequently have co-mutations in NPM1mut (3%), RUNX1mut (5%) and ASXL1mut (5%), compared to patients with TP53WT with NPM1mut (32%, p&lt;.001), RUNX1mut (24%, p=.002), and ASXL1mut (24%, p=.002), respectively. 22% of pts with TP53mut had received prior therapy for an antecedent hematological disorder, as compared to 24% in TP53WT (p= .793). Baseline characteristics of the pts is shown in Table 1.
The rate of CR/CRi in the whole cohort was 69% (n=84) with negative measurable residual disease (MRD) by flow cytometry (FCM) in 42% pts (n=51). Pts with TP53mut had a lower rate of CR at 35% compared to 57% in pts with TP53WT (p=.026), lower rate of CR/CRi at 54% vs. 76% in pts with TP53WT (p=.015), and lower rate of MRD negativity by FCM in 19% compared to 52% in TP53WT AML (p=.001, Table 2). The median time to response in TP53mut pts was 1.2 mo (IQR 1.0-1.4) and in TP53WT pts was 1.7 mo (IQR 1.2-2.8) and median number of cycles to response for both groups were 1 cycle (IQR 1-2; p=.259). The 60-day mortality was higher in the TP53mut pts at 27% (n=10/37) compared to 2% in TP53WT pts (n=2/84, p&lt;.001), all due to refractory disease in TP53mut pts. No pts in TP53mut group underwent stem-cell transplantation (SCT) after response compared to 16 (100%) pts in TP53WT group.
Median overall survival (OS) was 5.2 months (mo) in pts with TP53mut compared to 19.4 mo in TP53WT AML (hazard ratio [HR] 4.68, 95% CI 2.50, 8.78, p &lt;.001, Fig. 1). This survival difference of pts with TP53mut compared to wild type was significant after adjustment for other variables including age, gender, ECOG performance status, secondary AML including t-AML and AML history of antecedent hematologic disorder, NPM1mut, RUNX1mutand ASXL1mut, with an adjusted HR 5.41, 95% CI 2.76, 19.61, p&lt;.001. TP53mut pts who achieved CR had a median OS of 9.6 mo compared to CRi pts with median OS of 5.6 mo. Median duration of response (DOR) of CR/CRi in TP53mut AML was shorter compared to TP53WT with median CR/CRi DOR of 3.5 mo vs NR, HR 5.89, 95% CI 2.09, 16.6, p&lt;.001 (Fig. 2). TP53mut pts who achieved CR had a median DOR of 7.0 mo compared to CRi pts with median OS of 2.5 mo (p= .009).
Conclusion: TP53 mut is associated with inferior response with shorter response duration, higher MRD positivity and inferior survival outcomes in pts with AML receiving frontline therapy with VEN and DEC. Novel therapies are needed to overcome TP53-mediated resistance to VEN with hypomethylating agents in AML.

Disclosures
Maiti: Celgene: Research Funding. Kadia:Abbvie: Honoraria, Research Funding; Pulmotec: Research Funding; Celgene: Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; Cyclacel: Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding; Astellas: Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cellenkos: Research Funding. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Macrogenics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Daver:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Research Funding; Fate Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding. Pemmaraju:Blueprint Medicines: Honoraria; Novartis: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Plexxikon: Research Funding; MustangBio: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria; Cellectis: Research Funding; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; Incyte Corporation: Honoraria; Samus Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Roche Diagnostics: Honoraria; Affymetrix: Other: Grant Support, Research Funding; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding. Borthakur:Treadwell Therapeutics: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Jannsen: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy. Bose:Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Blueprint Medicines Corporation: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; NS Pharma: Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Short:Amgen: Honoraria; AstraZeneca: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Alvarado:Daiichi-Sankyo: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; Tolero Pharmaceuticals: Research Funding; FibroGen: Research Funding. Jabbour:Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding. Jain:Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; ADC Therapeutics: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thompson:Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria; AbbVie: Research Funding; Pharmacyclics: Research Funding. Garcia-Manero:Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding; Amphivena Therapeutics: Research Funding; Merck: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Kantarjian:Daiichi-Sankyo: Honoraria, Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Immunogen: Research Funding. DiNardo:MedImmune: Honoraria; Jazz: Honoraria; Novartis: Consultancy; Syros: Honoraria; Calithera: Research Funding; ImmuneOnc: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees. Konopleva:Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Calithera: Research Funding; Cellectis: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AstraZeneca: Research Funding; Eli Lilly: Research Funding; Ablynx: Research Funding; Ascentage: Research Funding; Rafael Pharmaceutical: Research Funding; Kisoji: Consultancy; Sanofi: Research Funding; Forty-Seven: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding.