Clinical and Molecular Profiling of AML Patients with Chromosome 7 or 7q Deletions Incontext of TP53 Alterations and Venetoclax Treatment

Background Deletions in chromosome 7 (del(7)) or its long arm (del(7q)) constitute the most common adverse cytogenetic events, seen in approximately 20-30% of newly diagnosed AML and portend worse outcomes (Grimwade et al., 1998). These deletions often co-occur in the context of complex karyotype and TP53 alterations (Rücker et al., 2012). The European Leukemia Network (ELN) 2017 classification in adult AML patients (Döhner et al., 2017) considers AML patients with del7q as an intermediate risk. However, del(7) was classified as adverse risk. Yet, for the purpose of clinical studies and therapeutic decisions, AML with del(7) and del(7q) are often consolidated as one cytogenetic group and able patients are generally recommended to undergo stem cell transplantation in first remission to mitigate the risk of relapse (DiNardo et al., 2020; Kalwinsky et al., 1990). However, in-depth clinical and molecular characterization comparing AML patients with del(7) versus del(7q) have been limited to small patient cohorts (Poiré et al., 2019). We herein aimed at conducting in-depth clinical and molecular characterization of AML patients with del(7) or del(7q) in the context of venetoclax therapy and TP53 mutations.

Methods We retrospectively analyzed 243 treatment-naive patients with AML and del(7) (168/243; 69%) or del(7q) (75/243; 31%) who did not receive any myeloid-directed therapy prior to AML diagnosis. Fifty-one percent of patients had targeted next-generation genomic sequencing, while another 46% had at least one other myeloid-related gene sequenced. The mutation profile yielded 374 mutations in 40 genes, and 169/243 (69.5%) patients had ≥1 mutation (Figure 1). Patients were stratified based on co-occuring TP53 alterations and venetoclax therapy.

Results Patients with del(7q) had similar demographic and molecular profiles compared to patients with del(7). The median OS duration for AML patients with del(7) compared to del(7q) was 7.4 vs 8.4 months respectively (p=0.20) and the median remission duration was 5.3 vs 6.2 months respectively (p=0.16). These data suggest that AML patients with chromosome 7 and 7q have similar clinical features and outcomes.

Since mutations in TP53 were the most common in our AML cohort, we investigated the significance of TP53 alterations on the outcomes of AML patients with del(7) or del(7q). Except for higher rate of complex cytogenetics in AML patients with TP53 alterations (p<0.0001), the clinical and demographic characteristics were similar among patients with del(7) or del(7q) with or without TP53 alterations. However, patients with del(7) or del(7q) who harbored TP53 alterations had significantly worse OS (5.5 vs 10.5 months p < 0.0001) and remission duration (4.7 vs 6.8 months p=0.0035) but not RFS (3.5 vs 3.4 months p=0.16) compared to those with TP53 wildtype. We next investigated the clinical outcomes of patients with del(7) and del(7q) treated with venetoclax-based therapies. A total of 39/243 (16%) of patients received VEN-based therapy as part of their frontline therapy (31/168 (18%) in del(7) versus 8/75 (11%) in del(7q), p= 0.13). Remarkably, AML patients with del(7) who received VEN-based therapy (Rx + Ven) had significantly worst outcomes than patients treated without VEN-based (Rx) regimens with or without TP53 mutation. Specifically, the median OS, RFS and remission duration for del(7) Rx + Ven were the shortest at 5.8 months (p=0.47), 0.1 months (p<0.0001) and 2.2 months (p=0.0015), respectively, compared to the other treatment groups (Figure 2). Among patients with TP53 alterations in del(7) and del(7q) subgroups, the addition of venetoclax did not improve clinical outcomes. The median OS for del(7) TP53-alt Rx vs del(7) TP53-alt Rx+Ven was 5.2 months vs 4.5 months, respectively (p = 0.6). The median OS for del(7q) TP53-alt Rx vs del(7q) TP53-alt Rx+Ven was 6.4 months vs 7.9 months respectively (p = 0.69).

Conclusion We conducted a comprehensive clinical and molecular analysis of AML patients with del(7) and del(7q) revealing differences in relapse-free survival in these patients, but not in OS or remission duration. This suggests that del(7q) should also be considered an adverse event. The co-occurrence of TP53 alterations conferred worse outcomes in del(7) and del(7q) patients, while addition of venetoclax did not improve outcomes. There is an unmet need to identify therapies that would improve outcomes in AML patients with del(7) or del(7q).

Kanagal-Shamanna:Amgen: Consultancy; Novartis: Consultancy; Aptitude Health: Speakers Bureau; Physicians Education Resource: Speakers Bureau. Short:Takeda Oncology: Consultancy, Research Funding; Pfizer: Consultancy; Novartis: Consultancy; Astellas: Research Funding; Stemline Therapeutics: Research Funding; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy. Issa:Novartis, Kura Oncology, Nuprobe: Consultancy; Celgene, Kura Oncology, Syndax, Merck, Cullinan and Novartis: Research Funding. Yilmaz:Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Jabbour:AbbVie: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Pfizer: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; Takeda: Other: Advisory Role, Research Funding. Borthakur:Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy. Garcia-Manero:Astex: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Aprea: Honoraria; BMS: Consultancy, Honoraria, Research Funding; Curis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Gilead Sciences: Research Funding; Acceleron Pharma: Consultancy. Andreeff:Medicxi: Consultancy; Daiichi-Sankyo Inc.: Consultancy, Research Funding; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pinot Bio: Research Funding; Oxford Biomedical UK: Research Funding; Glycomimetics: Consultancy; Brooklyn ITX: Research Funding; Oncolyze: Current holder of stock options in a privately-held company; Reata: Current holder of stock options in a privately-held company; Chimerix: Current holder of stock options in a privately-held company; AstraZeneca: Research Funding; Syndax: Consultancy, Research Funding; Breast Cancer Research Foundation: Research Funding; Senti Bio: Consultancy, Research Funding; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; Kintor Pharmaceutical: Research Funding. Daver:Novartis: Consultancy; Jazz: Consultancy; Amgen: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Arog: Consultancy; Glycometrics: Research Funding; Novimmune: Research Funding; Hanmi: Consultancy, Research Funding; Trovagene: Research Funding; FATE Therapeutics: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Consultancy; Syndax: Consultancy; Shattuck: Consultancy; Agios: Consultancy. Kadia:Iterion: Research Funding; Novartis: Consultancy; Delta-Fly: Research Funding; PinotBio: Consultancy; JAZZ: Consultancy, Research Funding; Astex: Honoraria; Glycomimetics: Research Funding; Genentech: Consultancy, Research Funding; cyclacel: Research Funding; Genfleet: Research Funding; Ascentage: Research Funding; cellenkos: Research Funding; Astellas: Research Funding; AstraZeneca: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Servier: Consultancy; BMS: Consultancy, Research Funding; Amgen: Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding. Konopleva:AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji; Janssen: Consultancy; AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, Astra Zeneca; Rafael Pharmaceutical; Sanofi, Forty-Seven: Research Funding; Stemline Therapeutics, F. Hoffman La-Roche; Janssen: Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals, Novartis and Eli Lilly: Patents & Royalties; Stocks, Reata Pharmaceuticals: Current equity holder in publicly-traded company; Forty-Seven; F. Hoffman LaRoche: Honoraria. DiNardo:GenMab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Astellas: Honoraria; Bluebird Bio: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; LOXO: Research Funding; Novartis: Honoraria; Takeda: Honoraria; Astex: Research Funding; Cleave: Research Funding; Forma: Research Funding; Gilead: Honoraria; Jazz: Honoraria. Ravandi:Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomea Fusion, Inc.: Research Funding; AstraZeneca: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Novartis: Consultancy; Syos: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Prelude: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding.