Distinct Prognostic Effects of TP53 Mutations in Newly Diagnosed Versus Relapsed/Refractory (R-R) Patients (pts) with B-Acute Lymphoblastic Leukemia (ALL) Treated with Mini-Hcvd-Inotuzumab Ozogamicin with or without Blinatumomab Regimens
Authors: Kanagal-Shamanna Rashmi , Kantarjian Hagop M. , Khoury Joseph D. , Takahashi Koichi , Montalban-Bravo Guillermo , Short Nicholas J. , Yin C. Cameron , Patel Keyur , Loghavi Sanam , Ravandi Farhad , Konopleva Marina , Jain Nitin , Garcia-Manero Guillermo , Daver Naval , Kadia Tapan M. , DiNardo Courtney D. , O'Brien Susan M. , Luthra Rajyalakshmi , Jabbour Elias 
Published: November 2020

Introduction
B-ALL with TP53 mutations (TP53MT) at diagnosis is associated with older age and frequent low-hypodiploid karyotype. We have previously shown that hyper-CVAD-based regimens negate the poor prognostic impact of TP53MT. However, the prognostic effect of TP53MT in B-ALL treated with mini-HCVD-inotuzumab with or without blinatumomab in the frontline and R-R settings have not been explored.
Methods
Older (≥60 yrs) pts with newly-diagnosed ALL and adults (≥18 yrs) with R-R ALL treated with mini-HCVD-inotuzumab ozogamicin with/without blinatumomab underwent testing for TP53MT. We compared the clinico-pathologic & outcome differences between TP53MT and TP53wt cases in both settings. Germline origin was inferred based on persistence of TP53MT at high variant allele frequency (VAF) during remission. Multiallelic (&gt;1) TP53 alteration was defined as a concurrent second TP53MT or deletion (TP53del).
Results
Of the 48 pts with newly diagnosed B-ALL, 19 (40%) pts had TP53MT at diagnosis; in 2 of 14 (14%), TP53MT was of germline origin. All pts were Philadelphia chromosome (Ph) negative; 1 pt had CRLF2 rearrangement (Ph-like immunophenotype); none had KMT2A rearrangement (KMT2Ar). Fifteen (83%) pts had 1 TP53MT, 2 had 2 mutations, and one pt had 3 mutations. The majority were missense (15, 83%), the rest included non-sense, frame-shift, and splice site mutation in 1 patient, each. The median TP53MT VAF was 46% (range, 4-80). Nine (56%) had multiallelic TP53 alteration, with 6 (38%) showing TP53del. Compared with TP53 wild-type (TP53wt), TP53MT had a higher frequency of low-hypodiploidy (40% vs. 8%, p=0.04), lower median platelet counts (34 vs. 55, p=0.02), and a trend for older age (median 71 vs. 68, p=0.09). There was no difference in morphologic response rates (89% vs. 100%; p=0.11) and minimal residual disease negativity [MRD neg] rates (94% vs. 75%; p=0.13) between mutated and wild type groups. Over a median follow-up (f/u) of 46 months, 21 (44%) patients died [9 (50%) mutated vs. 12 (44%) wild type]. There was no significant difference in the overall survival (median OS, 33 vs. 38 months, p=0.28; Fig 1A); the 3-year survival rates were 45% and 63% in TP53MT and TP53wt, respectively.
Of the 47 pts with R-R B-ALL, 16 (34%) had TP53MT. Three (3/12, 25%) had germline TP53MT. All were Ph-negative, and 1 patient was Ph-like ALL. All 16 patients had a single TP53MT; 9 (56%) had multiallelic TP53 alteration due to concurrent TP53del. Majority were missense (12, 75%), the rest included 2 non-sense, 1 frame-shift and 1 in-frame duplication. The median TP53MT VAF was 33% (range, 1-78). Except for a higher frequency of low-hypodiploidy (30% vs. 0%, p=0.01), no other significant clinico-pathologic differences were noted between the TP53MT and TP53wt groups. Pts with TP53MT had a higher morphologic response rate (100% vs. 67%, p=0.02) with no difference in MRD neg rates (78% vs. 85%, p=0.65). Over a median f/u of 33 months, 15 TP53MT pts (94%) died compared to 14 TP53wt pts (45%; p=0.001). Pts with TP53MT had significantly shorter median survival (5 months vs not reached, p=0.0003; Fig 1B); the 3-year survival rates were 0% and 52% in TP53MT and TP53wt, respectively.
Despite significant differences in outcome of TP53MT at diagnosis vs. relapse, there were no notable differences in TP53MT characteristics, except for enrichment of KMT2Ar in R-R (0% vs. 31%; p=0.04). We retrospectively reviewed the cytogenomic features at the time of diagnosis of 7 R-R B-ALL with TP53MT (non-germline). None had TP53delat diagnosis. TP53 NGS profiling at diagnosis on one KMT2Arpt was negative for TP53MT (1% sensitivity) and TP53del (Fig 1C). These findings suggest that TP53MT/TP53delclones (undetectable at diagnosis) expanded following chemotherapy and relapsed with cytogenetic evolution. TP53MT clones that survived the chemotherapy insult were inherently more aggressive than treatment naïve clones at diagnosis, and may explain the observed differences in outcome.
Conclusions
TP53MT is seen in up to 40% of B-ALL at diagnosis and ~35% at relapse, and are associated with low-hypodiploid karyotype. B-ALL with TP53MT at diagnosis shows no significant difference in OS compared to TP53wt in patients treated with frontline mini-HCVD-inotuzumab with or without blinatumomab regimen. In contrast, TP53MT confers a poor prognosis in pts with R-R disease. Sequencing studies on additional R/R TP53MT patients at diagnosis are underway.
Figure 1

Disclosures
Kantarjian: Pfizer: Honoraria, Research Funding; Astex: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Daiichi-Sankyo: Research Funding. Short:Astellas: Research Funding; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Amgen: Honoraria. Ravandi:Xencor: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Konopleva:Sanofi: Research Funding; Kisoji: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Cellectis: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Rafael Pharmaceutical: 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; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Agios: Research Funding; Ablynx: Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; Eli Lilly: Research Funding. Jain:Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Incyte: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: 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; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Cellectis: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; Merck: Research Funding; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; AbbVie: Honoraria, Research Funding. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, 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; 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; Trovagene: Research Funding; Fate Therapeutics: 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. Kadia:Genentech: Honoraria, Research Funding; Incyte: Research Funding; Novartis: Honoraria; Celgene: Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; Ascentage: Research Funding; Cellenkos: Research Funding; Astra Zeneca: Research Funding; Astellas: Research Funding; Cyclacel: Research Funding; Pulmotec: Research Funding. DiNardo:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Calithera: Research Funding; Jazz: Honoraria; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria. O'Brien:Kite, Regeneron, Acerta: Research Funding; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy. Jabbour:Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding.