Outcome of TP53-mutated CCUS and the risk of progression to myeloid neoplasms.

person Syed Naseem Shah Mayo Clinic, Rochester, MN info_outline Syed Naseem Shah, Marissa Li, Anmol Baranwal, Dong Chen, Rong He, Hassan B. Alkhateeb, Ayalew Tefferi, Abhishek A Mangaonkar, Aref Al-Kali, Mrinal S Patnaik, Mithun Vinod Shah

Authors person Syed Naseem Shah Mayo Clinic, Rochester, MN info_outline Syed Naseem Shah, Marissa Li, Anmol Baranwal, Dong Chen, Rong He, Hassan B. Alkhateeb, Ayalew Tefferi, Abhishek A Mangaonkar, Aref Al-Kali, Mrinal S Patnaik, Mithun Vinod Shah Organizations Mayo Clinic, Rochester, MN, Division of Hematology, Mayo Clinic, Rochester, MN Abstract Disclosures Research Funding No funding received None. Background: TP53 -mutated ( TP53 mut ) myeloid neoplasms (MN) are aggressive leukemia with poor survival. A subset of TP53 mut MN is preceded by TP53 mut CCUS that is conventionally considered to be high-risk premalignant condition, though evidence supporting the notion is lacking. We studied outcomes of TP53 mut CCUS compared to TP53 wild-type ( TP53 wt ) CCUS. Methods: Mayo Clinic Molecular Hematology Database (N=7593) was queried to identify patients (pts) harboring pathogenic variant(s) in exons 4-11 of the TP53 gene with ≥2% variance allele frequency (VAF). CCUS was defined using the 5 th edition of the WHO Classification for MN. Results: Of 457 pts with TP53 mut , 29 (5.9%) had TP53 mut CCUS. The median age at diagnosis was 67 years, 17 (59%) were female, and 20 (69%) had received cytotoxic therapies. One and ≥2 TP53 mut were seen in 26 (89.6%) and 3 (10.3%) pts, respectively. Median TP53 mut VAF was 9% (range 3-42), 3 had TP53 mut VAF ≥20%, and 4 (14%) had non-MDS defining cytogenetic anomalies. Of 16 pts with available follow up evaluation (median interval 22 months, Table), 3 (10.3%) progressed to TP53 mut MN at 5, 13, and 14 months from diagnosis. We next compared outcomes of TP53 mut CCUS to TP53 wt CCUS (n=138). The proportion of pts developing MN was not different between TP53 wt and TP53 mut CCUS (18.1 vs 10.3%, P = .42). Progression free survival of TP53 mut CCUS was comparable to TP53 wt CCUS at 1- (77 vs 83%), 2- (67 vs 67%), and 5-years (67 vs 59%, P =.9). Similarly, overall survival of TP53 mut vs TP53 wt CCUS at 1- (81 vs 89%), 2- (76 vs 76%), and 5-years (76 vs 67%) was comparable ( P = .94). Conclusions: In contrast to the prevalent notion, TP53 mut was not associated with a higher risk of MN progression or mortality compared to TP53 wt CCUS. Majority of TP53 mut clones showed remarkable stability over years. Pathologic characteristics of TP53 mut CCUS patients at baseline and last follow-up. Age/Sex Baseline Last Follow-up Interval (mo.) Cytogenetics NGS (% VAF) Phenotype Cytogenetics NGS (% VAF) 72F 46, XX TP53 (6) t-MDS 45, XX, add (5) (q11.2), -7 TP53 (82) 14 73M 46, XY PHF6 (12), TP53 (7) t-MDS 46, XY 13 61F 46, XX TP53 (7.5), TP53 (5.5) t-MDS 46, XY,del(7)(q22)/47,idem,+21 5 65F 46, XX TP53 (42), IDH1 (38), SRSF2 (43) CCUS 46, XX 24 65M 46, XY TP53 CCUS 46, XY 56 52F 46, XX TP53 (10) CCUS 46, XX TP53 (8) 22 71M 46, XY TP53 (6), DNMT3A (7), JAK2 ( 10) CCUS 46, XY TP53 (11), DNMT3 (15), JAK2 (6) 51 67M 45, X,Y,t(1;15)(q23;q15) TP53 (9) CCUS 45, X, -Y,t(1;15)(q23;q15) 22 71M 46, XY TP53 (9) CCUS 14 40F 46, XX TP53 (13) CCUS 46, XX TP53 (16) 72 58F 46, XX TP53 (19), TET2 (17) CCUS 46, XX TP53 (24), TET2 (21) 47 84F 46, XX TP53 (37) CCUS 46, XX,del(13)(q12q14) TP53 (5) 18 65F 45, X, -X TP53 (7) CCUS 45, X, -X TP53 (7) 30 16F 46, XX TP53 (5) CCUS 46, XX TP53 (5), TP53 (16) 19 52F 46, XX TP53 (7) CCUS 46, XX 43 60F 46, XX TP53 (6), TET2 (6) CCUS 46, XX 4 CCUS: clonal cytopenia of undetermined significance, NGS: next-generation sequencing, F: female, M: male, t-MDS: therapy-related myelodysplastic syndrome.