Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms

Current therapies for high-grade TP53 -mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete r...

Full description

Saved in:

Bibliographic Details
Published in:	Blood cancer journal (New York) Vol. 14; no. 1; pp. 99 - 11
Main Authors:	Kaur, Amandeep, Rojek, Alexandra E., Symes, Emily, Nawas, Mariam T., Patel, Anand A., Patel, Jay L., Sojitra, Payal, Aqil, Barina, Sukhanova, Madina, McNerney, Megan E., Wu, Leo P., Akmatbekov, Aibek, Segal, Jeremy, Tjota, Melissa Y., Gurbuxani, Sandeep, Cheng, Jason X., Yeon, Su-Yeon, Ravisankar, Harini V., Fitzpatrick, Carrie, Lager, Angela, Drazer, Michael W., Saygin, Caner, Wanjari, Pankhuri, Katsonis, Panagiotis, Lichtarge, Olivier, Churpek, Jane E., Ghosh, Sharmila B., Patel, Ami B., Menon, Madhu P., Arber, Daniel A., Wang, Peng, Venkataraman, Girish
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 18-06-2024 Springer Nature B.V Nature Publishing Group
Subjects:	45/23 692/308/575 692/499 692/700/1750/1976 Adult Aged Aged, 80 and over Biomedical and Life Sciences Biomedicine Cancer Research Female Hematology Humans Male Middle Aged Mutation Oncology Prognosis Treatment Outcome Tumor Suppressor Protein p53 - genetics Tumors
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Current therapies for high-grade TP53 -mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53 -mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender ( P = 0.026), ≥2 autosomal monosomies ( P < 0.001), −17/17p ( P = 0.011), multi-hit TP53 allelic state ( P < 0.001) and CUX1 co-alterations ( P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies ( P = 0.004), TP53 VAF > 25% ( P = 0.002), TP53 splice junction mutations ( P = 0.007) and antecedent treated myeloid neoplasm ( P = 0.001). In addition, mutations/deletions in CUX1 , U2AF1 , EZH2 , TET2 , CBL , or KRAS (‘ EPI6 ’ signature) predicted inferior OS24 (HR = 2.0 [1.5–2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals ( N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival ( P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2044-5385 2044-5385
DOI:	10.1038/s41408-024-01077-9