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. 2023 Jul 11;7(13):3169-3179.
doi: 10.1182/bloodadvances.2022009040.

Differential prognosis of single and multiple TP53 abnormalities in high-count MBL and untreated CLL

Rosalie Griffin  1 , Julia E Wiedmeier-Nutor  2 , Sameer A Parikh  3 , Chantal E McCabe  4 , Daniel R O'Brien  4 , Nicholas J Boddicker  1 , Geffen Kleinstern  1   5 , Kari G Rabe  4 , Laura Bruins  2 , Sochilt Brown  2 , Cecilia Bonolo de Campos  2 , Wei Ding  3 , Jose F Leis  2 , Paul J Hampel  3 , Timothy G Call  3 , Daniel L Van Dyke  3   6 , Neil E Kay  3 , James R Cerhan  7 , Huihuang Yan  1 , Susan L Slager  1   3 , Esteban Braggio  2
Affiliations

Differential prognosis of single and multiple TP53 abnormalities in high-count MBL and untreated CLL

Rosalie Griffin et al. Blood Adv. .

Abstract

TP53 aberrations, including mutations and deletion of 17p13, are important adverse prognostic markers in chronic lymphocytic leukemia (CLL) but are less studied in high count monoclonal B-cell lymphocytosis (HCMBL), an asymptomatic pre-malignant stage of CLL. Here we estimated the prevalence and impact of TP53 aberrations in 1,230 newly diagnosed treatment-naïve individuals (849 CLL, 381 HCMBL). We defined TP53 state as: wild-type (no TP53 mutations and normal 17p), single-hit (del(17p) or one TP53 mutation), or multi-hit (TP53 mutation and del(17p), TP53 mutation and loss of heterozygosity, or multiple TP53 mutations). Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time to first treatment and overall survival by TP53 state. We found 64 (7.5%) CLL patients and 17 (4.5%) HCMBL individuals had TP53 mutations with variant allele fraction >10%. Del(17p) was present in 58 (6.8%) of CLL and 11 (2.9%) of HCMBL cases. Most individuals had wild-type (N=1,128, 91.7%) TP53 state, followed by multi-hit (N=55, 4.5%) and then single-hit (N=47, 3.8%) TP53 state. The risk of shorter time to therapy and death increased with the number of TP53 abnormalities. Compared to wild-type patients, multi-hit patients had 3-fold and single-hit patients had 1.5-fold increased risk of requiring therapy. Multi-hit patients also had 2.9-fold increased risk of death compared to wild-type. These results remained stable after accounting for other known poor prognostic factors. Both TP53 mutations and del(17p) may provide important prognostic information for HCMBL and CLL that would be missed if only one were measured.

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Conflict of interest statement

Conflict-of-interest disclosure: N.E.K. serves on the advisory board for AbbVie, AstraZeneca, Beigene, Behring, Boehringer Ingelheim Pharmaceuticals Inc, Cytomx Therapy, Dava Oncology, Janssen, Juno Therapeutics, Oncotracker, Pharmacyclics, and Targeted Oncology; serves on the data safety monitoring committee for Agios Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Celgene, CytomX Therapeutics, Dren Bio, Janssen, MorphoSys, and Rigel; and has received research funding from AbbVie, Acerta Pharma, Bristol Myers Squibb, Celgene, Genentech, MEI Pharma, Pharmacyclics, Sunesis, TG Therapeutics, and Tolero Pharmaceuticals. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
TP53 mutations and del(17p) based on CLL and HCMBL. Note that only TP53 mutations with VAF >10% were considered. Rate of mutations and del(17p) in CLL (A) and HCMBL (B) cases. Gold indicates single-hit (∗ denotes multihit based on cnLOH), and blue indicates multihit TP53. (C) VAF of TP53 mutations. Box plot (quartiles and median shown) and violin plots show distribution. (D) Percent of cells with del(17p) by FISH. (E) Location, type, and counts of TP53 mutations. Num, number.
Figure 2.
Figure 2.
Kaplan-Meier curves and Cox regression forest plots. Based on TP53 normal, single-hit, and multihit state for TTFT (A-B) and OS (C-D). Note that only TP53 mutations with VAF >10% were considered.
Figure 3.
Figure 3.
Multivariate Cox regression. (A) TTFT and (B) OS. Note that only TP53 mutations with VAF >10% were considered.
See this image and copyright information in PMC

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