Predictors for Time-to-First-Treatment in Patients with Del(17p) and/or TP53-Mutated Chronic Lymphocytic Leukemia

Introduction

Most patients (pts) with chronic lymphocytic leukemia (CLL) are initially recommended a ‘watch and wait’ approach until they meet iwCLL criteria for treatment initiation. Several prognostic models (CLL-IPI, IPS-E, CLL1-PM) were developed to help predict time-to-first treatment (TTFT) among pts with newly diagnosed CLL. TP53 abnormalities (deletion (del)17p and/or mutations (m) in TP53) are an independent high-risk prognostic factor in pts with CLL and are often associated with shorter TTFT. However, within this high-risk population, there remains significant variability in TTFT. Our study aims to identify independent predictors of TTFT within the cohort of newly diagnosed pts with CLL with either del(17p) and/or TP53-m.

Methods

We included previously untreated pts with CLL or small lymphocytic lymphoma (SLL) who presented to MD Anderson Cancer Center between 01/2010 and 12/2020 with evidence of either del(17p) on FISH and/or TP53-m on NGS prior to the first treatment. Pt and disease characteristics within three months of diagnosis were collected. Results of next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) nearest to the date of diagnosis were collected. Kaplan-Meier method was used to calculate TTFT, defined as time from the date of diagnosis to the date of first treatment initiation or last follow up. Backward multivariable binary regression was performed to predict TTFT.

Results

A total of 231 pts were identified for these retrospective analyses. Of these, 192 (83%) pts had both NGS and FISH results available; 96/192 pts (50%) had both TP53-m and del(17p), 83/192 (43.2%) had only TP53-m, and 13/192 (6.8%) had only del(17p). Of the remaining 39 pts, 5 had TP53-m without FISH testing and 34 had del(17p) without NGS testing performed. NGS and FISH testing were done at a median time of 11 and 3.4 months (mo) from diagnosis, respectively. The median age of the entire cohort at diagnosis was 63 years. Among the pts with available IGHV mutation data (n=203), 140 (69%) and 63 (31%) had unmutated and mutated IGHV, respectively. FISH results were available for 226/231 (98%) pts; 143 (63%) had del(17p), 129 (57%) had del(13q), 30 (13%) had trisomy 12 and 30 (13%) had del(11q). The median follow-up was 105 mo (95% CI 0.3-218.1). A total of 165/231 (71.4%) pts required treatment with a median TTFT of 34.7 mo (95% CI 24.4-47.4). The median TTFT was significantly shorter in pts with the following characteristics: unmutated (n=140) versus mutated IGHV (n=63),18 vs. 113 mo (p<0.001); presence of del(11q) (n=30) versus absence of del(11q) (n=196),13 vs. 40 (p<0.005); presence of trisomy 12 (n=30) versus absence of trisomy 12 (n=196), 24 vs. 40 mo (p<0,005); presence of del(17p) (n=143) versus absence of del(17p) (n=83), 22 vs. 76 mo (p<0.001). The median TTFT was not affected by the presence (n=184) or absence of TP53-m (36 vs. 44 mo, p=0.216). However, only 13 pts were TP53 wild-type. Among pts with TP53-m, the presence of del(17p) (n=96 vs. 83) led to a significantly shorter TTFT (22 vs. 44 mo, p<0.001). In the multivariable analysis, independent factors associated with shorter TTFT were: elevated absolute lymphocyte count (ALC, HR-1.003, 95% CI 1.001-1.005, p=0.010); unmutated IGHV (HR-2.632, 95% CI 1.778-3.896, p<0.001); presence of del(17p) (HR-1.850, 95% CI 1.319-2.594, p<0.001), del (11q) (HR-1.972, 95% CI 1.256-3.096, p=0.003), trisomy 12 (HR-1.914, 95% CI 1.266-2.893, p=0.002).

Conclusions

The results of our study showed that among pts with CLL/SLL with del(17p) and/or TP53-m, presence of any of the following factors: elevated ALC, unmutated IGHV, del(17p), del(11q), trisomy 12 was independently associated with shorter TTFT. Predictors of TTFT are important for informing prognostication and management and may help identify pts within the del(17p)/TP53-m group who might benefit from early intervention strategies. Additional analyses including percentage FISH positivity for del(17p) and VAF for TP53-m are ongoing and will be presented at the annual meeting.

Swaminathan:Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sasaki:Daiichi-Sankyo: Consultancy; Pfizer: Consultancy; Enliven: Research Funding; Otsuka: Other: Lecture fees; Chugai: Other: Lecture fees; Novartis: Consultancy, Research Funding. Burger:Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; BeiGene: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Novartis: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; AstraZeneca: Research Funding. Ferrajoli:BeiGene: Membership on an entity's Board of Directors or advisory committees. Wierda:Kite: Research Funding; Numab Therapeutics: Research Funding; Gilead Sciences: Research Funding; Cyclacel Pharmaceuticals Inc: Research Funding; Juno Therapeutics: Research Funding; Eli Lilly: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; National Comprehensive Care Center (NCCN): Other: Financial relationship (Chair, CLL); Novartis: Research Funding; Oncternal Therapeutics: Research Funding; Accutar Biotechnology: Research Funding; Loxo Oncology: Research Funding; Oncternal Therapeutics: Research Funding; Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta Pharma: Research Funding; F. Hoffmann-La Roche Ltd.: Research Funding; GSK: Research Funding; Genentech, Inc.: Research Funding; Nurix Therapeutics: Research Funding; AbbVie: Research Funding. Jain:MEI Pharma: Consultancy, Honoraria, Other: Travel Support; Loxo Oncology: Research Funding; Servier: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; ADC Therapeutics: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; MingSight: Honoraria, Research Funding; Medisix: Research Funding; Ipsen: Consultancy, Honoraria, Other: Travel Support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; CareDx: Consultancy, Honoraria, Other: Travel Support; Pfizer: Research Funding; NovalGen: Research Funding; Newave: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Incyte: Research Funding; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Dialectic Therapeutics: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; TransThera Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Support; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding.