Treatment Patterns and Outcomes of Patients with Chronic Lymphocytic Leukemia with TP53 Mutations

Background: Aberration of the TP53 gene in chronic lymphocytic leukemia (CLL) is a well-established marker of poor prognosis and a predictor of chemorefractory disease. Identification of a TP53 gene mutation is clinically useful in determining which patients may benefit from small-molecule inhibitors such as Bruton tyrosine kinase (BTKi) and BCL2 inhibitors (BCL2i). However, the treatment patterns in routine practice and outcomes of patients harboring TP53 mutations in CLL is not well reported. We present a descriptive analysis of CLL patients treated at Mayo Clinic with TP53 mutations including their demographics, treatment patterns, and outcomes.

Methods: Patients with CLL who had a TP53 mutation detected by Sanger sequencing between June 2014 and April 2021 at Mayo Clinic Rochester were identified from a hematopathology database. Patient demographics, clinical and pathologic characteristics, treatment, and follow-up information were abstracted from the Mayo Clinic CLL database and by chart review. Date of TP53 mutation test was baseline. Discrete variables were compared using Chi-square or Fisher's exact tests; continuous variables were compared using Kruskal-Wallis test. Overall survival (OS) was calculated from date of TP53 mutation test until date of death from any cause or last known date alive. Rates of Richter transformation (RT) by prior treatment exposure were estimated by cumulative incidence accounting for competing risk of death.

Results: A total of 145 patients were identified; 70% were male, and the median age at diagnosis was 59 years (range: 36-92). At diagnosis, 15% of patients had Rai stage III-IV, 77% had unmutated IGHV, 38% had del17p, 92% had high or very high CLL-IPI, and 62% had ≥3 cytogenetic abnormalities (Table 1).

A TP53 gene mutation was identified prior to any CLL treatment in 63 patients (43%, Group 1) and after at least one prior line of treatment in 82 patients (57%, Group 2). The median time from CLL diagnosis to the first detected TP53 mutation was 3 months in Group 1 and 96 months in Group 2. There was significant heterogeneity in types of TP53 mutations with the majority of variants (n=102) being unique to an individual.

At the time of TP53 mutation detection, Group 2 patients more frequently had advanced Rai stage and unmutated IGHV status (Table 1). Del17p by FISH was present prior to or at time of TP53 mutation identification (+/- 3 months) in 54% of patients in Group 1 and 52% in Group 2.

Group 1 had a median follow-up of 26 months (from TP53 mutation detection date); 46/63 patients had initiated a first-line (1L) treatment (39 BTKi-based, 1 BCL2i-based, 2 BTKi+BCL2i-based, 4 chemoimmunotherapy [CIT]).

In Group 2, the median number of prior lines of therapy was 2 (range 1-16). Prior treatment exposure included 38 (46%) CIT only, 41 (50%) BTKi-based ± CIT, and 3 (4%) BTKi-based + BCL2i-based ± CIT. Median follow-up was 21 months; 56/82 patients had initiated a new line of therapy (subsequent 1L). For 38 patients with prior CIT only exposure, 28 had subsequent 1L including 21 BTKi-based, 2 BCL2i-based, and 5 CIT. For 44 patients with prior BTKi exposure, 28 had subsequent 1L including 5 BTKi-based, 5 BCL2i-based, 9 BTKi+BCL2i-based, and 9 CIT.

The median OS was not reached in Group 1 and was 40.6 months (95% CI 30.1-NE) in Group 2 (HR=0.21, 95% CI=0.10-0.45) (Figure 1). In Group 2, the median OS for patients with prior CIT only exposure was 55.5 (95% CI 30.1-NE) months and for patients with prior BTKi exposure was 33.3 (95% CI 14.7-NE) months (HR=0.59, 95% CI=0.31-1.12) (Figure 1). Three patients in Group 1 and 13 patients in Group 2 (3 prior CIT only, 10 prior BTKi) developed RT during the follow-up period; the cumulative incidence rates of RT at 2- and 5-year were 1.7% and 4.6%, respectively, in Group 1, and 10.8% and 21.0%, respectively, in Group 2.

Conclusions: Regardless of prior treatment exposure, enrichment for high-risk features was present at time of TP53 mutation detection. Majority of patients were treated with novel agents after known TP53 mutations. OS after TP53 mutation was inferior in patients who had been previously treated, particularly those who had BTKi exposure already prior to TP53 mutation detection, compared to previously untreated patients. Future studies are needed to understand the characteristics of clonal evolution before and after treatment and the clinical impact of specific TP53 mutations.

Wang:Eli Lilly and Company: Membership on an entity's Board of Directors or advisory committees; Genmab: Research Funding; MorphoSys: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Loxo@Lilly: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. He:Kura Oncology, Inc: Consultancy. Kenderian:Morphosys: Research Funding; LEAH Labs: Current holder of stock options in a privately-held company, Research Funding; Tolero: Research Funding; Lentigen: Research Funding; Viracta/Sunesis: Research Funding; Life Engine: Current holder of stock options in a privately-held company; Humanigen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: CART cell therapy , Research Funding, Speakers Bureau; MustangBio: Patents & Royalties; Mettaforge: Patents & Royalties; Juno/BMS: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Patents & Royalties: CART cell therapy , Research Funding, Speakers Bureau. Muchtar:Protego: Consultancy; Janssen: Honoraria. Kay:Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; BMS: Other: Data Safety Monitoring Committee, Research Funding; Dren Bio: Other: Data Safety Monitoring Committee; Morpho-sys: Other: Data Safety Monitoring Committee; Rigel: Other: Data Safety Monitoring Committee; Celgene: Other: Data Safety Monitoring Committee, Research Funding; Genentech: Research Funding; MEI Pharma: Research Funding; Sunesis: Research Funding; Cytomx Therapy: Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee; Behring: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Tolero Pharmaceuticals: Research Funding. Parikh:Phamacyclics: Consultancy, Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Janssen: Research Funding; Merck: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Ascentage Pharma: Research Funding; Adaptive Biotehcnologies: Consultancy; Genetech: Consultancy; GlaxoSmithKline: Consultancy. Ding:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; AbbVie: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; MEI pharama: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees.