1122 - Treatment Patterns and Outcomes of Patients with TP53-Mutated Chronic Lymphocytic Leukemia

Background: TP53 alterations are associated with inferior outcomes in chronic lymphocytic leukemia (CLL). However, the heterogeneity of TP53 alterations and the impact of single-hit vs multi-hit TP53 alterations on treatment outcomes are understudied. We present a descriptive analysis of outcomes of CLL patients with TP53 alterations treated at Mayo Clinic, including mutation profiles and the potential impact of single-hit versus multi-hit TP53 alterations.

Methods: Patients with CLL and TP53 mutation(s) detected by Sanger sequencing between June 2014 and April 2021 were identified. Patient demographics, clinical/pathologic characteristics, treatment, and follow-up data were abstracted from the Mayo Clinic CLL database and by chart review. We defined multi-hit TP53 status as presence of multiple TP53 mutations or both TP53 mutation(s) and del17p. Event-free survival (EFS) and overall survival (OS) were calculated from start of treatment after TP53 sequencing.

Results: A total of 145 patients with TP53 mutation(s) were identified (70% male). At time of TP53 mutation testing, median age was 69 years (range: 44-92), 39% of patients had Rai stage III-IV, 77% had unmutated IGHV, 53% had del17p, and 62% had ≥3 cytogenetic abnormalities.

A TP53 mutation was identified prior to CLL treatment in 63 patients (Group 1) and after at least one prior line of treatment in 82 patients (Group 2). Del17p by FISH was present at time of TP53 mutation identification in 54% of patients in Group 1 and 52% in Group 2. We identified a total of 170 TP53 mutations in 145 patients (74 in untreated, 54 in those who had previously received a novel agent, and 42 in those who had previously received chemoimmunotherapy [CIT] only) (Figure 1A). Of the 170 mutations, 102 (60%) were identified only once, suggesting that most of the mutations were unique to each patient. Overall, 55 patients had single-hit TP53 disruption and 90 had multi-hit TP53 disruption. Collectively, patients with single-hit and multi-hit TP53 disruption had a median EFS of 26.4 (95% CI 8.4-NE) and 26.3 months (95% CI 16.6-NE, p=0.76), respectively, and a median OS of NE (95% CI 40.3-NE) and 61.8 months (95% CI 47.1-NE, p=0.87), respectively.

In Group 1 (n=63), 46 patients had initiated first-line treatment (39 BTKi-based, 3 BCL2i±BTKi-based, 4 CIT). The median time from TP53 testing to treatment initiation was 1.2 months (95% CI 0.2-34.3). The median EFS following treatment initiation was 53.7 months (95% CI 29.9-NE), and the median OS was not reached (median follow-up 26 months after treatment initiation). Patients with single-hit (n=18) and multi-hit (n=28) TP53 alterations had a median EFS of 29.9 months (95% CI 20.2-NE) and 53.7 months (95% CI 31.1-NE, p=0.46), respectively (Figure 1B).

In Group 2 (n=82), the median number of prior lines of therapy was 2 (range 1-16). Prior treatment exposure included novel agent therapy (n=44, 54%) and CIT only (n=38, 46%). The median time from TP53 mutation detection to subsequent treatment initiation was 1.2 months (95% CI 0.0-44.5) among the 56 patients who were treated.

For 38 patients previously treated with CIT only, 28 had initiated subsequent treatment. The median EFS and OS from subsequent treatment initiation was 26.3 months (95% CI 13.5-NE) and 40.6 months (95% CI 27.5-NE), respectively. Patients with single-hit (n=11) and multi-hit (n=17) TP53 alterations had a median EFS of 29.8 months (95% CI 5.4-NE) and 26.3 months (95% CI 16.1-NE, p=0.69), respectively (Figure 1B), and a median OS of 40.3 months (95% CI 29.8-NE) and 53.7 months (95% CI 25.6-NE, p=0.52), respectively (Figure 1C).

For 44 patients previously treated with BTKi, 28 had initiated subsequent treatment. The median EFS and OS from subsequent treatment initiation was 4.6 months (95% CI 2.9-23.7) and 46.0 months (95% CI 13.2-NE), respectively. Patients with single-hit (n=9) and multi-hit (n=19) TP53 alterations had a median EFS of 8.4 months (95% CI 4.2-NE) and 4.6 months (95% CI 2.7-NE, p=0.76), respectively (Figure 1B), and a median OS of NE (95% CI 8.4-NE) and 46.0 months (95% CI 13.1-NE, p=0.81), respectively (Figure 1C).

Conclusions: Specific sites of TP53 mutations in our cohort were heterogeneous without clear differences in patients with or without prior treatment. Treatment outcomes did not differ significantly between patients with single-hit versus multi-hit TP53 alterations stratified by prior treatment status.