Complex Karyotype, but Not Isolated TP53 mutation, Predicts Overall Survival in Chronic Lymphocytic Leukemia Patients in the Era of Targeted Therapy

Background: Despite being incurable, chronic lymphocytic leukemia (CLL) survival rates have improved since the introduction of targeted therapy. Prognostic models from the chemoimmunotherapy (CIT) era may not apply for patients (pts) diagnosed within the last decade. This study aims to evaluate overall survival (OS) and the impact of prognostic factors in CLL pts over the past 10 years.

Methods: We conducted a retrospective analysis of the DFCI CLL Database. OS was measured from the diagnosis of CLL or small lymphocytic lymphoma to death from all causes. Kaplan-Meier curves estimated OS probability, with subgroup analyses using the log-rank test. Cox proportional hazards models were used to assess the impact of prognostic factors on OS.

Results: Of 3,528 pts in the database, 1,339 CLL pts who were diagnosed between 2013 and 2023 and had prognostic markers assessed before treatment were included in this study. The median age at diagnosis was 62.7 years (range 23-92), 60% were male, and 29% were CLL-IPI high or very-high risk. 598 (44.7%) pts received CLL treatment, with 77% receiving front-line targeted therapy (BTK inhibitor, BCL2 inhibitor, and/or PI3K inhibitor), including 68 pts who were treated with targeted therapy combined with CIT.

With a median follow-up of 58 months, the 5-year OS rate was 94.3%. Leading causes of death were infections (24 pts, including 5 from COVID-19 infection), second cancer (23 pts, including 4 from therapy-related myeloid neoplasm), disease progression (18 pts) and cardiovascular disease (9 pts).

Pts stratified by CLL-IPI showed 5-year OS rates of 98.7%, 95.2%, 90%, and 87.6% for low, intermediate, high, and very-high risk groups, respectively. No difference was found between low and intermediate risk (p=0.43), but high and very-high risk pts had higher mortality (p<0.001 for both low vs. high and low vs. very-high, p=0.002 for intermediate vs. high, p<0.001 for intermediate vs. very-high risk). In pts treated with first-line targeted therapy, 5-year OS rates of CLL-IPI groups were 96.3% (low), 98.9% (intermediate), 92.2% (high), and 87.8% (very-high), with significant differences between low vs. very-high (p=0.01), and intermediate vs. high (p=0.002) or very-high risk (p<0.001).

In a univariate analysis of the overall dataset, all CLL-IPI factors were associated with OS, including age>65 years (p<0.001), Rai stage I-IV (p=0.03), beta-2 microglobulin (B2M)>3.5mg/dL (p<0.001), unmutated IGHV (p=0.001), and TP53 aberration by having del(17p) and/or TP53 mutation (p<0.001). Stratifying the impact of TP53 aberration showed that biallelic TP53 (del(17p) and TP53 mutation) had the poorest outcome, followed by del(17p) alone, whereas TP53 mutation alone did not affect OS compared to patients without TP53 aberration (5-year OS 83%, 84.9%, 92.5%, and 95.7%, respectively). Additionally, complex karyotype (CK) (p<0.001), LDH>250U/L (p=0.01) and ZAP-70 expression (p=0.003) were associated with inferior OS. Del(11q), del(13q), trisomy 12, NOTCH1 mutation, and white blood cell count did not affect OS.

In a multivariate analysis, age>65 years (HR: 2.47, 1.57-3.88, p<0.001), B2M>3.5mg/dL (HR: 2.06, 1.29-3.28, p=0.002), and TP53 aberration (HR: 2.07, 1.3-3.32, p=0.002) were significant OS predictors. When CK was included, the predictive value of TP53 aberration was lost (HR: 0.98, 0.57-1.78, p=0.94). CK (HR: 2.92, 1.65-5.18, p<0.001), age>65 years (HR: 2.42, 1.42-4.1, p=0.001) and B2M>3.5mg/dL (HR: 2.04, 1.18-3.52, p=0.011) were significantly associated with OS.

Conclusion: Despite improvements in outcomes with targeted therapy, high and very-high risk CLL-IPI pts still experience worse OS. CK is a significant factor affecting OS, while isolated TP53 mutation is not. New therapeutic strategies targeting high and very-high risk CLL are necessary to improve outcomes for nearly one-third of CLL pts.