Clinicopathologic, genetic, and prognostic characteristics of single-hit versus multi-hit TP53-mutated chronic lymphocytic leukemia in the era of novel therapies.

BACKGROUND

TP53 alteration is the most important adverse prognostic genetic indicator in chronic lymphocytic leukemia (CLL); however, the significance of the allele status of TP53, i.e., single hit (SH) vs. multi hit (MH) state, is not well characterized, particularly in the context of biological targeted therapies.

METHODS

We retrospectively studied patients diagnosed with TP53-mutated CLL and treated with targeted therapies at our institution between 01/2019 and 05/2024. Clinical, genetic, and survival data were compared between SH and MH TP53-mutated CLL groups.

RESULTS

A total of 58 cases were identified, including 13 (22.5 %) with SH and 45 (77.5 %) with MH TP53 mutations. MH TP53-mutated CLLs showed significantly greater anemia, neutropenia, and thrombocytopenia, more frequent complex karyotypes (82.3 % vs. 25 %; p = 0.0001), and a higher number of co-mutated genes (median: 1.68 vs. 1.23 mutations/case; p = 0.03) compared to SH cases. However, the severity of clinical symptoms, frequency of splenomegaly, serum LDH, Rai staging, need for therapeutic intervention, time to first treatment, need for > 1 line of therapy, time to second treatment, incidence of Richter transformation, and overall survival (2 and 5-year survival rates for MH vs. SH: 69 % vs.75 % and 52 % vs.75 %, respectively; p = 0.48) did not differ significantly between SH and MH TP53-mutated CLLs.

CONCLUSION

Our study demonstrates that SH TP53-mutated CLLs share several of the adverse clinicopathologic attributes of their MH counterparts. Recognizing SH TP53-mutated CLL as a high-risk genetic subgroup is essential to ensure precise prognostication and optimal therapy for these patients.