A decade of ibrutinib for CLL with and without TP53 aberration: final report on an investigator-sponsored phase 2 study

Clinical Snapshot

Key Findings

• P Value: Not specified for primary comparisons

• Effect Size: TP53-aberrant patients: median PFS 5.6 years vs not reached in TP53-normal patients

• Primary Outcome: Median progression-free survival of 7.2 years overall

• Nnt Or Sensitivity: 10-year PFS for first-line TP53-aberrant CLL: 38.6%; 15.5% achieved undetectable MRD

• Confidence Interval: 10-year OS: 51.3% (TP53-aberrant) vs 75.3% (TP53-normal)

Clinical Application

Requires long-term monitoring for toxicity and disease progression; 36.9% discontinued for adverse events Ibrutinib PBS-listed for CLL including TP53-aberrant disease; results support current RACGP and haematology society guidelines for high-risk CLL management CLL patients with TP53 aberrations or elderly patients ≥65 years requiring systemic therapy

Abstract

Bruton tyrosine kinase inhibitors improve outcomes for patients with chronic lymphocytic leukemia (CLL). Long-term data with continuous therapy are limited. With a median follow-up of 10.0 years, we report final results on 84 patients with TP53 aberrations (deletion of chromosomal arm 17p or TP53 mutation) or ≥65 years of age treated with 420 mg of single-agent ibrutinib daily until progression or unacceptable toxicity. A total of 52 (61.9%) patients were previously untreated; 56 (66.7%) had unmutated immunoglobulin heavy-chain variable region; and 53 (63.1%) had TP53 aberrations, including 34 treatment naïve patients. As of 31July 2024, 9 (10.7%) patients continued ibrutinib, 39 (46.4%) discontinued ibrutinib for progressive disease, 31 (36.9%) for adverse events, and 5 (5.9%) withdrew consent. The median progression-free survival (PFS) was 7.2 years; median overall survival (OS) was not reached. In patients with and without TP53 aberrations, median PFS was 5.6 years and not reached, and 10-year OS was 51.3% and 75.3%, respectively. The estimated 10-year PFS and OS for patients with TP53-aberrant CLL treated in first line was 38.6% and 65.7%, respectively. Minimal residual disease (MRD) was quantified by peripheral blood flow cytometry annually. Undetectable MRD (uMRD; at 10-4) was achieved in 13 (15.5%) patients after a median of 5 years. Twelve patients maintained uMRD, the longest observation ongoing at 8.0 years. Seventeen (42.5%) patients with best response of high MRD (>10-2) remained progression-free for >5 years. These results highlight durable benefits and deepening responses with ibrutinib, including in high-risk CLL. Whether patients maintaining uMRD for years can safely discontinue therapy should be assessed prospectively. This trial was registered at www.clinicaltrials.gov as NCT01500733.

References

1. 1.Itsara, A., Rogness, V. M., Samples, L., Yuan, C. M., Wang, H.-W., Ahn, I. E., Farooqui, M. Z. H., Tian, X., Sun, C., Tomasulo, E., Soto, S., Superata, J., Bezkorovaynaya, L., Hughes, T. E., Nierman, P., & Wiestner, A. (2026). A decade of ibrutinib for CLL with and without TP53 aberration: final report on an investigator-sponsored phase 2 study. Blood. https://doi.org/10.1182/blood.2025029971