A decade of ibrutinib for CLL with and without <i>TP53</i> aberration: final report on an investigator-sponsored phase 2 study
Abstract
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 (&gt;10−2) remained progression-free for &gt;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.
Article Details
Authors (16)
Andy Itsara
1Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Victoria M. Rogness
1Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Laura Samples
1Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Constance M. Yuan
2Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD
Hao-Wei Wang
Inhye E. Ahn
1Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Mohammed Z. H. Farooqui
1Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Xin Tian
Wuya College of Innovation
Clare Sun
1Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Emily Tomasulo
1Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Susan Soto
1Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Jeanine Superata
1Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Larisa Bezkorovaynaya
6Office of the Clinical Director, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Thomas E. Hughes
Pia Nierman
1Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Adrian Wiestner
1Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD