Ibrutinib achieves durable remissions in TP53-aberrant CLL in both first- and second-line therapy.
Major finding: Ibrutinib achieves durable remissions in TP53-aberrant CLL in both first- and second-line therapy.
Approach: A phase II trial evaluated single-agent ibrutinib in CLL with deletion of 17p13.1 or TP53 mutations.
Impact: Ibrutinib should be considered for first-line treatment of patients with CLL with TP53 aberrations.
Patients with chronic lymphocytic leukemia (CLL) who harbor mutation and/or deletion of the TP53 tumor suppressor gene respond poorly to chemoimmunotherapy and frequently succumb to relapse. Previous clinical studies suggested that ibrutinib, a covalent inhibitor of Bruton tyrosine kinase, induces clinical responses in patients with relapsed or refractory CLL, including patients with deletion of 17p13.1, which contains TP53. In order to further evaluate the efficacy of ibrutinib in TP53-aberrant CLL, Farooqui and colleagues enrolled 51 patients, 35 of whom had previously untreated CLL and 16 of whom had relapsed or refractory disease, in an open-label, single-arm phase II trial. Forty-seven patients harbored deletion of 17p13.1 and four patients displayed TP53 mutation in the absence of 17p13.1 deletion. At 24 weeks, treatment with ibrutinib induced durable objective responses in 44 (92%) of the 48 evaluable patients, including 32 of 33 (97%) previously untreated patients and 12 of 15 (80%) patients with relapsed/refractory CLL. Disease progression occurred in five (10%) patients; however, 42 (82%) patients currently remain on treatment. Response to ibrutinib was rapid and increased with time, and at least a 50% reduction in tumor burden was observed in the bone marrow, spleen, and lymph nodes in the majority of patients. The estimated progression-free survival for all patients at 24 months was 82%, and overall survival at 24 months was 80%. Ibrutinib was well tolerated, and the most common grade 3 treatment-related adverse events included neutropenia, anemia, thrombocytopenia, and pneumonia. In addition, ibrutinib treatment appeared not to select for outgrowth of resistant tumor subclones with TP53 aberrations, suggesting that the mechanism of action is p53-independent. Together, these findings reinforce the notion that ibrutinib may be useful as a first-line therapy in patients with CLL harboring TP53 aberrations.
Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol 2014 Dec 30 [Epub ahead of print].
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