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Chronic lymphocytic leukemia (CLL) patients whose leukemic cells carry deletion or mutation of the TP53 tumor suppressor gene typically have poor outcomes and short survival, compared with other molecular subtypes, when treated with traditional immunochemotherapy regimens.
Now, investigators have conducted an industry-supported, phase II, single-institution trial of the Bruton's tyrosine kinase inhibitor ibrutinib in patients with the del(17p) or TP53 mutation who had previously untreated CLL or relapsed or refractory CLL. Patients received single-agent ibrutinib (420 mg daily) until disease progression or toxicity requiring treatment discontinuation.
Thirty-two of 33 previously untreated patients achieved partial remission after 6 months of treatment, as did 12 of 15 patients with relapsed or refractory disease. Responses improved over time, with about 10% ultimately achieving complete remission. Toxicity included grade 3 or 4 neutropenia in 24%, anemia in 14%, and thrombocytopenia in 10%. About half of patients experienced grade 1 or 2 arthralgias or diarrhea.
Farooqui MZ et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: A phase 2, single-arm trial. Lancet Oncol 2015 Feb; 16:169. (http://dx.doi.org/10.1016/S1470-2045(14)71182-9)
Comment
Inhibition of the B-cell receptor pathway leads to dramatic responses in all CLL subtypes, typically with a rapid shift of tumor cells from lymph nodes and spleen into the circulation, with subsequent regression of lymphocytosis over time. Ibrutinib should be included with initial therapy in del(17p) or TP53-mutated CLL. Ongoing clinical investigations are focused on improving the depth of response by combining B-cell–receptor inhibitors with anti-CD20 monoclonal antibodies, chemotherapy, and other targeted agents.