The RESONATE-17 Trial: Efficacy and Safety of Ibrutinib in Patients with Relapsed/Refractory CLL and del17p
Patients with chronic lymphocytic leukemia (CLL) and a deletion in chromosome 17p (del17p) follow an aggressive clinical course and demonstrate a median survival of more than 2 years, with a median progression-free survival (PFS) of only 11 months even after frontline therapy with the combination of fludarabine, cyclophosphamide, and rituximab (FCR) or alemtuzumab (Hallek M, et al. Lancet. 2010;376:1164-1174; Hillmen P, et al. J Clin Oncol. 2007;25:5616-5623). Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor that was shown to impart significant PFS and overall survival (OS) benefits as a single-agent therapy in relapsed or refractory CLL (Byrd JC, et al. N Engl J Med. 2014;371:213-223).
At ASH 2014, O’Brien and colleagues reported the safety and efficacy results from the RESONATE-17 trial, a phase 2, open-label, single-arm, multicenter study in 144 patients with relapsed/refractory CLL and del17p who received single-agent ibrutinib (Blood. 2014;124. Abstract 327). Many of these patients had advanced disease and/or had high-risk CLL (63% Rai stage III-IV, 49% with bulky disease, and 16% with concomitant del11q). They had undergone a median of 2 previous therapies (39% had undergone ?3 previous therapies), including with an alkylating agent, a purine analog, chemoimmunotherapy with an anti-CD20 antibody, alemtuzumab, lenalidomide plus thalidomide, or a PI3K inhibitor.
At a median follow-up of 11.5 months, the overall response rate (ORR) was 83% by investigator assessment and 65% by an Independent Review Committee. These responses were independent of Rai stage at baseline, presence or absence of bulky disease, number of previous systemic therapies, del17p and del11q status, and levels of serum ?2-microglobulin or lactic dehydrogenase. The median PFS and OS had not been reached in these patients, with a 12-month PFS rate of 79%. The most frequently reported adverse events (AEs) of any grade were diarrhea, fatigue, cough, and arthralgia. Atrial fibrillation of any grade was reported in 8% of patients (grade 3/4 in 3 [5%] patients), and grade 3/4 infectious AEs were noted in 24 (17%) patients.
In this largest prospective study of relapsed or refractory CLL with del17p, ibrutinib was effective and had a favorable risk-benefit profile. The PFS outcome reported was significantly better than that of patients with frontline del17p CLL that was treated with FCR or alemtuzumab.