Patients with chronic lymphocytic leukemia (CLL) with 17p deletion (del17p) have a poorer prognosis and worse overall survival (OS) than patients with non-del17p CLL. Previous research has shown that the Bruton tyrosine kinase inhibitor ibrutinib is effective in patients with del17p CLL or small lymphocytic lymphoma (SLL), and results from the recent phase II RESONATE-17 trial demonstrate that ibrutinib could be an option for patients with relapsed/refractory del17p CLL.
Treatment with ibrutinib resulted in a 64 percent overall response rate (ORR; the study’s primary endpoint) and had a “favorable” risk-benefit profile, according to a study led by Susan O’Brien, MD, of the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, and authors that was published in Lancet Oncology
“Before the approval of ibrutinib, no universal standard of care existed for patients with del17p CLL,” Dr. O’Brien and authors wrote. “The absence of an historical standard of care for patients with del17p CLL, the unmet medical need in this high-risk population, and the promising activity and safety profile of ibrutinib served as the basis for the RESONATE-17 study.”
In the multicenter, international, open-label, single-arm, non-randomized RESONATE-17 study, 144 patients (median age = 64 years; range = 57-72 years) with symptomatic relapsed/refractory del17p CLL (n=137) or SLL (n=7) were enrolled from 40 sites in the United States, Canada, Europe, Australia, and New Zealand.
Patients included in the study had received at least one previous systemic treatment (median = 2; range = 1-3), had adequate organ function, and had an Eastern Cooperative Oncology Group performance status of 0-1. Patients were excluded from the trial if they had received a hematopoietic cell transplantation within six months of study enrollment; had previous chemotherapy or immunotherapy, radiation therapy, or investigation drugs within four weeks of study treatment; or used corticosteroids within one week of first study dose.
Patients received 420 mg of ibrutinib once daily continuously until disease progression or unacceptable toxicity. Treatment response was assessed with computed tomography radiologic examination at the end of weeks nine, 17, 25, 37, 49, 61, 73, and 85, and every 24 weeks thereafter until disease progression.
The ORR of 64 percent was reported by an independent review committee (n=92; 95% CI 56-71).
Dr. O’Brien and authors reported an ORR of 83 percent (n=120; 95% CI 76-89) in a post-hoc, investigator-extended assessment with a median follow-up of 27.6 months (IQR=14.6-27.7 months), The 24-month, progression-free survival (PFS) rate was 63 percent (95% CI 54-70%) and the 24-month, overall survival rate was 75 percent (95% CI, 67-81%), but the median PFS and OS were not reached.
Seventy-nine percent of patients without cytopenia at baseline (n=72/91) experienced sustained hematologic improvement (defined as ≥50% increase over baseline or improvement to absolute neutrophil count >1.5 cells × 10⁹/L, hemoglobin >110 g/L, or platelets >100 cells × 10⁹/L that was sustained continuously for ≥56 days without a need for blood transfusion or growth factors).
The median duration of response (a secondary endpoint) also was not reached.
Half of the patients (n=72) discontinued ibrutinib. The most common reasons for treatment discontinuation were progressive disease (n=34; 24%) and adverse events, unacceptable toxicity, or death (n=24; 17%). In addition, 9 percent of patients experienced major bleeding.
Common grade 3–5 treatment-emergent adverse events (occurring in ≥5% of patients) were: neutropenia (n=24; 18%), pneumonia (n=19; 13%), hypertension (n=18; 13%), thrombocytopenia (n=12; 8%), anemia (n=14; 10%), and atrial fibrillation (n=8; 6%).
Ten patients (7%) underwent dose reductions of ibrutinib from 420 mg to 280 mg and four (3%) underwent dose reductions to 140 mg due to adverse events. The most common adverse events leading to dose reductions were pneumonia and spontaneous hematoma (two patients each).
Among the patients who had dose reductions, eight remained on treatment and six discontinued (three because of progressive disease and three because of adverse events).
“The safety profile of ibrutinib-treated patients in this study was consistent with previous reports, with most adverse events being mild to moderate in severity,” the researchers noted.
“Alongside data from other emerging treatments, ibrutinib might contribute to a reassessment of the role and timing of stem cell transplantation by changing the choice and sequence of treatments used for the management of high-risk CLL,” Dr. O’Brien and authors concluded. “These data mark an era of targeted therapeutics that is changing historical treatment algorithms for patients with del17p CLL or SLL, the most difficult subset of patients to treat.”
The study is limited by its single-arm, non-randomized design, and limited follow-up to determine the median PFS and OS.
O’Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicenter study. Lancet Oncol. 2016;17:1409-18.