At a median follow-up of 3 years, ibrutinib (Imbruvica) demonstrated continued activity with durable responses that improved in quality with extended treatment of patients with chronic lymphocytic leukemia (CLL). In addition, grade 3 toxicity and adverse events leading to treatment discontinuation diminished over time.
Collectively, the data from the extended follow-up of 132 patients with symptomatic treatment-naive and relapsed/refractory CLL or small lymphocytic leukemia (SLL) “provide evidence that ibrutinib controls CLL disease manifestations and is well tolerated for an extended period,” John C. Byrd, MD, of The Ohio State University in Columbus, and colleagues reported in Blood.
Single-agent ibrutinib, an orally administered inhibitor of Bruton’s tyrosine kinase, was approved by the U.S. Food and Drug Administration “for patients with CLL who have received at least one prior therapy and for all patients with del (17p) CLL,” the investigators noted. “As ibrutinib is a continuously administered oral once-daily therapy, data addressing the safety profile of ibrutinib over time, longer-term outcomes for those achieving partial response with lymphocytosis, and efficacy in patient subgroups become increasingly relevant.”
The extension study included 31 patients aged ≥ 65 years who were symptomatic but treatment naive and 101 patients who had relapsed/refractory disease. All had completed a minimum of six treatment cycles of ibrutinib and had no evidence of disease progression. The median age of the patients was 68, and 43% were ≥ 70 years old. Most patients (74%) were male.
“Treatment consisted of 420 or 840 mg/d of ibrutinib administered orally until progressive disease or poor tolerance,” the investigators stated. “Median time on treatment was 30 months (range, 0.3–44) for treatment-naive patients, with 81% remaining on study treatment, and 23 months (range, 0.3–45) for relapsed/refractory patients, with 53% remaining on study treatment. For treatment-naive and relapsed/refractory patients, 81% and 46% received ibrutinib for > 2 years, respectively,” the researchers reported.
“The primary endpoint of this analysis was safety, as assessed by the frequency and severity of grade 3 adverse events, serious adverse events, and adverse events requiring dose reduction or discontinuation,” the authors explained. The most common adverse events observed over 3 years of follow-up were hypertension, which occurred in 23% of treatment-naive and 20% of relapsed/refractory patients, and pneumonia, which occurred in 6% of treatment-naive and 25% of relapsed/refractory patients.
“For grade 3 adverse events occurring in 5% of patients during years 1, 2, and 3 on therapy, the frequency of pneumonia, neutropenia, thrombocytopenia, diarrhea, and fatigue generally decreased over time, whereas the frequency of hypertension and atrial fibrillation appeared constant. Overall, treatment-naive patients generally experienced fewer grade > 3 toxicities, particularly infectious and hematologic toxicities, compared with the previously treated cohort,” the investigators wrote.
“Dose reductions due to adverse events were reported for 13 patients and occurred primarily during the first year of treatment,” the authors added. “The primary reasons for discontinuing therapy for all patients included disease progression in 22 patients (17%) and adverse events in 17 patients (13%).” Only four adverse events requiring treatment discontinuation “were possibly related to ibrutinib treatment,” the researchers noted, and all were resolved.
Response and Survival
Additional endpoints included were overall response rate, achieved by 84% of previously untreated and 90% of relapsed/refractory patients, and complete response, achieved by 23% of treatment-naive and 7% of relapsed/refractory patients. “Response quality evolves over time, as the median time to complete response was 21.2 months (range, 4.6–42.5),” the investigators observed. With extended follow-up, 94% of patients who achieved partial response with lymphocytosis converted to either complete or partial response.
Median progression-free survival and overall survival times were not reached for all patients. At 30 months, the estimated progression-free survival rate was 96% for treatment-naive CLL/SLL patients and 69% for previously treated patients. The estimated 30-month overall survival rates were 97% for treatment-naive CLL and 79% for previously treated patients.
“Progression remains uncommon, occurring primarily in some patients with relapsed del(17)(p13.1) and/or del(11)(q22.3) disease,” the investigators noted. The 28.1-month progression-free survival “observed in the 34-patient cohort of relapsed patients with del(17p), with a median of four prior therapies, surpasses that observed with any therapy published for this group, including those receiving first-line treatment. Ibrutinib represents a significant advance in the treatment options available for these patients,” the researchers wrote.
“Notably, with 3 years of follow-up, 81% of treatment-naive patients continue to receive daily ibrutinib. There have been no further relapses for over 2 years. This gives some suggestion that the best outcomes may be seen when ibrutinib is administered as first-line rather than salvage therapy,” the authors stated.
Byrd JC, et al: Blood. February 23, 2015 (early release online). ■