FDA approves Ibrutinib treatment in CLL

Ibrutinib (IMBRUVICA, Pharmacyclics, Inc.) has just (On February 12, 2014) been granted accelerated approval by the U. S. Food and Drug Administration for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Ibrutinib is already approved in patients with mantle cell lymphoma who have had one previous therapy.

Ibrutinib is a kinase inhibitor and has demonstrated improvement in overall response rate in CLL. In an open-label, multi-center trial of 48 previously treated patients, ibrutinib (IMBRUVICA) was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. Included patients were mainly Caucasians (94%), male (71%) of age range 37-82 years and a median of 67 years. Baseline ECOG performance status in all patients was 0 or 1. At baseline, 46% of subjects had at least one tumor ≥ 5 cm. Median time since diagnosis was 6.7 years and the median number of prior treatments was 4 (range, 1 to 12 treatments). Efficacy was determined by overall response rate; 58.3% (95% CI: 43.2, 72.4) demonstrated partial responses, with none of the patients achieving complete response. Upon initiation of IMBRUVICA, an increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 77% of patients. The onset of isolated lymphocytosis occurs during the first month of IMBRUVICA therapy and resolves by a median of 23 weeks (range 1 – 104+ weeks).

The most commonly occurring adverse reactions (≥ 20%) noted were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness. The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain.

Earlier, RESONATE, a phase 3 head to head comparison study [oral ibrutinib (IMBRUVICA) was compared to IV ofatumumab (ARZERRA GSK)] . conducted at more than 70 clinical sites across 10 countries was stopped early (January 2014). The estimated study completion date was February 2016, with estimated primary completion date for final data collection of primary outcome measure in June 2015) by an Independent Data Monitoring Committee. The data collected had indicated that the primary and a key secondary endpoint of the study had already been met. Ibrutinib demonstrated a statistically significant improvement in progression-free survival (the primary end point of the study), as well as in overall survival (a secondary end point), when compared with ofatumumab. The study has included 391 patients with relapsed or refractory CLL or small lymphocytic leukemia who had received at least 1 previous therapy.

Most oncologists would welcome the approval of ibrutinib in CLL, which is now the second most common adult leukemia. Approximately 16,000 patients in the U.S. are diagnosed each year with CLL. The five-year survival is about 82% and commonly seen in the elderly.