1. Ibrutinib was superior to ofatumumab in a head-to-head trial in patients who have failed initial therapy for chronic lymphoid leukemia (CLL) and small lymphocytic leukemia (SLL).
2. The benefit of progression-free survival for those on ibrutinib was preserved across all subgroups including common poor prognostic indicators (e.g. specific cytogenetic abnormalities).
Evidence Rating Level: 1 (Excellent)
Study Rundown: Molecular therapy is continually changing the approach to treatment of hematologic malignancies such as chronic lymphoid leukemia (CLL) and small lymphocytic leukemia (SLL). Outcomes from these malignancies are often guided by a short duration to response to first-line therapy and certain cytogenetic abnormalities. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is a new chemoimmunotherapy for CLL and SLL that interferes with signaling and downstream B-cell function.
This open-label, multi-centered, phase 3 trial randomized patients with CLL or SLL to treatment with ibrutinib or another indicated anti-CD20 agent, ofatumumab. Only patients who have failed first-line (or more) therapy for CLL or SLL were enrolled in this trial. Ibrutinib was superior to ofatumumab for progression-free survival and this benefit was preserved across all subgroups (which typically predict poor prognosis) including age, number of prior treatments, and specific cytogenetic abnormalities.
Overall, ibrutinib is a new and promising therapy (as measured by progression-free survival) for those with CLL or SLL who have failed prior therapies or have other poor prognostic indicators. After 4 months from the start of this trial, crossover from ofatumumab to ibrutinib was approved. Among baseline characteristics, patients in the ibrutinib group received a median of 3 prior treatments versus 2 in the ofatumumab group; therefore, those in the ibrutinib group may have been treated more aggressively prior to randomization. Whether the benefit of ibrutinib is also preserved in patients who are treatment-naive remains to be studied.
In-Depth [randomized controlled trial]: This study randomized 391 patients (from the U.S., Australia, and seven European countries) to receive oral ibrutinib or an ofatumumab infusion protocol. In order to be enrolled, CLL and SLL patients had to have received at least one prior therapy and be deemed inappropriate for purine analogue treatment for various reasons. Baseline characteristics were well-matched between the two groups including age, gender, ECOG, various laboratory parameters, cytogenetics, and attempted previous therapies. The primary endpoint of median progression-free survival was not reached at 9.4 months follow-up for the ibrutinib group compared to 8.1 months for the ofatumumab group (hazard ratio, 0.22; P<0.001). A total of 57 patients from the ofatumumab group crossed over to receive ibrutinib after confirmed disease progression; however, the outcomes of these patients after crossover were not reported. Common non-hematologic adverse events in the ibrutinib group included diarrhea, fatigue, pyrexia and nausea. Treatment exposure was longer in the ibrutinib group with a median of 8.6 months compared to a median of 5.3 months in the ofatumumab group.
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