Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study
Mené sur 71 patients atteints d'une leucémie lymphocytaire chronique, cet essai évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout d'ofatumumab à l'ibrutinib selon trois protocoles d'administration
Ibrutinib combined with ofatumumab in relapsed CLL had had an ORR of 83% with median time to response of less than 3 months in all groups.All 3 sequences of administration were acceptably tolerated and active; responses were durable and median PFS was not yet reached. Ibrutinib represents a therapeutic advance in CLL but as monotherapy produces few complete remissions in previously treated patients. Anti-CD20 antibodies have improved response and progression-free survival when combined with chemotherapy. We evaluated the safety and activity of adding ofatumumab to ibrutinib in 3 different administration sequences. Patients with CLL/SLL, prolymphocytic leukemia or Richter's transformation who failed ≥2 prior therapies were enrolled. Patients received ibrutinib 420 mg daily and 12 doses of ofatumumab 300/2000 mg in 3 schedules: ibrutinib lead-in (group 1; n=27), concurrent start (group 2; n=20), or ofatumumab lead-in (group 3; n=24). Seventy-one patients were treated; most had high-risk disease including del(17)(p13.1) (44%) or del(11)(q22.3) (31%). The most frequent adverse events (any grade) were diarrhea (70%), infusion-related reaction (45%), and peripheral sensory neuropathy (44%). Overall response rates (ORR) in CLL/SLL patients (n=66) were 100%, 79%, and 71% in groups 1, 2, and 3, respectively. Estimated 12-month PFS for all patients were 89%, 85%, and 75%, respectively. Four patients in group 3 progressed prior to receiving ibrutinib. This study demonstrates the tolerability and clinical activity of this combination with quicker time to best response than single-agent ibrutinib, and with durable responses. This trial was registered at www.clinicaltrials.gov (NCT01217749).