Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study

Samantha M. Jaglowski, Jeffrey A. Jones, Veena Nagar, Joseph M. Flynn, Leslie A. Andritsos, Kami J. Maddocks, Jennifer A. Woyach, Kristie A. Blum, Michael R. Grever, Kelly Smucker, Amy S. Ruppert, Nyla A. Heerema, Gerard Lozanski, Mona Stefanos, Brian Munneke, Jamie-Sue West, Jutta K. Neuenburg, Danelle F. James, Nathan Hall, Amy J. Johnson and John C. Byrd

Key points

  • 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 (NCT01217749).

  • Submitted December 31, 2014.
  • Accepted June 4, 2015.