Efficacy results of a phase 2 trial of first-line idelalisib plus ofatumumab in chronic lymphocytic leukemia

Benjamin L. Lampson, Haesook T. Kim, Matthew S. Davids, Jeremy S. Abramson, Arnold S. Freedman, Caron A. Jacobson, Philippe A. Armand, Robin M. Joyce, Jon E. Arnason, Laura Z. Rassenti, Thomas J. Kipps, Joshua Fein, Stacey M. Fernandes, John R. Hanna, David C. Fisher and Jennifer R. Brown

Key Points

  • Idelalisib plus ofatumumab have a high ORR but short PFS when used for treatment-naïve CLL.

  • The short PFS is likely a result of high rates of therapy discontinuation in the setting of transaminitis, colitis, and infections.


PI3 kinase (PI3K) activity is critical for survival of neoplastic B cells in patients with chronic lymphocytic leukemia (CLL). Blockade of PI3K signaling with idelalisib is effective for the treatment of relapsed CLL in combination with the anti-CD20 antibody ofatumumab. In this single-arm, open-label, nonrandomized phase 2 study, we investigated the efficacy and safety of idelalisib with ofatumumab in 27 patients with treatment-naïve CLL in need of therapy. Patients were planned to receive idelalisib for 2 monthly cycles, then idelalisib and ofatumumab for 6 cycles, followed by idelalisib indefinitely. The study was closed early and all patients ceased therapy when an increased rate of death as a result of infection was observed on other first-line idelalisib trials. Median time on therapy was 8.1 months, and median duration of follow-up was 39.7 months. We previously reported high rates of hepatotoxicity in a smaller cohort of patients in this trial; toxicities necessitated therapy discontinuation in 15 patients after a median of 7.7 months. The most frequent grade ≥3 adverse events were transaminitis (52% of patients), neutropenia (33%), and colitis/diarrhea (15%). The best overall response rate (ORR) was 88.9%, including 1 complete response. Median progression-free survival (PFS) was 23 months (95% confidence interval [CI], 18-36 months); 11 patients have not yet required second-line therapy. Idelalisib and ofatumumab demonstrated an unacceptable safety profile in the first-line setting, which resulted in a short PFS despite a high ORR. Future development of PI3K inhibitors for use in treatment-naïve CLL will require novel approaches to mitigate toxicities. This trial was registered at as #NCT02135133.

  • Submitted December 19, 2018.
  • Accepted February 8, 2019.
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