Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy

Jennifer A. Woyach, Kelly Smucker, Lisa L. Smith, Arletta Lozanski, Yiming Zhong, Amy S. Ruppert, David Lucas, Katie Williams, Weiqiang Zhao, Laura Rassenti, Emanuela Ghia, Thomas J. Kipps, Rose Mantel, Jeffrey Jones, Joseph Flynn, Kami Maddocks, Susan O'Brien, Richard R. Furman, Danelle F. James, Fong Clow, Gerard Lozanski, Amy J. Johnson and John C. Byrd

Key points

  • Persistent CLL cells during ibrutinib therapy show evidence of biochemical activation, but inhibited BCR and no proliferation

  • Long lymphocytosis during ibrutinib therapy is not associated with adverse progression free survival


The Bruton's Tyrosine Kinase inhibitor ibrutinib has outstanding activity in patients with chronic lymphocytic leukemia (CLL). Most patients experience lymphocytosis, representing lymphocyte egress from nodal compartments. This resolves within 8 months in the majority of patients, but a subgroup has lymphocytosis lasting more than 12 months. Here we report a detailed characterization of patients with persistent lymphocytosis during ibrutinib therapy. Signaling evaluation showed that while BTK is inhibited, downstream mediators of B-cell receptor signaling are activated in persistent lymphocytes. These cells cannot be stimulated through the BCR and do not show evidence of target gene activation. Flow cytometry for kappa and lambda expression, IGHV sequencing, Zap-70 methylation, and targeted gene sequencing in these patients are identical at baseline and later time points, suggesting that persistent lymphocytes do not represent clonal evolution. In vitro treatment with targeted kinase inhibitors shows that they are not addicted to a single survival pathway. Finally, progression free survival is not inferior for patients with prolonged lymphocytosis versus those with traditional responses. Thus, prolonged lymphocytosis is common following ibrutinib treatment, likely represents the persistence of a quiescent clone, and does not predict a subgroup of patients likely to relapse early.

  • Submitted September 18, 2013.
  • Accepted December 30, 2013.