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

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

Blood (2014-01-15)
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, John C Byrd
ABSTRACT

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has outstanding activity in patients with chronic lymphocytic leukemia. 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 >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 (BCR) 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 κ and λ 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 vs 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phospholipase C from Clostridium perfringens (C. welchii), Type I, lyophilized powder, 10-50 units/mg protein
Sigma-Aldrich
Phospholipase C from Bacillus cereus, ≥200 units/mg protein
Sigma-Aldrich
Phospholipase C from Clostridium perfringens (C. welchii), Type XIV, lyophilized powder, ≥150 units/mg protein

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