title: Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy.
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.
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.forename: Kelly
authors.initials: K
authors.lastname: Smucker
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Smith
authors.forename: Arletta
authors.initials: A
authors.lastname: Lozanski
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhong
authors.forename: Amy S
authors.initials: AS
authors.lastname: Ruppert
authors.forename: David
authors.initials: D
authors.lastname: Lucas
authors.forename: Katie
authors.initials: K
authors.lastname: Williams
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhao
authors.forename: Laura
authors.initials: L
authors.lastname: Rassenti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ghia
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Rose
authors.initials: R
authors.lastname: Mantel
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jones
authors.forename: Joseph
authors.initials: J
authors.lastname: Flynn
authors.forename: Kami
authors.initials: K
authors.lastname: Maddocks
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Richard R
authors.initials: RR
authors.lastname: Furman
authors.forename: Danelle F
authors.initials: DF
authors.lastname: James
authors.forename: Fong
authors.initials: F
authors.lastname: Clow
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D023201:CD40 Ligand / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008218:Lymphocytosis / Q000097:blood / Q000209:etiology* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D010880:Piperidines; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000009:adverse effects*; D011743:Pyrimidines / Q000009:adverse effects*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; D023201:CD40 Ligand; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D051966:Phospholipase C gamma; D000225:Adenine