Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients.
Ibrutinib (PCI-32765) is a highly potent oral Bruton tyrosine kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR- and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLCγ2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This trial was registered at www.clinicaltrials.gov as #NCT00114738.
Research Department, Pharmacyclics, Inc., Sunnyvale, CA;
Betty Y
BY
Chang
Michelle
M
Francesco
Martin F M
MF
De Rooij
Padmaja
P
Magadala
Susanne M
SM
Steggerda
Min Mei
MM
Huang
Annemieke
A
Kuil
Sarah E M
SE
Herman
Stella
S
Chang
Steven T
ST
Pals
Wyndham
W
Wilson
Adrian
A
Wiestner
Marcel
M
Spaargaren
Joseph J
JJ
Buggy
Laurence
L
Elias
D000225:Adenine / Q000031:analogs & derivatives; D018941:Antigens, CD19 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D018956:CD5 Antigens / Q000096:biosynthesis; D002448:Cell Adhesion / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000097:blood* / Q000188:drug therapy; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*
D018941:Antigens, CD19; D000970:Antineoplastic Agents; D018956:CD5 Antigens; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine