Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT.
Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD.
Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.
Christine E
CE
Ryan
Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.
Bita
B
Sahaf
Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
Aaron C
AC
Logan
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
Susan
S
O'Brien
The Ohio State University Medical Center, Columbus, OH.
John C
JC
Byrd
St. James Institute of Oncology, The Leeds Teaching Hospitals, West Yorkshire, United Kingdom.
Peter
P
Hillmen
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA.
Jennifer R
JR
Brown
Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.
Martin J S
MJ
Dyer
Center for CLL, University of Pennsylvania, Philadelphia, PA.|Hackensack University Medical Center, Hackensack, NJ; and.
Anthony R
AR
Mato
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
Michael J
MJ
Keating
The Ohio State University Medical Center, Columbus, OH.
Samantha
S
Jaglowski
Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA.
Fong
F
Clow
Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.
Andrew R
AR
Rezvani
Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA.
Lori
L
Styles
Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.
Steven E
SE
Coutre
Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.
David B
DB
Miklos
D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D046528:Chimerism; D015331:Cohort Studies; D005260:Female; D018858:Germinal Center / Q000473:pathology; D006086:Graft vs Host Disease / Q000209:etiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D056747:Immunomodulation; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000628:therapy*; D008198:Lymph Nodes / Q000473:pathology; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual / Q000473:pathology; D010880:Piperidines; D011720:Pyrazoles / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous / Q000009:adverse effects; D016896:Treatment Outcome; D028761:Withholding Treatment
D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine