PMID- 27802969 OWN - NLM STAT- MEDLINE DCOM- 20170731 LR - 20211204 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 128 IP - 25 DP - 2016 Dec 22 TI - Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. PG - 2899-2908 LID - 10.1182/blood-2016-06-715284 [doi] AB - 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. CI - (c) 2016 by The American Society of Hematology. FAU - Ryan, Christine E AU - Ryan CE AD - Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA. FAU - Sahaf, Bita AU - Sahaf B AD - Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA. FAU - Logan, Aaron C AU - Logan AC AD - Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA. FAU - O'Brien, Susan AU - O'Brien S AD - Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Byrd, John C AU - Byrd JC AD - The Ohio State University Medical Center, Columbus, OH. FAU - Hillmen, Peter AU - Hillmen P AD - St. James Institute of Oncology, The Leeds Teaching Hospitals, West Yorkshire, United Kingdom. FAU - Brown, Jennifer R AU - Brown JR AD - Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA. FAU - Dyer, Martin J S AU - Dyer MJ AD - Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom. FAU - Mato, Anthony R AU - Mato AR AD - Center for CLL, University of Pennsylvania, Philadelphia, PA. AD - Hackensack University Medical Center, Hackensack, NJ; and. FAU - Keating, Michael J AU - Keating MJ AD - Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Jaglowski, Samantha AU - Jaglowski S AD - The Ohio State University Medical Center, Columbus, OH. FAU - Clow, Fong AU - Clow F AD - Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA. FAU - Rezvani, Andrew R AU - Rezvani AR AD - Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA. FAU - Styles, Lori AU - Styles L AD - Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA. FAU - Coutre, Steven E AU - Coutre SE AD - Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA. FAU - Miklos, David B AU - Miklos DB AD - Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA. LA - eng GR - P01 CA049605/CA/NCI NIH HHS/United States GR - P30 CA124435/CA/NCI NIH HHS/United States PT - Clinical Trial PT - Journal Article PT - Multicenter Study DEP - 20161101 PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Piperidines) RN - 0 (Pyrazoles) RN - 0 (Pyrimidines) RN - 1X70OSD4VX (ibrutinib) RN - JAC85A2161 (Adenine) SB - IM MH - Adenine/analogs & derivatives MH - Adult MH - Aged MH - B-Lymphocytes/drug effects/pathology MH - Chimerism MH - Cohort Studies MH - Female MH - Germinal Center/pathology MH - Graft vs Host Disease/etiology MH - Hematopoietic Stem Cell Transplantation/*adverse effects MH - Humans MH - Immunomodulation MH - Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy/*therapy MH - Lymph Nodes/pathology MH - Lymphocyte Depletion MH - Male MH - Middle Aged MH - Neoplasm, Residual/pathology MH - Piperidines MH - Pyrazoles/*adverse effects/pharmacology/*therapeutic use MH - Pyrimidines/*adverse effects/pharmacology/*therapeutic use MH - Recurrence MH - Th2 Cells/drug effects/immunology MH - Tissue Donors MH - Transplantation, Homologous/adverse effects MH - Treatment Outcome MH - Withholding Treatment PMC - PMC5179333 EDAT- 2016/11/03 06:00 MHDA- 2017/08/02 06:00 PMCR- 2016/12/22 CRDT- 2016/11/03 06:00 PHST- 2016/06/20 00:00 [received] PHST- 2016/10/15 00:00 [accepted] PHST- 2016/11/03 06:00 [pubmed] PHST- 2017/08/02 06:00 [medline] PHST- 2016/11/03 06:00 [entrez] PHST- 2016/12/22 00:00 [pmc-release] AID - S0006-4971(20)33873-8 [pii] AID - 2016/715284 [pii] AID - 10.1182/blood-2016-06-715284 [doi] PST - ppublish SO - Blood. 2016 Dec 22;128(25):2899-2908. doi: 10.1182/blood-2016-06-715284. Epub 2016 Nov 1.