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Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT

Christine E. Ryan, Bita Sahaf, Aaron C. Logan, Susan O'Brien, John C. Byrd, Peter Hillmen, Jennifer R. Brown, Martin J.S. Dyer, Anthony R. Mato, Michael J. Keating, Samantha Jaglowski, Fong Clow, Andrew R. Rezvani, Lori Styles, Steven E. Coutre and David B. Miklos

Key points

  • Ibrutinib provided effective salvage therapy in CLL relapse post-alloHCT, resulting in sustained MRD negativity without GVHD development.

  • Ibrutinib selectively depleted pre-germinal B cells and Th2 helper cells, and may enhance donor Th1 T cell-mediated GVL effects.

Abstract

Ibrutinib, a potent and irreversible small molecule inhibitor of both Bruton's tyrosine kinase (BTK) 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 transplantation 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 FDA approval of ibrutinib; seven (64%) achieved a complete response, and three (27%) achieved a partial response. Of the nine patients treated at Stanford who had mixed chimerism-associated CLL relapse, four (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of eleven (36%) patients evaluated by ClonoSeq™ achieved minimal residual disease (MRD) negativity with CLL <1/10,000 WBC, which persisted even after ibrutinib was discontinued, in one case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following Ibrutinib initiation. We postulate that ibrutinib augments 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.

  • Submitted June 21, 2016.
  • Accepted October 15, 2016.