Autoimmune haemolytic anaemia occurring during ibrutinib therapy for chronic lymphocytic leukaemia--response to Rider et al.

Abstract

Rider et al report on a challenging case of a patient with chronic lymphocytic leukaemia (CLL) with high disease burden and TP53 abnormality who achieved a partial response following therapy with alemtuzumab and methylprednisolone, and subsequently developed acute haemolysis within 4 weeks after ibrutinib therapy, which was successfully managed with prednisone. As the authors point out, autoimmune haemolytic anaemia (AIHA) typically results from B-cell mediated production of ‘warm’ immunoglobulin G (IgG) type antibodies (directed against red blood cells) (Hamblin et al, 1986). Ibrutinib, an inhibitor of Bruton tyrosine kinase (BTK), was shown to inhibit production of auto-antibodies in murine models of autoimmunity (Honigberg et al, 2010), suggesting its potential efficacy in autoimmune conditions. Furthermore, in addition to BTK, ibrutinib inhibits interleukin-2 (IL2) inducible T-cell kinase, and thereby can block activation of certain T-cell subsets that contribute to the development of the autoimmune process. T-helper cell, type 1 (Th1) cytokines (IFNγ, IL12 and TNFα) are reduced in autoimmune conditions, including AIHA (Singh et al, 1999; Barcellini et al, 2000), and recent data suggest that ibrutinib can potentiate Th1-mediated immune responses (Dubovsky et al, 2013). Therefore, a question arises whether ibrutinib could aid the control of a haemolytic process in CLL. While AIHA is a common complication of CLL, clinical trials with ibrutinib excluded patients with uncontrolled haemolysis. We recently reported a case of a patient with CLL with del (17p) who presented to us with AIHA and in whom control of a haemolytic process was achieved with ibrutinib (Manda et al, 2015). A retrospective analysis conducted at the Ohio State University showed that 11 of the 22 patients who presented with autoimmune cytopenias prior to start of therapy with ibrutinib on a clinical trial were able to discontinue immunosuppressive therapy (Rogers et al, 2014). This study identified four subjects with treatment-emergent AIHA over 458 patient-years of ibrutinib exposure, of which three were able to resume ibrutinib therapy, as was the case presented by Rider et al. Unlike the case with fludarabine (Weiss et al, 1998), it appears likely that AIHA emergent on ibrutinib represents disease activity in CLL, rather than an ibrutinib-mediated process. The role of ibrutinib in management of AIHA in CLL remains undefined, yet the scant data hint at its potential adjunct role in this setting. For now, it seems to be safe to assume that (i) therapy with ibrutinib may help control AIHA in some patients with CLL; and (ii) patients who develop AIHA during therapy with ibrutinib can be safely re-challenged with the drug. Alexey V. Danilov is supported by the Lymphoma Research Foundation Clinical Investigator Career Development Award. Alexey V. Danilov wrote the paper. No conflict of interest.