Blood
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Ibrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of patients with relapsed refractory chronic lymphocytic leukemia (RR-CLL). We describe the characteristics, causes of discontinuation, and outcomes in patients who discontinued treatment with ibrutinib. One hundred twenty-seven patients were enrolled in various clinical trials of ibrutinib, with or without rituximab, at our center. ⋯ Causes of discontinuation were disease transformation (7), progressive CLL (7), stem cell transplantation (3), adverse events (11), serious adverse events/deaths (3), and miscellaneous reasons (2). Twenty five patients (76%) died after discontinuing ibrutinib; the median overall survival was 3.1 months after discontinuation. Most patients with RR-CLL who discontinued ibrutinib early were difficult to treat and had poor outcomes.
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In this issue of Blood, Jain et al reported on the poor outcomes of patients with chronic lymphocytic leukemia (CLL) after the discontinuation of ibrutinib.
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Letter Case Reports
The efficacy of ibrutinib in the treatment of Richter syndrome.
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Familial hemophagocytic lymphohistiocytosis (F-HLH) and Griscelli syndrome type 2 (GS) are life-threatening immunodeficiencies characterized by impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell lytic activity. In the majority of cases, these disorders are caused by biallelic inactivating germline mutations in genes such as RAB27A (GS) and PRF1, UNC13D, STX11, and STXBP2 (F-HLH). Although monoallelic (ie, heterozygous) mutations have been identified in certain patients, the clinical significance and molecular mechanisms by which these mutations influence CTL and NK cell function remain poorly understood. ⋯ However, presence of Munc18-2(R65Q/W) in patient-derived lymphocytes and forced expression in control CTLs and NK cells diminishes degranulation and cytotoxic activity. Mechanistic studies reveal that mutations affecting R65 hinder membrane fusion in vitro by arresting the late steps of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-complex assembly. Collectively, these results reveal a direct role for SEC/MUNC18 proteins in promoting SNARE-complex assembly in vivo and suggest that STXBP2 R65 mutations operate in a novel dominant-negative fashion to impair lytic granule fusion and contribute to HLH.
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In this issue of Blood, Crudele et al describe a novel study of adeno-associated virus (AAV) vector-mediated gene therapy that induced immune tolerance to factor IX (FIX) in a hemophilia B (HB) dog with previously formed anti-FIX inhibitor antibodies (IAs).