Ibrutinib‐associated hemophagocytic lymphohistiocytosis: A case series from Johns Hopkins
Authors: Alexander J. Ambinder, Bryan Hambley, Satish Shanbhag, Samuel A. Merrill
Journal: American Journal of Hematology (2019)

Hemophagocytic lymphohistiocytosis (HLH) is a disorder characterized by ineffective T/NK-cell mediated cytotoxicity and excessive cytokine release, resulting in an often-fatal inflammatory syndrome. Primary HLH results from deleterious germline mutations that impair granzyme function, whereas secondary HLH occurs more frequently in adults. This is the result of another process such as malignancy, infection, autoimmunity, immunodeficiency, or as an adverse effect of a medication. The diagnosis of HLH is based upon the HLH-2004 diagnostic criteria,1 which requires five of the eight following clinical/laboratory characteristics for a diagnosis. They are fevers, cytopenias, coagulopathy, hepatosplenomegaly, hyperferritinemia, defects in NK cell function, elevated soluble interleukin 2 receptor (sIL2R) levels, and the presence of hemophagocytosis in the reticuloendothelial system. Ibrutinib is an irreversible inhibitor of Bruton's Tyrosine Kinase (BTK), that is now approved by the United States Food and Drug Administration for the treatment of several hematologic conditions.2 Herein, we report a series of three cases from a single institution in which HLH developed after exposure to ibrutinib. Case 1: A 77-year-old woman with a history of IgM kappa monoclonal gammopathy experienced an asymptomatic decrease in her hemoglobin, which was detected on routine blood work. Her hematologist suspected that the cause was an underlying lymphoplasmacytic lymphoma (LPL), so she was started on ibrutinib. Two weeks later, she developed fevers, pancytopenia, elevated liver enzymes and hyperbilirubinemia. Patient characteristics are summarized in Table 1. A bone marrow biopsy revealed marked hemophagocytosis, but no evidence of LPL. Her ferritin was 5812 ng/mL (reference range: 13-150 ng/mL), triglycerides were 246 mg/dL (reference range: 0-150 mg/dL), fibrinogen was 176 mg/dL (reference range: 150-450 mg/dL), and sIl2R was 151 941 pg/mL (reference range: 532-1892 pg/mL). Extensive testing for autoimmune and infectious triggers (including EBV PCR) was negative. She was transferred to our institution for further management. She was diagnosed with HLH and treatment was initiated with dexamethasone and etoposide. The protocol was modified to accommodate her concomitant renal and liver dysfunction and for pancytopenia. Her treatment course is summarized in a figure that is available as Figure S1. After 4 weeks, etoposide was discontinued, and steroids were tapered due to profound myelosuppression and patient preference. Her symptoms recurred and her biomarkers increased, so she resumed treatment with etoposide, dexamethasone and cyclosporine. Despite treatment, she remained pancytopenic and suffered recurring bacterial infections, eventually transitioning to hospice care. Case 2: A 61-year-old man with CLL previously treated with fludarabine, cyclophosphamide, and rituximab developed relapsed disease with lymphadenopathy, lymphocytosis and pancytopenia. A lymph node biopsy did not show transformation, so he was started on ibrutinib. Within 1 week, he developed fevers and was hospitalized. His cultures were negative, and his fevers were attributed to his malignancy. He was continued on ibrutinib and was discharged home. One week later, he was re-admitted with persistent fevers, pancytopenia and hyperbilirubinemia. His ferritin was 51 902 mg/dL and fibrinogen was 37 mg/dL. He was transferred to our institution with multiorgan failure, triglycerides of 435 mg/dL and sIl2R of 2533 pg/mL. A bone marrow biopsy showed hemophagocytosis. He was diagnosed with HLH and treated with dose-reduced etoposide, dexamethasone 10 mg/m2 daily, and IVIG 0.5 g/kg. He had persistent multiorgan failure without evidence of improvement after 1 week of therapy, so his family decided to stop treatment and pursue comfort measures alone. Case 3: A 63-year-old man with CLL treated with bendamustine and rituximab relapsed 1 year later, and was started on ibrutinib and had a complete response. Six months later, he developed fevers, weight loss, pancytopenia, elevated liver enzymes, and hyperbilirubinemia. A PET/CT showed diffuse FDG-avid bone marrow, hepatosplenomegaly and lymphadenopathy. A bone marrow biopsy revealed hemophagocytosis and residual CLL, but no evidence of Richter's transformation. Upon arrival to our institution, his ferritin was 73 861 ng/mL, triglycerides were 294 mg/dL, fibrinogen was 150 mg/dL, and sIl2R was 9051 pg/mL. He met criteria for HLH, a diagnosis supported by the presence of activated T-cells with an immunophenotype typically seen in HLH on peripheral blood flow cytometry.4 He was treated with cyclophosphamide and steroids for cytoreduction and was then initiated on cyclosporine. He died 33 days after the onset of HLH. There are two other published case reports that associate ibrutinib with HLH. Cavallari et al reported a case of a 70-year-old man with relapsed CLL, who was started on ibrutinib and developed HLH within 7 days of initiation.5 Poole et al described another case of HLH that developed within 5 days of initiation of ibrutinib.6 That same patient was treated with ibrutinib 1 year earlier, but developed febrile neutropenia leading to its discontinuation. Secondary HLH is a rare, but well described complication of hematologic malignancies, particularly those of NK/T-cell lineages; however, HLH is rare in B-cell CLL. In the literature, there are two cases of patients with CLL developing HLH, in association with CMV and histoplasmosis.7, 8 Two other cases describe HLH developing in the setting of EBV-driven Richter's transformation, and after treatment with FCR, respectively.9, 10 There are only two cases describing HLH arising out of CLL without another trigger.11, 12 In our own HLH series,13 there were only two other cases of CLL-associated HLH, one occurring after bone marrow transplantation, and another in the setting of transformation. In the three cases described in this manuscript, extensive testing for autoimmune and infectious etiologies was negative. The five cases of ibrutinib-associated HLH raise the possibility that ibrutinib may rarely contribute to the development of HLH. In four of the cases, there is a clear temporal relationship between the initiation of ibrutinib and the onset of HLH. Furthermore, Poole et al proposed a plausible biological mechanism; they hypothesized that ibrutinib may trigger HLH via irreversible inhibition of IL-2 inducible T-cell kinase (ITK), a member of the Tec family of kinases to which BTK belongs. The Fc receptor binding stimulates ITK expression, which in turn mediates NK-cell calcium mobilization, granule release and cytotoxicity. In vitro, ibrutinib inhibits FcR-stimulated NK cell degranulation and attenuates antibody dependent cellular cytotoxicity, hallmarks of HLH pathophysiology.14 This mechanism is further supported by the fact that patients with congenital ITK deficiency also have an increased risk of developing HLH.15 Further investigation into the association between ibrutinib and HLH is warranted before any definitive conclusions can be made. However, hematologists treating patients with ibrutinib and those caring for patients with HLH should be aware of the possible contribution of ibrutinib to the development of HLH. These observations should be also be taken into consideration as researchers investigate other applications for BTK inhibitors. This study was supported by research funding from the Raymond Stralka Fund for Research to Satish Shanbhag. SAM reports institutional research support from Pfizer outside the subject matter of this manuscript. SS reports institutional research support from American Regent/Daiichi-Sankyo and consulting for Takeda oncology outside the subject matter of this manuscript. Conceptualization: A.J.A., B.H., S.S., S.A.M. Data curation: A.J.A., B.H., S.A.M. Writing—original draft: A.J.A. Writing—review and editing: B.H., S.S., S.A.M. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.