Hemophagocytic Lymphohistiocytosis in a Patient with Relapsed Chronic Lymphocytic Leukemia Treated with Ibrutinib

Introduction Hemophagocytic Lymphohistiocytosis (HLH) is a rare disorder characterized by an ineffective T-cell and NK response resulting in an exuberant cytokine production. Ibrutinib is an oral irreversible inhibitor of Bruton Tyrosine Kinase (Btk) significantly improving objective responses in patients with relapsed/refractory Chronic Lymphocytic Leukemia (CLL). We report the diagnostic work up and the clinical course of a case of HLH occurring in a patient with relapsed CLL during treatment with ibrutinib. Case report: the patient was a 77-years-old male diagnosed with CLL at the age of 70. At time diagnosis, the disease presented with unfavorable prognostic markers (CD38pos, ZAP70pos and unmutated IGVH). Two years later, the patient developed progressive lymphoadenopathy and a fludarabine-based regimen was administered. No objective response was observed and multiple lines of treatment attained only partial short lasting responses. In the presence of refractory disease with del17p Ibrutinib at a daily dose of 420 mg was started. On day 7 of treatment, febrile neutropenia occurred that did not benefit from antibiotics therapy. Due to persistent fever and deterioration of the clinical picture on day 16, Ibrutinib was hold and the patient hospitalized. Blood counts progressively dropped and disseminated intravascular coagulation complicated the clinical course. Additionaly, splenomegaly, hypertriglyceridemia and unexplainable severe hyperferritinemia (23,023 ng/mL) were encountered. The occurrence of 5 out of 8 diagnostic criteria allowed for a diagnosis of HLH to be made and treatment with dexamethasone, in combination with cyclosporin A and intravenous immunoglobulin, was started (Figure 1). We performed viral genome load and cytokine dosage tests on sera samples, showing high serum EBV genome title. In consideration of the activity of anticytokine treatment in the setting of HLH, the patient was treated by anti-interleukin(IL)-6 receptor Tocilizumab. Despite intensive supportive treatment, irreversible multiorgan failure developed with life-threatening bleeding and death.

We retrospectively measured at two different time points the levels of interleukin (IL)1beta, IL2, IL6, IL10, IL12, IL18 and TNFalfa. In both samples, the IL1beta, IL6, IL10 and IL18 were significantly elevated compared with two healthy controls (Figure 2). Conclusion: HLH is a rare occurrence in CLL and the relationship with ibrutinib treatment is uncertain in this patient. However it is worth noting that off-target effects of ibrutinib may include downregulation of CD8/NK activity which may be involved in initiating HLH. The demonstration of IL6 elevated levels confirmed that Tocilizumb may be effective in the treatment of HLH.

Figure 1.

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Clinical and laboratory parameters trend in a patient with CLL developing HLH. Serum ferritin and temperature were significantly elevated from hospital admission to death. Although frozen plasma, red packed cells and platelet transfusions, the fibrinogen, hemoglobin and platelet count progressively dropped. Ferritin, serum ferritin in ng/mL; plt, platelet count, x10e3/mm³; fibrinogen, plasma fibrinogen mg/dL; Hb, hemoglobin in g/dL; and T, temperature in Celsius grade (°C).

Figure 1.

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Clinical and laboratory parameters trend in a patient with CLL developing HLH. Serum ferritin and temperature were significantly elevated from hospital admission to death. Although frozen plasma, red packed cells and platelet transfusions, the fibrinogen, hemoglobin and platelet count progressively dropped. Ferritin, serum ferritin in ng/mL; plt, platelet count, x10e3/mm³; fibrinogen, plasma fibrinogen mg/dL; Hb, hemoglobin in g/dL; and T, temperature in Celsius grade (°C).

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Figure 2.

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Cytokines levels before the administration of Tocilizumab. IL18, IL1beta, IL10, and IL6 serum levels were significantly elevated at two different time points (3512 and 3515) compared with the serum from two healthy donors (Control1, CTRL1; and control2, CTRL2).

Figure 2.

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Cytokines levels before the administration of Tocilizumab. IL18, IL1beta, IL10, and IL6 serum levels were significantly elevated at two different time points (3512 and 3515) compared with the serum from two healthy donors (Control1, CTRL1; and control2, CTRL2).

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