Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: A single patient experience
Authors: Jessica Slostad, Patrick Hoversten, Candace L. Haddox, Kamila Cisak, Jonas Paludo, Ayalew Tefferi
Journal: American Journal of Hematology (2017)

Hemophagocytic lymphohistiocytosis (HLH) is a rare, but fatal syndrome characterized by an excessive inflammatory response, leading to hemophagocytosis, cytopenias, and multi-organ failure. Primary HLH commonly presents in infancy, and is associated with various germline mutations that affect NK or T cell activity or immunoregulation.1 Secondary HLH primarily affects adolescents and adults, and is typically triggered by infection, autoimmune disease, or malignancy. Secondary HLH treatment protocols have been derived from pediatric protocols in primary HLH, utilizing etoposide, cyclosporine, dexamethasone, and intrathecal methotrexate for central nervous system involvement, and potentially followed by hematopoietic stem cell transplant (HLA-94 and HLA-2004).2 Mortality in adults is greater than 40%, and 30% of patients have refractor disease that requires additional therapy to attempt to achieve remission.2 Several reports suggest that a cytokine-targeted approach may be effective for secondary HLH as adjunctive in relapsed/refractory disease. In particular, ruxolitinib demonstrated efficacy in preclinical murine models of primary HLH by blunting cytokine release via inhibition of Janus kinase (JAK) 1/2, resulting in decreased interferon γ (IFN-γ), interleukin-6 (IL-6), and interleukin 12 (IL-12) signaling.2-5 Moreover, ruxolitinib was recently used to treat an adult patient with refractory secondary HLH, and a phase I clinical trial (NCT02400463) using ruxolitinib to treat secondary HLH is actively recruiting patients.2, 6 Herein, we present the first case of ruxolitinib as a first line agent to treat secondary HLH in a critically ill patient with disseminated histoplasmosis. A 71-year-old woman with rheumatoid arthritis, on methotrexate and hydroxychloroquine, and coronary artery disease was admitted to the hospital for 2 weeks of diarrhea, fevers, and malaise. On admission, she had thrombocytopenia, anemia, and transaminitis. A peripheral blood smear and ADAMTS-13 assay were obtained, which showed no schistocytes and mildly reduced ADAMTS13 activity at 57%, making thrombotic thrombocytopenic purpura less likely. Given the clinical stability of her rheumatoid arthritis, autoimmune associated illness was thought to be unlikely. Infectious disease workup was initiated, and included a negative tick borne panel, HIV, EBV, CMV, and hepatitis B and C. Serum and urine histoplasma antigen were positive. On hospital day 5, the patient was diagnosed with disseminated histoplasmosis involving the liver and gastrointestinal tract, and treatment with amphotericin was started. Given the cyotpenias, fevers, high ferritin, and low fibrinogen, there was concern for HLH, and a bone marrow biopsy was performed on hospital day 7. This demonstrated increased macrophages and histiocytes with morphologic features of hemophagocytosis without any morphologic features of malignant lymphoma, plasma cell proliferative disorder, or other malignant processes. Bone marrow fungal stains were negative. She met 5 out of 8 criteria for HLH, including elevated ferritin (13 850 mcg/L), bilineage cytopenia, fever, bone marrow findings, and hypofibrinogenemia (116 mg/dL). She had normal triglycerides (126 mg/dL). Soluble CD25 and NK cell activity were not analyzed given high clinical suspicion of secondary HLH with other supportive laboratory diagnostics. Despite supportive therapy, she developed distributive shock, worsening cytopenias, renal and hepatic failure, altered mental status, and hypoxic respiratory failure on hospital day 8. Broad spectrum antibiotics and stress-dose corticosteroids were initiated to cover septic shock and adrenal insufficiency secondary to disseminated histoplasmosis, respectively. Given the patient's critical illness, multiorgan failure, and age, conventional cytotoxic chemotherapy was likely to be poorly tolerated. As an alternative, ruxolitinib was initiated on day 8 of hospitalization after detailed discussion with the patient and family. Ruxolitinib 10 mg p.o. twice daily was started with a dose reduction due to renal failure and severe thrombocytopenia (standard therapy 15–20 mg twice daily). Daily ferritin, fibrinogen, CRP, liver function tests, and CBC were monitored (Figure 1A,B). There were no immediate adverse effects, and her shock, mental status, and respiratory failure improved within two days of initiating therapy. The antibiotics were rapidly de-escalated as no additional infectious agent was identified, and her steroids were tapered without incident. Her abnormal liver and renal function was thought to be a combination of medication effects, disseminated histoplasmosis, and HLH. Therefore, the patient was carefully monitored without stopping treatment. On hospital day 12, her liver abnormalities peaked to total bilirubin 10.1, AST 424, and AST 324 before downtrending, and her cytopenias gradually improved thereafter (Figure 1A,B). Given clinical and laboratory improvement on hospital day 15, ruxolitinib was slowly tapered over 3 weeks given the risk of hepatotoxicity. Itraconazole was started on hospital day 18, and amphotericin was discontinued once itraconazole levels were therapeutic. A, Normalized trend of inflammatory markers during ruxolitinib treatment of secondary HLH. B, Laboratory values throughout ruxolitinib treatment. Abbreviations: Ampho = amphotericin, BM = bone marrow, Rux = ruxolitinib, Itra = itraconazole, CRP = C-reactive protein, AST = aspartate aminotransferase Secondary HLH is a life-threatening illness that requires prompt diagnosis and treatment of both the triggering disease process and the HLH syndrome. The current standard treatment of secondary HLH includes cytotoxic chemotherapy that has poor tolerability and efficacy, particularly in adults with comorbidities and secondary multiorgan failure.2 Our case highlights that ruxolitinib is a promising alternative to cytotoxic chemotherapy in HLH, garnering further support for a cytokine-targeted strategy in first-line therapy. In other contexts, ruxolitinib has been associated with cytopenias and hepatocellular injury, but this could not be evaluated in our case given the likelihood of multifactorial renal and hepatic injury. In our patient, multiorgan failure prompted a dose reduction compared to other protocols; however, a good clinical and laboratory response was still achieved. Our case also suggests that a short duration with a taper to avoid a rebound cytokine storm is sufficient to reverse the HLH syndrome. Further investigation with clinical trials is needed to identify the optimal dose, duration, and adverse effects of ruxolitinib in secondary HLH. Our case is the first to demonstrate the use of ruxolitinib as a first-line treatment option for critically ill patients with secondary HLH who may not be good candidates for traditional chemotherapy. The rapid improvement and promising outcome support the ongoing investigation of cytokine-directed approaches in front-line treatment of secondary HLH. Authors would like to thank our patient for generously agreeing to share her case for publication. The authors do not report any disclosures related to this manuscript.