Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a devastating disorder with protean clinical manifestations caused by the overproduction of T-cell derived cytokines. Cytokine-dependent activation of the Janus family kinases (JAK) is a hallmark of the final common pathway in HLH pathogenesis. Therefore, we initiated a single center, open-label, investigator-initiated trial to assess the efficacy and safety of ruxolitinib in adult patients with secondary HLH.

Methods: Adult patients (≥18 years) who fulfilled 5 of 8 diagnostic criteria were eligible. Patients with CNS involvement or an active malignancy were ineligible. Patients who had received any prior systemic therapy (excluding corticosteroids) within 7 days of treatment were ineligible. Patients with normal renal function received oral ruxolitinib 15 mg twice daily on a continuous, 28-day cycle. Dose reductions for renal insufficiency and toxicity are permitted. Treatment was continued indefinitely until disease progression, unacceptable toxicity, or any other conditions for treatment discontinuation were met. The first patient was enrolled in February, 2016 and enrollment is ongoing. The primary endpoint is overall survival at 2 months. Secondary endpoints include the response rate, duration of response, progression-free and overall survival. Adverse events were graded and attributed in accordance with the National Cancer Institute Guidelines for the Cancer Therapy Evaluation Program. Disease parameters evaluable for response included all quantifiable signs and laboratory abnormalities included in the diagnostic criteria for HLH. A complete response (CR) required normalization of all signs and laboratory abnormalities. At least 25% improvement in two or more signs/laboratory abnormalities was required for a partial response (PR). At least a 50% worsening in two or more signs/laboratory abnormalities was considered progressive disease (PD), while failure to fulfill any of these criteria was considered stable disease (SD).

Results: A total of 4 patient have been enrolled, all of whom fulfilled at least 5 of 8 diagnostic criteria for HLH. Hemophagocytosis, a pathologic hallmark of HLH, was observed in every patient. At the time of treatment initiation, all patients were anemic [median hemoglobin 7.1 g/dL (range: 6.2-7.5 g/dL)] and thrombocytopenic [median platelet count 47 K/uL (range: 14-107 K/uL)]. Three patients were neutropenic [median ANC 0.95 K/uL (range: 0-1.9 K/uL)]. HLH was secondary to an autoimmune disorder (n=3), infection (n=1), and a homozygous mutation in the STXBP2 gene, recently identified as a causative defect in primary HLH, was observed in one patient. Cytopenias significantly improved within the first week of treatment in all patients. On day +7, the mean increase in hemoglobin was 1.88 g/dL (0.2-3 g/dL), in ANC was 1.53 K/uL (range 0.1-5.3 K/uL) and platelet count was 74 K/uL (range 17-116 K/uL). Neutropenia resolved by day +40 and thrombocytopenia resolved by day +47 in all patients. Three of four patients became transfusion independent within 2 days of treatment initiation. Three of four patients received corticosteroids prior to and after initiation of ruxolitinib. The mean corticosteroid (prednisone equivalent) dose prior to treatment initiation was 225 mg/day (range: 60-391 mg/day) and was 38 mg/day (range: 0-75 mg/day) on day +30. Within 47 days of treatment initiation, corticosteroids were discontinued in 2 patients, and were discontinued in all patients by day +54. Significant improvements in ferritin and sIL-2R were also observed with a median 92.6% decrease in ferritin by day +30 (range 86.4-92.6%) and 86% median decrease in sIL-2R by day +30 (range 66.6-92.7%). All patients achieved at least a PR, and 2 patients remain on treatment (>2 months, >8 months). Two patients discontinued treatment, one for progressive disease (due to recurrent symptoms), and another for drug intolerance (neuropathic foot pain). No severe adverse events have been observed. In addition to the patients enrolled in this study, two additional patients who met eligibility criteria were similarly treated (off study) at another institution. Both of these patients achieved at least a PR and remain on treatment (>8 months, >14 months).

Conclusions: Ruxolitinib led to rapid and durable responses and was well tolerated in adult patients with secondary HLH.


Devata:Affimed: Research Funding. Phillips:Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy. Sood:Bayer: Research Funding. Wilcox:Incyte, Corp: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.

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