Successful management of familial hemophagocytic lymphohistiocytosis by the JAK 1/2 inhibitor ruxolitinib

Abstract

To the Editor: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only available curative treatment for familial hemophagocytic lymphohistiocytosis (FHL).1 Success of HSCT is dependent on complete control of the disease prior to transplantation.2 More targeted and less toxic treatment regimens would be a major advancement for FHL. Recent studies in FHL murine models using perforin-deficient mice demonstrated the therapeutic efficacy of ruxolitinib, a Janus Kinase (JAK)-1/2 inhibitor, on FHL manifestations.3–5 In children, a few patients with FHL that escaped etoposide-based regimens were rescued with ruxolitinib as a bridge to transplantation.6–8 In adults, secondary hemophagocytic lymphohistiocytosis (HLH)was also treated in some cases by ruxolitinib as a novel first-line9,10 or salvage treatment.11,12 Recently, a boy with HLH and active hepatitis B infection received ruxolitinib as a first-line treatment of secondary HLH.13 Here, we report a case of a child with FHL treated with ruxolitinib in first intention, prior to undergoing a successful HSCT. This 15-month-old female child initially presentedwith diffusemacular rash and livedo, hands and feet edema, and cervical adenopathy (Figure 1 A and B). She fulfilled six criteria for FHL14: (1) prolonged fever (11 days); (2) splenomegaly; (3) anemia (89 g/L), thrombocytopenia (97 × 109/L), and neutropenia (0.6 × 109/L); (4) increased triglyceride (6.01 mmol/L) and reduced fibrinogen (1.21 g/L) levels; (5) hemophagocytosis in her bone marrow biopsy; and (6) presence of high percentage of activated HLA-DR CD8 T cells (51%) (Figure 1C), but only modestly elevated ferritin levels (286 μg/L). Level of HLA-DR+ expression was recently reported to have a strong positive predictive value for HLH.15 Brainmagnetic resonance imaging was negative, and lumbar puncture showed 12 white blood cells. Flow cytometry revealed absent perforin expression in CD8 T and natural killer (NK) cells (Figure 1D). Perforin deficiency was confirmed genetically with the presence of two previously reported mutations in PRF1 (c.445G>A and c.116C>A).16 The patient was initially treated with methylprednisolone with a prednisolone relay (2 mg/kg/day) which abrogated fever, normalized C reactive protein, and corrected anemia, but did not correct splenomegaly nor the other activation markers (Table S1). Reassured by the absence of any neurological involvement and infectious trigger, ruxolitinib was initiated at a dose of 50 mg/m2/day, in combination with dexamethasone (10 mg/m2/day). This treatment led to rapid normalization of the neutropenia (48 h), complete resolution of the splenomegaly (10 days), and disappearance of all FHL biological markers. The patient also received one intrathecal administration of methotrexate and hydrocortisone. Dexamethasone was weaned every 2 weeks and stopped after 8 weeks. Ruxolitinib was well tolerated with no side effects. The patient presented a paucisymptomatic enterovirus/rhinovirus infection a month into the treatment, which did not reactivate FHL. She remained in remission on ruxolitinib alone until her conditioning regimen was initiated (week 10). At the time of conditioning, her complete work up revealed an excellent control of her FHL, with absent FHL biological markers (Table S1). While in complete remission of her FHL, a busulfan-basedmyeloablative conditioning regimen was initiated that included four doses of busulfan (17.4 mg/kg, target area under the curve 18,800 μM⋅min, D-6 to D-3), fludarabine (180 mg/m2, D-8 to D-3) and three doses of alemtuzumab (0.165mg/kg/dose, D-8 to D-6). Ruxolitinib was weaned over 1 week (D-8 to D-1) and stopped 1 day prior to a 9/10 unrelated transplant. The posttransplant period was complicated by grade III mucositis and a veno-occlusive disease (D+18) that responded rapidly to defibrotide treatment. Corticosteroid-resistant skin grade III and ocular grade I graft-versus host disease (GVHD) appeared atD+24 and was controlled by the reintroduction of ruxolitinib (2.5 mg bid) and a switch from ciclosporin prophylaxis to tacrolimus. She was discharged from hospital 41 days following HSCT. Her evolution was complicated by a relapse of her GVHD (+6 months) upon weaning of ruxolitinib that was cortico-sensitive. At 16 months post-HSCT, she remains fully engrafted, with no stigmata of FHL. This case describes a patient with FLH successfully treated in first intention by a combination of dexamethasone and ruxolitinib, which remained in complete remissionwith ruxolitinib aloneuntil a successful HSCT.Ourobservation suggests that this less-toxic treatment regimen, which does not include etoposide or high-dose alemtuzumab, is effective, well-tolerated, and could be used in first intent to treat FHL. By blocking JAK-1 and JAK-2, ruxolitinib inhibits signaling downstream of interferon gamma (IFN-γ), the pivotal cytokine in this disease. Indeed, emapalumab, an anti-IFN-γ blocking antibody, has been reported to be effective in controlling FHL, with results comparable to standard etoposide-based regimens.17 However, the efficacy of emapalumab in controlling FHL is questioned by mostly partial clinical responses and the need to add other maintenance therapy (antithymocyte globulin, alemtuzumab, etoposide) to a majority of the patients in the study.18 Moreover, other cytokines besides IFN-γ contribute to the pathogene-