LAUSR

Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening immune-dysregulatory disorder manifested as fever, splenomegaly, and cytopenia. HLH is often refractory to standard treatments and poses a significant risk of death, and therefore, it is of great need to discover effective salvage therapies to control refractory HLH and bridge to the curative allogeneic stem cell transplantation (allo-SCT) [1]. Ruxolitinib, a Janus kinase 1/2 inhibitor, has shown a promising efficacy in murine models. Until now, only two case reports described the successful experience using salvage ruxolitinib for refractory HLH. They focus on the clinical changes, however, no data reveal the immunological changes in patients with HLH taking ruxolitinib [2, 3]. It is still unknown whether the drug could be safely employed as a bridge to allo-SCT. The optimal timing and dosing of ruxolitinib before allo-SCT is unclear. Herein, we present a case with refractory HLH, who relapsed after graft failure of allo-SCT and experienced dramatic clinical and immunological improvements with dose-escalating ruxolitinib monotherapy, and was successfully bridged to second allo-SCT. A 14-year-old girl presented to our clinic in March 2015 with keratitis and symptoms consistent with infection mononucleosis. Laboratory assessment showed transaminitis and elevated EBV-DNA load (> 10 copies/ml). The symptoms persisted for 6 months. Flow cytometry showed an abnormal NK-cell clone in her peripheral blood; SortingPCR showed EBV predominantly in the NK cells. She was diagnosed with NK-cell chronic active EBV infection. She was treated with ganciclovir, interferon α, and intravenous immunoglobulin; the symptoms improved, but the EBVDNA fluctuated above 10 copies/ml. In April 2017, the patient again presented with recurrent fever, pancytopenia, splenomegaly, and up-trending ferritin (>5000 ng/mL); significant hemophagocytosis in the bone marrow; the EBV-DNA load increased to 10 copies/ml; indicating evolving HLH. Further workup showed impaired NK-cell cytotoxicity (14.7%). Stimulation of PBMCs with PMA showed decreased expression of CD107a, a marker of degranulation, of only 0.515%. Next-generation genomic DNA sequencing from peripheral blood mononuclear cells detected heterozygous mutations in exon 7 of RAB27A at nucleotide 560 G>A (p.Arg187Gln). Cells collected with buccal swab were analyzed with the mutation for her family. The RAB27A heterozygous mutation, was found to be inherited from her father (Fig. 1), which could delay cytolytic granules polarization, and impair NK degranulation and cytolytic activity, contributing to HLH occurrence [4]. A HLH-04 regimen was initiated as dexamethasone (10 mg/m/d), etoposide (15 mg/m twice a week), and cyclosporin A. Intrathecal methotrexate was administered to prevent CNS involvement. The symptoms deteriorated after 6 weeks. A salvage haploidentical allo-SCT from her brother was performed using reduced intensity conditioning regimen (RIC) [5]. The post-transplantation period was * He Huang [email protected]