Successful remission induction in refractory familial hemophagocytic lymphohistiocytosis with ruxolitinib as a bridge to hematopoietic stem cell transplantation

To the Editor: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive hyperinflammatory disorder driven by the uncontrolled activation and proliferation of CD8+ T lymphocytes and macrophages.1 Hematopoietic stem cell transplantation (HSCT) is recommended in children with a primary or familial HLH as the only curative option available.2 Eighty percent of patients have at least a partial response to front-line therapy with dexamethasone and etoposide, while patients who lack a satisfactory responsemay require second-line agents.3 Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, has shown promise in mouse models of primary HLH. Ruxolinitib when administered empirically to perforin-deficientmice inhibits interferon γ (IFN-γ), interleukin (IL)-6, and IL-12 production with reduction in cytokine production and tissue damage in active HLH.4,5 A 3-year-old female child born of third-degree consanguineous marriage presented to our center in April 2018 with fever of 2 weeks duration and sudden onset cervical lymphadenopathy. She had received a short course of steroids (oral prednisolone) and oral amoxycillin elsewhere. Cervical lymph node biopsy was performed, which was reported to have hyperplasia with no atypical features and was positive for Epstein Barr virus (EBV) on FISH. On evaluation, she was found to have elevated levels of serum ferritin, low fibrinogen, and normal triglycerides. Clinical exome sequencing was performed, which revealed homozygous deficiency of UNC13D suggestive of familial HLH type III. She was started on HLH 2004 protocol in June 2018 including dexamethasone, etoposide, cyclosporine, and intrathecal methotrexate. She completed induction in August 2018. Due to social reasons, further treatment was abandoned by the family. She presented to our center yet again in February 2019with a similar clinical profile. Investigations revealed recurrence of HLH disease and she was restarted on induction chemotherapy as per HLH 2004 protocol. The reinductionwas complicated by prolonged admission for febrile neutropenia. She developed features of right-sided preseptal cellulitis. Computed tomography scan of paranasal sinuses was performed to look for an active focus for infection and was reported to reveal rightmaxillary sinusitis. Right antral fluid lavagewas performed, which did not reveal any specific etiology. EBV copies per milliliter were found to be 3049 and she was given one dose of rituximab at 375 mg/m2. Subsequently she developed progressively increasinghepatosplenomegaly, cervical lymphadenopathy, and persistent fever. Positron emission tomography-computed tomography was performed that revealed FDG uptake in multiple cervical, mediastinal, supraclavicular, axillary, abdominal, retroperitoneal and pelvic nodes, hypermetabolic pulmonary nodules, and diffuse fluorodeoxyglucose uptake in spleen. A repeat biopsy of the left cervical lymph node revealed lymphohistiocytic infiltrate and immunohistochemistry was negative for malignancy. In view of refractory HLH and possibility of associated fungal infection, oral ruxolitinib with hydrocortisone was commenced for the HLH therapy. Ruxolitinib was started at a dose of 2.5 mg twice a day and hydrocortisone at a dose of 1 mg/kg/dose three times a day. Amphotericin B at 3 mg/sq.m was started concurrently for the fungal infection. She improved with stabilization of all clinical and laboratory parameters. She recovered from pancytopenia with improvement in total white cell counts from 1200 to 3500 μL–1, platelet counts from 23 000 to 160 000 μL–1, serum ferritin from 7600 to 1200 ng/mL. Clinically, her fever subsided complete and regression was noted in the cervical lymphadenopathy and hepatosplenomegaly. She was continued on the above medications and was taken up for HSCT after 4 weeks. Both parents were found to be haplo-matched and there were no compatible matched donors in unrelated registries worldwide. She was taken up for a haploidentical stem cell transplant from her father with negative donor specific antibodies. Conditioning chemotherapy included rabbit anti-thymocyte globulin, fludarabine, treosulphan, and one dose of total body irradiation of 200 centigray. Posttransplant cyclophosphamide was given on Day +3 and Day +4 at 50 mg/kg/day. She achieved neutrophil engraftment by day 16 to 20 postinfusion. She is currently 100-day post HSCT with no significant graft-versus-host disease or post-HSCT complications with 100% donor chimerism documented on two occasions. The JAK1/2 pathway is activated by cytokines, specifically IFNgamma, IL-2 and IL-6, which are critical contributors to inflammation in HLH. Ruxolitinib inhibits the activation of JAK1/2 and its downstream signaling pathways.6 The U.S. Food and Drug Administration approved JAK 1/2 inhibitors, such as ruxolitinib for the treatment of polycythemia vera andmyelofibrosis in adults. Recent data support the efficacy of ruxolitinib in reducing the symptoms of proinflammatory diseases and graft-versus-host disease. Our patient had a dramatic improvement when she was started on ruxolitinib treatment, thereby facilitating symptom resolution, bringing in remission and served as an effective bridge to HSCT.