Pediatric Blood & Cancer | 2021
Combined use of emapalumab and ruxolitinib in a patient with refractory hemophagocytic lymphohistiocytosis was safe and effective
Abstract
To the Editor: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome of immune dysregulation driven by abnormal lymphocyte and macrophage activation and proliferation. CD8+ T lymphocytes secrete interferon-gamma (IFN-γ) on activation, which then causes macrophages to produce inflammatory cytokines, including chemokine motif ligand (CXCL)-9. Many HLH cases are related to an inability to control a viral infection, such as Epstein–Barr virus (EBV). Some cases of EBV-driven HLH are due to chronic active EBV (CA-EBV), wherein EBVmay infect T andNKwith progression to lymphoproliferative neoplasms. We report a case of CA-EBV-associated HLH, with central nervous system (CNS) involvement, that was refractory to HLH-2004 treatment and interleukin-1 blockade (anakinra). He achieved remission with the novel combination of emapalumab and ruxolitinib. This is the first report to our knowledge combining these drugs. This combination therapy was well tolerated, resulted in a complete disease remission, and allowed a successful hematopoietic stem cell transplant (HSCT) with 100% donor chimerism. The patient was diagnosed with HLH at 26 years of age when he presented with recurrent fevers, hemophagocytosis on BM biopsy, hypogammaglobulinemia (109 mg/dl), and EBV viremia (362,318 IU/ ml). Hemet additional criteria for HLH (Table S1). Bonemarrow biopsy was notable for absence of B cells. Fourteen months prior he had been diagnosed with nephrotic syndrome (NS), including proteinuria, hypogammaglobulinemia (234 mg/dl), and kidney biopsy consistent with minimal change disease. EBV viremia (43,006 IU/ml) had been observed 7months prior to HLH diagnosis. NSwas treated with steroids and cyclosporin A (CSA). Based on his duration of EBV viremia and presence of EBV in non-B cells (T andNK cells, Table S2), hewas diagnosedwith CA-EBV. Genetic testing for causes ofHLH (Cincinnati Children’sMolecularGenetic Lab) was negative. Whole exome sequencing was performed at the Children’s Hospital of Philadelphia and did not identify a variant in genes known to be associated with inborn errors of immunity.1 He was of Afro-Carribean andmixedNorthernEuropean ancestry, had no full siblings, and no family history of HLH or immunodeficiency. His history was remarkable for recurrent ear infections, including during childhood and adolescence. Hehad anHLH flare after 8weeks of dexamethasone therapy,which necessitated addition of etoposide. There was no sign of CNS involvement. He developed prolonged severe cytopenias with etoposide, sepsis secondary to Escherichia coli bacteremia, and nonhealing pressure ulcers. He developed steroid-induced deliriumwhile hospitalized. This improved with weaning steroids; CSA and anakinra were added. He developed significant steroid-induced myopathy and depression; Karnofsky performance score fell to 50. One month later, he had a second HLH flare while off therapeutic steroids, but with subtherapeutic CSA. Blood CXCL9 was 12,260 pg/ml (upper limit of normal [ULN]:121). Relapse featured significant CNS involvement complicated by status epilepticus. Cerebrospinal fluid neopterin was 283.5 nmol/L (ULN:16.5). Etoposide and dexamethasone were restarted. The treatment with intrathecal methotrexate was held given the refractory seizures and altered mental status. His Karnofsky performance status declined to 40. Because of CNS disease and medication intolerance, emapalumab was started twice a week for 2 months (17 doses). His CXCL9 rapidly decreased (Figure 1) to 5185 pg/ml, 6 days after starting therapy. His mental health declined with appearance of suicidal ideation. Given refractory HLH, inadequate performance status for HSCT eligibility, and suicidal ideation, ruxolitinib was started 2 weeks after emapalumab. Ruxolitinib was up-titrated to 25 mg/m2/day (50% dose reduction based on posaconazole interaction). He tolerated the combination well; his only infection was severe Herpes simplex virus (HSV) stomatitis, treated with acyclovir/ valacyclovir. His Karnofsky performance score improved to 60 after physical rehabilitation. He received a mismatched (9/10) unrelated donor peripheral stem cell transplant with TCRαβ/CD19-depletion (NCT03145545) after conditioning with thymoglobulin, busulfan, fludarabine, thiotepa, and posttransplant rituximab. Emapalumab was last given day -16 from transplant and ruxolitinib day -12, two days prior to conditioning. He had persistent fevers starting on day -3, with hyperferritinemia (19,076 mg/dl), and increased CXCL9 (434 pg/ml); presumedHLH flare was treated withmethylprednisolone. He engrafted at day 13 (absolute neutrophil count > 500/mm3 × 3 days). Day 28 chimerism studies showed 99% donor in nonenriched peripheral blood cells and 98% T cell, 100% myeloid cell, and 100% NK donor cells. Peripheral blood at day 60 and 120 showed 100% chimerism (B cells were insufficient). EBV DNA by PCR decreased from 169,787 IU/ml prior to transplant to <5700 IU/ml 1 week after transplant. EBV PCR was negative 2 months after HSCT. He developed mild acute graft-versus-host disease of the skin (stage 2, grade