Comment on: The use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis1Paige Vicenzi, OMS-IV, 2Zahra Jiwani, DO, 3Ricardo Guirola, MD,1,4Tyler Hamby, PhD, 5Anish Ray, MD1Texas College of Osteopathic Medicine, University of North Texas Health Science Center2Department of Pediatrics, Children’s Hospital of Michigan3Department of Pediatric Rheumatology, Cook Children’s Health Care System4Department of Research Operations, Cook Children’s Health Care System5Department of Pediatric Hematology/Oncology, Cook Children’s Health Care SystemCorresponding Author:Anish Ray, MD1500 Cooper St., 5th floor,Fort Worth, TX 76104Phone: [email protected] Count: 497Number of Tables: 0Number of Figures: 1Running Title: Anakinra in Secondary HLHKeywords: hemophagocytic lymphohistiocytosis, anakinra, pediatricThe authors have no financial support or conflicts of interest.Hemophagocytic lymphohistiocytosis (HLH) is a rare yet potentially fatal systemic disease arising from uncontrolled activation of the immune system. According to the Histiocyte Society’s 2004 guidelines, patients must meet five of eight criteria to be diagnosed with HLH [1]. HLH may be classified into primary and secondary. Primary, or familial, HLH is attributed to underlying defects in genes that control natural killer (NK) and cytotoxic T-lymphocyte (CTL) cell degranulation. Secondary HLH, in contrast, may occur in the context of triggers, such as malignancy, rheumatologic disease, or infection. Systemic-onset juvenile idiopathic arthritis (SoJIA) is a well-recognized trigger of HLH and both share overlapping features (e.g. fever and elevated ferritin). Management of SoJIA includes the immunomodulator Anakinra, an interleukin 1 (IL-1) receptor antagonist hypothesized to dampen an overactive immune system. Three patients treated for HLH with concomitant SoJIA diagnosis at Cook Children’s Medical Center between 2014 and 2019 are described below in order to examine the role of immunomodulators in their clinical course and outcome.Three Hispanic patients (aged 8-15) presented with a constellation of systemic symptoms, including fever, generalized rash, fatigue, and weight loss. Upon fulfilment of necessary criteria and subsequent diagnosis of HLH, they were treated accordingly with HLH-2004 protocol. Case 3, whose HLH was suspected to be secondary to Epstein-Barr Virus (EBV) infection, rapidly responded to treatment and, therefore, briefly discontinued Etoposide; however, she tolerated this poorly and resumed treatment after a six-week hiatus with the addition of weekly Rituximab to mitigate rising EBV titers. All patients achieved remission.Past medical history for case 3 included autoimmune disorders such as celiac disease, type 1 diabetes and suspected idiopathic juvenile arthritis for which she did not require ongoing care prior to presenting with features of secondary HLH. Cases 1 and 2 were diagnosed with SoJIA following their HLH diagnosis. Cases 1 and 3 relapsed with HLH within months of their initial encounter. Due to their concurrent diagnosis of SoJIA, both received daily Anakinra. Case 3 experienced rapid resolution of symptoms. In contrast, Case 1 had unsatisfactory response of musculoskeletal manifestations prompting switch from Anakinra to weekly Tocilizumab—another biologic that antagonizes IL-6 receptor—with favorable response. Case 2 was started on daily Anakinra immediately following his diagnosis of SoJIA and has yet to relapse. In summary, all cases have yet to experience an additional relapse following introduction of Anakinra or Tocilizumab. Figure 1 provides the treatment timelines for Cases 1-3 who had 5.37, 2.87, and 4.62 years of follow up, respectively.Though traditional therapy for HLH includes intensive courses of etoposide and corticosteroids with substantial risk for morbidity and mortality, biologics represent a newer class of medications highly effective in treating diseases with inflammatory or immune-mediated components [2]. In a reimaging of the HLH treatment algorithm, a recent study proposes Anakinra as initial treatment with sequential escalation of immunosuppression to mitigate adverse effects [3]. This case series reinforces that immunomodulators, such as Anakinra, are safe and promising treatment options in pediatric patients with secondary HLH.

Comment on: Langerhans cell histiocytosis with BRAF p.N486_P490del or MAP2K1 p.K57_G61del treated by the MEK inhibitor trametinib1Paige Vicenzi, OMS-IV, 2Anish Ray, MD1Texas College of Osteopathic Medicine, University of North Texas Health Science Center2Department of Pediatric Hematology/Oncology, Cook Children’s Health Care SystemCorresponding Author:Anish Ray, MD1500 Cooper St., 5th floor,Fort Worth, TX 76104Phone: [email protected] Count: 513Number of Tables: 0Number of Figures: 0Running Title: Langerhans cell histiocytosis treated by trametinibKeywords: Langerhans cell histiocytosis, MAP2K1, trametinib, pediatricThe authors have no financial support or conflicts of interest.Langerhans cell histiocytosis (LCH) is a rare but heterogenous myeloid malignancy. The discovery of mitogen-activated protein kinase (MAPK) pathway activating mutations as key oncogenic drivers offered only equivocal implications at best; the promise of targeted therapy was often eclipsed by a more severe clinical course, risk organ involvement, poorer response to standard therapy, and higher risk of relapse.1 There is, however, mounting evidence in support of MAPK pathway inhibition for patients with BRAF V600E mutations. A recent report outlines rapid and durable response of relapsed, multisystemic LCH with either BRAF p.N486_P490 or MAP2K1 p.K57_G61 deletion to MEK inhibitor trametinib.2 Two of the three patients achieved nonactive disease, including a 2-year-old male with MAP2K1 deletion who, despite reports attributing trametinib resistance to MAP2K1 mutations3, continues to thrive. We take this opportunity to describe an analogous experience treating a relapsed LCH patient with trametinib at Cook Children’s Medical Center from early 2020 to present.Our patient is a 4-year-old male who presented in March 2017 with new onset central diabetes insipidus (DI) and skin rash; skin biopsy provided diagnosis of LCH, but skeletal survey was negative for bone involvement. He was treated with twelve cycles of cytarabine (100 milligram (mg)/m2 intravenous daily for five days, every four weeks) and DDAVP for DI. At the completion of cytarabine, a second skin biopsy revealed recurrence of LCH, which warranted treatment with hydroxyurea (20 mg/kilogram (Kg) daily) and methotrexate (2.5 mg at 0.12 mg/Kg twice a week). This was continued for 52 weeks despite a brief interruption of methotrexate due to dermatitis. Three months following completion of this therapy, brain MRI revealed a 7 mm lesion of the skull. Curettage by neurosurgery confirmed relapse of LCH in January 2020. Genetic testing of this sample was negative forBRAF mutation, but positive for a mutation in the MAP2K1 gene, specifically a point mutation resulting in a substitution of Q56P. Shortly after his biopsy, the patient developed a soft tissue swelling on his skull. Due to these results and his multiple relapses, the patient was started on trametinib (2.5 mg daily) in February 2020 with rapid resolution of skull swelling and transient but dramatic reduction of his desmopressin dose from 3.2 mg twice a day to 0.2 mg twice a day. He has not experienced toxicity and continues to tolerate the drug well.Though trametinib presents a promising treatment for high-risk, relapsed LCH, it is not without limitations. In 2020, we also treated a 15-year-old male with relapsed LCH and BRAF V600E with trametinib monotherapy. Due to skin rash (Grade II), the patient became noncompliant. Despite stopping altogether after a month of treatment, he has yet to experience disease recurrence. But as stated in the aforementioned report, sufficient dose and treatment length to attain MAPK pathway suppression merits further investigation. In our similar experience treating a young child with multisystemic LCH and MAP2K1 mutation, we remain encouraged that MEK inhibition via trametinib monotherapy is a viable treatment option. In the context of genomic landscaping, we hope to incite further exploration of targeted therapy, and consequently, greater consensus on LCH management.

Hemophagocytic lymphohistiocytosis (HLH) is a rare yet potentially fatal systemic disease arising from uncontrolled activation of the immune system. According to the Histiocyte Society’s 2004 guidelines, patients must meet five of eight criteria to be diagnosed with HLH [1]. HLH may be classified into primary and secondary. Primary, or familial, HLH is attributed to underlying defects in genes that control natural killer (NK) and cytotoxic T-lymphocyte (CTL) cell degranulation. Secondary HLH, in contrast, may occur in the context of triggers, such as malignancy, rheumatologic disease, or infection. Systemic-onset juvenile idiopathic arthritis (SoJIA) is a well-recognized trigger of HLH and both share overlapping features (e.g. fever and elevated ferritin). Management of SoJIA includes the immunomodulator Anakinra, an interleukin 1 (IL-1) receptor antagonist hypothesized to dampen an overactive immune system. Three patients treated for HLH with concomitant SoJIA diagnosis at Cook Children’s Medical Center between 2014 and 2019 are described below in order to examine the role of immunomodulators in their clinical course and outcome.Three Hispanic patients (aged 8-15) presented with a constellation of systemic symptoms, including fever, generalized rash, fatigue, and weight loss. Upon fulfilment of necessary criteria and subsequent diagnosis of HLH, they were treated accordingly with HLH-2004 protocol. Case 3, whose HLH was suspected to be secondary to Epstein-Barr Virus (EBV) infection, rapidly responded to treatment and, therefore, briefly discontinued Etoposide; however, she tolerated this poorly and resumed treatment after a six-week hiatus with the addition of weekly Rituximab to mitigate rising EBV titers. All patients achieved remission.Past medical history for case 3 included autoimmune disorders such as celiac disease, type 1 diabetes and suspected idiopathic juvenile arthritis for which she did not require ongoing care prior to presenting with features of secondary HLH. Cases 1 and 2 were diagnosed with SoJIA following their HLH diagnosis. Cases 1 and 3 relapsed with HLH within months of their initial encounter. Due to their concurrent diagnosis of SoJIA, both received daily Anakinra. Case 3 experienced rapid resolution of symptoms. In contrast, Case 1 had unsatisfactory response of musculoskeletal manifestations prompting switch from Anakinra to weekly Tocilizumab—another biologic that antagonizes IL-6 receptor—with favorable response. Case 2 was started on daily Anakinra immediately following his diagnosis of SoJIA and has yet to relapse. In summary, all cases have yet to experience an additional relapse following introduction of Anakinra or Tocilizumab. Figure 1 provides the treatment timelines for Cases 1-3 who had 5.37, 2.87, and 4.62 years of follow up, respectively.The diagnosis of HLH remains elusive and is often accompanied with multiple systemic manifestations that overlap with other disorders. Though traditional therapy for HLH includes intensive courses of etoposide and corticosteroids, biologics represent a newer class of medications highly effective in treating diseases with inflammatory or immune-mediated components [2]. This case series reinforces that immunomodulators, such as Anakinra, are promising treatment options in pediatric patients with HLH secondary to SoJIA.