Response-Adapted Ruxolitinib-Containing Regimen for the Treatment of Hemophagocytic Lymphohistiocytosis

Inclusion Criteria

• FRONTLINE ARM: Patient is >= 6 weeks and =< 22 years of age
• FRONTLINE ARM: Patient weighs >= 3 kg
• FRONTLINE ARM: Patient is able to take medication PO and/or patient or parent is willing to have nasogastric (NG) tube placed if patient is unable to take medications PO
• FRONTLINE ARM: Patient has active HLH if >= 5 of 8 diagnostic HLH criteria listed below OR patient has known familial (f)HLH (e.g., patient has pathogenic/likely pathogenic germline variant[s] in genes such as PRF1, UNC13D, STX11, STXBP2, LYST, RAB27A, XIAP, SH2D1A, NLCR4) and meets >= 4 of the diagnostic HLH criteria listed below, OR patient has high likelihood of fHLH based on absent perforin, SAP, XIAP expression and meets >= 4 of the diagnostic HLH criteria listed below: * Fever * Splenomegaly if present at any point prior to starting study drug * Cytopenias affecting >= 2 of 3 cell lineages in the peripheral blood (hemoglobin < 9 g/dL, platelets < 100 x 10^9/L, absolute neutrophil count (ANC) < 1000 mm^3) * Hypertriglyceridemia (fasting triglycerides >= 265 mg/dL) or hypofibrinogenemia (fibrinogen =< 150 mg/dL) * Presence of hemophagocytosis in bone marrow (BM) or other tissues * Low or absent natural killer (NK)-cell activity (if present at any point prior to starting study drug) OR decreased CD107a mobilization (if present at any point prior to starting study drug) * Ferritin >= 500 ng/mL * Soluble IL-2 receptor (CD25) >= 2400 U/mL
• FRONTLINE ARM: Patient has not received prior HLH therapy, except steroids (any dose or length of therapy is allowed) OR anakinra (any dose or length of therapy is allowed)
• FRONTLINE ARM: Patient, parent, or legal authorized representative (LAR) must provide informed consent
• SALVAGE ARM: Patient weighs >= 3 kg
• SALVAGE ARM: Patient or parent is willing to have the NG tube placed if patient is unable to take medications PO
• SALVAGE ARM: Patient has past history of HLH, defined as meeting >= 5 of 8 HLH-2004 diagnostic criteria for those with no known HLH-associated mutations, OR >= 4 of 8 HLH-2004 diagnostic criteria for those with known familial disease
• SALVAGE ARM: Patient must have active HLH at the time of eligibility assessment, defined as 3 or more of the following relapsed/refractory HLH criteria: * Fever * Splenomegaly (recurrent or worsening) * ANC < 1000 mm^3 x 2 assessments over at least 3 days OR platelets < 100 x 10^9/L x 2 assessments over at least 3 days, OR need for platelet transfusions * Hypofibrinogenemia (fibrinogen =< 150 mg/dL) * Soluble IL-2 receptor level >= 2400 U/mL * Worsening central nervous system (CNS) symptoms OR new abnormal brain magnetic resonance imaging (MRI) findings deemed consistent with CNS HLH by the primary treating physician OR cerebrospinal fluid (CSF) cell count > 5/mm^3 (with or without hemophagocytosis) OR CSF protein higher than the institutional upper limit of normal OR CSF neopterin higher than the institutional upper limit of normal * Presence of hemophagocytosis in BM or other tissues * Increasing ferritin x 2 assessments over at least 3 days (both levels must be > 2000 ng/mL)
• SALVAGE ARM: Patient must be deemed by the primary treating physician to have not responded to prior therapy by either not having or maintaining a response
• SALVAGE ARM: Patient must have received prior HLH-directed therapy: * At least 2 weeks of steroids (equivalent to at least 5 mg/m^2/day dexamethasone or 1 mg/kg/day methylprednisolone) AND at least 2 doses of etoposide OR * At least 1 dose of anti-thymocyte globulin (ATG)
• SALVAGE ARM: Patient or parent/LAR must provide informed consent

Exclusion Criteria

• Patient is < 6 weeks or > 22 years of age
• Patient weighs < 3 kg
• Patient has isolated CNS disease
• Life expectancy is < 2 weeks
• Patient is likely to require < 4 weeks of therapy (e.g., HSCT is imminent)
• Patients with creatinine clearance (CrCl) < 15 mL/min who are NOT receiving dialysis
• Patient has evidence of severe organ dysfunction, defined as: severe liver dysfunction (alanine aminotransferase [ALT] > 1000 U/L), OR cardiorespiratory failure requiring any ionotropic support OR extracorporeal life support, OR high frequency oscillatory ventilation, other forms of respiratory support or ventilation are allowed if the patient is not on vasopressors)
• Patient with pre-existing rheumatologic disorder
• Patient with known active malignancy
• Patient with previous HSCT, except when HSCT was for treatment of HLH
• Patient is pregnant or lactating
• Patients who expect to conceive or father children within the projected duration of the study and/or who are unwilling to use highly effective methods of contraception throughout the duration of the study, starting with the screening visit through the end of the treatment visit
• Patient has suspected or known fungal disease
• Patient is unable to tolerate administration of drugs PO or NG
• Patient is taking rifampin or St. John’s wort
• Patient is taking another investigational agent or is enrolled on another treatment protocol
• Patient, parent, or LAR are unable or unwilling to provide informed consent
• FRONTLINE ARM: Patient has or is receiving treatment with a JAK inhibitor (including ruxolitinib), ATG, alemtuzumab, etoposide, tocilizumab, emapalumab or any other HLH-directed therapy other than steroids or anakinra
• SALVAGE ARM: Patient has or is receiving treatment with a JAK inhibitor (including ruxolitinib), alemtuzumab, within the last 3 months
• SALVAGE ARM: Patient has received therapy on the Frontline Arm of this trial