Ruxolitinib With De-Intensified HLH-94 for the Treatment of Hemophagocytic Lymphohistiocytosis (HLH)

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consentdocument.

• Males and females, 18 years of age or older at the time of enrollment.

• Participants must have active HLH and meet >= 5 of 8 of the HLH-2004 diagnosticcriteria, or have familial/primary HLH with pathogenic/likely pathogenic germlinevariant(s) in genes known to cause HLH (e.g., PRF1, UNC13D, Syntaxin 11 (STX11),Syntaxin-binding protein 2 (STXBP2), RAB27A, SH2 domain-containing protein 1A (SH2D1A), baculovirus inhibitor of apoptosis repeat containing protein 4 (BIRC4),Lysosomal trafficking regulator (LYST), interleukin-2-inducible T-cell kinase (ITK),SLC7A7, X-linked immunodeficiency with magnesium defect, Epstein-Barr virusinfection, and neoplasia (XMEN), Hermansky-Pudlak syndrome (HPS), NLR family CARDdomain-containing protein 4 (NLCR4) or other immune regulatory genes.

• Fever >= 38.5 degrees Celsius (C) (or >= 38 degrees C if acetaminophen given inprior 6 hours).

• Splenomegaly.

• Peripheral cytopenias involving >= 2 of 3 cell lines (absolute neutrophil count < 1000/uL; hemoglobin < 9 g/dL; platelets < 100,000/uL).

• Hypertriglyceridemia (fasting triglycerides >= 265 mg/dL) or Hypofibrinogenemia (fibrinogen =< 150 g/dL).

• Hemophagocytosis on tissue biopsy, such as in the bone marrow, spleen, lymphnode, or liver.

• Low/absent natural killer (NK)-cell activity/perforin and/or decreased CD107amobilization.

• Ferritin >= 500 ug/L.

• Soluble IL-2 receptor (sCD25) > 2400 U/mL or two standard deviations aboveage-adjusted laboratory-specific norms.

• The effects of ruxolitinib on the developing human fetus are unknown. For thisreason, women of child-bearing potential and men must agree to use adequatecontraception for the duration of study participation and for two months after lastadministration of study treatment.

• Should a woman become pregnant or suspect she is pregnant while she or herpartner is participating in this study, she should inform her treatingphysician immediately.

• Men treated or enrolled on this protocol must also agree to use adequatecontraception prior to the study, for the duration of study participation, andtwo months after last administration of study treatment.

Exclusion Criteria:

• Participant is receiving or received any other investigational agent within 1 weekof the first dose of treatment.

• Females who are pregnant or breastfeeding. Female participants of child-bearingpotential must have a negative pregnancy test within 7 days of treatment andlactating females must discontinue breast feeding during treatment and until twoweeks after the final dose of ruxolitinib.

• Males who expect to conceive children, and/or who decline highly effective methodsof contraception during the entire duration of the study.

• Patient cannot take medications orally or via a nasogastric/orogastric tube.

• Poor life expectancy < 2 weeks.

• Clinically significant or uncontrolled cardiovascular disease, including unstableangina, acute myocardial infarction, or stroke within 6 months, New York HeartAssociation class III or IV. congestive heart failure, and arrhythmia requiringtherapy or uncontrolled hypertension (blood pressure > 170/100 mmHg) unless approvedby the sponsor- investigator.

• Estimated creatine clearance (CrCl) < 15 mL/min while not on dialysis.

• Known (biopsy-confirmed) liver cirrhosis or suspected cirrhosis with a Model forEnd- Stage Liver Disease (MELD) score of > 20, or aspartate aminotransferase (AST)or alanine transaminase (ALT) values > 1000 not expected to improve with HLHtherapy.

• Severe organ dysfunction, such as cardiorespiratory failure requiring inotropicmedications or extracorporeal life support. Respiratory support includingintubation/ventilation is allowed.

• Vasopressors are allowed if not required other than low dose vasoconstrictors tocompensate the effects of sedation.

• Newly diagnosed acute and clinically active tuberculosis, hepatitis B, and/orhepatitis C.

• Patients with active human immunodeficiency virus (HIV) are not excluded fromthis study but must be on antiretrovirals.

• Patients with hepatitis B or C viremia can be on study if the hepatitis is notconsidered clinically active and/or if it is chronic. These patients should bediscussed with the principal investigator.

• Individuals with a prior malignancy whose natural history or treatment has thepotential to interfere with the safety or efficacy assessment of the investigationalregimen.

• Individuals with chimeric antigen receptor (CAR)-T-associated HLH.

• No prior HLH-directed therapy except corticosteroids for < 2 consecutive weeks andanakinra.

• Adjunctive approaches such as rituximab for Epstein-Barr virus (EBV) viremia orIVIG for viral infection are permitted.

• Emapalumab, alemtuzumab, anti-thymocyte globulin (ATG), tocilizumab,siltuximab, or prior ruxolitinib are NOT permitted. Cyclosporine and tacrolimusare not permitted in the initial induction period.

• Hypersensitivity to ruxolitinib or any of its excipients