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 consent document. * 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 diagnostic criteria, or have familial/primary HLH with pathogenic/likely pathogenic germline variant(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 virus infection, and neoplasia (XMEN), Hermansky-Pudlak syndrome (HPS), NLR family CARD domain-containing protein 4 (NLCR4) or other immune regulatory genes. * Fever \>= 38.5 degrees Celsius (C) (or \>= 38 degrees C if acetaminophen given in prior 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, lymph node, or liver. * Low/absent natural killer (NK)-cell activity/perforin and/or decreased CD107a mobilization. * Ferritin \>= 500 ug/L. * Soluble IL-2 receptor (sCD25) \> 2400 U/mL or two standard deviations above age-adjusted laboratory-specific norms. * The effects of ruxolitinib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception for the duration of study participation and for two months after last administration of study treatment. * Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. * Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and two months after last administration of study treatment. Exclusion Criteria: * Participant is receiving or received any other investigational agent within 1 week of the first dose of treatment. * Females who are pregnant or breastfeeding. Female participants of child-bearing potential must have a negative pregnancy test within 7 days of treatment and lactating females must discontinue breast feeding during treatment and until two weeks after the final dose of ruxolitinib. * Males who expect to conceive children, and/or who decline highly effective methods of 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 unstable angina, acute myocardial infarction, or stroke within 6 months, New York Heart Association class III or IV. congestive heart failure, and arrhythmia requiring therapy or uncontrolled hypertension (blood pressure \> 170/100 mmHg) unless approved by 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 for End- Stage Liver Disease (MELD) score of \> 20, or aspartate aminotransferase (AST) or alanine transaminase (ALT) values \> 1000 not expected to improve with HLH therapy. * Severe organ dysfunction, such as cardiorespiratory failure requiring inotropic medications or extracorporeal life support. Respiratory support including intubation/ventilation is allowed. \* Vasopressors are allowed if not required other than low dose vasoconstrictors to compensate the effects of sedation. * Newly diagnosed acute and clinically active tuberculosis, hepatitis B, and/or hepatitis C. * Patients with active human immunodeficiency virus (HIV) are not excluded from this study but must be on antiretrovirals. * Patients with hepatitis B or C viremia can be on study if the hepatitis is not considered clinically active and/or if it is chronic. These patients should be discussed with the principal investigator. * Individuals with a prior malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen. * Individuals with chimeric antigen receptor (CAR)-T-associated HLH. * No prior HLH-directed therapy except corticosteroids for \< 2 consecutive weeks and anakinra. * Adjunctive approaches such as rituximab for Epstein-Barr virus (EBV) viremia or IVIG for viral infection are permitted. * Emapalumab, alemtuzumab, anti-thymocyte globulin (ATG), tocilizumab, siltuximab, or prior ruxolitinib are NOT permitted. Cyclosporine and tacrolimus are not permitted in the initial induction period. * Hypersensitivity to ruxolitinib or any of its excipients