Use Of A Response-Adapted Ruxolitinib-Containing Regimen For The Treatment Of Hemophagocytic Lymphohistiocytosis

Frontline Arm: Safety Phase and Expansion Phase Safety Phase: The Frontline Arm will begin with a Safety Phase to identify a feasible and safe dose of ruxolitinib to be given in combination with the "gold standard" HLH-directed agents dexamethasone and etoposide using a response-adapted approach. For this part of the trial, a minimum of 6 newly diagnosed HLH patients will be included. These patients will first receive ruxolitinib 25 mg/m\^2/dose by mouth BID (twice a day) and dexamethasone 5 mg/m\^2/dose PO or IV BID. For patients whose HLH responds favorably (as outlined in the protocol), ruxolitinib will be continued for 8 weeks if it is tolerated. Dexamethasone will be weaned, as tolerated, over 8 weeks and then discontinued. For patients whose HLH does not respond favorably (as outlined in the protocol), etoposide 150 mg/m2 IV weekly will be added. The dose of ruxolitinib may be escalated or de-escalated as needed, based on observed toxicities and surrogates of disease response. Expansion Phase: When a dose of ruxolitinib deemed feasible and safe is identified, the Expansion Phase of the Frontline Arm will begin. Patients with newly diagnosed HLH in the Expansion Phase will receive ruxolitinib (at the maximally tolerated dose \[MTD\] established in the Safety Phase) and dexamethasone 5 mg/m\^2/dose by mouth or IV BID. For patients whose HLH responds favorably (as outlined in the protocol), ruxolitinib will be continued for 8 weeks if it is tolerated. Dexamethasone will be weaned, as tolerated, over 8 weeks and then discontinued. For patients whose HLH does not respond favorably (as outlined in the protocol), etoposide 150 mg/m\^2 IV weekly will be added. The first dose of dexamethasone will be given at least 8 hours after the first dose of ruxolitinib for PK testing purposes, but patients will not be excluded if dexamethasone has already been started before initiating of ruxolitinib. Disease response evaluations will be completed at 1, 2, 4, 6, and 8 weeks. Treatment will be individualized based on response. Patients whose HLH responds favorably after 1 week (SD 8) of therapy (e.g., favorable response (FR), Week 1) will remain on ruxolitinib and dexamethasone. As long as patients show a CR or partial response (PR) at Week 2 (SD15), ruxolitinib and dexamethasone are tolerated, and patients are clinically stable, they will remain on both agents for the remainder of the 8-week study period. Dexamethasone will be weaned every 2 weeks as tolerated. In case of disease reactivation, therapy will be re-intensified. Patients whose HLH responds unfavorably after 1 week (SD8) of therapy (e.g., unfavorable response, Week 1) will have etoposide added (150 mg/m\^2/dose, IV weekly). If patient meets CR or PR at Week 2 (SD15), then combination treatment with ruxolitinib, dexamethasone, and etoposide will be continued until Week 4 disease evaluation (SD 29). If patients have a CR or PR at the Week 4 disease evaluation (SD 29) or later, further etoposide doses may be held at site PI discretion. Dexamethasone weaning may continue beyond the 8-week study period. Patients whose HLH does not respond favorably (e.g., exhibit non-response (NR), progressive disease (PD)) despite treatment with ruxolitinib, dexamethasone, and etoposide will be taken off treatment and salvage therapy will be considered and decided by the treating physician. Salvage Arm: Patients with relapsed/refractory HLH will be treated on the Salvage Arm. They will not be included in the Safety Phase but will use the same response-adapted approach. Patients may be enrolled on the Salvage Arm as the Safety Phase is ongoing. Patients will receive ruxolitinib 25 mg/m\^2/dose by mouth BID and dexamethasone 5 mg/m\^2/dose by mouth or IV BID. The first dose of dexamethasone will be given at least 8 hours after the first dose of ruxolitinib for PK testing purposes, but patients will not be excluded if dexamethasone has already been started before starting ruxolitinib. Disease response evaluations will be completed at 1, 2, 4, 6, and 8 weeks. Treatment will be individualized based on response as described for the Expansion Phase of the Frontline Arm. When the MTD of ruxolitinib has been determined on the Safety Phase of the Frontline Arm, it will be the dose used for any additional patients enrolled on the Salvage Arm. Any patients already on the Salvage Arm who show no adverse effects or toxicity at an assigned dose of 25 mg/m\^2 BID will be continued on this dose for the 8 week study period. HLH Reactivation: For patients who initially respond favorably but then worsen (e.g., "reactivate") during the later phases of induction when dexamethasone is weaned, dexamethasone will be increased back to 5 mg/m\^2/dose PO/IV BID (10 mg/m\^2/day). If the patient is on a reduced dose of ruxolitinib due to prior toxicity(ies), the ruxolitinib dose may be increased to patient's starting dose, provided the prior toxicity(ies) has resolved for at least 1 week. Patients whose HLH responds favorably will continue to receive ruxolitinib and dexamethasone or ruxolitinib, dexamethasone and etoposide. Patients receiving ruxolitinib, dexamethasone and etoposide whose HLH responds unfavorably will be taken off treatment and be considered for an alternative salvage therapy. For patients receiving ruxolitinib and dexamethasone whose HLH responds unfavorably, etoposide may be added. If the response is favorable, the patient will continue on all 3 medications. If the response is unfavorable after adding etoposide, the patient will be taken off treatment and will be considered for an alternative salvage therapy. All patients with CNS disease will receive intrathecal (IT) MTX and hydrocortisone (HC), per age-based dosing, once per week for up to 4 weeks. Patients will be followed for one year after starting protocol therapy or 1 year after HSCT (for those undergoing HSCT).