Use Of A Response-Adapted Ruxolitinib-Containing Regimen For The Treatment Of Hemophagocytic Lymphohistiocytosis
Hemophagocytic Lymphohistiocytosis
About this trial
This is an interventional treatment trial for Hemophagocytic Lymphohistiocytosis focused on measuring Hemophagocytic lymphohistiocytosis, Newly Diagnosed, Frontline therapy, Refractory, Relapsed, Response-adapted, Salvage therapy
Eligibility Criteria
Inclusion Criteria: Frontline Arm:
- Patient is ≥6 weeks and ≤22 years of age.
- Patient weighs ≥3 kg.
- Patient is able to take medication PO and/or patient or parent is willing to have NG tube placed if patient is unable to take medications PO.
Patient has active HLH if ≥5 of 8 HLH-2004 diagnostic criteria listed below OR patient has known fHLH (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 HLH-2004 diagnostic criteria listed below:
- Fever
- Splenomegaly
- Cytopenias affecting ≥2 of 3 cell lineages in the peripheral blood (hemoglobin <9 g/dL, platelets <100 × 10^9/L, neutrophils <1000 × 10^6/L)
- Hypertriglyceridemia (fasting triglycerides ≥265 mg/dL) or hypofibrinogenemia (fibrinogen ≤150 g/dL)
- Presence of hemophagocytosis in BM or other tissues
- Low or absent NK-cell activity OR decreased CD107a mobilization
- Ferritin ≥500 ng/mL
- Soluble IL-2 receptor (CD25) ≥2400 U/mL
- Patient has not received prior HLH therapy, except steroids (any dose is allowed, but patient must not have been treated for more than 2 consecutive weeks) OR anakinra (any dose or length of therapy is allowed).
- Patient, parent, or legal authorized representative (LAR) must provide informed consent.
Inclusion Criteria: Salvage Arm:
- Patient is ≥6 weeks and ≤22 years of age.
- Patient weighs ≥3 kg.
- Patient or parent is willing to have the NG tube placed if patient is unable to take medications PO.
- 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.
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)
- Neutrophils <1000 × 10^6/L × 2 assessments over at least 3 days OR platelets <100 × 10^9/L × 2 assessments over at least 3 days, OR need for platelet transfusions
- Hypofibrinogenemia (fibrinogen <150 g/dL)
- Soluble IL-2 receptor level ≥ 2400 U/L
- Worsening CNS symptoms OR new abnormal brain magnetic resonance imaging (MRI) findings deemed consistent with CNS HLH by the primary treating physician OR CSF cell count >5 (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 the BM or other tissues
- Increasing ferritin × 2 assessments over at least 3 days (both levels must be >2000 ng/dL)
- Patient must be deemed by the primary treating physician to have not responded to prior therapy by either not having or maintaining a response
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 (with at least 7 days between the last etoposide dose and starting ruxolitinib); OR
- At least 1 dose of ATG (with at least 7 days between the last ATG dose and starting ruxolitinib)
- Patient or parent/LAR must provide informed consent.
Exclusion Criteria: Frontline and Salvage Arms:
- 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 (i.e., 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 (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.
Additional Exclusion Criteria for the 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 (as defined in the Frontline Arm Inclusion Criteria, #5).
Additional Exclusion Criteria for the Salvage Arm:
- Patient has or is receiving treatment with a JAK inhibitor (including ruxolitinib), tocilizumab, alemtuzumab, OR emapalumab within the last 3 months.
- Patient has received therapy on the Frontline Arm of this trial.
Sites / Locations
- Phoenix Children's HospitalRecruiting
- Children's Hospital of Orange CountyRecruiting
- University of California San FranciscoRecruiting
- Children's National Medical CenterRecruiting
- John Hopkins UniversityRecruiting
- Dana-Farber Cancer InstituteRecruiting
- Cohen Children's Medical CenterRecruiting
- Levine Children's HospitalRecruiting
- Children's Hospital of PhiladelphiaRecruiting
- St. Jude Children's Research HospitalRecruiting
- Children's Wisconsin/Medical College of WisconsinRecruiting
Arms of the Study
Arm 1
Arm 2
Experimental
Experimental
Frontline Arm
Salvage Arm
Safety Phase: Patients with newly diagnosed HLH will receive ruxolitinib PO or NGT, dexamethasone, PO or IV and etoposide IV. Expansion Phase: Patients with newly diagnosed HLH treatment will begin with ruxolitinib PO or NGT at the MTD dose. Dexamethasone will be administered PO or IV. Etoposide IV will be added based on disease response.
Patients with relapsed/refractory HLH will receive ruxolitinib PO or NGT and dexamethasone PO or IV. Etoposide IV will be added based on disease response.