This phase II trial tests the effects of ruxolitinib in combination with a de-intensified HLH-94 drug regimen has on patients with newly diagnosed hemophagocytic lymphohistiocytosis (HLH), a disorder caused by dysregulated immune responses (that is, immune responses that are too strong and cause inflammatory damage to normal tissues). The therapy used for HLH decreases the activity of the immune system. Ruxolitinib is a type of drug called a kinase inhibitor. It works by blocking the signals that cause inflammatory cells to multiply. De-intensified HLH-94 is a treatment regimen that includes 4 weeks of dexamethasone with the dose being decreased each week, and up to 4 weeks of etoposide. This combination is commonly used to treat HLH. Dexamethasone is a steroid medication that works by fighting inflammation. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and deoxyribonucleic acid (DNA) repair and may kill cancer cells and is used to kill the types of white blood cells in HLH that are attacking the body. Giving ruxolitinib in combination with a de-intensified HLH-94 drug regimen may reduce toxic exposure to therapy while maintaining efficacy in patients with HLH.
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).
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.
Single group
Ruxolitinib
DrugAdministered Orally (PO)
Etoposide
DrugAdministered IV
Dexamethasone
DrugAdministered PO or IV
Non-interventional Imaging
Procedure/SurgeryParticipants undergo abdominal ultrasound and/or magnetic resonance imaging (MRI)
Research Biopsy
Procedure/SurgeryBone marrow biopsy and lymph node biopsy will be obtained during screening and as clinically indicated throughout the trial.
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Overall response rate (ORR)
The proportion of responder (complete response (CR), complete response with incomplete hematologic recovery, or partial response (PR)) or non-responder at the end of induction using a physician developed response criteria will be reported. Those with non-malignant HLH (nmHLH) will be assessed for response, defined as complete response (CR) + partial response (PR) at 4 weeks. Participants diagnosed with a malignant trigger are recommended to undergo cancer-directed therapy once acute hypercytokinemia improves. The primary endpoint for malignant HLH (mHLH) is achievement of PR or better and initiation of cancer-directed therapy (non-HLH specific therapy) by 4 weeks.
Proportion of participants reporting high-grade adverse events
Safety analyses will be descriptive and performed based on the safety population, defined as patients who received at least one dose of study drug. Serious adverse events (SAEs), adverse events (AEs) ≥ grade 3, and AEs resulting in discontinuation of treatment, withdrawal from the study, and deaths on-study will be tabulated.
Best Response Rate
The proportion of responders by best response defined as a complete response (CR), complete response with incomplete hematologic recovery, partial response (PR) or stable disease (SD)) using a physician developed response criteria will be reported.
Median Time to Best Response
The median time in months from the time of treatment initiation until participants best response at 12 months after the end of continuation therapy will be reported.
Median Duration of Best Response
The median time in months from the participants obtained a best response from until 12 months after the end of continuation therapy, participant withdrawal, or death will be reported.
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Jerry Lee, MD, MSc, MPhil
Lead sponsor
University of California, San Francisco
Sponsor institution
Incyte Corporation
Collaborator
UC Hematological Malignancies Consortium (UCHMC)
Collaborator
