Ruxolitinib Combination for Hemophagocytic Lymphohistiocytosis

Overseen By Charles Sydnor

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Francisco

Must not be taking: Emapalumab, Alemtuzumab

Disqualifiers: Pregnancy, Cardiovascular disease, Liver cirrhosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 30

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effects of combining ruxolitinib, a drug that blocks signals causing inflammation, with a less intense version of a common treatment for hemophagocytic lymphohistiocytosis (HLH). HLH occurs when the immune system becomes overly active and attacks the body's own tissues. The trial aims to determine if this combination is effective while reducing side effects. Suitable participants have newly diagnosed HLH with symptoms such as persistent fever and an enlarged spleen. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, certain medications like cyclosporine and tacrolimus are not allowed during the initial induction period, and prior use of some HLH-directed therapies is restricted.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the treatment combination for hemophagocytic lymphohistiocytosis (HLH) using ruxolitinib, dexamethasone, and etoposide is generally well-tolerated.

Ruxolitinib calms the immune system. Studies have found it safe for people with HLH, with patients experiencing fewer symptoms and better survival rates.

Dexamethasone, a steroid that reduces inflammation, is considered safe and effective for treating HLH. It is often used with ruxolitinib in studies, showing good results.

Etoposide targets certain white blood cells that attack the body. As a standard part of HLH treatment, it has improved survival rates.

Overall, these treatments have been studied for safety in people with HLH and have shown positive results, with manageable side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for HLH?

Researchers are excited about the combination of ruxolitinib, dexamethasone, and etoposide for treating Hemophagocytic Lymphohistiocytosis (HLH) because it introduces a novel approach by incorporating ruxolitinib, a JAK1/2 inhibitor, which is not part of the standard treatment. Most existing HLH treatments rely heavily on immunosuppressive and chemotherapy drugs like dexamethasone and etoposide. However, ruxolitinib offers a targeted mechanism by blocking specific pathways (JAK1/2) that are crucial in the inflammatory process of HLH. This precise targeting may lead to better control of inflammation and potentially fewer side effects compared to traditional therapies. The integration of ruxolitinib alongside established drugs could enhance overall treatment efficacy and transform HLH management.

What evidence suggests that this treatment might be an effective treatment for HLH?

In this trial, participants will receive a combination treatment of ruxolitinib, dexamethasone, and etoposide for hemophagocytic lymphohistiocytosis (HLH). Research has shown that ruxolitinib yields promising results for HLH, helping patients live longer and feel better compared to usual treatments. One study found that combining ruxolitinib with dexamethasone was effective and safe, with all patients showing improvement. Dexamethasone is a type of steroid, and etoposide is a chemotherapy drug. These are part of the HLH-94 treatment plan, which has led to better outcomes and higher survival rates. Specifically, etoposide-based therapy has improved patient response and survival. This combination treatment aims to effectively manage the overactive immune system in HLH. ^{1 2 4 6 7}

Who Is on the Research Team?

Jerry Lee, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

Adults with newly diagnosed hemophagocytic lymphohistiocytosis (HLH) who meet specific diagnostic criteria, including fever, spleen enlargement, low blood cell counts, and high levels of certain immune markers. Participants must not be pregnant or breastfeeding and agree to use contraception. Excluded are those with severe organ dysfunction, recent investigational drug use, certain viral infections unless controlled by medication, prior malignancies that may affect the trial's safety assessment or have received other HLH treatments.

Inclusion Criteria

My biopsy showed signs of hemophagocytosis.

My immune system's natural killer cells are not working well.

I have active HLH and meet most of its diagnostic criteria or have a genetic form of HLH.

Exclusion Criteria

I have not taken emapalumab, alemtuzumab, ATG, tocilizumab, siltuximab, or ruxolitinib.

I am not pregnant or breastfeeding.

I have hepatitis B or C, but it's not active or it's chronic and under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Participants receive ruxolitinib plus de-intensified HLH-94 induction with dexamethasone and etoposide for 4 weeks, with potential extension based on response

4-6 weeks

Multiple visits for drug administration

Continuation Therapy

Participants receive continuation therapy with ruxolitinib for up to 6 months

6 months

Monthly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

12 months

Follow-up visits at 30 days, 3, 6, and 12 months

What Are the Treatments Tested in This Trial?

Interventions

• Dexamethasone
• Etoposide
• Ruxolitinib

Trial Overview The trial is testing ruxolitinib combined with a reduced intensity version of the HLH-94 regimen in patients with HLH. Ruxolitinib is expected to block signals causing inflammation while dexamethasone fights inflammation and etoposide targets white blood cells causing damage in HLH.

How Is the Trial Designed?

Group I: Treatment (ruxolitinib, dexamethasone, etoposide) Experimental Treatment 6 Interventions

During induction therapy, participants receive ruxolitinib orally (PO) twice daily (BID) plus de-intensified HLH-94 induction with dexamethasone PO or intravenously (IV) once daily (QD) or BID for 4 weeks and etoposide IV twice a week (BIW) for 2 weeks and then based on response, once a week (QW) for another 2 weeks in the absence of disease progression or unacceptable toxicity. After induction therapy, participants receive continuation therapy with ruxolitinib PO BID on days 1-28 of each cycle. Treatment repeats every 28 days for a total of up to 6 months after first administration of study drug in the absence of disease progression or unacceptable toxicity.

Dexamethasone is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases
• Immune system disorders

Approved in United States as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders
• Neoplastic diseases
• Nervous system disorders

Approved in Canada as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases

Approved in Japan as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Aaron Logan, MD

Lead Sponsor

Trials

1

Recruited

40+

Jerry Lee, MD, MSc, MPhil

Lead Sponsor

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Published Research Related to This Trial

Ruxolitinib was effective in treating refractory hemophagocytic lymphohistiocytosis (HLH) in two children after hematopoietic cell transplantation, leading to resolution of symptoms like fever and hyperferritinemia.

The treatment also showed a positive impact on the cytokine storm associated with HLH, suggesting that ruxolitinib could be a promising therapeutic option for this severe complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for hematopoietic cell transplantation-associated hemophagocytic lymphohistiocytosis. Ono, R., Ashiarai, M., Hirabayashi, S., et al.[2021]

In a pilot study involving five adults with secondary hemophagocytic lymphohistiocytosis, ruxolitinib demonstrated a 100% overall survival rate at 2 months, indicating its potential efficacy as a treatment.

Ruxolitinib was well tolerated, with improvements in symptoms and laboratory abnormalities observed in all patients, and only one serious adverse event reported, suggesting it may be a safe option for managing this severe inflammatory syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial. Ahmed, A., Merrill, SA., Alsawah, F., et al.[2021]

Ruxolitinib, a JAK1/2 inhibitor, showed rapid and sustained improvement in four adult patients with secondary hemophagocytic lymphohistiocytosis (HLH), indicating its efficacy in managing this severe condition.

While three patients experienced manageable infections after treatment, the overall safety profile of ruxolitinib appears favorable, making it a promising option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib as adjunctive therapy for secondary hemophagocytic lymphohistiocytosis: A case series. Hansen, S., Alduaij, W., Biggs, CM., et al.[2021]

Ruxolitinib, a targeted treatment for myelofibrosis, shows significant benefits in reducing spleen size and improving 5-year overall survival, especially when used in combination with other therapies like prednisone and thalidomide.

Ruxolitinib-based combination therapies generally result in fewer treatment-related adverse events compared to ruxolitinib alone, indicating improved safety and tolerability, although genetic testing prior to treatment is recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib-based combinations in the treatment of myelofibrosis: worth looking forward to. Li, Y., Zhu, S., Liu, W., et al.[2021]

In a study of 70 patients with lymphoma-associated hemophagocytic syndrome (LAHS), the R-DED treatment regimen (which includes ruxolitinib) significantly improved clinical responses, with an 83.3% response rate at 2 weeks compared to 54.8% for the HLH-94 regimen.

Patients treated with the R-DED regimen also had a significantly longer overall survival (5 months) compared to those on HLH-94 (1.5 months), indicating that ruxolitinib may enhance treatment efficacy without increasing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib combined with doxorubicin, etoposide, and dexamethasone for the treatment of the lymphoma-associated hemophagocytic syndrome. Zhou, L., Liu, Y., Wen, Z., et al.[2021]

Ruxolitinib, a JAK1/2 inhibitor, showed potential in managing symptoms of hemophagocytic lymphohistiocytosis in two patients with lymphoma, leading to resolution of most symptoms within two weeks for one patient.

Despite initial symptom control, both patients experienced disease progression, raising concerns about the safety and efficacy of ruxolitinib in this context, suggesting that caution is warranted until further data is available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of lymphoma-associated hemophagocytic lymphohistiocytosis: A cautionary tale. Trantham, T., Auten, J., Muluneh, B., et al.[2022]

The study investigates the effects of ruxolitinib, a JAK1/2 inhibitor, in murine models of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), which are severe immune disorders.

The findings suggest that ruxolitinib may provide a therapeutic benefit in managing these conditions by targeting the underlying immune dysregulation, although specific efficacy results and safety profiles were not detailed in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alleviating the storm: ruxolitinib in HLH. La Rosée, P.[2021]

Ruxolitinib, a JAK 1/2 inhibitor, was successfully used as a first-line treatment for a 35-year-old patient with secondary lymphohistiocytosis caused by CMV/EBV infection, leading to rapid clinical and biochemical improvement.

The patient achieved transfusion independence without complications, highlighting ruxolitinib's potential as a safe and effective treatment option for severe inflammatory conditions when standard chemotherapy is not feasible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib as first-line therapy in secondary hemophagocytic lymphohistiocytosis and HIV infection. Gálvez Acosta, S., Javalera Rincón, M.[2021]

Baricitinib, a JAK1/JAK2 inhibitor, was effective in treating a case of hemophagocytic lymphohistiocytosis (HLH) that did not respond to traditional treatments like glucocorticoids and cyclosporine.

This case suggests that JAK inhibitors like baricitinib may offer a promising alternative treatment for treatment-resistant HLH, highlighting the need for further research to confirm its efficacy in larger patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of hemophagocytic lymphohistiocytosis with a significant response to baricitinib: a first report with review of literature. Irino, K., Jinnouchi, F., Nakano, S., et al.[2023]

In a phase II study, ruxolitinib, starting at a low dose of 5 mg twice daily, showed significant efficacy in myelofibrosis patients with low platelet counts (50-100 × 10^9/L), with 62% of patients achieving stable doses of 10 mg twice daily by week 24, and median reductions in spleen volume and symptoms of 24.2% and 43.8%, respectively.

While some patients experienced thrombocytopenia requiring dose adjustments, the treatment was generally manageable, with mean hemoglobin levels remaining stable, indicating that ruxolitinib can be safely administered to this subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. Talpaz, M., Paquette, R., Afrin, L., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5785801/

Confirmed efficacy of etoposide and dexamethasone in HLH ... It resulted in a remarkably improved outcome with a 5-year probability of survival (pSu) of 54% ± 6%. Moreover, XLP, GS2, and CHS also responded well. However, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11542428/

Hemophagocytic lymphohistiocytosis: current treatment ... About 30% of HLH patients did not respond to the standard HLH-94 protocol, and lower than 60% of them achieved disease-free survival through ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.e19578

Secondary hemophagocytic lymphohistiocytosis (HLH) Patients with these three criteria were urgently treated with dexamethasone-etoposide (HLH-94 protocol) or dexamethasone alone (autoimmune ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0006497125006135

Ruxolitinib combined with dexamethasone for adult ... A prospective study demonstrated that ruxolitinib is effective and safe in adults with secondary HLH, with all patients responding to the ...

5. journal.chestnet.org journal.chestnet.org/article/S0012-3692(21)02084-5/fulltext

DEXAMETHASONE AND AMPHOTERICIN B TO THE RESCUE DEXAMETHASONE AND AMPHOTERICIN B TO THE RESCUE: A CASE OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ... Research is needed to improve outcomes for patients with HLH ...

6. ashpublications.org ashpublications.org/blood/article/130/25/2728/36884/Confirmed-efficacy-of-etoposide-and-dexamethasone

Confirmed efficacy of etoposide and dexamethasone in HLH ... In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, ...

7. ard.bmj.com ard.bmj.com/content/82/10/1271

The 2022 EULAR/ACR points to consider at the early stages ... The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation ...