Ruxolitinib-Based Regimen for Hemophagocytic Lymphohistiocytosis

Not currently recruiting at 15 trial locations

Overseen By Kim E. Nichols, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: Rifampin, St. John's Wort

Disqualifiers: Rheumatologic disorder, Active malignancy, others

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

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for individuals diagnosed with hemophagocytic lymphohistiocytosis (HLH), a serious immune condition. The treatment combines three drugs—ruxolitinib (used for certain blood disorders), dexamethasone, and etoposide—to evaluate their effectiveness and tolerability as an initial treatment or for cases where HLH has returned or resisted other therapies. Participants include those with active HLH who have not received significant prior treatments or whose HLH has returned or persisted despite past treatments. The trial aims to identify a better treatment option for managing HLH symptoms and improving patient outcomes. As a Phase 1, Phase 2 trial, the research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking rifampin, St. John's Wort, or another investigational agent. If you are on these, you may need to stop them before joining the trial.

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

Research has shown that ruxolitinib is generally safe and well-tolerated for people with hemophagocytic lymphohistiocytosis (HLH). Studies have used it to treat patients whose HLH did not respond to other treatments or recurred after treatment. It can be managed outside of a hospital, which is promising for both new and returning cases.

Dexamethasone, a type of steroid, often reduces inflammation in HLH. It is commonly included in HLH treatment plans, and most patients tolerate it well, although it can cause side effects like mood changes or increased appetite.

Etoposide, another drug in the trial, has improved outcomes for HLH patients. However, it can increase the risk of infections, so patients need close monitoring while taking it.

Overall, these treatments have been used in different settings to manage HLH and are usually well-tolerated, but monitoring for side effects remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using ruxolitinib for hemophagocytic lymphohistiocytosis (HLH) because it targets a different pathway than standard treatments. Unlike traditional options that mainly suppress the immune system, ruxolitinib inhibits the JAK1/JAK2 pathway, which could more precisely control the overactive immune response seen in HLH. Additionally, the use of ruxolitinib in combination with dexamethasone and etoposide allows for a potentially more targeted and effective approach, especially for patients who have relapsed or not responded to initial treatments. This innovative approach could offer a new hope for better managing this challenging condition.

What evidence suggests that this trial's treatments could be effective for hemophagocytic lymphohistiocytosis?

Research has shown that the combination of ruxolitinib, dexamethasone, and etoposide may help treat hemophagocytic lymphohistiocytosis (HLH). In this trial, participants in the Frontline Arm, who are newly diagnosed, will receive ruxolitinib and dexamethasone, with etoposide added based on disease response. Participants in the Salvage Arm, who have relapsed or refractory HLH, will also receive ruxolitinib and dexamethasone, with etoposide added as needed. Ruxolitinib has improved survival and reduced symptoms in HLH patients compared to standard treatments. Studies indicate that using ruxolitinib with dexamethasone results in a positive response, benefiting many patients. Adding etoposide has further improved survival rates. Overall, this drug combination effectively manages HLH symptoms and improves patient outcomes. ^{3 6 7 8 9}

Who Is on the Research Team?

Kim E. Nichols, MD

Principal Investigator

St. Jude Children's Research Hospital

Melissa Hines, MD

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

This trial is for patients aged 6 weeks to 22 years with newly diagnosed or relapsed/refractory Hemophagocytic Lymphohistiocytosis (HLH). They must weigh at least 3 kg and be able to take oral medication or agree to an NG tube. Participants should meet specific HLH diagnostic criteria but not have received certain prior treatments, except steroids or anakinra. Pregnant individuals, those with severe organ dysfunction, active malignancy, or on other investigational drugs are excluded.

Inclusion Criteria

Patient, parent, or legal authorized representative (LAR) must provide informed consent.

I am willing to use a feeding tube if I can't take medicine by mouth.

I have a genetic form of HLH and meet at least 4 of its diagnostic criteria.

Exclusion Criteria

I have been treated with a JAK inhibitor or alemtuzumab in the last 3 months.

My liver is not severely damaged (ALT not over 1000 U/L).

I have an active cancer diagnosis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Phase

Identify a feasible and safe dose of ruxolitinib in combination with dexamethasone and etoposide for newly diagnosed HLH patients

8 weeks

Weekly visits for dose adjustments and response evaluations

Expansion Phase

Administer ruxolitinib at the maximally tolerated dose with dexamethasone, adding etoposide based on response

8 weeks

Visits at 1, 2, 4, 6, and 8 weeks for disease response evaluations

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Regular follow-up visits up to 1 year after starting protocol therapy or HSCT

What Are the Treatments Tested in This Trial?

Interventions

• Dexamethasone
• Etoposide
• Ruxolitinib

Trial Overview The study tests a regimen combining Ruxolitinib with Dexamethasone and Etoposide in two scenarios: as initial treatment for new HLH cases (Frontline therapy) and as secondary treatment when previous therapies failed (Salvage therapy). It's a Phase Ib/II trial aiming to assess the efficacy and tolerability of this combination while also exploring pharmacokinetics and immunologic biomarkers.

How Is the Trial Designed?

Group I: Salvage Arm Experimental Treatment 3 Interventions

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.

Group II: Frontline Arm Experimental Treatment 3 Interventions

Safety Phase: Patients with newly diagnosed HLH will receive ruxolitinib PO or NGT and dexamethasone, PO or IV. Etoposide IV will be added based on disease response. 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.

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?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

North American Consortium for Histiocytosis

Collaborator

Trials

5

Recruited

1,700+

Cures Within Reach

Collaborator

Trials

25

Recruited

2,100+

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

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]

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 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 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]

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. ashpublications.org ashpublications.org/blood/article/146/3/318/536099/Ruxolitinib-combined-with-dexamethasone-for-adult

Ruxolitinib combined with dexamethasone for adult patients ... A prospective study demonstrated that ruxolitinib is effective and safe in adults with secondary HLH,14 with all patients responding to the treatment and ...

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

Ruxolitinib combined with dexamethasone for adult ... The Ru-D regimen was well tolerated, resulting in OS rates of 85.7%, 67.9%, and 53.6% at 2 months, 6 months, and 2 years, respectively.

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK557776/

Hemophagocytic Lymphohistiocytosis - StatPearls - NCBI - NIH HLH is a severe, life-threatening hyperinflammatory syndrome characterized by excessive immune activation, leading to tissue damage, multiorgan failure, and ...

7. haematologica.org haematologica.org/article/view/4753

Hemophagocytic lymphohistiocytosis as severe adverse ... Hemophagocytic lymphohistiocytosis (HLH) during childhood cancer treatment is a rare adverse event posing major diagnostic and therapeutic challenges.

8. ashpublications.org ashpublications.org/blood/article/133/23/2465/273833/Recommendations-for-the-management-of

Recommendations for the management of hemophagocytic ... These patients benefit from anti-inflammatory treatment with corticosteroids (prednisolone 1-2 mg/kg or dexamethasone 5-10 mg/m2) and, possibly, ...

9. jhoonline.biomedcentral.com jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01621-x

Hemophagocytic lymphohistiocytosis: current treatment ... This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH