Leflunomide for Chronic Graft Versus Host Disease

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must be taking: Steroids

Must not be taking: New immunosuppressives

Disqualifiers: Active infection, Uncontrolled illness, Active malignancies, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects of leflunomide in treating patients with steroid dependent chronic graft versus host disease (cGVHD). cGVHD is a common complication of bone marrow transplant. GVHD occurs when immune cells transplanted from a donor (the graft) recognize the transplant recipient (the host) as foreign, and cause damage to the skin, gastrointestinal tract or other organs. Steroids are the first line of therapy and benefits are seen in about one-third of patients with cGVHD. Prolonged use of steroids is associated with multiple complications. Leflunomide may decrease the body's immune response and reduce inflammation associated with cGVHD.

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 must not have started any new immunosuppressive medications in the 4 weeks before joining. You should discuss your current medications with the study team to ensure they are compatible with the trial requirements.

Is leflunomide safe for humans?

Leflunomide (Arava) is generally considered safe for humans, but it can cause side effects like diarrhea, nausea, skin rash, and liver enzyme changes. There are concerns about its potential liver toxicity, and it has a long-lasting effect in the body. ^{1 2 3 4 5}

How is the drug leflunomide unique for treating chronic graft versus host disease?

Leflunomide is unique because it is an immunomodulating drug (a drug that modifies the immune response) that has shown promise in preventing and treating graft-versus-host disease in animal models, and it is already used safely in humans for rheumatoid arthritis. Its ability to work in synergy with other immunosuppressive drugs and its potential to inhibit virus replication make it a novel option for this condition. ^{1 2 4 6 7}

Research Team

Amandeep Salhotra

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for patients with chronic graft versus host disease (cGVHD) after a bone marrow transplant, who are dependent on steroids without full relief of symptoms. Participants must have stable organ function and blood counts, be able to swallow pills, and not be pregnant or breastfeeding. They should agree to use birth control and have no active infections or other serious health issues that could interfere with the study.

Inclusion Criteria

I can swallow pills.

Assent, when appropriate, will be obtained per institutional guidelines

Documented informed consent of the participant and/or legally authorized representative

Exclusion Criteria

I received a donor lymphocyte infusion within the last 100 days.

I haven't taken new immunosuppressive drugs in the last 4 weeks.

I need a machine to help me breathe.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive leflunomide orally once daily for days 1-28, repeated every 28 days for 6 cycles

24 weeks

Optional Extension

Participants may optionally continue leflunomide for an additional 6 cycles if response or stable disease is maintained

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 weeks

Treatment Details

Interventions

• Leflunomide

Trial Overview The trial is testing Leflunomide's effectiveness in treating cGVHD symptoms when steroids alone aren't enough. It aims to see if this drug can reduce the immune response causing inflammation without the complications linked to prolonged steroid use.

Participant Groups

Group I: Treatment (leflunomide) Experimental Treatment 1 Intervention

Patients receive leflunomide PO QD for days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may optionally continue leflunomide for an additional 6 cycles as long as response or stable disease is maintained.

Leflunomide is already approved in European Union, United States, United Kingdom for the following indications:

Approved in European Union as Arava for:

• Rheumatoid arthritis
• Psoriatic arthritis

Approved in United States as Arava for:

• Rheumatoid arthritis
• Psoriatic arthritis

Approved in United Kingdom as Arava for:

• Rheumatoid arthritis
• Psoriatic arthritis

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Leflunomide shows significant immunosuppressive effects in liver and kidney transplant recipients, allowing for reductions in conventional immunosuppressive drugs like cyclosporine and prednisone without evidence of acute rejection.

The drug was well tolerated in patients with lower serum creatinine levels, but those with higher levels experienced more side effects, highlighting the importance of monitoring serum drug levels for safe and effective dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experiences with leflunomide in solid organ transplantation. Williams, JW., Mital, D., Chong, A., et al.[2022]

A 64-year-old woman developed a lichenoid drug reaction after two months of treatment with leflunomide for rheumatoid arthritis, indicating a potential adverse effect of this immunomodulator.

The reaction improved significantly after stopping the medication and using colestyramine and topical corticosteroids, suggesting that leflunomide can cause serious skin reactions, although such side effects are generally rare and benign.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Lichenoid drug reaction to leflunomide]. Canonne-Courivaud, D., Carpentier, O., Dejobert, Y., et al.[2018]

Leflunomide is an effective treatment for active rheumatoid arthritis (RA), showing comparable efficacy and safety to methotrexate and sulfasalazine in phase III clinical trials.

While leflunomide is generally safe, it can cause side effects like diarrhea and liver enzyme elevations, and it has a much longer half-life than other RA medications, raising concerns about potential hepatotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of leflunomide]. Hirohata, S.[2018]

In a study of 32 sarcoidosis patients, leflunomide was found to be effective, with a complete or partial response in 12 out of 17 patients treated with leflunomide alone and 13 out of 15 patients receiving it alongside methotrexate.

Leflunomide was well tolerated, with only three patients experiencing nausea, and no serious adverse reactions reported, suggesting it may be a safer alternative to methotrexate for patients who cannot tolerate it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide for chronic sarcoidosis. Baughman, RP., Lower, EE.[2019]

The combination of leflunomide with biological agents has been evaluated for its efficacy in treating rheumatoid arthritis, suggesting potential benefits in managing the disease.

Safety profiles of this combination therapy were also assessed, indicating that it may be a viable option for patients with rheumatoid arthritis, although specific safety outcomes were not detailed in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy and safety of the combination of leflunomide (Arava) and biological agents in treatment of rheumatoid arthritis]. Novak, S.[2018]

Leflunomide treatment in a hamster-to-mouse heart transplantation model effectively prevents the formation of xenoantibodies (XAb) and chronic rejection in the first transplanted hearts, indicating its potential as an immunosuppressive agent for xenotransplantation.

The study suggests that leflunomide induces T-independent B-lymphocyte xenotolerance, as it prevents rejection of the first grafts while allowing for chronic lesions in second grafts after treatment withdrawal, highlighting its role in modulating immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a short course of leflunomide on T-independent B-lymphocyte xenoreactivity and on susceptibility of xenografts to acute or chronic rejection. Yan, Y., Verbeken, E., Yu, L., et al.[2019]

Leflunomide effectively prevents and treats acute graft-versus-host disease (GVHD) in a rat model, demonstrating its potential as a powerful immunomodulating drug.

Given its safety and efficacy in treating chronic rheumatoid arthritis in humans, leflunomide may be a promising candidate for clinical trials aimed at preventing GVHD in bone marrow transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of the acute graft-versus-host disease (GVHD) in rats by the immunomodulating drug leflunomide. Mrowka, C., Thoenes, GH., Langer, KH., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Experiences with leflunomide in solid organ transplantation. [2022]

2. France pubmed.ncbi.nlm.nih.gov

[Lichenoid drug reaction to leflunomide]. [2018]

3. Japan pubmed.ncbi.nlm.nih.gov

[Efficacy of leflunomide]. [2018]

4. Italy pubmed.ncbi.nlm.nih.gov

Leflunomide for chronic sarcoidosis. [2019]

5. Croatia pubmed.ncbi.nlm.nih.gov

[The efficacy and safety of the combination of leflunomide (Arava) and biological agents in treatment of rheumatoid arthritis]. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Effects of a short course of leflunomide on T-independent B-lymphocyte xenoreactivity and on susceptibility of xenografts to acute or chronic rejection. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

Prevention of the acute graft-versus-host disease (GVHD) in rats by the immunomodulating drug leflunomide. [2019]