Leflunomide + Steroids for 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: Investigational agents

Disqualifiers: Multiple HCT, Uncontrolled illness, HIV, others

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

Compensation: Varies

Number of Visits: 28

Duration: 8 weeks

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for acute graft-versus-host disease (aGVHD), a condition where donor stem cells attack a patient's body after a stem cell transplant. The study tests whether combining leflunomide (also known as Arava, Lefumide, or Arabloc) with corticosteroids can safely reduce this immune response. Participants must have been diagnosed with aGVHD after a stem cell transplant for blood cancers and must not have received more than 72 hours of steroid treatment for it. The trial aims to determine if these medications together can effectively and safely manage aGVHD. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment approach.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot use other drugs for treating acute graft-versus-host disease during the study. It's best to discuss your current medications with the study team to see if they are allowed.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that leflunomide is safe for people with chronic graft-versus-host disease (GVHD). One study found that patients tolerated it well, and many experienced improvements, suggesting its safety for similar conditions. Leflunomide has also been tested in animals for GVHD and proved effective.

Steroids, the other treatment in this trial, are commonly used in medicine. They help manage the immune system and are generally safe when used as doctors advise. These findings suggest that combining leflunomide with steroids could safely treat acute GVHD. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for acute graft-versus-host disease (aGVHD), which typically rely solely on steroid therapy, the combination of leflunomide and steroids offers a new approach. Leflunomide introduces a unique mechanism by targeting the immune system differently, potentially reducing inflammation and immune response more effectively than steroids alone. Researchers are excited about this treatment because it could enhance patient outcomes by minimizing disease progression and reducing toxicity, offering a promising alternative to existing therapies.

What evidence suggests that leflunomide and steroids might be an effective treatment for acute graft-versus-host disease?

Research has shown that leflunomide may help treat graft-versus-host disease (GVHD) based on animal studies. It has proven safe and effective for people with chronic GVHD, with many patients responding well. Leflunomide calms the immune system, preventing donor cells from attacking the body's own cells. In this trial, participants will receive a combination of leflunomide and steroids. Steroids, also used in this study, are a common treatment for GVHD and help reduce swelling. Combining leflunomide and steroids might effectively manage acute GVHD after a stem cell transplant. ^{2 3 5 6 7}

Who Is on the Research Team?

Monzr M. Al Malki

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

Adults (18+) who've had a stem cell transplant for blood cancer and are now facing acute graft-versus-host disease can join. They must be able to take oral meds, have no severe organ issues unrelated to the disease, not be on dialysis or have uncontrolled infections, and agree to birth control if applicable. Prior leflunomide use or more than 72 hours of steroids for this condition disqualifies them.

Inclusion Criteria

I am capable of having children and have not been surgically sterilized.

I have only used prednisone for acute GvHD for less than 72 hours.

Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy

Exclusion Criteria

I have received more than one bone marrow transplant from a donor.

I haven't had cancer other than my current one in the last 3 years.

I do not have severe organ problems not caused by GvHD.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive steroid therapy and leflunomide orally once daily on days 1-28, with tapering from day 29 to day 56 if responsive

8 weeks

Weekly visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Follow-up visits at 28 days, 56 days, 100 days, and 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Leflunomide
• Steroid Therapy

Trial Overview The trial is testing the safety of combining leflunomide with steroids in treating acute graft-versus-host disease post-stem cell transplant. It's seeing if this combo helps manage immune responses better so that donor cells don't attack the patient's body.

How Is the Trial Designed?

Group I: Treatment of aGVHD (steroid therapy, leflunomide) Experimental Treatment 3 Interventions

Patients receive steroid therapy at the discretion of the treating physician. Beginning within 3 days of starting steroids, patients receive leflunomide PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. Patients who respond to leflunomide treatment will be tapered off from day 29 until day 56.

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+

Published Research Related to This Trial

Leflunomide (LEF) significantly reduces the percentage of CD4(+)CD25(+) T regulatory cells (Treg) in the spleens of mice, which may impact immune tolerance, suggesting it might not be suitable for treating autoimmune diseases or preventing graft rejection.

In a mouse model of allogeneic bone marrow transplantation, LEF treatment decreased Treg cells in both naïve and immunized mice, indicating a potential risk for impaired immune regulation in these contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of leflunomide on CD4(+)CD25 (+)Foxp3 (+) T regulatory cells in mice receiving allogeneic bone marrow transplantation. Jin, D., Duan, K., Zhang, L., et al.[2021]

In a clinical trial involving 12 patients with chronic oral graft versus host disease (GVHD), budesonide mouthwash demonstrated positive responses in all participants, with 7 achieving 'good' or 'complete' recovery within 3 months.

The treatment showed an early response within 2 to 3 weeks, indicating its potential effectiveness as an alternative therapy for chronic oral GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Budesonide: a novel treatment for oral chronic graft versus host disease. Elad, S., Or, R., Garfunkel, AA., et al.[2004]

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 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]

In a review of three randomized clinical trials involving 76 patients with oral graft versus host disease (GVHD), all three topical corticosteroids—dexamethasone, clobetasol, and budesonide—demonstrated effectiveness in treatment with a satisfactory safety profile.

Budesonide showed the best overall response for treating oral GVHD, followed by clobetasol and then dexamethasone, although the limited number of studies and patients for some treatments suggests a need for further high-quality research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical Corticosteroids a Viable Solution for Oral Graft Versus Host Disease? A Systematic Insight on Randomized Clinical Trials. Sava, A., Piciu, A., Pasca, S., et al.[2021]

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]

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]

In a trial involving 22 patients with acute intestinal GVHD, the addition of oral budesonide (9 mg/day) to increased systemic immunosuppression led to a 70% resolution rate of GVHD, compared to only 33% in a control group of 19 patients receiving systemic treatment alone.

Budesonide treatment not only improved GVHD outcomes but also allowed for a reduction in systemic immunosuppressive therapy without causing severe intestinal infections, suggesting it may be a safer and effective option for managing acute intestinal GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and response to budesonide as topical corticosteroid therapy for acute intestinal GVHD. Bertz, H., Afting, M., Kreisel, W., et al.[2022]

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]

Topical tacrolimus 0.05% was found to be more effective than topical methylprednisolone 0.5% in reducing corneal fluorescein staining and improving tear film break-up time in patients with ocular graft-versus-host disease (GVHD) after 10 weeks of treatment.

Both treatments were generally safe, but tacrolimus had a lower risk of increasing intraocular pressure compared to methylprednisolone, which showed a significant increase in IOP, highlighting tacrolimus as a safer option for managing ocular GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Clinical Trial Comparing the Safety and Efficacy of Topical Tacrolimus versus Methylprednisolone in Ocular Graft-versus-Host Disease. Abud, TB., Amparo, F., Saboo, US., et al.[2022]

In a study of 50 patients with oral symptoms of chronic graft-versus-host disease (cGVHD), topical budesonide showed a greater reduction in cGVHD examination scores compared to dexamethasone after one month, indicating it may be more effective for this condition.

Both treatments significantly reduced oral pain severity, but while budesonide had a higher overall treatment response rate (53.8%) compared to dexamethasone (29.2%), the difference was not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of budesonide and dexamethasone for local treatment of oral chronic graft-versus-host disease. Park, AR., La, HO., Cho, BS., et al.[2019]

Citations

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Leflunomide: Is It the Game Changer in Musculoskeletal ... Leflunomide has been shown to be effective in prevention and treatment of GVHD in various animal models [4, 5]. We describe our patient with Musculoskeletal ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04932564

Leflunomide for Musculoskeletal GVHD After Allogeneic ... Leflunomide is relatively cheap and potentially more effective compared to other more expensive alternatives.

3. astctjournal.org astctjournal.org/article/S2666-6367(23)02116-4/fulltext

Phase 1 Trial Investigating the Safety and Tolerability of ... Leflunomide is safe in patients with cGVHD, and is associated with a promising ORR in patients with multisystem cGVHD involvement.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0952791525001256

Emerging novel therapies for steroid-refractory acute graft- ... In a phase 2 clinical trial examining AAT administration for 40 patients with SR-aGVHD, 65% and 35% of the patients achieved an ORR and CR, respectively, by day ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11971137/

Recent advances in acute gastrointestinal graft versus host ... About 50% of aGVHD patients respond to the standard first-line therapy with systemic, high-dose glucocorticoids (GC) [13], but the response rate ...

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NCT05443425 | Leflunomide in Combination With Steroids ... This phase I trial tests the safety and side effects of leflunomide in combination with steroids in treating patients with acute graft versus host disease ...

7. researchgate.net researchgate.net/publication/378059903_Phase_1_Trial_Investigating_the_Safety_and_Tolerability_of_Leflunomide_in_Patients_with_Steroid-Dependent_Chronic_Graft-Versus-Host_Disease_cGVHD_after_Allogeneic_Hematopoietic_Cell_Transplant_alloHCT?_tp=eyJjb250ZXh0Ijp7InBhZ2UiOiJzY2llbnRpZmljQ29udHJpYnV0aW9ucyIsInByZXZpb3VzUGFnZSI6bnVsbH19

Phase 1 Trial Investigating the Safety and Tolerability of ... Phase 1 Trial Investigating the Safety and Tolerability of Leflunomide in Patients with Steroid-Dependent Chronic Graft-Versus-Host Disease ( ...