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

Trial Summary

What is the purpose of this trial?

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 who have undergone done stem cell transplant for blood cancers (hematologic malignancies). Sometimes the transplanted cells from a donor can attack the body's normal cells (called graft-versus-host disease). Leflunomide and steroids are immunosuppressive drugs that work in different ways to lower the body's immune response so that the new donor immune cells do not attack the body's normal cells. Giving leflunomide in combination with steroids may help treat acute graft versus host disease in patients after stem cell transplant for hematologic malignancies.

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.

What data supports the effectiveness of the drug Leflunomide for treating graft-versus-host disease?

Research in rats has shown that Leflunomide can effectively prevent and treat graft-versus-host disease, a serious condition that can occur after a transplant. This suggests it might be useful in human cases as well. ^{1 2 3 4 5}

Is the combination of Leflunomide and Steroids safe for treating Graft-versus-Host Disease?

The safety of steroids, including budesonide, for treating Graft-versus-Host Disease (GVHD) has been studied, showing a satisfactory safety profile with no severe intestinal infections reported. However, specific safety data for the combination of Leflunomide and steroids in GVHD is not provided in the available research. ^{6 7 8 9 10}

How is the drug Leflunomide + Steroids unique for treating graft-versus-host disease?

Leflunomide, combined with steroids, is unique for treating graft-versus-host disease because it is an immunomodulating drug that has shown promise in preventing and treating this condition in animal models, and it has a background of being effective in autoimmune diseases and transplantation reactions. Its ability to work in synergy with other immunosuppressive agents and its lower toxicity compared to some alternatives make it a novel option for this condition. ^{1 3 4 5 11}

Research Team

Monzr M. Al Malki

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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 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 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 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 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]

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 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]

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]

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]

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]

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. Germany pubmed.ncbi.nlm.nih.gov

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

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

Leflunomide for chronic sarcoidosis. [2019]

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

Feasibility and response to budesonide as topical corticosteroid therapy for acute intestinal GVHD. [2022]

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

A Clinical Trial Comparing the Safety and Efficacy of Topical Tacrolimus versus Methylprednisolone in Ocular Graft-versus-Host Disease. [2022]

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

Budesonide: a novel treatment for oral chronic graft versus host disease. [2004]

9. England pubmed.ncbi.nlm.nih.gov

Comparison of budesonide and dexamethasone for local treatment of oral chronic graft-versus-host disease. [2019]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Topical Corticosteroids a Viable Solution for Oral Graft Versus Host Disease? A Systematic Insight on Randomized Clinical Trials. [2021]

11. Switzerland pubmed.ncbi.nlm.nih.gov

The effects of leflunomide on CD4(+)CD25 (+)Foxp3 (+) T regulatory cells in mice receiving allogeneic bone marrow transplantation. [2021]