Steroid Tapering for Pediatric Graft-versus-Host Disease

Recruiting at 10 trial locations

Overseen By Janna Baez

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: John Levine

Must not be taking: Corticosteroids

Disqualifiers: Uncontrolled infection, Chronic GVHD, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 90

Duration: 4 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

The standard treatment for acute graft-vs-host disease (GVHD) is to suppress the activity of the donor immune cells using steroid medications such as prednisone. Although most GVHD, especially in children, responds well to treatment, sometimes (around 1/3 of the time) there is either no response to steroids or the response does not last. In those cases, the GVHD can become dangerous and even life-threatening. Unfortunately, doctors cannot predict who will have a good response to treatment based on symptom severity or initial response to steroids. As a result, nearly all children who develop GVHD are treated with long courses of high dose steroids even though that means many patients receive more treatment than they probably need. Steroid treatment can cause short-term complications like infections, high blood sugar, high blood pressure, muscle weakness, depression, anxiety, and problems sleeping and long-term complications like bone damage, cataracts in the eyes, and decreased growth. The risk of these complications increases with higher doses of steroids and longer treatment. It is important to find ways to decrease the steroid treatment in patients who do not need long courses. The doctors conducting this research have developed a blood test (GVHD biomarkers) that predicts whether a patient will respond well to steroids. The study team found that children who have low GVHD biomarkers at the start of treatment and for the first two weeks of treatment have a very high response rate to steroids. In this study, the study team will monitor GVHD symptoms and biomarkers during treatment and taper steroids quickly in patients who have GVHD that is expected to respond very well to treatment. The study team will assess how many patients respond well to lower steroid dosing and what steroid complications develop. The study team will also use surveys to obtain the patient's own assessment of their quality of life (down to age 5 years).

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking corticosteroids at more than 0.1 mg/kg prednisone (or equivalent) for any reason within 7 days before the onset of acute GVHD, you may not be eligible to participate.

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 patients should not have been treated with certain doses of steroids recently. It's best to discuss your current medications with the trial team to see if they affect your eligibility.

What data supports the idea that Steroid Tapering for Pediatric Graft-versus-Host Disease is an effective drug?

The available research shows that steroid tapering, specifically using prednisone, is effective for treating graft-versus-host disease (GVHD). In one study, patients who received a longer tapering schedule of prednisone saw their symptoms resolve faster than those on a shorter schedule. Another study found that using a lower dose of prednisone was just as effective as a higher dose, with fewer side effects. Additionally, when comparing prednisone alone to a combination of prednisone and another drug, cyclosporine, there was no significant difference in survival rates, suggesting prednisone alone is effective. Overall, these studies indicate that steroid tapering with prednisone is a successful approach for managing GVHD. ^{1 2 3 4 5}

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

Research shows that Prednisone can effectively resolve acute graft-versus-host disease (GVHD) in many patients, with studies indicating that both short and long tapering schedules can lead to resolution of the disease. Additionally, using lower doses of Prednisone for initial treatment does not compromise disease control or increase mortality, and may reduce side effects. ^{1 2 3 4 5}

What safety data is available for steroid tapering in pediatric graft-versus-host disease treatment?

Several studies provide safety data for steroid tapering in graft-versus-host disease (GVHD) treatment. A phase III study found that lower dose prednisone is effective and safe for acute GVHD without increasing secondary treatment incidence. Another study compared short versus long-term prednisone tapering, showing similar steroid-related complications and survival rates, suggesting rapid tapering might minimize steroid-related morbidity. A retrospective analysis indicated that low-dose prednisone does not compromise disease control or mortality and reduces toxicity. However, a study on chronic GVHD found that cyclosporine plus prednisone may reduce steroid-related toxicity but does not significantly affect transplantation-related mortality. Another study noted that cyclosporine-prednisone prophylaxis is associated with a higher risk of chronic GVHD compared to cyclosporine with methotrexate. ^{1 2 3 4 6}

Is steroid tapering with prednisone safe for treating graft-versus-host disease in children?

Research shows that using prednisone for graft-versus-host disease is generally safe, with similar rates of complications whether using low or standard doses. However, combining prednisone with cyclosporine may increase the risk of chronic graft-versus-host disease. ^{1 2 3 4 6}

Is the drug Prednisone a promising treatment for pediatric graft-versus-host disease?

Yes, Prednisone is a promising drug for treating graft-versus-host disease. Studies show that it can effectively control the disease, whether used alone or with other treatments. It helps resolve symptoms quickly and can be used in different doses without compromising patient outcomes. ^{1 2 3 4 7}

How does the drug prednisone differ from other treatments for pediatric graft-versus-host disease?

Prednisone is unique in its use for pediatric graft-versus-host disease because it can be administered in varying tapering schedules, which may help minimize steroid-related side effects while effectively resolving the condition. Unlike some other treatments, prednisone can be used alone or in combination with other drugs like cyclosporine, offering flexibility in managing both acute and chronic forms of the disease. ^{1 2 3 4 7}

Research Team

Muna Qayed, MD, MS

Principal Investigator

Children's Healthcare of Atlanta, Emory University School of Medicine

John E Levine

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

This trial is for children and young adults (0-21 years) with a specific immune reaction called GVHD after bone marrow transplant. They must have certain biomarkers, not been treated with systemic steroids for GVHD before, and be in good physical condition. Pregnant individuals or those with severe liver disease, uncontrolled infections, or serious organ dysfunction cannot participate.

Inclusion Criteria

My condition is diagnosed with Grade 1 GVHD based on biomarkers.

I have been newly diagnosed with GVHD, but it's not just a skin rash or only in my upper GI tract.

I am mostly active and can care for myself.

Exclusion Criteria

My liver is not functioning well, shown by high bilirubin or liver enzyme levels.

I do not have an infection that is getting worse despite treatment.

My cancer is getting worse or not improving, needing a change in my immune therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive steroid treatment with dose adjustments based on biomarker and clinical response over four weeks

4 weeks

Weekly visits for dose adjustment and biomarker assessment

Follow-up

Participants are monitored for safety, effectiveness, and complications such as serious infections and overall survival

12 months

Bi-weekly visits through day 90, then periodic follow-ups

Treatment Details

Interventions

• Prednisone

Trial Overview The trial tests if tapering steroid medication quickly can effectively treat GVHD in patients who are likely to respond well based on their biomarker levels. It aims to reduce the duration of high-dose steroid treatment to minimize side effects while monitoring symptoms and quality of life.

Participant Groups

Group I: Steroid Taper Experimental Treatment 1 Intervention

All enrolled patients start on the same dose of steroids for treatment of GVHD, blood samples are taken at week 1 and 2 post study start and biomarkers plus clinical response determines how steroid treatment is continued

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

Approved in United States as Prednisone for:

• Allergic reactions
• Asthma
• Blood disorders
• Cancer
• Eye problems
• Immune system disorders
• Inflammatory conditions
• Multiple sclerosis
• Organ transplantation
• Rheumatoid arthritis
• Skin conditions

Approved in European Union as Prednisone for:

• Allergic reactions
• Asthma
• Blood disorders
• Cancer
• Eye problems
• Immune system disorders
• Inflammatory conditions
• Multiple sclerosis
• Organ transplantation
• Rheumatoid arthritis
• Skin conditions

Approved in Canada as Prednisone for:

• Allergic reactions
• Asthma
• Blood disorders
• Cancer
• Eye problems
• Immune system disorders
• Inflammatory conditions
• Multiple sclerosis
• Organ transplantation
• Rheumatoid arthritis
• Skin conditions

Who Is Running the Clinical Trial?

John Levine

Lead Sponsor

Trials

4

Recruited

230+

Findings from Research

In a phase III study involving 164 patients with newly diagnosed acute graft-versus-host disease, initial treatment with lower dose prednisone (0.5 mg/kg/day for grade IIa and 1 mg/kg/day for grade IIb or higher) was found to be effective without increasing the need for secondary immunosuppressive therapy in grade IIa patients.

However, for patients with grade IIb or higher manifestations, the lower dose was associated with a significantly higher risk (41% vs. 7%) of requiring additional immunosuppressive treatment, indicating that while lower doses may be safe for some, they may not be sufficient for more severe cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial. Mielcarek, M., Furlong, T., Storer, BE., et al.[2022]

In a study of 733 transplant patients, initial treatment of acute graft-versus-host disease (GVHD) with low-dose glucocorticoids (1 mg/kg/day) was found to be as effective as standard-dose glucocorticoids (2 mg/kg/day) in terms of overall mortality and disease relapse.

Patients receiving low-dose glucocorticoids experienced reduced risks of invasive fungal infections and shorter hospital stays, indicating that this treatment approach may lead to lower toxicity without compromising treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes. Mielcarek, M., Storer, BE., Boeckh, M., et al.[2021]

In a study of 30 bone marrow transplant patients with moderate/severe acute graft-versus-host disease (GVHD), a longer tapering schedule of corticosteroids led to faster resolution of GVHD symptoms compared to a shorter taper, with median resolution times of 30 days versus 42 days, respectively.

Both tapering schedules resulted in similar rates of chronic GVHD and survival at 6 months, indicating that while the tapering duration affects the speed of symptom resolution, it does not impact long-term outcomes or steroid-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prednisone therapy for acute graft-versus-host disease: short- versus long-term treatment. A prospective randomized trial. Hings, IM., Filipovich, AH., Miller, WJ., et al.[2019]

In a randomized trial involving 287 patients with chronic graft-versus-host disease (GVHD), the combination of cyclosporine (CSP) and prednisone did not significantly reduce transplantation-related mortality compared to prednisone alone, with 5-year mortality rates of 17% and 13%, respectively.

However, the combination treatment with CSP and prednisone was associated with a lower incidence of avascular necrosis (13% vs. 22%), suggesting it may help reduce steroid-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Koc, S., Leisenring, W., Flowers, ME., et al.[2021]

In a study of 864 patients treated with prednisone for acute graft-versus-host disease (GVHD), the response at day 28 was found to be a strong predictor of 2-year transplantation-related mortality (TRM), making it the optimal early endpoint for therapeutic trials.

Patients who did not respond by day 28 were 2.78 times more likely to experience TRM within 2 years, highlighting the importance of early response assessment in managing GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The best endpoint for acute GVHD treatment trials. MacMillan, ML., DeFor, TE., Weisdorf, DJ.[2021]

In a study of 196 allogeneic blood and marrow transplant patients, prophylaxis with cyclosporine and prednisone (CYA-PRED) was linked to a significantly higher risk of developing chronic graft-versus-host disease (cGVHD) compared to cyclosporine with methotrexate (CYA-MTX), with a risk ratio of 3.5.

Patients receiving CYA-PRED also had a higher cumulative probability of extensive cGVHD at 2 years, indicating that the choice of GVHD prophylaxis can greatly influence patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prophylaxis of graft-versus-host disease with cyclosporine-prednisone is associated with increased risk of chronic graft-versus-host disease. Kumar, S., Chen, MG., Gastineau, DA., et al.[2013]

In a study of 745 patients with chronic graft-versus-host disease (cGVHD), variations in initial treatment approaches, including different doses of prednisone and the use of non-steroid therapies, did not significantly impact failure-free survival, overall survival, or non-relapse mortality.

The findings highlight the need for prospective trials to explore the efficacy of reduced-dose prednisone or prednisone-free treatment strategies, as current practices show considerable heterogeneity without clear outcomes benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial therapy for chronic graft-versus-host disease: analysis of practice variation and failure-free survival. Pidala, J., Onstad, L., Martin, PJ., et al.[2022]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial. [2022]

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

Initial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes. [2021]

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

Prednisone therapy for acute graft-versus-host disease: short- versus long-term treatment. A prospective randomized trial. [2019]

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

Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. [2021]

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

The best endpoint for acute GVHD treatment trials. [2021]

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

Prophylaxis of graft-versus-host disease with cyclosporine-prednisone is associated with increased risk of chronic graft-versus-host disease. [2013]

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

Initial therapy for chronic graft-versus-host disease: analysis of practice variation and failure-free survival. [2022]