High Dose Vitamin A for Stem Cell Transplant Recipients

Overseen By Rachel Dalton

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Ohio State University Comprehensive Cancer Center

Disqualifiers: Vitamin A allergy, Abnormal liver enzymes, Pregnancy, others

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

Compensation: Varies

Number of Visits: 1

Duration: 2 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether high doses of vitamin A can prevent gastrointestinal graft versus host disease (GVHD), a condition that may occur after a donor stem cell transplant. Vitamin A plays a crucial role in maintaining healthy intestines and may reduce the risk of GVHD. Participants will be divided into two groups: one will receive vitamin A treatment, while the other will continue with usual care. The trial seeks adults scheduled for an allogeneic (donor) stem cell transplant. As an unphased trial, it offers participants the chance to contribute to significant research that could lead to new preventative strategies for GVHD.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you have a history of allergic reactions to Vitamin A or similar issues, it might affect your participation.

Is there any evidence suggesting that high dose vitamin A is likely to be safe for humans?

Research has shown that high doses of vitamin A are generally safe for individuals undergoing stem cell transplants. In one study, none of the patients who took vitamin A developed acute gastrointestinal GVHD within 180 days post-transplant, while 12.5% of those on a placebo did. This suggests that vitamin A might lower the risk of this condition.

Another study found that oral high-dose vitamin A was safe and had very few side effects, particularly in children. Experts believe that higher levels of vitamin A could help maintain gut health and reduce "leakiness," potentially lowering the risk of GVHD.

Overall, these findings suggest that high-dose vitamin A is well-tolerated and may reduce the risk of GVHD without significant side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike the standard of care for stem cell transplant recipients, which generally involves supportive care and immunosuppressive medications, the high-dose vitamin A compound is unique because it aims to enhance recovery by potentially boosting the immune system. Vitamin A is known for its role in immune function and cell growth, so researchers are excited about its potential to improve outcomes by promoting faster healing and reducing complications post-transplant. This treatment is delivered orally or enterally, making it a straightforward addition to existing care protocols.

What evidence suggests that high dose vitamin A might be an effective treatment for preventing gastrointestinal GVHD?

Research has shown that high doses of vitamin A can lower the risk of graft versus host disease (GVHD) in people undergoing stem cell transplants. In this trial, participants in the treatment cohort will receive a vitamin A compound before their transplant. Earlier studies found that administering high-dose vitamin A prior to the transplant reduces the chances of both short-term and long-term GVHD. This effect may occur because vitamin A helps regulate cell growth and function in the gut, making GVHD less likely. Additionally, a deficiency in vitamin A has been linked to a higher risk of GVHD, suggesting that supplements might be beneficial. Overall, evidence suggests that vitamin A could effectively help prevent this condition in transplant patients. ^{3 5 6 7 8}

Who Is on the Research Team?

Hannah Choe, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults set to have a stem cell transplant from a donor who matches their human leukocyte antigen (HLA) or is slightly mismatched. They should be undergoing this procedure due to blood cancers and can have either intense or less intense pre-transplant treatments.

Inclusion Criteria

Adult patients planned to undergo an allogeneic stem cell transplant (SCT) with an human leukocyte antigen (HLA)-matched (unrelated or related) or 1 allele mismatched (7/8) donor or haploidentical donor who received either myeloablative or nonmyeloablative conditioning for hematologic malignancies are eligible

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single, high dose of vitamin A orally or enterally prior to stem cell transplant. A second dose may be administered two weeks after transplant if vitamin A levels have not improved.

2 weeks

1 visit (in-person) for initial dose, potential follow-up for second dose

Follow-up

Participants are monitored for safety, effectiveness, and incidence of gastrointestinal GVHD after treatment. Stool samples are collected for microbiome analysis.

28 days

Periodic follow-up visits

Long-term follow-up

Participants are monitored for the incidence of gastrointestinal GVHD up to 180 days after stem cell transplant.

180 days

What Are the Treatments Tested in This Trial?

Interventions

• Vitamin A Compound

Trial Overview The study tests if high doses of vitamin A can prevent gastrointestinal problems after receiving a stem cell transplant from a donor. It's in the early stages, focusing on safety and how well it works to stop these complications.

How Is the Trial Designed?

Group I: Treatment Cohort (vitamin A compound) Experimental Treatment 1 Intervention

Participants receive vitamin A compound PO or enterally once prior to stem cell transplant. once over a given 24 hour period with or without food. We will re-dose at 2000 IU/kg (maximum 120,000 IU) if Week 2 Vitamin A levels remain within 10% of baseline Vitamin A.

Group II: Control Cohort (usual care) Active Control 1 Intervention

Patients receive usual care.

Who Is Running the Clinical Trial?

Ohio State University Comprehensive Cancer Center

Lead Sponsor

Trials

350

Recruited

295,000+

Published Research Related to This Trial

Oral retinoids have a well-established safety profile, but rare side effects can still occur, highlighting the importance of careful patient selection and monitoring.

The main concern with oral retinoids is their potential teratogenicity, which can be effectively managed by adhering to recommended precautions during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side effects of systemic retinoids and their clinical management. Saurat, JH.[2019]

In a study of 100 patients with metastatic breast carcinoma undergoing chemotherapy, high doses of Vitamin A (350,000 to 500,000 IU) significantly increased the complete response rate, particularly in post-menopausal women.

Post-menopausal patients showed a notable increase in serum retinol levels and improved response rates, duration of response, and projected survival, highlighting the potential benefits of Vitamin A in this specific subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Vitamin A augmentation of the effects of chemotherapy in metastatic breast cancers after menopause. Randomized trial in 100 patients]. Israël, L., Hajji, O., Grefft-Alami, A., et al.[2007]

In a study involving 248 patients with early-stage melanoma, oral vitamin A (100,000 IU/d for 18 months) did not improve disease-free survival or overall survival compared to observation, indicating it may not be an effective adjuvant therapy.

While 12% of patients receiving vitamin A experienced significant toxicities (grade 3 or 4), the lack of survival benefits suggests that further research on vitamin A for melanoma treatment is not justified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a Southwest Oncology Group study. Meyskens, FL., Liu, PY., Tuthill, RJ., et al.[2017]

An infant experienced severe anemia and thrombocytopenia after being given an excessive dose of 62,000 IU/day of vitamin A for 80 days, indicating the dangers of hypervitaminosis A.

The study found that high levels of vitamin A directly inhibited the proliferation of bone marrow cells, likely through the up-regulation of specific cell cycle inhibitors, suggesting that excessive vitamin A intake can lead to significant bone marrow dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infant hypervitaminosis A causes severe anemia and thrombocytopenia: evidence of a retinol-dependent bone marrow cell growth inhibition. Perrotta, S., Nobili, B., Rossi, F., et al.[2021]

All-trans retinoic acid (RA) significantly enhances the engraftment of unrelated umbilical cord blood stem/progenitor cells in a murine model, leading to faster hematopoiesis and immune recovery compared to untreated controls.

Mice treated with RA showed improved survival rates after transplantation, with 30 and 60-day survival rates increasing from 41.67% to 72.23% and 70.83% respectively for higher cell doses, indicating RA's potential as a supportive treatment in clinical umbilical cord blood transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Experimental study on promoting the engraftment of hematopoietic stem/progenitor cell by all-trans retinoic acid]. Mai, HR., Huang, SL., Xu, HG., et al.[2013]

All-trans retinoic acid (ATRA) significantly enhances the maintenance and production of short-term and long-term repopulating stem cells from murine hematopoietic precursors, indicating its potential as a therapeutic agent in stem cell biology.

In contrast, the RAR antagonist AGN 193109 reduces the repopulating ability of these stem cells by promoting their differentiation into more mature cells, highlighting the critical role of retinoids in regulating hematopoietic stem cell differentiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

All-trans retinoic acid enhances the long-term repopulating activity of cultured hematopoietic stem cells. Purton, LE., Bernstein, ID., Collins, SJ.[2021]

In a phase I trial involving 13 cancer patients, daily doses of retinol (vitamin A) showed dose-limiting toxicities, particularly neuropsychiatric changes and hepatomegaly, at higher doses (above 240,000 U/m2).

Due to observed toxicities, a maximum safe dose of 200,000 U/m2/day of retinol is recommended for future studies, highlighting the need for careful monitoring of side effects in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of retinol in cancer patients. Goodman, GE., Alberts, DS., Earnst, DL., et al.[2017]

Synthetic retinoids, developed from vitamin A, aim to treat skin disorders with abnormal keratinization while having a better therapeutic-toxicity ratio than retinol, but they still require high doses that can lead to side effects.

Most side effects from retinoids resemble those from excessive vitamin A intake, affecting various body systems, and while many are reversible, there is still uncertainty about the long-term effects and reversibility of toxicity after stopping the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side effects and long-term toxicity of synthetic retinoids. Yob, EH., Pochi, PE.[2016]

Intravenous liposomal all-trans-retinoic acid (L-ATRA) maintains significantly higher and stable plasma concentrations compared to oral ATRA, with 13- and 22-fold greater AUC values on days 1 and 9, respectively, indicating a more effective delivery method.

Despite higher plasma levels of L-ATRA, the side effects were similar to those of oral ATRA, although L-ATRA was associated with dermal exfoliation in 31% of subjects, while oral ATRA led to abnormal liver function tests in 23% of subjects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers. Ozpolat, B., Lopez-Berestein, G., Adamson, P., et al.[2022]

In a study involving 135 patients, the addition of calcipotriol ointment to systemic treatment with acitretin significantly improved psoriasis outcomes, with 67% of patients in the calcipotriol group achieving clearance or marked improvement compared to 41% in the placebo group.

The combination therapy allowed patients to achieve these results with a lower cumulative dose of acitretin, indicating that calcipotriol not only enhances efficacy but also helps reduce the amount of acitretin needed, while maintaining a good safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of addition of calcipotriol ointment (50 micrograms/g) to acitretin therapy in psoriasis. van de Kerkhof, PC., Cambazard, F., Hutchinson, PE., et al.[2019]

Retinol at a concentration of 1 µmol/L significantly enhances the expression of stem cell factor (SCF) and colony-stimulating factor 1 (CSF1) in cultured human umbilical-derived mesenchymal stem cells (UCMSCs).

The study confirmed that while retinol positively affects SCF and CSF1 levels, it does not alter the expressions of epidermal growth factor (EGF) or leukemia inhibitory factor (LIF) in these cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of retinol on expressions of epidermal growth factor, stem cell factor, colony-stimulating factor 1 and leukemia inhibitory factor in human umbilical cord-derived mesenchymal stem cells]. Zhuo, HL., Bai, LP., Liu, D., et al.[2020]

Retinoids, which are derivatives of vitamin A, play a crucial role in regulating immune functions and cancer development by interacting with nuclear receptors, specifically retinoic acid receptors (RARs) and retinoid X receptors (RXRs).

These compounds have shown promise in treating certain cancers, such as acute promyelocytic leukemia and cutaneous T cell lymphomas, and ongoing clinical trials are exploring their effectiveness against solid tumors and B-cell malignancies, highlighting their potential to enhance immune responses in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retinoids as critical modulators of immune functions: new therapeutic perspectives for old compounds. Montrone, M., Martorelli, D., Rosato, A., et al.[2021]

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High Dose Vitamin A for Stem Cell Transplant Recipients This phase I trial studies the side effects and how well high dose vitamin A works in preventing gastrointestinal graft versus host disease (GVHD) in ...

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Vitamin requirements during stem cell transplantation It is unclear whether patients undergoing SCT are at higher risk of vitamin B1, vitamin C, vitamin D, vitamin B9 (folate), vitamin A and vitamin ...

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Vitamin A May Reduce CVHD Risk After Stem Cell ... Cincinnati Children's stem cell transplant experts report high-dose oral vitamin A reduces the incidence of acute and chronic GVHD.

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Vitamin A to Keep GVHD Away: Single Oral High-Dose ... The cumulative incidence of acute GI GVHD by day 180 post-HSCT was 0% in the vitamin A arm and 12.5% in the placebo group (p=0.02; Figure), ...

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Lower levels of vitamin A are associated with increased ... We hypothesized that higher vitamin A levels would reduce the risk of graft-versus-host disease (GVHD) through reduced gastrointestinal (GI) permeability.

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Study Details | NCT03039257 | Vitamin A Replacement in ... The primary objective of this study is to establish that single dose vitamin A supplementation is feasible and safe in pediatric and young adult bone marrow ...