Epigenetics, Vitamin C and Abnormal Hematopoiesis - Pilot Study

Study Overview
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Brief Summary
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This study evaluates whether vitamin C improves responses to epigenetic therapy with DNMTis. Half of the patients will receive vitamin C and DNMTi while the other half will receive placebo and DNMTi.

Detailed Description
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Recently, it was documented that hematological cancer patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) exhibited severe vitamin C deficiency. Vitamin C is an essential co-factor for ten-eleven translocation (TET) enzymes, which initiate DNA demethylation through oxidation of 5-methylcytosine (mC) to 5-hydroxy-methylcytosine (hmC). In-vitro studies show that vitamin C at physiological doses added to DNA methyltransferase inhibitors (DNMTis), induce a synergistic inhibition of cell proliferation and enhanced apoptosis. These effects are mediated via a viral mimicry response recently associated with cancer stem-like cell death and enhanced immune signals including increased expression of bi-directionally transcribed endogenous retrovirus (ERV) transcripts, increased presence of cytosolic double stranded RNAs, and activation of an interferon inducing cellular response to these transcripts. Data suggest that correction of vitamin C deficiency may improve responses to epigenetic therapy with DNMTis. In the EVITA pilot study, the investigators include MDS/AML patients and explore the potential role of restoring vitamin C within the normal physiological range in treatment of hematological cancer with DNMTis.

Official Title
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Restoring Physiological Vitamin C Levels to the Normal Range: Influence on Epigenetic Regulation in Normal and Malignant Hematopoiesis

Conditions
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Myelodysplastic Syndrome, Acute Myeloid Leukemia

Intervention / Treatment
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* Dietary Supplement: Vitamin C
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: MDS/AML patient in treatment with DNMTi Exclusion Criteria: Intake of vitamin C as a dietary supplement including multivitamin Non-compliance

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin C<br>Oral intake of vitamin C tablet (500 mg) daily for 56 days | Dietary Supplement: Vitamin C<br>* Oral intake of vitamin C tablet (500 mg) daily for 56 days<br>|
| Placebo Comparator: Placebo<br>Oral intake of placebo tablet daily for 56 days | Dietary Supplement: Placebo<br>* Oral intake of placebo tablet daily for 56 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall 5-hmC/5-mC ratio |  | Change from baseline to day 84 | 
| Overall lysine methylation levels |  | Change from baseline to day 84 | 
| 5-hmC/5-mC ratio at regulatory genomic regions of genes involved in hematopoietic development |  | Change from baseline to day 84 | 
| Accumulation of 5-hmC/5-mC at regulatory regions of ERVs |  | Change from baseline to day 84 | 
| Aberrant histone methylation associated with hematopoietic development |  | Change from baseline to day 84 | 
| Aberrant histone methylation associated with ERVs |  | Change from baseline to day 84 | 
| Expression levels of ERVs |  | Change from baseline to day 84 | 
| Activity of the viral defense pathway measured by RNA and protein expression |  | Change from baseline to day 84 | 
| ERV specific T-cell recognition in vivo |  | Change from baseline to day 84 |