Vitamin C linked to fewer adverse events in pre-leukemia trial

A randomized, double-blind, placebo-controlled phase 2 clinical trial found that people with pre-leukemia blood disorders who received 1,000 mg of oral vitamin C daily for one year experienced fewer adverse events during the trial and follow-up period than participants who received a placebo. The EVITA study also found changes in circulating cytokines, molecules involved in inflammatory signaling, that were associated with better outcomes. It did not find a significant difference between the groups in the growth rates of abnormal blood cells.

In an exploratory analysis, participants assigned vitamin C were significantly more likely to be alive after approximately three years of follow-up, but that result requires confirmation in a larger phase 3 trial. EVITA enrolled 109 people diagnosed with clinical cytopenia of unknown significance, also called CCUS, or myelodysplastic syndrome, described in the trial as a lower-risk myeloid malignancy. These blood disorders can progress to acute myeloid leukemia, or AML, a difficult-to-treat cancer.

The investigators described EVITA as the first double-blind, randomized, placebo-controlled trial to evaluate oral vitamin C in people with pre-leukemia conditions or lower-risk myeloid malignancies. The international study was led by the Van Andel Institute–Stand Up To Cancer Epigenetics Dream Team, with trial sites in Denmark and the United States. Participants were randomly assigned to one of two groups.

The treatment group received 1,000 mg of oral vitamin C each day for one year, while the control group received a placebo that looked, tasted and smelled identical but contained no vitamin C. Participants and trial staff did not know their assignments until the end of the trial. None of the participants was undergoing cancer treatment at the time of the trial. Investigators said the design was intended to minimize bias and support objective evaluation of the supplement’s effects in a population whose disorders were being monitored rather than actively treated for leukemia.

Blood samples collected during the trial were analyzed to measure participants’ vitamin C concentrations. More than half were vitamin C-deficient at the start of the study, and participants in the vitamin C group saw their levels normalize after they began taking the supplement. Unlike earlier vitamin C trials, which used intravenous delivery, EVITA tested an oral dose matching that found in many over-the-counter supplements.

Earlier studies also focused on solid tumors rather than pre-cancer blood disorders and early-stage blood cancers. The trial therefore evaluated both the feasibility of raising blood vitamin C through oral supplementation and its possible clinical and biological effects in people at risk of leukemia progression. The reported clinical findings were not uniform across outcomes.

Participants receiving vitamin C had fewer adverse events during the intervention and subsequent follow-up, although the supplied report did not provide numerical event rates, an effect size or a statistical estimate for that difference. The investigators found no significant difference between the vitamin C and placebo groups in the growth rates of abnormal blood cells, a measure used to assess progression toward leukemia. By contrast, the apparent survival advantage came from an exploratory analysis rather than the trial’s main comparison.

Approximately three years after enrollment, vitamin C recipients were significantly more likely to be alive than placebo recipients, a finding that remains provisional until tested independently in a larger cohort. The cytokine analyses provided a biological signal accompanying the clinical observations. Vitamin C altered the levels of inflammatory signaling molecules in ways associated with better outcomes, and these shifts suggested that supplementation may affect inflammatory pathways linked to the growth and progression of pre-cancerous blood cells.

The analysis did not establish that the cytokine changes caused either the reduction in adverse events or the exploratory survival difference. Instead, it showed that the molecular response differed between treatment conditions in a manner that investigators considered relevant to the clinical results. Additional analysis of the EVITA data is under way to examine the mechanisms that could contribute to the observed survival difference.

The investigators connected the human findings to earlier work on vitamin C and epigenetic regulation. Vitamin C is an essential partner of TET2, an enzyme that regulates whether certain genes are active or inactive and suppresses cancer-cell growth. Mutations in TET2 can allow malignant cells to proliferate and are common in leukemia and related disorders.

Cancer-model studies found that vitamin C appeared to prevent cancer-related cellular changes and impede leukemia progression, with the greatest benefit observed when supplementation began before disease was fully established. EVITA extended this line of investigation to a controlled human trial in people with pre-leukemia conditions, rather than evaluating the supplement only in laboratory systems or through intravenous administration. The phase 2 trial followed a clinical pilot conducted by the same research team in 2016.

That earlier work assessed whether oral supplementation was sufficient to raise vitamin C levels in the blood and found the approach feasible. The EVITA trial began in 2017, using the knowledge gained from the pilot to conduct a larger randomized comparison. Its sites included Copenhagen University Hospital–Rigshospitalet, Copenhagen University Hospital–Herlev, Aalborg University Hospital and Keck Hospital of the University of Southern California.

Kirsten Grønbæk of the University of Copenhagen led the international trial, while Peter A. Jones of Van Andel Institute was a co-corresponding author and co-leader of the research team. The results remain preliminary and do not show that vitamin C prevents CCUS or MDS from progressing to leukemia. There are no approved therapies that prevent CCUS progression, while MDS can be treated with stem-cell transplantation, although many people—particularly older adults or those with other conditions—cannot undergo transplantation.

Monitoring blood-cell counts is the standard approach for many people with pre-leukemia disorders. Against that background, EVITA directly tested whether a simple oral supplement could affect outcomes in people who otherwise faced prolonged surveillance. Even so, the trial does not establish that clinicians should prescribe vitamin C specifically to prevent progression, and the researchers emphasized that definitive recommendations would be premature.

The current evidence supports several narrower conclusions: EVITA was a 109-participant study of oral vitamin C in CCUS and lower-risk MDS; one year of supplementation normalized vitamin C levels in the treatment group; the trial was associated with fewer adverse events; and it produced changes in cytokines associated with better outcomes. The trial did not show a significant difference in abnormal blood-cell growth, while the approximately three-year survival advantage was exploratory. Taken together, the findings justify further controlled research but do not yet demonstrate that vitamin C changes pre-leukemia disease progression or prevents acute myeloid leukemia.

Subject of Research: Phase 2 randomized trial of oral vitamin C in people with CCUS and lower-risk myelodysplastic syndrome.

Article Title: Phase 2 trial suggests vitamin C may benefit people with pre-cancer blood disorders

Article References: Phase 2 trial suggests vitamin C may benefit people with pre-cancer blood disorders. Original publication (Bibliographic details unavailable.)

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Keywords: vitamin C, pre-leukemia, CCUS, myelodysplastic syndrome, acute myeloid leukemia, randomized trial, adverse events, survival, cytokines, TET2, Phase, trial