Vitamin C Trial Finds Survival Signal in Precancerous Blood Disorders

The phase 2 EVITA trial has produced a finding that merits follow-up: among people with precancerous blood disorders or lower-risk myeloid disease, those assigned daily vitamin C were more likely to be alive after about three years than those given a placebo. The survival result came from an exploratory analysis, so it’s a signal for further research rather than evidence that vitamin C prevents leukemia or extends life.

EVITA also found fewer adverse events in the vitamin C group during the study and follow-up, along with changes in immune signaling molecules associated with more favorable outcomes. The supplement did not significantly change the rate at which abnormal blood cells expanded. That distinction matters: the trial points to possible effects on health and survival, but it hasn’t shown that vitamin C slows the underlying cell growth.

A trial built around an unmet need

The randomized, double-blind, placebo-controlled study enrolled 109 people with clonal cytopenia of undetermined significance (CCUS) or myelodysplastic syndrome (MDS). Both conditions can progress to acute myeloid leukemia (AML), an aggressive blood cancer. The likelihood of developing CCUS and related disorders increases with age, and the trial participants were not receiving cancer treatment during the study.

There are few options for people in this position. No approved treatment can prevent CCUS from progressing to leukemia. Stem cell transplantation can treat MDS, but age and other medical conditions can make a patient ineligible. For many, care consists of monitoring blood counts and watching for signs of progression.

“The standard approach for patients with pre-cancer blood disorders is to monitor their blood cell counts over time,” said Casey O’Connell, M.D., FACP, the Lawrence and Jane Kelly Chair in Hematology at the University of Southern California and lead clinician at USC’s trial location. O’Connell said that this watch-and-wait approach can be frustrating for patients, and described EVITA as an effort to examine whether vitamin C might address factors involved in leukemia development.

Participants were assigned to take either 1,000 milligrams of oral vitamin C each day for 12 months or a placebo matched in appearance, taste, and smell. Neither patients nor clinical staff knew who received the supplement until the study concluded. The trial was conducted at Copenhagen University Hospital-Rigshospitalet, Copenhagen University Hospital-Herlev, Aalborg University Hospital, and Keck Hospital of the University of Southern California.

Led internationally by Kirsten Grønbæk, M.D., Ph.D., a hematologist and professor at the University of Copenhagen, EVITA was the first randomized, double-blind, placebo-controlled study to test oral vitamin C in people with conditions that can precede leukemia or with lower-risk myeloid cancers. Earlier research had mainly examined intravenous vitamin C and solid tumors. The oral dose in EVITA is comparable to amounts available in many over-the-counter supplements.

What the study measured

More than half of participants began the trial with insufficient vitamin C levels. Blood samples taken throughout the study showed that levels returned to normal among participants assigned to supplementation. This confirms that the daily oral dose raised blood concentrations in the study group; it does not, by itself, establish a clinical benefit.

The researchers also tracked adverse events and measured cytokines, molecules involved in immune signaling. The vitamin C group experienced fewer adverse events during the trial and follow-up. Cytokine levels shifted in ways linked with more favorable outcomes, offering a possible clue about how supplementation could affect inflammation-related processes connected to abnormal blood cells.

The survival finding came from an exploratory analysis: participants assigned vitamin C were significantly more likely to be alive after approximately three years of follow-up than participants assigned placebo. The trial did not find a significant effect on the expansion rate of abnormal blood cells, and the researchers say the survival result requires confirmation in a larger phase 3 study.

“These exciting preliminary findings lay the groundwork for a larger clinical trial to explore vitamin C as a possible way to improve patient outcomes,” Grønbæk said. She cautioned that it is too early to make definitive recommendations based on EVITA and said a larger study could provide further insight.

Why researchers are studying vitamin C

Interest in vitamin C and cancer stretches back more than seven decades, but earlier studies produced inconsistent results and used different methods. Research over the past decade has clarified that vitamin C is involved in processes beyond nutrition and immune function, including gene activity and normal cell development.

One focus is TET2, an enzyme that helps regulate whether particular genes are switched on or off. Vitamin C supports TET2 activity. Mutations affecting TET2 are common in leukemia and related blood disorders; when the enzyme’s function is disrupted, abnormal cells may have more opportunity to multiply and progress.

Laboratory cancer models have suggested that vitamin C can interfere with cellular changes associated with cancer and slow leukemia progression. The strongest effects in those experiments appeared when vitamin C was given before cancer was established. That work helped motivate researchers to test whether supplementation could act earlier in the disease process, when blood cells carry changes that may precede leukemia.

Before EVITA, the Van Andel Institute-Stand Up To Cancer® Epigenetics Dream Team ran a pilot clinical study in 2016 to assess whether oral vitamin C could raise blood concentrations. The findings supported using oral supplementation in a larger trial, which began in 2017. Stine Ulrik Mikkelsen, M.D., Ph.D., the study’s first author and a clinician researcher in Grønbæk’s laboratory, said that early work helped provide the foundation for EVITA.

The next evidence threshold

Peter A. Jones, Ph.D., D.Sc. (hon), distinguished professor at Van Andel Institute, co-corresponding author, and co-leader of the VAI-SU2C Epigenetics Dream Team, said the team is cautiously optimistic that the results could eventually inform care for people with pre-leukemia disorders. He said the researchers are investigating how vitamin C interacts with precancerous cells, including whether it helps restore normal epigenetic function in blood cells at risk of becoming leukemia.

The team is continuing to analyze EVITA data to understand the biological processes that might account for the survival result. The next test is whether a larger clinical trial can reproduce that finding and clarify which patients, if any, benefit. For now, EVITA offers a rationale for further study of an accessible supplement, while leaving its effect on leukemia risk and survival unresolved.

Other authors include Ali Al-Mousawi, M.D., Amalie Bach Puglisi, M.D., Anders Pommer Vallentin, M.D., Astrid Østergaard Mortensen, Heidi Naomi Ottesen, Linn Gillberg, M.Sc., Ph.D., Morten Tulstrup, M.D., M.Sc., Ph.D., Jakob Werner Hansen, M.D., Ph.D., and Mette Klarskov Andersen, M.D., D.MSc., of the University of Copenhagen and Copenhagen University Hospital-Rigshospitalet; Zachary Madaj, M.S., Toshinori Hinoue, Ph.D., Stacey L. Thomas, Ph.D., Christine N. Isaguirre, Ryan D. Sheldon, Ph.D., Marie Adams, M.S., Ryan Burgos, and Peter W. Laird, Ph.D., of Van Andel Institute; Jakob Schmidt Jespersen, M.Sc., Ph.D., Niels Richard Hansen, M.Sc., and Jens Lykkesfeldt, Ph.D., D.MSc., of the University of Copenhagen; Stephen Baylin, M.D., of Johns Hopkins University and Van Andel Institute; Bo Kok Mortensen, M.D., Ph.D., of Copenhagen University Hospital-Rigshospitalet and Copenhagen University Hospital-Herlev; and Marianne Tang Severinsen, M.D., Ph.D., of Aalborg University Hospital.

Funding came from Van Andel Institute through the Van Andel Institute-Stand Up To Cancer® Epigenetics Dream Team, the Danish Cancer Society, and Greater Copenhagen Health Science Partners.

Materials provided by Van Andel Research Institute. Note: Content may be edited for style and length.

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