A randomized trial of daily oral vitamin C in people with pre-leukemia blood disorders found that those who took it were significantly more likely to be alive about three years later than those who took a placebo. The researchers call the survival result exploratory and say patients should not start taking it on that basis.
The trial, called EVITA, enrolled 109 people with clonal cytopenia of undetermined significance, known as CCUS, or lower-risk myelodysplastic syndrome, known as MDS. The Van Andel Institute reported that the paper was published Sept. 21 in the journal Cancer. The work has received far less attention than most cancer headlines, partly because the main goal of the study was not met.
What the EVITA Trial Tested in Vitamin C
EVITA was a phase 2, randomized, double-blind, placebo-controlled trial. Participants took either 1,000 milligrams of vitamin C by mouth daily for one year or a placebo that looked, tasted and smelled identical, according to the institute’s release. Neither participants nor trial staff learned who got which until the study ended.
The sites were Copenhagen University Hospital-Rigshospitalet, Copenhagen University Hospital-Herlev, Aalborg University Hospital and Keck Hospital of the University of Southern California. The Van Andel Institute-Stand Up To Cancer Epigenetics Dream Team led the work, with funding from the institute, the Danish Cancer Society and Greater Copenhagen Health Science Partners.
CCUS and MDS can progress to acute myeloid leukemia, a cancer that is hard to treat. Both conditions are more common in older adults. The institute said no approved therapy prevents CCUS from progressing to leukemia. Stem cell transplant can treat MDS, but many older patients have other conditions that rule it out. For many patients the standard approach is to watch blood counts over time.
None of the participants was receiving cancer treatment when the trial began. The release also said earlier vitamin C trials used intravenous dosing and focused on solid tumors, and that EVITA was the first double-blind, placebo-controlled study of oral vitamin C in these blood conditions.
Why Researchers Looked at Vitamin C and TET2
The idea rests on an enzyme called TET2. Vitamin C works with TET2 to help suppress cancer cell growth by regulating gene activity, the institute said. TET2 mutations are common in leukemia and related disorders and can let malignant cells multiply. In an interview with CancerNetwork, the trial’s lead investigator, Kirsten Grønbæk, a professor at the University of Copenhagen and chief physician in hematology at Copenhagen University Hospital, described the reasoning. TET2 mutations are the most common mutations in CCUS.
A mouse study from UT Southwestern had reported that vitamin C appeared to nearly cure leukemia in mice with reduced TET2 function. Peter Jones, a Van Andel Institute professor and co-leader of the Dream Team, had earlier shown in cell lines that vitamin C prevented malignant clone formation. Grønbæk hypothesized a preventive effect along the path from clonal hematopoiesis to CCUS to MDS.
Animal models suggested the greatest benefit came when vitamin C started before the disease was established, the institute said. That is why the team enrolled people at the earliest stages. A 2016 pilot study had shown oral supplements could raise blood vitamin C levels, and the phase 2 trial began in 2017.
What the Vitamin C Trial Results Showed
The primary measure did not move. The institute said vitamin C produced no significant difference from placebo in the growth rate of abnormal blood cells, a common marker of progression toward leukemia. The survival result came from an exploratory analysis. Vitamin C recipients were significantly more likely to be alive after roughly three years of follow-up.
The institute said the survival difference was statistically significant and that participants given vitamin C had fewer adverse events during the trial and follow-up. The release did not give the underlying survival percentages, and the researchers say the finding needs confirmation before anyone treats it as established.
More than half of participants had insufficient vitamin C levels at the start, the institute said. Levels normalized in the vitamin C group. Grønbæk told CancerNetwork she was surprised so many patients were deficient and that the same pattern has appeared in Dutch patients. She said she did not know how much of any effect comes from correcting the deficiency versus switching on TET activity inside cells.
Vitamin C also shifted levels of inflammatory signaling molecules called cytokines in ways linked to better outcomes. Grønbæk said a prior study tied certain high inflammatory markers to poor-risk MDS, and the shift in EVITA lines up with better survival. The mechanism is still under investigation.
Safety and Dosing in the Vitamin C Trial
The trial dose was 10 times the standard 100 milligram dose, Grønbæk said. The goal was to saturate vitamin C in bone marrow stem cells, where TET2-mutant cells arise, without causing side effects. Levels stayed high through the year in the treatment group but not in the placebo group, and adherence was good.
The team excluded patients with a history of kidney stones because high-dose vitamin C raises the risk of new stones. Grønbæk reported gastrointestinal side effects, mainly gastritis, in 3 of 54 patients. She said the survival gap puzzled the team, and that they checked for differences between the groups and tried to rule them out. “This has been very puzzling to us,” she said in the interview. A calculation from Grønbæk’s figure: 3 of 54 is about 6%, so gastrointestinal side effects affected a small minority of the group she described. She did not say whether the 54 were all vitamin C recipients.
What Patients Should Know before Taking Vitamin C
Vitamin C is sold over the counter, and the finding invites patients to try it. The researchers asked them to wait. “It is too early to make definitive recommendations based on our results,” Grønbæk said in the institute’s release. Jones, a co-corresponding author, said the team was cautiously optimistic that the results could one day lead to a simple way to help patients, according to the same release.
Grønbæk told CancerNetwork that patients who take vitamin C on their own should tell their doctors. She said the risk is probably lower for people on watchful waiting without other drugs, while physicians treating patients with other medications need to know about the supplement. She also said peer reviewers worried the paper could send the wrong message too early.
Casey O’Connell, who holds the Lawrence and Jane Kelly Chair in Hematology at the University of Southern California and led the clinician work at the university’s site, described the current standard for patients with these disorders as monitoring their blood counts over time, the institute said. That is the gap a cheap supplement could fill if the finding holds.
The Phase 3 Plan for Vitamin C
A larger phase 3 trial is needed to confirm the survival finding, the institute said. Grønbæk told CancerNetwork it will enroll the same population in a larger group powered for overall survival, with all-cause mortality as the primary endpoint. She said patients with these conditions die of infections and other causes and not only progression, and that CCUS may carry more cardiovascular disease.
The team does not plan to divide patients by specific mutations because the groups would be too small. The institute said ongoing analyses are examining the biology behind the survival difference. Researchers plan to study how vitamin C interacts with pre-cancerous cells, including whether it helps restore normal epigenetic function in at-risk blood cells.
