The randomized, double-blind, placebo-controlled trial was conducted by the Van Andel Institute-Stand Up To Cancer^® Epigenetics Dream Team. The results, published in the Journal of the American Cancer Society, found that patients who took 1,000 milligrams of oral vitamin C daily for one year experienced fewer adverse events during the study and follow-up period.

Vitamin C supplementation also changed levels of certain immune signaling molecules called cytokines. These changes were associated with more favorable outcomes and suggest that vitamin C may influence inflammation-related processes involved in abnormal blood cell growth and progression.

Vitamin C did not significantly affect the growth rate of abnormal blood cells. However, an exploratory analysis found that participants who took vitamin C were significantly more likely to survive after approximately three years of follow-up than participants who received a placebo.

Researchers emphasize that this potential survival benefit must be evaluated in larger Phase 3 clinical trials before vitamin C can be recommended as a treatment.

Vitamin C May Help Patients at Risk of Leukemia

“We are very excited and cautiously optimistic that our results may one day lead to simple ways to improve care and outcomes for patients with pre-leukemic disease,” said Dr. Peter A. Jones, distinguished professor at the Van Andel Institute. Jones is co-corresponding author of the study and co-leader of the VAI-SU2C Epigenetics Dream Team.

“Our approach reflects the increasing emphasis on stopping cancer, intervening before it takes hold. We are working to build on our trial results by investigating how exactly vitamin C interacts with precancerous cells, including the idea that vitamin C may help restore normal epigenetic function in blood cells at risk of developing leukemia.”

The international research effort was led by Kirsten Grønbæk, MD, a hematologist, professor at the University of Copenhagen and member of the VAI-SU2C Epigenetics Dream Team.

“These interesting preliminary findings lay the foundation for a larger clinical trial to investigate vitamin C as a potential way to improve patient outcomes,” Grønbæk said. “While it is too early to make final recommendations based on our results, we hope that broader research will provide further insights.”

EVITA Trial Tested Daily Vitamin C in CCUS and MDS

The study enrolled 109 patients with either clonal cytopenia of undetermined significance (CCUS) or myelodysplastic syndrome (MDS). Both conditions can progress to acute myeloid leukemia (AML), an aggressive blood cancer that can be difficult to treat.

The likelihood of developing CCUS and related blood disorders increases with age, and these conditions are especially common in older adults. Currently, no approved treatments can prevent CCUS from progressing to leukemia.

Stem cell transplantation is one treatment option for MDS, but many patients cannot undergo the procedure because of their age or other medical conditions. None of the participants in the EVITA trial were receiving cancer treatment when the study was conducted.

Researchers randomly assigned participants to one of two groups. One group received 1,000 milligrams of oral vitamin C daily for 12 months. The other received a placebo designed to look, taste and smell like the supplement but containing no vitamin C.

Neither the participants nor the clinical staff knew who was receiving vitamin C until the end of the study. This randomized, double-blind, placebo-controlled design is considered the gold standard for clinical research because it reduces potential bias and allows researchers to assess treatment effects more objectively.

The trial was conducted at four hospitals:

• Copenhagen University Hospital–Rigshospitalet
• Copenhagen University Hospital–Herlev
• Aalborg University Hospital
• Keck Hospital of the University of Southern California

EVITA is notable because it is the first randomized, double-blind, placebo-controlled trial to investigate oral vitamin C in people with conditions that may precede leukemia or low-risk myeloid cancer. Previous studies have primarily examined intravenous vitamin C in people with solid tumors rather than patients with precancerous blood disorders or early-stage blood cancers.

EVITA evaluated daily oral doses comparable to those found in many commercially available vitamin C supplements.

More Than Half of Participants Had Low Vitamin C Levels

Researchers collected blood samples throughout the study to track vitamin C levels and determine whether supplementation corrected vitamin C deficiency.

More than half of the participants had insufficient vitamin C levels at the beginning of the trial. Among participants assigned to the supplement group, blood vitamin C levels returned to normal after they began taking vitamin C.

The possibility of an accessible intervention is particularly important for people with conditions that may eventually progress to leukemia. Doctors often have few options beyond monitoring the disease and watching for signs of progression.

“The standard approach for patients with precancerous blood disorders is to monitor their blood cell counts over time, which is understandably very frustrating. No one wants to hear that they have a disease that increases their risk of leukemia, but there’s nothing you can do but watch,” said Casey O’Connell, MD, FACP, Lawrence and Jane Kelly Professor of Hematology at the University of Southern California and lead clinician at the USC trial site.

“The EVITA trial addressed this challenge by exploring the potential of vitamin C to address the underlying factors that promote the development of leukemia.”

How Might Vitamin C Affect Cancer Development?

Scientists have studied vitamin C as a possible cancer treatment for more than 70 years. Evidence has remained uncertain because previous studies produced inconsistent results and used different research methods.

Advances in research techniques over the past decade have revealed that vitamin C has functions beyond nutrition and immune support. In particular, scientists have identified a role for vitamin C in controlling gene activity and supporting normal cell development.

One important discovery involves TET2, an enzyme that helps prevent cancer growth by controlling whether certain genes are switched on or off. Vitamin C supports TET2 activity and helps maintain normal patterns of gene regulation.

Mutations affecting TET2 are frequently found in leukemia and related blood diseases. When the normal function of enzymes involved in gene regulation is disrupted, abnormal cells may grow and eventually develop into cancer.

Experiments using cancer models have provided additional evidence of vitamin C’s potential protective effects. These studies found that vitamin C may interfere with cellular changes associated with cancer and slow leukemia progression. The strongest effects were observed when vitamin C was introduced before cancer had become established.

These findings helped support the idea of using vitamin C as an early intervention that could target biological changes occurring before leukemia develops.

Researchers Plan Larger Clinical Trials

Before launching EVITA, the VAI-SU2C Epigenetics Dream Team conducted a pilot clinical study in 2016 to determine whether oral vitamin C could meaningfully increase blood vitamin C levels.

The initial findings suggested that oral supplementation was a practical approach. Encouraged by those results, researchers initiated the Phase 2 EVITA trial in 2017.

“This initial study was extremely important because it provided the basis for developing the current test,” said Stein-Ulrik Mikkelsen, MD, lead author of the study and a clinician-investigator in the Grønbæk lab.

“Vitamin C is important because it is involved in a variety of biological functions, including the activity of enzymes that regulate normal cell function.”

Researchers continue to analyze EVITA data to better understand the biological processes that may explain why patients who received vitamin C showed improved survival.

Although the findings provide a promising direction for future research, additional clinical studies are needed to determine whether vitamin C supplementation can reliably improve outcomes for people with precancerous blood disorders and early-stage blood cancers.

Additional authors include Ali Al Moussawi, MD; Amalie Bach-Paglisi, MD; Anders Pommer Valentin, MD; Astrid Ostergaard Mortensen; Heidi Naomi Ottesen; Lynn Gilberg, MD, PhD; Morten Thulstrup, MD, PhD; Jacob Werner Hansen, MD, PhD; Mette Klarskov Andersen, MD, MSc; Zachary Madaj, MS; Toshinori Higami, PhD; Stacey L. Thomas, PhD; Christine N. Izaguirre, PhD; Ryan D. Sheldon, PhD; Marie Adams, MS; Ryan Burgos, PhD; Peter W. Laird, PhD; Jakob Schmidt Jespersen, MA, PhD; Niels Richard Hansen, MA; Jens Rükesfeld, PhD, MA; Stephen Beilin, MD; Bo Kok Mortensen, MD, PhD; and Marianne Tan Severinsen, MD. The authors are affiliated with the University of Copenhagen, Copenhagen University Hospital–Rigshospitalet, the Van Andel Institute, Johns Hopkins University, Copenhagen University Hospital–Herlev and Aalborg University Hospital.

Funding for the study was provided by the 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.