Vitamin C did not slow abnormal blood cell growth in a 109-person trial; an unplanned tally found fewer deaths

A year of daily vitamin C did not do what a trial in Denmark and the United States was built to test. In 109 people with early blood cancers or a condition that can lead to them, mutated blood cells grew at the same rate with the vitamin as with a placebo, or dummy pill.

Something else happened that the researchers had not set out to measure. Over about three years, 11 of the people assigned to vitamin C died, compared with 24 of those assigned to placebo. The trial was published on September 21 in the journal Cancer.

The two results pull in different directions, and the second rests on an analysis added after the trial was designed. The authors call it a reason for a larger trial.

What clonal cytopenia and early blood cancers are

Blood cells are made in the bone marrow by stem cells. With age, a stem cell can pick up a mutation and produce a growing family of identical descendants, called a clone. Cytopenia means a low count of one or more types of blood cell.

Put together, the two terms give the condition its name, clonal cytopenia of undetermined significance (CCUS), which describes people who have both. CCUS was identified as a precursor condition for myeloid malignancies, the paper explains, meaning cancers of the marrow cells that make most blood cells. The best known of these cancers are the myelodysplastic syndromes, in which the marrow fails to make enough healthy blood, and which can progress to leukemia.

Low blood counts with no clear cause are common in later life. Unexplained blood cytopenias, in particular anemia, are often found in older persons, an Italian team wrote in 2017. In their study of people sent for testing, 435 of 683 patients carried a somatic mutation in at least 1 of the genes examined, somatic meaning acquired during life and not inherited. Among people whose tests were otherwise inconclusive, carrying such a mutation was associated with a high probability of developing a myeloid neoplasm during follow-up, another name for a myeloid cancer.

For people at this stage there is little to offer. Patients are usually monitored, as no interception strategy is currently available, interception meaning a treatment that heads the disease off. That gap is what the trial set out to address.

Why vitamin C was tested against blood cell clones

Vitamin C helps a family of proteins called TET enzymes do their work, which is to remove chemical tags from DNA and so help control which genes are switched on. One of the genes most often mutated in these blood conditions carries the instructions for a TET enzyme. The idea was that extra vitamin C might restore some of the lost activity.

Animal work supported it. In 2017 a team in Texas reported that blood stem cells in people and mice had unusually high levels of ascorbate, the chemical name for vitamin C. When mice were deprived of it, leukemia developed faster, in a manner that was reversed by dietary ascorbate.

There was also a practical observation. Vitamin C deficiency is common among patients with blood cancers, the authors note. In their own trial, 57% (62 of 109) of participants had blood plasma vitamin C concentrations in the deficient or inadequate ranges at the start.

How the vitamin C trial was run

The trial, called EVITA, was conducted in Denmark and the United States. It enrolled adults with CCUS or with lower-risk myeloid cancers who were not receiving anticancer therapy. A total of 54 patients were randomly assigned to receive placebo, and 55 patients were assigned to receive oral vitamin C.

The dose was 1,000 mg a day for 12 months. Neither the patients nor their doctors knew who was taking which pill. After the year of treatment, participants were followed without any restriction on what supplements they took.

The primary end point was the median clonal growth rate from baseline to end of treatment. In plain terms, the researchers tracked what share of each person’s blood cells carried the mutations, and asked whether that share rose more slowly on vitamin C.

Blood tests confirmed that the pills were taken and absorbed. In the vitamin C group, the typical blood level nearly doubled over the year, while in the placebo group it did not change.

The main result: clone growth did not change

The mutated clones grew at the same pace in both groups. There was no difference in the primary end point, clonal growth rate, between patients treated with oral vitamin C for 12 months and those receiving placebo, the authors write.

Laboratory measures of the chemical tags on DNA, the mechanism the trial was built around, did not shift either. The one biological change the team detected was in inflammation: several signaling molecules that rise with more advanced disease rose less, or fell, in the vitamin C group.

Fewer serious complications and fewer deaths with vitamin C

Other counts did differ. There were fewer serious adverse events in the vitamin C group. The term covers any medical event leading to hospital admission or worse, whatever its cause.

Outcome	Vitamin C	Placebo
Growth rate of mutated clones	Same in both groups	Same in both groups
People with a serious adverse event	18 of 55 (33%)	30 of 53 (57%)
Pneumonia	1 of 55	8 of 53
Progression to higher-risk disease	5	9
Deaths over a median of 33.6 months	11	24

Serious adverse events were counted among 53 of the 54 people assigned to placebo, the figure the paper reports.

Anemia, pneumonia and internal bleeding occurred more frequently in the placebo group than in the vitamin C group. Stomach and gut problems went the other way: diarrhea, inflammation of the esophagus and gut infections were each recorded in a few more people taking the vitamin.

Then there were the deaths. At a median follow-up of 33.6 months, 35 deaths were recorded from randomization to end of study, including 24 in the placebo group and 11 in the vitamin C group. The median overall survival was 42.2 months in the placebo group, the median being the point by which half of the patients are estimated to have died. In the vitamin C group too few had died for that point to be estimated. The rate of death in the vitamin C group was 0.35 times that in the placebo group, with a plausible range of 0.17 to 0.71.

Bacterial infection was the leading cause of death in both groups.

Fewer people on vitamin C progressed to more dangerous disease, but with 14 recorded progression events, nine in the placebo group and five in the vitamin C group, that gap could easily be chance.

Where this fits: vitamin C and cancer before this trial

Vitamin C has been promoted as a cancer treatment for half a century, and the earlier tests were discouraging. The best known were run at the Mayo Clinic.

In the first, published in 1979, one hundred and fifty patients with advanced cancer participated in a controlled double-blind study of 10 grams a day. The median survival for all patients was about seven weeks, and the survival curves essentially overlapped, meaning the two groups died at the same pace.

Supporters objected that those patients had been weakened by chemotherapy. So the same group ran a second trial, published in 1985, in which 100 patients with advanced colorectal cancer were randomly assigned to treatment with either high-dose vitamin C (10 g daily) or placebo, none of them previously treated with chemotherapy. The result was the same. The authors concluded that high-dose vitamin C therapy is not effective against advanced malignant disease.

The new trial differs from those in two ways that matter. It used a tenth of the dose, an amount that corrects a shortfall and does not flood the body. And it enrolled people at the earliest stage, some before any cancer had been diagnosed.

Only one other human study has tested vitamin C in this group, the authors say. It gave very high doses by drip to 10 patients, with no comparison group, and no hematological responses were observed at 20 weeks, meaning blood counts did not improve.

Where the vitamin C trial falls short

The survival result was not what the trial was designed to test. Overall survival was analyzed as a post hoc exploratory end point, post hoc meaning chosen after the plan was written. The authors say plainly that the study was neither powered nor designed to assess survival outcomes, powered meaning large enough to give a reliable answer. When a trial misses its main target and many other outcomes are then examined, one of them can look striking by chance.

The groups were not identical at the start. The placebo group had a slightly higher median age, more male patients and lower blood counts, whereas the vitamin C group had a higher mutational burden and poorer disease prognostic scores, meaning more mutated cells and worse scores on a scale that predicts how the disease will go. The difference in deaths held after adjustment for age, sex, diagnosis and the level of hemoglobin, the oxygen-carrying protein in red blood cells, at 0.42 times the rate, with a plausible range of 0.20 to 0.88.

The trial was small. Its limitations include the relatively small sample size and lack of a formal sample size calculation. And after the first 12 months nobody recorded who took vitamin C on their own, so undocumented posttreatment vitamin C exposure may have introduced informal crossover, meaning some people assigned to placebo may have ended up taking the vitamin.

The vitamin was not free of harm. One case of kidney stones requiring intervention occurred during treatment in the vitamin C group, in a patient who had had kidney stones before.

Nothing here applies to people without these conditions, or to higher doses.

The researchers were cautious in public. “Although it is too soon to make recommendations based on our results, we are hopeful that a larger study will give us more definitive answers,” said Kirsten Grønbæk of Copenhagen University Hospital, a senior author. The other senior author, Peter Jones of the Van Andel Institute in Michigan, described the purpose of the next step. “The EVITA trial gives us a strong rationale to continue exploring if and how vitamin C might benefit people with certain pre-cancer or early-stage blood cancers,” Jones said.

Whether a supplement is suitable for someone with a blood disorder depends on their condition and treatment, which is assessed by their doctor.

Daily vitamin C left the growth of mutated blood cells unchanged in 109 people with early myeloid disease, and the lower death count that came with it is an unplanned observation from a small trial that a larger one would have to repeat.