To date, there is an unmet need for disease-modifying strategies in patients with low-risk myeloid cancers and the precursor condition clonal cytopenia of undetermined significance (CCUS). The phase II EVI-2 study is the first study to report on vitamin C supplementation in this population. Vitamin C deficiency was effectively ameliorated in patients receiving vitamin C treatment and the significantly longer overall survival in the vitamin C group compared to the placebo group warrants further investigation in a sufficiently powered phase III study.
Vitamin C is a cofactor for the important epigenetic regulator, TET2. However, patients with haematological cancer are often vitamine C deficient. Acquired epigenetic changes are a hallmark of myeloid malignancies and TET2 loss-of-function mutations are common drivers of leukemogenesis. Thus, vitamin C supplementation may be an attractive therapeutic strategy in patients with early-stage myeloid malignancies and precursor conditions. The phase II EVI-2 study investigated if oral vitamin C supplementation is safe and may change molecular and clinical disease characteristics and outcomes in patients with low-risk myeloid malignancies and the precursor condition CCUS.
Study design
The phase II EVI-2 trial randomised patients aged ≥18 years with myeloid malignancies and precursor conditions to oral vitamin C 1000 mg/day or placebo for 12 months. Patients were eligible if they had a diagnosis of CCUS, MDS or lower-risk MDS/MPN (according to the 2016 WHO criteria). For MDS, an IPSS-R risk score of ≤3 AND bone marrow blasts <5% applied. Patients had to exhibit somatic gene mutations that are common in myeloid malignancies. Patients with active cancer treatment within the past 6 months were excluded from the study. Patients were not allowed to take additional vitamin C supplementation during the study. The primary endpoint was the change in the variant allele frequency of somatic mutations in CD34+ haematopoietic stem and progenitor cells from inclusion to end of treatment. Important secondary endpoints were vitamin C concentration in peripheral blood plasma, overall survival (OS) and safety. All participating patients were followed after the 12-month treatment period until death, withdrawal of consent, loss to follow-up or study termination.
Results
In total, 55 patients were randomised to the vitamin C arm and 54 patients to the placebo arm. Patient characteristics at the start of the study were comparable between the two groups, with the exception of the median age (vitamin C group 72.3 years vs. placebo group 75.0 years), the percentage of men (65% vs. 78%) and the percentage diagnosed with CCUS (40% vs. 31%).
At baseline, the vitamine C concentration in peripheral blood was inadequate (< 50 µmol/L) in 57% of the study population. Among the patients receiving vitamin C supplementation, there was a significant increase in median vitamin C plasma concentration (45.85 µmol/L at baseline to 81.90 µmol/L at twelve months, p< 1 x 10-7), whereas no stastically significant changes were observed in the placebo group (43.75 µmol/L at baseline to 48.73 µmol/L at twelve months, p= 0.92). Preliminary analysis (N= 66) revealed no differences between or within treatment groups in variant allele frequency from inclusion to end of treatment. Serious adverse events (AEs) were reported at a higher rate in the placebo arm as compared to the vitamin C arm (56% vs. 33%). Two deaths (4%) occurred in the placebo group during study treatment, whereas no deaths occurred during study treatment in the vitamin C group. After a median follow-up of 33.5 months, 11 deaths have occured in the vitamin C group and 24 deaths in the placebo group. Median OS was not reached in the vitamin C arm and was 42.2 months in the placebo arm (HR[95%CI]: 0.35[0.17-0.71], p= 0.0025). Death was disease-related in 58% of cases in the placebo-group and in 45% of cases in the vitamin C group.
Conclusion
The EVI-2 study is the first study to report on vitamin C supplementation in patients with low-risk myeloid malignancies and precursor conditions. Oral vitamin C showed ability to elevate plasma vitamin C concentrations to the high end of the normal range in nearly all patients. Mean clone size did not change or differ between treatment groups at end of treatment. Study treatment was generally safe and well-tolerated. Oral vitamin C treatment was associated with a significant improvement in overall survival, though results should be interpreted with caution. A such, further investigation of oral vitamin C in patients with low-risk myeloid malignancies and precursor conditions in a phase III study powered for overall survival is warranted.
Reference
Mikkelsen SU, et al. Vitamin C supplementation in patient with clonal cytopenia of undetermined significance or low-risk myeloid malignancies: results form EVI-2, a randomized, placebo-controlled phase 2 study. Presented at EHA 2024; Abstract LB3444.
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