Patients Undergoing Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation Exhibit Depleted Vitamin C Status in Association with Febrile Neutropenia

Abstract

Patients undergoing myeloablative chemotherapy and hematopoietic stem cell transplantation (HSCT) experience profound neutropenia and vulnerability to infection. Previous research has indicated that patients with infections have depleted vitamin C status. In this study, we recruited 38 patients with hematopoietic cancer who were undergoing conditioning chemotherapy and HSCT. Blood samples were collected prior to transplantation, at one week, two weeks and four weeks following transplantation. Vitamin C status and biomarkers of inflammation (C-reactive protein) and oxidative stress (protein carbonyls and thiobarbituric acid reactive substances) were assessed in association with febrile neutropenia. The vitamin C status of the study participants decreased from 44 ± 7 µmol/L to 29 ± 5 µmol/L by week one (p = 0.001) and 19 ± 6 µmol/L by week two (p < 0.001), by which time all of the participants had undergone a febrile episode. By week four, vitamin C status had increased to 37 ± 10 µmol/L (p = 0.1). Pre-transplantation, the cohort comprised 19% with hypovitaminosis C (i.e., <23 µmol/L) and 8% with deficiency (i.e., <11 µmol/L). At week one, those with hypovitaminosis C had increased to 38%, and at week two, 72% had hypovitaminosis C, and 34% had outright deficiency. C-reactive protein concentrations increased from 3.5 ± 1.8 mg/L to 20 ± 11 mg/L at week one (p = 0.002), and 119 ± 25 mg/L at week two (p < 0.001), corresponding to the development of febrile neutropenia in the patients. By week four, these values had dropped to 17 ± 8 mg/L (p < 0.001). There was a significant inverse correlation between C-reactive protein concentrations and vitamin C status (r = −0.424, p < 0.001). Lipid oxidation (thiobarbituric acid reactive substances (TBARS)) increased significantly from 2.0 ± 0.3 µmol/L at baseline to 3.3 ± 0.6 µmol/L by week one (p < 0.001), and remained elevated at week two (p = 0.003), returning to baseline concentrations by week four (p = 0.3). Overall, the lowest mean vitamin C values (recorded at week two) corresponded with the highest mean C-reactive protein values and lowest mean neutrophil counts. Thus, depleted vitamin C status in the HSCT patients coincides with febrile neutropenia and elevated inflammation and oxidative stress.

Epigenetic Regulation of Genomic Stability by Vitamin C

“…Vitamin C supplementation is being explored as an adjuvant to many existing cancer therapies (Figure 3B). As cancer patients frequently present with decreased plasma vitamin C levels (Waldo and Zipf, 1955;Anthony and Schorah, 1982;Mayland et al, 2005;Carr et al, 2020) that are further FIGURE 3 | Vitamin C uptake and therapeutic potential as an anti-cancer agent. (A) Structures of ascorbate (ASC) and dehydroascorbate (DHA).…”

“…Mild vitamin C deficiency may be underreported owing to its non-specific symptoms such as fatigue, irritability, dull aching pains, and weight loss ( Prinzo, 1999 ; Schleicher et al, 2009 ). All-cause mortality decreases when vitamin C serum levels rise above 60 μM ( Goyal et al, 2013 ; Wang et al, 2018 ), while in cancer patients, low serum vitamin C levels of <20–30 μM are frequently observed ( Waldo and Zipf, 1955 ; Anthony and Schorah, 1982 ; Mayland et al, 2005 ; Carr et al, 2020 ). A study of leukocytes isolated from colon cancer patients showed decreased levels of 5mC and 5hmC that correlated with blood plasma ascorbate below 20 μM, while expression of TET genes was not significantly changed ( Starczak et al, 2018 ).…”

“…Vitamin C supplementation is being explored as an adjuvant to many existing cancer therapies ( Figure 3B ). As cancer patients frequently present with decreased plasma vitamin C levels ( Waldo and Zipf, 1955 ; Anthony and Schorah, 1982 ; Mayland et al, 2005 ; Carr et al, 2020 ) that are further decreased by chemotherapy ( Mousseau et al, 2005 ; Carr et al, 2020 ), vitamin C treatment to restore normal amounts in the circulation as an adjuvant for standard chemotherapy could be of therapeutic benefit. The vast majority of patients are TET2 haploinsufficient ( Abdel-Wahab et al, 2009 ; Delhommeau et al, 2009 ; Kosmider et al, 2009 ; Langemeijer et al, 2009 ), suggesting that enhancing residual TET2 activity, or restoring the activity of functionally defective mutant TET2 proteins, could be a particularly viable therapeutic strategy for TET2 deficient hematological malignancies.…”

Emerging epigenetic therapeutics for myeloid leukemia: modulating demethylase activity with ascorbate

“…Indeed, ascorbate deficiency was able to cooperate with Flt3 ITD to promote leukemogenesis in a manner similar to Tet2 loss. 52 A number of studies have found that patients with hematologic cancers are ascorbate deficient, [53][54][55] and these patients are likely to have decreased TET2 activity even in the absence of TET2 mutations.…”

Vitamin C: From Bench to Bedside

“…Cancer research: Dr Wang and colleagues have identified key molecular targets of vitamin C activity in triple-negative breast cancer metastasis in cell culture and a xenograft model [ 7 ], indicating that vitamin C can potentially inhibit metastasis by modulating the expression of SYNPO2 and YAP1. Observational research by Carr and colleagues has indicated that patients undergoing chemotherapy in association with stem cell transplantation exhibit depleted vitamin C status in association with febrile neutropenia [ 8 ]. Further observational research by Dachs and colleagues indicated that low vitamin C status in patients with cancer is associated with both patient and tumor characteristics [ 9 ].…”