Clinical Outcomes in Allogeneic Stem Cell Transplantation for Myeloid Malignancies; Can Vitamin C Improve Clinical Outcomes?

Myeloid malignancies have superior clinical outcomes when preceded by myeloablative conditioning regimens, however transplant related mortality exacts a significant toll. High dose therapy with ionizing radiation and alkylating agents damages DNA, with oxidative stress causing epithelial injury and production of inflammatory cytokines, which in turn contributes to graft vs. host disease (GVHD) pathogenesis. Myeloid malignancies frequently harbor mutations in TET-2 pathway which relies on vitamin C for cell cycle independent DNA hypomethylation. This trial was approved by the Institutional Review Board (IRB) at Virginia Commonwealth University (NCT03613727), FDA IND 138924. In this phase I/II clinical trial, parenteral vitamin C was administered following allogeneic hematopoietic stem cell transplant (SCT) to attenuate oxidative injury, inflammatory response and modify transplant related mortality risk. The following subset analysis gives the results for patients transplanted for myeloid malignancies (MDS, AML and CML) who received IV vitamin C, 50mg/kg/d, in 3 divided doses on days 1-14 after HSCT, followed by 500 mg bid oral until 6 months.

Because of the frequency of DNA hypermethylation in myeloid malignancies, the clinical outcomes in these patients were examined comparing trial patients with their propensity-matched historical controls (accounting for diagnosis, conditioning regimen and CIBMTR risk index). The study cohort had n=41; 78% MUD recipients, with an equal number of historical controls (71% MUD). In this myeloid malignancy cohort, there was a significant beneficial impact of vitamin C on clinical outcomes. Overall survival was superior amongst the vitamin C recipients with myeloid malignancy (p = 0.0167) (HR = 0.32, 95% CI: 0.12, 0.84, p = 0.02), likely attributable to a lower risk of NRM in these patients (10%) compared with historical controls (37%) (HR = 0.22, 95% CI: 0.07, 0.69, p-value = 0.009). The rate of chronic GVHD was lower in Vitamin C recipients (12 vs. 24%; adj HR = 0.56, 95% CI: 0.17, 1.8 2, p-value = 0.383). There was a trend for less acute GVHD in the Vitamin C recipients (23% vs 34%, p-value = 0.38); relapse rates were similar between the 2 groups (20% and 24%; p-value = 0.397). CMV reactivation rates was slightly higher in the study cohort (29% vs 46%; p-value= 0.10).

This prospective trial evaluating parenteral vitamin C in allogeneic HCT, demonstrated its safety and efficacy in patients with myeloid malignancies. There was a non-relapse mortality and survival benefit observed when compared with propensity-matched historical controls, adjusting for diagnosis, disease risk and conditioning intensity. Vitamin C repletion following high-dose therapy and HCT may benefit patients undergoing T cell replete allografts and possibly reduce relapse risk, as well. This simple, cost effective intervention is applicable on a global scale, particularly in economically challenged regions.