Safety and Tolerability of Intra-Venous Ascorbic Acid in Allogeneic Hematopoietic Cell Transplant Recipients: A Matched Historical Control Study

Intravenous (IV) ascorbic acid (AA) improves organ function and reduces inflammation in sepsis, an inflammatory state similar to the post-hematopoietic cell transplant (HCT) milieu. This salutary effect is mediated by antioxidant activity as well transcriptional modulation by AA. HCT recipients are deficient in AA, therefore we evaluated the safety and efficacy of patients receiving parenteral AA after myeloablative conditioning for allogeneic HCT compared to similarly treated historical controls who did not receive AA.

Methods: Patients with hematologic malignancies, AML (48% of patients), ALL (28%), and CML+MDS (25%) were enrolled in an IRB approved prospective phase 2 clinical trial (NCT03613727). IV AA 50 mg/kg/d divided in 3 doses was given on days 1-14 after HCT, followed by oral AA 500 mg bid from day 15 until 6 months post HCT (FDA-IND 138924). Conditioning regimens utilized included; fludarabine & melphalan (45%), cyclophosphamide with either busulfan (30%) or total body irradiation (25%). GVHD prophylaxis included calcineurin inhibitors and methotrexate or cellcept along with anti-thymocyte globulin (ATG). Primary endpoint was reduction in TRM at 1 year. Propensity score matching was used for matching study patients with similarly treated historical controls, matching for diagnosis, conditioning regimen, and CIBMTR disease risk category for comparison of clinical outcomes. Cox-proportional hazard models were used to estimate adjusted hazard ratios (AHR) between the time-to-event outcomes and study group, adjusted for patient age, donor type, stem cell source, diagnosis, conditioning regimen, and CIBMTR disease risk. Results of an interim analysis following a period of COVID 19 mandated suspension of study accrual are reported.

Results: As of March 2020, 40 patients have received IV AA: these include HLA-matched related donor (MRD; n=11), and either 10/10 or 9/10 HLA- matched unrelated donor (MUD; n=22 & 7 respectively) recipients. Graft source was either peripheral blood (n=38) or bone marrow (n=2); 88% patients had CIBMTR high risk disease. Median age was 55 years; males (19). All patients enrolled were deficient in AA at day 0, median AA level 0.3 mg/dL (range: 0.1-0.5); post AA infusion level was normal at 1.6 (1.2-5.7) on day 14. Median neutrophil and platelet recovery was by 12 days (range: 9-15 & 8-21 days respectively) with sustained donor engraftment. Median absolute CD3+ cell count at day 30 was 330 cells/microL. With a median follow up of 220 days in AA recipients, no statistically significant difference was observed in transplant related mortality between propensity matched historical controls and study patients (AHR 0.6, 95% CI: 0.2-1.5; p-value = 0.27); univariate survival analysis is depicted in Figure 1. Relapse was also similar (AHR 1.2, 95% CI: 0.3-4.5; p-value = 0.82), and despite a larger number of HLA mismatched unrelated donor recipients, acute GVHD (Grade II-IV) rates were similar in the two groups for both grade II-IV (AHR 0.8, 95% CI: 0.7-1.7; p-value = 0.65) and grade III-IV disease (AHR 0.6, 95% CI: 0.2-1.6; p-value = 0.32). Chronic GVHD rates were also similar (AHR 0.4, 95% CI: 0.1-2.7; p-value = 0.74). There are no attributable grade 3 - 4 toxicities from AA; CMV and EBV reactivation rates were not different in the two groups.

Conclusions: In patients undergoing myeloablative allogeneic HCT the administration of IV ascorbic acid is safe and does not negatively impact myeloid engraftment or immune reconstitution. In this interim analysis, transplant related mortality, relapse and GVHD are not increased in IV AA recipients compared to historical controls. Thus, given its safety and tolerability, and possible salutary impact on survival and relapse in these high-risk patients, we posit the feasibility of a randomized phase 3 trial with IV AA in the post-transplant setting to determine its effect on relapse and TRM.