Parenteral Ascorbic Acid in Allogeneic HCT Recipients Is Safe and Ameliorates the Cytokine Milieu and Endothelial Injury Following Myeloablative Conditioning (2020)

Intravenous (IV) ascorbic acid (AA) improves organ function and reduces inflammation in sepsis, an inflammatory state similar to post-hematopoietic cell transplant (HCT) milieu. This salutary effect is mediated by antioxidant activity as well transcriptional modulation by AA. We evaluated the safety and efficacy of IV AA in ameliorating the inflammatory milieu following myeloablative conditioning and allogeneic HCT.Methods: Patients with advanced hematologic malignancies (CML, AML, ALL, MDS) were enrolled in an IRB approved prospective phase 2 clinical trial (NCT03613727). IV AA 50mg/kg/d divided in 3 doses was given on days 1-14 after HCT followed by oral AA 500mg bid from day 15 until 6 months post HCT (IND 138924). The treatment regimens included myeloablative fludarabine & melphalan, or cyclophosphamide with either busulfan or total body irradiation. GVHD prophylaxis included ATG. FDA mandated safety lead-in cohort enrollment for the trial is complete with ongoing accrual to target primary end point of reducing 1-year non-relapse mortality. Cytokines were measured at various time points following HCT.Results: As of October 2019 21 patients have received IV AA: these include HLA-MRD (n=5), and 10/10 or 9/10 HLA-MUD (12 & 4 respectively) recipients. Graft source was either peripheral blood (19) or bone marrow (2). Median age was 56 years; males (11). All patients enrolled were deficient in AA at day 0, median 0.3 mg/dL (range: 0.1-0.5), day 14, post AA infusion level was normal at 1.6 (1.2-5.7). Neutrophil recovery was by 11 days (9-15 days) and platelets by 12 (9-19) with sustained donor engraftment. Median absolute CD3+ cell count at day 30 was 390/mL (55-2288) with 100% donor chimerism. Pro-inflammatory cytokines IL-1b, IL-2, IL-6, IL-12, TNF-α, IFN-γ, as well as soluble thrombomodulin remained unchanged between day 0 and day 14 & day 30 after HCT (P=NS for all comparisons Figure 1). At a median follow up of 201 days (13-335) there is a 95% survival observed (Figure 2). There was no VOD and no attributable grade 3 and 4 toxicities to AA. Mucositis was mild and TPN was required in only 43% of patients. The cumulative incidences of grades II–IV and grades III–IV acute GVHD were 33% and 9% respectively, and moderate chronic GVHD 21%. No severe cGVHD has been observed, only one relapse has occurred.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. Pro-inflammatory cytokines and endothelial injury markers remain around baseline levels, with no VOD and low rates of GVHD observed. IV AA requires further investigation in HCT given its safety, and low cost (∼$450 for 14 day infusion in a 80 KG recipient) and potential for worldwide use. Intravenous (IV) ascorbic acid (AA) improves organ function and reduces inflammation in sepsis, an inflammatory state similar to post-hematopoietic cell transplant (HCT) milieu. This salutary effect is mediated by antioxidant activity as well transcriptional modulation by AA. We evaluated the safety and efficacy of IV AA in ameliorating the inflammatory milieu following myeloablative conditioning and allogeneic HCT. Methods: Patients with advanced hematologic malignancies (CML, AML, ALL, MDS) were enrolled in an IRB approved prospective phase 2 clinical trial (NCT03613727). IV AA 50mg/kg/d divided in 3 doses was given on days 1-14 after HCT followed by oral AA 500mg bid from day 15 until 6 months post HCT (IND 138924). The treatment regimens included myeloablative fludarabine & melphalan, or cyclophosphamide with either busulfan or total body irradiation. GVHD prophylaxis included ATG. FDA mandated safety lead-in cohort enrollment for the trial is complete with ongoing accrual to target primary end point of reducing 1-year non-relapse mortality. Cytokines were measured at various time points following HCT. Results: As of October 2019 21 patients have received IV AA: these include HLA-MRD (n=5), and 10/10 or 9/10 HLA-MUD (12 & 4 respectively) recipients. Graft source was either peripheral blood (19) or bone marrow (2). Median age was 56 years; males (11). All patients enrolled were deficient in AA at day 0, median 0.3 mg/dL (range: 0.1-0.5), day 14, post AA infusion level was normal at 1.6 (1.2-5.7). Neutrophil recovery was by 11 days (9-15 days) and platelets by 12 (9-19) with sustained donor engraftment. Median absolute CD3+ cell count at day 30 was 390/mL (55-2288) with 100% donor chimerism. Pro-inflammatory cytokines IL-1b, IL-2, IL-6, IL-12, TNF-α, IFN-γ, as well as soluble thrombomodulin remained unchanged between day 0 and day 14 & day 30 after HCT (P=NS for all comparisons Figure 1). At a median follow up of 201 days (13-335) there is a 95% survival observed (Figure 2). There was no VOD and no attributable grade 3 and 4 toxicities to AA. Mucositis was mild and TPN was required in only 43% of patients. The cumulative incidences of grades II–IV and grades III–IV acute GVHD were 33% and 9% respectively, and moderate chronic GVHD 21%. No severe cGVHD has been observed, only one relapse has occurred. 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. Pro-inflammatory cytokines and endothelial injury markers remain around baseline levels, with no VOD and low rates of GVHD observed. IV AA requires further investigation in HCT given its safety, and low cost (∼$450 for 14 day infusion in a 80 KG recipient) and potential for worldwide use. Figure 1, Figure 2.Figure 2Overall survival following HCT with IV AA from day 1-14.View Large Image Figure ViewerDownload Hi-res image Download (PPT)