Phase II trial assessing safety and preliminary efficacy of high-dose intravenous ascorbic acid in patients with TET2-mutant clonal cytopenias of undetermined significance.
Authors: Xie Zhuoer , Lasho Terra L. , Fernandez Jenna , Finke Christy , Amundson Michelle , LaPlant Betsy , Mangaonkar Abhishek Avinash , Witzig Thomas E. , Patnaik Mrinal Mahesh 
Published: June 2022

TPS7076 Background: Clonal cytopenias of undetermined significance (CCUS) is operationally defined as unexplained persistent cytopenias arising in the context of leukemia-associated somatic driver mutations in hematopoietic stem and progenitor cells, without morphologic evidence for an underlying hematological neoplasm. Patients with TET2 mutant ( TET2MT) CCUS have a high probability of progression to myeloid neoplasms, with approximated 10-year cumulative rates of progression being 90%. To date, no FDA-approved treatment for CCUS has been established, and we have shown that these patients can have transfusion burdens akin to patients with myelodysplastic syndrome (MDS) (Li M et al. Blood Adv 2020). Thus there is an urgent and unmet need for therapies for these patients. Intravenous (IV) ascorbic acid (AA) dosed at pharmacologic concentrations could have anti-cancer activity via two mechanisms: (1) hydrogen peroxide-induced oxidative stress and (2) DNA demethylation mediated by TET activation (cofactor for TET1/2/3). TET2, the primary enzyme for catalyzing oxidative reactions, converts 5-methylcytosine to 5-hydroxymethylcytosine, a crucial step leading to iterative DNA demethylation. Our study hypothesis is that IV AA in TET2MT CCUS will restore hematopoiesis and limit clonal progression by stimulating TET2 (the unmutated allele) and TET3 activities. Methods: LS1781 (NCT03418038) is an investigator-initiated, prospective, single-arm, single-institution, phase II trial assessing the safety and preliminary efficacy of high dose of IV AA for patients with TET2MT CCUS (harboring ≥1 TET2MT or TET2MT combined with concurrent spliceosome MTs). IV AA (1g/kg, maximum 100g) is given 3 times weekly for 12 weeks through a central line with assessments being carried out before each cycle (4 weeks), at 12 weeks, and one year. The primary endpoint is the hematologic response rates determined by MDS IWG 2018 criteria. Secondary endpoints include safety and side effects. Exploratory endpoints include the impact of AA on TET2MT variant allele fraction, plasma cytokine levels, DNA methylation, and hydroxymethylation (as measured by Infinium MethylationEPIC array), and TET activity. Patients 18 years or older with TET2MT CCUS, and with any of the following laboratory criteria: (1) hemoglobin ≤10g/dL, (2) absolute neutrophil count (ANC) ≤1000/mm3, (3) platelet count ≤100,000/mm3 are eligible. Fifteen patients will be enrolled at Mayo Clinic Rochester and the Mayo Clinic Health System. Dose modifications have been established and will be considered based on adverse events. Treatment will be discontinued for disease progression or in the event of ≥Grade 3 adverse events that don’t resolve promptly. Enrollment to the trial began in June 2021, with 7 patients enrolled at abstract submission. Clinical trial information: NCT03418038.