Intracellular cytarabine triphosphate in circulating blasts post-treatment predicts remission status in patients with acute myeloid leukemia.

Abstract

Cytarabine remains the backbone of therapy in acute myeloid leukemia (AML). The ability to assess intracellular cytarabine triphosphate (ara-CTP) levels in patients receiving cytarabine represents a major goal in the prediction of treatment response. This study, conducted within a clinical setting, aimed to assess ara-CTP levels in circulating peripheral blasts from non-M3 AML patients receiving cytarabine at one of three dosing levels, using a novel biosensor assay. Results from the initial 72 hours post-commencement were correlated with day 28 remission status, with feasibility parameters concurrently assessed. Intracellular ara-CTP was detectable in ex vivo blasts post-treatment for standard-dose (SD) and high-dose (HD) patients (p < 0.05), and quantification revealed a 27-fold increase in intracellular steady-state concentration between the two dosing levels. For low-dose cytarabine, high rates of patient discharge and low intracellular concentrations limited analysis; however, assessment of intracellular ara-CTP concentration was achievable in a dwindling population of blasts for SD and HD treatment cohorts, with 4 hours post-treatment commencement potentially being most predictive of clinical response (r = -0.912, p = 0.0113). Concurrent assessment of peripheral leukemia-associated immunophenotype (LAIP)-positive cells revealed a decline in burden (0-72 hours), which correlated with remission status (p < 0.05). Unexpectedly high rates of night sampling led to challenges associated with sampling rates, but did not have an impact on patient compliance. Additional training of night staff improved feasibility substantially. Multiple peripheral sampling during the initial 72 hours of treatment is feasible in newly diagnosed patients, and ara-CTP is detectable over the initial 24 hours, facilitating prediction of chemosensitivity of leukemic blasts to cytarabine.

• Authors: Elizabeth Anderson, Barbara Rees, Jonathon Hull, Jonathan Heywood, Andrea Preston, Rachel Protheroe, Emily Foulstone, Rosemary Greenwood, Vyv Salisbury, Priyanka Mehta
• Journal: Experimental hematology (Exp Hematol) Vol. 74 Pg. 13-18.e3 (06 2019) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 31054867 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier Inc.

Chemical References

• Arabinofuranosylcytosine Triphosphate

Topics

• Aged
• Arabinofuranosylcytosine Triphosphate (administration & dosage, pharmacokinetics)
• Blast Crisis (blood, drug therapy, mortality)
• Disease-Free Survival
• Female
• Humans
• Leukemia, Myeloid, Acute (blood, drug therapy, mortality)
• Male
• Middle Aged
• Remission Induction
• Survival Rate
• Time Factors