A phase 1 study to evaluate the safety, pharmacology, and feasibility of continuous infusion nelarabine in patients with relapsed and/or refractory lymphoid malignancies.

in Cancer by Prajwal C Boddu, Jayastu Senapati, Farhad Ravandi-Kashani, Elias J Jabbour, Nitin Jain, Mary Ayres, Yuling Chen, Michael J Keating, Hagop M Kantarjian, Varsha Gandhi, Tapan M Kadia

TLDR

  • A phase 1 study evaluated the pharmacokinetics and toxicity of nelarabine administered as a continuous infusion for 5 days in patients with R/R T-ALL, T-LBL, or T-PLL, showing an acceptable safety profile, clinical activity, and potential for broader use in combination therapies.

Abstract

Nelarabine is a purine nucleoside analogue prodrug approved for the treatment of relapsed and refractory T-cell acute lymphoblastic leukemia (R/R T-ALL) and lymphoblastic lymphoma (T-LBL). Although effective in R/R T-ALL, significant neurotoxicity is dose-limiting and such neurotoxicity associated with nucleoside analogues can be related to dosing schedule. The authors conducted a phase 1 study to evaluate the pharmacokinetics and toxicity of nelarabine administered as a continuous infusion (CI) for 5 days (120 hours), rather than the standard, short-infusion approach. Twenty-nine patients with R/R T-ALL/LBL or T-cell prolymphocytic leukemia (T-PLL) were treated, with escalating doses of nelarabine from 100 to 800 mg/m/day × 5 days. The median age of the patients was 39 years (range, 14-77 years). The overall response rate was 31%, including 27% complete remission (CR) or CR with incomplete platelet recovery (CRp). Peripheral neuropathy was observed in 34% of patients, including four ≥grade 3 events related to nelarabine. Notably, there was no nelarabine-related central neurotoxicity on study. The maximum tolerated dose was not reached. Pharmacokinetic data suggested no relationship between dose of nelarabine and accumulation of active intracellular ara-GTP metabolite. Higher intracellular ara-GTP concentrations were statistically associated with a favorable clinical response. Preliminary evaluation of continuous infusion schedule of nelarabine suggests that the safety profile is acceptable for this patient population, with clinical activity observed even at low doses and could broaden the use of nelarabine both as single agent and in combinations by potentially mitigating the risk of central nervous system toxicities.

Overview

  • The study aimed to evaluate the pharmacokinetics and toxicity of nelarabine administered as a continuous infusion for 5 days, instead of the standard short-infusion approach.
  • The study enrolled 29 patients with relapsed and refractory T-cell acute lymphoblastic leukemia (R/R T-ALL), lymphoblastic lymphoma (T-LBL), or T-cell prolymphocytic leukemia (T-PLL) to receive escalating doses of nelarabine from 100 to 800 mg/m²/day × 5 days.
  • The primary objective was to determine the maximum tolerated dose (MTD) of nelarabine administered as a continuous infusion and to evaluate its pharmacokinetics and toxicity profile.

Comparative Analysis & Findings

  • The overall response rate was 31%, with 27% complete remission (CR) or CR with incomplete platelet recovery (CRp).
  • Peripheral neuropathy was observed in 34% of patients, with four ≥grade 3 events related to nelarabine.
  • Pharmacokinetic data showed no relationship between dose of nelarabine and accumulation of active intracellular ara-GTP metabolite, and higher intracellular ara-GTP concentrations were statistically associated with a favorable clinical response.

Implications and Future Directions

  • The study suggests that the continuous infusion schedule of nelarabine is potentially feasible and can broaden its use as a single agent or in combinations, potentially mitigating the risk of central nervous system toxicities.
  • Future studies can investigate the optimal dose and scheduling of nelarabine to maximize its therapeutic benefit while minimizing its toxicity.
  • The study highlights the importance of further research into the pharmacokinetics and pharmacodynamics of nelarabine to better understand its mechanism of action and optimize its use in clinical practice.
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