DNA-TG and risk of sinusoidal obstruction syndrome in childhood acute lymphoblastic leukemia

Abstract

TO THE EDITOR: DNA-incorporated thioguanine nucleotides (DNA-TG) is a novel and promising target for therapeutic drug monitoring, since it integrates upstream metabolites of thiopurines and methotrexate (MTX) used during maintenance therapy for childhood acute lymphoblastic leukemia (ALL). Lower DNA-TG has been associated with increased risk of relapse, especially in patients who are minimal residual disease positive at the end of induction therapy [1, 2], and thus provides a deeper layer for understanding maintenance efficacy. The European ALLTogether consortium is currently conducting a randomized trial, testing whether the addition of very lowdosed, slowly titrated, 6-thioguanine (6-TG) to the conventional MTX/6-mercaptopurine (6-MP) maintenance backbone can increase event-free survival in the patient group stratified to intermediate risk-high (risk stratification in ALLTogether described in Supplementary; Supplementary Figs. 1 and 2); a group comprising ~40% of patients, and in which 60% of relapses are expected to occur (Clinicaltrials.gov Identifier: NCT04307576; EudraCT: 2018-001795-38). This strategy, referred to as the Thiopurine Enhanced ALL Maintenance (TEAM) strategy, should theoretically increase DNA-TG markedly, since 6-TG leads to markedly higher intracellular thioguanine nucleotide levels compared to 6-MP [3], while MTX-polyglutamates and methylated 6-MP metabolites can inhibit purine de novo synthesis, and thus enhance DNA-TG incorporation [1]. In the TEAM strategy incremental, but very low, doses of 6-TG (2.5–12.5 mg/m/day) are added to a maintenance backbone of 6-MP (50 mg/m/day) and MTX (20 mg/m/week). The TEAM strategy was feasible and welltolerated in a pilot study of 33 patients and led to significantly higher DNA-TG levels when compared to historical data from the NOPHO ALL2008 maintenance sub-study (median DNA-TG on TEAM 764 fmol/μg vs 492 fmol/μg in NOPHO ALL2008; p < 0.0001) [4]. In relation to re-introducing 6-TG in maintenance treatment, a concern has been raised regarding the risk of acute liver toxicity in the form of sinusoidal obstruction syndrome (SOS), formerly known as veno-occlusive disease (VOD). SOS is a microcirculatory disorder, presumably caused by toxic damage to hepatic sinusoidal cells, subsequently leading to sloughing off of the endothelial lining and obstruction of blood flow causing hepatocyte necrosis. Clinically it spans the spectrum from mild, reversible toxicity to chronic toxicity and ensuing portal hypertension [5]. In three randomized trials investigating the replacement of 6-MP with 6-TG in maintenance therapy at doses of 40–60mg/m/ day [6–8], 10–25% of patients receiving 6-TG experienced SOS in two trials [7, 8] or moderate to severe thrombocytopenia (potentially reflecting endothelial damage) in two [6, 8]. In a meta-analysis analyzing individual patient data from 4000 patients randomized in these three trials, the odds ratio for SOS between patients randomized to 6-TG versus 6-MP was 7.16 (95% confidence interval [CI]: 5.66–9.06) [9]. No mortality due to SOS was reported in these trials, but two patients received liver transplants [7, 8]. Meanwhile, a recent systematic review evaluating liver toxicity during long-term use of 6-TG in patients with ALL or inflammatory bowel disease concluded that both the occurrence and severity of 6-TG-related liver toxicity appear to be highly dose-dependent and rarely occurs at doses below 12mg/m/day [10]. However, the risk of SOS during low-dose 6-TG treatment added to a MTX/6-MP backbone has not been evaluated in the ALL setting. Furthermore, when 6-TG is administered in combination with 6MP, the angio-protective effect of the latter may further reduce the risk of SOS [11]. A previous study of thiopurine metabolism in children who developed SOS during 6-TG treatment in the UKALL97 trial found no relation with erythrocyte thioguanine nucleotide levels, but lower activity of the thiopurine metabolizing enzyme thiopurine methyl transferase (TPMT) in children who developed SOS [12]. A previous investigation from the Children’s Oncology Group trial that similarly randomized patients to receive 6-TG vs. 6-MP during maintenance (CCG-1952) [8] found no relation with TPMT genoype