Possible Advantage of Twice-Daily 6-Mercaptopurine Dosing in Children with Acute Lymphoblastic Leukemia (ALL).
Authors: Carson Thaddeus Y. , Bell Beverly A. , Erdmann Gary , Bostrom Bruce , Camitta Bruce M. , Devidas Meenakshi 
Published: October 2019

Abstract
6-Mercaptopurine (MP) has been part of the backbone of ALL treatment for more than 50 years. Hepatic enzymes metabolize MP into two major intracellular metabolites, thioguanine nucleotides (TGN) and methylated mercaptopurines (mMP), which have been shown to be cytotoxic in vitro. The short plasma half-life and S-phase dependent pharmacokinetics of MP suggest that a biologically active concentration and longer exposure to MP may be important for maximum cell kill. We hypothesized that dividing the traditional once-daily (qd) MP dose into a twice-daily (bid) dose might produce higher levels of active MP metabolites and increase cell kill. In Pediatric Oncology Group (POG) protocol 9605, 1088 patients with standard risk ALL were randomized to qd or bid dosing. A subset of 242 patients in the continuation phase of the study had steady state red blood cell TGN and mMP levels measured as surrogates for levels in leukemic cells. 16 of these patients were ineligible because either the sample was unsatisfactory (2/16) or timing was unknown (4/16) or incorrect (10/16). 118/226 received MP 75 mg/m2 qd and 108/226 received MP 37.5 mg/m2 bid. Statistical inferences were made with univariate analysis of variance (ANOVA) with two sided P-values. The mean mMP concentration in the qd group was 691 ng/8×108 RBC greater than the bid group (P<.001) and the mean TGN concentration was 7.5 ng/8×108 RBC greater (P=.078) [Table 1]. Despite lower metabolite levels the bid dosing group trended towards a better patient outcome. Patients on bid dosing had a decrease of 5.7% in patient death rate (P=.067) and a decrease of 8.5% in patient bone marrow relapse (P=.063) [Table 1]. Analysis of the total POG 9605 patient population will be necessary to determine if these trends will become statistically significant. Patients on bid dosing had a slight increase of 3.4% in reported cases of toxicity* (P=.309) and only 0.13% more reported missed doses (P=.842).
Table 1. Metabolite and Outcome Data (TGN and mMP measured in ng/8×108 RBC) Group N Mean TGN (SD) Mean mMP (SD) Death Rate (SD) BM Relapse Rate (SD) % Missed Doses (SD) *Toxic events were defined as a 3–4 on the NIH toxicity scale qd 118 47.54 (35) 2277.89 (1559) 8.5% (.280) 17.8% (.384) 4.38% (.055) bid 108 40.09 (27) 1586.58 (1240) 2.8% (.165) 9.3% (.291) 4.51% (.040) P-value 0.078 <.001 0.067 0.063 0.842
The patients were also examined according to the recommended MP metabolite levels used by current diagnostic laboratories which are based on an inflammatory bowl disease patient population. The patients within the recommended TGN range, 230–400 pmol/8×108 RBC (39–66 ng/8×108 RBC), did not show a statistically significant increase in outcome with a 2.89% decrease in bone marrow relapse (P=.545) and a 3.47% decrease in death rate (P=.281) compared to those outside the recommended range. In conclusion, bid MP dosing did not produce the expected elevation of metabolites but did produce a trend toward improvement in clinical outcome.