[851] Possible Advantage of Twice-Daily 6-Mercaptopurine Dosing in Children with Acute Lymphoblastic Leukemia (ALL). Session Type: Poster Session, Board #5-I

Thaddeus Y. Carson, Beverly A. Bell, Gary Erdmann, Bruce Bostrom, Bruce M. Camitta, Meenakshi Devidas Pediatric Hematology/Oncology, Medical College of Georgia, Augusta, GA, USA; College of Pharmacy, North Dakota State University, Fargo, ND, USA; Pediatric Hematology/Oncology, Childrens Hospitals Clinics of Minnesota, Minneapolis, MN, USA; Pediatric Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; Statistics, Childrens Oncology Group University of Florida, Gainesville, FL, USA

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/810⁸ RBC greater than the bid group (P<.001) and the mean TGN concentration was 7.5 ng/810⁸ 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/810⁸ RBC)

Group	N	Mean TGN (SD)	Mean mMP (SD)	Death Rate (SD)	BM Relapse Rate (SD)	% Missed Doses (SD)
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

*Toxic events were defined as a 3-4 on the NIH toxicity scale

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/810⁸ RBC (39-66 ng/810⁸ 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.
Abstract #851 appears in Blood, Volume 110, issue 11, November 16, 2007
Keywords: Leukemia|Pharmacokinetic|Pediatric
Disclosure: No relevant conflicts of interest to declare.

Saturday, December 8, 2007 5:30 PM

Session Info:  Poster Session: Acute Lymphocytic Leukemias: Therapy, excluding Transplantation I (5:30 p.m.-7:30 p.m.)