A Comparison of Hepatotoxicity and Neutropenia in Children Given Oral Mercaptopurine on a Twice-Daily Versus Once-Daily Dosing Schedule for Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study.

Abstract

Pediatric Oncology Group (POG) protocol 9605, a phase III study of standard risk acute lymphoblastic leukemia (ALL), was designed in part to compare daily (QD) versus twice-daily (BID) mercaptopurine (MP) dosing during intensification and continuation therapy. 1082 patients were enrolled between 1996 and 1999. MP is an important antimetabolite in the treatment of ALL. Due to its S-phase dependence and short half-life, dosing frequency may be crucial to toxicity and/or efficacy. MP is converted into two major metabolites, 6-thioguanine (TGN) and 6-methylthioinosinic acid (mMP). Correlations of toxicity and dose frequency were tabulated. Red blood cell (RBC) TGN and mMP levels measured in a randomized subpopulation (226/1082 patients) on POG 9605 found markedly elevated mMP in the QD versus BID group (2020 versus 1275 ng/8x108 RBC) with slightly higher levels of TGN in the QD group (42 versus 40 ng/8x108 RBC). Toxicity events occurring during treatment were recorded according to toxicity code, grade and week of therapy. Toxicity events for 1037/1082 patients were analyzed. For each toxicity, QD and BID groups were compared based on total number of events, number of individual patients, and average number of events per patient. A comparison of the incidence of neutropenia and hepatotoxicity between QD and BID groups became the focus. 518/1037 patients received 6MP 75 mg/m2 daily and 519/1037 patients received 6MP 37.5 mg/m2 twice daily. Decreased ANC were coded as grade 3 (0.5–0.9 x 103/mm3) or grade 4 (less than 0.5 x 103/mm3). Decreased WBC were coded as grade 3 (1.0–1.9 x 103/mm3) or grade 4 (less than 1.0 x 103/mm3). Elevated aminotransferase (ALT/AST) were coded as grade 3 (5.1–20 x normal) or grade 4 (greater than 20 x normal). For grade 4 neutropenia, the QD group had a significantly higher average number of events per patient than the BID group (4.67 versus 4.22, p=0.021). Also for grade 3 ALT/AST, the QD group had a significantly higher average number of events per patient than the BID group (2.40 versus 2.10, p=0.046). In previous studies, higher mMP levels were found to be correlated with elevated aminotransferases. The subpopulation (n=226/1082) data was analyzed to compare metabolite levels in patients who experienced various toxicities. In the QD arm, TGN was significantly elevated in those patients with grades 3 and 4 WBC (p=0.026) and grades 3 and 4 ANC (p=0.032). MMP was significantly elevated in those with grades 3 and 4 WBC (p=0.0066), grades 3 and 4 ANC (p=0.009) and grades 3 and 4 ALT/AST (p=0.0082). QD administration of 6MP is associated with increased levels of methylated metabolites, elevated ALT/AST and decreased ANC. Neutropenia correlates with elevations of both TGN and mMP. Hepatotoxicity correlates with elevations in mMP. Issues of adherence to dosing may also play a role. Implications for patient outcome await data maturation.