Assessment on the use of allopurinol to improve safety and efficacy of mercaptopurine in pediatric patients with Acute Lymphoblastic Leukemia and Lymphoma during maintenance therapy

Abstract

Abstract Background Mercaptopurine is an important component of acute lymphoblastic leukemia (ALL) and lymphoma (LLy) maintenance therapy. The 6‐thioguanine nucleosides (6‐TGN) are believed to be the primary contributor to myelosuppression and immunosuppressive effects, while 6‐methylmercaptopurine (6‐MMPN) is believed to be responsible for several toxicities including hepatotoxicity, pancreatitis, and hypoglycemia. Previous reports suggest the addition of allopurinol may reduce these toxicities. Aims To assess the use of allopurinol to improve both safety and efficacy of mercaptopurine in pediatric patients with ALL and LLy during maintenance therapy. Secondary objectives included evaluating patient tolerability and skewed metabolism. In addition, we also analyzed mercaptopurine daily dose reduction upon allopurinol initiation. Methods and Results The primary endpoint was time within goal ANC prior to and after initiation of allopurinol. Secondary endpoints included; improvement in selective toxicities (hepatotoxicity, pancreatitis, and hypoglycemia) and 6‐MMPN to 6‐TGN ratio prior to and after allopurinol initiation. In addition, an exploratory endpoint assessing mercaptopurine daily dose reduction prior to and after allopurinol initiation was included. Sixteen patients met inclusion criteria and 15 (94%) of which were included in this study. Median percent of maintenance days within goal ANC prior to and after initiation of allopurinol was 27.8 (IQR 22.6–44.9) and 41.6 (IQR 20.2–58.2) respectively. All patients experienced selective toxicities; 15 (100%) hepatotoxicity, 1 (7%) pancreatitis, and 3 (20%) hypoglycemia. Improvement of toxicities was seen in 13/15 (87%), 1/1 (100%), and 2/3 (67%) respectively. Average 6‐MMPN:6‐TGN ratio prior to allopurinol initiation was 304:1 and after, allopurinol initiation improved to 15:1, resulting in a 95% reduction. Average mercaptopurine dose prior to and after allopurinol initiation decreased by about 56% (63 to 28 mg/m2/day). Conclusion Results suggest that the use of allopurinol in pediatric patients with ALL and LLy receiving mercaptopurine during maintenance therapy is both safe and effective.

Keywords

• absolute neutrophil count
• acute lymphoblastic leukemia and lymphoma
• allopurinol
• hepatotoxicity
• mercaptopurine