Allopurinol Add-on Treatment - Promising Approach to Opitimize Maintenance Therapy for Acute Lymphoblastic Leukemia in Children

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.2809-2809
• Main Authors: Källström, Jonatan, Niinimäki, Riitta, Fredlund, Johan, Vogt, Hartmut, Korhonen, Laura, Castor, Anders, Schmiegelow, Kjeld, Thastrup, Maria, Abrahamsson, Jonas, Ek, Torben
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-193127

Introduction Allopurinol can be used in maintenance therapy (MT) for acute lymphoblastic leukemia (ALL) to mitigate hepatic toxicity in patients with skewed 6-mercaptopurine (6MP) metabolism. These patients have high erythrocyte levels of methylated mercaptopurine metabolites (e-MeMP) associated with liver toxicity, including transaminitis and hypoglycemia, and low erythrocyte levels of thioguanine nucleotides (e-TGN), the key intermediate metabolites mediating the antileukemic effect. Retrospective studies and case reports show that the unfavorable metabolite ratio (high e-MeMP/TGN) can be modified by adding allopurinol leading to lower MeMP and higher TGN. In a recent publication https://doi.org/10.3324/haematol.2023.284390 we showed that allopurinol leads to a similar metabolic shift also in unselected pediatric ALL-patients, without previous severe liver toxicity or other signs of skewed 6MP metabolism. We have now analysed the levels of DNA incorporated TGN (DNA-TG) in our cohort since more recent studies, e.g. https://doi.org/10.1016/s1470-2045(17)30154-7, suggests that relapse-free survival is better correlated to DNA-TG than to e-TGN. Methods Pediatric ALL patients on NOPHO ALL-2008 non-high risk protocols with thiopurine methyltransferase wild-type were studied in a prospective before-after trial, NCT03022747. 6MP metabolites were measured, in total 9 blood samples per patient, during 12 weeks of standard MT, followed by 12 weeks of MT with addition of allopurinol 50 mg/m2 and finally 4 weeks of MT without allopurinol. Mean DNA-TG for each patient was calculated for all study phases separately. DNA-TG/e-TGN ratio was calculated as there was a concern that a decrease in e-MeMP might reduce the DNA incorporation of TGN, since e-MeMP is known to inhibit de novo purine synthesis. The 6MP dose was reduced by 50% when allopurinol was initiated to prevent excessive myelosuppression. DNA-TG was quantified using the same method as in the study cited above, with 1−2 µg DNA purified from whole blood and thioguanine measured with ultra-performance liquid chromatography tandem mass spectrometry. Results 51 patients from Sweden and Finland, age 0-15 (median 4) years, were included, of whom 48 completed the study. In paired analysis DNA-TG was 393 fmol/mg DNA higher (1248 vs 855) (p