Stine N Nielsen1, Frank Eriksson2, Susanne Rosthoej2, Mette K Andersen3, Erik Forestier4, Henrik Hasle5, Lisa L Hjalgrim1, Ann Aasberg6, Jonas Abrahamsson7, Mats Heyman8, Ólafur G Jónsson9, Kaie Pruunsild10, Goda E Vaitkeviciené11, Kim Vettenranta12, Kjeld Schmiegelow1,13. 1. Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 2. Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. 3. Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark. 4. Department of Medical Biosciences, Clinical Genetics, Umeå University, Umeå, Sweden. 5. Department of Paediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark. 6. Department of Paediatrics, University Hospital of Trondheim, Trondheim, Norway. 7. Department of Pediatrics, Institution for Clinical Sciences Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 8. Department of Paediatric Oncology, Karolinska University Hospital, Stockholm, Sweden. 9. Pediatric Hematology-Oncology, Children's Hospital, Barnaspitali Hringsins, Landspitali University Hospital, Reykjavik, Iceland. 10. Department of Oncology and Hematology, Tallinn Children's Hospital, Tallinn, Estonia. 11. Centre for Paediatric Oncology and Haematology, University Children's Hospital, Vilnius, Lithuania. 12. Department of Paediatrics, University of Tampere, Tampere, Finland. 13. Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark.
Abstract
BACKGROUND: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. PROCEDURE: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. RESULTS: After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47). CONCLUSIONS: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.
BACKGROUND: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. PROCEDURE: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. RESULTS: After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47). CONCLUSIONS: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.