Treatment failure in pediatric acute myeloid leukemia: factors associated with frequency and outcome of resistant disease and relapse

Abstract: Although the prognosis for childhood acute myeloid leukemia (AML) has improved over the last decades to a survival of over 70%, still 30-40 % relapse and 5-10% experience resistant disease with poor prognosis. The aim of this thesis was to perform a detailed analysis of disease characteristics and treatment in children with relapsed and resistant AML to provide means to improve prognosis. Also, since early response to therapy is one of the strongest prognostic factors for outcome, kinetics of the reduction in fusion transcript levels during induction was investigated. The thesis consists of three population-based studies and one descriptive study. Paper I included 208 children with relapsed AML treated on two consecutive NOPHO protocols, 1993 and 2004. In the second paper fusion transcript levels were measured in fifteen children during induction. The third paper included all 66 children with resistant AML treated on the NOPHO93, NOPHO2004, DB AML-01 and NOPHO2012 protocols. The fourth paper included 326 children with relapsed AML treated on the NOPHO2004, DB AML-01 and the NOPHO2012 protocols. Reinduction therapy, followed by stem cell transplant gave the best outcome in both relapsed AML and resistant AML. In children with relapse, we found that time to relapse has been constant over the last decades and that 90% of relapses occur within 2 years from end of therapy. Children <2 years had shorter time to relapse. Given that the overall survival for children with relapsed and resistant AML continues to be poor, increased enrollment of these patients in collaborative trials are needed. Additional refinement of risk stratification, especially for standard and intermediate risk patients could prevent relapses.