Improved outcomes and treatment guidance in pediatric therapy-related AML: AML-BFM study group recommendations

Therapy-related acute myeloid leukemia (AML; tAML) is one of the most feared therapy-emergent complications. This study aims to determine the clinical and pathological significance and define therapeutic implications and poor prognosticators in pediatric tAML. We analyzed a total of 119 pediatric patients (aged 2-20 years) who were centrally diagnosed with tAML within the Acute Myeloid Leukemia Berlin-Frankfurt-Münster (AML-BFM) study group between 1993 and 2019. Compared with de novo AML, tAML was associated with decreased white blood count and involvement of the central nervous system. Latency to tAML was inversely correlated with age at primary malignancy. Patients with tAML were more likely to have abnormal karyotypes, overrepresenting KMT2A rearrangements, the unfavorable cytogenetics -7/del(7q), as well as complex and monosomal karyotypes, whereas core-binding AML was underrepresented. The occurrence of stratification-relevant molecular genetics was comparable with de novo AML, whereas CEBPAdm was absent in tAML. Survival rates in tAML improved from 10% ± 6% in AML-BFM 1993/1998 to 50% ± 10% in the registries 2012/2017; however, this is still worse than de novo AML. Hematopoietic stem cell transplantation (HSCT) in no evidence of leukemia (NEL; <5% blasts) after 2 induction cycles greatly improved survival. Adverse cytogenetics, previous ionizing radiation (>35 Gy), and latency ≤1 year were identified as the strongest poor prognosticators. Over the past 26 years, outcome and survival significantly improved in pediatric tAML. Our results suggest that HSCT in NEL after 2 induction cycles is the most promising therapeutic approach for achieving improved survival. Radiation, adverse cytogenetics, and latency ≤1 year should be considered as poor prognosticators in pediatric tAML.