Improved Outcome and Therapeutic Directions in Pediatric Therapy-related AML: Recommendations by the AML-BFM Study Group

• Outcome in pediatric tAML has improved significantly with prior radiation and adverse cytogenetics being the most relevant prognosticators

• Patients transplanted with no evidence of leukemia with two instead of four preceding induction cycles achieved the best survival rates.

Therapy-related acute myeloid leukemia (tAML) is one of the most feared therapy-emergent complications. This study aims to determine the clinical and pathological significance, to define therapeutic implications and poor prognosticators in pediatric tAML. We analyze a total of 119 pediatric patients (2 to 20 years), who were centrally diagnosed with tAML within the 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, over-representing KMT2A-rearrangements, the unfavorable cytogenetics -7/del(7q), complex and monosomal karyotypes while core-binding AML were underrepresented. The occurrence of stratification-relevant molecular genetics was comparable with de-novo AML while CEBPAdm was absent in tAML. Survival rates in tAML improved from 10±6% in AML-BFM 93/98 to 50±10% in the registries 2012/2017, though, this is still worse compared to de-novo AML. Hematopoietic stem-cell transplantation (HSCT) in no evidence of leukemia (NEL, < 5% blasts) following two induction cycles greatly improved survival. Adverse cytogenetics, previous ionizing radiation (> 35 Gray), 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 HSCT in NEL following two induction cycles as the most promising therapeutic approaches for achieving improved survival. Radiation, adverse cytogenetics, and latency ≤ 1 year should be considered as poor prognosticators in pediatric tAML.