Central nervous system disease in pediatric acute myeloid leukemia: A report from the Children's Oncology Group

Abstract

Background The prognostic impact of central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) has varied in past trials, and controversy exists over the degree of involvement requiring intensified CNS therapy. Two recent Children’s Oncology Group protocols, AAML03P1 and AAML0531, directed additional intrathecal (IT) therapy to patients with CNS2 (≤5 white blood cell [WBC] with blasts) or CNS3 (>5 WBC with blasts or CNS symptoms) disease at diagnosis. Methods We examined disease characteristics and outcomes of the 1,344 patients on these protocols, 949 with CNS1 (no blasts), 217 with CNS2, and 178 with CNS3, with the latter two receiving additional IT therapy. Results Young age (P = 0.003), hyperleukocytosis (P < 0.001), and the presence of inversion 16 (P < 0.001) were the only factors more prevalent in patients with CNS2 or CNS3 disease. Complete remission at the end of induction (EOI) 2 was achieved less often in patients with CNS involvement (P < 0.001). From diagnosis, event-free survival (EFS) for patients with CNS involvement was significantly worse (P < 0.001), whereas overall survival (OS) was not (P = 0.16). From the EOI1, there was a higher relapse rate (RR) and worse disease-free survival (DFS), but less impact on OS (CNS1:DFS 58.9%, RR 34.1%, OS 69.3%; CNS2:DFS 53.2%, RR 40.9%, OS 74.7%; CNS3:DFS 45.2%, RR 48.8%, OS 60.8%; P = 0.006, P < 0.001, P = 0.045, respectively). Multivariable analysis showed that independently CNS2 and CNS3 status adversely affected RR and DFS. Traumatic diagnostic lumbar puncture was not associated with worse outcome. Conclusions CNS leukemia confers greater relapse risk despite more aggressive locally directed therapy. Novel approaches need to be investigated in this group of patients.

Stage at diagnosis for children with blood cancers in Australia: Application of the Toronto Paediatric Cancer Stage Guidelines in a population‐based national childhood cancer registry

“…In line with what we have reported here, CNS involvement has been shown in clinical trials elsewhere to have a negligible impact on overall survival for children with AML, even though relapse is more common in the presence of CNS disease. This similarity in survival irrespective of CNS involvement is at least in part because intrathecal chemotherapy has proven to be effective in the treatment of CNS disease associated with AML, but the optimal regime is yet to be determined .…”

“…In line with what we have reported here, CNS involvement has been shown in clinical trials elsewhere to have a negligible impact on overall survival for children with AML, even though relapse is more common in the presence of CNS disease. This similarity in survival irrespective of CNS involvement is at least in part because intrathecal chemotherapy has proven to be effective in the treatment of CNS disease associated with AML, but the optimal regime is yet to be determined . Prognosis for AML is instead primarily dictated by cytogenetic and molecular characteristics at diagnosis, raising the question of whether an alternative definition of stage for children with AML that incorporates these characteristics may be of more benefit.…”

Central nervous system disease in pediatric acute myeloid leukemia

“…Patient characteristics from studies in this issue by Johnston et al., Creutzig et al, and Stove et al. confirm several of the features that have been previously associated with CNS disease at diagnosis (Table ) . Some of these characteristics are related, in particular that of inversion (16), which is a low‐risk cytogenetic group that is associated with French‐American‐British classification (FAB) M4 morphologic phenotype and often presents with high tumor burden.…”

“…Central nervous system (CNS) involvement at diagnosis for pediatric patients with acute myeloid leukemia (AML) occurs in 10–30% of patients . Despite this high frequency, controversy still exists regarding the clinical management of such patients.…”

“…Johnston et al., Creutzig et al, and Stove et al. revisit the issue with analyses of patients treated in the modern era (Table ) . In all studies, patients received four to five courses of chemotherapy with two to three blocks that contained high‐dose cytarabine.…”