Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions

Abstract

Leukemia, the most common childhood cancer, has long been recognized to occasionally run in families. The first clues about the genetic mechanisms underlying familial leukemia emerged in 1990 when Li-Fraumeni syndrome was linked to TP53 mutations. Since this discovery, many other genes associated with hereditary predisposition to leukemia have been identified. Although several of these disorders also predispose individuals to solid tumors, certain conditions exist in which individuals are specifically at increased risk to develop myelodysplastic syndrome (MDS) and/or acute leukemia. The increasing identification of affected individuals and families has raised questions around the efficacy, timing, and optimal methods of surveillance. As part of the AACR Childhood Cancer Predisposition Workshop, an expert panel met to review the spectrum of leukemia-predisposing conditions, with the aim to develop consensus recommendations for surveillance for pediatric patients. The panel recognized that for several conditions, routine monitoring with complete blood counts and bone marrow evaluations is essential to identify disease evolution and enable early intervention with allogeneic hematopoietic stem cell transplantation. However, for others, less intensive surveillance may be considered. Because few reports describing the efficacy of surveillance exist, the recommendations derived by this panel are based on opinion, and local experience and will need to be revised over time. The development of registries and clinical trials is urgently needed to enhance understanding of the natural history of the leukemia-predisposing conditions, such that these surveillance recommendations can be optimized to further enhance long-term outcomes.

Treatment and biology of pediatric acute lymphoblastic leukemia

“…Moreover, various germline mutations in genes encoding transcription factors, such as paired box 5 ( PAX5 ), IKAROS family zinc finger 1 ( IKZF1 ), and ETV6 , have also been identified as a cause of familial ALL . These findings led to the recent proposal of surveillance recommendation for children with leukemia‐predisposing conditions …”

“…74 These findings led to the recent proposal of surveillance recommendation for children with leukemia-predisposing conditions. 75 These pathogenic variants, however, can explain only a small fraction of pediatric ALL. To investigate common genetic variants influencing leukemia susceptibility, genomewide association studies (GWAS) comparing the frequency of single-nucleotide polymorphisms (SNP) between sporadic ALL patients and controls have been conducted.…”

Pediatric leukemia susceptibility disorders: manifestations and management

“…These recommendations stress referral to experts, education on the signs and symptoms of leukemia, consultation with transplant specialists, and surveillance. 44 Patients with leukemia syndromes associated with pancytopenia and/or MDS should have a bone marrow aspirate with cytogenetics and biopsy at diagnosis. Subsequent bone marrow evaluations should then be tailored based on the underlying syndrome.…”

Novel phenotypes observed in patients withETV6-linked leukaemia/familial thrombocytopenia syndrome and a biallelicARID5Brisk allele as leukaemogenic cofactor

“…As a heterogeneous group of rare conditions, the diagnosis of congenital thrombocytopenia is often delayed due to misdiagnosis as the more frequent immune thrombocytopenia (ITP). Some of the inherited platelet disorders are associated with syndromic features and/or an increased risk of haematological malignancies 6 7. One recently recognised type of inherited thrombocytopenia with leukaemia predisposition is due to dominant germline mutations in E26 transformation-specific (ETS) variant 6 ( ETV6 8; recently reviewed in Hock and Shimamura9 and Di Paola and Porter10).…”