Abstract
Patterns of mutation and clonal evolution in relapsed acute lymphoblastic leukemia
Relapsed acute lymphoblastic leukemia remains a major cause of childhood cancer death, and this remains true despite the advent of new targeted and immunotherapeutic approaches. Recent years have witnessed the use of broad and deep serial genomic profiling approaches to dissect the relationship of genetic variegation to clonal evolution and relapse. Studies of over 90 children treated on St Jude Total Therapy protocols, incorporating genome, exome and transcriptome sequencing, coupled with limiting dilution xenografting to formally elucidate clonal structure have provided multiple key insights. In the majority of cases, the relapse-fated clone is a minor clone at diagnosis, that harbors resistance-enriched (and thus relapse-promoting) mutations at diagnosis, and/or acquires additional mutations the confer resistance after initial therapy. Approximately one third of cases relapse from a major clone, or show polyclonal evolution, and such cases typically have a shorter time to disease recurrence and relapse. A subset of cases exhibit complete discordance for somatic non-silent mutations, DNA copy number alterations and antigen receptor rearrangements between diagnosis and relapse, suggesting relapse represents a second leukemia; however such cases typically preserve the founding chromosomal rearrangement and a subset of non-coding mutations, indicating that relapse arises from an ancestral clone that has undergone divergent evolution early in leukemogenesis. Conversely, a subset of cases relapse with myeloid or lineage ambiguous leukemia but preserve genomic alterations indicating a common clonal origin but lineage plasticity: thus, careful genomic analysis is required to interpret the nature of disease recurrence/relapse. Approximately 15% of cases exhibit hypermutation, particularly in aneuploid leukemia and second or later relapse, associated with distinct mutational signatures and kinetics of hypermutation, thus identifying this process as a driver of treatment failure in a subset of ALL cases. Integrated analysis has identified over 80 recurrent targets of alteration at relapse that show variable patterns of enrichment in rising and falling clones. Importantly, several targets (e.g. NT5C2) are never identified at diagnosis despite deep sequencing approaches, suggesting adverse effects on leukemic fitness, and/or an absolute requirement of prior drug exposure to initiate mutagenesis. Integration of limiting dilution xenografting, coupled with genomic analysis of xenografts and drug exposure has not only formally confirmed and extended inferential clonal structures, but shown that in a subset of cases resistance is present at initial diagnosis, rather than being acquired after drug exposure. Finally, several groups have shown that the relationship of relapse-enriched mutations and relapse by be drug agnostic (e.g. IKZF1) or drug specific (e.g. NT5C2 and thiopurine resistance, and CREBBP and glucocorticoid resistance). As such mutations may now be detected at levels suitable for tracking of minimal residual disease, these insights offer the opportunity to identify the relapse-fated clone early in disease evolution, and modulate therapy accordingly to circumvent relapse.
Disclosures
Mullighan: Pfizer: Honoraria, Research Funding, Speakers Bureau; Cancer Prevention and Research Institute of Texas: Consultancy; Loxo Oncology: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Speakers Bureau.
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