Age-related prognoses of genetic subtypes in B-cell acute lymphoblastic leukemia/lymphoma (B-ALL): insights from a decade of national data

Abstract

Recurrent chromosomal rearrangements and aneuploidies are founding genetic hallmarks in ~90% of B-lymphoblastic leukemia/lymphoma (B-ALL). Advances in our understanding of B-ALL genetics have transformed the modern classification and management of B-ALL, underscoring the integral role of molecular profiling [1,2,3,4]. Although contemporary risk-directed therapeutic regimens have improved outcomes for patients with B-ALL, not all ages benefit equally. Overall, patient survival rates are inversely correlated with age, from a 5-year overall survival (OS) of >90% in children to <30% in older adults (60+ yr) with standard chemotherapy-based management [5]. The etiology of this age-related decline in B-ALL survival rates remains unclear. Potential explanations include unique underlying distributions of genetic alterations (e.g., with adverse alterations such as BCR::ABL1 enriched in older patients, whereas favorable genetic subtypes such as ETV6::RUNX1 predominate in younger patients), and worse tolerance of chemotherapy in older adults [6, 7]. We therefore examined the relationships of B-ALL genetic subtype, patient age and outcomes; and whether rare B-ALL genetic subtypes exhibited unique clinicopathologic features.

Patients diagnosed with B-ALL between 2010 and 2021 were identified from the National Cancer Database (NCDB), which is maintained by the American College of Surgeons and American Cancer Society, and captures >63% of new leukemia diagnoses across the United States from approximately 1,500 Commission on Cancer-accredited academic and community hospitals [8]. The NCDB contains deidentified national data that qualifies for human subjects research exemption. In 2010, cancer registries began collecting data for seven genetically defined B-ALL subtypes introduced in the World Health Organization (WHO) Classification 4th edition (and persist into the 5th edition), as defined by their ICD-O-3 codes: B-ALL with BCR::ABL1 (9812/3), ETV6::RUNX1 (9814/3), (high) hyperdiploidy (9815/3), KMT2A-rearrangement (9813/3), hypodiploidy (9816/3), TCF3::PBX1 (9818/3), and IGH::IL3 (9817/3) [1].