Assessment of Comprehensive Mutational Profiling in T-lymphoblastic leukemia/lymphoma (T-ALL/LBL): A Single Center Experience

Abstract

Abstract Introduction/Objective T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) is a malignancy arising from immature precursor T cells with T-ALL involving bone marrow/blood and T-LBL occurring in the thymus and nodal/extranodal sites. Studies have now revealed >100 recurrently altered genes that are not necessarily disease initiating but can provide diagnostic, prognostic, and predictive information which can then be utilized in personalized therapy. Methods/Case Report Next-generation sequencing was performed on DNA and/or RNA extracted from blood/marrow aspirates or tissue at an external CLIA-certified, CAP-accredited laboratory. The hematology panel sequenced DNA of 406 genes, introns of 31 gene rearrangements, and RNA of 265 genes. This retrospective single-center study highlights salient findings noted in genomic profiles of 15 T-ALL/LBL cases out of 83 total patients with ALL from 2018-2021. While the majority were B-ALL cases, T-ALL accounted for 18%, and all but 1 case were pediatric patients (ages 9-21 years). Results (if a Case Study enter NA) In our pediatric cohort (14 patients; 9 males, 5 females), as in literature, NOTCH signaling was most frequently involved with NOTCH1 (50%) and FBXW7 (36%) mutations, followed by those in cell cycle process CDKN2A/2B (36%) and PTEN (28%) mutations. Other mutations: PHF6 (21%), BCOR and TAL1 (14%) each. The prognostic effect of mutations: NOTCH1 favorable, FBXW7 no effect but trend toward favorable when FBXW7 co-occurs with NOTCH1 while PTEN is unfavorable (3 patients had relapses). Some unusual or useful findings: a patient diagnosed initially as AML with aberrant CD3 was re-classified as early T-cell precursor ALL, supported by RELN mutation (occurs in 4% ETP-ALL). The adult with NOTCH1 and BCOR mutations in addition to BCR-ABL1 fusion was diagnosed as having T-ALL blasts with CML. We could not study detailed nuances in mutational profiles of T-ALL vs T-LBL with only 1 case of T-LBL showing FBXW7, PTEN, NF1, RB1, BCOR and NRAS mutations (latter is typically noted in pediatric T-LBL cases). Conclusion Clinical molecular testing in our pediatric T-ALL patients revealed gene alterations that provide refinement of diagnosis, prognosis, and risk stratification. It also contributes a useful data set for further analysis and potential use of clinically actionable therapeutic targets in some cases. Longer term follow-up incorporating therapy and outcomes information would be valuable.