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FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): the Mayo Clinic experience

Year: 2024

Type: article

Abstract: FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): the Mayo Clinic experience Translocation (6;9)(p23;q34.1) is detected in 1% of acute myeloid leukemia (AML) cases and is considered a high-risk subtype by European Leukemia Network (ELN) 2022 criteria.1 Compared to AML overall, t(6;9) AML affects younger adults with a median age of 35-38 years at diagnosis, and is historically associated with poor overall survival (OS) of roughly 14 months.2,3 Most cases (62-88%) harbor internal tandem duplications of fms-like tyrosine kinase 3 (FLT3-ITD).[2][3][4][5][6] While preliminary data suggest that FLT3 inhibitors (FLT3i) might provide benefit, 7,8 this has not yet been confirmed in larger studies.Although outcomes have improved with allogeneic hematopoietic cell transplantation (alloHCT), 6,9,10 survival remains dismal for patients ineligible for transplant.3 This report describes a three-site experience with t(6;9) AML at an academic tertiary care center with a large HCT referral program.After institutional review board approval, all patients with t(6;9)(p23;q34.1)AML seen across the three Mayo Clinic sites in the US between 2010-2023 were identified via retrospective chart review; this included eight previously-published patients.11 A separate AML cohort excluding t(6;9) was curated pragmatically over a similar time frame.Data from the time of diagnosis or presentation to Mayo Clinic were abstracted.Mutation assessment was performed as described.12 When necessary, FLT3 allelic ratio was estimated from the variant allele fraction (VAF).12,13 Classification and response were assessed by ELN 2022 criteria.1 Measurable residual disease (MRD) was assessed by t(6;9)(p23;q34.1)specific fluorescence in situ hybridization (FISH) of ≥500 nuclei (sensitivity 0.6%) or multiparametric flow cytometry (MFC; sensitivity 0.01%).Categorical variables were compared by Fisher exact or Pearson c 2 tests and continuous variables by Mann-Whitney U tests or two-way ANOVA with Tukey correction.Univariate and multivariate analyses utilized Cox proportional hazards models.Survival was assessed via the Kaplan-Meier method with log-rank comparisons.Calculations were performed with BlueSky Statistics (v10.3.1) or GraphPad Prism (v.10.1.2).P<0.05 was considered significant.Twenty-one patients (12 females, 57%) with t(6;9) AML were identified with median age 39 years (Table 1).Anemia was common (N=19, 90%) and thrombocytopenia was universal.Peripheral blasts were identified in 19 (90%) patients.Cytogenetic analyses identified isolated t(6;9)(p23;q34.1) in eight (40%) cases, whereas three (15%) exhibited a complex karyotype.Most cases (N=14, 70%) harbored FLT3-ITD mutations (median VAF 39%), which were the sole mutations identified in all 14 cases that harbored them (Online Sup-

Source: Haematologica

DOI: 10.3324/haematol.2024.285359