Clinical characteristics and outcomes of children with T-cell acute lymphoblastic leukemia harboring ABL-class fusions: A report from the ponte di legno consortium

Abstract Introduction: ABL-class acute lymphoblastic leukemia (ALL) is characterized by rearrangements of ABL1 or other ABL-family tyrosine kinases that drive uncontrolled cell growth. Children with ABL-class B-ALL treated without tyrosine kinase inhibitors (TKIs) achieve 5-year event-free survival (EFS) of 59% (Den Boer et al., Lancet Haematology, 2021). The addition of TKIs to chemotherapy-based therapy has substantially improved outcomes for BCR::ABL1-positive B-ALL. ABL-class fusions occur in 5-10% of T-cell ALL (T-ALL) cases, and small case series report aggressive disease with poor outcomes. However, comprehensive outcome data for pediatric ABL-class T-ALL remain limited. We describe the clinical characteristics, outcomes, and prognostic factors of children with T-ALL harboring ABL-class fusions. Methods: We conducted a multinational retrospective cohort study encompassing 14 collaborative groups from the Ponte di Legno (PdL) consortium. Demographic, clinical, treatment, and outcome data were collected for newly-diagnosed pediatric T-ALL patients harboring ABL-class fusions between 1987 and 2023. Results: The cohort comprised 196 patients with ABL-class T-ALL: 16 (8.2%) with BCR::ABL1 fusions, 136 (69.4%) with NUP214::ABL1 fusions and the remaining 44 (22.4%) with other ABL-class fusions “other-ABL” involving non-NUP214 ABL1 (n=28), ABL2 (n=2), PDGFRA (n=6) and PDGFRB (n=8). The median age at diagnosis was 8 years (range: 1 – 22 years). The median white blood cell (WBC) count was 82,600 cells/mm³ (range: 2,000-1,471,000). Patients with other-ABL had higher median WBC compared to those with BCR::ABL1 or NUP214::ABL1 fusions (217,500 vs. 39,000 vs. 72,400; p=0.0129). Of those with available treatment dates, 77.5% were treated in 2010 or later. Central nervous system (CNS) involvement was classified as CNS-2 in 35 patients (18.7%) and CNS-3 in 7 patients (3.7%). Cranial radiotherapy was administered to 35.9% of patients. Consolidation with hematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) was performed in 18.6% of patients. TKIs were administered to 27 of 157 (17.2%) patients with available treatment data: BCR::ABL1 (n=9), NUP214::ABL1 (n=9) and other-ABL (n=9). Overall, 149/167 (89.2%) patients achieved morphologic complete remission (CR). Failure to achieve CR was highest among patients with other-ABL (25.0%) compared to those with BCR::ABL1 (15.4%) and NUP214::ABL1 (4.5%) fusions; p=0.0025. Among 140 patients with available end of induction (EOI) minimal residual disease (MRD) data, 45 (32.1%) patients were EOI MRD negative at the 0.01% threshold, 50 (35.7%) patients had MRD levels of 0.01% to <1% and 45 (32.1%) patients had levels ≥1%. With a median follow-up of 6.1 years for the 162 patients with outcome data, the 5-year EFS and overall survival (OS) for the entire cohort were 78.1% (95% CI 71.7% - 85.2%) and 83.6% (95% CI 77.7% - 90.1%), respectively. By fusion subtype, 5-year EFS and OS were 67.7% (95% CI 46.0% - 99.7%) and 75.5% (95% CI 54.9% - 100%) for BCR::ABL1; 80.8% (95% CI 73.2% - 89.3%) and 85.7% (95% CI 78.7% - 93.3%) for NUP214::ABL1; and 74.6% (95% CI 62.2% - 89.6%) and 81.2% (95% CI 69.5% - 94.9%) for other-ABL. The 5-year cumulative incidence of relapse was 16.2±10.5% for patients with BCR::ABL1, 14.1±3.6% for patients with NUP214::ABL1 and 13.0± 5.4% for patients with other-ABL. Among patients with non-BCR::ABL1 ABL-class T-ALL, the 5-year EFS was 70.0% (95% CI 51.0%- 96.2%) for those treated with TKIs (n=18) versus 79.8% (95% CI 72.5% - 87.7%) for those not treated with TKIs (n=117); p=0.5082. Among the 18 TKI-treated patients, there were 2 induction failures, 2 relapses and 1 treatment-related death. In univariate Cox regression analyses, only HSCT in CR1 (HR=3.21; p=0.006) was associated with inferior EFS for patients with non-BCR::ABL1 ABL-class T-ALL. In univariate analyses, none of the variables were significantly associated with OS. Conclusion: This large international cohort study has established the baseline characteristics and outcomes of children with ABL-class T-ALL. In contrast to ABL-class B-ALL, ABL-class T-ALL demonstrated comparable outcomes to non-ABL-class T-ALL. We could not demonstrate the benefit of TKI treatment among patients with non-BCR::ABL1 ABL-class T-ALL, although numbers in the TKI group were small. These findings provide important baseline data for future prospective studies evaluating novel therapies in pediatric ABL-class T-ALL.

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