Outcome of ABL-class acute lymphoblastic leukemia in children in the pre-tyrosine kinase inhibitor era; an international retrospective study of the Ponte di Legno group
In the last decade, it has become clear that ABL-class gene fusions other than BCR-ABL1 are detected in ~3% of children with acute lymphoblastic leukemia (ALL). Preclinical studies suggest that leukemic cells carrying ABL-class fusions can be targeted successfully by tyrosine kinase inhibitors (TKIs). The addition of TKIs to the therapy of BCR-ABL1-positive ALL has significantly improved the outcome but it is unknown whether this holds true for ALL with other ABL-class fusions. Moreover, the ABL-class fusion group is heterogeneous and includes patients with ABL1, ABL2, CSF1R and PDGFRB fusion types. The outcome for patients with these subtypes of ALL is not known because their occurrences are rare. This international study establishes the baseline characteristics and outcome of ABL-class ALL patients in the pre-TKI era.
Patients’ characteristics and outcome of 122 children with ABL-class B-cell precursor ALL were retrospectively collected through the Ponte di Legno consortium. Patients were enrolled in pediatric trials between 2000 and 2018 and were not exposed to TKIs during their first-line protocols. Event-free (EFS) and overall survival (OS) were determined by Kaplan-Meier methodology, and the cumulative incidence of relapse (CIR) and treatment-related mortality by a competing risk model.
Outcome of all ABL-class cases at 5 years was 31.0% (SD 4.6) for CIR, 59.1% (95%CI 50.5-69.1) for EFS and 76.1% (95%CI 68.6-84.5) for OS. ABL-class patients displayed a high frequency of poor prednisone response (49%) and IKZF1 deletions (61%), but both features lacked prognostic value. MRD-levels at the end of induction therapy (EOI) were very high (≥1x10-2) in 66% of ABL-class cases, and most prevalent detected in ABL2 (86%) and PDGFRB-fusion (88%) cases. MRD-EOI ≥1x10-2 was predictive of an unfavorable outcome among ABL-class patients (HREFS 3.33, 95%CI 1.46-7.56; p=0.0039. The 5-year EFS was 80% (95%CI 58.7-100) for CSF1R (n=10), 68.6% (95%CI 54.5-86.3) for ABL1 (n=40), 52.9% (95%CI 41.5-67.5) for PDGFRB (n=64), and 37.5% (95%CI 15.3-91.7) for ABL2 (n=8) fusion cases (p=0.059). Sixty-nine percent of relapses (25 of 36) occurred within 3 years after diagnosis. The 5-years CIR of patients who received hematopoietic stem cell transplantation (n=41; 17.8% SD 6.2) was lower compared to the non-transplanted group (n=43; 45.1% SD 8.4; p=0.013), but EFS and OS did not differ between the two groups.
Children with ABL-class B-ALL have a poor outcome on therapies without TKIs despite the use of high-risk chemotherapy regimens and frequent transplantation in first remission. This paper provides baseline outcome for evaluating the potential benefit of upfront TKI usage in ABL-class patients.