Background: The BCR-ABL1 fusion gene, a hallmark of chronic myeloid leukemia (CML), is also present in several types of acute leukemia. In Philadelphia chromosome-positive (Ph+) acute B-cell lymphoblastic leukemia (B-ALL), up to 70% of patients express the e1a2 transcript variant. Compared to the e13a2 or e14a2 transcripts, the e1a2 transcript may be associated with a more favorable prognosis. While most Ph⁺ leukemia patients express one of these canonical transcripts, atypical transcript variants are observed in a small subset of cases. Due to their extreme rarity, the clinical significance of these non-canonical transcripts remains poorly understood.

Objective: This study aims to retrospectively analyze and investigate the clinical and laboratory characteristics of 21 patients with acute lymphoblastic leukemia (ALL) harboring atypical BCR::ABL1 fusion genes, and to compare the genetic differences among different BCR::ABL1 transcripts.

Methods: A total of 786 acute lymphoblastic leukemia (ALL) patients meeting the criteria of chromosomal karyotype analysis showing the presence of t(9;22) (q34;q11) or BCR::ABL1 positivity in FISH testing, with qPCR testing revealed Positive for e13a2, e14a2, e1a2, e19a2 or atypical BCR::ABL1 fusion transcripts, were collected from Sino-US Diagnostics Lab between October 2015 and July 2025. Next-generation sequencing (NGS) analysis was conducted on 13 atypical ALL patients. Additionally, a retrospective analysis was performed on the clinical and laboratory data of the patients.

Results: A total of 786 Ph+ ALL patients were collected, including 765 typical ALL patients (446 e1a2, 319 e14a2/e13a2) and 21 atypical ALL patients (11 e1a3, 3 e13a3, 1 e13a2 with an insertion of 54bp in ABL1 intron1, 1 e14a3, 1 e12a2, 1 e6a2, 1 e1a4 and 2 untyped). Among the 21 atypical ALL patients, the median age was 46.5 years (range 10-67), with a relatively even distribution across age groups; the male proportion was 53.3% (11/21), similar to that of typical e1a2 (48.8%, 218/446), while typical e14a2/e13a2 was more likely to occur in male patients (61.8%, 197/319) (P=0.00). The median WBC was 6.13×109/L (range 2.1-234×109/L), PLT was 52.5×109/L (range 4-768×109/L), and HGB was 94 g/L (range 44-150 g/L). In genetic analysis, among the 11 atypical ALL patients, 8 (72.7%) had additional abnormal karyotypes, including 7 (63.6%) with an additional -7 chromosome abnormality, which was significantly higher than that in typical e14a2/e13a2 (12.4%, 27/218) and e1a2 (10.2%, 25/246) (P=0.00).In addition, 5(62.5%) atypical ALL patients harbored ABL1 mutations, including 2(25.0%) cases had ≥2 mutations, which was significantly higher than that in typical e14a2/e13a2 (6.0%, 9/149) (P=0.04) and e1a2 (6.7%, 14/210) (P=0.05). NGS results from 13 atypical ALL patients showed that 69.2% (9/13) had ≥1 mutation, 2 (15.4%) patients showed a markedly higher incidence of BCORL1 mutation compared with e1a2 (3/187 1.60%) (p=0.00), while another 2 displayed a significantly elevated rate of PAX1 mutation relative to e14a2/e13a2 (1/117 0.85%) (p=0.00). In survival analyses, relapse-free survival (RFS) differed significantly among e14a2/e13a2, e1a2, and e1a3 (60.9% vs. 47.4% vs. 75.0%) (P=0.01), with e14a2/e13a2 showing markedly shorter RFS than e1a2 (P=0.01).

Conclusion: Atypical ALL patients are mainly characterized by the e1a3 subtype. Compared with typical ALL, atypical ALL patients are more likely to have additional -7 chromosome abnormalities, BCORL1, PAX1, and ABL1 (≥2)mutations. Compared with e1a2, e14a2/e13a2 is associated with significantly shorter RFS.

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2025
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