Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology

We used the genomic breakpoint between <i>BCR</i> and <i>ABL1</i> genes for the DNA-based monitoring of minimal residual disease (MRD) in 48 patients with childhood acute lymphoblastic leukemia (ALL). Comparing the results with standard MRD monitoring based on immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements and with quantification of <i>IKZF1</i> deletion, we observed very good correlation for the methods in a majority of patients; however, >20% of children (25% [8/32] with minor and 12.5% [1/8] with major-<i>BCR-ABL1</i> variants in the consecutive cohorts) had significantly (>1 log) higher levels of <i>BCR-ABL1</i> fusion than Ig/TCR rearrangements and/or <i>IKZF1</i> deletion. We performed cell sorting of the diagnostic material and assessed the frequency of <i>BCR-ABL1</i>-positive cells in various hematopoietic subpopulations; 12% to 83% of non-ALL B lymphocytes, T cells, and/or myeloid cells harbored the <i>BCR-ABL1</i> fusion in patients with discrepant MRD results. The multilineage involvement of the <i>BCR-ABL1</i>-positive clone demonstrates that in some patients diagnosed with <i>BCR-ABL1</i>-positive ALL, a multipotent hematopoietic progenitor is affected by the <i>BCR-ABL1</i> fusion. These patients have <i>BCR-ABL1</i>-positive clonal hematopoiesis resembling a chronic myeloid leukemia (CML)-like disease manifesting in "lymphoid blast crisis." The biological heterogeneity of <i>BCR-ABL1</i>-positive ALL may impact the patient outcomes and optimal treatment (early stem cell transplantation vs long-term administration of tyrosine-kinase inhibitors) as well as on MRD testing. Therefore, we recommend further investigations on CML-like <i>BCR-ABL1</i>-positive ALL.