Multilineage involvement in BCR::ABL1 and ABL-class fusion–positive pediatric B-cell acute lymphoblastic leukemia: CML-like biology
BCR::ABL1 and ABL-class fusion-positive B-cell acute lymphoblastic leukemia (B-ALL) account for approximately 5 to 8% of pediatric and 25% of adult B-ALL cases. ABL-class fusion-positive B-ALL is characterized by tyrosine kinases ABL1, ABL2, PDGFRB, or CSF1R fused to various partner genes, excluding the BCR::ABL1 fusion. ABL-class fusion-positive B-ALL shares several characteristics with BCR::ABL1-positive B-ALL, including a similar gene expression profile, poor response to chemotherapy only, and sensitivity to tyrosine kinase inhibitors. In 20-30% of children and more than 30% of adults diagnosed with BCR::ABL1-positive ALL the BCR::ABL1 fusion is present in a wider clone, involving myeloid cells, non-ALL B-cells and T-cells. Therefore, BCR::ABL1-positive B-ALL can be subdivided into two biologically distinct subtypes: BCR::ABL1-positive B-ALL with lymphoid involvement only and BCR::ABL1-positive B-ALL with multilineage involvement (referred to as CML-like) which is also incorporated in the recent international consensus classification of myeloid neoplasms and acute leukemias. Recently we discovered multilineage involvement in child with ABL-class fusion-positive B-ALL.
See results.
We describe one case of pediatric B-ALL with ABL-class fusion (CDC88C::PDGFRB fusion) with multilineage involvement and two cases of pediatric BCR::ABL1-positive B-ALL with multilineage involvement. Cases are characterized by discordant minimal residual disease (MRD) levels during treatment with persistence of BCR::ABL1 or ABL-class fusion MRD-positivity despite Ig/TCR MRD negativity. Fusion gene detection after immunophenotypic sorting of remission bone marrow confirmed multilineage involvement. CDC88C::PDGFRB fusion gene positivity was detected in myeloid and lymphoid cell fractions. BCR::ABL1-fusion was detected in normal T- and B-lymphocytes without evidence of myeloid involvement. All cases were successfully treated with chemotherapy with or without addition of a tyrosine kinase inhibitor (TKI). According to (inter)national treatment protocols, allogeneic stem cell transplantation (SCT) was not indicated in first complete remission. All three patients developed a second episode of BCR::ABL1-positive of ABL-class fusion-positive B-ALL harboring different Ig/TCR rearrangement.
We identified a new biological entity of ABL-class fusion-positive B-ALL characterized by multilineage involvement, which resembles BCR::ABL1-positive B-ALL with multilineage involvement also referred to as “CML-like” biology, wherein persistent BCR::ABL1 or ABL-class fusion-positivity extends beyond the original blast population and involves multiple hematopoietic compartments, with a ‘dormant’ persisting BCR::ABL1 of ABL-class fusion-positive clone which may serve as a reservoir for future disease episodes. Presence of multilineage involvement might impact on treatment strategies such as intensity and duration of therapy including the role immunotherapies or allogeneic SCT. Prospective follow-up of this subgroup is essential to determine whether outcome differences exist and to guide evidence-based, individualized treatment strategies.