ABL-Class Fusion Gene Induced Pediatric CML Presenting As ALL
Authors: Hoogerbrugge Peter M. , Luesink Maaike , Boer Judith M. , Van Outersterp Inge , Sonneveld Edwin , De Jong Anja , Nierkens Stefan , Van Der Velden Vincent H.J. , Buijs Arjan , den Boer Monique L. 
Published: December 2024

A lymphoid blast crisis in CML may mimic Philadelphia-positive ALL in children carrying the BCR::ABL1 fusion gene (Hovorkova, Blood 2017). Investigating the presence of the BCR-ABL1 fusion gene in leukemic cells and normal hematopoietic cells of multiple lineages may be needed to discriminate between these two diseases and find the optimal treatment of the patient. So far, it has not been reported whether also ABL-class fusions other than BCR::ABL1, which occur in approximately 3% of children with ALL, may be present in multiple hematopoietic cell lineages, resulting a ‘CML-like disease’.
We recently found multilineage involvement of an ABL-class fusion gene (CCDC88C::PDGFRB fusion) in a child initially diagnosed as ALL. The child was diagnosed in November 2015 with BCP-ALL at the age of 2 and treated according to the DCOG-ALL10 protocol (Pieters, JCO, 2016). Because of M2 marrow and persisting high levels of MRD at end of induction, he was treated with high-risk (HR) courses followed by maintenance therapy. He became MRD-negative after one HR course as determined by IG/TR specific primers, and stayed negative during the rest of his treatment. One year after cessation of therapy (December 2018), he was diagnosed with what was considered to be a relapse of his disease. Molecular analysis showed a CCDC88C::PDGFRB ABL-class fusion, which, in retrospect, was already present at initial diagnosis as well. The IG/TR targets identified at diagnosis were lost at ‘relapse’ and chromosomal abnormalities detected at the initial diagnosis were not present at ‘relapse’, and conversely, those identified at ‘relapse’ were distinct from those at initial diagnosis, suggesting a clonally unrelated ‘relapse’. For his ‘relapse’, he was treated according to DCOG-ALL11 MR protocol (Pieters, JCO 2024) plus Imatinib for two years, resulting in a rapid response and persistent complete remission.
In a retrospective study to the use of patient-specific MRD detection by ABL-class fusion genomic breakpoint Q-PCR, the blood and marrow samples of the patient were analyzed. The results showed discordant MRD results at all timepoints of the initial treatment, with ABL-class fusion MRD positivity at the level of 1-10%, despite morphological remission and Ig/TCR MRD-negativity. At ‘relapse’, the patient specific ABL-class fusion MRD was 100%, and decreased to 'positive-not quantifiable (NQ)' and 10-5 during treatment. Based on these retrospective findings, the patient was invited for a bone marrow aspiration in June 2023, 2.5 years after the end of treatment for his 'relapse'. The patient was in good clinical condition, with normal blood cell counts. BM and blood analysis showed complete remission, MRD-negativity with IG/TR analysis, and MRD of 10-3 with ABL-class fusion PCR. Additionally, we sorted the myeloid and lymphoid fractions of stored bone marrow samples obtained in first complete remission (CR1) and the bone marrow sample after completion of ‘relapse’ treatment. Analyses of both samples by FISH and PCR showed the presence of the fusion gene in both the myeloid and lymphoid cell fraction at similar percentages in both fractions (sample taken in CR1: 20% in myeloid fraction, 10% in lymphoid fraction; sample taken after cessation of ‘relapse’ treatment: 0.1% in myeloid fraction, pos-NQ in lymphoid fraction). These results confirmed that the ABL-class fusion gene was not only present in the blasts of the patient, but also in multiple normal hematopoietic cell lineages. Monotherapy with Imatinib was started, resulting in CCDC88C::PDGFRB fusion MRD negativity (last follow-up July 2024).
In conclusion, the patient described in this study presented as ALL, but appeared to suffer from a lymphoid blast crisis of a so far not reported, CML-like disease, caused by an ABL-class fusion other than the classical BCR::ABL1 fusion, present in lymphoid blasts and normal hematopoietic lineages.