The Emergence of a Novel Insertional Mutation in the BCR::ABL/p210 Oncogene in B-Cell Acute Lymphoblastic Leukemia (B-ALL) Correlates with the Development of Resistance to Several Tyrosine Kinase Inhibitors.

A patient with an immunophenotype characteristic of B-cell acute lymphoblastic leukemia (B-ALL) was found to carry the chromosomal translocation t(9;22)(q34;q11), or Philadelphia (Ph) chromosome and less common variant of the chimeric oncogene BCR::ABL/p210. No additional mutations in the BCR::ABL gene, including point mutations, insertions, or deletions, were identified in the disease onset characterized by elevated blast cell (77.6%) and leukocyte (48×109/L) counts. Ph+ALL-2012m chemotherapy with imatinib (600 mg) and two consolidation phases resulted in complete hematologic remission and a profound molecular response. However, six months later, the patient had relapsed (blasts: 15%, BCR::ABL/p210: 105%). Three weeks after the initiation of dasatinib therapy (100 mg), the number of blasts had decreased to 4.8%, while the expression level of BCR::ABL/p210 had dropped to 11.8%. Sanger sequencing identified two mutations in the BCR::ABL oncogene; namely, the point mutation F317L and a new insertion of nine nucleotides previously not detected. In the latter case, the amino acid lysine at position 294 was replaced by four new amino acid residues: K294SPSQ. Therapy with bosutinib and inotuzumab led to the disappearance of one leukemia clone with the F317L mutation, but the presence of another clone carrying a nine-nucleotide insertion was observed. The switch to ponatinib+blinatumomab chemotherapy was effective, resulting in the disappearance of the insertion. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an available HLA-matched unrelated donor resulted in complete clinical and hematologic remission, including a complete molecular response. Six months after allo-HSCT, minimal residual disease monitoring showed maintenance of complete remission.