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

TL;DR

A patient with B-cell acute lymphoblastic leukemia developed resistance to multiple drugs due to a new mutation in the BCR::ABL/p210 oncogene, which was eventually overcome through targeted therapies and a stem cell transplant.

Contribution

The study reports the emergence of a novel nine-nucleotide insertion in the BCR::ABL/p210 oncogene associated with drug resistance in B-ALL.

Findings

A new nine-nucleotide insertion in the BCR::ABL/p210 oncogene was identified in a relapsed B-ALL patient.

The insertion mutation persisted through several therapies but was eliminated with ponatinib and blinatumomab.

Allogeneic stem cell transplantation led to complete remission and molecular response.

Abstract

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.

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