Imatinib failure and response to dasatinib in a patient with chronic myeloid leukemia in blast crisis and a novel, nine-nucleotide BCR-ABL insertion mutation

In chronic phase chronic myeloid leukemia (CML), the BCR-ABL kinase inhibitor imatinib leads to complete cytogenetic responses in the majority of cases. Resistance towards imatinib is associated with BCR-ABL kinase domain mutations, leading to structural changes that prevent imatinib from binding. In cases of failure towards imatinib treatment, second generation BCR-ABL kinase inhibitors such as dasatinib or nilotinib have demonstrated activity in CML. Both drugs are capable of suppressing imatinib-resistant, mutant forms of BCR-ABL. Most of the mutations in the BCR-ABL gene mediating inhibitor resistance are point mutations, replacing single nucleotides. Splice mutations in BCR-ABL leading to deletion or insertion of nucleotide stretches have rarely been described. Here, we report on a patient with CML in blast crisis after imatinib failure and second-line treatment with dasatinib harboring a so far undescribed p.K294S_insFPQ mutation (g.68009_68010ins GTTTCCCTC). A 37-year-old female patient initially presented with malaise, lymphadenopathy and splenomegaly. Her white blood cell count was 122.7/nl with 47% blasts. Bone marrow morphology showed 80% blast infiltration. Immunophenotyping revealed expression of CD34, HLA-DR, CD19, CD10, TdT and cyCD22. A Philadelphia chromosome-positive CML with fusion transcript-type M-BCR (p210, b2a2) in primary lymphoid blast crisis was diagnosed with a BCR-ABL/ABL ratio of 276%. Chemotherapy with daunorubicine and cytarabine and treatment with imatinib at a daily dose of 800mg was started. Imatinib was later reduced to 600 and 400mg due to pancytopenia. The BCR-ABL/ABL ratio only decreased to 139.6 and 48.2% on day 50 and 89, respectively, with persistence of 10–15% bone marrow blasts and 17% blasts in the peripheral blood, indicating failure of treatment. At day 99, BCR-ABL mutation analysis revealed a ninenucleotide insertion mutation (K294S_insFPQ) in the ABL kinase domain. Imatinib was discontinued, dasatinib was started at a dose of 100mg daily and three doses of vincristine and dexamethasone were given. On day 131, BCR-ABL/ABL ratio decreased to 13.8% and to 0.9% by day 173 under dasatinib treatment, indicating molecular response. Bone marrow analysis revealed o5% blast cells. The level of hemoglobin was 8.8 g/dl, leukocytes 0.9/nl with 0% blasts and platelet 30/nl, indicating complete remission with incomplete blood count recovery. BCRABL/ABL ratio had decreased to 13.8% under dasatinib treatment indicating molecular response. On day 173, the hemoglobin level was 8.6 g/dl, leukocytes 3.6/nl with 0% blasts and platelets 29/nl, indicating complete hematologic remission with incomplete recovery of platelets. BCR-ABL/ABL ratio was 0.9%. Allogeneic HLA-(A*) antigen-mismatched peripheral blood stem cell transplantation (aSCT) was performed after conditioning with