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Imatinib resistance in chronic myeloid leukemia due to a rare mutation

Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm that is characterized by the BCR-ABL1 fusion gene, which encodes a chimeric protein with increased tyrosine kinase activity. Imatinib mesylate is a potent and selective competitive inhibitor of the BCR-ABL protein tyrosine kinase. It is used as the first-line therapy for CML and induces complete hematological and cytogenetic response in most patients with CML in chronic phase.[1] The disease can relapse due to acquired imatinib resistance, most commonly due to point mutations in the ABL kinase domain. We report a case of CML with imatinib resistance due to the rare p.L298V mutation. A 35-year-old male presented with a history of fatigue and splenomegaly in September 2009 at our center and was diagnosed as Ph positive CML in chronic phase. He was started on imatinib at a dose of 400mg/day. He achieved complete hematologic response in January 2010, but there was no cytogenetic response. Cytogenetic analysis detected 46, XY, t(9;22)(q34;q11) in 2 out of 10 metaphases studied. He was not compliant with the treatment and was subsequently lost to followup after November 2011. In January 2016, he presented with abdominal pain, headache, and splenomegaly. On investigating further, he had hemoglobin of 9.4 g/dl, leucocytosis with total leucocyte count of 1,18,000/cu mm and platelet count of 42,000/cu mm. Peripheral blood smear examination showed the presence of 2% blasts, 6% basophils, 57% myelocytes, and metamyelocytes with three nucleated RBCs per 100 WBCs and thrombocytopenia. Bone marrow aspirate showed myeloid hyperplasia with 6% blasts and 18% basophils. The hybrid transcript of BCR/ABL was quantitated using Minor Groove Binder Real Time RT-PCR assay and the BCRABL1/ABL1 transcript ratio was 46.65%. Imatinib resistance was suspected based on the initial incomplete cytogenetic response and recent increase in BCR-ABL transcripts. Subsequently, imatinib resistance mutation analysis (IRMA) was performed by DNA sequencing on GeXP Beckmann Coulter (Brea, CA) as described by Willis et al. [2] Point mutation at 298, replacing guanine for cytosine and amino acids valine for leucine (Figure 1) was detected. The patient is currently on an enhanced dose – 600mg/day of imatinib for last 8 months. CML results from the balanced translocation of c-ABL on chromosome 9 and BCR on chromosome 22, which leads to the formation of BCR-ABL1 chimeric oncoprotein with constitutive tyrosine kinase activity.[1] The ABL1 kinase domain has the N-terminal, C-terminal, P-loop, and an activation region A-loop. Mutations in any of these key regions of the ABL1 kinase domain can lead to resistance to BCR-ABL1 TKIs. The A-loop has a conserved DFG (aspartate–phenylalanine–glycine) motif. Imatinib targets the tyrosine kinase activity of BCR-ABL1. It acts by binding to the ATP-binding site within the catalytic site of ABL1 and stabilizes the inactive form of the kinase with the A-loop in a closed DFG-out conformation and the ATP-binding P-loop in a distorted conformation.[3] Secondary or acquired resistance to imatinib can be seen in 20 to 25% of patients.[1] Till-date, more than 90 discrete resistance-conferring point mutations at 57 residues in the ABL kinase domain have been documented.[4] P-loop and T315I mutations were the most frequent mutations identified (28% and 20% of all mutations respectively) in a study on 89 patients with imatinib resistance in CML. Five mutations were beyond the P-loop -Y320C, L324Q, F359L, F376V, and L298V, the latter in the SH3-contact region.[5] L298V, which involves imatinib-binding site, has been found at low frequency in few studies.[5–10] It can either occur alone or in association with other point mutations.[5–10] It caused resistance to imatinib and these patients were treated with second generation tyrosine kinase inhibitor, mostly Dasatanib. Recent reports of 297 CML patients on imatinib,[11] 258 CML patients each, on dasatinib 100mg once daily and imatinib 400mg once daily,[12] 1110 CML patients on imatinib [13] 282, 281,283 CML patients on nilotinib 300mg twice daily, nilotinib 400mg twice daily, and imatinib 400mg once daily, respectively, [14] and 385 CML patients [15] do not mention this mutation. T315, F359, G250, M351, E255, M244, Y253, E355, and F317 accounted