ABL Mutations In Early Chronic Phase Chronic Myeloid Leukemia (CP-CML) Are Associated with a Greater Likelihood of Progression and Shorter Survival

Abstract 4458

Acquired resistance to Imatinib in advanced phase of CML has been associated with mutations in the kinase domain (KD) of BCR-ABL. We have recently reviewed the status of the mutations in 52 patients with early CP-CML on the samples collected at diagnosis. Mutations were identified by direct sequency (DS) with BidDye Terminator V1.1. cycle sequencing kit and analyzed with a 3130 AB capillary electrophoresis system. Twenty-eight patients had low risk, 10 intermediate risk and 14 high risk, according to Sokal/Euro. Ten out of 14 high Sokal risk patients showed the following mutations: Y253C, S265R, E255K, F359Y, N374S, E255V, E255V, E255V, R332L, E334G. Three of these patients progressed during Imatinib and second-line TKIs and died of blastic phase CML at 23, 33 and 69 months. Curiously, S265R and N374S mutations disappeared during Imatinib treatment but were substituted during follow-up by other two mutations: E255L and H396R. The patient carrying E255L mutation died in blastic phase at 33 months and the one with mutation H396R was well controlled by Nilotinib and he is now alive in CMR 26 months after. Only one out of the 10 intermediate Sokal risk carried KD mutations at diagnosis (D363G). This patient is alive in MMR at 26 months after diagnosis under Imatinib. None of the 28 low Sokal risk patients carried KD mutations at diagnosis and no patients developed cytogenetic evolution while on treatment. In conclusion, the fact that KD mutations were more present in patients with high Sokal risk supports the hypothesis that the probability developing a mutation is related to the basic biology of the disease rather than being merely a random event.