Brief communicationLow-level Bcr–Abl mutations are very rare in chronic myeloid leukemia patients who are in major molecular response on first-line nilotinib
Introduction
Point mutations in the Bcr–Abl kinase domain (KD) are frequently detectable in chronic myeloid leukemia (CML) patients who develop resistance to imatinib. However, they have also been documented in a variable proportion of residual Ph+ cells in some patients with stable responses [1], [2]. In general, the higher the sensitivity of the screening method, the greater the number of patients found to harbour mutations – although the relevance, from a clinical standpoint, of low-level mutations is still controversial [1], [3]. Nilotinib is a more potent and selective imatinib derivative capable to induce major molecular responses (MMR; Bcr–Abl transcript level < 0.1% according to the International Scale [IS]) much faster and in much higher percentages of patients [4], [5], [6]. We wondered whether Bcr–Abl KD mutations are detectable in patients in MMR on nilotinib. To address this issue, we retrospectively analyzed the samples collected after 12 months of therapy from 12 patients enrolled on a phase II study of nilotinib 400 mg BID as frontline treatment of CML [4], who had achieved a stable MMR.
Section snippets
Patients
This mutation screening was retrospectively performed on bone marrow samples collected after 12 months of nilotinib therapy from twelve patients in MMR [4]. Baseline features and outcome of these patients are detailed in Table 1.
Mutation screening
To increase the sensitivity of mutation screening, we adopted a subcloning and sequencing approach. A single fragment corresponding to the KD region where the reported Bcr–Abl mutations map (codons 240-502) was generated by nested RT-PCR using the ProofStart DNA
Results and discussion
Our screening approach showed evidence of Bcr–Abl KD mutations in one out of twelve patients analyzed. In this high Sokal risk patient, an A to T nucleotide substitution translating into a Q346L mutation, was detected in 3/150 independent clones. An additional C to T nucleotide substitution corresponding to the T315I mutation was present in 2 out of these 3 clones. The KD sequence of one the clones carrying both mutations is shown in Fig. 1. The remaining eleven patients analyzed scored
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Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase
2013, BloodCitation Excerpt :The decreased emergence of mutations seen with nilotinib relative to imatinib in this study may be a contributing factor to the improved outcomes seen with nilotinib. A study by Soverini et al35 demonstrated that patients treated with frontline nilotinib therapy who achieved and maintained MMR rarely had BCR-ABL mutations, even when evaluated by high-sensitivity methods. However, because high-sensitivity screening was not performed in this study, it cannot be excluded that BCR-ABL kinase mutations existed below the level of detection in patients who achieved deeper responses with nilotinib.
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