them were found Valproate to have already carried KD mutations even before TKI exposure. Clinical parameters of CML patients carrying KD mutations versus wild type The population of CML patients bearing the KD mutations had a slightly higher number of males to females. The median age of imatinib treated patients with or without nebivolol clinical trial KD mutation was 45 and 50 years, respectively, whereas the median age of imatinib na?ve patients with or without mutations was 41 and 44 years, respectively. Most of the patients in both groups with or without KD mutation were in chronic phase. About one third of mutated cases in TKI exposed and about half of mutated cases in na?ve cases were in advanced phase whereas about one fourth of wild type cases in both groups were in advanced phase.
The median WBC and PLT counts were higher and the Hb was lower in Irbesartan structure the na?ve CML cases as compared to the TKI treated cases. Types of KD mutations in TKI exposed and TKI na?ve CML patients Twenty one types of mutations were found in 37 patients including 13 known mutations and 8 previously unidentified mutations. A known single nucleotide polymorphism, L354L, was detected in 2 patients. The most common type of mutation was T315I mutation which was found in 9 cases. Other less common mutations included 13 cases of various P loop mutations, and 5 cases of M351T. About 75% of all mutations recognized in our population were among the eight most common types and most of them were insensitive and intermediately sensitive types of mutations. The M388L was considered sensitive to imatinib while M351T was shown to have a low level of insensitivity to imatinib.
The location Lopinavir solubility of each mutation is depicted in Fig. 1. Most mutations in the na?ve cases were localized in the C helix domain/SH3 contact site whereas most mutations in the exposed cases were localized in the drug contact site, P loop, and catalytic domain. In na?ve patients, there were 3 known mutations and 5 novel KD mutations. In TKI exposed patients, there were 11 known mutations and 3 novel mutations. Four of the ten mutations in the patients who received both imatinib and second generation TKI and all three mutations in the patients with advanced phase who received only second generation TKI were T315I. The elution profiles of all eight novel mutations identified by DHPLC and sequencing analysis are shown in Fig. 2.
Twenty seven unity cases had a single mutation while 8 cases had multiple mutations including T315IL354L, F359VL354L, G250EF359V, L387F M388L, Y253HT315I and L301HE255K. Two cases with a SNP were found to have coexisting mutations including T315I and F359V. The responses to imatinib in CML patients with 8 novel mutations discovered in this study are summarized in Table 3. Among 3 novel mutations in the TKI exposed cases, all of them were intolerant or resistant toimatinib. Only 2 of 5 na?ve cases with novel mutations were subsequently treated with imatinib and both of them failed to have a good response. One patient with H295H is still on hydroxyurea and in chronic phase while another patient with p.Pro218GlnfsX27 died at 3 months after allogeneic stem cell transplantation. E258E was undetectable at 3 months after imatinib although a partial cytogenetic response was achieved.
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