Academic literature on the topic 'T315I mutation'
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Journal articles on the topic "T315I mutation"
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Chen, Jiaqi, Hongxing Liu, Fang Wang, Yang Zhang, Xue Chen, Daijing Nie, Yu Li, Yincheng Tan, Yuanli Xu, and Xiaoli Ma. "Dynamic Evolution of Ponatinib Resistant BCR-ABL1 T315 and Compound Mutations." Blood 134, Supplement_1 (November 13, 2019): 3796. http://dx.doi.org/10.1182/blood-2019-129579.
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The third-generation tyrosine kinase inhibitor (TKI) ponatinib exhibits activity against all common BCR-ABL1 kinase domain (KD) single mutations, including the highly resistant gatekeeper T315I. However, the drug response is variable and the clinical resistance mutations may still befall with few reports to date. We performed next-generation sequencing (NGS) detection of BCR-ABL1 KD mutations in sequential samples of three BCR-ABL1-positive leukemia patients who developed clinical resistance to ponatinib, to explore the dynamic evolution of ponatinib mutations. Case 1 was diagnosed as chronic myeloid leukemia (CML) chronic phase when he was 29 years old in 2009. His maintenance therapies were imatinib and dasatinib for seven years and then replaced with ponatinib due to the blast crisis of CML and the T315I mutation with variant allele frequency (VAF) of 46%. He did not achieved molecular remission after attempting multiple combined chemotherapy and TKIs including ponatinib, with the T315I mutation persists and eventually increases to VAF of 97%. He was then was medicated with a combined chemotherapy plus dasatinib and ponatinib. But NGS KD mutation investigation showed multiple T315I compound mutations, T315M and T315I mutations six months later. The patients went through salvage allogenic hemopoietic stem cell transplantation (allo-HSCT), and the above polyclonal and compound mutations were still carried after transplantation. Finally, Q252H/T315I (VAF,50%) became the dominant clone, and ponatinib and HQP1351 (domestic TKI designed for T315I) were ineffective for this compound mutation (Figure a). A similar dynamic evolution to the BCR-ABL1 KD mutation of Case1 also occurred in case 2. The 7-year-old boy was diagnosed with BCR-ABL1-positive acute B-lymphocytic leukemia (Ph+B-ALL) in April 2014. NGS results showed that he had D276G (7%), F311I (27%) and F317L (31%) polyclonal mutations in BCR-ABL1 KD after 18 months of imatinib administration which were subsequently treated with ponatinib. After 5 months of treatment with ponatinib, F311I and F317L mutations disappeared, but G250E (5%) and D276G/T315L (4%) compound mutation appeared; subsequent progression to D276G/T315L (32%), G250W/E255V/F311I (4%) and F311I/T315I (58%) polyclonal compound mutations; long induction chemotherapy combined with ponatinib treatment remained unresolved, and finally there was only D276G/T315L compound mutation (VAF, 100%, figure b and d). Notably, a rare mutation T315L (c.943_945delinsCTC/p.T315L) appeared in the BCR-ABL1 KD. D276G is known to be sensitive to various TKIs, so we speculate that ponatinib is ineffective for the T315L mutation. Case 3 was a 46-year-old woman who diagnosed with Ph+B-ALL in July 2018. The Q252H (20%) and T315I (44%) double mutations appeared after oral administration of imatinib for 2 months, and then switched to ponatinib for remission. After 8 months, the bone marrow and peripheral blood samples showed not only the T315I/F359V compound mutation (VAF, 90% and 94%), but also the T315L mutation (VAF, 5% and 6%, c.943_944AC>CT/p.T315L). The clinician combined her BCR-ABL1 KD mutation and condition, ponatinib was discontinued. After 1 month of chemotherapy combined with dasatinib, the patient's condition improved, but the BCR-ABL1 KD mutation progressed to T315L (18%, figure c and e) and T315I/F359V compound mutation (76%). She eventually died from severe pulmonary infection and sepsis. NGS analysis identify KD mutation with sensitivity about 2%, and can also distinguish between compound and polyclonal mutations. All of the ultimately dominant ponatinib resistant mutations (Q252H/T315I, D276G/T315L, and T351I/F359V) in these three cases were T315 compound mutations derived from the T315I or other original mutation with additional mutation event. The T315L/M mutations and compound mutations collaborated by T315 and other KD mutations may confer the major component of ponatinib resistance. The dynamic resistant mutation in these three patients adds to the currently less content compendium of ponatinib clinical resistance. All of the three patients encountered ponatinib toxic side effects and had to discontinue or reduce the dose, which also confer favorable opportunity for the development of drug-resistant mutations. Figure Disclosures No relevant conflicts of interest to declare.
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Manrique, Gonzalo, Roberta Bittencout, Verónica Pérez, Vanesa Sholl, Monica Cappetta, Noel Zubillaga, Rocio Hassan, et al. "Detection of BCR-ABL Kinase Domain Mutations in Chronic Myeloid Leukemia Patients Treated with Tirosin-Kinase Inhibitors." Blood 112, no. 11 (November 16, 2008): 4261. http://dx.doi.org/10.1182/blood.v112.11.4261.4261.
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Abstract Background. Point mutations in the kinase domain (KD) of the BCR-ABL are the most frequent mechanism of drug resistance in CML patients treated with kinase inhibitors (TKI). More than 80 mutations with different frequency and clinical significance have been reported. One of them, the T315I confers resistance to all TKIs available. The detection of mutations in KD allows early identification of high-risk patients and therefore guides clinical therapy decisions. Aim. To assess the mutation status of a group of CML pts resistant to TKI from Uruguay (n=35) and Brazil (n=30). Methods. KD mutation screening was performed by RT-PCR and direct sequencing according to Branford et al. (2002). Additionally, we developed a rapid, specific, sensitive and low cost allele specific (AS)-RT-PCR assay to identify T315I, using Branford’s KD amplification primers in combination with an allele specific primer for the T315I point mutation detection. BCR-ABL transcript levels were also measured by RQ-PCR according to international recommendations. Results and Discussion. RT-PCR and direct sequencing analyses performed in all pts showed the presence of T315l mutation in 3/65 cases. Other 11 showed the alternative mutations Y253H (n=2), E450A, G250E (n=2), E459K (n=2), E450G, F317L (n=2) and E255K; and the remaining 55 showed no mutations in the ABL KD. All 65 samples together with cDNA from 15 non-resistant CML pts and 10 cDNA from non-CML were analyzed by AS-RT-PCR assay for T315l mutation in order to validate the method. T315l was identified in the 3 samples in which the mutation was previously detected by direct sequencing and in 1 pt that had been classified as KD mutation negative. This result was then confirmed by direct sequencing of the AS-PCR product. T315 was neither detected in samples positive for other mutations nor in samples of non-resistant CML and non-CML patients, supporting the specificity of the method. Assessment of the sensitivity of the AS-RT-PCR was performed on serial dilutions experiments using RNA from T315 positive pt into RNA from CML-T315l negative pt, showing that the T315I mutation was detectable to a level of 0.01 % by AS-PCR, while through direct sequencing method the sensitivity was 10–20%. The prevalence of mutations in our study was 15/65 (23%). Conclusions. Our results showed that the AS-RT-PCR described here is a convenient and easy tool to be used in a clinical routine laboratory for rapid screening for BCR-ABL T315. This, together with direct sequencing, constitutes a suitable approach for CML resistance monitoring and therapeutic choice.
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Soverini, Simona, Giovanni Martinelli, Sabrina Colarossi, Alessandra Gnani, Fausto Castagnetti, Gianantonio Rosti, Costanza Bosi, et al. "Mutations at Residues 315 and 317 in the ABL Kinase Domain Are the Main Cause of Resistance to Dasatinib in Philadelphia-Positive (Ph+) Leukemia Patients (pts)." Blood 108, no. 11 (November 16, 2006): 836. http://dx.doi.org/10.1182/blood.v108.11.836.836.
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Abstract Dasatinib (BMS-354825) is a second-generation BCR-ABL inhibitor active against several imatinib-insensitive BCR-ABL mutant forms. We have treated in the phase II program with dasatinib a total of forty-five Ph+ pts who were resistant to or intolerant of imatinib. At the time of writing, twenty pts have failed to respond to or relapsed on dasatinib therapy. In order to assess which pre-existent or emerging ABL kinase domain (KD) mutations are challenging for dasatinib clinical efficacy, we retrospectively analyzed ABL KD sequences before the start of treatment and every month thereafter, until dasatinib discontinuation. Mutation monitoring was done by D-HPLC, followed by sequencing in D-HPLC-positive cases. Eight pts had primary resistance to dasatinib (Table 1). In all cases, a T315I or a F317L mutation was already detectable before the onset of treatment or became detectable after one month. The mutations persisted up to the time of disease progression, which occurred at a median of 1.5 months (range, 1–4) from dasatinib start. Twelve pts had acquired resistance to dasatinib (Table 1). Relapse occurred after a median of 7.5 months (range, 3–15) from dasatinib start. Mutation analysis performed before the onset of treatment showed that five of these pts had a wild-type ABL sequence, while the remaining seven pts had evidence of various imatinib-resistant KD mutations (G250E, Y253H, E255K, D276G, M351T). At the time of relapse, however, most of the original mutant clones had disappeared, whereas mutations at residues 315 (T315I or T315A) and/or 317 (F317L or F317I) had invariably emerged in all but one pt. This pt was found to have developed a novel K356R mutation which is now under characterization. Our results indicate that residues 315 and 317 are mutation hotspots in dasatinib-resistant pts, according to the experimental observation that they are both involved in inhibitor binding. They also provide a proof of principle that novel, inhibitor-specific mutant variants (i.e., T315A, F317I, K356R) may be selected, and raise some concerns about the limitations of single-agent treatment in the long term disease control of advanced phase-CML or Ph+ ALL pts. Supported by European LeukemiaNet, AIL, AIRC, FIRB and PRIN projects. Table 1 Pt Disease Mutation(s) before dasatinib start Best HR Best CgR Months on dasatinib Mutation(s) at relapse NE, not evaluated Primary resistance 1 CML/AP WT NR none 4 T315I 2 CML/AP T315I NR NE 1 T315I 3 CML/myBC T315I NR NE 1 T315I 4 CML/myBC F317L NR none 3 F317L 5 CML/lyBC T315I NR NE 1 T315I 6 Ph+ ALL T315I, M351T, L387M NR NE 2 T315I, M351T, L387M 7 Ph+ ALL T315I NR NE 1 T315I 8 Ph+ ALL F359V NR NE 2 T315I Acquired resistance 9 CP WT CHR minor 15 T315I 10 CML/myBC G250E NEL none 8 F317L 11 CML/lyBC Y253H CHR complete 9 CHR T315I 12 CML/lyBC WT CHR complete 4 T315I 13 CML/lyBC E255K CHR none 3 E255K, T315I 14 CML/lyBC D276G CHR complete 7 T315I 15 CML/lyBC WT CHR partial 9 F317L 16 Ph+ ALL E255K CHR NE 4 T315I 17 Ph+ ALL Y253H CHR complete 13 T315A, F317L, D276G 18 Ph+ ALL M351T CHR complete 13 M351T, F317L 19 Ph+ ALL WT CHR complete 6 F317I 20 Ph+ ALL WT CHR complete 4 K356R
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Smith, Catherine C., Michael Brown, Jason Chin, Corynn Kasap, Sara Salerno, Lauren E. Damon, Kevin Travers, et al. "Single Molecule Real Time (SMRT™) Sequencing Sensitively Detects Polyclonal and Compound BCR-ABL in Patients Who Relapse on Kinase Inhibitor Therapy,." Blood 118, no. 21 (November 18, 2011): 3752. http://dx.doi.org/10.1182/blood.v118.21.3752.3752.
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Abstract Abstract 3752 Background: Secondary kinase domain (KD) mutations are the most well-recognized mechanism of resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) and other cancers. In some cases, multiple drug resistant KD mutations can coexist in an individual patient (“polyclonality”). Alternatively, more than one mutation can occur in tandem on a single allele (“compound mutations”) following response and relapse to sequentially administered TKI therapy. Distinguishing between these two scenarios can inform the clinical choice of subsequent TKI treatment. There is currently no clinically adaptable methodology that offers the ability to distinguish polyclonal from compound mutations. Due to the size of the BCR-ABL KD where TKI-resistant mutations are detected, next-generation platforms are unable to generate reads of sufficient length to determine if two mutations separated by 500 nt reside on the same allele. Pacific Biosciences RS Single Molecule Real Time (SMRT) circular consensus sequencing technology is a novel third generation deep sequencing technology capable of rapidly and reliably achieving average read lengths of ∼1000bp (Travers et al, 2010) and frequently beyond 3000bp, allowing sequencing of the entire ABL KD on single strand of DNA. We sought to address the ability of SMRT sequencing technology to distinguish polyclonal from compound mutations using clinical samples obtained from patients who have relapsed on BCR-ABL TKI treatment. Results: We analyzed an 863bp area of the BCR-ABL KD in 6 patients who had clinically relapsed on ABL kinase inhibitor therapy. SMRT sequencing detected mutations at a sensitivity of ∼1–2% of the total sequenced population, and successfully distinguished polyclonal from compound BCR-ABL KD mutations in several patient samples. Results were largely consistent with those obtained by PCR subcloning and sequencing, although SMRT sequencing detected additional mutations and/or mutation combinations. In the most complex case, 7 distinct mutation-bearing alleles were detected in an individual patient after sequential relapse on imatinib and dasatinib. Mutant clones contained single and compound mutations combining distinct mutations (Y253H, T315F, T315A, T315I, T319A, E355G). Three distinct substitutions at residue T315 were detected: T315A, T315I and T315F. Notably, these findings are clinically important as the T315A mutation confers resistance to dasatinib but not imatinib, while the T315F and T315I mutations are resistant to all three clinically approved BCR/ABL inhibitors (imatinib, dasatinib, and nilotinib). Phospho-flow analysis for p-Crkl, a direct substrate of BCR-ABL, was conducted following ex vivo exposure of patient cells from the same time point to all three BCR-ABL inhibitors, and demonstrated the existence of distinct populations of cells with varying sensitivity to each drug (i.e. polyclonal drug sensitivity), underscoring the potential clinical importance of distinguishing polyclonal from compound mutations. Additionally, SMRT sequencing routinely detected alleles harboring compound mutations not detectable by conventional direct sequencing. Data analysis of samples from additional patients is ongoing and will be presented. Conclusions: Pacific Biosciences RS SMRT sequencing sensitively detects KD mutations in patient samples and can distinguish TKI-resistant clones containing compound mutations to reveal a complex mutational landscape in an individual patient not detectable by conventional sequencing. SMRT sequencing of the BCR-ABL KD can feasibly be developed into a rapid and economical clinical test with the additional advantages of increased sensitivity and reliability over current methods. Given the growing numbers of patients exposed to multiple TKIs in a sequential manner, the ability to accurately and sensitively characterize drug-resistant alleles promises to further facilitate a personalized approach to patient management. Disclosures: Brown: Pacific Biosciences: Employment. Chin:Pacific Biosciences: Employment. Travers:Pacific Biosciences: Employment. Wang:Pacific Biosciences: Employment. Kasarskis:Pacific Biosciences: Employment, Equity Ownership. Schadt:Pacific Biosciences: Employment, Equity Ownership.
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Shah, Neil P., John M. Nicoll, Susan Branford, Timothy P. Hughes, Ronald L. Paquette, Moshe Talpaz, Claude Nicaise, Fei Huang, and Charles L. Sawyers. "Molecular Analysis of Dasatinib Resistance Mechanisms in CML Patients Identifies Novel BCR-ABL Mutations Predicted To Retain Sensitivity to Imatinib: Rationale for Combination Tyrosine Kinase Inhibitor Therapy." Blood 106, no. 11 (November 16, 2005): 1093. http://dx.doi.org/10.1182/blood.v106.11.1093.1093.
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Abstract Point mutations within the BCR-ABL kinase domain represent the most common mechanism of resistance to imatinib in patients with CML. Preclinical studies have shown that dasatinib (BMS-354825) is effective at inhibiting the kinase activity of imatinib-resistant BCR-ABL mutants with the notable exception of the T315I mutation, which remains highly resistant to imatinib, dasatinib, and AMN107 (Gorre et al, Science 2001; Shah et al, Science 2004; Weisberg et al, Cancer Cell, 2005). Clinical data from Phase I and II studies of dasatinib in CML confirms the in vitro findings. Each of three imatinib-resistant patients bearing the T315I mutation (CP=1; AP=2) did not achieve objective hematologic or cytogenetic responses during treatment with dasatanib on a Phase I study. Additionally, each of two phase II patients with the T315I mutation (CP=1; LBC=1) treated at UCLA showed no evidence of objective response. We have also detected the T315I mutation in each of two cases of acquired resistance in a phase II (LBC =2) study, and in seven of nine patients with acquired resistance to dasatinib in phase I and II studies (CP=1; MBC=3; LBC=2; Ph+ ALL=1). Notably, we detected a novel BCR-ABL mutation, T315A, in one of the two patients who relapsed without a detectable T315I mutation. The patient is a 53 year-old female whose chronic phase CML had progressed to myeloid blast phase while being treated with imatinib. The imatinib-resistant mutation M244V was identified prior to dasatinib treatment. The patient achieved a major hematologic response (<5% blasts with partial recovery of peripheral blood counts) on dasatinib 90 mg orally given twice daily, but relapsed with MBC after six months. Sequence analysis of the BCR-ABL kinase domain at the time of relapse revealed the presence of the imatinib-resistant mutation M244V as well as the novel mutation T315A. This finding is of particular interest because T315A and several other novel BCR-ABL mutations were recently recovered in a saturation mutagenesis study designed to define potential mechanisms of dasatinib resistance. Remarkably, many of these mutations retain sensitivity to imatinib in vitro (Burgess et al, PNAS, 2005). Through periodic molecular monitoring of other dasatinib-treated patients, we have identified a second novel BCR-ABL mutant, F317I, that developed in an imatinib-resistant CP patient after 9 months of treatment. Similar to T315A, F317I was isolated in the saturation mutagenesis screen for dasatinib resistance and is predicted to retain sensitivity to imatinib. Taken together, our findings implicate the T315I mutation as the principle mechanism of resistance to dasatinib, but more importantly, strongly support the use for combination kinase inhibitor therapy in CML to prevent emergence of drug resistant clones. A phase I trial to assess the safety of combining imatinib with dasatinib is planned.
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Deininger, Michael W. N., Michael J. Mauro, Yousif Matloub, Ritwik Sinha, Lynn Ploughman, David Liu, and Jerald Radich. "Prevalence of T315I, Dasatinib-Specific Resistant Mutations (F317L, V299L, and T315A), and Nilotinib-Specific Resistant Mutations (P-loop and F359) at the Time of Imatinib Resistance in Chronic-Phase Chronic Myeloid Leukemia (CP-CML)." Blood 112, no. 11 (November 16, 2008): 3236. http://dx.doi.org/10.1182/blood.v112.11.3236.3236.
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Abstract Mutations in the catalytic domain of ABL kinase (AKD) are a major mechanism of resistance to imatinib. Over 70 mutations in more than 50 amino acid residues have been reported to date. The ‘gatekeeper’ mutation, T315I, which causes complete resistance to all three FDA-approved tyrosine kinase inhibitors (TKIs), was reported to be not uncommon among a heterogeneous set of patients who had failed first-line imatinib therapy. In addition, the F317L, V299L, and T315A mutations were reported to convey a high degree of resistance to dasatinib, and higher frequency mutations within the P-loop (Y253H/F, E255V/K) and F359 mutations were associated with a high degree of resistance to nilotinib. We studied the prevalence of AKD mutations in the START-C phase II trial of dasatinib in patients who have failed imatinib (resistance or intolerance). Baseline mutation data were available for 95 of 99 patients with imatinib intolerance, and 274 of 288 patients with imatinib resistance. Of these patients, 13 (14%) with imatinib intolerance and 136 (50%) with imatinib resistance had AKD mutations. Of the 149 patients with mutations, only 3 (2%) had the T315I mutation. A total of 57 (38%) subjects had mutations in the P-loop (between 248–256): 13 patients with Y253H/F (9%), and 6 patients with E255V/K (4%). Four subjects (3%) had the F317L mutation, and 8 (5%) had F359 mutations. No subjects with V299L or T315A mutations were detected at baseline. The rates of complete cytogenetic response (CCyR) were 52% in patients with any mutation, 69% in patients with Y253H/F, 40% among those with E255V/K, 0% for T315I mutations, 0% for F317L mutations, and 50% for F359 mutations. Patients without mutations achieved a 55% rate of CCyR. These results confirm that select P-loop and F359 mutations are sensitive to dasatinib, while F317L and T315I mutations are resistant to dasatinib treatment. However, the overall incidence of these dasatinib-resistant mutants is low. In contrast, nilotinibresistant mutations in the P-loop (Y253H/F, E255V/K) or at F359 are more common, representing 15% and 5% of all patients with mutations, respectively. Therefore, the likelihood of harboring a nilotinib-resistant mutation at the time of imatinib resistance appears higher than the likelihood of harboring a dasatinib-resistant mutation, and suggests mutation testing may become instrumental for choosing between the various second-line TKI inhibitors to optimize outcomes.
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Kim, Dong-Wook, Dongho Kim, Soo-Hyun Kim, Saengsuree Jootar, Hyun-Gyung Goh, Jeong Lee, Soo-Young Choi, Young-Seok Lee, and Sang-Mi Oh. "Dynamics and Characteristics of BCR-ABL Multiple Mutations In Tyrosine Kinase Inhibitor Resistant Chronic Myeloid Leukemia." Blood 116, no. 21 (November 19, 2010): 3443. http://dx.doi.org/10.1182/blood.v116.21.3443.3443.
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Abstract Abstract 3443 BCR-ABL kinase domain (KD) point mutation causes resistance to tyrosine kinase inhibitors (TKI) in CML patients through impaired binding of TKI to the target site. One of the characteristics of patients with BCR-ABL kinase domain point mutations is the fact that some patients have multiple mutations. However there have not been many studies showing that data about clinical relevance or dynamics of multiple mutation during CML treatment. From January 2002 to June 2010 at Seoul St Mary's Hospital, 277 CML patients were screened for mutation analysis due to sign of resistance to tyrosine kinase inhibitors including imatinib, nilotinib, dasatinib or bosutinib. We found that 95 patients have point mutation in BCR-ABL kinase domain through direct sequencing or ASO-PCR. Among them, 17 patients showed multiple mutation containing more than one type of point mutations in BCR-ABL KD. We investigated the patients with multiple mutations to characterize its clinical relevance and dynamics. Once mutation found, follow-up samples from the corresponding patients were collected and analyzed prospectively, or mutation status was analyzed retrospectively with cryopreserved samples if they were available. Status of the patients with multiple mutation is shown in Table 1. In order to investigate whether the multiple mutations are on same clone or on separated clone, we cloned serial samples from the 17 patients. Cloning of cDNA region corresponding to BCR-ABL KD into plasmid was performed and followed by transformation into competent cells, colony formation, plasmid preparation of 20 colonies from each sample, and then direct sequencing. Multiple mutations of 88% patients (15 out of 17) existed compound mutation which means the individual mutant types are located on the same BCR-ABL molecule. In addition of major mutation types which were detectable in direct sequencing analysis, all the patients showed to have minor types of mutations which were found only through BCR-ABL KD cloning and subsequent colony sequencing. To make sure that this minor mutation types were not caused by sequencing error, we also analyzed of 3 patients who showed TKI resistance, but had no BCR-ABL mutation. In addition, samples from 3 normal persons were analyzed with the same method. The frequency of appearance of the minor types of point mutation was reduced in the patient group who showed TKI resistance, but had no BCR-ABL mutation, and then dramatically decreased in the normal person group, indicating that BCR-ABL gene in patients with point mutation are relatively unstable. Analysis of serial samples from a same patient provided evidence of dynamic change of portion of compound mutation. In most case, portion of the clone containing compound mutation was increased as treatment went on, indicating the clone harboring compound mutation can take survival advantage over TKI treatment in comparison of the clone containing individual type of mutation. In addition, some patients showed change in individual mutation type comprising multiple mutation as treatment went on. Currently investigation of clinical relevance of compound mutation and other analyses are being carried on and more results will be provided in detail at the conference. Table 1. Patients Tx at mutation detection (mg) Compound type Compound % 1 Nilotinib400 G250E+T315I 6.7 G250E+D444G 33.3 T315I+D444G 6.7 2 Nilotinib400 M244V+T315I 95.0 3 Dasatinib100 Y253H+T315I 95.0 4 Dasatinib140 T315I+E459K 55.6 5 Dasatinib200 T315I+M351T 66.7 6 Dasatinib100 NCM Dasatinib80 NCM Dasatinib100 M244V+F359V 16.7 7 Bosutinib500 NCM 8 Dasatinib140 T315I+F359C 35.3 9 Imatinib400 E255K+T315I 5.6 10 Dasatinib80 E255V+T315I 90.0 11 Imatinib800 E255K+T315I 10.5 12 Nilotinib800 E255K+T315I 12.5 13 Dasatinib100 F311I+T315I 35.0 F311I+F317Lb 10.0 Imatinib400 F311I+T315I 10.0 F311I+F317La 15.0 F311I+F317Lb 55.0 14 Nilotinib800 Y253H+F359I 5.6 15 Bosutinib500 V299L+E459K 95.0 Nilotinib400 + Dasatinib100 V299L+F359I 5.0 V299L+E459K 55.0 V299L+F317La+E459K 15.0 V299L+F359I+E459K 15.0 V299L+F317La+F359I+E459K 5.0 16 Imatinib600 NCM 17 Imatinib400 NCM NCM: no compound mutation. Disclosures: No relevant conflicts of interest to declare.
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Deininger, Michael W. N., Jorge E. Cortes, Dong-Wook Kim, Franck E. Nicolini, Moshe Talpaz, Michele Baccarani, Martin C. Müller, et al. "Impact of baseline mutations on response to ponatinib and end of treatment mutation analysis in patients with chronic myeloid leukemia." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 7001. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.7001.
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7001 Background: BCR-ABL kinase domain mutations frequently cause tyrosine kinase inhibitor (TKI) failure in chronic myeloid leukemia (CML). Ponatinib, a potent oral pan-BCR-ABL TKI, has shown preclinical activity against all single mutants tested, including T315I. The impact of baseline (BL) mutations on response to ponatinib (45 mg once daily) and end of treatment (EOT) mutations in pts discontinuing treatment were evaluated in the phase II PACE trial. Methods: Heavily pretreated chronic phase (CP) CML pts (93% received ≥2 prior TKIs, 60% ≥3) resistant or intolerant to dasatinib or nilotinib (N=203) or with T315I confirmed at BL (N=64) were enrolled. The primary endpt was major cytogenetic response (MCyR). Min follow up at analysis (9 Nov 2012) was 12 mos (median 15 [0.1-25]). Sanger sequencing was done at one central laboratory. Results: At BL, no mutations were detected in 51% of pts, 1 mutation in 39%, and ≥2 mutations in 10%; 26 unique mutations were observed. Responses were observed regardless of BL mutation status. MCyR rates were: 56% overall, 49% in pts with no mutations, 64% 1 mutation, 62% ≥2 mutations; 57% in pts with mutation(s) other than T315I, 74% T315I only, 57% T315I + other mutation(s). Responses were seen against each of the 15 mutations present in >1 pt at BL, including T315I, E255V, F359V, Y253H. 99 pts discontinued, 56 had EOT mutations assessed. 5 pts lost a mutation, 46 had no change, 5 gained mutations (Table). 11 pts lost MCyR (none with T315I); of the 6 discontinuing, 4 had EOT mutations assessed and no changes from BL were seen. Conclusions: Responses to ponatinib were observed regardless of BL mutation status. No single mutation conferring resistance to ponatinib in CP-CML has been observed to date. Data with a minimum follow up of 18 mos, including pts with advanced disease, will be presented. Clinical trial information: NCT01207440. [Table: see text]
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Jabbour, Elias, Hagop Kantarjian, Dan Jones, Srdan Verstovsek, Alessandra Ferrajoli, Farhad Ravandi, Susan O’Brien, and Jorge Cortes. "Characteristics and Outcome of Patients with Chronic Myeloid Leukemia (CML) and T315I Mutation Following Failure of Imatinib Mesylate Therapy." Blood 110, no. 11 (November 16, 2007): 1943. http://dx.doi.org/10.1182/blood.v110.11.1943.1943.
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Abstract Background. T315I is an imatinib pocket binding mutation within the Bcr-Abl kinase domain that is highly resistant, both in vitro and in vivo, to imatinib and to 2nd generation tyrosine kinase inhibitors (TKIs). Several studies have suggested that patients with T315I have a poor outcome. Study Aims. The objectives of this study were to define the clinical characteristics of patients harboring the T315I mutation, and to assess their outcome after imatinib failure. Results. T315I was detected in 27 pts: 20 among a series of 186 pts assayed after imatinib failure (11% of all pts; 21% of all mutations detected) after a median of 37 months (mos) from start of imatinib, and 7 among 23 pts who developed new mutations after a median of 10 mos on therapy with a 2nd generation TKI. Median age was 52 years. Median time from diagnosis to T315I was 41 mos, and the median follow-up from the detection of mutation is 18 mos. At the time of T315I detection, 10 pts were in CP, 9 in AP, and 8 in BP. Fifteen pts (56%) had transformed to accelerated or blast phase at the time of T315I detection. Best response to TKI immediately preceding development of T315I (20 imatinib, 2 nilotinib, 2 dasatinib, 2 bosutinib, 1 INNO-406) was CHR in 13 (48%) and CyR in 9 (33%; complete in 6, partial in 1, minor in 2). The median duration of response was 44 mos. Except for the lack of response to a second TKI (p=0.001), there was no difference in pt characteristics between pts with or without T315I, other mutations, or no mutations. Among the 20 pts with T315I present prior to start of 2nd TKI, 5 responded, all hematologic (3 complete hematologic response -CHR-, 2 partial hematologic response -PHR-, 1 return to chronic phase); in contrast all 5 pts without T315I prior to 2nd TKI, responded (1 major molecular response -MMR-, 2 Minor cytogenetic response -CyR-, 1 CHR, 1 PHR); and among the 2 pts with unknown T315I status at start of 2nd TKI 1 had PHR and 1 complete cytogenetic response -CCyR-. Responses were usually transient but 3 pts had sustained responses for some time despite presence of T315I: 1 pt in AP harboring simultaneously F317L and G250E acquired a T315I mutation 5 mos after the start of nilotinib and achieved MMR that was sustained for 21 mos eventually lost to major CyR. A 2nd pt in AP treated with bosutinib acquired a T315I mutation 6 months after the start of bosutinib, but nonetheless achieved a minor CyR that has been sustained for more than 8 mos. A third patient with Y253H mutation developed T315I 1 mo after therapy with INNO-406 for CML AP; at the last follow-up, 4 months into therapy, he maintained a PHR. 4/14 pts (38%) treated with T315I-directed agents (aurora kinase inhibitors, homoharringtonine) responded. 4 pts received allogeneic stem cell transplant (ASCT) and 2 are alive: 1 in CMR 24+ months after ASCT and 1 in CCyR 9 months after ASCT, wit molecular relapse and recurrence of T315I. 11/27 pts with T315I (40%) died. Patients in CP had better outcome with 87% 2-year survival, compared to 45% in AP and 20% in BP. Survival of patients with T315I was similar to those with other mutations or without mutations (p=0.64). Conclusion. Altough T315I is a mutation highly resistant to conventional BCR-ABL TKI, occasional responses can be observed. Overall survival of patients with T315I mutations is mostly dependent on the stage of the disease.
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Jabbour, Elias, Hagop Kantarjian, Dan Jones, Megan Breeden, Guillermo Garcia-Manero, Susan O'Brien, Farhad Ravandi, Gautam Borthakur, and Jorge Cortes. "Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy." Blood 112, no. 1 (July 1, 2008): 53–55. http://dx.doi.org/10.1182/blood-2007-11-123950.
Full textAbstract:
AbstractChronic myeloid leukemia (CML) with T315I mutation has been reported to have poor prognosis. We analyzed 27 patients with T315I, including 20 who developed T315I after imatinib failure (representing 11% of 186 patients with imatinib failure), and 7 of 23 who developed new mutations after second tyrosine kinase inhibitor (TKI). Median follow-up from mutation detection was 18 months. At the time of T315I detection, 10 were in chronic phase (CP), 9 in accelerated phase, and 8 in blast phase. Except for the lack of response to second TKIs (P = .002), there was no difference in patient characteristics and outcome between patients with T315I and those with other or no mutations. Patients in CP had a 2-year survival rate of 87%. Although the T315I mutation is resistant to currently available TKIs, survival of patients with T315I remains mostly dependent on the stage of the disease, with many CP patients having an indolent course.
Dissertations / Theses on the topic "T315I mutation"
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Nagao, Rina. "Growth inhibition of imatinib-resistant CML cells with the T315I mutation and hypoxia-adaptation by AV65 - a novel Wnt/β-catenin signaling inhibitor." Kyoto University, 2012. http://hdl.handle.net/2433/157488.
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Lee, Oi-Lin. "The role of cytokines in governing the expansion of the T315I mutation in chronic myeloid leukaemia." Thesis, 2014. http://hdl.handle.net/2440/95313.
Full textAbstract:
Since the introduction of imatinib, the outlook for patients with chronic myeloid leukaemia (CML) has dramatically improved. However, approximately 30-40% of patients develop intolerance or resistance to the drug and cease therapy. Among those who develop resistance, the most common cause is the development of point mutations in the kinase domain (KD) of BCR-ABL1 which impair drug binding and hence result in the loss of kinase inhibition. The T315I mutation (gatekeeper mutation) is of particular significance as it is one of the most common mutations and it is resistant to all 3 tyrosine kinase inhibitors (TKI) currently approved for therapeutic use in Australia. There is evidence to suggest that KD mutations in BCR-ABL1 may alter the biological activity of Bcr-Abl. Both in vitro and clinical studies have suggested that the T315I mutation results in greater oncogenic potential. Patients harbouring this mutation have poorer prognoses and a significantly higher rate of progression compared to other mutations. There is also ample evidence to suggest that secretion of cytokines and growth factors play a role in rendering BCR-ABL1 positive cells resistant to TKI. This thesis focuses on the role of cytokines in the resistance mechanism of cells with the T315I mutation and how this mechanism is achieved. K562-T315I cells were developed in our laboratory by exposing them to increasing levels of dasatinib over several months. HL60 cell lines were virally transduced with the BCR-ABL1p210 [p210 in superscript] and BCR-ABL1T315I [T315I in superscript] constructs. Investigations have identified that several soluble factors are preferentially secreted by cells with the T315I mutation namely, FGF-2, IL-8, MCP-1 and G-CSF. Additionally, the supernatant of K562-T315I cells also contains higher concentrations of GM-CSF and IL-6. These studies also identified that FGF-2 was able to protect K562 naïve cells from TKI-induced cell death and suggests that this occurs via activation of the MAPK and STAT5 pathways. Thus, in addition to acquiring point mutations that result in the inability of TKIs to bind Bcr-Abl, the T315I mutation also results in overexpression of FGF-2 which can confer resistance to non-mutated cells. Furthermore, in the presence of imatinib, dasatinib and nilotinib, K562-T315I cells proliferate and survive better than in the absence of a TKI. This is due to hyperactivation of the MAPK pathway whereas signalling of other pathways, JAK/STAT5 and PI3K/Akt are not increased. This phenomenon was demonstrated especially with nilotinib but studies did not indicate a cytokine mediated effect through an autocrine hypersecretion by the K562-T315I cells. Nevertheless, this finding may be one of the reasons why the T315I mutation confers a worse outcome in patients with CML if they remain on imatinib, nilotinib and dasatinib treatment.Thesis (M.Phil.) -- University of Adelaide, School of Medicine, 2014
Book chapters on the topic "T315I mutation"
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Noronha, Glen, Jianguo Cao, Chun Chow, Elena Dneprovskaia, Linda Hwang, Dan Lohse, Chi Ching Mak, et al. "Targeting Drug Resistant Mutations Using Novel Binding Interactions - Lessons Learned from Abl-T315I and their Implications in D." In Frontiers in Drug Design & Discovery (Volume 3), 121–44. BENTHAM SCIENCE PUBLISHERS, 2012. http://dx.doi.org/10.2174/978160805201110703010121.
Full textConference papers on the topic "T315I mutation"
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Hong, Soon-Sun, Soo Jung Kim, Kyung Hee Jung, Hong Hua Yan, Zhenghuan Fang, Joo Han Lim, and Jeong Seon Ryu. "Abstract 5389: Novel kinase inhibitor for imatinib-resistant chronic myeloid leukemia with T315I mutation." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-5389.
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Gupta, Pranav, Guannan Zhang, Anna Maria Barbuti, Ke Ding, Jingxuan Pan, Brian J. Druker, and Zhe-Sheng Chen. "Abstract 1980: S116836 overcomes BCR-ABL T315I mutation mediated imatinib resistance in chronic myeloid leukemia." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1980.
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Zhu, Xiaotian, Tianjun Zhou, William C. Shakespeare, Wei-Sheng Huang, Lois Commodore, Chester A. Metcalf, Yihan Wang, et al. "Abstract 2671: Structural analysis of the inhibitory mechanism of AP24534, a pan-BCR-ABL inhibitor overriding the T315I gatekeeper mutation." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-2671.
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Gupta, Pranav, Rishil Kathawala, Liuya Wei, Fang Wang, XiaoKun Wang, Brian J. Druker, Li-Wu FU, and Zhe-Sheng Chen. "Abstract 4158: Targeting the imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia through a novel BCR-ABL inhibitor." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-4158.
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