http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.
변환된 중국어를 복사하여 사용하시면 됩니다.
Kim, TaeHyung,Tyndel, Marc S.,Zhang, Zhaolei,Ahn, Jaesook,Choi, Seunghyun,Szardenings, Michael,Lipton, Jeffrey H.,Kim, Hyeoung-Joon,Kim Dong Hwan, Dennis Elsevier 2017 Leukemia research Vol.59 No.-
<P><B>Abstract</B></P> <P><B>Objective</B></P> <P>The development of tyrosine kinase inhibitors (TKIs) has significantly improved the treatment of chronic myeloid leukemia (CML). However, approximately one third of patients are resistant to TKI and/or progress to advanced disease stages. TKI therapy failure has a well-known association with <I>ABL1</I> kinase domain (KD) mutations, but only around half of TKI non-responders have detectable <I>ABL1</I> KD mutations.</P> <P><B>Method</B></P> <P>We attempt to identify genetic markers associated with TKI therapy failure in 13 patients (5 resistant, 8 progressed) without <I>ABL1</I> KD mutations using whole-exome sequencing.</P> <P><B>Results</B></P> <P>In 6 patients, we detected mutations in 6 genes commonly mutated in other myeloid neoplasms: <I>ABL1</I>, <I>ASXL1</I>, <I>DNMT3A</I>, <I>IDH1</I>, <I>SETBP1</I>, and <I>TP63</I>. We then used targeted deep sequencing to validate our finding in an independent cohort consisting of 100 CML patients with varying drug responses (74 responsive, 18 resistant, and 8 progressed patients). Mutations in genes associated with epigenetic regulations such as <I>DNMT3A</I> and <I>ASXL1</I> seem to play an important role in the pathogenesis of CML progression and TKI-resistance independent of <I>ABL1</I> KD mutations.</P> <P><B>Conclusion</B></P> <P>This study suggests the involvement of other somatic mutations in the development of TKI resistant progression to advanced disease stages in CML, particularly in patients lacking <I>ABL1</I> KD mutations.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Acquisition of somatic mutation is associated with TKI therapy failure and progression in CML patients. </LI> <LI> Exome sequencing revealed mutations in 6 genes: <I>ABL1, ASXL1, DNMT3A, IDH1, SETBP1,</I> and <I>TP63.</I> </LI> <LI> Somatic mutations is responsible for TKI resistance esp. lacking <I>ABL1</I> KD mutations. </LI> </UL> </P>
Kim, TaeHyung,Tyndel, Marc S.,Kim, Hyeoung Joon,Ahn, Jae-Sook,Choi, Seung Hyun,Park, Hee Jeong,Kim, Yeo-kyeoung,Kim, Soo Young,Lipton, Jeffrey H.,Zhang, Zhaolei,Kim, Dennis (Dong Hwan) American Society of Hematology 2017 Blood Vol. No.
<P>Somatic mutations commonly detected in a variety of myeloid neoplasms have not been systematically investigated in chronic myeloid leukemia (CML). We performed targeted deep sequencing on a total of 300 serial samples from 100 CML patients; 37 patients carried mutations. Sixteen of these had evidence of mutations originating from preleukemic clones. Using unsupervised hierarchical clustering, we identified 5 distinct patterns of mutation dynamics arising following tyrosine kinase inhibitor (TKI) therapy. This study demonstrates that patterns of mutation acquisition, persistence, and clearance vary but have a number of interesting correlations with clinical outcomes. Mutation burden often persisted despite successful TKI response (pattern 1), providing indirect evidence that these mutations also originated from preleukemic mutations, whereas patients exhibiting mutation clearance (pattern 3) showed mixed clinical outcomes. Unsurprisingly, patients acquiring new mutations during treatment failed TKI therapy (pattern 2). These patterns show that CML mutation dynamics following TKI therapy are markedly distinct from other myeloid neoplasms. In summary, clinical implications of mutation profiles and dynamics in CML should be interpreted with caution.</P>
Guilhot, Francois,Apperley, Jane,Kim, Dong-Wook,Bullorsky, Eduardo O.,Baccarani, Michele,Roboz, Gail J.,Amadori, Sergio,de Souza, Carmino A.,Lipton, Jeffrey H.,Hochhaus, Andreas,Heim, Dominik,Larson, American Society of Hematology 2007 Blood Vol.109 No.10
<B>Abstract</B><P>Treatment options are limited for patients with imatinib-resistant or -intolerant accelerated phase chronic myeloid leukemia (CML-AP). Dasatinib is a novel, potent, oral, multitargeted kinase inhibitor of BCR-ABL and SRC-family kinases that showed marked efficacy in a phase 1 trial of patients with imatinib-resistant CML. Results are presented for 107 patients with CML-AP with imatinib-resistance or -intolerance from a phase 2, open-label study further evaluating dasatinib efficacy and safety. At 8 months' minimum follow-up, 81%, 64%, and 39% of patients achieved overall, major (MaHR), and complete hematologic responses, respectively, whereas 33% and 24% attained major and complete cytogenetic remission. Of 69 patients who achieved MaHR, 7 progressed. Seventy-six percent of patients are estimated to be alive and progression-free at 10 months. Response rates for the 60% of patients with baseline BCR-ABL mutations did not differ from the total population. Dasatinib was well tolerated: most nonhematologic adverse events (AEs) were mild to moderate; no imatinib-intolerant patients discontinued dasatinib because of AEs. Although common (76% of patients with severe neutropenia), cytopenias were manageable through dose modification. In summary, dasatinib induced significant hematologic and cytogenetic responses in patients with imatinib resistance or intolerance, was well tolerated, and may represent a potent new therapeutic option for CML-AP. Further follow-up is warranted. This trial was registered at www.clinicaltrials.gov as #CA180005.</P>