High-Sensitivity Mutational Analysis of BCR-ABL Mutations in the Kinase Domain Using Pyrosequencing Could Provides Alternative Methodology for Monitoring the Proportion of Mutant Alleles in Patient with Chronic Myelogenous Leukemia.
Il-Kwon LeeJu Hyun YunYeo‐Kyeoung KimHee Nam KimKyeong-Soo ParkMyung‐Geun ShinChan ChoiHyeoung Joon Kim
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Pyrosequencing
Imatinib Mesylate
Chronic myelogenous leukemia
Protein kinase domain
ABL
CHICAGO—In patients with newly diagnosed chronic myelogenous leukemia in chronic phase (CML-CP), treatment with dasa-tinib showed significantly higher and faster rates of complete cytogenetic response and major molecular response at 12 months compared with imatinib, according to data reported here at the ASCO Annual Meeting. “Given the predictive value of 12-month complete cytogenetic response and major molecular response and the favorable tolerability of dasatinib, dasatinib may improve long-term outcomes in patients with newly diagnosed CML-CP, and it may become a viable option in newly diagnosed disease,” said principal investigator Hagop M. Kantarjian, MD, Chairman and Professor of the Department of Leukemia at the University of Texas MD Anderson Cancer Center. Patients taking the second-generation tyrosine kinase inhibitor also had a lower rate of progression—1.9% vs imatinib at 3.5%, he said. The data were published in the New England Journal of Medicine (2010;362:2260–2270) on the same day as Dr. Kantarjian’s ASCO report (June 5). The study was supported by Bristol-Myers Squibb, which makes dasatinib under the trade name Sprycel. As background, Dr. Kantarjian noted that once-daily dasatinib, a BCR-ABL kinase inhibitor, had already been proven effective in patients with CML-CP after imatinib failure, with a 73% rate of progression-free survival and 87% for overall survival at three years. The study, called DASISION—Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients—included 519 patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase, randomly selected to receive either dasatinib at 100 mg daily (259 patients) or imatinib at 400 mg daily (260 patients). The study took place in 108 centers in 26 countries. As of the time of the report, 85% of dasatinib patients and 81% of imatinib patients remained on study. Results At five years, the confirmed complete cytogenetic response rate was superior for dasatinib—77% vs 66% for imatinib, Dr. Kantarjian reported. Similarly, the 12-month complete cytogenetic response rate was higher for dasatinib (83% vs 72%), as was the major molecular response rate (46% vs 28%). “Complete cytogenetic responses and major molecular responses were obtained significantly faster with dasatinib,” Dr. Kantarjian said. The rates of transformation to the accelerate phase or blast crisis were 1.9% (five patients) for dasatinib and 3.5% (nine) for imatinib. In terms of toxicity, the rate of Grade 3/4 anemia was similar for both groups—10% for dasatinib vs 7% for imatinib—as was neutropenia—21% vs 20%, respectively. But the rate of thrombocytopenia was more common for dasatinib, at 19% vs 10%; there were no Grade 3/4 pleural effusions. Comfort, Cost Dr. Kantarjian was asked in an interview for this article what data clinical oncologists will want to see before considering dasatinib over imatinib for first-line treatment, once it is approved. He said CML experts and community oncologists have differing opinions about the potential use of these drugs in front line. “The question of their use becomes very much dependent on the comfort zone of the physician and patient about long-term versus short-term follow-up, differential toxicities, and the differential in cost.” He noted that a year’s treatment with imatinib (Gleevec) today costs $40,000 to $50,000, and dasatinib and erlotinib are $65,000 to $70,000—not all that different. “But five years down the road Gleevec will become generic and the price could go under $20,000 a year,” he said. “So the question is: how much more money do you pay for what kind of difference in the long term?” Short Follow-up Sonali Smith, MD, co-moderator of a news conference where Dr. Kantarjian’s study was discussed, said that the short follow-up period is one caveat with this report, although a cytogenetic response is still a very good surrogate marker for how patients will do in the future. “Another issue is that we don’t have long-term survival, and since these patients are living for many years we won’t have that data for quite some time,” she said.Asked what data clinical oncologists will want to see before considering whether to use dasatinib, when approved, instead of imatinib for first-line treatment, HAGOP M. KANTARJIAN, MD, said that CML experts and community oncologists have differing opinions about the potential use of these drugs in that setting: “The question of their use becomes very much dependent on the comfort zone of the physician and patient about long-term versus short-term follow-up, differential toxicities, and the differential in cost.” Although now dasatinib is only a little more expensive than imatinib, “five years down the road Gleevec will become generic and the price could be less than $20,000 a year. So the question is: how much more money do you pay for what kind of difference in the long term?”Dr. Smith also noted that other second-generation tyrosine kinase inhibitors have also been tested in this setting against imatinib for patients with newly diagnosed but previously untreated CML. At the present time, she said, the two major challenges in treating CML are primary resistance to imatinib, and secondary resistance or intolerance to imatinib. “That makes this study data profound, in that it gives our patients another option for front-line management, and continues to further our efforts to develop personalized treatments for these patients,” Dr. Smith said. The other co-moderator, Lynn M. Schuchter, MD, Professor of Medicine and Chief of Hematology/Oncology at the University of Pennsylvania, added in explaining why the study was included in the news conference, that even though it may seem too soon to emphasize the data in that highlighted way for a study with such a short follow-up, it is “an amazing proof of principal—and this pathway also appears to be relevant in may other cancers. So that is why we thought it important to highlight this study.”
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This chapter contains sections titled: Introduction Discussion Clinical Findings and Summary References
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Treatment with imatinib has demonstrated high response rates and improved prognosis in chronic myelogenous leukemia. However, while the short-term response to imatinib is high, there are some concerns that the long-term response is substantially lower. Durable response with imatinib is difficult to achieve in patients with resistant disease. The use of higher doses has also been associated with increased toxicity and intolerance. Dasatinib is a new SRC–ABL-kinase inhibitor that has been developed for treating chronic myelogenous leukemia patients, across all phases of disease, who are resistant or intolerant to imatinib. This article details the existing evidence on the clinical efficacy, safety and value for money of dasatinib in the treatment of imatinib-resistant and -intolerant patients with chronic myelogenous leukemia. Dasatinib is associated with higher levels of response compared with high-dose imatinib. In addition, higher levels of response are associated with improved health outcomes in terms of both quality- and quantity-of-life years.
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To retrospectively analyze the efficacy of interferon plus imatinib (IM) in patients with chronic-phase chronic myelogenous leukemia(CML-CP)and ABL kinase domain mutations. The mutation rates of ABL kinase region in patients with Sokal score low, medium and high risk CML-CP were statistically significant (6.25%, 9.42% and 47.06%, P<0.05). The response rates of interferon plus IM versus second-generation TKI in CML-CP with non-T315I ABL kinase domain mutations were comparable (61.11% vs 65.52%, P>0.05). When CML-CP patients with ABL kinase domain mutations were resistant to TKI or not accessible to second-generation TKI, interferon plus IM can be an alternative choice.
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The article contains results of meta-analysis of experience in use of second-generation tyrosine kinase inhibitors – dasatinib. The results of clinical trials dasatinib therapy in chronic myelogenous leukemia imatinib-resistant or intolerant patients are presented. The dasatinib and imatinib comparative analysis in first-line therapy in newly diagnosed chronic myelogenous leukemia patients are demonstrated. The range and frequency of dasatinib therapy adverse events are analyzed. Toxicities management recommendations are listed. Perspectives of dasatinib therapy cessation in patients with long lasting deep molecular responses – treatment free chronic myelogenous leukemia remissions are descripted. Also, there is an information about dasatinib usage in treatment of Philadelphia-positive acute lymphoblastic leukemia.
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diarrhea and hematochezia.The patient had a history of chronic myelogenous leukemia (CML), depression, high blood pressure, and obstructive sleep apnea.He was receiving dasatinib for the CML for two and a half years, following a previous imatinib therapy that failed due to drug resistance.Hematological remission had been achieved with dasatinib 2 months prior to the gastroenterological consultation.A control colonoscopy was performed and showed colonic loss of the normal submucosal vascular pattern with multiple areas characterized by edema, erythematous and papular lesions associated with erosions, small ulcers, and exudation (Fig. 1).This pattern was diffuse throughout the colon but more severe in the descending and sigmoid segments and rectum.The histopathological examination allowed the identification of mild irregular and branched crypts, diffuse lamina propria hemorrhage, and presence of eosinophils, neutrophils, and some eosinophilic crypt abscesses (Fig. 2).Apoptotic bodies and intraepithelial lymphocytes were absent.Cytomegalovirus infection was excluded with sample immunochemistry staining and Clostridium difficile infection was also excluded due to absence of the pathogenic toxin in a stool analysis.These endoscopic and pathological features are consistent with the diagnosis of dasatinib-induced colitis (DIC) [1,2].
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Dasatinib, a thiazole carboxamide derivative, is a second-generation tyrosine kinase inhibitor (TKI), similar in structure to imatinib, that is used for the treatment of chronic myelogenous leukemia (CML). We report a case of extensive dasatinib-induced leukotrichia in a patient with refractory CML.
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