Dasatinib versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia
About: This article is published in Yearbook of Oncology.The article was published on 2010-01-01. It has received 850 citations till now. The article focuses on the topics: Dasatinib & Imatinib.
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University of Bologna1, University of Utah2, University of Jena3, Imperial College London4, University of Barcelona5, Royal Liverpool and Broadgreen University Hospital NHS Trust6, University of Texas MD Anderson Cancer Center7, University of Poitiers8, Norwegian University of Science and Technology9, University of Adelaide10, Catholic University of Korea11, University of Chicago12, University of Toronto13, University of Bordeaux14, Masaryk University15, Heidelberg University16, Leipzig University17, University of Naples Federico II18, Fred Hutchinson Cancer Research Center19, University of Turin20, Wayne State University21, Cornell University22, Uppsala University23
TL;DR: Optimal responders to chronic myeloid leukemia treatment should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.
1,679 citations
Cites background from "Dasatinib versus Imatinib in Newly ..."
...Several studies of imatinib firstline have been updated or newly reported (15-39)....
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...It is recommended that in practice outside of clinical trials, the firstline treatment of CP CML can be any of the 3 TKIs that have been approved for this indication and are available nearly worldwide, namely imatinib (400mg once daily), nilotinib (300mg twice daily), and dasatinib (100 mg once daily)....
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...The use of TKI may require a change of the boundaries between CP, AP, and BP and modify to some extent the classic subdivision of CML in 3 phases, but the data are not yet sufficient for a revision....
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...For several years, dasatinib and nilotinib have been approved for second-line treatment of CML patients intolerant of or in whom imatinib treatment failed, based on reported CCyR rates of 40% to 60%.5,42 Two major companysponsored, phase 2, single-arm studies have been updated, reporting anMMR rate of 28% after 2 years (nilotinib)43,44 and 42% after 5 years (dasatinib)45,46; stability of the CCyR, once achieved; and PFS of 57% at 4 years with nilotinib44 and of 56% at 5 yearswith dasatinib.46 However, in both studies the proportion of patients who were still taking core treatment at 4 to 5 years was only 30% and 31%, respectively....
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...Currently, we recommend that a patient with CMLwho is responding optimally to treatment continues indefinitely at the standard recommended dose....
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TL;DR: The MEK1(C121S) mutation was shown to increase kinase activity and confer robust resistance to both RAF and MEK inhibition in vitro, and the use of emerging technologies in a manner that may accelerate personalized cancer medicine is illustrated.
Abstract: A detailed understanding of the mechanisms by which tumors acquire resistance to targeted anticancer agents should speed the development of treatment strategies with lasting clinical efficacy. RAF inhibition in BRAF-mutant melanoma exemplifies the promise and challenge of many targeted drugs; although response rates are high, resistance invariably develops. Here, we articulate overarching principles of resistance to kinase inhibitors, as well as a translational approach to characterize resistance in the clinical setting through tumor mutation profiling. As a proof of principle, we performed targeted, massively parallel sequencing of 138 cancer genes in a tumor obtained from a patient with melanoma who developed resistance to PLX4032 after an initial dramatic response. The resulting profile identified an activating mutation at codon 121 in the downstream kinase MEK1 that was absent in the corresponding pretreatment tumor. The MEK1 C121S mutation was shown to increase kinase activity and confer robust resistance to both RAF and MEK inhibition in vitro. Thus, MEK1 C121S or functionally similar mutations are predicted to confer resistance to combined MEK/RAF inhibition. These results provide an instructive framework for assessing mechanisms of acquired resistance to kinase inhibition and illustrate the use of emerging technologies in a manner that may accelerate personalized cancer medicine. J Clin Oncol 29:3085-3096. © 2011 by American Society of Clinical Oncology
936 citations
University of Jena1, University of Chicago2, Fred Hutchinson Cancer Research Center3, University of South Australia4, University of Adelaide5, University of Bologna6, University of Utah7, University of Barcelona8, Novartis9, University of Texas MD Anderson Cancer Center10, Newcastle University11, Oregon Health & Science University12
TL;DR: Almost 11 years of follow-up showed that the efficacy of Imatinib persisted over time and that long‐term administration of imatinib was not associated with unacceptable cumulative or late toxic effects.
Abstract: BackgroundImatinib, a selective BCR-ABL1 kinase inhibitor, improved the prognosis for patients with chronic myeloid leukemia (CML). We conducted efficacy and safety analyses on the basis of more than 10 years of follow-up in patients with CML who were treated with imatinib as initial therapy. MethodsIn this open-label, multicenter trial with crossover design, we randomly assigned patients with newly diagnosed CML in the chronic phase to receive either imatinib or interferon alfa plus cytarabine. Long-term analyses included overall survival, response to treatment, and serious adverse events. ResultsThe median follow-up was 10.9 years. Given the high rate of crossover among patients who had been randomly assigned to receive interferon alfa plus cytarabine (65.6%) and the short duration of therapy before crossover in these patients (median, 0.8 years), the current analyses focused on patients who had been randomly assigned to receive imatinib. Among the patients in the imatinib group, the estimated overall s...
823 citations
TL;DR: Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations.
Abstract: A b s t r ac t Background Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph- positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly re- sistant to tyrosine kinase inhibitors. Methods In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hema- tologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140). Results Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hema- tologic response and 62% had a major cytogenetic response. Responses among pa- tients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response. Conclusions Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuti- cals and others; ClinicalTrials.gov number, NCT00660920.)
667 citations
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TL;DR: Examination of cellular data with patient experience improves confidence that concomitant treatment of certain lung, head and neck, or colorectal cancers with cetuximab and an anti-ERBB2 drug may prevent or delay the development of drug resistance.
Abstract: Cetuximab, an antibody directed against the epidermal growth factor receptor, is an effective clinical therapy for patients with colorectal, head and neck, and non–small cell lung cancer, particularly for those with KRAS and BRAF wild-type cancers. Treatment in all patients is limited eventually by the development of acquired resistance, but little is known about the underlying mechanism. Here, we show that activation of ERBB2 signaling in cell lines, either through ERBB2 amplification or through heregulin up-regulation, leads to persistent extracellular signal–regulated kinase 1/2 signaling and consequently to cetuximab resistance. Inhibition of ERBB2 or disruption of ERBB2/ERBB3 heterodimerization restores cetuximab sensitivity in vitro and in vivo. A subset of colorectal cancer patients who exhibit either de novo or acquired resistance to cetuximab-based therapy has ERBB2 amplification or high levels of circulating heregulin. Collectively, these findings identify two distinct resistance mechanisms, both of which promote aberrant ERBB2 signaling, that mediate cetuximab resistance. Moreover, these results suggest that ERBB2 inhibitors, in combination with cetuximab, represent a rational therapeutic strategy that should be assessed in patients with cetuximab-resistant cancers.
574 citations
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TL;DR: Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long- term outcomes among patients with newly diagnosed chronic-phase CML.
Abstract: Background Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid leukemia (CML) in the chronic phase, after failure of imatinib treatment. We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML. Methods In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). The primary end point was complete cytogenetic response by 12 months, confirmed on two consecutive assessments at least 28 days apart. Secondary end points, including major molecular response, were tested at a significance level of 0.0001 to adjust for multiple comparisons. Results After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with dasatinib than with imatinib (77% vs. 66%, P = 0.007), as was the rate of complete cytogenetic response observed on at least one assessment (83% vs. 72%, P = 0.001). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P<0.0001), and responses were achieved in a shorter time with dasatinib (P<0.0001). Progression to the accelerated or blastic phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%). The safety profiles of the two treatments were similar. Conclusions Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247.)
1,386 citations