Dasatinib versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia

Kantarjian, Hagop M.; Shah, Neil P.; Hochhaus, Andreas; Cortes, Jorge; Shah, Sandip; Ayala, Manuel; Moiraghi, Beatriz; Shen, Zhi-Xiang; Mayer, Jiřı́; Pasqüini, Ricardo; Nakamae, Hirohisa; Huguet, Françoise; Boqué, Concepción; Chuah, Charles; Bleickardt, Eric; Bradley-Garelik, M. Brigid; Zhu, Chao; Szatrowski, Ted P.; Shapiro, D. A.; Baccarani, Michele

doi:10.1056/nejmoa1002315

Cited by 1,414 publications

(1,358 citation statements)

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“…QTc prolongation was frequent (>5% of patients experiencing CTCAE scale grade I QTc prolongation) in patients treated with dasatinib, vandetanib, sorafenib, or sunitinib. Dasatinib is used to treat hematological malignancies and has been associated with QTc prolongation in 8% of treated patients (range, 1%–70%), but QTc >500 ms was seen only in <1% 13, 18, 20, 21, 22, 25, 32, 40, 42, 75…”

Section: Resultsmentioning

confidence: 99%

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Porta‐Sánchez

Gilbert

Spears

et al. 2017

JAHA

159

142

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BackgroundThe cardiovascular complications of cancer therapeutics are the focus of the burgeoning field of cardio‐oncology. A common challenge in this field is the impact of cancer drugs on cardiac repolarization (ie, QT prolongation) and the potential risk for the life‐threatening arrhythmia torsades de pointes. Although QT prolongation is not a perfect marker of arrhythmia risk, this has become a primary safety metric among oncologists. Cardiologists caring for patients receiving cancer treatment should become familiar with the drugs associated with QT prolongation, its incidence, and appropriate management strategies to provide meaningful consultation in this complex clinical scenario.Methods and ResultsIn this article, we performed a systematic review (using Preferred Reporting Items of Systematic Reviews and Meta‐Analyses (PRISMA) guidelines) of commonly used cancer drugs to determine the incidence of QT prolongation and clinically relevant arrhythmias. We calculated summary estimates of the incidence of all and clinically relevant QT prolongation as well as arrhythmias and sudden cardiac death. We then describe strategies to prevent, identify, and manage QT prolongation in patients receiving cancer therapy. We identified a total of 173 relevant publications. The weighted incidence of any corrected QT (QTc) prolongation in our systematic review in patients treated with conventional therapies (eg, anthracyclines) ranged from 0% to 22%, although QTc >500 ms, arrhythmias, or sudden cardiac death was extremely rare. The risk of QTc prolongation with targeted therapies (eg, small molecular tyrosine kinase inhibitors) ranged between 0% and 22.7% with severe prolongation (QTc >500 ms) reported in 0% to 5.2% of the patients. Arrhythmias and sudden cardiac death were rare.ConclusionsOur systematic review demonstrates that there is variability in the incidence of QTc prolongation of various cancer drugs; however, the clinical consequence, as defined by arrhythmias or sudden cardiac death, remains rare.

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Section: Resultsmentioning

confidence: 99%

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Porta‐Sánchez

Gilbert

Spears

et al. 2017

JAHA

159

142

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“…14 In the DASISION trial, 46% of patients treated with dasatinib 100 mg once daily achieved MMR by 12 months, whereas only 28% achieved MMR on imatinib (Po0.0001). 10 By 24 months, CMR 4.5 was achieved in 17% and 8% of patients treated with dasatinib or imatinib (P ¼ 0.002 vs imatinib). 15 Similar response to dasatinib has also been demonstrated in the phase 2 MDACC trial, with 6% of patients achieving CMR 4.5 by 18 months, 7 and in the Southwestern Oncology Group trial, with 27% of patients achieving CMR 4 at 12 months in evaluable patients (P ¼ 0.31 vs imatinib).…”

Section: Second-generation Tki's In the Front-line Setting: Molecularmentioning

confidence: 95%

“…5,6 Similarly, the Southwestern Oncology Group and MDACC trials of dasatinib in patients with newly diagnosed CML-CP demonstrated CCyR rates of 82-98% by 12 months. 7,8 The pivotal phase 3 nilotinib (ENESTnd) 9 and dasatinib (DASISION) 10 trials showed rates of CCyR of 80% and 83% for nilotinib and dasatinib, respectively, by 12 months (rates of CCyR in the phase 3 studies are likely lower than those in phase 2 studies due to the 1 application of the intention-to-treat principle and that patients with missing or non-evaluable samples were considered as nonresponders). In the ENESTnd trial, 55% of patients treated with nilotinib 300 mg twice daily achieved MMR by 12 months, whereas only 27% achieved MMR on imatinib (Po0.0001).…”

Section: Second-generation Tki's In the Front-line Setting: Molecularmentioning

confidence: 99%

Standardized definitions of molecular response in chronic myeloid leukemia

et al. 2012

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“…7 When dasatinib was tested, first-line treatment compared with imatinib, the responses were faster and superior, and the molecular response was also deeper. 19,20 The follow-up of the patients treated first line with dasatinib is still short, less than 3 years. The major side effects of dasatinib are leucopenia, thrombocytopenia, pleural effusion and pulmonary complications.…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Initial treatment for patients with chronic myeloid leukemia

Baccarani

2012

Leukemia Suppl

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The first-line treatment of chronic myeloid leukemia is based on the three currently available tyrosine kinase inhibitors (TKIs), namely imatinib, nilotinib and dasatinib. Nilotinib and dasatinib are more potent, and it is predicted that, in comparison with imatinib, they can reduce the risk of progression and increase the number of the patients who can discontinue the treatment without relapsing. Other TKIs are still being developed and may help to improve treatment options further on. Hydroxyurea has no longer a role. Allogeneic stem cell transplantation is the treatment of choice for the advanced phases, and in case of resistance to at least two TKIs.Leukemia Supplements (2012) 1, S37--S39; doi:10.1038/leusup.2012.21Keywords: chronic myeloid leukemia; BCR-ABL; Philadelphia chromosome; imatinib; nilotinib; dasatinib The initial treatment of Philadelphia-positive (Ph þ ), BCR-ABL þ chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKI), a class of small molecules that can inhibit the phosphorylative function of the proteins that are coded by the BCR-ABL fusion gene on chromosome 22q. 1--4 These proteins are located in the cytoplasm, where they activate a number of downstream signals of proliferation and survival, resulting in the transformation of normal hematopoietic stem cells to leukemic cells. The Ph þ leukemic stem and progenitor cells on one hand proliferate and mature, expanding the myeloid tissue in the bone marrow and in the spleen, and causing leukocytosis, whereas on the other hand, they are genetically unstable and develop a number of secondary genomic lesions, leading to the progression from chronic to accelerated and blastic phase. 1--4 Therefore, the first goal of treatment is to prevent progression, and the second one is to eliminate the leukemic clone. Achieving the first goal may be sufficient to ensure a normal survival. Achieving the second goal may be necessary to cure the disease and discontinue the treatment safely. Both goals can be achieved with TKIs, although achieving the second goal may require other agents. TYROSINE KINASE INHIBITORSThe TKIs are a class of small molecules that have been designed with the purpose of inhibiting the phosphorylative activity of the TK. Several TKIs are able to inhibit the BCR-ABL proteins, although none is truly specific, because they inhibit other TKs as well. The TKIs that have been selected and registered so far for their activity on BCR-ABL, then for the treatment of CML, both first-line and second-line treatment, are as follows:Imatinib (Glivec or Gleevec, Novartis Pharma) 2,5 Nilotinib (Tasigna, Novartis Pharma) 2,6 Dasatinib (Sprycel, Bristol-Myers Squibb) 2,7 Another compound (Bosutinib, Pfizer) has already been tested in first-line and second-line treatment. 8 A fifth compound (Ponatinib, Ariad) has been tested in second-line and third-line treatment. 9 Imatinib, first of the class, was introduced more than 10 years ago. With imatinib, the complete hematologic response rate is close to 100%, the complete cytogenetic respon...

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Dasatinib versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia

Cited by 1,414 publications

References 29 publications

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

Standardized definitions of molecular response in chronic myeloid leukemia

Initial treatment for patients with chronic myeloid leukemia

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