A Phase I/II study of nilotinib in Japanese patients with imatinib-resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL

Tojo, Arinobu; Usuki, Kensuke; Urabe, Akio; Maeda, Yasuhiro; Kobayashi, Yasuhito; Jinnai, Itsuro; Ohyashiki, Kazuma; Nishimura, Miki; Kawaguchi, Tatsuya; Tanaka, Hideo; Miyamura, Koichi; Miyazaki, Yasushi; Hughes, Timothy P.; Branford, Susan; Okamoto, Shinichiro; Ishikawa, Jun; Okada, Masaya; Usui, Noriko; Tanii, Hiromi; Amagasaki, Taro; Natori, H.; Naoe, Tomoki

doi:10.1007/s12185-009-0327-0

Cited by 39 publications

(39 citation statements)

References 15 publications

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“…The weighted proportion of QTc prolongation of any grade with nilotinib was 2.7% with QTc of >500 ms, seen in 0.3% of cases. Caution and periodic ECG monitoring are advised when using nilotinib 71, 73, 74, 76, 77, 79, 80. QTc prolongation was common (37%) in patients with hepatic impairment treated with bosutinib,10 but this was not seen in other smaller studies 11, 12.…”

Section: Resultsmentioning

confidence: 98%

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

Porta‐Sánchez

Gilbert

Spears

et al. 2017

JAHA

146

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: 98%

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

Porta‐Sánchez

Gilbert

Spears

et al. 2017

JAHA

146

142

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“…In one study in the relapsed setting, a partial response of 10% was found 31 . In the second study in the relapsed setting, a cr rate of 43% was achieved 45 .…”

Section: 23mentioning

confidence: 92%

“…As discussed earlier, three of the studies included both de novo and relapsed patients who had been given a tki. In five of the eighteen, a tki was given during induction for only a limited duration 23,31,32,44,71 ; ten studies gave a tki indefinitely until progression or toxicity 11,[14][15][16]45,61,72,85,86,88 ; and one study gave imatinib from 24 weeks onwards (that is, indefinitely) 13 . In addition, one study gave imatinib only as maintenance 55 .…”

Section: 22mentioning

confidence: 99%

“…Nilotinib: Three studies in a total of 70 patients examined the efficacy of nilotinib: one in de novo patients and two in relapsed patients 31,45,79 . In the de novo study, induction with nilotinib plus chemotherapy was given to 50 patients with Ph+ all.…”

Section: 23mentioning

confidence: 99%

“…A major hematologic response was reported in 17 of 46 patients (37%) and a cytogenetic response was reported in 11 of 41 patients (27%). 31,45,79 , and ponatinib 86 have been studied in patients who are resistant or intolerant to imatinib. Those agents have produced hematologic and cytogenetic responses in that group of patients.…”

Section: 23mentioning

confidence: 99%

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Evidence-Based Guidelines for the Use of Tyrosine Kinase Inhibitors in Adults with Philadelphia Chromosome–Positive or Bcr-Abl–Positive Acute Lymphoblastic Leukemia: A Canadian Consensus

Couban¹,

Savoie²,

Mourad

et al. 2014

Current Oncology

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Adult Philadelphia chromosome–positive (Ph+) or BCR-ABL–positive (BCR-ABL+) acute lymphoblastic leukemia (ALL) is an acute leukemia previously associated with a high relapse rate, short disease-free survival, and poor overall survival. In adults, allogeneic hematopoietic cell transplant in first remission remains the only proven curative strategy for transplant-eligible patients. The introduction of tyrosine kinase inhibitors (TKIS) in the treatment of patients with Ph+ or BCR-ABL+ ALL has significantly improved the depth and duration of complete remission, allowing more patients to proceed to transplantation. Although tkis are now considered a standard of care in this setting, few randomized trials have examined the optimal use of TKIS in patients with Ph+ ALL. Questions of major importance remain, including the best way to administer these medications, the choice of tki to administer, and the schedule and the duration to use. We present the results of a systematic review of the literature with consensus recommendations based on the available evidence.

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Pharmacokinetics of nilotinib in imatinib‐resistant/intolerant chronic myeloid leukemia patients on hemodialysis for chronic renal failure

Onaka¹,

Takahashi²,

Miura³

et al. 2012

American J Hematol

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To the editor: Nilotinib is a second-generation tyrosine kinase inhibitor used to treat patients with imatinib-resistant/intolerant chronic myeloid leukemia (CML). The safety and efficacy of nilotinib are well established [1]; however, very little data is available for patients with end-stage renal disease. Here, we report successful treatment of three CML patients on maintenance hemodialysis (HD) for chronic renal failure (CRF). To evaluate the pharmacokinetics of nilotinib in patients on HD, plasma nilotinib levels were determined by high-performance liquid chromatography [2]. Patient 1: In 2008, a 46-year-old woman on maintenance HD for polycystic kidney disease was diagnosed as Philadelphia-positive CML chronic-phase and initially administrated imatinib 300-mg QD. Although plasma imatinib levels reached 1,400 ng/ml and no ABL point mutations were detected, a major molecular response (MMR) was not achieved after 2 years of imatinib treatment. She was therefore switched to nilotinib 200 mg BID. The only adverse event was grade-2 muscle pain, and a MMR was achieved 6 months after switching to nilotinib. Patient 2: In 2007, a 61-year-old man on HD for CRF was diagnosed with CML chronic-phase and was started on imatinib 200-mg QD. A complete cytogenetic response was achieved in 12 months, but he was forced to stop imatinib after developing interstitial pneumonia and gastric bleeding. He was then switched to nilotinib 200-mg BID. One month later, the nilotinib treatment had to be interrupted due to QT interval prolongation, and reduction of the dose to 200-mg QD was necessary to resolve this adverse event. Nonetheless, a MMR was achieved 8 months after switching to nilotinib. Patient 3: In 2010, a 78-year-old woman on HD for diabetic nephropathy was diagnosed with CML chronic-phase and started on imatinib 400-mg QD. After 3 months, the imatinib was discontinued due to nausea and vomiting that persisted even though she received adequate supportive care. She was then switched to nilotinib 200-mg BID. The nilotinib also caused nausea initially, but it gradually disappeared, enabling the patient to continue taking the drug without a dose reduction. A MMR was achieved 3 months after switching to nilotinib. Pharmacokinetics of Nilotinib: There were no significant differences between the plasma nilotinib concentrations before and after HD in the three patients described above (P 5 1.0000, Wilcoxon signed-rank test, Table 1). This suggests that nilotinib in plasma is not cleared by HD, nor are the pharmacokinetics of nilotinib influenced by HD. Moreover, the dose-adjusted AUCs for nilotinib in patients on HD are similar to those previously observed in a Japanese Phase I/II study [3]. Our results indicate that the pharmacokinetics of nilotinib likely do not change in patients on HD for end-stage renal disease. Thus, although we reduced the dosage of nilotinib to prevent unexpected adverse events in one of these three patients, our findings indicate that, as with imatinib [4,5], the standard dose of nilotinib can be safely ...

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A Phase I/II study of nilotinib in Japanese patients with imatinib-resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL

Cited by 39 publications

References 15 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

Evidence-Based Guidelines for the Use of Tyrosine Kinase Inhibitors in Adults with Philadelphia Chromosome–Positive or Bcr-Abl–Positive Acute Lymphoblastic Leukemia: A Canadian Consensus

Pharmacokinetics of nilotinib in imatinib‐resistant/intolerant chronic myeloid leukemia patients on hemodialysis for chronic renal failure

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