Efficacy of nilotinib (AMN107) in patients (Pts) with newly diagnosed, previously untreated philadelphia chromosome (Ph)- positive chronic myelogenous leukemia in early chronic phase (CML-CP)

Cortés, Javier; O’Brien, Susan; Ferrajoli, A.; Borthakur, G.; Burger, Jacobus W. A.; Wierda, WG; Garcia-Manero, G.; Letvak, Laurie; Kantarjian, Hagop

doi:10.1200/jco.2008.26.15_suppl.7016

Cited by 35 publications

(37 citation statements)

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“…Both CCyRs and MMRs were maintained for 12 months. 78 In another study, the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) CML Working Party reported a 97% CCyR rate on nilotinib by 6 months and an MMR rate of 75%. 79 Dasatinib also has been evaluated as frontline therapy in a phase 2 study that is being conducted at MDACC.…”

Section: Dasatinibmentioning

confidence: 99%

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Kantarjian

Cortés

Rosée

et al. 2010

Cancer

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Identification of BCR‐ABL as the defining leukemogenic event in chronic myelogenous leukemia (CML) revolutionized the treatment of the disease. Imatinib, a potent BCR‐ABL inhibitor, is the standard of care for the first‐line treatment of patients with chronic‐phase CML because of its high long‐term response rates and favorable tolerability profile compared with previous standard therapies. However, resistance to imatinib develops in 2% to 4% of patients annually. For patients with acquired cytogenetic resistance to standard‐dose imatinib (400 mg daily), imatinib dose escalation (600‐800 mg daily) is an excellent first option for managing patients and achieving cytogenetic responses. However, for patients with primary resistance to imatinib, hematologic disease recurrence, or emergent BCR‐ABL kinase domain mutations, imatinib dose escalation may not be sufficient to control the disease. For these patients, the potent second‐generation tyrosine kinase inhibitors dasatinib and nilotinib are available. Both agents provide effective therapeutic options for patients with imatinib resistance or intolerance. For the current overview, the authors reviewed the data supporting the use of both dasatinib and nilotinib in imatinib‐resistant or imatinib‐intolerant patients, and they have highlighted the future of CML therapy. Overall, the article is intended to offer physicians a comprehensive review of the current literature and to provide data supporting various treatment options for patients with CML throughout the course of imatinib therapy and beyond. Cancer 2010. © 2010 American Cancer Society.

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Section: Dasatinibmentioning

confidence: 99%

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Kantarjian

Cortés

Rosée

et al. 2010

Cancer

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“…20 Similar to imatinib, nilotinib inhibits c-KIT (IC 50 ¼ 90 nM) 18,19 and PDGFR (IC 50 ¼ 72 nM). 13,19 Nilotinib also inhibits the ABL-related kinase ARG, DDR1 kinase, the oxidoreductase NQO2, 20,21 and has some activity against the ephrin receptor EPHB4, but displays no activity against the Src family of kinases. 13,22 Similar to nilotinib, dasatinib also inhibits most imatinib-resistant BCR-ABL forms, except T315I, in vitro.…”

Section: Differential Kinase Inhibition Profiles Of Tkis In CML Treatmentioning

confidence: 99%

“…Cross-intolerance of dasatinib treatment is most typically a result of neutropenia and/or thrombocytopenia. [95][96][97][98][99][100] Patients who switched to dasatinib because of imatinib intolerance subsequently discontinued dasatinib due to intolerance at similar levels to nilotinib.…”

Section: C-kit Inhibition: Dermatologic Toxicity Myelosuppression Anmentioning

confidence: 99%

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

2009

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Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia (CML), offering patients several targeted therapeutic options that provide the possibility of sustained remissions and prolonged survival. With the availability of imatinib, nilotinib and dasatinib, physicians must weigh the efficacy and safety profile of each agent when choosing the best therapeutic option for individual patients. Each agent targets tyrosine kinases within the cell uniquely to cause the desired antiproliferative effect. In addition to inhibiting the BCR-ABL kinase, imatinib and nilotinib target the same array of other tyrosine kinases, including c-KIT and plateletderived growth factor receptor (PDGFR), albeit with differing potencies. While targeting BCR-ABL with the highest potency among approved agents in CML, dasatinib also targets a broad array of off-target kinases, including SRC family members, PDGFR and EPHB4. The differences in kinase inhibition profiles among these agents in vitro probably account for the differing clinical safety profiles of these agents. This paper reviews the various kinases inhibited by imatinib, nilotinib and dasatinib, and describes the potential impact of kinase inhibition on the efficacy and safety of each agent.

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“…Preliminary results show that CCyRs were achieved in 94% of patients at 6 months, and in all evaluable patients (100%) at 12 months. Nilotinib 800 mg/day elicited similar activity [86]; CCyR rates at 6 and 12 months were 100%. Both drugs elicited significantly (P \ 0.001) deeper responses at these time points than imatinib (historical controls) [85,86].…”

Section: Use Of Second-line Tkis In the First-linementioning

confidence: 81%

“…Nilotinib 800 mg/day elicited similar activity [86]; CCyR rates at 6 and 12 months were 100%. Both drugs elicited significantly (P \ 0.001) deeper responses at these time points than imatinib (historical controls) [85,86]. Marked superiority over imatinib in this setting can also be demonstrated by comparing the response rates discussed above with those obtained for first-line imatinib in the IRIS study; after 18 months of follow-up in this trial the CCyR rate was 74% [9].…”

Section: Use Of Second-line Tkis In the First-linementioning

confidence: 81%

Extending the duration of response in chronic myelogenous leukemia: targeted therapy with sequential tyrosine kinase inhibitors

Martin

DiPersio

2009

Oncol Rev

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Tyrosine kinase inhibitors (TKIs) are the mainstay for treatment of chronic myelogenous leukemia (CML). Imatinib was the first TKI approved for use in CML, but resistance to this therapy has emerged as a significant issue, and second-line options are often necessary. Increased-dose imatinib may elicit responses in some patients, but clinical evidence suggests only a minority experience sustained benefit. The second-generation TKIs, dasatinib and nilotinib, have demonstrated efficacy in patients resistant or intolerant to imatinib. Changes in therapy, with the aim of inducing durable response, should occur promptly after imatinib failure is identified as all agents are more effective in chronic phase disease than in later stages. Selection of second-line agents should be driven by efficacy and safety: dasatinib may be more effective in patients with P-loop or F359C mutations; nilotinib may be more effective in those with F317L mutations.

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Efficacy of nilotinib (AMN107) in patients (Pts) with newly diagnosed, previously untreated philadelphia chromosome (Ph)- positive chronic myelogenous leukemia in early chronic phase (CML-CP)

Cited by 35 publications

References 0 publications

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

Extending the duration of response in chronic myelogenous leukemia: targeted therapy with sequential tyrosine kinase inhibitors

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