Nilotinib in patients with imatinib-resistant or -intolerant chronic myelogenous leukemia in chronic phase (CML-CP): Updated phase II results

Kantarjian, Hagop; Giles, Francis J.; Hochhaus, Andreas; Bhalla, K. N.; Ossenkoppele, G. J.; Gattermann, Norbert; Haque, Ariful; Gallagher, Neil J.; Castagnetti, Fausto; Coutre, Philipp le

doi:10.1200/jco.2008.26.15_suppl.7010

Cited by 19 publications

(18 citation statements)

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“…44,45,64,87 However, their safety profiles differ substantially (Tables 3 and 4). The most common nonhematologic grade 3/4 adverse events for patients with CML-CP treated with nilotinib include lipase elevation (16%), bilirubin elevation (7%) and hyperglycemia (12%).…”

Section: C-kit Inhibition: Dermatologic Toxicity Myelosuppression Anmentioning

confidence: 99%

“…16,43 Specifically, CML-CP patients displayed grade 3/4 neutropenia and thrombocytopenia at respective rates of 50 and 49% with dasatinib therapy, and 30 and 28% with nilotinib therapy. 44,45 Overall, rates of myelosuppression are higher in CML-AP patients with both agents. However, rates of grade 3/4 anemia, neutropenia and thrombocytopenia were still higher in CML-AP patients receiving dasatinib: 70, 74 and 83%, respectively, compared with CML-AP patients receiving nilotinib: 27, 41 and 36%, respectively.…”

Section: Src Kinase Inhibition: Myelosuppressionmentioning

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%

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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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Section: C-kit Inhibition: Dermatologic Toxicity Myelosuppression Anmentioning

confidence: 99%

Section: Src Kinase Inhibition: Myelosuppressionmentioning

confidence: 99%

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

2009

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“…In patients with chronic phase CML (n = 318), nilotinib 400 mg twice daily was associated with $Grade 3 neutropenia (28%) and thrombocytopenia (28%). 93 Increased $Grade 3 rates of myelosuppression (neutropenia 37%, thrombocytopenia 37%) have been reported in patients (n = 119) with advanced accelerated phase CML. 9 Dose reductions are not warranted for Grade 1/2 toxicities.…”

Section: Hematologic Toxicitymentioning

confidence: 99%

Critical appraisal of nilotinib in frontline treatment of chronic myeloid leukemia

DeRemer¹,

Katsanevas²,

Üstün³

2011

CMAR

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Abstract:The development of imatinib has revolutionized the treatment of chronic myeloid leukemia. Follow-up analysis of IRIS trial participants continues to demonstrate durable responses for imatinib at 400 mg/day. However, 10%-15% of patients with chronic myeloid leukemia will become imatinib-resistant or intolerant of adverse events. Phase II studies have shown that most of these patients will respond to second-generation tyrosine kinase inhibitors, such as nilotinib, dasatinib, and bosutinib. Both nilotinib and dasatinib have recently demonstrated clinical efficacy as frontline therapy in Phase III studies. In the ENESTnd trial, nilotinib 600-800 mg/day produced significantly higher major molecular rates and complete cytogenetic response rates in comparison with imatinib at 12 months. Recently, 18-month follow-up analysis of this trial continues to demonstrate superiority for nilotinib. It is unknown whether this will ultimately translate into improved long-term outcomes, such as event-free survival or overall survival. Nilotinib continues to be generally well tolerated and tends to produce less Grade 3/4 toxicity in frontline therapy when compared with its use following imatinib failure. With three tyrosine kinase inhibitors for potential frontline therapy and an active drug discovery pipeline, treatment for chronic myeloid leukemia is still subject to change with time as clinical algorithms continue to evolve.

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“…Results from Phase II clinical trials with nilotinib are summarized in Table 2. [11][12][13] Nilotinib is well tolerated, and common ad-verse events included grade 3-4 myelosuppression, elevated bilirubin and lipase levels.…”

Section: Nilotinibmentioning

confidence: 99%

Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond

Melo

Chuah²

2008

Hematology

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The emergence of resistance to imatinib has become a significant problem despite the remarkable clinical results achieved with this tyrosine kinase inhibitor in the treatment of chronic myeloid leukaemia. The most common cause of imatinib resistance is the selection of leukemic clones with point mutations in the Abl kinase domain. These mutations lead to amino acid substitutions and prevent the appropriate binding of imatinib. Genomic amplification of BCR-ABL, modulation of drug efflux or influx transporters, and Bcr-Ablindependent mechanisms also play important roles in the development of resistance. Persistent disease is another therapeutic challenge and may in part, be due to the inability of imatinib to eradicate primitive stem cell progenitors. A multitude of novel agents have been developed and have shown in vitro and in vivo efficacy in overcoming imatinib resistance. In this review, we will discuss the current status of the ATPcompetitive and non-ATP-competitive Bcr-Abl tyrosine kinase inhibitors. We will also describe inhibitors acting on targets found in signaling pathways downstream of Bcr-Abl, such as the Ras-Rafmitogen-activated protein kinase and phosphatidylinositol-3 kinase-Akt-mammalian target of rapamycin pathways, and targets without established links with Bcr-Abl.

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Nilotinib in patients with imatinib-resistant or -intolerant chronic myelogenous leukemia in chronic phase (CML-CP): Updated phase II results

Cited by 19 publications

References 0 publications

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

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

Critical appraisal of nilotinib in frontline treatment of chronic myeloid leukemia

Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond

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