Rosti, G. et al Nilotinib for the frontline treatment of Ph+ chronic myeloid leukaemia. Blood 114, 4933-4938

Department of Hematology-Oncology, L. and A. Seràgnoli, University of Bologna, S. Orsola-Malpighi Hospital, 40138 Bologna, Italy.
Blood (Impact Factor: 10.45). 10/2009; 114(24):4933-8. DOI: 10.1182/blood-2009-07-232595
Source: PubMed


Nilotinib has a higher binding affinity and selectivity for BCR-ABL with respect to imatinib and is an effective treatment of chronic myeloid leukemia (CML) after imatinib failure. In a phase 2 study, 73 early chronic-phase, untreated, Ph(+) CML patients, received nilotinib at a dose of 400 mg twice daily. The primary endpoint was the complete cytogenetic response (CCgR) rate at 1 year. With a median follow-up of 15 months, the CCgR rate at 1 year was 96%, and the major molecular response rate 85%. Responses were rapid, with 78% CCgR and 52% major molecular response at 3 months. During the first year, the treatment was interrupted at least once in 38 patients (52%). The mean daily dose ranged between 600 and 800 mg in 74% of patients, 400 and 599 mg in 18% of patients, and was less than 400 mg in 8% of patients. Dose interruptions were mainly due to nonhematologic and biochemical side effects. Myelosuppression was irrelevant. One patient progressed to blastic crisis after 6 months; one went off-treatment for lipase increase grade 4 (no pancreatitis). Nilotinib is safe and very active in early chronic-phase CML. These data support a role for nilotinib for the frontline treatment of CML. This study was registered at as NCT00481052.

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    • "Progression rates at the end of 24 months to accelerated phase or blast crisis in patients was significantly lower in both the nilotinib arms as compared to imatinib arm. GIMEMA and MDACC studies also confirmed that patients on nilotinib had higher and faster achievement of MMR and complete cytogenetic response (CCyR).[121516] "
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    ABSTRACT: Monitoring of CML patients while on therapy is vitally important and ENL has come up with specific guidelines for the same. Since we are currently talking about operational cure, this review shall focus on evaluating the emerging data to optimize response. This requires attention to all outstanding controversial issues. Only careful, accurate and regular monitoring with specific attention to grey areas will help us select first line therapy, decide when to discontinue TKIs and also move to second line TKIs in a timely manner.
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    • "Like Imatinib, Nilotinib is a TKI with better tolerability profile [94, 167], suggesting a better compliance, especially in frail patients such as those with steroid-refractory cGVHD. In vitro models suggest that the PDGF-R inhibitory effect of Nilotinib is at least not inferior than Imatinib and that serum levels, obtained with an oral dose of 400 mg/die of Imatinib, can achieve an inhibitory effect on fibroblasts activity comparable to that obtained with 800 mg/die of Nilotinib [138]. "
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    ABSTRACT: Chronic Graft Versus Host Disease (cGVHD) is a major complication of allogeneic stem-cell transplantation (SCT). In many inflammatory fibrotic diseases, such as Systemic Scleroderma (SSc) and cGVHD with fibrotic features, an abnormal activation of transforming growth factor (TGFβ) and platelet-derived growth factor receptor (PDGF-R) pathways have been observed. Tyrosin Kinase Inhibitors (TKIs), which are currently used for treatment of patients with Chronic Myeloid Leukemia (CML), share potent antifibrotic and antiinflammatory properties, being powerful dual inhibitors of both PDGF-R and TGFβ pathways. Moreover accumulating in vitro data confirm that TKIs, interacting with the TCR and other signalling molecules, carry potent immunomodulatory effects, being involved in both T-cell and B-cell response. Translation to the clinical setting revealed that treatment with Imatinib can achieve encouraging responses in patients with autoimmune diseases and steroid-refractory cGVHD, showing a favourable toxicity profile. While the exact mechanisms leading to such efficacy are still under investigation, use of TKIs in the context of clinical trials should be promoted, aiming to evaluate the biological changes induced in vivo by TKIs and to assess the long term outcome of these patients. Second-generation TKIs, with more favourable toxicity profile are under evaluation in the same setting.
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    • "In the ENESTnd trial, grade 3-4 neutropenia was less common in the nilotinib 300 or 400 mg BID arms (12% and 10%, respectively) compared with the imatinib arm (20%), whereas grade 3-4 thrombocytopenia (10% vs 12% vs 9%) and anemia (3% vs 3% vs 5%) were similar between treatment arms [14]. In the MDACC study of nilotinib, grade 3-4 neutropenia, thrombocytopenia, and anemia occurred in 12%, 11%, and 5% of patients, respectively [15], whereas low rates (4%, 2%, and 0%) were reported in the GIMEMA study [4]. "
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    ABSTRACT: Imatinib, a tyrosine kinase inhibitor (TKI) of BCR-ABL, was the standard first-line therapy for chronic myeloid leukemia (CML) for almost 10 years. Dasatinib and nilotinib, two newer drugs with higher potency than imatinib against BCR-ABL and activity against most imatinib-resistant BCR-ABL mutations, have each shown superior efficacy compared with imatinib for first-line treatment of chronic-phase CML in randomized phase 3 trials. With 14 months follow-up time, available data suggest no obvious differences in efficacy between dasatinib and nilotinib. Compared with imatinib, dasatinib is associated with higher rates of pleural effusion and thrombocytopenia, but lower rates of edema, gastrointestinal AEs, musculoskeletal AEs, and rash. Nilotinib is associated with higher rates of dermatologic toxicity, headache, and biochemical abnormalities associated with hepatic and pancreatic toxicity compared with imatinib, but lower rates of edema, gastrointestinal AEs, muscle spasm, and neutropenia. Several studies have shown that poor adherence to imatinib detrimentally affects responses and should be considered in patients with a suboptimal response. The different dosing requirements of dasatinib (once daily with or without food) and nilotinib (twice daily with fasting) may be an additional factor in selecting frontline agents. This review compares and contrasts the three FDA approved first line TKI agents.
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