Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia

O’Brien, Stephen G.; Guilhot, Joëlle; Larson, Richard A.; Gathmann, Insa; Baccarani, Michele; Cervantes, Francisco; Cornelissen, Jan J.; Fischer, Thomas; Hochhaus, Andreas; Hughes, Timothy P.; Lechner, Klaus; Nielsen, Johan Lanng; Rousselot, Philippe; Reiffers, Josy; Saglio, Giuseppe; Shepherd, John; Simonsson, Bengt; Gratwohl, Aloïs; Goldman, John M.; Kantarjian, Hagop M.; Taylor, Kerry; Verhoef, Gregor; Bolton, Ann E.; Capdeville, Renaud; Druker, Brian J.

doi:10.1056/nejmoa022457

Cited by 3,196 publications

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“…The resulting p210 Bcr-Abl protein is a constitutively active tyrosine kinase, phosphorylating a variety of substrates that activate multiple signaling pathways, including among others phosphatidylinositol 3-kinase (PI3K), Janus kinase (JAK)/signal transducers and activator of transcription (STAT) and the Ras/MAP kinase/ERK kinase (MEK)/ extracellular signal-regulated protein kinase (Erk)1/2 pathways, thus conferring growth factor-independent proliferation and survival of myeloid progenitor cells (Deininger et al, 2000;Steelman et al, 2004). Imatinib mesylate (Gleevec, STI571) has emerged as the lead compound to treat the chronic phase of CML (O'Brien et al, 2003). It is well established that the drug targets the ATP-binding site of Bcr-Abl, thereby inhibiting its tyrosine kinase activity (Roskoski, 2003).…”

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confidence: 99%

Apoptosis and erythroid differentiation triggered by Bcr-Abl inhibitors in CML cell lines are fully distinguishable processes that exhibit different sensitivity to caspase inhibition

et al. 2006

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Section: Introductionmentioning

confidence: 99%

Apoptosis and erythroid differentiation triggered by Bcr-Abl inhibitors in CML cell lines are fully distinguishable processes that exhibit different sensitivity to caspase inhibition

et al. 2006

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“…Nilotinib (Tasigna, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) is a second‐generation BCR‐ABL1 tyrosine kinase inhibitor approved for the treatment of patients with newly diagnosed chronic myeloid leukaemia in chronic phase (CML‐CP) and for those with resistance to or intolerance of imatinib (Gleevec, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) (Novartis Pharmaceuticals Corporation, 2016), the first approved BCR‐ABL1 tyrosine kinase inhibitor (O'Brien et al , 2003). The recommended dose of nilotinib for patients with newly diagnosed CML‐CP is 300 mg twice daily (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022068s024lbl.pdf).…”

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Nilotinib dose‐optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd

et al. 2017

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SummaryThe Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose‐optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re‐escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2–75·1%) achieved major molecular response (BCR‐ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re‐escalation). The safety profile of nilotinib was consistent with prior studies. The most common non‐haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).

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“…1,2 In newly diagnosed patients with chronic-phase CML, imatinib produced complete cytogenetic responses in 60 -75% of patients; the estimated 2-year survival rate was 97%. 7 Bone marrow fibrosis occurring prior to treatment and serially has been shown to be associated independently with adverse prognosis. 8,9 Its resolution with imatinib therapy may improve the prognosis of CML patients, in parallel with other positive effects (e.g., the suppression of Ph-positive cells).…”

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Imatinib mesylate therapy reduces bone marrow fibrosis in patients with chronic myelogenous leukemia

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Talpaz

et al. 2004

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BACKGROUNDReticulin‐stained bone marrow fibrosis is associated with a poor prognosis in patients with chronic myelogenous leukemia (CML). Resolution of fibrosis with therapy may improve patient outcome.METHODSThe effect of imatinib therapy on bone marrow fibrosis was evaluated in 40 patients with chronic‐phase CML who were treated after interferon‐α failure.RESULTSThirty‐one patients (78%) had severe (Grade 3 or 4) reticulin fibrosis prior to therapy. After imatinib therapy was administered for 3 to > 24 months, fibrosis was reduced by at least 2 grades in 19 of the 31 patients (61%) and by at least 1 grade in 34 patients (85%). There was no correlation noted between reduction of fibrosis and cytogenetic response. However, a reduction in fibrosis was found to correlate with a reduction in bone marrow megakaryocytosis (P = 0.002).CONCLUSIONSTreatment with imatinib mesylate appears to reduce CML‐associated bone marrow fibrosis in most patients who are treated during the chronic phase of disease. This effect may be independent of the degree of suppression of Philadelphia chromosome‐positive cells, and may improve prognosis in patients with CML. Cancer 2004. © 2004 American Cancer Society.

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Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia

Cited by 3,196 publications

References 33 publications

Apoptosis and erythroid differentiation triggered by Bcr-Abl inhibitors in CML cell lines are fully distinguishable processes that exhibit different sensitivity to caspase inhibition

Apoptosis and erythroid differentiation triggered by Bcr-Abl inhibitors in CML cell lines are fully distinguishable processes that exhibit different sensitivity to caspase inhibition

Nilotinib dose‐optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd

Imatinib mesylate therapy reduces bone marrow fibrosis in patients with chronic myelogenous leukemia

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