Tyrosine Kinase Inhibitor Screen Identifies the Multikinase Inhibitor, Foretinib, As a Sensitisor of Treatment-resistant B-Precursor ALL to Core Chemotherapeutic Agents
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Viability assay
Bosutinib
Imatinib Mesylate
Dasatinib is a second-generation tyrosine kinase inhibitor that is approved for the treatment of imatinib-resistant or imatinib-intolerant chronic myeloid leukemia. It has a 325 times stronger in vitro activity against to native BCR-ABL when comparing with imatinib. Little is known about the effects of dasatinib on renal function. A literature review revealed only one case with imatinib-resistant chronic myeloid leukemia that developed renal failure after being placed on dasatinib therapy. Here we report a patient with imatinib-resistant chronic myeloid leukemia who developed gastroenteritis and acute renal failure after a short time from the initiation of dasatinib therapy. After dasatinib interruption, these side effects resolved completely in days. In summary, dasatinib is a potent drug in the treatment of chronic myeloid leukemia, but close clinical monitoring and the timely interruption of the therapy in patients who developed acute renal failure are warranted.
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Tyrosine kinase inhibitors (TKIs) targeting BCR/ABL such as imatinib, nilotinib, dasatinib, bosutinib and ponatinib have revolutionised the management of patients with chronic myeloid leukaemia (CML) [1]. Pleural effusions and pulmonary arterial hypertension (PAH) have been reported in patients treated with these agents [2–4]. These side-effects are more frequently observed with dasatinib use, with partial or complete reversibility after drug withdrawal [3]. Bosutinib is a second-generation TKI prescribed in case of intolerance or resistance to imatinib, nilotinib or dasatinib. In the present report, we describe two cases of worsening of dasatinib-induced PAH and two cases of severe pleural effusions, suggesting overlapping pulmonary toxicity of bosutinib and dasatinib. Pulmonary complications of bosutinib therapy and potential cross-intolerance with dasatinib We acknowledge the French pulmonary hypertension pharmacovigilance network, VIGIAPATH, supported by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM).
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The development of imatinib for the treatment of chronic myeloid leukemia (CML) has proven to be an example of medical success in the era of targeted therapy.However, imatinib resistance or intolerance occurs in a substantial number of patients.Additionally, patients who have progressed beyond the chronic phase of CML do relatively poorly with imatinib therapy.Mechanisms of imatinib resistance include BCR-ABL point mutations resulting in decreased imatinib binding, as well as mutation-independent causes of resistance such as SRC family kinase dysregulation, BCR-ABL gene amplifi cation, drug infl ux/effl ux mechanisms and other poorly understood processes.The options for therapy in these patients include stem cell transplantation, imatinib dose escalation as well as the use of second-generation tyrosine kinase inhibitors.Dasatinib is a second-generation multi-kinase inhibitor with several theoretical and mechanistic advantages over imatinib.Moreover, several studies have evaluated dasatinib in patients who have progressed on imatinib therapy with encouraging results.Other novel agents such as mTOR inhibitors, bosutinib and INNO 406 have also shown promise in this setting.Although treatment options have increased, the choice of second-line therapy in patients with CML is infl uenced by concerns surrounding the duration of response as well as toxicity.Consequently, there is no agreed upon optimal second-line agent.This paper reviews the current data and attempts to address these issues.
Bosutinib
Imatinib Mesylate
Chronic myelogenous leukemia
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Chronic myelogenous leukemia
Imatinib Mesylate
Philadelphia chromosome
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Treatment with the tyrosine kinase inhibitor imatinib is the standard of care for newly diagnosed patients with chronic myeloid leukemia. In recent years, several second-generation inhibitors - such as dasatinib and nilotinib - have become available: these promise to overcome some of the mutations associated with acquired resistance to imatinib. Despite eliciting similar clinical responses, the molecular effects of these agents on different subpopulations of leukemic cells remain incompletely understood. Furthermore, the consequences of using high-dose imatinib therapy have not been investigated in detail. Here we utilized clinical data from patients treated with dasatinib, nilotinib, or high-dose imatinib, together with a statistical data analysis and mathematical modeling approach, to investigate the molecular treatment response of leukemic cells to these agents. We found that these drugs elicit very similar responses if administered front-line. However, patients display significantly different kinetics when treated second-line, both in terms of differences between front-line and second-line treatment for the same drug, and among agents when used as second-line. We then utilized a mathematical framework describing the behavior of four differentiation levels of leukemic cells during therapy to predict the treatment response kinetics for the different cohorts of patients. The dynamics of BCR-ABL1 clearance observed in our study suggest that the use of standard or high-dose imatinib or a second-generation tyrosine kinase inhibitor such as nilotinib or dasatinib elicits similar responses when administered as front-line therapy for patients with chronic myeloid leukemia in chronic phase.
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We read with interest the recent correspondences from Hickey et al . [1] and Riou et al . [2] reporting bosutinib-associated pulmonary arterial hypertension (PAH) and pleural effusion. Tyrosine kinase inhibitors (TKIs) have revolutionised the treatment of chronic myeloid leukaemia (CML). However, TKIs are associated with potentially serious lung complications, which are particularly associated with dasatinib; the incidence of dasatinib-induced pleural effusion ranges from 15% to 35% [3, 4]. Dasatinib-related PAH has been reported in ∼0.45% of dasatinib-treated patients [5]. Bosutinib (developed by Pfizer (New York, NY, USA) in 2015) is a second-generation TKI approved for patients with CML that is resistant or intolerant to imatinib, nilotinib or dasatinib [6]. Bosutinib can induce parenchymal, pleural and vascular lung disease
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Chronic myelogenous leukemia
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The clinical outcome for patients with chronic myeloid leukemia in chronic phase (CML-CP) is currently very favorable due to the availability of tyrosine kinase inhibitors (TKIs) that are well tolerated and effectively suppress the constitutively activated BCR-ABL1 kinase that underlies the pathogenesis of this malignancy. Three TKIs -imatinib, nilotinib and dasatinib- have been approved as frontline therapy in CML-CP. Another TKI, bosutinib, inhibits with high potency numerous tyrosine kinases, including BCR-ABL1, Src family of kinases and MAPK, among others. Like nilotinib and dasatinib, bosutinib is a second-generation TKI that inhibits the majority of mutations associated with imatinib resistance, with the exception of T315I. In patients with CML-CP with prior intolerance or resistance to imatinib therapy, bosutinib rendered response rates similar to those observed in the same patient population treated with nilotinib or dasatinib. Preliminary results from the ongoing phase III BELA study in which bosutinib is compared in a randomized fashion to imatinib for patients with newly diagnosed CML-CP have been recently reported. We herein summarize the preclinical and clinical experience of bosutinib in CML.
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A 52-year-old man was diagnosed with chronic myeloid leukemia in the chronic phase (CML-CP). He experienced bosutinib-induced pulmonary arterial hypertension (PAH) recurrence following dasatinib use. Symptoms and examination findings associated with PAH improved after bosutinib cessation. Although nilotinib was started because of the loss of response after bosutinib cessation, a deep molecular response without PAH recurrence was achieved 3 months after the initiation of nilotinib therapy. PAH recurrence after switching to bosutinib due to dasatinib-induced PAH should be closely monitored. In addition, nilotinib therapy might be an effective approach in PAH cases related to dasatinib and/or bosutinib in patients with CML-CP.
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