Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia

Réa, Delphine; Mirault, Tristan; Cluzeau, Thomas; Gautier, Jean‐François; Guilhot, Joëlle; Dombret, Hervé; Messas, Emmanuel

doi:10.3324/haematol.2014.104075

Cited by 121 publications

(85 citation statements)

References 40 publications

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“…Our case displayed early (i.e., within 6 months) complete cytogenetic and molecular responses that lasted for more than 6 years. Albeit its efficacy, nilotinib is known to be associated with higher incidence of pancreatic and metabolic abnormalities [8,9] and, more recently, with a significant incidence of progressive PAOD [10]. In line with this, after 5 years of nilotinib, our patient progressively develops signs of PAOD that required revascularization and dose reduction.…”

supporting

confidence: 73%

Long-term efficacy and safety of nilotinib therapy after imatinib failure in eosinophilic myeloproliferative neoplasm and ETV6-ABL rearrangement

et al. 2015

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Dear Editor, The ETV6 gene, previously known as TEL, is a member of the ETS family of transcription factors located at 12p13. Its role in leukemogenesis was initially estabilished as a fusion partner to the PDGFR-beta gene in a case of chronic myelomonocytic leukemia with t (5;12)(q33;p13) [1]. The ETV6-ABL gene product has been demonstrated to have tyrosine kinase activity remarkably similar to that of BCR-ABL, despite the fusion partners for ABL being completely different [2]. Several studies proved the efficacy of imatinib for patients with hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL), especially in those who express the FIP1L1-PDGFRα fusion gene [3][4][5]. As development of resistance or intollerance to Imatinib in these patients may parallel that seen in chronic myeloid leukemia (CML), the evaluation of second-generation tyrosine kinase inhibitors (TKIs), such as nilotinib, has been reported [6]. However, to date, little is known on long-term efficacy and safety of secondgeneration TKIs after imatinib failure in patients with eosinophilic neoplasms.A 65-year-old male was found to have hemoglobin 13.0 g/dL, platelets 302×10 3 /μL, leukocytes 16.7×10 3 /μL, with 65 % neutrophilis, 3 % metamyelocytes, 3 % myelocytes, 10 % eosinophils, 8 % basophils, 8 % lymphocytes, and 3 % monocytes. The physical exam was negative. Bone marrow biopsy and aspirate were consistent with a chronic phase myeloproliferative neoplasm (MPN). Karyotype was 46,XY,t(9;12)(q34;p12); molecular analysis was negative for BCR/ABL and for rearrangements involving PDGFRα and β and FIP1L1 gene, while showing a fusion between ETV6 and ABL genes.

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supporting

confidence: 73%

Long-term efficacy and safety of nilotinib therapy after imatinib failure in eosinophilic myeloproliferative neoplasm and ETV6-ABL rearrangement

et al. 2015

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“…The young age and low frequency of preexisting cardiovascular risk factors among patients in this study, as well as the limited follow-up duration for this analysis, may have contributed to the lack of observed cardiovascular safety issues; in other studies with longer follow-up, higher frequencies of cardiovascular events (ie, ischemic heart disease, ischemic cerebrovascular events, and peripheral artery disease) were reported during nilotinib treatment, particularly in older patients and those with preexisting risk factors. 7,22,23 Moreover, although new onset of diabetes during treatment with nilotinib has been reported in other studies, including ENESTnd, 24,25 no patient in ENESTchina without a prior history of diabetes mellitus developed grade 3/4 glucose elevation or an AE of diabetes mellitus by the cutoff date for this analysis.…”

mentioning

confidence: 66%

Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina

Wang

Shen

Saglio

et al. 2015

Blood

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Key Points• Chinese patients with newly diagnosed CML-CP achieved higher rates of MMR with nilotinib vs imatinib.• Nilotinib was well tolerated, and no new safety signals were observed.Treatment with a tyrosine kinase inhibitor (TKI) targeting BCR-ABL1 is currently the standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP).In this study, we present results of the ENESTchina (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-China) that was conducted to investigate nilotinib 300 mg twice daily vs imatinib 400 mg once daily in a Chinese population. ENESTchina met its primary end point with a statistically significant higher rate of major molecular response (MMR; BCR-ABL1 £0.1% on the International Scale) at 12 months in the nilotinib arm vs the imatinib arm (52.2% vs 27.8%; P < .0001), and MMR rates remained higher with nilotinib vs imatinib throughout the follow-up period. Rates of complete cytogenetic response (0% Philadelphia chromosome-positive [Ph1] metaphases by standard cytogenetics) were comparable and ‡80% by 24 months in both arms. The estimated rate of freedom from progression to accelerated phase/blast crisis at 24 months was 95.4% in each arm. The safety profiles of both drugs were similar to those from previous studies. In conclusion, rates of MMR at 12 months were superior with nilotinib vs imatinib in Chinese patients with newly diagnosed Ph1 CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01275196. (Blood. 2015;125(18):2771-2778

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“…12,17,29,41 Moreover, the cholesterol level may increase. 42,43 Other nonhematologic AEs include constipation, diarrhea, and a folliculitis-like skin rash (supplemental Table 1). 17,41 During the past few years, more and more data suggest that severe peripheral arterial occlusive disease (PAOD) and other cardiovascular events develop in patients receiving nilotinib.…”

Section: -32mentioning

confidence: 99%

Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors

Valent

Hadzijusufovic

Schernthaner

et al. 2015

Blood

248

219

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Vascular safety is an emerging issue in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). Whereas imatinib exhibits a well-documented and favorable long-term safety profile without obvious accumulation of vascular events, several types of vascular adverse events (VAEs) have been described in patients receiving second- or third-generation BCR/ABL1 TKIs. Such VAEs include pulmonary hypertension in patients treated with dasatinib, peripheral arterial occlusive disease and other arterial disorders in patients receiving nilotinib, and venous and arterial vascular occlusive events during ponatinib. Although each TKI interacts with a unique profile of molecular targets and has been associated with a unique pattern of adverse events, the mechanisms of drug-induced vasculopathy are not well understood. Here, recent data and concepts around VAEs in TKI-treated patients with CML are discussed, with special reference to potential mechanisms, event management, and strategies aimed at avoiding occurrence of such events in long-term treated patients.

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Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia

Cited by 121 publications

References 40 publications

Long-term efficacy and safety of nilotinib therapy after imatinib failure in eosinophilic myeloproliferative neoplasm and ETV6-ABL rearrangement

Long-term efficacy and safety of nilotinib therapy after imatinib failure in eosinophilic myeloproliferative neoplasm and ETV6-ABL rearrangement

Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina

Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors

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