Extending the reach of nilotinib in chronic myeloid leukemia.
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ABSTRACT:
SUBMITTER: Mauro MJ
PROVIDER: S-EPMC4077069 | biostudies-literature | 2014 Jul
REPOSITORIES: biostudies-literature
Publications
Extending the reach of nilotinib in chronic myeloid leukemia.
Haematologica 20140701 7
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Project description:BackgroundNilotinib, a second-generation BCR-ABL tyrosine kinase inhibitor (TKI), is highly effective in the treatment of patients with chronic myeloid leukemia (CML), despite being more vasculotoxic than older TKIs such as imatinib. Herein, we present a case of nilotinib-associated vasospastic angina confirmed by an acetylcholine spasm provocation test.Case presentationA 62-year-old CML patient treated with 300 mg nilotinib twice daily complained of several episodes of rest angina and was hospitalized at our institution. Coronary angiography revealed no severe organic stenosis, and the acetylcholine spasm provocation test confirmed the diagnosis of vasospastic angina. Although treatment with a calcium channel blocker and nicorandil reduced the frequency of chest pain, angina symptoms continued to occur. At 10 months post discharge, the patient complained of increased frequency of angina; therefore, the nilotinib dosage was reduced to 150 mg twice daily. Consequently, the patient reported a significant improvement in chest symptoms.ConclusionsThis case report highlights the potential vasculotoxic effects of nilotinib. Cardiologists and hematologists should be vigilant for coronary artery spasm as a possible vascular adverse event caused by nilotinib.
| S-EPMC8393793 | biostudies-literature
Project description:The introduction of second-generation tyrosine kinase inhibitors (TKIs) targeting the protein-tyrosine kinase (PTK) BCR-ABL1 has improved treatment response in chronic myeloid leukemia (CML). However, in some patients response still remains suboptimal. Protein-tyrosine phosphatases (PTPs) are natural counter-actors of PTK activity and can affect TKI sensitivity, but the impact of PTPs on treatment response to second-generation TKIs is unknown. We assessed the mRNA expression level of 38 PTPs in 66 newly diagnosed CML patients and analyzed the potential relation with treatment outcome after 9 months of nilotinib medication. A significantly positive association with response was observed for higher PTPN13, PTPRA, PTPRC (also known as CD45), PTPRG, and PTPRM expression. Selected PTPs were then subjected to a functional analysis in CML cell line models using PTP gene knockout by CRISPR/Cas9 technology or PTP overexpression. These analyses revealed PTPRG positively and PTPRC negatively modulating nilotinib response. Consistently, PTPRG negatively and PTPRC positively affected BCR-ABL1 dependent transformation. We identified BCR-ABL1 signaling events, which were affected by modulating PTP levels or nilotinib treatment in the same direction. In conclusion, the PTP status of CML cells is important for the response to second generation TKIs and may help in optimizing therapeutic strategies.
| S-EPMC5823647 | biostudies-literature
Project description: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.
| S-EPMC3000369 | biostudies-literature
Project description:Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase. Although ABL1-specific tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML, the TKI efficacy depends on the individual patient. In this work, we found that the patients with different nilotinib responses can be classified by using the estimated parameters of our simple dynamical model with two common laboratory findings. Furthermore, our proposed method identified patients who failed to achieve a treatment goal with high fidelity according to the data collected only at three initial time points during nilotinib therapy. Since our model relies on the general properties of TKI response, our framework would be applicable to CML patients who receive frontline nilotinib or other TKIs.
| S-EPMC9561725 | biostudies-literature
Project description:BackgroundTyrosine kinases are highly expressed in platelets and play an important role in their activation process. Some studies have reported the blocking effects of tyrosine kinase inhibitors on different platelet functions.ObjectivesEvaluate the effects of nilotinib on platelets aggregation in 42 patients with chronic phase of CML and correlate the results with clinical and hematological parameters: age, complete blood count and presentation.Patients and methodsThis study was conducted on 42 patients diagnosed as Chronic Phase of Chronic Myeloid Leukemia based on clinical, morphological and cytogenetic study. All patients were on Nilotinib treatment and were attending the National Center of Hematology in Baghdad. About 9 mL of venous blood sample were collected from each patient and control subjects, samples divided into 3 parts for complete blood count, platelet aggregation test and PT and aPTT.ResultsThe mean age was 41.3 ± 1.7 (mean ± SEM) years old. M:F ratio of 1.2:1. Mean duration of nilotinib therapy(1.4 years). All patients had normal PT and aPTT.Only 16 (38%) patients had abnormal aggregation response to epinephrine, but there was no statistically significant differences with control group.ConclusionNilotinib had no adverse effect on platelet function nor patients clotting tests.
| S-EPMC6594045 | biostudies-literature
Project description:PurposeAlthough most patients with chronic myeloid leukemia (CML) in chronic phase respond well to front-line therapy with imatinib, some patients do not achieve the desirable end point, and others may eventually lose response or are intolerant.Patients and methodsPatients with newly diagnosed CML in chronic phase were treated with nilotinib 400 mg twice daily on an empty stomach as initial therapy.ResultsAmong 51 patients in chronic phase observed for at least 3 months, 50 (98%) achieved a complete cytogenetic remission (CCyR), and 39 (76%) achieved a major molecular response (MMR). Responses occurred rapidly, with 96% of patients achieving CCyR by 3 months and 98% achieving CCyR by 6 months. The projected event-free survival at 24 months is 90%, and all patients are alive after a median follow-up time of 17 months. Grade >or= 3 neutropenia occurred in 12% of patients, and thrombocytopenia in occurred 11%. Nonhematologic toxicity was usually grade 1 to 2 and manageable. The actual median dose at 12 months was 800 mg (range, 200 to 800 mg).ConclusionNilotinib is an effective option for the initial management of CML in early chronic phase, producing high rates of CCyR and MMR, with most patients reaching these responses early during their therapy.
| S-EPMC2815701 | biostudies-literature
Project description:Gene mutations independent of BCR::ABL1 have been identified in newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase, whereby mutations in epigenetic modifier genes were most common. These findings prompted the systematic analysis of prevalence, dynamics, and prognostic significance of such mutations, in a clinically well-characterized patient population of 222 CML patients from the TIGER study (CML-V) by targeted next-generation sequencing covering 54 myeloid leukemia-associated genes. In total, 53/222 CML patients (24%) carried 60 mutations at diagnosis with ASXL1 being most commonly affected (n = 20). To study mutation dynamics, longitudinal deep sequencing analysis of serial samples was performed in 100 patients after 12, 24, and 36 months of therapy. Typical patterns of clonal evolution included eradication, persistence, and emergence of mutated clones. Patients carrying an ASXL1 mutation at diagnosis showed a less favorable molecular response to nilotinib treatment, as a major molecular response (MMR) was achieved less frequently at month 12, 18, and 24 compared to all other patients. Patients with ASXL1 mutations were also younger and more frequently found in the high risk category, suggesting a central role of clonal evolution associated with ASXL1 mutations in CML pathogenesis.
| S-EPMC9417980 | biostudies-literature
Project description:Tyrosine kinase inhibitors may have deleterious effects on spermatogenesis or folliculogenesis, resulting in male or female subfertility. The aim of this study is to determine the effect of nilotinib, which is used routinely to treat chronic myeloid leukemia, on spermatogenesis and folliculogenesis by using histopathological parameters.Ten male and ten female mice were orally treated with nilotinib at 20 mg/kg body weight dissolved in drinking water daily for 2 months.When compared with the control group, a statistically significant decrease was demonstrated in the total follicle numbers of the female mice in the nilotinib group (268±110 vs. 170±60; p=0.03). Active spermatogenesis was observed in each tubule sample taken from the mice in the control and nilotinib groups. Spermatogenic activity was similar in the two groups.We have demonstrated that even though spermatogenesis is preserved, folliculogenesis is inhibited by the usage of a continuous nilotinib treatment dose in chronic myeloid leukemia.
| S-EPMC5440865 | biostudies-other
Project description:An increase in the serum concentration of pancreatic enzymes (amylase and lipase) was reported in a proportion of imatinib-resistant and/or intolerant Philadelphia-positive chronic myeloid leukemia patients treated with nilotinib. Acute pancreatitis was very rare, and the relevance of these laboratory alterations remains unknown. We report on 8 chronic myeloid leukemia patients who developed serum lipase/amylase elevation during treatment with nilotinib. After a median follow-up of 26 months, none of these patients developed an acute pancreatitis or clinical signs of pancreatic disease. Pancreatic hyperenzymemia never led to permanent drug discontinuation and required nilotinib temporary interruption in one case only. The median cumulative duration of dose interruptions and response to treatment were comparable in patients with or without pancreatic enzyme elevation. The mechanisms of action of nilotinib on pancreatic enzymes deserves to be investigated: however, in our experience, the relevance of pancreatic hyperenzymemia was clinically very limited.
| S-EPMC2791949 | biostudies-literature
Project description:The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR(4) (BCR-ABL1⩽0.01% on the International Scale or undetectable BCR-ABL1 with ⩾10,000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and ⩽3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR(4) at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal.
| S-EPMC4705425 | biostudies-literature