Results of plasma N-terminal pro B-type natriuretic peptide and cardiac troponin monitoring in GIST patients do not support the existence of imatinib-induced cardiotoxicity

Background: Recently, case reports of patients treated withimatinib (imatinib mesylate; Gleevec®; Glivec®) indicatedthat this tyrosine kinase inhibitor may induce cardiomyopathy.Consequently, careful cardiac monitoring was advocated for clinicalstudies. The purpose of this study was to prospectively evaluatewhether imatinib (Gleevec) induces early, subclinical, cardiactoxicity. Patients and methods: History and physical examination werecarried out with special attention for symptoms of heart failure.Additionally, assessments of serial plasma N-terminal pro B-typenatriuretic peptide (NT-proBNP) and serum cardiac troponin T(cTnT) measurement before and 1 and 3 months after the startof imatinib treatment (400–800 mg daily) were done inpatients with advanced and/or metastatic gastrointestinal stromaltumours (GIST). Results: A total of 55 GIST patients were enrolled. Only onepatient, with a normal pretreatment NT-proBNP, showed an increasein NT-proBNP to above age-specific normal values during imatinibtreatment and developed symptomatic heart failure due to pre-existentcardiac valvular disease. cTnT levels remained stable. Conclusions: In our study population, imatinib treatment forGIST was not associated with an increase in plasma NT-proBNPlevels, indicating that the risk of subclinical cardiac toxicityis limited with the use of this agent. These results do notsupport the current strategy to standard cardiac monitoringin all patients. This may be restricted to GIST patients witha history of cardiac disease. Key words: cardiotoxicity, GIST, imatinib mesylate, NT-proBNP, troponin T Received for publication August 15, 2007. Revision received August 24, 2007. Accepted for publication August 29, 2007.     

Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib

Following the initial success of imatinib as frontline therapy for chronic myeloid leukemia (CML), several second-generation therapeutics have been developed with increased potency and the ability to inhibit the majority of imatinib-resistant mutations. Here, we review the current knowledge about the target specificity of the two new inhibitors nilotinib and dasatinib in comparison to imatinib, including the recent large-scale chemical proteomics screens.     

甲磺酸伊马替尼治疗手术后复发和/或转移的胃肠道间质瘤的疗效分析

目的:评价甲磺酸伊马替尼治疗无法手术完全切除、术后复发和(或)转移性胃肠间质瘤(GIST)的临床疗效及不良反应。方法:2004年8月～2007年2月间经术后病理证实为GIST,术中无法完全切除病灶或术后复发、转移,失去手术机会,给予甲磺酸伊马替尼治疗400～600mg/d口服的患者21例。结果:21例全部随访,完全缓解(CR)者2例(9.5%),部分缓解(PR)者11例(52.4%),病情稳定(SD)者5例(23.8%),病情进展(PD)3例(14.3%),其中死亡2例(9.5%)。患者获益(CR+PR+SD)率(85.7%),1年、2年生存率分别为100%、83.3%。结论:甲磺酸伊马替尼治疗GIST疗效肯定,不良反应轻,毒性可耐受。     

Cytogenetic remission with imatinib therapy in hypereosinophilic syndrome with trisomy 8 and resolution of severe cardiac dysfunction

We report a 50-year-old patient with idiopathic hypereosinophilic syndrome with trisomy 8 who experienced a complete and durable hematological and cytogenetic remission with low-dose imatinib therapy. He also had a significant reversal of cardiac dysfunction with a reduction in cardiac hypertrophy, resolution of pericardial effusion and mitral and tricuspid regurgitation. He remained in remission 3 years after therapy.     

Lack of clinical efficacy of imatinib in metastatic melanoma

This two-centre phase-II trial aimed at investigating the efficacy of imatinib in metastasised melanoma patients in correlation to the tumour expression profile of the imatinib targets c-kit and platelet-derived growth factor receptor (PDGF-R). The primary study end point was objective response according to RECIST, secondary end points were safety, overall and progression-free survival. In all, 18 patients with treatment-refractory advanced melanoma received imatinib 800 mg day(-1). In 16 evaluable patients no objective responses could be observed. The median overall survival was 3.9 months, the median time to progression was 1.9 months. Tumour biopsy specimens were obtained from 12 patients prior to imatinib therapy and analysed for c-kit, PDGF-Ralpha and -Rbeta expression by immunohistochemistry. In four cases, cell lines established from these tumour specimens were tested for the antiproliferative effects of imatinib and for functional mutations of genes encoding the imatinib target molecules. The tumour specimens stained positive for CD117/c-kit in nine out of 12 cases (75%), for PDGF-Ralpha in seven out of 12 cases (58%) and for PDGF-Rbeta in eight out of 12 cases (67%). The melanoma cell lines showed a heterogenous expression of the imatinib target molecules without functional mutations in the corresponding amino-acid sequences. In vitro imatinib treatment of the cell lines showed no antiproliferative effect. In conclusion, this study did not reveal an efficacy of imatinib in advanced metastatic melanoma, regardless of the expression pattern of the imatinib target molecules c-kit and PDGF-R.     

Unexpected rapid progression of metastatic adenoid cystic carcinoma during treatment with imatinib mesylate

BACKGROUND: There is a lack of effective treatment for metastatic adenoid cystic carcinoma (ACC), a usually indolent tumor. We studied the efficacy of imatinib mesylate, a potent inhibitor of KIT tyrosine kinase, in patients with KIT-positive metastatic ACC. METHOD: Five patients with lung metastasis were treated in a pilot study with imatinib 400 mg by mouth twice a day. Mutations of c-kit and platelet-derived growth factor receptor (PDGFR)-alpha in tumors from these patients were analyzed. RESULTS: Disease progression was noted in three of five patients during the short treatment periods, ranging from 2 to 3 weeks. Three patients died of disease within 6 months. No detectable mutations were found in c-kit and PDGFR-alpha. CONCLUSION: We observed an unexpected high progression rate of metastatic ACC within short periods during imatinib treatment. Use of imatinib to treat cancers without c-kit or PDGFR-alpha mutation should be approached with caution.     

Concurrent male gynecomastia and testicular hydrocele after imatinib mesylate treatment of a gastrointestinal stromal tumor

We report a gastrointestinal stromal tumor (GIST) patient with male gynecomastia and testicular hydrocele after treatment with imatinib mesylate. A 42 yr-old male patient presented for management of hepatic masses. Two years earlier, he had undergone a small bowel resection to remove an intraabdominal mass later shown to be a GIST, followed by adjuvant radiation therapy. At presentation, CT scan revealed multiple hepatic masses, which were compatible with metastatic GIST, and he was prescribed imatinib 400 mg/day. During treatment, he experienced painful enlargement of the left breast and scrotal swelling. Three months after cessation of imatinib treatment, the tumors recurred, and, upon recommencing imatinib, he experienced painful enlargement of the right breast and scrotal swelling. He was diagnosed with male gynecomastia caused by decreased testosterone and noncommunicative testicular hydrocele. He was given androgen support and a hydrocelectomy, which improved his gynecomastia. The mechanism by which imatinib induces gynecomastia and hydrocele is thought to be associated with an inhibition of c-KIT and platelet-derive growth factor. This is the first report, to our knowledge, describing concurrent male gynecomastia and testicular hydrocele after imatinib treatment of a patient with GIST.     

Imatinib mesylate: an attractive alternative in young children with large, surgically challenging dermatofibrosarcoma protuberans

To document the clinical activity of imatinib mesyalte in a child with a dermatofibrosarcoma protuberans (DFSP). An 18-month-old girl presented with a large extremity DFSP. As surgical resection would have caused unacceptable functional defects, imatinib mesylate was administered to induce tumor reduction and or stabilization. After 23 weeks of therapy, magnetic resonance imaging (MRI) of the tumor showed a reduction in the subcutaneous thickness in the transverse plane. The drug was tolerated well without any adverse reactions. Imatinib mesylate offers a non-surgical alternative for the treatment of large DFSP in children.