Imatinib scientific update |
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2010 Jul 2. [Epub ahead of print]
Rappa G, Anzanello F, Lorico A.
Department of Drug Development, Nevada Cancer Institute, One Breakthrough Way, Las Vegas, NV, 89135, USA.
Imatinib mesylate enhances the malignant behavior of human breast carcinoma cells.
PURPOSE: Imatinib mesylate (Imatinib), clinically employed for chronic myeloid leukemia and gastrointestinal stromal tumors, is a selective inhibitor of the tyrosine kinases, c-abl, c-kit and PDGFRs. Due to the frequent expression of these genes in breast cancer cells, the clinical efficacy of Imatinib has recently been investigated in patients with advanced and metastatic breast cancer. Here, we have studied the effects of Imatinib on human MA-11 breast carcinoma cells, expressing both c-abl and PDGFRbeta, in vitro and in mouse xenografts. METHODS: The effects of Imatinib mesylate on the human MA-11 breast carcinoma cell line were studied in vitro and in xenografts. RESULTS: Daily intraperitoneal treatment with 60 mg/kg Imatinib for 9 days of athymic nude mice pre-implanted subcutaneously with MA-11 cells did not result in an anti-tumor effect, but rather increased the take rate of 3 x 10(4) cells from 30.8 to 84.6% and caused the appearance of large abdominal masses in 30% of mice. To investigate the mechanism(s) of the observed effects of Imatinib on MA-11 tumors, we exposed the cells in vitro to Imatinib for 9 days. The surviving population, expanded in culture, showed increased motility and over-expressed a set of genes associated with aggressive behavior. Also, several genes belonging to the Wnt and the MAPK pathway were differentially expressed. In promoter activation assays, Imatinib increased the promoter activity driven by both Wnt and MAPK/ERK-1/2. CONCLUSIONS: Our data suggest caution in the clinical use of Imatinib in breast cancer patients; the comparison of Imatinib-surviving breast cancer cells with parental cells may help define the regulatory pathways involved in the increased malignancy of residual tumor cells that survive therapy, ultimately providing important therapeutic targets.
2010 Jul 1. [Epub ahead of print]
Nishioka C, Ikezoe T, Yang J, Yokoyama A.
[1] Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan [2] Japanese Society for the Promotion of Science (JSPS), Tokyo, Japan.
Long-term exposure of leukemia cells to multi-targeted tyrosine kinase inhibitor induces activations of AKT, ERK and STAT5 signaling via epigenetic silencing of the PTEN gene.
Imatinib induces complete molecular response in patients with chronic myeloid leukemia (CML) and chronic eosinophilic leukemia (CEL). However, development of resistance to imatinib has emerged as an important clinical problem for molecular-targeted therapy in CML and CEL. In this study, we have established the imatinib-resistant CEL EOL-1 sub-lines (designated as EOL-1R) by culturing cells with increasing concentrations of imatinib for 6 months. Interestingly, EOL-1R cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (PTEN) gene. Exposure of EOL-1R cells to imatinib failed to dephosphorylate AKT, ERK and STAT5, although PDGFRalpha was effectively inactivated. The forced expression of PTEN negatively regulated these signal pathways and sensitized EOL-1R cells to imatinib. Notably, hypermethylation of the promoter region of the PTEN gene in association with the downregulation of this gene's transcripts was identified in imatinib-resistant leukemia cells isolated from individuals with CEL, CML and Philadelphia-positive acute lymphoblastic leukemia. In addition, anti-epigenetic agents restored PTEN expression, resulting in the sensitization of EOL-1R cells to imatinib. Taken together, epigenetic silence of PTEN is one of the mechanisms that cause drug resistance in individuals with leukemia after exposure to imatinib. Anti-epigenetic agents may be useful for overcoming drug resistance in such a case.Leukemia advance online publication, 1 July 2010; doi:10.1038/leu.2010.145.
2010 Jun 25. [Epub ahead of print]
Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, Peacock AJ, Barst RJ, Shapiro S, Golpon H, Toshner M, Grimminger F, Pascoe S.
University Hospital Giessen and Marburg GmbH, Giessen, Germany.
Imatinib in Pulmonary Arterial Hypertension Patients with Inadequate Response to Established Therapy.
BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive condition with a poor prognosis. Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in its pathobiology. Methods and RESULTS: Patients with PAH in functional classes IIâIV were enrolled in a 24-week randomized, double-blind, placebo-controlled pilot study. Patients received imatinib (an inhibitor of PDGFR activity) 200 mg orally once daily (or placebo), which was increased to 400 mg if the initial dose was well tolerated. The primary endpoints were safety and change from baseline in the 6-minute walking distance (6MWD). Secondary endpoints included hemodynamics and functional classification. Fifty-nine patients enrolled (imatinib [n = 28]; placebo [n = 31]); 42 completed the study. Dropouts were equally matched between the two groups. In the intention-to-treat (ITT) population there was no significant change in the 6MWD (mean+/-SD) in the imatinib versus placebo group (+22+/-63 vs â1.0+/-53 m). There was a significant decrease in pulmonary vascular resistance (imatinib â300+/-347 vs placebo â 78+/-269 dynes.sec.cm(-5), P < 0.01) and increase in cardiac output (imatinib +0.6+/-1.2 vs placebo â0.1+/-0.9 L/min, P = 0.02). Serious adverse events occurred in 11 imatinib recipients (39%) and 7 placebo recipients (23%). Three deaths occurred in each group. Post-hoc subgroup analyses suggest that patients with greater hemodynamic impairment may respond better than patients with less impairment. CONCLUSIONS: These data from a Phase II study are consistent with imatinib being well tolerated in PAH patients, and provide proof of concept for further studies evaluating its safety, tolerability and efficacy in PAH. Clinical Trials Registry Information: ID#NCT00477269 registered at www.clinicaltrials.gov.
2010 Jun 25. [Epub ahead of print]
Nagai T, Takeuchi J, Dobashi N, Kanakura Y, Taniguchi S, Ezaki K, Nakaseko C, Hiraoka A, Okada M, Miyazaki Y, Motoji T, Higashihara M, Tsukamoto N, Kiyoi H, Nakao S,Shinagawa K, Ohno R, Naoe T, Ohnishi K, Usui N.
Division of Hematology, Jichi Medical University Hospital, Shimotsuke, 329-0498, Japan, t-nagai@jichi.ac.jp.
Imatinib for newly diagnosed chronic-phase chronic myeloid leukemia: results of a prospective study in Japan.
Although imatinib has become the current standard treatment for chronic myeloid leukemia (CML), there is limited information regarding its efficacy and safety among Japanese patients. We therefore conducted a prospective multi-center open-label study of imatinib for Japanese patients with newly diagnosed chronic-phase CML (CP-CML). A total of 107 patients were enrolled and treated with imatinib at an initial daily dose of 400 mg. Eighty-three patients completed 3 years of study treatment. The cumulative rates of major cytogenetic response and complete cytogenetic response (CCyR) were 90.9 and 90.2% at 3 years, respectively. The safety profile was not very different from that reported in the IRIS study, although grade >/=3 neutropenia occurred relatively frequently (31.8 vs. 14.3%). Only seven patients discontinued the study due to adverse events, as did four patients due to insufficient efficacy. The 3-year probabilities of overall survival and progression-free survival were 93.2 and 91.4%, respectively. Higher average daily doses (i.e., >/=350 mg) were significantly associated not only with higher rates of achieving CCyR, but also with longer duration of CCyR. These findings confirm the clinical utility of imatinib in Japanese patients with newly diagnosed CP-CML, and suggest detrimental effect of low average daily dose on treatment results.
2010 Jul;85(7):482-6.
Guillem VM, Cervantes F, Martínez J, Alvarez-Larrán A, Collado M, Camós M, Sureda A, Maffioli M, Marugán I, Hernández-Boluda JC.
Hematology and Medical Oncology Department, Hospital Clínico Universitario, Avd. Blasco Ibáñez 17, Valencia, Spain.
XPC genetic polymorphisms correlate with the response to imatinib treatment in patients with chronic phase chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is driven by the BCR-ABL protein, which promotes the proliferation and viability of the leukemic cells. Moreover, BCR-ABL induces genomic instability that can contribute to the emergence of resistant clones to the ABL kinase inhibitors. It is currently unknown whether the inherited individual capability to repair DNA damage could affect the treatment results. To address this, a comprehensive analysis of single nucleotide polymorphisms (SNPs) on the nucleotide excision repair (NER) genes (ERCC2-ERCC8, RPA1-RPA3, LIG1, RAD23B, XPA, XPC) was performed in 92 chronic phase CML patients treated with imatinib upfront. ERCC5 and XPC SNPs correlated with the response to imatinib. Haplotype analysis of XPC showed that the wild-type haplotype (499C-939A) was associated with a better response to imatinib. Moreover, the 5-year failure free survival for CA carriers was significantly better than that of the non-CA carriers (98% vs. 73%; P = 0.02). In the multivariate logistic model with genetic data and clinical covariates, the hemoglobin (Hb) level and the XPC haplotype were independently associated with the treatment response, with patients having a Hb < or =11 g/dl (Odds ratio [OR] = 5.0, 95% confidence interval [CI] = 1.5-16.1) or a non-CA XPC haplotype (OR = 4.1, 95% CI = 1.6-10.6) being at higher risk of suboptimal response/treatment failure. Our findings suggest that genetic polymorphisms in the NER pathway may influence the results to imatinib treatment in CML. (c) 2010 Wiley-Liss, Inc.
2009 Sep-Dec;61(5-6):559-64.
Ascenzi P, Orienti L, Okoro U, Raspanti A, Ucchino G.
Porretta and Vergato Department of Surgery, Porretta Terme Hospital, Bologna.
Gastrointestinal stromal tumours. Is aggressive surgical treatment reasonable in locally advanced cases?
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and have only recently been described based on their specific immunohistochemistry and the presence of particular kit-related mutations which potentially make them targets for tyrosine kinase inhibition. Most GISTs are respectable, with survival mainly depending upon mitotic count and completeness of resection. Our own and other studies suggest that, in locally advanced cases, complete surgical resection (R0 resection) and adjuvant molecular therapy with imatinib yield good outcomes in terms of survival and disease-free status at 12 and 18 months. This approach, in the light of such integrated surgical-molecular therapy and of the new pharmaceuticals currently under research, means that we can now offer a real chance of recovery and a longer survival period to patients even with advanced-stage illness or local recurrence.
2009 Oct-Dec;5(4):267-71.
Seshadri RA, Rajendranath R.
Department of Surgical Oncology, Cancer Institute (WIA), Annexe Campus, Guindy, Chennai, India.
Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors.
AIM: To study the role of neoadjuvant imatinib mesylate in downsizing tumors in patients with locally advanced nonmetastatic gastrointestinal stromal tumors (GISTs), thus improving the possibility of complete resection. MATERIALS AND METHODS: We used neoadjuvant imatinib in six patients with locally advanced GISTs, at a dose of 400 mg daily, given orally in all patients for a median period of 3.5 months (range 1-20 months). All patients had a computerized tomography scan (CT scan) once before starting the treatment and a repeat CT scan 1 month after starting imatinib. Some patients had another CT scan done at 3 months. The tumor volume was calculated using the formula V=4/3 pir3. RESULTS: Following imatinib therapy, the median reduction in the tumor volume was 40% (range 20-50%). Four of the six patients underwent successful complete resection of the tumor following neoadjuvant imatinib for a median period of 2 months, and are disease free after a median follow-up of 10.5 months (range 3-20 months). Two patients in whom the tumors were deemed to be operable after downsizing refused surgery and are continuing imatinib. Imatinib did not produce serious toxicity in any patient. CONCLUSION: Neoadjuvant imatinib can be used successfully in patients with locally advanced nonmetastatic GISTs to improve the rates of complete resection and reduce the chance of tumor spill. The optimal duration of neoadjuvant treatment needs to be tailored based on response assessment at frequent intervals to identify the ideal window period for surgery.
2009;31 Pt 2:2459-69.
Yin OQ, Gallagher N, Tanaka C, Fisher D, Sethuraman V, Zhou W, Lin TH, Heuman D, Schran H.
Novartis Pharmaceuticals Corporation, Florham Park, New Jersey 07932-0675, USA. Ophelia.yin@novartis.com
Effects of hepatic impairment on the pharmacokinetics of nilotinib: an open-label, single-dose, parallel-group study.
BACKGROUND: Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor approved for the treatment of patients who have imatinib-resistant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic or accelerated phase or who are unable to tolerate imatinib. Nilotinib is metabolized in the liver via oxidation and hydroxylation pathways, mediated primarily by the cytochrome P450 3A4 isozyme. Interpatient variability in systemic exposure to nilotinib has been reported to range from 32% to 64%. OBJECTIVE: This study compared the pharmacokinetics of nilotinib in subjects with hepatic impairment and subjects with normal hepatic function. METHODS: Hepatic impairment was classified as mild (Child-Pugh grade A), moderate (Child-Pugh grade B), or severe (Child-Pugh grade C). Healthy control subjects were matched with hepatically impaired subjects by age (+/-10 years) and body weight (+/-20%). All subjects received a single oral dose of nilotinib 200 mg under fasted conditions, and serial blood samples were collected at specific times up to 120 hours after dosing. Serum nilotinib concentrations were measured using a validated LC-MS/MS assay with a lower limit of quantification of 2.5 ng/mL. The pharmacokinetic parameters analyzed were C(max), T(max), AUC(0-last), AUC(0-infinity), t(1/2), CL/F, and Vz/F. Tolerability assessments included adverse events (AEs), regular monitoring of clinical laboratory measures (eg, hematology, blood chemistry, urinalysis), physical examinations, vital signs, and ECGs. Each AE was evaluated in terms of its clinical significance, severity, duration, relation to study drug, and action taken. RESULTS: The study enrolled 18 subjects with hepatic impairment (all male; age range, 47-67 years; weight range, 73.9-103.9 kg) and 9 healthy controls (all male; age range, 36-62 years; weight range, 73.3-109.5 kg). Among subjects with hepatic impairment, 6 had mild impairment, 6 moderate impairment, and 6 severe impairment. The nilotinib AUC(0-infinity) was a mean of 35%, 35%, and 19% higher in subjects with mild, moderate, and severe impairment, respectively, compared with healthy controls. The nilotinib CL/F was lower in all hepatic-impairment groups compared with healthy controls. The mean (SD) t(1/2) was 15.1 (4.97) and 16.0 (9.13) hours in the mild-impairment and control groups, respectively, but was 21.6 (7.77) and 32.4 (10.7) hours in the moderate- and severe-impairment groups, respectively, reflecting the decrease in CL/F and/or increase in Vz/F in the latter 2 groups. All AEs were mild or moderate, and the frequency of AEs was not associated with the degree of hepatic impairment. AEs included abdominal pain (1 subject with mild impairment), dyspepsia (2 with mild impairment), flatulence (1 with severe impairment), nausea (1 with mild impairment), urinary tract infection (1 with mild impairment), back pain (1 each with mild impairment and severe impairment, 1 control subject), and headache (1 each with mild impairment and severe impairment). CONCLUSIONS: After a single 200-mg dose, nilotinib pharmacokinetics were modestly affected by hepatic impairment. The extent of change in nilotinib exposure in subjects with hepatic impairment was generally within the range of variability that has been observed clinically. The results of this study suggest that dose adjustment may not be necessary in patients with hepatic impairment. Nilotinib should be used with caution, and careful clinical monitoring is recommended in this population. ClinicalTrials.gov identifier: NCT00418626. Copyright 2009 Excerpta Medica Inc. All rights reserved.
2009 Nov;7(11):S1, S3-11.
Egorin MJ, Mauro MJ, Trent JC.
University of Pittsburgh Cancer Institute, PA, USA.
Drug plasma monitoring in CML and GIST: A case-based discussion.
Drug plasma monitoring has emerged as an important tool to obtain optimal levels of a particular drug among individual patients. Plasma monitoring of imatinib levels would appear to be practical in cases where there is lack of response, heightened toxicity, or evidence of poor adherence to therapy. However, the potential role of monitoring plasma drug concentrations in guiding treatment decisions and optimizing patient therapy has yet to be established. Currently, there are no clinical recommendations regarding how to incorporate imatinib drug plasma monitoring in patients with either chronic myeloid leukemia or gastrointestinal stromal tumors, indications for which imatinib is approved. Here, the latest research and evidence regarding imatinib drug plasma monitoring is discussed. Three cases are presented to illustrate the most common examples where monitoring imatinib plasma concentrations may help to guide treatment decisions. These cases include a suboptimal response to imatinib treatment, lack of patient adherence to imatinib, and imatinib-related toxicity. By understanding the potential role of monitoring plasma imatinib concentrations in patients with chronic myeloid leukemia or gastrointestinal stromal tumors, physicians can identify patients who may benefit from drug plasma monitoring and consider incorporating the data in order to improve patient outcomes.
2009 Dec;50 Suppl 2:1-8.
Aguayo A, Couban S.
Department of Oncology and Hematology, National Institute of Medical Sciences and Nutrition Salvador Zubiran, México City, Mexico.
State-of-the-art in the management of chronic myelogenous leukemia in the era of the tyrosine kinase inhibitors: evolutionary trends in diagnosis, monitoring and treatment.
The treatment of patients with chronic myeloid leukemia (CML) continues to evolve rapidly as we gain better insights into the best monitoring strategies and as there is experience with the second generation tyrosine kinase inhibitors (TKI). Certain observations about CML and its clinical course remain relevant, such at its triphasic course and the prognostic value of the Sokal and Hasford scores. Other aspects of the disease including the most appropriate clinical monitoring and follow-up strategies and indications for changing therapy are evolving more rapidly. Best practice recommendations for monitoring of response have not only evolved over time but also affected by the availability and reliability of standard cytogenetics, FISH and molecular monitoring. Standard dose imatinib remains the best first-line therapy for most patients with first chronic phase CML. Patient and disease-related factors to evaluate when considering alternatives such as higher doses of imatinib, dasatinib, nilotinib and allogeneic transplant are discussed.
2008 Sep;2(3):491-500.
Karp JE, Lancet JE.
Division of Hematologic Malignancies, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA;
Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia.
Farnesyltransferase inhibitors (FTIs) represent a new class of signal transduction inhibitors that block the processing of cellular polypeptides that have cysteine terminal residues and, by so doing, interdict multiple pathways involved in proliferation and survival of diverse malignant cell types. Tipifarnib is an orally bioavailable, nonpeptidomimetic methylquinolone FTI that has exhibited clinical activity in patients with myeloid malignancies including elderly adults with acute myelogenous leukemia (AML) who are not candidates for traditional cytotoxic chemotherapy, patients with high-risk myelodysplasia, myeloproliferative disorders, and imatinib-resistant chronic myelogenous leukemia. Because of its relatively low toxicity profile, tipifarnib provides an important alternative to traditional cytotoxic approaches for elderly patients who are not likely to tolerate or even benefit from aggressive chemotherapy. In this review, we will focus on the clinical development of tipifarnib for treatment of newly diagnosed AML, both as induction therapy for elderly adults with poor-risk AML and as maintenance therapy following achievement of first complete remission following induction and consolidation therapies for poor-risk AML. As with all other malignancies, the optimal approach is likely to lie in rational combinations of tipifarnib with cytotoxic, biologic and/or immunomodulatory agents with non-cross-resistant mechanisms of action. Gene expression profiling has identified networks of differentially expressed genes and gene combinations capable of predicting response to single agent tipifarnib. The clinical and correlative laboratory trials in progress and under development will provide the critical foundations for defining the optimal roles of tipifarnib and in patients with AMl and other hematologic malignancies.
2008 Jul;24(3):343-7.
Rekha PR, Rajendiran S, Rao S, Shroff S, Joseph LD, Prathiba D.
Histological reclassification, histochemical characterization and c-kit immunoexpression in renal cell carcinoma.
OBJECTIVES: Renal cell carcinoma is the most lethal of all urologic malignancies. Several parameters such as histological subtype, nuclear grade and TNM staging help in determining the prognosis and treatment options. A newer therapeutic modality has been suggested based on expression of c-kit antigen by the tumor cells. This study was designed to evaluate various histological parameters and correlate them with c-kit expression. MATERIALS AND METHODS: The study was done on 40 consecutive cases of renal epithelial tumors. Histological sections were reviewed and reclassified according to WHO (2004) classification and nuclear grade assessed. Hale's colloidal iron stain was done to identify the chromophobe variant. Immunostaining with c-kit was done and its expression was studied. The results were correlated and statistical significance was assessed. RESULTS: The age range was 31-81 years, with a male to female ratio of 2:1. Seventy per cent of the cases were clear cell RCC (ClRCC), 17.5% were chromophobe type, 7.5% were papillary RCCs and 5% cases were oncocytomas. Fuhrman nuclear grading revealed 60.5% cases to be of low grade and 39.5% high grade. Hale's colloidal iron staining was positive in chromophobe RCC and oncocytomas, while it was negative in ClRCC. Immunostaining with c-kit was positive only in oncocytomas. CONCLUSIONS: Clear cell RCC was the most common histological subtype of RCC. Clear cell RCC known to have a poor prognosis, showed a statistically significant higher nuclear grade than chromophobe and papillary RCCs which have a better prognosis. Hale's colloidal iron staining was extremely useful in distinguishing chromophobe RCC and oncocytoma from the granular cell variant of clear RCC. Our study revealed c-kit negativity in all RCC. As Imatinib could be ineffective in such tumors, its clinical activity has to be carefully assessed in such tumors through further studies.
2008 Dec;17(98):226-8.
Imatinib: a second look. Longer follow-up in chronic myeloid leukaemia: clear advantages.
(1) In 2002/2003, the clinical evaluation of imatinib, a tyrosine kinase inhibitor, in the treatment of chronic myeloid leukaemia left many questions unanswered. This article examines data published since then; (2) The only new data on first-line efficacy are the 5-year results of an unblinded trial comparing imatinib versus the interferon plus cytarabine combination. The survival rate was 89% with imatinib, versus about 70% in previous clinical trials of interferon plus cytarabine. Fewer than 2% of patients relapsed after responding to imatinib; (3) As second-line treatment for patients in the chronic phase, we now have non-comparative follow-up data on 532 patients in whom interferon had failed. At 5 years the overall survival rate was 79%, versus about 50% with standard treatments; (4) As second-line treatment for patients in the accelerated phase, we now have non-comparative follow-up data on 235 patients. After 3 years 55% of the patients were still alive, while the usual survival time is 3 to 18 months; (5) As second-line treatment of the blast crisis, we now have non-comparative follow-up data on 260 patients. After 3 years 14% of the patients were still alive, while the usual survival time for patients at this stage is 2 to 4 months; (6) The only new study is a non-comparative follow-up study of 50 children and adolescents aged 2 to 19 years treated with imatinib. The estimated 2-year survival rate was 84%. The haematological and cytogenetic response rates were similar to those reported in adults; (7) The initial clinical evaluation of imatinib showed that its main adverse effects were nausea and vomiting, oedema, fluid retention, muscle cramps, and cutaneous disorders. It was estimated that heart failure occurred in 1 to 10 per 1000 patients. A study of 54 patients confirmed the high incidence of cutaneous disorders. Cases of prostate and bladder cancer have been reported in patients treated with imatinib in France. A study of 16 patients suggests that imatinib might alter bone metabolism; (8) In France, treatment with imatinib costs about 25% more than the interferon plus cytarabine combination; (9) In practice, imatinib seems to increase survival time when used as a first-line or second-line treatment for patients in different phases of chronic myeloid leukaemia. Adverse effects must continue to be closely monitored.
2008 Nov;35(11):1863-7.
Imataki O, Shintani T, Waki F, Ohnishi H, Ishida T.
Division of Hematology, Dept. of Internal Medicine, Kagawa University.
[Tolerability of imatinib for patients with chronic myelogeneous leukemia (CML)] [Article in Japanese]
The adequate dose of imatinib has not been defined for the Japanese population. Indeed, about half of patients experience mild to moderate adverse events due to this drug, some of which result in intolerance. We reviewed a patients' cohort treated with imatinib in our hospital in 2007 for chronic myelogeneous leukemia (CML). The cohort included 14 patients (5 men and 9 women) whose median age was 53 (range 16-81). The disease status at onset was chronic phase in 13 patients and accelerated phase in 1. During the 2-year observation period, 2 patients (14%) failed to respond and 6 (42%) became intolerant to imatinib. After the appearance of the intolerance, 5 of the 6 patients were treated with a reduced dose of imatinib (300 mg/day in 4, 200 mg/day in 1). In 4 of these 6 intolerant cases, CR was maintained 2 years after the start of imatinib therapy. Nevertheless, 42% of patients were intolerant to imatinib therapy through 2 years, and progression-free survival was 86%. In conclusion, an adjusted dose exerting minimal toxicity and showing a favorable outcome should be researched in Japanese patients including the elderly.
2008 Jul 18;6:77.
Date RS, Stylianides NA, Pursnani KG, Ward JB, Mughal MM.
Department of Gastrointestinal Surgery, Lancashire Teaching Hospital NHS, Foundation Trust, Preston Road, Chorley, Lancashire, PR7 1PP, UK. ravidate@hotmail.com
Management of gastrointestinal stromal tumours in the Imatinib era: a surgeon's perspective.
BACKGROUND: Surgical resection has remained the mainstay of treatment of GIST with a 5-year-survival of 28-35%. Tyrosine kinase inhibitor (Imatinib) has revolutionised the treatment of these tumours. The current research is directed towards expanding the role of this drug in the treatment of GIST. We present our experience of managing GIST in this institute. METHODS: This is a case note study of patients identified from a prospectively kept database from January 2000 to August 2007. RESULTS: 16 patients were diagnosed with GIST. The median age was 66 years (range 46 to 82) and the male to female ratio was 9:7. Eleven patients underwent surgery, 9 of which had R0 resection (2 laparoscopic, 1 converted to open), one had an open biopsy and one had a debulking procedure. 3 patients were inoperable and 2 were found to be unfit for surgery. Five patients received Imatinib (2 postoperatively). The risk assessment based on morphological criteria showed that 4 patients had low, 4 had intermediate and 8 had high malignant potential. The median follow up was for 12 months (range 3-72); 2 patients died of unrelated causes at 6 and 9 months after diagnosis. CONCLUSION: Most GISTs can be managed effectively using existing protocols. However currently there is no evidence based guidance available on the management of GIST in the following situations-role of debulking surgery, the follow up of benign tumours not requiring surgical resection and role of laparoscopic surgery. Further research is needed to answer these questions.
2007;73(5-6):324-7. Epub 2008 May 23.
Zhu J, Wang Y, Hou M, Li HY, Zhang J.
3rd Department of Cancer Center, West China Hospital, Cheng Du, China. zhujiang1@medmail.com.cn
Imatinib mesylate treatment for advanced gastrointestinal stromal tumor: a pilot study focusing on patients experiencing sole liver metastasis after a prior radical resection.
BACKGROUND: About 80% of patients with gastrointestinal stromal tumor (GIST) experience tumor recurrence or metastasis after a prior radical resection, and the most common metastatic site is the liver. Imatinib mesylate has been proven to be effective in advanced GIST. The current pilot study was designed to observe imatinib mesylate treatment for GIST patients who experienced sole liver metastasis after primary tumor resection. METHODS: From June 2004 to July 2005, 21 patients who met the eligibility criteria were enrolled in this study. They were administered Glivec at an initial dose of 400 mg/day. The primary end points were grade 3-4 hematological or non-hematological toxicity and progression-free survival; the secondary end points were response rate and overall survival. RESULTS: Edema was the most common toxicity, whereas grade 3 and 4 side effects were rare. The overall response rate was 52.4%. Only 1 patient died in the course of the study; the 2-year progression-free and overall survival rates were 85.7 and 95.2%, respectively. CONCLUSIONS: Imatinib mesylate treatment proved safe and effective for GIST patients who had liver metastasis alone. A prolonged survival was observed, and long-term follow-up is still continued. 2008 S. Karger AG, Basel.
2007 Dec 25;87(48):3399-405.
Wang XD, Qiu L, Lu RZ, Chen LJ, Zhan ZM, Han BH, Zhang BL, Ma J.
Institute of Hematology & Oncology, Harbin 150010, China.
[Growth inhibition and differentiation of imatinib-resistant chronic myeloid leukemia cell induced by cell differentiation agent in vitro] [Article in Chinese]
OBJECTIVE: To investigate the effects of uroacitide (CDA-2), a cell differentiation agent, on the growth inhibition and differentiation of imatinib-(IM) resistant chronic myeloid leukemia (CML) cells. METHODS: IM resistant CML cell line K562R was established from the line K562. K562 and K562R CML cells were cultured with CDA-2 of different concentrations. MTI method was used to detect the survival rates. Bone marrow cells of IM-resistant and non-IM-resistant CML patients were collected and co-incubated with K562 and K562R cells. MTT and colony-forming assays were used to evaluate the efficacy of CDA-2 treatment for cell growth in K562 and K562R cell lines, and IM-resistant or non-IM-resistant bone marrow cells of the CML patients; Annexin-V staining was employed to detect the apoptosis. Cell differentiation was assessed by flow cytometry analysis with CD11b/CD14 markers, reverse transcriptase PCR (RT-PCR) for mRNA levels of NCF-1 and ORM-1 genes and Giemsa staining for the observation in morphology. Cell cycle distribution was detected by stained with propidium iodide and then analyzed by flow cytometer. RT-PCR also was employed for the expression of DNA methyltransferase. RESULTS: Significant cell growth inhibition was found at a dose-dependent manner in the IM-resistant K562R cell line and IM-resistant bone marrow cells of the CML patients compared with the non-resistant K562 cell line and bone marrow cells of the CML patients following 7 days exposure to CDA-2. Although CDA-2 could significantly induce the apoptosis of K562R (15.38%) compared with K562 (5.28%) (P < 0.05), the major reason for the cell growth inhibition of K562R is CDA-2-induced cell differentiation, including the increase of expression of differentiation-related antigens CD11b/CD14, mRNA expression of NCF-1 and ORM-1, and cell cycle arrest in G1-phase at a dose-dependent manner. Because CDA-2 could significantly activate the p21 and p27 gene expression, downregulate the expression of cyclin D1, and down-regulate the expressions of DNMT1 and DNMT(3B) at mRNA level, CDA-2 might be a DNMT inhibitor for restoring some gene function that involved in cell cycle control by demethylation. CONCLUSION: Inhibiting the growth and inducing the differentiation of K562R cells, CDA-2 is very likely to be a potential agent for the treatment of IM resistance CML patients.
2007 Nov;28(11):721-6.
Jiang Q, Chen SS, Jiang B, Jiang H, Qiu JY, Liu YR, Zhang Y, Qin YQ, Lu Y, Huang XJ, Lu DP.
Peking University, Institute of Hematology, People's Hospital, Beijing, China.
[The efficacy of imatinib mesylate for 124 patients with chronic myeloid leukemia in accelerated and blastic phase] [Article in Chinese]
OBJECTIVES: To evaluate the efficacy and safety of imatinib mesylate (imatinib) for patients with Philadelphia chromosome-positive (Ph+ ) chronic myeloid leukemia (CML) in accelerated and blastic phase. METHODS: Seventy-five Ph+ CML patients in accelerated phase and 49 in blastic phase were treated with 400 mg or 600 mg of imatinib once daily. RESULTS: For patients in accelerated phase, the cumulative hematological response (HR) rate was 93.3%, including complete HR (CHR) rate 85.3%, and returning to chronic phase (RCP) rate 8% in a median follow-up of 23.0 (1.0 -64.0 ) months. Cumulative major cytogenetic response (MCyR) rate was 33.0%, and complete cytogenetic response (CCyR) rate 28.0%. For patients with CCyR, the major molecular response (MMoR) rate was 47.6%. The estimated 4-year progression-free survival (PFS) rate and overall survival (OS) rate were 48.2% and 52.2% in patients with HR, respectively. Severe leukocytopenia, anemia and thrombocytopenia occurred in 37.3%, 34.6% and 45.3% of all patients, respectively. For patients in blastic phase, the cumulative HR rate was 63.3%, including CHR rate 44.9%, and RCP rate 18.4% in a median follow-up of 4.5 (0.3 -63.0) months. Cumulative MCyR rate and CCyR rate were both 12.2%. For patients with CCyR, the MMoR rate was 33.3%. For patients with HR, the estimated 1-year/2-year PFS and OS rates were 32.8%/15.8% and 46.0%/ 21.0% respectively. Severe leukocytopenia, anemia and thrombocytopenia occurred in 75.5%, 71.4% and 73.5% of all patients, respectively. CONCLUSIONS: The efficiency of imatinib was decreasing, and severer hematological toxicities increasing with the disease progressing in patients with Ph+ CML. Imatinib improves progression-free survival significantly in most patients in accelerated phase, particularly in those with continuous CCyR or MMoR. The response duration in majority of blastic phase patients is short, and the relapse rate is high.
2007;9(1):64-70.
Gomez D, Al-Mukthar A, Menon KV, Toogood GJ, Lodge JP, Prasad KR.
Hepatobiliary and Transplantation Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
Aggressive surgical resection for the management of hepatic metastases from gastrointestinal stromal tumours: a single centre experience.
BACKGROUND: The outcome of surgical intervention for hepatic metastases from gastrointestinal stromal tumours (GIST) is still uncertain. This study evaluated the outcome of patients following aggressive surgical resection and Imatinib mesylate therapy (IM). PATIENTS AND METHODS: This was a retrospective analysis of patients managed with hepatic metastases from GIST over a 13-year period (January 1993 to December 2005). RESULTS: Twelve patients were identified with a median age at diagnosis of 62 (32-78) years. The primary sites of GIST were stomach (n=5), jejunum (n=4), sigmoid (n=1), peritoneum (n=1) and pancreas (n=1). Eleven patients underwent surgical resection with curative intent and one patient had cytoreductive surgery. Following surgery with curative intent (n=11), the overall 2- and 5-year survival rates were both 91%, whereas the 2- and 5-year disease-free rates following primary hepatic resection were 30% and 10%, respectively. The median disease-free period was 17 (3-72) months. Eight patients had recurrent disease and were managed with further surgery (n=3), radiofrequency ablation (RFA) (n=2) and IM (n=8). Overall, there are four patients who are currently disease-free: two patients following initial hepatic resection and two patients following further treatment for recurrent disease. There was no significant association in clinicopathological characteristics between patients with recurrent disease within 2 years and patients who were disease-free for 2 years or more. Overall morbidity was 50% (n=6), with one postoperative death. The follow-up period was 43 (3-72) months. CONCLUSION: Surgical resection for hepatic GIST metastases may improve survival in selected patients. Recurrent disease can be managed with surgery, RFA and IM.
2007;91:169-76.
Sotlar K.
Institut für Pathologie, Universitäitsklinikum Tübingen.
[Therapeutically relevant mutations in the receptor tyrosine kinase KIT in mastocytosis] [Article in German]
Mastocytosis is characterized by an abnormal proliferation and accumulation of mast cells (MC) in one or more organ systems. The current WHO classification discriminates cutaneous mastocytosis (CM) and various forms of systemic mastocytosis (SM). While CM usually follows a bening and often self-limiting course, SM is a persistent disease in which a somatic KIT mutation at codon 816 (i.e. D816V) is detectable in MC in at least 80% of cases. Symptoms in mastocytosis result from MC-derived mediators and, less frequently, from destructive tissue infiltration by MC. The clinical course of SM is usually indolent, but sometimes it may be highly aggressive and rapidly devastating. KIT is a transmembrane class III receptor tyrosine kinase which is required for MC growth, differentiation, and functional activation. Mutations in codon 816 of the KIT gene result in ligand-independent (constitutive) activation of KIT signaling and, thus, may play a central role in the pathogenesis of SM. Since there are no curative options, therapy for the aggressive forms of SM is based on cytoreductive agents, e.g. interferon-alpha (IFN-alpha) and cladribine. The expression of KIT in neoplastic MC has led to the development of targeted therapies using tyrosine kinase inhibitors (TKI) like STI571 (Imatinib, Gleevec). Unfortunately, the KIT mutation D816V is associated with relative resistance against STI571. However, TKIs with activity against KIT D816V-positive cells have recently been developed, and some of them (dasatinib, nilotinib/AMN107, PKC412) are already tested in phase I/II trials. In addition, non-TK KIT signaling inhibitors (e.g. geldanamycin, rapamycin) or monoclonal antibodies directed against neoplastic MC may evolve as future therapeutic options.
Endocr Metab Immune Disord Drug Targets. 2009 Oct 19.
Zoubir M, Tursz T, Ménard C, Zitvogel L, Chaput N.
Centre d'Investigation Clinique Biothérapie 507, Laboratoire de Thérapie Cellulaire, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France.
Imatinib Mesylate (Gleevec(c)): Targeted Therapy against Cancer with Immune Properties.
The treatment against cancer is being flooded by targeted therapies. Imatinib mesylate (Gleevec(c)) was the first molecule to provide the proof of principle that targeting an aberrant tyrosine kinase responsible for the uncontrolled cell cycle progression allows for the eradication of tumors. The ideal targeted therapy should eliminate the molecular event responsible for the disease, an oncogenic product such as c-KIT, ABL/BCR and PDGFRa in the case of Gleevec(c). Two issues related to this conceptual advance are raised in clinical practice. First, these therapies might target additional pathways generating side effects. Secondly, non tumoral cells bearing the molecular target might respond and induce additional biological outcomes. This review will summarize the by-stander immune modulations promoted by the paradigmatic compound Gleevec(c), leading to unexpected new therapeutic indications.
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