Patients Receiving Imatinib Treatment Research Articles

Imatinib pharmacokinetics and creatine kinase levels in chronic myeloid leukemia patients: implications for therapeutic response and monitoring.

Imatinib treatment for certain cancers can lead to elevated creatine kinase (CK) levels, potentially indicating muscle injury, and ongoing research aims to understand the correlation between imatinib levels and creatine kinase to assess its impact on treatment response. This single-center observational study involved 76 chronic myeloid leukemia (CML) patients receiving imatinib treatment, focusing on evaluating drug and metabolite levels using liquid chromatography-mass spectrometry (LC-MS-MS) instrumentation. Serum CK and creatine kinase-MB (CK-MB) levels were assessed using Colorimetric kits. CK and CK-MB levels were measured, CK showed a median value of 211.5 IU/l and CK-MB showed a median value of 4.4 IU/l. Comparing low and high CK groups, significant differences were found in peak and trough plasma concentrations of imatinib and its metabolites. Correlations between CK levels and pharmacokinetic parameters were explored, with notable associations identified. Binary logistic regression revealed predictors influencing the therapeutic response to imatinib and categorized expected CK levels into high or low, with peak levels of imatinib emerging as a significant predictor for CK level categorization. The study highlights the link between imatinib's pharmacokinetics and elevated CK levels, indicating a possible correlation between specific metabolites and improved treatment response. Individualized monitoring of CK levels and imatinib pharmacokinetics could enhance care for CML patients.

Altered Expression of Pdgfrα and Its Downstream Signalling Components May be Causal in the Development of Imatinib Induced Thrombocytopenia in CML Patients Receiving Imatinib Treatment

Background:The main regulators of most of the cellular signalling pathways are protein kinases. Among these the receptor tyrosine kinases (RTKs) play important roles in cellular growth and proliferation by transmitting extracellular messages to intracellular signalling circuits. An important component of the intracellular circuits is the (PDGFR/PI3K/Akt/mTOR) pathway. Aberrant functioning of this pathway is known to occur in a number of diseases through various mechanisms. We report here that expression of PDGFRα gene and its downstream signalling components viz. PI3K and AKT is down regulated after imatinib treatment in some CML patients on imatinib therapy and may be a causal in the development of imatinib induced thrombocytopenia in these patients.Methods:A cohort of 100 chronic phase CML patients admitted to the Lok Nayak Hospital, New Delhi, India were included in this study. After initiation of imatinib treatment, haematological response of CML patients was monitored regularly for two years, in which development of thrombocytopenia was the primary end point.Total RNA, from blood samples of CML patients, was extracted using Trizol method. RNA concentration was determined by measuring absorbance at 260 nm. A cDNA synthesis kit (ThermoFisher Scientific, USA) was used for cDNA synthesis according to the manufacturer's instructions. The mRNA expression of all the genes was evaluated by quantitative SYBR Green based real time polymerase chain reaction (qRT-PCR) and results were expressed as fold change (2-∆∆ct). Results:Expression of PDGFRα, PI3K and AKT1 genes was significantly downregulated after imatinib treatment with a fold change (Mean + SD) of (2.12 + 0.41, 2.38 + 0.53 and 4.78 + 0.38 respectively) in CML patients receiving imatinib therapy (p < 0.0001). Further, we analysed the expression of PDGFRα, PI3K and AKT1 genes in two groups of CML patients- one that developed thrombocytopenia after imatinib treatment and the other that did not. We observed that there was a differential expression of PDGFRα and AKT1genes in thrombocytopenic and nonthrombocytopenic CML patients. Thrombocytopenic CML patients had a lower expression of PDGFRα and AKT1 genes in comparison to non-thrombocytopenic CML patients and this difference reached a statistical significance with a p-value of 0.02 and 0.04 respectively. Moreover, the expression of PI3K gene was also slightly downregulated in thrombocytopenic CML patients (fold change = 2.21+ 0.47 ) compared to nonthrombocytopenic ones (fold change = -2.55 + 0.57) but this difference did not reach a statistical significance (p=0.14). DisclosuresNo relevant conflicts of interest to declare.

Association between C1236T Genetic Variant of ABCB1 Gene and Molecular Response to Imatinib in Indonesian Chronic Myeloid Patients.

Objective:Imatinib is the first-line drug used for the treatment of chronic myeloid leukemia (CML) patients due to high molecular response and overall survival rate. However, some patients develop resistance to imatinib even after attaining a response. Mutation in ABCB1 efflux transporters is one of the known mechanisms of resistance to imatinib in chronic myeloid leukemia patients. This study was aimed to investigate the association of ABCB1 C1236T polymorphism in Indonesian chronic myeloid patients with molecular response to imatinib treatment. Methods:We analyzed 120 samples from chronic myeloid leukemia patients in the chronic phase, who had been on imatinib treatment for at least 12 months. We analyzed the C1236T variant of the ABCB1 gene using PCR, followed by direct sequencing, and associate them with the achievement of major molecular response (MMR). Results:The major molecular response was achieved in 28% of patients. The frequencies of the SNPs were CC (40%), CT (46%), and TT (14%). Our result showed that there was a lack of association between polymorphism of ABCB1 C1236T and imatinib response in Indonesian patients, with OR = 0.646 (95% CI: 0.283, 1.471; p>0.05). Conclusion:There was no association between ABCB1 C1236T variants with the major molecular response in Indonesian chronic myeloid leukemia patients receiving imatinib treatment.

Effect of Additional Chromosomal Abnormalities on the Outcome of CML-CP Patients Receiving TKI Therapy

To explore the effect of additional chromosomal abnormalities on the prognosis and outcome of CML-CP patients receiving imatinib therapy. The clinical and genetic data of 589 CML-CP patients receiving imatinib treatment between May 2009 and October 2014 in the 1st Affiliated Hospital of Soochow University were analyzed, the 589 patients were divided into 5 groups according to the karyotypes at the initial diagnosis. The OS(overall survival), PFS (progression-free survival), EFS (event-free survival), Cumulative MMR (major molecular remission) and Cumulative CCyR (complete cytogenetic remission) were calculated by using the Kaplan-Meier method and compared by using the log-rank text by Graphpad 6.0. The χ2 test was used to compare the frequency of optimal molecular response at 3, 6, 12 months among the 5 groups. There was significant difference about the frequency of optimal molecular response at 3 and 6 months between CML-CP patients with additional chromosomal abnormalities and those with classic t(9;22) ［50%（12/24） vs. 73.94%(261 /353), P<0.05; 50%(10 /20) vs. 72.05%(232 /322) (P<0.05)］, and the same significant difference was found at 6 months between the group with variant translocations and that with classic t(9;22) ［53.3% (16 /30) vs. 72.05%(232 /322) (P<0.05)］. The P values of cumulative CCyR (P<0.05) and EFS (P<0.01) for 4 years were statistically significant between CML-CP patients with additional chromosomal abnormalities and the other 4 groups. Compared one to another, there was the significant difference in cumulative CCyR and EFS for 4 years between CML-CP patients with additional chromosomal.abnormalities and those with classic t(9;22) (47.25% vs. 84.01%)(P<0.05); (75.03% vs. 90.01%)(P<0.01). The additional chromosomal abnormalities influence the outcome of CML-CP patients receiving imatinib treatment, which make poor prognosis.

Effect of MDR1 and CYP3A5 gene polymorphisms on outcomes of patients receiving imatinib treatment for chronic myeloid leukemia

To study the effect of MDR1 and CYP3A5 gene polymorphisms on the outcomes of imatinib treatment in patients with chronic myeloid leukemia (CML). A total of 100 patients with CML treated with imatinib were enrolled in this study, including 50 patients with cytogenetic relapse (study group) and 50 without cytogenetic relapse (control group) during the follow-up for 45 months. For all the patients, single nucleotide polymorphisms (SNPs) of C1236T, C3435T, and G2677T/A loci in the MDR1 gene and A6986G locus in CYP3A5 gene were genotyped and the trough levels of imatinib was measured using LC-MS/MS. The relationship between SNPs of the loci and the risk of cytogenetic relapse were analyzed. The risk of cytogenetic recurrence was significantly higher in patients with CC genotypes of MDR1-C1236T and MDR1-C3435T than in those with CT + TT genotypes (P < 0.05). The median survival time of the patients with TT genotypes of MDR1-C3435T and MDR1-C1236T was significantly higher than that of patients with CC genotypes and CT genotypes (P < 0.05). The incidences of hematologic toxicity and neutropenia were significantly higher in patients with cytogenetic relapse than in those without cytogenetic relapse (P < 0.05). MDR1-C3435T genotype and imatinib concentration were independent predictors of cytogenetic relapse of CML. The risk of cytogenetic relapse of CML was significantly affected by SNPs of C1236T and C3435T loci of MDR1 gene and blood imatinib concentration. MDR1-C3435T genotype can be used as a potential biomarker for predicting cytogenetic relapse in CML patients.

Hepatic Metastatic GIST: Diagnostic and Therapeutic Difficulties in Souro Sanou Teaching Hospital in Bobo Dioulasso, Burkina Faso

Introduction: Gastrointestinal stromal tumor (GIST) is the most common non-epithelial, mesenchymal tumor of the digestive tract. Targeted therapy has improved the prognosis but the diagnosis must be accurate before using the existing drugs. Aim: To report the diagnostic difficulty in our context through the clinical polymorphism and define the position of targeted therapy in the management of GIST metastatic stomach. Casuistry: We report 3 cases of gastric GIST with liver metastasis in different circumstances of discovery. Patients were 21, 45, and 73 years old. Discovery circumstances were respectively digestive hemorrhage, severe clinical anemia, abdominal tumor and gastric tumor. There was hepatic metastasis in the three cases. The three patients received Imatinib treatment, adjuvant treatment for the first two cases, and neo-adjuvant treatment for the third case, with a very good clinical response and CT response on metastases. Conclusion: Because of their rarity, GISTs are often difficult to diagnose, and necessarily require immunohistochemistry which is not available in our work context. The effectiveness of targeted therapy even on metastasis needs a rigorous diagnostic approach to improve patient survival.

PDGFRα promoter polymorphisms and expression patterns influence risk of development of imatinib-induced thrombocytopenia in chronic myeloid leukemia: A study from India.

Platelet-derived growth factor receptor has been implicated in many malignant and non-malignant diseases. Platelet-derived growth factor receptor-α is a tyrosine kinase and a side target for imatinib, a revolutionary drug for the treatment of chronic myeloid leukemia that has dramatically improved the survival of chronic myeloid leukemia patients. Given the importance of platelet-derived growth factor receptor in platelet development and its inhibition by imatinib, it was intriguing to analyze the role of platelet-derived growth factor receptor-α in relation to imatinib treatment in the development of imatinib-induced thrombocytopenia in chronic myeloid leukemia patients. We hypothesized that two known functional polymorphisms, +68GA insertion/deletion and -909C/A, in the promoter region of the platelet-derived growth factor receptor-α gene may affect the susceptibility of chronic myeloid leukemia patients receiving imatinib treatment to the development of thrombocytopenia. A case-control study was conducted among a cohort of chronic myeloid leukemia patients admitted to the Lok Nayak Hospital, New Delhi, India. A set of 100 patients of chronic myeloid leukemia in chronic phase and 100 age- and sex-matched healthy controls were studied. After initiation of imatinib treatment, the hematological response of chronic myeloid leukemia patients was monitored regularly for 2 years, in which the development of thrombocytopenia was the primary end point. Platelet-derived growth factor receptor-α promoter polymorphisms +68GA ins/del and -909C/A were studied by allele-specific polymerase chain reaction. Platelet-derived growth factor receptor-α messenger RNA expression was evaluated by quantitative real-time polymerase chain reaction. The messenger RNA expression results were expressed as 2-Δct ± standard deviation. The distribution of +68GA ins/del promoter polymorphism genotypes differed significantly between the thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p < 0.0001). Moreover, +68GA del/del and ins/del genotypes in imatinib-treated chronic myeloid leukemia patients were associated with an increased risk of developing thrombocytopenia, with odds ratios 6.5 (95% confidence interval = 2.02-0.89, p = 0.001) and 6.0 (95% confidence interval = 2.26-15.91, p = 0.0002), respectively. Similarly, -909C/A promoter polymorphism genotype distribution also differed significantly between thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p = 0.02), and a significantly increased risk of imatinib-induced thrombocytopenia was associated with -909C/A polymorphism mutant homozygous (AA) genotypes the odds ratio being 7.7 (95% confidence interval 1.50 to 39.91, p = 0.009). However, no significant risk of imatinib-induced thrombocytopenia was found to be associated with heterozygous genotype (-909C/A) with odds ratio 1.9 (95% confidence interval = 0.86-4.56, p = 1.14). Platelet-derived growth factor receptor-α messenger RNA expression was significantly higher in chronic myeloid leukemia patients compared to controls (p = 0.008). Moreover, patients with imatinib-induced thrombocytopenia had a significantly lower platelet-derived growth factor receptor-α messenger RNA expression, compared to patients without thrombocytopenia (p = 0.01). A differential expression of platelet-derived growth factor receptor-α messenger RNA was observed with respect to different +68 GA ins/del and -909C/A polymorphism genotypes. The +68GA deletion allele and -909A allele were significantly associated with lower expression of platelet-derived growth factor receptor-α messenger RNA. The platelet-derived growth factor receptor-α +68GA del/del, +68GA ins/del, and -909AA genotypes are associated with an increased risk of developing thrombocytopenia in imatinib-treated chronic myeloid leukemia patients. A significantly lower platelet-derived growth factor receptor-α messenger RNA expression accompanies the +68GA deletion allele in an allele dose-dependent manner. Platelet-derived growth factor receptor-α -909AA genotype is also associated with lower expression of platelet-derived growth factor receptor-α. The downregulation of platelet-derived growth factor receptor-α expression may play a causative role in imatinib-induced thrombocytopenia, a common side effect, in the subset of chronic myeloid leukemia patients with platelet-derived growth factor receptor-α +68 GA ins/del, +68 GA del/del, and -909C/A genotypes.

Clinical characteristics and treatment outcome in a large multicentre observational cohort of PDGFRA exon 18 mutated gastrointestinal stromal tumour patients

PurposePatients, platelet-derived growth factor receptor alpha (PDGFRA) D842V-mutated gastrointestinal stromal tumours (GISTs) are known for their insensitivity to imatinib. However, in clinical practice responses have been observed in some patients. We describe the natural history and treatment outcomes in a cohort of PDGFRA exon 18 mutated GIST patients. Patients and methodsA retrospective cohort study was conducted in PDGFRA exon 18 mutation GIST patients treated in six expert centres in the Netherlands and the United States. Two independent radiologists assessed radiological response to imatinib according to Choi's criteria in all patients with measurable disease treated with imatinib in neo-adjuvant or palliative intent. ResultsSeventy-one patients with PDGFRA exon 18 mutation were identified of whom 48 patients (69%) had a D842V mutation. Twenty-two (45.8%) D842V-mutated GIST patients received imatinib treatment, 16 had measurable disease. Fourteen out of the 23 (60.9%) patients with non-D842V mutations received imatinib treatment, eight had measurable disease. Two out of 16 (12.5%) D842V-mutated GIST patients had partial response, 3 patients (18.8%) had stable disease and 9 patients (56.3%) had progressive disease as best response. Two patients did not have follow-up computed tomography scans to assess response. Six out of 8 (75%) patients with non-D842V exon 18 mutations had partial response and two (25%) had stable disease as best response. ConclusionPatients with D842V-mutated GISTs can occasionally respond to imatinib. In the absence of better therapeutic options, imatinib should therefore not be universally withheld in patients with this mutation.

Molecular mechanism of gastrointestinal stromal tumors and progress in drug research

The functional mutation of c-kit and platelet-derived growth factor receptor α (PDGFRA) which encode proto-oncogene receptor tyrosine kinase are the crucial pathogeneses of gastrointestinal stromal tumors(GISTs). 80%-85% c-kit gene mutation including exon 11,exon 9,exon 13,exon 17 and 5%-10% PDGFRA gene mutation such as exon 18, exon 12 are examined in GISTs. Neither of c-kit or PDGFRA gene mutation are called wide type GISTs. The pathogeneses of wild type GISTs are not clear. The deficiency of succinate dehydrogenase B(SDHB)-related insulin-like growth factor 1(IGF-1R) activation, BRAF gene mutation and neurofibromatosis type 1 may be related to progression of wild type GISTs. More than half of metastatic GISTs patients receiving imatinib treatment can develop to c-kit secondary mutations, which are responsible for secondary resistance. However, the reasons of imatinib resistance in GISTs without c-kit secondary mutation need to be explored. At present, many clinical trials are ongoing to evaluate new drugs in GISTs treatment, including nilotinib, masitinib, pazopanib, dovitinib, ponatinib, dasatinib, crenolanib, linsitinib and immunotherapy, which may bring resistance GISTs treatment to new hope. Next generation sequencing (NGS) and liquid biopsy will be very important in GISTs research and clinical practice.

The prognostic value of early BCR-ABL transcripts level in 251 patients with chronic myeloid leukemia after treatment with imatinib

目的了解慢性髓性白血病（CML）患者伊马替尼治疗早期BCR-ABL转录本水平的预后价值，为CML患者早期预后评估和治疗选择提供依据。方法回顾性分析251例接受伊马替尼一线治疗CML慢性期（CML-CP）患者的临床资料，分别比较治疗后3个月及6个月不同BCR-ABL转录本水平患者的无进展生存（PFS）率及总体生存（OS）率，并采用卡方检验及Logistic回归分析方法分析疾病进展的危险因素。结果伊马替尼治疗3个月BCR-ABL转录本>10％组（92例）、>1%~10％组（94例）、≤1％组（65例）的PFS率分别为53.3%、71.3%、86.2%（P<0.05），OS率分别为92.4%、96.8％和93.8%（P>0.05）。伊马替尼治疗后6个月时BCR-ABL转录本>10％组（22例）、>1%~10%（50例）组、≤1%（110例）组PFS率分别为27.3%、66.0%和82.7%（P<0.05），OS率分别为86.4%、94.0%、100%（P<0.05）。Logistic回归分析结果显示3个月及6个月BCR-ABL转录本水平为影响疾病进展的独立危险因素。结论伊马替尼治疗3个月及6个月BCR-ABL转录本水平对CML患者预后评估具有重要价值。

Clinicopathological analysis of 80 patients with duodenum gastrointestinal stromal tumors

To explore the clinicopathological characteristics, efficacy, and prognostic factors for patients with duodenum gastrointestinal stromal tumor(GIST). Clinicopathological and follow-up data of 80 patients with duodenum GIST in the Zhongshan Hospital from January 2000 to December 2013 were analyzed retrospectively. There were 38 male and 42 female patients with a median age of 54 years. The major symptoms were upper alimentary tract hemorrhage and abdominal pain. Thirty-nine patients received local tumor excision, 18 patients underwent segmental duodenectomy, 23 patients were subjected to pancreaticoduodenectomy, all these operations were R0 resection. Thirty patients received imatinib treatment after operation, and 11 among them had metastasis relapse. Recurrence-free survival rates of 1-, 3-, and 5-years were 96.2%, 90.6%and 78.6% retrospectively. Overall survival rates of 1-, 3-, and 5-years were 100%, 98.3% and 96.1%. Multivariate Cox analysis showed tumor size >5 cm, mitotic count >5 mitosis/50 HPF and intermediate/high NIH risk classification were associated with an increased risk of recurrence. The significant difference was not detected between the limited resection group and pancreaticoduodenectomy group in OS and RFS. Surgery is still the main treatment for duodenum GIST. The surgical program is mainly determined by the location and size of tumor. Imatinib therapy should be used if necessary.

Recombinant erythropoietin for the anaemia of patients with advanced Gastrointestinal Stromal Tumours (GIST) receiving imatinib: an active agent only in non progressive patients

Recombinant erythropoietin for the anaemia of patients with advanced Gastrointestinal Stromal Tumours (GIST) receiving imatinib : an active agent only in non progressive patients.BackgroundImatinib is a standard treatment for advanced/metastatic GIST and in adjuvant setting. Anaemia is frequently observed in patients with advanced GIST, and is one of the most frequent side effects of imatinib with grade 3–4 anaemia in 10% of patients. Whether EPO treatment is useful in the management of GIST patients receiving imatinib treatment is unknown.MethodsA retrospective study of EPO treatment in GIST patients receiving imatinib was undertaken in 4 centres. Thirty four patients received EPO treatment among the 319 GIST patients treated with imatinib in clinical trials or with compassionate use between 2001 and 2003. The efficacy of EPO on the anaemia of patients with GIST treated with imatinib was analyzed.ResultsThere were 18 males and 16 females with a median age of 59 years. Median WHO-PS was 1. Primary tumour sites were mainly gastric (32%) and small bowel (29%). Sites of metastases were mainly liver (82%) and peritoneum (79%). The median delay between the initiation of imatinib treatment and EPO was 58 days (range 0–553). Median haemoglobin (Hb) level prior to EPO was 9 g/dL (range 6,9-11,8) and 11,7 g/dL (range 6,8-14,4) after 2 months. An increase of more than 2 g/dL was observed in 18 (53%) of patients. None of the 7 patients who progressed (PD) under imatinib treatment (400 mg/day) experienced HB response, as compared to 66% (18/27) of the remaining patients (PR + SD) (p = 0,002). Primary tumour site, liver metastases, peritoneal metastases, age, gender did not correlate with HB response to EPO. Response to EPO was observed in 2/11 patients receiving high-dose imatinib (800 mg/day) vs 16/23 of others. Using logistic regression, only PD before EPO treatment was retained as a predictive factor for EPO response.ConclusionEPO enables to increase Hb in most anaemic GIST patients who do not progress under imatinib, but not in patients with progressive disease.

Prognostic analysis of chronic myeloid leukemia in Chinese population in an imatinib era

We evaluated the outcomes of chronic myeloid leukemia (CML) patients receiving imatinib treatment in chronic (CP), accelerated (AP), and blast crisis (BP) phases. The single-institution treatment experiences of Chinese patients with CML were presented. A total of 275 CML patients (CP, 210; AP, 24; and BP, 41) who received imatinib between February 2001 and April 2008 were enrolled in this study. We evaluated the treatment responses (hematologic, cytogenetic, and molecular), overall survival (OS), event-free survival (EFS), and prognostic factors of outcome. At the cut-off point, the complete cytogenetic response (CCyR) and complete molecular response rates of patients in the CP were 84.7% and 61.9%, respectively, which were significantly higher than those of patients in the AP (50% and 29.1%, respectively, both P < 0.001) and BP (24.3% and 9.7%, respectively, both P < 0.001). The estimated five-year OS and five-year EFS rates were 93.2% and 86.4% for CP patients, as well as 64.5% and 50.9% for AP patients, which were significantly higher than those for BP patients (P < 0.001). In CP patients, univariate analysis revealed that early treatment with imatinib, achieving CCyR within 12 months, additional cytogenetic abnormalities, and kinase domain mutations were associated with the treatment outcome. More patients are needed to carry out multivariate analysis.

Correlation between Imatinib Trough Concentration and Efficacy in Chinese Chronic Myelocytic Leukemia Patients

Background: Trough imatinib plasma concentration, intracellular drug levels and expression of drug transporters can be indicative of clinical responses in chronic myelocytic leukemia (CML) patients receiving imatinib. We aimed to determine plasma imatinib concentration, intracellular imatinib concentration, human organic cation transporter 1 (hOCT1) and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) mRNA expression in bone marrow cells of CML patients in order to evaluate the potential usefulness of these measures as markers of imatinib efficacy and understand their clinical relationships. Methods: Eighty-four CML patients receiving imatinib treatment were included in this study. Imatinib trough concentration was determined by high-performance liquid chromatography-tandem mass spectrometry. Real-time quantitative PCR with a TaqMan probe was used to assess hOCT1 and ABCB1 mRNA expression in bone marrow cells. All patients were divided into the major molecular response (MMR), complete cytogenetic response (CCyR), partial cytogenetic response (PCyR) or drug-resistant groups according to their response. Results: The plasma imatinib trough concentration was significantly higher in the MMR group than in the PCyR (p = 0.002) or drug-resistant groups (p = 0.011). The plasma imatinib trough concentration was also significantly higher in the CCyR group than in the PCyR group (p = 0.027). There were no significant differences between the CCyR and MMR groups with regard to the plasma imatinib trough concentration (p = 0.136). The intracellular imatinib concentration in bone marrow cells was significantly higher in the CCyR group compared to the drug-resistant or PCyR groups (p = 0.013). The hOCT1 mRNA expression in bone marrow cells was significantly higher in the CCyR group than in the drug-resistant or PCyR groups (p = 0.036). The ABCB1 mRNA expression in bone marrow cells was significantly higher in the drug-resistant group than in the CCyR or PCyR groups (p = 0.013). Plasma imatinib trough concentration was positively correlated with α₁-acid glycoprotein (r = 0.443, p < 0.001) or dose (r = 0.422, p < 0.001). Conclusions: Clinical responses in CML patients are correlated with both the plasma trough concentrations and intracellular levels of imatinib.

Long-Term Outcome of Imatinib Treatment in Chronic Myeloid Leukemia (CML) Patients in Shanghai: An International Patient Assistance Programs (GIPAP) Analysis.

Abstract 4275Imatinib as an oral Bcr-Abl tyrosine kinase inhibitor is approved as first-line therapy for patients with CML chronic phase (CP), accelerated phase (AP) and blast crisis (BC). As the appointed clinical center for the International Patient Assistance Programs (GIPAP) program, a total of 339 CML patients with CML-CP (n=274), AP (n=30) and BC (n=35) were registered and received imatinib treatment in our center. The starting dose of Imatinib treatment was 400mg daily and dose escalation to 600mg was allowed in patients of CML-AP or BC and in patients who failed to obtained optimal response. All patients were evaluated regularly according to the GIPAP protocol. In this study, we analysed the outcome of Imatinib treatment in these patients in terms of cytogenetic response, overall and progression-free survival and adverse events. The median age was 42 (13-81) years old. The median time from diagnosis to imatinib therapy was 4.4 (0-273) months. The median follow-up was 29 (3-103) months. The overall survival for patients received Imatinib treatment were 92.8±3.1%, 57.3+11.3% and 12.3±9.7% for CML-CP, AP and BC respectively. Among patients with CML-CP, the cumulative complete cytogenetic response (CCyR) were 71.9% at 12 months and 79.9% at the censored follow-up timepoint. In prognosis analysis, there were two major impact factors associated with progression-free survival (PFS) for the CML-CP patients: achievement of CcyR and Imatinib as initial therapy. The estimated 60 month PFS was 87.1±3.7% for patients who achieved a CCyR irrespective of time and only 46.7±1.37% for patients who failed to obtain a CCyR (P<0.0001). For those patients who received imatinib as initial therapy (95.6±1.85%) had a significantly superior PFS than those patients received imatinib as secondary treatment after initial interferon therapy either due to intolerance or failed to obtain optimal response (65.9±6.4%, P<0.0001). Overall Imatinib was well tolerated and no patient switched to other treatment due to toxicity of Imatinib treatment. Overall, Imatinib as initial treatment for CML-CP was effective and safe in the first analysis of GIPAP program in Shanghai. Disclosures:No relevant conflicts of interest to declare.

Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by RQ-PCR for BCR-ABL

Real-time quantitative polymerase chain reaction (PCR) for BCR-ABL mRNA in the peripheral blood (RQ-PCR) provides an accurate and reliable measure of response to therapy in chronic myeloid leukaemia (CML). We wanted to determine in what circumstances additional clinically relevant information was provided by simultaneous cytogenetic analysis in RQ-PCR monitored patients receiving imatinib treatment. We analysed 828 simultaneous RQ-PCR and bone marrow cytogenetic analyses from 183 patients with chronic phase CML with a median follow-up of 20 months. Cytogenetic progression was defined as Philadelphia (Ph)-positive clonal evolution, loss of complete cytogenetic response or an increase of > or = 20% Ph-positive cells. Cytogenetic progression occurred in 24/183 (13%) patients. At the time of cytogenetic progression, none of the 24 patients had a major molecular response (MMR; > or = 3-log reduction in BCR-ABL from standardised baseline). There were 320 RQ-PCR results from 95 patients indicating MMR. No abnormality was detected in any of the corresponding cytogenetic analyses. A policy of regular RQ-PCR monitoring with cytogenetic analysis targetted only to patients who have not achieved, or have lost MMR would represent a rational approach to monitoring and spare most patients the discomfort of multiple marrow aspirates. This approach depends upon availability of an accurate, reproducible RQ-PCR assay with ongoing quality assurance.

Erythropoietin for anemia treatment of patients with GIST receiving imatinib

9046 Background:Imatinib (Glivec®) is a c-kit tyrosine kinase inhibitor recently established as the standard treatment for advanced/metastatic GIST. Anemia is frequently observed in patients with advanced GIST, and is one of the most frequent side effects of imatinib (89% of patients) while this drug causes grade 3–4 anemia in 10% of patients. Whether EPO treatment is useful in the management of GIST patients receiving imatinib treatment is unknown. Methods:A retrospective study of EPO treatment in GIST patients receiving imatinib was undertaken in 4 centers. Thirty four patients received EPO treatment among the 319 GIST patients treated with imatinib in clinical trials or with compassionate use since 2001. The impact of EPO treatment on the anemia and the predictive factors of efficacy were investigated. Results:34 patients were included as follows: Male/Female=18/16; median age= 59 years; median WHO-PS= 1; metastatic/advanced GIST= 32/2. Original site of disease was mainly gastric (32%) and small bowel ...