Imatinib Mesylate In Patients Research Articles

Safety outcomes of low versus high dose imatinib mesylate in patients with advanced, metastatic, or nonresectable gastrointestinal stromal tumors: A systematic review.

Gastrointestinal stromal tumors (GIST) are a rare cancer where tumors grow along the gastrointestinal tract. While treatment options aim towards surgical resection, some patients present with advanced metastatic and/or nonresectable diseases. The tyrosine kinase inhibitor imatinib mesylate is approved for this indication. However, dose escalation from 400 to 600 mg/d or 800 mg/d is allowed. The present study systematically evaluates the safety outcomes, particularly the incidence of grade ⩾ 3 adverse events (AEs) with low dose compared with high dose imatinib in these patients. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines were utilized to identify relevant studies through the PubMed, Cochrane Library, and Ovid databases and included randomized and non-randomized clinical trials comparing a low dose intervention of imatinib 400 mg/d with a high dose comparator of 600 or 800 mg/d in patients with histologically confirmed advanced metastatic and/or nonresectable GIST. Four studies were reviewed regarding study summaries and patient characteristics, patient demographics, and risk of bias, with a main emphasis on the evaluation of both efficacy outcomes and safety outcomes. Three of the four studies did not provide significant differences in response outcomes; however, all four studies reported a higher incidence of grade ⩾ 3 AEs in the high dose imatinib groups. Individual study reports of more high dose patients experiencing a grade ⩾ 3 event ranged from 0.6% to 19.8%, while combined low and high dose patient arms revealed a 17.1% difference favoring a high dose patient event. A sub-analysis of the three most frequently occurring categories, blood and lymphatic system disorders, gastrointestinal disorders, and general disorders and administration site conditions each revealed more high dose patients experiencing said category events compared to those low dose counterparts. Low dose imatinib provides clinically meaningful response and demonstrated better tolerability with less frequently reported reactions. This evidence supports further research into the maintenance of 400 mg/d for this patient population compared to a dose escalation.

CML-344 Adherence to Imatinib Mesylate in Patients Newly Diagnosed With Chronic Myeloid Leukemia in India Over the First Year of Treatment and How to Improve Compliance

Chronic myeloid leukemia (CML) is treated with the first-line agent imatinib; however, it was seen that adherence to treatment had been poor in many patients. Therefore, a study was carried out to find causative reasons for the discontinuation of treatment, with the ultimate goal to improve rates of compliance. The aim of the study was to identify reasons for adherence failure in patients treated with imatinib for CML and to detect a way to improve adherence. A prospective review of 160 patients with newly diagnosed Philadelphia chromosome-positive CML was undertaken to check for rates of adherence to treatment with imatinib. The patients were equally distributed with 77 men and 83 women and had an average age of 40 years. Due to imatinib being the only option for most patients in India for CML, those who discontinued it were reinforced about the importance of being compliant with treatment. The rates of patients who restarted imatinib after reinforcement were recorded. It was found that out of 160 patients over the initial year of treatment, 87 patients (54.3%) continued to take imatinib and 73 patients (45.6%) discontinued treatment. The most common reasons for discontinuation of treatment were due to adverse drug events such as headaches, weight gain, musculoskeletal symptoms, and GI disturbances. Of the 73 patients, 60 (82.3%) stopped taking imatinib due to adverse drug events, 10 (13.6%) patients were lost to follow-up, and 3 (4.1%) patients wanted to pursue holistic methods of treatment. The 60 patients who stopped taking imatinib due to adverse drug events were counseled on the benefits of pursuing treatment despite some adverse effects. Out of the 60 patients who stopped imatinib due to adverse effects after counseling, 43 (71.6%) patients restarted imatinib. The patients' adherence to imatinib in our study was found to be 46%, with the majority of patients discontinuing treatment due to adverse effects. However, after counseling patients on the overall benefits of taking imatinib, compliance improved. The authors believe that compliance can be improved by taking the time to educate patients on the benefits of treatment with reinforcement.

Modulation of Plasma 25-Hydroxyvitamin D3 Level by Imatinib Mesylate in Patients with Chronic Myelogenous Leukemia: The Role of Uptake and Efflux Transporters

BackgroundVitamin D deficiency is a common side effect of imatinib mesylate (IM) therapy. Transporter polypeptides involved in the disposition of IM may be required for maintenance of adequate vitamin D concentrations.ObjectiveThe aim of the present work is to study the association between the plasma concentrations of IM and plasma 25-hydroxyvitamin (25[OH]) D3 with transporter genotypes in patients with chronic myelogenous leukemia.MethodsA total of 77 adult patients with chronic myelogenous leukemia treated with IM participated in this study. Peak and trough plasma IM and 25(OH) vitamin D3 concentrations were measured and compared to the results of single nucleotide polymorphisms of the efflux transporting gene ABCB1-1236 C>T and the uptake transporting gene OATP1B3-334 T>G. Multiple linear regressions were used to examine the associations between 25(OH) vitamin D3 concentrations and a number of patient characteristics, including responses to therapy. Binary logistic regression analysis was used to predict odd ratios for the clinical response to IM.ResultsPlasma 25(OH) vitamin D3 concentration quartile values were: 25%, 8.2 ng/mL; 50%, 9.8 ng/mL; and 75%, 12 ng/mL. High IM peak concentration, being OATP1B3-334 T>G (TT), and/ or ABCB1-1236 C>T (CT) are associated with lower concentrations of 25(OH) vitamin D3. Moreover, IM peak concentration, IM trough concentration, and plasma concentration of 25(OH) vitamin D3 were associated with the clinical response to IM.Conclusionsvitamin D, IM concentration, as well as the genotype of OATP1B3-334 T>G, had an influence on the response of patients with chronic myelogenous leukemia.

Multicenter Phase II Study to Evaluate Therapeutic Efficacy of Imatinib Mesylate in Patients with Steroid-Refractory Chronic Graft-Versus-Host Disease

BackgroundGraft-versus-host disease (GVHD), where T- and B-cells derived from the graft attack host, is still a vital hurdle to overcome for successful allogeneic stem cell transplantation (allo-SCT). In particular, chronic GVHD (cGVHD) occurs approximately 30-70% of the patients and it is the most relevant cause of non-relapse morbidity (NRM) after allo-SCT. This multicenter, phase II study evaluated the safety and efficacy of imatinib mesylate in patients with steroid-resistant cGVHD. In addition, we scored the quality of life of the enrolled patients using Short Form Health Survey Questionnaire (SF-36).Patients and methodsA total of 36 patients who diagnosed with steroid-refractory cGVHD participated in this study and treated with imatinib from March 2013 to February 2019. Enrolled patients received 100mg of imatinib daily for 2 weeks. Every 2 weeks, imatinib dosage was increased up to 400 mg/day if the patients did not have any grade 3-4 adverse event. Patients who showed stable disease (SD), partial remission (PR) and complete remission (CR) in the 3-month response evaluation continued the imatinib up to 6 months. Treatment response was evaluated every 2 weeks for 6 months according to the NIH global scoring system. Survival outcomes of the enrolled patients were followed up to 2 years. Quality of life was also evaluated using SF-36 at 1, 3, and 6 months after starting imatinib treatment.Response of cGVHD was evaluated based on the NIH response criteria by scoring each involved organ sites with four-point scale (0-3). CR was defined as resolution of all reversible manifestations related to cGVHD. Partial response (PR) of cGVHD was defined clinical score reduction of at least one point in one or more affected organs. Disease progression or treatment failure was defined as increased score at least one point in one or more organs or occurrence of any new symptoms or signs of c GVHD. Failure-free survival (FFS) and overall survival (OS) were calculated from the day of starting imatinib.ResultMedian age was 47.5 years (23-63). Majority of the patients were diagnosed with acute leukemia (75%) and myelodysplastic syndrome (16.9%), and underwent allo-SCT in CR disease status (69.5%). Twenty-five (69.4%) patients experienced acute GVHD. Most of the patients presented overlap symptoms. Skin GVHD was identified in 23 (63.9%) patients. Lung, mouth, and eye involvement were found in 16 (44.4%), 14 (38.9%), and 14 (38.9%) patients, respectively. All of the enrolled patients had been treated with steroid due to moderate (55.6%), and severe (44.4%) grade cGVHD.Overall, median duration of imatinib therapy was 5.4 months and no severe adverse effect over grade 3 was reported. The last therapeutic mean dosage of imatinib was 305.6 mg/day. Three patients (8.3%) achieved CR, and 18 (50%) and 12 patients (33.3%) were reported as PR and SD. Treatment failure was identified in three patients (8.3%). Overall response rate (ORR) of imatinib was 58.3% and 25 patients (69.4%) could reduce the steroid. According to the each involved organ site, ORR of the gastrointestinal (GI) and liver cGHVD were 70.5% and 66.7%, while skin and lung were 34.8% and 25.0%, respectively. The efficacy of imatinib was better in GI, liver, and mouth than skin and lung in the current clinical study. With the median follow-up duration of 28.5 months, two-year FFS and OS rate were 76% and 88.5%. Responders to the imatinib therapy showed a superior tendency in OS than non-responders (p = 0.066). In the patients-reported QOL evaluation with SF-36, both physical and mental component score were improved. Particularly, a factor representing emotional well-being was significantly improved (p = 0.002).ConclusionThis multicenter clinical study showed that imatinib is an effective option not only for skin GVHD but also for GI and liver involvement. Moreover, QOL of the patients tended to improve during imatinib treatment with steroid dose reduction. [Display omitted] DisclosuresLee: Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board; Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees.

Evaluation of Myelosupression during Imatinib Mesylate Therapy in Patients with Chronic Myeloid Leukaemia

Introduction:Chronic Myloid Leukaemia (CML) is a myeloproliferative neoplasm that originates in an abnormal pluripotent stem cell. Imatinib, a tyrosine kinase inhibitor, is the drug of choice for CML in the present time. During therapy, a few patients develop myelosuppression and present with cytopenias.
 Objectives: To evaluate myelosupression during therapy with Imatinib mesylate in patients with Chronic myloid leukaemia in chronic phase.
 Materials and Methods: This cross sectional observational study was carried out at department of Haematology, Combined Military Hospital, Dhaka and Haematology OPD, Bangabandhu Sheikh Mujib Medical University (BSMMU) from October 2011 to September 2012. A total of 30 patients fulfilling the inclusion criteria were included in this study. Data were collected in a structured proforma, analyzed with SPSS and expressed in mean, frequency and percentage.
 Results: Patients mean age was 38.96±9.37 years ranging from 23 to 56 years. Among 30 study subjects, male and female patients were 22(73%) and 08(27%) respectively. Most of the patients presented with generalized weakness (83.3%), weight loss (53.3%), fever (26.7%), pain abdomen (36.6%) and fullness of abdomen (33.3%). Twenty (66.67%) cases develop anaemia, 02(10%) cases leucopenia, 07(23.33%) cases thrombocytopenia and 11(36.6%) patients develop different combination of bicytopenia and 2% patients developed pancytopenia after being treated with Imatinib.
 Conclusion: Various degrees of myelosupression with cytopenias may occur in few patients of CML on Imatinib therapy. Regular hematologic follow-up is required so that the drug may be stopped or dose modified as per the individual’s needs.
 JAFMC Bangladesh. Vol 15, No 2 (December) 2019: 189-192

Long-term efficacy of imatinib mesylate in patients with advanced Tenosynovial Giant Cell Tumor

Tenosynovial giant cell tumors (TGCT), are rare colony stimulating factor-1(CSF-1)-driven proliferative disorders affecting joints. Diffuse-type TGCT often causes significant morbidity due to local recurrences necessitating multiple surgeries. Imatinib mesylate (IM) blocks the CSF-1 receptor. This study investigated the long term effects of IM in TGCT. We conducted an international multi-institutional retrospective study to assess the activity of IM: data was collected anonymously from individual patients with locally advanced, recurrent or metastatic TGCT. Sixty-two patients from 12 institutions across Europe, Australia and the United States were identified. Four patients with metastatic TGCT progressed rapidly on IM and were excluded for further analyses. Seventeen of 58 evaluable patients achieved complete response (CR) or partial response (PR). One- and five-year progression-free survival rates were 71% and 48%, respectively. Thirty-eight (66%) patients discontinued IM after a median of 7 (range 1–80) months. Reported adverse events in 45 (78%) patients were among other edema (48%) and fatigue (50%), mostly grade 1–2 (89%). Five patients experienced grade 3–4 toxicities. This study confirms, with additional follow-up, the efficacy of IM in TGCT. In responding cases we confirmed prolonged IM activity on TGCT symptoms even after discontinuation, but with high rates of treatment interruption and additional treatments.

Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results

After identification of activating mutations of the KIT gene in gastrointestinal stromal tumor (GIST)-the most common sarcomaof the gastrointestinal tract-a phase 2 study demonstrated efficacy of imatinib mesylate in patients with metastatic GIST harboring a KIT exon 11 mutation. Initial results of long-term follow-up have found a survival benefit in this subgroup of patients. To assess the long-term survival of patients with GIST who were treated in SWOG study S0033 and to present new molecular data regarding treatment outcomes. In this follow-up of randomized clinical trial participants (from December 15, 2000, to September 1, 2001), patients were required to have advanced GIST that was not surgically curable. Postprotocol data collection occurred from August 29, 2011, to July 15, 2015. Using modern sequencing technologies, 20 cases originally classified as having wild-type tumors underwent reanalysis. This intergroup study was coordinated by SWOG, a cooperative group member within the National Clinical Trials Network, with participation by member/affiliate institutions. This follow-up was not planned as part of the initial study. Patients were randomized to 1 of 2 dose levels of imatinib mesylate, including 400 mg once daily (400 mg/d) vs 400 mg twice daily (800 mg/d), and were treated until disease progression or unacceptable toxic effects of the drug occurred. The primary end point was overall survival. Updated survival data were correlated with clinical and molecular factors, and patterns of postprotocol therapies were enumerated and described in long-term survivors. Of 695 eligible patients (376 men [54.1%]; 319 women [45.9%]; mean [SD] age, 60.1 [14.0] years), 189 survived 8 years or longer, including 95 in the 400-mg/d dose arm and 94 in the 800-mg/d arm. The 10-year estimate of overall survival was 23% (95% CI, 20%-26%). Among 142 long-term survivors, imatinib was the sole therapy administered in 69 (48.6%), with additional systemic agents administered to 54 patients (38.0%). Resequencing studies of 20 cases originally classified as KIT/PDGFRA wild-type GIST revealed that 17 (85.0%) harbored a pathogenic mutation, most commonly a mutation of a subunit of the succinate dehydrogenase complex. A subset of patients with metastatic GIST experiences durable, long-term overall survival with imatinib treatment. Although this study provides guidance for management of GIST harboring the most common KIT and PDGFRA mutations, optimal management of other genotypic subtypes remains unclear. clinicaltrials.gov Identifier: NCT00009906.

Adherence and/or discontinuation of imatinib mesylate in patients with chronic myeloid leukemia

Adherence to mesylate improves clinical outcomes and promotes a reduction in health expenditure. However, treatment duration and lack of efficacy decrease adherence to pharmacotherapy, resulting in increased mortality associated with Chronic Myeloid Leukemia. This study aimed to evaluate and compare adherence and/or discontinuation of mesylate in different studies from the literature. An integrative review of original articles published between the years of 2004 and 2014 was performed using the databases PubMed/MEDLINE, Scopus and SciELO. The descriptor imatinib was used in two combinations employing the connector AND between terms: medication adherence'' AND ''imatinib AND leukemia'' and ''patient compliance'' AND imatinib AND leukemia. We identified 476 studies, being 14 included in the study. The rates of adherence and discontinuation were diverse, ranging from 19.0 to 97.0% and from 1.8 and 41.0%, respectively, and a high number of longitudinal studies was observed (71.4%). Most studies used questionnaires as an indirect method to assess adherence and factors related to poor adherence were adverse drug reactions, dose changes and unavailability of the medication. Patient education associated with follow up by pharmacists and other health professionals can improve patient adherence and minimize the pharmacotherapy discontinuation.

Concurrent effects of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp genetic polymorphisms with risk of cancer, clinical output, and response to treatment with imatinib mesylate in patients with chronic myeloid leukemia.

There are a paucity and contradicted data about the impact of concurrent heredity of polymorphic genes and risk of chronic myeloid leukemia (CML). In the present study, the concurrent effects of three polymorphisms affecting the integrity of DNA consist of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp on development of chronic myeloid leukemia were studied. Furthermore, the role of these polymorphisms in clinical and laboratory outcomes of patients was evaluated. In this case-control study, 70 CML patients and 140 healthy individuals were enrolled in the study. The clinical features of patients such as phase of disease and response to treatment and laboratory data before and after treatment with imatinib mesylate were collected. ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp single nucleotide polymorphisms were evaluated by restriction fragment length polymorphism-polymerase chain reaction. The T allele of ABCB1 C3435T, T allele of XRCC1 Arg194Trp, and C allele of ABCG2 C421A polymorphisms were significantly higher in patients than controls. TT genotype of ABCB1 and TT genotype of XRCC1 were associated with higher risk of chronic myeloid leukemia development. CC421 ABCG2/TT3435 ABCB1 and CC421 ABCG2/TT27157 XRCC1 were also correlated with a higher risk of CML. Patients with C allele of ABCB1 had poor cytogenetic response, and correlation of CC421 ABCG2/TT3435 ABCB1 diplotype with accelerated phase of CML was significant. Patients with CC421 ABCG2/TT3435 ABCB1 and CC421 ABCG2/TT27157 XRCC1 diplotypes might be at higher risk to rapid and severe development of CML and have weaker response to treatments with imatinib.

P0172Clinical relevance of a pharmacogenetic approach using multiple transporter genes to predict response and resistance to imatinib therapy in Malaysian patients with chronic myeloid leukaemia

Background Despite success with imatinib mesylate in patients with chronic myeloid leukaemia (CML), emergence of clinical resistance in 30% of patients treated with imatinib mesylate still remains a problem. Resistance could be due to a heterogenous array of mechanisms. Pharamcogenetic variability as a result of genetic polymorphisms in the imatinib mesylate transporter genes ABCB1 , ABCG2 , ABCC1 , and ABCC2 could be potential determinants of variability in imatinib mesylate disposition and efficacy. This study investigated the association between ten polymorphisms of ABCB1 (1236 T>C, 2677G>T/A, 3435C>T), ABCG2 (34G>A, 421 C>A), ABCC1 (2012G>T, 2168G>A), and ABCC2 (−24C>T, 1249G>A, 3972 C>T) genes and response to imatinib mesylate with the ultimate aim of identifying putative genotypes and haplotypes associated with good response or resistance. Methods Blood samples from 215 patients with CML (107 with a good response to imatinib mesylate and 108 who were resistant to imatinib mesylate) were genotyped for the 10 polymorphisms using PCR-RFLP. After determining the genotype and haplotype frequencies, their association with imatinib mesylate response was determined with odds ratio (OR). Findings Resistance was significantly associated with patients who had homozygous ABCB1 1236CC genotype (OR 2.79, p = 0.01). ABCG2 421AA genotype was associated with a good response (OR 0.29, p = 0.01) while 421CC genotype was associated with imatinib mesylate resistance (OR 1.87, p = 0.02). Haplotypes ABCB1 C 1236 G 2677 C 3435 and ABCC2 T- 24 G 1249 T 3972 were associated with imatinib mesylate resistance ( p = 0.04 and p = 0.03 respectively) while ABCG2 A 34 A 421 haplotype was associated with a good response to imatinib mesylate ( p = 0.03). Interpretation Genetic variation in these imatinib mesylate transporter genes might have consequences on mRNA stability, expression, protein folding degradation, intracellular localisation, substrate binding, and/or transporter kinetics and thus modulate variation in response. Pretreatment genotyping of these SNPs in patients with CML could be useful for predicting imatinib mesylate resistance which may allow the best choice of drug treatment for patients with CML.

Mechanisms of resistance to imatinib mesylate in KIT-positive metastatic uveal melanoma

Imatinib mesylate is used in targeted therapy of cancer to inhibit type III tyrosine kinase receptors, such as KIT and platelet-derived growth factor receptors (PDGFRs). Expression of KIT in uveal melanoma (UM) suggests that this receptor may be the target of imatinib mesylate therapy. However, phase II multicenter clinical studies have shown no effect of imatinib mesylate in patients with unresectable liver metastases of UM. We therefore investigated which molecular mechanisms promote imatinib mesylate-resistance in metastatic UM. Expression of KIT, stem cell factor (SCF), PDGFRα and PDGFRβ, was analyzed by RT-PCR, immunostaining, and Western blot in twenty-four samples of UM liver metastases, as well as UM primary tumor and metastatic cell lines. Soluble SCF was quantified in UM cell lines using enzyme-linked immunosorbent assay. Cell viability of UM cell lines treated with imatinib mesylate and grown in SCF-supplemented medium or in microvascular endothelial cells-conditioned medium was studied by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assays. UM liver metastases and cell lines expressed KIT and SCF, but not the PDGFRs. Ninety-five percent of liver metastases expressed KIT at the protein level, but PDGFRs were not detected in these samples. Imatinib mesylate reduced the viability of UM metastatic cell lines in a concentration-dependent manner, but an increased resistance to this drug was observed when cells were incubated in SCF-supplemented or microvascular endothelial cells-conditioned medium. This study provides evidence that tumor microenvironment cytokines such as SCF may promote resistance to imatinib mesylate in metastatic UM.

Assessment of cytogenetic response after treatment with imatinib mesylate in patients with chronic phase chronic myeloid leukemia

Assessment of cytogenetic response after treatment with imatinib mesylate in patients with chronic phase chronic myeloid leukemia

Response to Imatinib Mesylate in Patients with Early Chronic Phase Chronic Myeloid Leukemia and Derivative Chromosome 9 Deletion or Clonal Evolution

Objectives: The significance of clonal evolution and derivative chromosome 9 in Philadelphia-positive CML is not fully characterized and studies have yielded conflicting results. After working on emergence of clonal evolution from our region, we continued to find out the response of Imatinib Mesylate on such cases of CML treated in our center. Materials and methods: We conducted a cross sectional, prospective analysis on response of Imatinib Mesylate on patients with Philadelphia positive chronic myeloid leukemia with clonal evolution treated from period of September 2007 till 2010. Patients were grouped on basis of cytogenetic analysis performed by conventional cytogenetic and fluorescence in situ hybridization (FISH) techniques and followed for three years to see the response rate of imatinib mesylate. Results: We reported here the response rate in one hundred and two previously untreated cases of chronic myeloid leukemia (Philadelphia positive). Twelve patients (11.7%) exhibit derivative chromosome 9, three had trisomy 8, one with addition 15 and one had deletion 16. At follow-up of 30 months 78 cases were evaluable and 45% and 61% showed complete and major cytogenetic response respectively. There is no significant association of derivative chromosome 9 with the response of imatinib mesylate in our group. Conclusion: Imatinib mesylate is the first line therapy in chronic phase of CML but the role in patients with clonal evolution need to be established by larger group of patients.

Regional Evaluation of Tolerability and Efficacy of Imatinib Mesylate in Patients with Chronic Phase CML in Mashhad (Iran, Southwest Asia)

Sixty patients with Chronic Myeloid Leukemia (CML) who were on oral imatinib were included in this study. The study aimed to evaluate patients characteristic, tolerability and efficacy and clinical outcome in Iranian patients who have been treated with generic imatinib. The median age of patients was 48 years, and the median follow up was 44 months. 94% of patients achieved complete hematologic response (CHR) during the 3 months of beginning imatinib, and after 12 - 24 months of imatinib therapy 46.8% achieved molecular response. The most common non-hematologic toxicity was fluid retention (64%), fatigue (43%) and moderate to severe hematologic side effect included anemia 10%, neutropenia 10%, and thrombocytopenia 6.6%. About 13% of patients transformed into accelerated phase (AP) or blastic crisis (BC) and the death rate during this period was 7%. In conclusion, there is heterogeneity in different areas in characteristic of CML (especially in age), and also response rate and side effect of patients with CML that treated with imatinib are different.

Report of chronic myeloid leukemia in chronic phase from Ashirwad Hematology Centre, Mumbai, 2002-2009

We have analyzed our experience regarding use of tyrosine kinase inhibitors especially imatinib mesylate in patients of chronic myeloid leukemia-chronic phase over last 7 years at our center (2002-2009). The object was to report long-term efficacy (hematological, cytogenetic and molecular) and toxicity. Overall, 775 patients were treated. Out of these, 576 were analyzable with a median follow-up of 3.6 years. The median age was 42 years. Complete cytogenetic response (CCyR) was achieved in 351/576 patients, i.e., 62.1%. Grade 3/4 adverse effects were observed in 36 patients, i.e., 6.25%. Age under 40 years, low Sokal score, complete hematological response and CCyR were significant predictive factors for event free survival (EFS) on univariate analysis while low Sokal score and early chronic phase were significant predictive factors for EFS on multivariate analysis. Our results are almost similar to those reported from various studies from western population.

Randomized phase II trial of gemcitabine versus gemcitabine and imatinib mesylate in patients with previously treated metastatic breast cancer.

1091 Background: Gemcitabine (GEM) as a standard 30-min infusion has activity as a single-agent in metastatic breast cancer (mbc). Prolonged infusion of GEM at a fixed dose rate (FDR) of 10 mg/m2/min is associated with greater formation of active metabolite and may result in improved antitumor activity. Imatinib mesylate (IM)-mediated inhibition of PDGFR reduces tumor interstitial fluid pressure allowing for improved chemotherapy penetration into tumors. We evaluated the addition of IM to FDR GEM in patients (pts) with previously treated mbc. Methods: This was a randomized phase II trial in mbc pts who progressed after 1 but no more than 2 prior cytotoxic regimens. Eligibility included measurable disease; no prior GEM or IM exposure. Group 1 received FDR GEM IV 1250 mg/m2 at 10 mg/m2/min (over 120 min) on days 3 and 10 every 21 days; Group 2 received the same FDR GEM dose and schedule plus IM 400 mg orally daily on days 1-5 and 8-12 every 21 days. Primary endpoint was time to progression (TTP). Sample size of 40 pts per group was needed to detect an 8 mo increase in TTP with the combination (80% power, α = .05, 2-sided). Secondary endpoints included ORR and safety. Results: Between 5/2006-4/2011, 44 pts were randomized (22 per group). Study closed early due to slow accrual. Median age 54 (31-75); median ECOG PS 1 (0-2); 52% were hormone receptor-positive and HER2-negative; 27% triple-negative, and 20% HER2-positive. Median number of cycles was 2 in Group 1 (range 1-12) and 3.5 in Group 2 (range 1-13). Most common adverse events (%) of any grade, Group 1 vs Group 2 were neutropenia (68 vs. 78), anemia (48 vs. 65), thrombocytopenia (24 vs. 47), nausea (40 vs. 52) and vomiting (24 vs. 21). One gr 4 thrombotic thrombocytopenic purpura occurred in Group 2. Median TTP were 2 mo (95% CI: 1-5 mo) in Group 1 and 2.5 mo (95% CI: 1-5 mo) in Group 2 (p = 0.3 log rank test). ORR was 9.1% in each group (95% CI: 1.6-30.6%), with 2 PRs in each group. Stable disease (≥ 3 mo) was 32% in Group 1 and 41% in Group 2. Conclusions: This study was underpowered to draw any conclusion regarding a difference in TTP between the two groups at the time it was prematurely closed. Combination of IM and FDR GEM showed a trend to increased toxicity compared to FDR GEM alone. Clinical trial information: NCT00323063.

Effects of imatinib mesylate in patients with polycythemia vera: results of a phase II study

The antiproliferative effects of the tyrosine kinase inhibitor imatinib mesylate were reported in single cases with polycythemia vera (PV). We, therefore, conducted a clinical phase II study to assess the rate and quality of response in patients with PV. Thirty-one patients, with a median age of 64 years (range, 45-84 years), were included. All but one patient were on phlebotomy; 14 (45%) had previously received cytoreductive therapy. Imatinib was started with 400 mg/day. In 26% of patients, dose escalation up to 800 mg was performed. After a median treatment duration of 8.3 months (range, 0.1-62.1 months), the overall response rate was 55%. No complete remission (normalization of all parameters: hematocrit, white blood cell (WBC) count, platelet count, and spleen size determined by ultrasound examination) was reached because the spleen remained enlarged in all patients. Thirteen patients (42%) achieved partial remission (≥25% reduction of at least one of the previously mentioned parameters); in 10 of these, the respective reduction was ≥50%. In four patients (13%) with minor response, the reduction was <25%. No change or progressive disease was seen in 14 patients (45%). The nonresponders had a longer previous disease duration and had received more antecedent cytoreductive therapy (p = 0.009). Compared to baseline characteristics, imatinib induced the reduction of phlebotomies (p = 0.003), of WBC count (p = 0.002), and of platelet count (p = 0.04). Three patients became free from phlebotomies. In six investigated patients, no significant reduction of the JAK2V617F burden was observed despite clinical improvement. The results show that imatinib has moderate cytoreductive effects in PV.

Comment on: Determination of serum levels of imatinib mesylate in patients with chronic myeloid leukemia: validation and application of a new analytical method to monitor treatment compliance

Whether therapeutic drug monitoring is beneficial for imatinib mesylate used in the treatment of chronic myeloid leukemia is currently under investigation(1), but most previous studies have indicated a significant association between trough serum concentrations greater than 1000 ng/mL and positive clinical response(2). In this issue, a mass spectrometry (MS)-based method for determination of imatinib concentrations in human serum is presented(3). While MS is often regarded as a difficult and expensive technique, requiring highly skilled personnel, the authors have chosen a robust and economical single-quadrupole instrument that is appropriate for the clinical lab setting. However, although compatible methods have been reported(4), most MS-based procedures, including the earliest reported assays(5,6), have required tandem mass spectrometry (MS/MS)(2), a technique for which single-quadrupole mass spectrometers are not well-suited. Therefore, new methods for imatinib quantitation compatible with low-cost single-quadrupole instruments are clearly valuable, especially in light of the expected increase in demand if therapeutic drug monitoring does become standard practice. Selectivity is often advanced to justify using MS for therapeutic drug monitoring. Improved selectivity, by enabling analyte quantitation in more complex matrices, allows sample preparation procedures to be simplified, which can reduce bias and total analysis time. Only protein removal by methanol precipitation was required in the presented method. MS is most powerful when combined with an appropriate separation. While gas chromatography is important for volatile molecules, liquid chromatography (LC) has wider applicability. Electrospray ionization (ESI) is the LC-MS interface of choice since the predominance of molecular ions simplifies data analysis. Sensitivity is enhanced by techniques like selected ion monitoring (SIM), where the instrument acts as a filter allowing only a single ion to reach the detector. SIM can be extended, by switching rapidly between targeted ions, to allow small numbers of components to be simultaneously monitored. Calibration curves must be established for the matrix in question to allow absolute quantitation. The presented method follows this SIM approach, targeting imatinib, the imatinib metabolite CGP 74588, and an internal standard. While not required in the presented method, the instrument used is capable of concurrent SIM of more than three analytes. Furthermore, simultaneous analysis is often unnecessary because an ion need only be targeted around the expected elution time, increasing the number of compounds that can be monitored. A further advantage of MS is that isotopically labeled analogs of targeted analytes can be used as internal standards. Deuterated analogs behave nearly identically to targets, while using heavier isotopes (e.g., 13C, 15N, 18O) results in standards that are essentially indistinguishable until a mass spectrum is recorded. However, deuterated analogs are usually the more economical choice (imatinib-D8 was used in the presented method). In contrast to most other methods, where similar compounds must be used, the use of isotopically labeled standards gives greater confidence in assessments of sample preparation losses and biases. While LC-MS with SIM can often be sufficient, as it was in the presented method, interfering species having similar mass-to-charge (m/z) ratios and elution times to targets will sometimes be encountered. If modifications to the chromatographic method are not successful in separating target from interfering molecules, selected reaction monitoring (SRM) can be used. SRM relies on MS/MS to distinguish ions having the same or similar m/z ratios. In this technique, characteristic fragment ions are monitored in addition to the molecular ion. By following a number of fragments (or transitions) for each analyte, exceptional selectivity can be achieved. However, as mentioned above, single-quadrupole instruments, such as that used in the presented method, are not appropriate for this approach (in-source fragmentation MS/MS is possible in single-quadrupole mass spectrometers, but targeted ions cannot be isolated prior to fragmentation). As referred to previously, the chief drawbacks of LC-MS approaches are often held to be cost and the requirement for highly skilled personnel. Furthermore, sample preparation protocols designed for other detection methods can sometimes be difficult to adapt for MS (e.g., ESI is incompatible with detergents). While current single-quadrupole instruments are among the most robust and accessible mass spectrometers available, training requirements are certainly more demanding than for techniques like LC with absorbance detection. However, well-designed software can somewhat alleviate such concerns. In the future, cost-control may be enhanced through innovative solutions where, for example, multiple chromatographic systems share a single mass spectrometer(7). Runs on each LC system are staggered, with eluate only directed toward the MS interface when targeted peaks are expected. Since elution windows for key peaks are often only a small fraction of the total operating cycle time, sample throughput can be greatly increased without requiring additional MS instrumentation.

Determination of serum levels of imatinib mesylate in patients with chronic myeloid leukemia: validation and application of a new analytical method to monitor treatment compliance

Objective The goal of this study was to monitor imatinib mesylate therapeutically in the Tumor Biology Laboratory, Department of Hematology and Hemotherapy, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (USP). A simple and sensitive method to quantify imatinib and its metabolite (CGP74588) in human serum was developed and fully validated in order to monitor treatment compliance. Methods The method used to quantify these compounds in serum included protein precipitation extraction followed by instrumental analysis using high performance liquid chromatography coupled with mass spectrometry. The method was validated for several parameters, including selectivity, precision, accuracy, recovery and linearity. Results The parameters evaluated during the validation stage exhibited satisfactory results based on the Food and Drug Administration and the Brazilian Health Surveillance Agency (ANVISA) guidelines for validating bioanalytical methods. These parameters also showed a linear correlation greater than 0.99 for the concentration range between 0.500 µg/mL and 10.0 µg/mL and a total analysis time of 13 minutes per sample. This study includes results (imatinib serum concentrations) for 308 samples from patients being treated with imatinib mesylate.ConclusionThe method developed in this study was successfully validated and is being efficiently used to measure imatinib concentrations in samples from chronic myeloid leukemia patients to check treatment compliance. The imatinib serum levels of patients achieving a major molecular response were significantly higher than those of patients who did not achieve this result. These results are thus consistent with published reports concerning other populations.

Changes of serum fibroblast growth factor 2 levels before and after treatment with imatinib mesylate in patients with unresectable or metastatic gastrointestinal stromal tumor

Objective To explore changes of serum fibroblast growth factor 2 (FGF2) levels after treatment with imatinib mesylate in patients with unresectable or metastatic gastrointestinal sromal tumor.Methods Serum FGF2 levels (with ELISA) were determined in 27 patients with unresectable or metastatic gastrointestinal stromal tumor both before and after treatment with imatinib mesylate.Results Before treatment with imatinib mesylate,of 27 cases of unresectable or metastatic gastrointestinal stromal tumor,17 cases (63.0 ％) were found positive for serum FGF2,after treatment with imatinib mesylate,9 cases (33.3 ％) were found positive for serum FGF2 (P ＜ 0.05).Using imatinib mesylate for 3 months,complete remission rate was 0,partial remission rate was 51.9 ％ (14/27),stable disease rate was 48.1％ (13/27) and progressive rate was 0.Conclusion Patients with unresectable or metastatic gastrointestinal stromal tumor have elevated serum FGF2 levels.Imatinib mesylate treatment can reduce serum FGF2 levels in patients with unresectable or metastatic gastrointestinal stromal tumor. Key words: Gastrointestinal stromal tumor; Fibroblast growth factor 2; Imatinib mesylate