Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group.

PURPOSE: Imatinib is the standard treatment of advanced GI stromal tumors (GISTs). It is not known whether imatinib may be stopped in patients in whom disease is controlled. METHODS: This prospective, randomized, multicentric phase III study was designed to compare continuous (CONT) compared with interrupted (INT) imatinib beyond 1 year of treatment in patients with advanced GIST. The primary end point was progression-free survival. Secondary end points included overall survival, response rate after reinitiation of imatinib, and quality of life. Early stopping rules in cases of rapid progression of disease were defined, with preplanned interim analyses. RESULTS: Between May 2002 and April 2004, 182 patients with advanced GIST were enrolled. Between May 2003 and April 2004, 98 patients in response or stable disease under imatinib reached more than 1 year of follow-up. Forty were not eligible for randomization, and 58 patients were randomly assigned, 32 and 26 patients in the INT and CONT arms, respectively. As of October 15, 2005, eight of 26 patients in the CONT group and 26 of 32 patients in the INT group had documented disease progression (P < .0001). Twenty-four of 26 patients with documented progression in the INT arm responded to imatinib reintroduction. No differences in overall survival or imatinib resistance were observed between the two arms. Quality of life evaluated 6 months after random assignment using the 30-item Quality of Life Questionnaire was not significantly different between the two groups of randomly assigned patients. CONCLUSION: Imatinib interruption results in rapid progression in most patients with advanced GIST, and cannot be recommended in routine practice unless patient experience significant toxicity

Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors.

PURPOSE: This study explored factors affecting the pharmacokinetic variability of imatinib and CGP 74588, and the pharmacokinetic-pharmacodynamic correlations in patients with advanced gastrointestinal stromal tumors. EXPERIMENTAL DESIGN: Thirty-five patients with advanced gastrointestinal stromal tumors received 400 mg of imatinib daily. Six blood samples were drawn: before intake, during 1- to 3- and 6- to 9-hour intervals after intake on day 1, and before intake on days 2, 30, and 60. Plasma imatinib and CGP 74588 concentrations were quantified by reverse-phase high-performance liquid chromatography coupled with tandem mass spectrometry, and analyzed by the population pharmacokinetic method (NONMEM program). The influence of 17 covariates on imatinib clearance (CL) and CGP 74588 clearance (CLM/fm) was studied. These covariates included clinical and biological variables and occasion (OCC = 0 for pharmacokinetic data corresponding to the first administration, or OCC = 1 for the day 30 or 60 administrations). RESULTS: The best regression formulas were: CL (L/h) = 7.97 (AAG/1.15)(-0.52), and CLM/fm (L/h) = 58.6 (AAG/1.15)(-0.60) x 0.55(OCC), with the plasma alpha1-acid glycoprotein (AAG) levels indicating that both clearance values decreased at a higher AAG level. A significant time-dependent decrease in CLM/fm was evidenced with a mean (+SD) CGP 74588/imatinib area under the curve (AUC) ratio of 0.25 (+/-0.07) at steady state, compared with 0.14 (+/-0.03) on day 1. Hematologic toxicity was correlated with pharmacokinetic variables: the correlation observed with the estimated unbound imatinib AUC at steady-state (r = 0.56, P < 0.001) was larger than that of the total imatinib AUC (r = 0.32, NS). CONCLUSIONS: The plasma AAG levels influenced imatinib pharmacokinetics. A protein-binding phenomenon needs to be considered when exploring the correlations between pharmacokinetics and pharmacodynamics.

Quantification of imatinib in human plasma by high-performance liquid chromatography-tandem mass spectrometry.

Imatinib, also known as Gleevec or Glivec, is a selective tyrosine kinase inhibitor currently used for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) and for other malignant pathologies. We have developed a LC-MS-MS [corrected] method that could be used for imatinib therapeutic drug monitoring in plasma. After a liquid-liquid extraction, the imatinib and its deuterated internal standard were eluted on an XTerra RP18 column with a gradient of acetonitrile-ammonium formiate buffer 4 mmol/L, pH 3.2. Imatinib was detected by electrospray ionization mass spectrometry with multiple reaction-monitoring mode. The calibration curves were linear over the range 10-5000 ng/mL. The limit of quantification was set at 10 ng/mL. The bias was lower than 8%. Intra-day and inter-day precisions were lower than 8%. The extraction recovery was higher than 90%. This method is simple, adapted to routine application, and allows accurate therapeutic monitoring of imatinib. It can be used to evaluate patient adherence to daily oral therapy, drug-drug interactions, or pharmacokinetic/pharmacodynamic relationships.

Management of chronic myeloid leukemia in France: a multicentered cross-sectional study on 538 patients.

PURPOSE: Little is known about the actual management and treatment of chronic myeloid leukemia (CML) in clinical practice, although there have been many recent changes, such as the introduction of imatinib. PATIENTS AND METHODS: A two-phase cross-sectional observational study with retrospective data collection was conducted in France. In the first phase information regarding health services treating patients with CML was collected. In the second phase, centers caring for 10 or more patients were asked to provide data regarding patients diagnosed with CML that had had a consultation or been hospitalized in the last 3 months. RESULTS: All French departments of hematology (n=218) were contacted by phone. The median number of patients followed per center is 6 (range 0--200). The median number of new patients seen during the last 12 months was 2 (range 0--60). In the second phase 538 patients were included, the sex ratio being 1.14 and median age 55. At the time of diagnosis, 96.8% (n=519) were in chronic phase, 2.2% (n=12) in accelerated phase and 0.9% (n=5) in blastic phase. Eighty-two percent (n=443) of the patients have been treated by interferon (IFN). Sixteen point 3% (n=87) of the patients received a bone marrow transplantation (BMT). Forty-six percent (n=236) of the patients were treated with imatinib. CONCLUSIONS: This is the first study providing detailed descriptive data concerning the use of medications and procedures in a large population of patients from the medical centers involved in treating CML patients in France. Further observational studies are needed to assess the impact of different treatment strategies and economic impact of CML care in France.

Relationship between elevated levels of the alpha 1 acid glycoprotein in chronic myelogenous leukemia in blast crisis and pharmacological resistance to imatinib (Gleevec) in vitro and in vivo.

The Abl tyrosine kinase inhibitor imatinb is becoming a standard for the treatment of chronic myelogenous leukemia (CML). However, Bcr-Abl gene mutations have been reported mainly in relapsing or resistant patients. In primary resistant patients, only few mutations have been documented so far, suggesting alternative mechanisms. We aimed to investigate if alpha 1 acid glycoprotein (AGP), an acute phase drug binding protein, could be a biological marker for pharmacological resistance to imatinib in nine patients in acute phase CML. All patients (3/3) with high AGP dosages (2.31+/-0.17 mg/mL; normal values, 0.5-1.3mg/mL) were primary resistant to imatinib whereas an early clinical response was observed for the six patients with normal AGP levels (1.13+/-0.2mg/mL). No mutation in the adenosine triphosphate domain of Abl were detected before the initiation of imatinib therapy. By using in vitro tests combining various imatinib concentrations (1-10 microM) with purified human AGP (1 and 3 mg/mL), we demonstrate that imatinib-induced apoptosis of K562 or fresh leukemic CML cells is abrogated or reduced. The same effect was observed using sera from donors with high AGP levels (1.9-3.28 mg/mL). In patients with CML in blastic phase, AGP levels could reflect pharmacological resistance to imatinib, suggesting that increased dosage of imatinib or the use of a competitor to drug binding should be recommended to optimize the therapeutic effect of the drug.

Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase.

In chronic myelogenous leukemia (CML) imatinib mesylate has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr-abl fusion protein. Using this agent alone high rates of cytogenetic responses were recorded. However, several mechanisms of resistance have been described. In vitro studies examining the effects of imatinib mesylate plus cytarabine have shown synergistic antiproliferative effects of this combination. Thus, the CML French Group decided to perform a phase 2 trial testing a combination of imatinib mesylate and low-dose cytarabine in 30 previously untreated patients in chronic phase. Treatment was administered on 28-day cycles. Patients were treated continuously with imatinib mesylate orally at a dose of 400 mg daily. Cytarabine was given on days 15 to 28 of each cycle at an initial dose of 20 mg/m2/d via subcutaneous injection. Adverse events were frequently observed with grade 3 or 4 hematologic toxicities and nonhematologic toxicities in 53% (n = 16) and 23% (n = 7) of patients, respectively. The cumulative incidence of complete cytogenetic response (CCR) at 12 months was 83% and at 6 months 100% of the patients achieved complete hematologic response (CHR). We concluded that the combination was safe and promising given the rates of response.

Imatinib in combination with cytarabine for the treatment of Philadelphia-positive chronic myelogenous leukemia chronic-phase patients: rationale and design of phase I/II trials.

Imatinib (Gleevec) (formerly STI571) has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic BCR-ABL fusion protein of chronic myelogenous leukemia (CML) cells. In recent phase I and II studies testing this new compound in patients who had failed to respond to interferon (IFN), hematological and cytogenetic responses were reported in most of those with chronic-phase CML. However, in some patients resistance has been associated with a single amino acid substitution in a threonine residue of the Abl kinase domain. In vitro studies examining the effects of imatinib plus cytarabine (Ara-C) using CML cell lines and colony-forming assays of CML patient samples have shown synergistic antiproliferative effects of this combination. Thus several groups decided to investigate this new combination with the hypothesis that cell resistance would be less frequent. The CML French Group performed a phase II trial to determine the safety and tolerability of a combination of imatinib and Ara-C for previously untreated patients with chronic-phase CML. Treatment was administered on 28-day cycles for 12 months. Patients were treated continuously with imatinib orally at a dose of 400 mg daily. Ara-C was given on days 14 to 28 of each cycle at an initial dose of 20 mg/m(2)/d via subcutaneous injection, hydroxyurea (HU) being stopped at least 7 days before imatinib. Recently, the Dutch group decided to explore a combination of high-dose Ara-C with imatinib in patients in chronic-phase CML. Preliminary results are encouraging. However, a long follow-up is required before concluding that these strategies will overcome cell resistance.

Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: a prospective study of 54 patients.

BACKGROUND: Imatinib is a new major treatment in chronic myeloid leukemia. OBJECTIVE: To study the cutaneous reactions induced by imatinib. METHODS: All inpatients and outpatients with Philadelphia chromosome-positive leukemia treated by imatinib were included in this prospective study. Clinical features, pathologic findings, evolution of each case, and analysis of potential risk factors were recorded. RESULTS: A total of 54 patients were included, 48 of whom experienced at least 1 cutaneous reaction. These reactions consisted of 36 rashes, 35 edemas, and 22 pruritus. The rash was severe in 5 patients, resulting in temporary interruption of treatment in 3. Highly significant relationships were observed between the daily dose of imatinib and both rashes and edema. In a multivariate analysis, female sex and the daily dose of imatinib were independent risk factors for the development of rashes. CONCLUSION: Adverse cutaneous reactions induced by imatinib are frequent, generally moderate, and dose-dependent.