Complete pathological response to Imatinib mesylate in an extraintestinal gastrointestinal stromal tumor

INTRODUCTION

Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the digestive tract. Extraintestinal locations (EGIST) have been described showing similar pattern of immunohistochemical markers than GIST. Inhibitors of tyrosine kinases such as Imatinib or Sunitinib are the mainstay treatment in the management of advanced or metastatic GIST. Complete pathological response to these agents is an extremely rare event, especially in the case of EGIST due to its more aggressive behavior reported.

PRESENTATION OF CASE

Here we describe the case of a 61 years old woman, with an advanced GIST, who was operated after 10 months of Imatinib mesylate. The biopsy demonstrated the extra intestinal location of the tumor and a complete pathological response was confirmed.

DISCUSSION

Complete pathological response to Imatinib is a rare event. To our knowledge, this is the first report of complete response in an EGIST. New clinical, radiological and metabolic criteria of tumoral response to neoadjuvant treatment are revised.

CONCLUSION

EGIST complete pathological response to Imatinib can be achieved. However, recommendation of systematic neoadjuvant therapy with Imatinib remains investigational and more studies are warranted in the future.     

The use of imatinib mesylate has no adverse effects on the heart function. Results of a pilot study in patients with chronic myeloid leukemia

To investigate cardiac effects of imatinib at an extended follow-up (median 12.4 months), 12 chronic myeloid leukemia patients underwent cardiac screening. No significant changes on the frequency of cardiovascular signs and symptoms, electrocardiographic abnormalities, echocardiographic measurements and BNP levels were observed. Median ejection fraction was 67% at baseline versus 68% at follow-up (median intra-patient change 0.5%). Median BNP levels were 8.3 versus 7.3 pg/mL (median intra-patient change 0.2 pg/mL). Troponin I measures were below the lower limit of detection, whereas strain measures were similar to healthy control. This pilot study suggests that it is probably safe to perform cardiac monitoring on an annual basis.     

伊马替尼治疗Ph染色体阳性慢性粒细胞白血病的临床观察

目的:评价酪氨酸激酶抑制剂伊马替尼治疗Ph染色体阳性慢性粒细胞白血病的有效性及安全性。方法:90例慢性粒细胞白血病患者,其中慢性期67例,非慢性期23例(加速期14例,急变期9例),每天应用剂量分别为400,600mg。每周复查血常规,每3个月进行骨髓象及细胞遗传学检查,根据血象和骨髓象调整剂量。结果:观察截止时,84例(93.3%)获得血液学完全缓解;68例可评价遗传学效应,35例(51.5%)发生主要遗传学效应(慢性期30例,加速期3例,急变期2例),其中31例(88.6%)为遗传学完全缓解(慢性期27例,加速期2例,急变期2例)。11例(12.2%)患者发生严重白细胞和/或血小板减少,但可通过调整剂量控制。严重非血液学不良反应发生较少。结论:伊马替尼治疗Ph染色体阳性慢性粒细胞白血病患者疗效较好,可获得较高的完全血液学缓解率和主要细胞遗传学缓解率,起效迅速,且不良反应较少,可耐受或自行消失。     

Docosahexaenoic acid enhances the toxic effect of imatinib on Bcr-Abl expressing HL-60 cells

The effect of docosahexaenoic acid (DHA) on the killing efficacy of imatinib on HL-60 cells expressing the Bcr-Abl protein was investigated. Imatinib is an Abl tyrosine kinase inhibitor used in the treatment of patients with chronic myeloid leukemia. The pre-treatment with DHA for 24 h raised the effect of imatinib at 100 μM concentration only. On the other hand, after 72 h pre-treatment, all concentrations of DHA tested (25, 50 and 100 μM) enhanced the toxic effect of imatinib. These results indicate that long-term pre-treatment with DHA makes Bcr-Abl HL-60 cells more susceptible to the toxic effect of imatinib.     

Simultaneously occurring chronic myelogenous leukemia and gastrointestinal stromal tumors treated with imatinib

Imatinib mesylate (imatinib, STI571, Gleevec; Novartis Pharma) is an orally administered competitive inhibitor of BCR-ABL tyrosine kinase that has demonstrated significant efficacy in chronic myelogenous leukemia (CML). Imatinib is also a potent inhibitor of the receptor-type KIT tyrosine kinase with demonstrated benefits in KIT-expressing gastrointestinal stromal tumors (GISTs). This article presents the case of a patient with simultaneous occurrence of CML and GIST who was treated with the single agent imatinib. To our knowledge, this is the first report of simultaneous occurrence of these two malignancies and of the efficacy of imatinib in concurrent treatment of both neoplasms in a single patient.     

Effect of Imatinib (STI571) on Metastatic Gastrointestinal Stromal Tumors: Report of a Case

The prognosis for advanced gastrointestinal stromal tumor (GIST) is poor. However, recent reports from Europe have described the effects of imatinib against metastatic GIST. We herein report the case of a Japanese patient treated with imatinib for advanced GIST. Imatinib at 400mg daily was given to an adult with multiple liver and peritoneal metastases 17 months after undergoing a GIST resection. The sum of the diameter of all target lesions decreased from 37.7 to 10.9cm at 6 months. Tinnitus (grade 2), which has not been reported elsewhere as an adverse effect, developed at 2 months. However, it did not require any treatment. Other adverse effects, nausea (grade 2) and anemia (grade 2), resolved spontaneously. Our results are consistent with previous reports that show imatinib to be effective for the treatment of metastatic GIST, and also suggest that imatinib at 400mg daily for more than 7 months is well tolerated in Japanese adults.     

Chronic myeloid leukemia: a model for oncology

Leukemias have traditionally served as model systems for research on neoplasia because of the easy availability of cell material from blood and marrow for diagnosis, monitoring and studies on pathophysiology. Beyond these more technical aspects, chronic myeloid leukemia (CML) became the first neoplasia in which the elucidation of the genotype led to a rationally designed therapy of the phenotype. Targeting of the pathogenetically relevant BCR-ABL tyrosine kinase with the selective kinase inhibitor imatinib has induced remissions with almost complete disappearance of any signs and symptoms of CML. This therapeutic success has triggered an intensive search for target structures in other cancers and has led to the development of numerous inhibitors of potential targets, which are being studied in preclinical and clinical trials worldwide. This review deals with some of the recent developments that have evolved since our last review in this journal in 2000 (Hehlmann R, Hochhaus A, Berger U, Reiter A (2000) Current trends in the management of chronic myelogenous leukemia. Ann Hematol 79:345–354).     

Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588

Despite the remarkable clinical response rates to imatinib in the treatment of bcr-abl leukemic patients, pharmacokinetic data on this relatively novel substance are needed to improve our understanding of the emergence of resistance, the interindividual variations of clinical response and the clinical and biologic relevance of its main metabolite N-desmethyl-imatinib. We present here pharmacokinetic data obtained with a newly designed HPLC approach in 97 patients with chronic myeloid leukemia or acute lymphatic leukemia (ALL) under treatment with imatinib that allowed us to calculate the AUC (39.5 g·h/ml for an oral dose of 400 mg daily), the t_1/2 (18.2 h) and the peak concentration (1.92 /ml for an oral dose of 400 mg daily) of imatinib in plasma. In a subgroup of patients, the same parameters were analyzed for N-desmethyl-imatinib. We also provide data on the imatinib concentration in the cerebrospinal fluid (CSF) of ALL patients and demonstrate that oral administration of imatinib resulted only in a marginal flux across the blood-brain barrier. Finally, in an in vitro setting, we determined cellular concentrations of imatinib in HL-60 cells and showed an over-proportional uptake both in RPMI medium and in human plasma. Using an arithmetical approach combining all parameters obtained in imatinib-treated patients, we finally provide a conclusive approximation of basic pharmacokinetic data for both imatinib and its main metabolite N-desmethyl-imatinib.     

Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571)

Isolated central nervous system (CNS) relapse occurred in 5 out of 24 patients (20.8%) with chronic myeloid leukemia (CML) lymphoid blast crisis (2), Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (ALL) (2) or CML with biphenotypic markers (1) treated on imatinib mesylate (IM) protocols at our institution. CNS relapse occurred despite peripheral blood (5) and bone marrow (3) complete responses. Median time to CNS relapse was day 32 (range 23 to 100). This observation raised the possibility that IM may not penetrate into the CNS. Simultaneous plasma and cerebral spinal fluid (CSF) IM levels were determined in four subsequent patients by liquid chromatography and mass spectrophotometric assay. Levels of IM were found to be approximately two logs lower in CSF than in plasma (0.044 μg/ml (0.088 ± 0.029 μM) vs 3.27 μg/ml (6.54 ± 0.93 μM)). CSF levels were substantially below the concentration required for inhibition of BCR-ABL and killing of cell lines in vitro. These results suggest that IM may not penetrate the intact blood/brain barrier and its implications are discussed.