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).     

Intranasal loteprednol etabonate in healthy male subjects: pharmacokinetics and effects on endogenous cortisol

Loteprednol etabonate (LE) is a glucocorticoid soft drug that is currently in development for intranasal use. The main objectives of this study were to examine the pharmacokinetics and potential effects on systemic cortisol of two intranasal suspension formulations of LE and to compare these findings with placebo and fluticasone propionate (FP, Flonase) control treatments. In this randomized, double-blind (except for FP), parallel-group study (n = 8/group), all subjects received for 14 days once daily in the morning two puffs of the following nasal spray formulations into each nostril: LE 0.1% (400 microg/day), LE 0.2% (800 microg/day), FP 0.05% (200 microg/day), and placebo. Drug trough levels were determined on days 1, 5, 12, 13, and 14, and a full pharmacokinetic profile was established on day 14, and 24-hour serum cortisol profiles were assessed prior to treatment (i.e., at baseline) and after the last dose. All subjects completed the protocol without treatment-emergent adverse findings. All formulations were rapidly absorbed (t(max) less than 1 h). The rather short mean terminal half-lives of 2.2 +/- 1.5 hours and 1.8 +/- 1.0 hours for LE 400 microg and LE 800 microg, respectively, and 4.2 +/- 1.8 hours for the 200-microg FP treatment explained the lack of any accumulation. Mean peak concentrations (C(max)) were 139 +/- 57 pg/mL with LE 400 microg and 164 +/- 54 pg/mL with LE 800 microg and thus fairly independent from dose. The 200-microg FP treatment resulted in a C(max) of only 15.5 +/- 5.9 pg/mL. Mean measured AUC(0-t) values (193 +/- 87 pg/h/mL(-1), 300 +/- 183 pg/h/mL(-1), and 40 +/- 34 pg/h/mL(-1) for LE 400 microg, LE 800 microg, and FP 200 microg, respectively) showed high variability and suggested nonlinear pharmacokinetics for the LE formulations, indicative of a less complete systemic uptake of LE from the 0.2% concentration. None of the treatments (LE 400 microg, LE 800 microg, and FP 200 microg) showed evidence for serum cortisol suppression when compared with placebo, respectively. The uptake and systemic exposure appears less complete from the 0.2% LE concentration, which principally favors this formulation for further clinical development.     

Pegylated liposomal doxorubicin in combination with mitomycin C, infusional 5-fluorouracil and sodium folinic acid. A phase-I-study in patients with upper gastrointestinal cancer

Mitomycin C (MMC) in combination with infusional 5-fluorouracil (FU) plus folinic acid (FA) is an effective treatment for metastatic gastrointestinal cancer. Anthracyclines are commonly used in the treatment of upper gastrointestinal cancer. The aim of this study was to determine the maximum tolerated dose of liposomal, pegylated doxorubicin (Caelyx) in combination with infusional 5-FU/sodium FA and MMC. Escalating doses of Caelyx (15-25-30-35 mg m(-2) corresponding to dose levels I-IV) were applied on days 1 and 29, given to fixed doses of 24-h 5-FU (2000 mg m(-2)) and sodium FA (500 mg m(-2), mixed with 5-FU in one pump) weekly for 6 weeks, and MMC 7 mg m(-2) on days 8 and 36. At least three patients were treated at each dose level. A total of 25 patients are evaluable. No dose-limiting toxicity (DLT) was observed on level I (n=3). On level II, DLT occurred in three out of five patients (mucositis and leucopenia). Owing to the early DLTs at this dose, we added a 20 mg m(-2) Caelyx dose level (Ia). In total, 17 patients were treated at this dose level. Among these, only two patients experienced DLT in cycle one and 37 complete cycles have been administered in association with a low toxicity profile. The median dose intensity was 100% for each drug during the first course and no treatment delay exceeding 7 days was required. The recommended dose of 4-weekly Caelyx in combination with weekly 24-h 5-FU/sodium FA and 4-weekly MMC is 20 mg m(-2). Preliminary antitumour activity has been observed in patients with pretreated pancreatic cancer and in untreated gastric cancer.     

Monitoring of minimal residual disease in chronic myeloid leukemia

Detection and monitoring of minimal residual disease has become one of the most prevalent topics in chronic myeloid leukemia(CML) therapy. The goal of early detection of residual disease is to allow timely therapeutic intervention before overt relapse of therapy resistant disease occurs. The most powerful tool to serve this purpose is polymerase chain reaction (PCR). Major improvements in assay techniques have advanced PCR from a purely qualitative test with considerable variability of test results to a real-time quantitative assay with far more reproducible results than were possible before. At the same time, treatment of CML has changed dramatically since the introduction of imatinib. Integration of therapy and molecular assays such as PCR, in addition to a profound understanding of the pathophysiology of CML, has assumed even more importance. Quantitative PCR testing has become the standard monitoring strategy for patients undergoing stem cell transplantation.Although correlations have been established between positive test results and probability of relapse, no absolute guidelines for monitoring exist, especially for patients treated with imatinib.     

Possibilities in improvement of glucocorticoid treatments in asthma with special reference to loteprednol etabonate

Allergic conditions contribute significantly to the burden of chronic disease in the industrialized world. The increasing prevalence has lead research into the discovery and development of various new therapeutic strategies. Despite considerable efforts of the pharmaceutical industry, the leukotriene antagonists were the only new class of asthma treatments to be licensed in the past 30 years. Topical glucocorticoids (GCs) are the most potent and effective therapy for treating allergic diseases. However, their use is limited by diverse undesired effects. Changes in pharmacokinetic parameters of GCs may be an interesting and promising approach to improve efficacy and safety of inhaled GCs. Loteprednol etabonate has been developed on the basis of the retrometabolic drug design. In animal studies, it has been demonstrated to have long-lasting anti-allergic (anti-asthmatic) effects without influencing the hypothalamic-pituitary axis (HPA). This soft steroid is now in phase III of the clinical development. Recently, loteprednol has been proven to be effective in the management of allergic rhinitis (400 microg once daily). No suppression of HPA was observed at clinically effective and higher doses. In conclusion, loteprednol as the first representative of soft steroids elicits marked anti-inflammatory effects, but has no impact on endocrine responses. It may represent a promising new therapy in the treatment of allergic rhinitis and asthma.     

ABL-kinase domain point mutation as a cause of imatinib (STI571) resistance in CML patient who progress to myeloid blast crisis

Imatinib mesylate (STI571) is a major therapeutic advance for the management of chronic myeloid leukaemia (CML), however, a proportion of patients are refractory to it, particularly those in more advanced phases of CML. Different mechanisms of resistance to imatinib are suggested, including point mutations within ABL-kinase domains. A point mutation leading to substitution at the ATP binding site of ABL-kinase and insensitivity to imatinib was detected in our patient treated with imatinib, who progressed to blast crisis. Additionally, clonal evolution could lead to BCR–ABL-independent proliferation. Early detection of ABL-kinase mutation could predict the progression of CML treated with imatinib.     

AraC-based pharmacotherapy of chronic myeloid leukaemia

In interferon-alpha (IFN) treated chronic phase chronic myeloid leukaemia (CML) patients, survival depends on individual risk profile and achievement of a complete haematological response (CHR) and a major cytogenetic response (MCR) (< 35% Philadelphia-chromosome-positive metaphases). The highest cytogenetic response rates have been achieved with the combination of IFN and low-dose sc. AraC (10 mg daily to 10-20 mg/m2 for 10-14 days/month). Whether the higher cytogenetic response rates are also associated with a significant improvement of survival still remains controversial. The different results obtained from large randomised and observational trials may be due to the numbers of patients enrolled, distribution of risk profiles and the treatment schedule, which is influenced greatly by the haematological and gastrointestinal toxicity of AraC. An oral formulation (YNK01), which is lipophilic and resistant to deamination, is currently under investigation. Clinically, it has similar activity, but toxicity leads to discontinuation of treatment in a considerable proportion of patients. The clinical benefits may therefore be outweighed by the dose-limiting toxicity for both application forms. Combinations with other drugs, e.g., STI571 or homoharringtonine, have shown promising early results in vitro and in vivo.     

Pharmacokinetics of Plasmid DNA in the Rat

Purpose. The pharmacokinetics of plasmid DNA after IV bolus administration in the rat by following supercoiled (SC), open circular (OC), and linear (L) pDNA forms of the plasmid.Methods. SC, OC, and L pDNA were injected at 2500, 500, 333, and 250 g doses. The concentrations in the bloodstream of OC and L pDNA were monitored.Results. SC pDNA was detectable in the bloodstream only after a 2500 g dose, and had a clearance of 390(±50) ml/min and V_d of 81(±8) ml. The pharmacokinetics of OC pDNA exhibited non-linear characteristics with clearance ranging from 8.3(±0.8) to 1.3(±0.2) ml/min and a V_d of 39(±19) ml. L pDNA was cleared at 7.6(±2.3) ml/min and had a V_d of 37(±17) ml. AUC analysis revealed that 60(±10) % of the SC was converted to the OC form, and nearly complete conversion of the OC pDNA to L pDNA. Clearance of SC pDNA was decreased after liposome complexation to 87(±30) ml/min. However the clearance of OC and L pDNA was increased relative to naked pDNA at an equivalent dose to 37(±9) ml/min and 95(±37) ml/min respectively.Conclusions. SC pDNA is rapidly metabolized and cleared from the circulation. OC pDNA displays non-linear pharmacokinetics. Linear pDNA exhibits first order kinetics. Liposome complexation protects the SC topoform, but the complexes are more rapidly cleared than the naked pDNA.