Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.

PURPOSE: This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM). METHODS: Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395). RESULTS: Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml). CONCLUSIONS: This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.

Single agent rituximab in patients with follicular or mantle cell lymphoma: clinical and biological factors that are predictive of response and event-free survival as well as the effect of rituximab on the immune system: a study of the Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: Predictive factors of rituximab efficacy and its effect on the immune system are still not defined. PATIENTS AND METHODS: Three hundred and six patients with follicular or mantle cell lymphoma received four weekly doses of rituximab (induction) and no further treatment (arm A) or four more doses at 2-month intervals (arm B). RESULTS: Response rate to induction was 44%. Independent predictive factors for response were disease bulk <5 cm, follicular histology, normal hemoglobin and low lymphocyte count. Factors associated with event-free survival (EFS) were having responded to induction, having received not more than one line of therapy, Ann Arbor stage I-III, high lymphocyte count, disease bulk <5 cm, Fc-gamma receptor genotype VV and receiving prolonged treatment. B cells were suppressed by treatment but recovered after a median of 12 months in arm A and 18 months in arm B. The median IgM level after 1 year was normal in arm A but was decreased to 73% of baseline in arm B. We observed 24 serious adverse events, equally distributed between arms. Ten patients receiving induction only and six patients receiving prolonged treatment developed a second tumor. CONCLUSIONS: We defined the characteristics predicting response and EFS to rituximab. Prolonged treatment results in longer EFS at the cost of a longer reduction in B cell and IgM levels, but without additional clinical toxicity.

Antihypertensive efficacy of amlodipine in children with chronic kidney diseases.

In adults the calcium antagonist amlodipine given once a day has proved to be an attractive addition to the antihypertensive armamentarium. The present report describes our experience in 43 paediatric outpatients (26 boys and 17 girls, aged between 1.1 and 19, median 9.8 years) with chronic kidney diseases. The patients were given amlodipine for 16 weeks as part of their antihypertensive treatment. Before amlodipine arterial pressure was 150 (142-163)/90 (84-95) mm Hg (median and interquartile range). Six patients withdrew from amlodipine because of oedema, flushing or headache. In the remaining patients amlodipine 7.7 (6.9-9.4) mg/m(2) body surface area once a day significantly decreased arterial pressure by 17 (13-22)/10 (7-13) mm Hg. The efficacy of amlodipine was more pronounced in girls than in boys. No changes in heart rate, body weight and circulating haemoglobin, sodium, potassium and creatinine were noted. In none of the patients circulating potassium, sodium or creatinine changed by more than 0.5 mmol/l, 5 mmol/l respectively 20%. In 11 patients concomitantly treated with cyclosporine the dosage and the trough-level of this agent were stable throughout the trial. In conclusion the present experience in paediatric outpatients with chronic kidney diseases supports the view that amlodipine is an effective and rather well tolerated antihypertensive drug when given once a day.

[Patient with recurrent gastrointestinal hemorrhage in acquired von Willebrand disease]. / Patientin mit rezidivierenden gastrointestinalen Blutungen bei akquiriertem Morbus von Willebrand.

A 61-year-old female without prior history of bleeding experienced several symptomatic episodes of gastrointestinal bleeding in the last few years. A source of gastrointestinal bleeding could not be found although several tests of occult blood in the stool were positive. Diagnostically, a significant deficiency of von Willebrand factor could be found due to a shortened half-life of the von Willebrand factor. This acquired von Willebrand factor deficiency most likely can be explained by an immunological mechanism (e.g. antibodies against von Willebrand factor). Neither an immunosuppressive therapy with steroids nor cyclophosphamide could normalize the von Willebrand factor and the bleeding continued. Only tranexamic acid (inhibiting fibrinolysis) could at last stop the symptomatic episodes of gastrointestinal bleeding despite the fact of decreasing von Willebrand factor.

[Autologous blood donation--good clinical practice and good recuperation practice]. / Eigenblutspenden--gute klinische Praxis und gute Herstellungspraxis.

Since October 1987, autologous blood donations have been performed in Bern and in 1994 reached a total of 946, representing 3% of all blood donations. This value is lower than the 4.9% for Switzerland as a whole. We report on the motivation and reasons of patients in favour of autologous blood donations and compare the results of 1989 with 1995. In the 6 years' period, the median patient's age increased from 54 to 63 years. The motivation for autologous blood donations changed from "routine surgical office" to "doctors". More than 50% of the patients mentioned the risk of acquiring an infectious disease, especially HIV, as the main reason for autologous blood donations. Labeling, testing or storage of autologous blood products of 37 out of 100 patients was incorrect, and in a another 20% an enquiry at the donation centres was needed to confirm the required quality of the autologous blood products. In 7 cases only one out of several blood bags was screened for viral diseases, and in 5 cases, unfortunately, none of the autologous blood products were tested for HIV or hepatitis B and C. Considering the negative cost-effectiveness of autologous blood transfusion, it is strongly recommended that the intrinsically low clinical benefit of autologous blood product should not be compromised by lack of good clinical practice and good manufacturing practice.

Severe neutropenia in T-large granular lymphocyte leukemia corrected by intensive immunosuppression.

Optimum treatment of severe neutropenia, a major factor for morbidity and mortality in T-large granular lymphocyte (LGL) leukemia, is undefined. We observed a rapid improvement of the neutrophil count in a patient with T-LGL leukemia and severe neutropenia after the combined administration of antilymphocyte-globulin (ALG), cyclosporin A, prednisone, and granulocyte colony-stimulating factor (G-CSF). Although G-CSF treatment was terminated after 7 days, the neutrophil count has persisted above 1.0 x 10(9)/1 for up to 6 months now. Oral methotrexate is given continuously as treatment for T-LGL leukemia. The response to this immunosuppressive regimen suggests a T-cell-mediated mechanism as the underlying cause for neutropenia in T-LGL leukemia.

Patterns of drug resistance parameters in adult leukemia.

P-glycoprotein (Pgp), Glutathione (GSH), Glutathione S-Transferase (GST), and O6-Alkylguanine-DNA Alkyltransferase (ATase) were measured in parallel as putative indicators of drug resistance in adult leukemia. The patterns of resistance parameter expression of chronic and acute leukemia were different. In acute leukemia on average all parameters were increased as compared to normal bone marrow. In chronic leukemia GSH and GST were increased, whereas Atase, GPx and frequency of Pgp-expression were low. Treatment with cytostatic drugs did not influence median levels of expression/activity of the resistance parameters. Resistance parameter expression/activity of leukemic cells was also compared with various other tissue and tumor types. Generally the pattern of resistance parameter expression reflected the resistance status of the tissue, constitutively resistant tumor types and their corresponding normal tissue on average having higher levels than leukemic cells and other tissue and tumor types with acquired resistance. For individual patients with acute leukemia, however, none of the parameters was directly correlated with response to treatment.

Evaluation of back pain secondary to spinal epidural hematoma associated with aspirin intake and a partial platelet glycoprotein Ia/IIa deficiency.

We report a case of spontaneous spinal epidural hemorrhage with three unusual features: (1) the hemorrhage was associated with aspirin ingestion and a reduced level of platelet glycoprotein Ia/IIa; (2) the patient presented with typical severe back pain but without neurologic dysfunction; and (3) the patient initially recovered without surgical decompression but suffered from recurrent epidural hematoma.

Atrial natriuretic factor and autonomic nervous system function in man.

To delineate a possible interaction of atrial natriuretic peptide ANF-(99-126) with autonomic nervous system function in humans, a spectrum of indices were assessed in 10 healthy young men during a 90 min iv administration of a) synthetic ANF-(99-126) 50 micrograms bolus followed by 0.025 micrograms.kg-1.min-1, b) the potent vasodilator sodium nitroprusside (SNP) 0.35 micrograms.kg-1. min-1, or c) vehicle 0.9% NaCl40 ml and 20% albumin 5 ml, in random sequence. Plasma immunoreactive ANF (irANF) rose from 32 to 1700 pg.ml-1 during the ANF-(99-126) infusion and was stable during SNP or vehicle. Infusion of ANF-(99-126) and SNP, but not vehicle, decreased diastolic blood pressure (BP) on average by -9 and -7.5%, respectively; systolic BP was largely unchanged. Heart rate (HR, + 15 and 12%) or plasma norepinephrine (NE) rose similarly during ANF-(99-126) and SNP infusions, and the systolic BP response to orthostasis was similar (-18 mmHg). The following autonomic indices did not differ significantly after the 3 infusions: responses of HR and NE to orthrostasis; reflex bradycardic response to phenylephrine (PE)-induced rise in systolic BP (+ 20 mmHg); responses of BP to hyperventilation, PE, or 3 min of sustained handgrip; and beat-to-beat variation (R-R interval) during deep breathing. The immediate orthostatic HR response (30/15 R-R interval ratio) fell similarly during infusion of ANF-(99-126) or nitroprusside. The findings indicate that in healthy men the function of the autonomic nervous system is not notably impaired by high circulating ANF levels.(ABSTRACT TRUNCATED AT 250 WORDS)