Effectiveness of Long-Term Treatment of Multiple Myeloma in Regular Care: Comparison of a Longitudinal and a Cross-Sectional Analysis Approach.

INTRODUCTION: New drugs for multiple myeloma have considerably increased the options for consecutive treatment lines in regular care. Official treatment guidelines still discuss several regimens per line, and therefore, current practice is of topical interest. Large cross-sectional studies revealed a greater than linear loss of patients reaching consecutive treatment lines of ever decreasing effectiveness. METHODS: In a longitudinal approach, we analyzed data of all 145 multiple myeloma patients treated in our outpatient clinic in Germany between January 1, 2012, and December 31, 2019, using a time-to-event analysis with death as competitive risk. RESULTS: The estimated incidences of reaching the 2nd, 3rd, 4th, and 5th lines of therapy were 88, 66, 44, and 30%, respectively. Median times to subsequent treatment lines were 34, 18, 14, 13, and 15 months, respectively. DISCUSSION: Percentages of patients reaching later therapy lines were considerably greater than predicted by cross-sectional studies and median times after the 1st line did not suggest a further decrease in effectiveness, while use of new drug regimens was similar to that reported in cross-sectional studies. CONCLUSION: Effectiveness of later therapy lines appears to be underestimated by cross-sectional analyses, and the conveyed focus on 1st-line treatment for multiple myeloma needs to be scrutinized.

Re-evaluation of laboratory predictors of response to current anemia treatment regimens of erythropoiesis stimulating agents in cancer patients.

BACKGROUND: Anemia is a major cause of morbidity in cancer. Erythropoiesis stimulating agents (ESA) are a mainstay of treatment, although some patients lack response for unknown reasons. Recently, ESA dosing recommendations have changed and iron is increasingly used as an adjunct. Due to these changes, potential laboratory predictors of response were re-evaluated. METHODS: This was a multi-center, observational study in cancer outpatients developing anemia under standard chemotherapy without absolute iron deficiency. For up to 12 weeks, laboratory data was collected while patients were treated with darbepoetin α (DA) either alone or along with intravenous iron. Baseline erythropoietin (Epo), changes in soluble transferrin receptor (sTfR) and in hemoglobin (Hb) early after treatment initiation were re-evaluated as response predictors, based on logistic regression models. RESULTS: Overall, 279 patients (mean age 66.1 years, 59.5% female) entered the study; 171 (61%) received at least one iron dose along with DA. Response and its predictability hardly increased through adjunct iron, although baseline ferritin <100 mg/L resulted in a 10 times higher probability of response to the combination than to ESA alone. Baseline Epo had low predictive value, regardless of tumor type or use of adjunct iron, although it varied with sex and age. If criteria for all three - Epo, sTfR, and Hb - were met, probability of preventing transfusions was 97%, dropping to 44%, if all three failed. CONCLUSIONS: Changes in ESA treatment recommendations had no impact on the predictability of response. Best prediction is still based on the immediacy of Hb increase.

Clinical decision rules for the use of liquor diagnostics in hospitalized neurology patients reduced costs without affecting clinical outcomes.

OBJECTIVES: Excessive use of laboratory diagnostics has been common. This study aimed to evaluate whether clinical decision rules for the use of liquor diagnostics would enable cost containment without affecting medical care. METHODS: This was a single-center, retrospective, cost-minimization study based on the records of all 16,319 patients hospitalized and discharged at a Neurology Clinic in Austria between 2004 and 2006. Cost of liquor diagnostics, discharge diagnosis, duration of hospital stay, and mortality were compared along the line before, during, and after implementation of decision rules in mid-2005. RESULTS: There were no significant changes in patient characteristics over time, not in the diagnoses at discharge, nor in the percentage of patients undergoing liquor diagnostics. The average number of tests per patient significantly decreased. Standard tests largely replaced serological tests for infections, regardless of diagnosis. Annual costs for liquor diagnostics decreased by 32.9 percent. Overall, the duration of hospital stay and mortality significantly decreased as well; however, differences were not significant for any single diagnosis-related group. CONCLUSIONS: Diagnostic algorithms may allow cost containment without affecting medical care.

A new high-throughput screening method for the detection of chronic lymphatic leukemia and myelodysplastic syndrome.

BACKGROUND: The VCS technology of Beckman Coulter differentiates white blood cells based on measures of their volume, conductivity and light scatter. The current study investigated the predictive value of index measures, known as research population data, for the detection of chronic lymphatic leukemia and myelodysplastic syndrome. METHODS: Blood cell counts were performed in samples from 44 patients with chronic lymphatic leukemia, 19 patients with myelodysplastic syndrome and 199 healthy blood donors using the Beckman Coulter LH750. Means and standard deviations of volume, conductivity and scatter of lymphocytes and neutrophils were evaluated as predictors for both diseases. Their specificity and selectivity were evaluated by logistic regression and receiver operating characteristic curve analysis. RESULTS: Research population data were significantly different among groups. For chronic lymphatic leukemia, standard deviations of lymphocytes scatter and volume showed most relevant differences in comparison to healthy blood donors (sensitivity 88.6%, specificity 84.4%). For myelodysplastic syndrome, standard deviations of neutrophils conductivity were most predictive (sensitivity 73.7%, specificity 93.0%). Areas under corresponding receiver operating characteristic curves were 0.941 and 0.951, respectively. CONCLUSIONS: Based on their high predictive value, research population data could be routinely used to screen for chronic lymphatic leukemia and myelodysplastic syndrome.

Prediction of the responsiveness to treatment with erythropoiesis-stimulating factors: a prospective clinical study in patients with solid tumors.

OBJECTIVE: Treatment with erythropoiesis-stimulating factors (ESFs) can ameliorate anemia associated with cancer and chemotherapy. However, half of anemic cancer patients do not respond even to high doses. To determine factors that are predictive of a treatment response, a multicenter, prospective study was performed. PATIENTS AND METHODS: Investigated factors were baseline erythropoietin, reticulocytes and soluble transferrin receptor (sTfR) after 2 weeks, and reticulocytes and hemoglobin after 4 weeks. Anemic patients with solid tumors received 150 microg/week of darbepoetin concomitantly with chemotherapy. The dose was doubled if hemoglobin did not increase by >1 g/dl after 4 weeks. Patients were considered responders if hemoglobin increased by >or=2 g/dl or reached a level >or=12 g/dl within 8-12 weeks. RESULTS: In total, 196 patients were enrolled; 61% of the intention-to-treat (ITT) and 68% of the per-protocol population were responders. In the ITT population, the hemoglobin increase after 4 weeks indicated an 11-fold higher chance of response (odds ratio, 11.0; 95% confidence interval [CI], 5.1-23.6; sensitivity, 88%; specificity, 60%). In a multiple logistic regression model including all factors, the area under the receiver operating characteristic curve was 0.78 (95% CI, 0.71-0.84). The combination of sTfR after 2 weeks and hemoglobin after 4 weeks was as predictive as the combination of all five tested factors. CONCLUSION: So far, an early hemoglobin increase remains the single most predictive factor for response to ESF treatment. In contrast to anemic patients with lymphoproliferative malignancies, serum erythropoietin had little predictive value in patients with solid tumors.

Non-frozen transports of whole blood samples do not cause relevant bias for global coagulation tests in clinical trials evaluating the drug safety.

Sample shipments with dry ice have a large economic impact on clinical research. Therefore, the bias caused for global coagulation tests by non-frozen transports of whole blood instead of frozen plasma was investigated experimentally and by a meta-analysis of 6-year central laboratory data. In the experiment, aliquots from 14 healthy volunteers were kept as whole blood at 20+/-2 degrees C and as frozen plasma until an analysis of prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), and antithrombin III (ATIII) at day 0, 1, 2, and 3 from collection. Within these 3 days only PT and aPTT demonstrated any changes: in blood samples kept at 20+/-2 degrees C these amounted about 10% for both. In frozen plasma, aPTT did not change whereas PT increased by 14%. In a meta-analysis of central laboratory data, PT and aPTT results were grouped across various phase II-IV trials by the type of sample transfer, either as frozen plasma on dry ice or non-frozen as whole blood. For the latter the mean difference to a reference group of phase I trials with same-day analysis was in line with the amount of bias found in the experiment (aPTT, 34.6+/-6.0 vs. 31.6+/-3.5 s; PT, 87.7+/-13.3 vs. 97.3+/-7.9%). The consistent bias resulted in shifted, but still normal distribution curves with a total rate of clinically relevant outliers of about 1.9% for aPTT and 2.4% for PT. Biases thus appear irrelevant for a common safety evaluation within clinical trials. Non-frozen whole blood transports for the measurement of global coagulation tests appear justified for this purpose, if protocols do not require frozen shipments for other reasons. However, transit time must not exceed 2 days and pre-analytical conditions should be consistent within the same trial.