Decreased Iron Overload and Oxidative Stress in Transfusion Dependent Patients with Myelodysplastic Syndromes (MDS) with the Oral Iron Chelator Deferiprone

Background: The majority of the patients with low risk myelodysplastic syndrome (MDS) become RBC-transfusion-dependent and thus symptoms resulting from iron overload and oxidative stress may develop. Yet, iron-chelation has not been part of the standard treatment for these patients. The purpose of this study was to assess the effect of deferiprone (L1), an iron chelator, on oxidative stress parameters in iron overloaded and blood dependent patients with low risk MDS. Methods: This work was supported by a grant from Apopharma. Nineteen low risk MDS patients were enrolled. Patients were classified as very low-, low- and intermediate-risk disease, according to the Revised International Prognostic Scoring System (IPSS-R). Inclusion criteria were a cumulative transfusion burden of >20 red blood cells (RBC) units and evidence of iron overload (serum ferritin >1,000 ng/mL). Deferiprone at a dose of up to a maximum dose of 100 mg/kg was administrated for 4 months. Blood samples were taken at baseline, at each monthly visit, and at the end of the study. The samples were tested for oxidative stress parameters: reactive oxygen species (ROS), phosphatidylserine (PS), glutathione (GSH) and membrane lipid peroxidation (LP); iron parameters: serum ferritin and cellular labile iron pool (LIP), and CBC. The primary efficacy variable as a measurement of oxidative stress was ROS. Student's t-test was applied for statistical analyses. Results: Patients (n=19) were treated with deferiprone in a daily dose of 25-100 mg/kg, median of 50 mg/kg/day. Eight patients received treatment for 120 days and completed the study. One of them had mild neutropenia that resolved after short discontinuation of the study drug and finished the study with no more complications. Eleven patients did not finish the study: eight patients due to gastrointestinal (GI) adverse effects, two patients withdrew their consent (one of them after mild neutropenia that resolved) and one patient was killed in a car accident. We thus had measurements of at least two time points for 16 of the patients. The median number of RBC transfusions during study period was 11 (2-20). The primary efficacy variable ROS, as a measurement of oxidative stress, was significantly decreased, in all three lineages: platelet, RBC and neutrophils (decrease of 32%, 33% and 32% respectively, each at P=0.001). Deferiprone administration was also associated with a reduction in other cellular markers of oxidative stress in RBC: PS, GSH, LP and LIP (decrease of 54%, 98%, 300%, and 42% respectively, each at P=0.001). No significant changes were observed in serum ferritin levels, likely due to the short treatment period in patients on repeated transfusion requirements. Conclusions: This is the first prospective study on chelation with Deferiprone in MDS patients. Our data provide preliminary evidence that administration of Deferiprone in a median daily dose of at 50 mg/kg can decrease iron-induced oxidative stress in iron-overloaded MDS patients. Of note, no events of agranulocytosis were observed. The future remains challenge is to prove that reduction in iron toxicity will eventually translate into a clinically meaningful improvement. Prof. Rachmilewitz who unfortunately passed away last year, had a significant contribution to the conception and design of this study. Disclosures No relevant conflicts of interest to declare.

Efficacy and tolerability of a complex homeopathic drug in children suffering from dry cough-A double-blind, placebo-controlled, clinical trial

Background A randomised, placebo-controlled clinical trial in children suffering from acute dry cough was performed to assess the efficacy and tolerability of a complex homeopathic drug (Drosera, Coccus cacti, Cuprum Sulfuricum, Ipecacuanha=Monapax syrup, short: verum). Methods 89 children received verum and 91 received placebo daily for 7 days (age groups 0.5–3, 4–7 and 8–12 years). The primary efficacy variable was the improvement of the Cough Assessment Score. Tolerability and compliance were also assessed. A confirmatory statistical analysis was performed for the primary efficacy variable and a descriptive analysis for the secondary parameters. Results The Cough Assessment Score showed an improvement of 5.2±2.6 points for children treated with verum and 3.2±2.6 points in the placebo group (p<0.0001). The difference of the least square means of the improvements was 1.9±0.4. The effect size of Cohen´s d was d=0.77. In all secondary parameters the patients in the verum group showed higher rates of improvement and remission than those in the placebo group. In 15 patients (verum: n=6; placebo: n=9) 18 adverse drug reactions of mild or moderate intensity were observed. Conclusions Administering verum resulted in a statistically significantly greater improvement of the Cough Assessment Score than the placebo. The tolerability was good and not inferior to that of the placebo.

Canakinumab treatment for patients with active recurrent or chronic TNF receptor-associated periodic syndrome (TRAPS): an open-label, phase II study

ObjectiveTo evaluate the efficacy of canakinumab, a high-affinity human monoclonal anti-interleukin-1β antibody, in inducing complete or almost complete responses in patients with active tumour necrosis factor receptor-associated periodic syndrome (TRAPS).MethodsTwenty patients (aged 7–78 years) with active recurrent or chronic TRAPS were treated with canakinumab 150 mg every 4 weeks for 4 months (2 mg/kg for those ≤40 kg) in this open-label, proof-of-concept, phase II study. Canakinumab was then withdrawn for up to 5 months, with reintroduction on relapse, and 4 weekly administration (subsequently increased to every 8 weeks) for 24 months. The primary efficacy variable was the proportion of patients achieving complete or almost complete response at day 15, defined as clinical remission (Physician's Global Assessment score ≤1) and full or partial serological remission.ResultsNineteen patients (19/20, 95%; 95% CI 75.1% to 99.9%) achieved the primary efficacy variable. Responses to canakinumab occurred rapidly; median time to clinical remission 4 days (95% CI 3 to 8 days). All patients relapsed after canakinumab was withdrawn; median time to relapse 91.5 days (95% CI 65 to 117 days). On reintroduction of canakinumab, clinical and serological responses were similar to those seen during the first phase, and were sustained throughout treatment. Canakinumab was well tolerated and clinical responses were accompanied by rapid and sustained improvement in health-related quality of life. Weight normalised pharmacokinetics of canakinumab, although limited, appeared to be consistent with historical canakinumab data.ConclusionsCanakinumab induces rapid disease control in patients with active TRAPS, and clinical benefits are sustained during long-term treatment.Trial registration numberNCT01242813; Results.

Exercise as migraine prophylaxis: A randomized study using relaxation and topiramate as controls

Aim: Scientific evidence regarding exercise in migraine prophylaxis is required. Therefore this study aimed to evaluate the effects of exercise in migraine prevention. Methods: In a randomized, controlled trial of adults with migraine, exercising for 40 minutes three times a week was compared to relaxation according to a recorded programme or daily topiramate use, which was slowly increased to the individual’s highest tolerable dose (maximum 200 mg/day). The treatment period lasted for 3 months, and migraine status, quality of life, level of physical activity, and oxygen uptake were evaluated. The primary efficacy variable was the mean reduction of the frequency of migraine attacks during the final month of treatment compared with the baseline. Results: Ninety-one patients were randomized and included in the intention-to-treat analysis. The primary efficacy variable showed a mean reduction of 0.93 (95% confidence interval (CI) 0.31–1.54) attacks in the exercise group, 0.83 (95% CI 0.22–1.45) attacks in the relaxation group, and 0.97 (95% CI 0.36–1.58) attacks in the topiramate group. No significant difference was observed between the groups ( p = 0.95). Conclusion: Exercise may be an option for the prophylactic treatment of migraine in patients who do not benefit from or do not want to take daily medication.

A Randomized and Blinded Single-Center Trial Comparing the Effect of Intracranial Pressure and Intracranial Pressure Wave Amplitude-Guided Intensive Care Management on Early Clinical State and 12-Month Outcome in Patients With Aneurysmal Subarachnoid Hemorrhage

BACKGROUND In patients with aneurysmal subarachnoid hemorrhage (SAH), preliminary results indicate that the amplitude of the single intracranial pressure (ICP) wave is a better predictor of the early clinical state and 6-month outcome than the mean ICP. OBJECTIVE To perform a randomized and blinded single-center trial comparing the effect of mean ICP vs mean ICP wave amplitude (MWA)-guided intensive care management on early clinical state and outcome in patients with aneurysmal SAH. METHODS Patients were randomized to 2 different types of ICP management: maintenance of mean ICP less than 20 mm Hg and MWA less than 5 mm Hg. Early clinical state was assessed daily using the Glasgow Coma Scale. The primary efficacy variable was 12-month outcome in terms of the Rankin Stroke Score. RESULTS Ninety-seven patients were included in the study. There were no significant differences in treatment between the 2 groups apart from a larger volume of cerebrospinal fluid drained during week 1 in the MWA group. There was a tendency toward higher Glasgow Coma Scale scores in the MWA group during weeks 1 (P = .08) and 2 (P = .07). Outcome in terms of Rankin Stroke Score at 12 months was significantly better in the MWA group (P &lt; .05). CONCLUSION This randomized and blinded trial disclosed a significant better primary efficacy variable (Rankin Stroke Score after 12 months) in the MWA patient group. We suggest that proactive intensive care management with MWA-tailored cerebrospinal fluid drainage during the first week improves aneurysmal SAH outcome.

Influenza and Meningococcal Vaccinations Are Effective in Healthy Subjects Treated with the Interleukin-1β-Blocking Antibody Canakinumab: Results of an Open-Label, Parallel Group, Randomized, Single-Center Study

ABSTRACT The objective of this study was to evaluate the efficacy of influenza and meningococcal vaccines in healthy subjects exposed to the anti-interleukin-1β (anti-IL-1β) monoclonal antibody canakinumab. This was an open-label, parallel group, randomized, single-center study of healthy subjects (aged 18 to 45 years). At baseline, antibody (Ab) titers were measured and subjects were randomized (1:1) to a single 300-mg canakinumab dose administered subcutaneously (s.c.) or received no treatment (control group). After 2 weeks, subjects were treated with inactivated, unadjuvanted influenza and conjugated group C meningococcal (MenC) vaccines, administered intramuscularly (i.m.). The primary efficacy variable was the response (≥2-fold increase in Ab titer in ≥2 of 3 influenza virus strains) after 4 weeks in subjects treated with canakinumab compared to the control group. Secondary efficacy variables were the antibody response to vaccines at different thresholds and time points. Fifty-one of 112 subjects screened were randomized to canakinumab (n = 25) or the control group (n = 26). Antibody responses to vaccinations measured against different influenza virus strains and one MenC strain at 4 weeks were comparable in the canakinumab and control groups. The primary efficacy variable, the response to influenza vaccination (≥2-fold increase in Ab titer in ≥2 of 3 serotypes) at 4 weeks, was shown in 24/25 subjects in the canakinumab group compared to 25/25 subjects in the control group. Antibody responses remained comparable in the two groups at the different time points assessed. Headache was the most frequently reported adverse event. No deaths or serious adverse events were reported during the study. We concluded that a single dose of 300 mg canakinumab s.c. does not affect the induction or persistence of antibody responses after vaccination with unadjuvanted influenza or alum-adjuvanted MenC vaccines in healthy subjects.

A Prospective Study of Imatinib 400 mg vs 800 mg Frontline in High Risk Ph+ Chronic Myeloid Leukemia (CML) Patients.

Background: imatinib mesylate (IM) is the drug of choice for the front-line treatment of Ph+ CML, at a dose of 400 mg daily (M. Baccarani et al Blood2006;108:1809–1820). Several biological and clinical observations suggest that increasing the dose may improve the results. The cytogenetic response to IM 400 mg daily is significantly related with Sokal relative risk. High risk patients could benefit of a dose increase front-line. Aim: to compare the effects of 400 mg and 800 mg daily in previously untreated, early chronic phase patients, high Sokal risk. The primary efficacy variable of the study is the complete cytogenetic response (CCgR) rate after 12 months, on an intention-to-treat analysis. Patients and Methods: this is a multicentric international study running in Italy, Sweden, Denmark, Finland, Norway, Turkey and Israel, approved by the local Ethic Committees, conducted according to Helsinki Declaration and Good Clinical Practice. 215 patients with confirmed Ph+ CML previously untreated, high risk according to Sokal formulation (J. Sokal et al Blood1984;63:789–799) were enrolled over a 3-year period and were randomized (1:1) to receive IM 400 or 800 mg daily. Cytogenetic response was assessed by conventional cytogenetics and FISH analysis after 3, 6 and 12 months. Molecular response was evaluated every three months. Results: as of August 2007, 137 patients are evaluable for CCgR rate at 12 months (primary efficacy variable). Patients in CCgR at that time were 78/137 (57%). Treatment failures during the study (no complete hematologic response or 100% Ph+ at 6 months, or loss of response) were 24/137 (17%), patients off-treatment for protocol violations or refusal were 10/137 (7%), patients off-treatment for toxicity were 7/137 (5%). Conclusions: the results of this preliminary analysis show that the CCgR rate at 12 months is overall 57%, in line with the results of the IRIS trial (imatinib 400 mg daily - T. Hughes et al, NEJM 2003, 349;15: 1423–1432) in the same risk category (69% all risks, 49% high Sokal risk). At the time of writing is too early to analyze the results by arm: a second analysis will be performed in November (datalock, October 31) and the results will be presented on site.

Infusion-related reactions (IRR) associated with cetuximab plus irinotecan treatment in patients with irinotecan-resistant metastatic colorectal cancer (mCRC): Findings from the MABEL study

4137 Background: Cetuximab is an IgG1 anti-EGFR monoclonal antibody, active alone and in combination with irinotecan in mCRC patients (pts) who have failed prior irinotecan therapy. In previous studies with cetuximab, IRRs were observed in a small proportion of pts especially at the first infusion. Methods: MABEL investigated cetuximab plus irinotecan in pts with EGFR-detectable mCRC whose last treatment regimen contained irinotecan. A secondary objective of MABEL was to further study cetuximab-related adverse events. Study treatment was cetuximab, initial dose 400 mg/m2, weekly 250 mg/m2, plus irinotecan with dose and schedule as pre-study. Data analyzed included prophylactic pre-medication, IRRs and medication for IRRs. Prophylactic medication given before the first cetuximab infusion was categorized as chlorphenamine antihistamines, antihistamines other than chlorphenamine, and any antihistamines plus corticosteroids. Results: Overall, 1147 pts were treated in this study: median age was 62 years [25–84], Karnofsky performance status was =70% and 64% pts were male. 1,122 patients were pre-treated with antihistamines. The frequency of IRRs was lower in pts who received antihistamines plus corticosteroids than in pts who received antihistamines alone (9.6% vs 25.6% any grade, 1% vs 4.7% grade 3/4 IRRs). The primary efficacy variable of MABEL was the 12-weeks progression-free survival (PFS) status. Efficacy results by pre-medication groups for PFS (see table ) and overall survival do not suggest differences related to prophylactic pre-medication. Conclusions: The data suggest that the type of pre-medication impacts on the occurrence of IRRs, and that the addition of corticosteroids to antihistamines reduces IRRs without altering antitumor efficacy in the analyzed pre-medication groups. [Table: see text] No significant financial relationships to disclose.

Evaluation of the Effectiveness of Imiquimod and 5-Fluorouracil for the Treatment of Actinic Keratosis: Critical Review and Meta-Analysis of Efficacy Studies

Background: Actinic keratosis lesions occur frequently on sun-exposed skin of Caucasians. They become more prevalent with advancing age and are important in identifying the risk factor of those people possibly predisposed to invasive squamous cell carcinoma. Topical therapies are useful alternatives to cryotherapy for treating diffuse actinic damage and a number of preparations have been developed for treating actinic keratosis. Objectives: A cumulative meta-analysis was performed to determine the efficacy of imiquimod 5% cream, which presents a new alternative topical therapy for actinic keratosis, and to compare it to 5-fluorouracil for the treatment of actinic keratosis lesions of the face and scalp. Methods: We searched MEDLINE (1966 to October 2004) for relevant studies evaluating the efficacy of actinic keratosis topical agents imiquimod and 5-fluorouracil (0.5%, 1%, and 5%). Studies included in this meta-analysis required a dosage regimen that was not significantly different from that approved by Health Canada and the U.S. FDA. Studies also required a well-defined treatment duration and followup period, with the primary efficacy variable being the complete (100%) clearance of all actinic keratosis lesions defined as the proportion of patients at followup with no clinically visible lesions in the treatment area. To determine the average efficacy rate for both drugs, the data from each study were combined for that drug. Results: Ten studies were included in the analysis. The average efficacy rate for each drug (with 95% confidence interval) was 5-fluorouracil, 52 ± 18% ( n = 6 studies, 145 subjects) and imiquimod, 70 ± 12% ( n = 4 studies, 393 subjects). Conclusions: The results of this meta-analysis show that both imiquimod and 5-fluorouracil are effective methods for the treatment of actinic keratosis and provide a useful alternative to cryotherapy. However, this analysis suggests that imiquimod may have higher efficacy than 5-fluorouracil for actinic keratosis lesions located on the face and scalp and therefore provides another option to dermatologists.

Efficacy of an Aqueous and a Powder Formulation of Nasal Budesonide Compared in Patients with Nasal Polyps

Nasal polyps are commonly treated surgically. Intranasal administration of topical corticosteroids has gained increased acceptance as a treatment alternative. The aim of our study was to compare the efficacy of treatment of two formulations of budesonide with placebo on nasal polyps. At four Danish clinics 138 patients suffering from moderate or severe nasal polyps were randomized to a twice daily treatment with Rhinocort® Aqua 128 μg, Rhinocort Turbuhaler® 140 μg or placebo (Astra Draco, Sweden) for 6 weeks. Polyp size (primary efficacy variable), nasal symptoms, sense of smell, and patients’ overall evaluation of treatment of efficacy were assessed by scores. Polyp size was reduced significantly in both budesonide treated groups compared with placebo, but there was no statistical difference between the two actively treated groups. Patients’ nasal symptom scores was significantly more reduced in the Aqua compared to the Turbuhaler treated group, and both reduced symptom scores were significantly better compared to placebo. Sense of smell was significantly improved in the actively treated groups compared to placebo. The proportion of patients rating substantial or total control over symptoms after 6 weeks treatment was 60.9% and 48.2% in the Aqua and Turbuhaler-treated groups, respectively, which was significantly better compared with 29.8% in the placebo-treated group. Rhinocort Aqua and Rhinocort Turbuhaler were equally well tolerated.