Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis.

OBJECTIVES: Mavrilimumab, a human monoclonal antibody targeting the alpha subunit of the granulocyte-macrophage colony-stimulating factor receptor, was evaluated in a phase 2 randomised, double-blind, placebo-controlled study to investigate efficacy and safety in subjects with rheumatoid arthritis (RA). METHODS: Subcutaneous mavrilimumab (10 mg, 30 mg, 50 mg, or 100 mg) or placebo was administered every other week for 12 weeks in subjects on stable background methotrexate therapy. The primary endpoint was the proportion of subjects achieving a ≥1.2 decrease from baseline in Disease Activity Score (DAS28-CRP) at week 12. RESULTS: 55.7% of mavrilimumab-treated subjects met the primary endpoint versus 34.7% placebo (p=0.003) at week 12; for the 10 mg, 30 mg, 50 mg, and 100 mg groups, responses were 41.0% (p=0.543), 61.0% (p=0.011), 53.8% (p=0.071), and 66.7% (p=0.001) respectively. Response rate differences from placebo were observed at week 2 and increased throughout the treatment period. The 100 mg dose demonstrated a significant effect versus placebo on DAS28-CRP<2.6 (23.1% vs 6.7%, p=0.016), all categories of the American College of Rheumatology (ACR) criteria (ACR20: 69.2% vs 40.0%, p=0.005; ACR50: 30.8% vs 12.0%, p=0.021; ACR70: 17.9% vs 4.0%, p=0.030), and the Health Assessment Questionnaire Disability Index (-0.48 vs -0.25, p=0.005). A biomarker-based disease activity score showed a dose-dependent decrease at week 12, indicating suppression of disease-related biological pathways. Adverse events were generally mild or moderate in intensity. No significant hypersensitivity reactions, serious or opportunistic infections, or changes in pulmonary parameters were observed. CONCLUSIONS: Mavrilimumab induced rapid clinically significant responses in RA subjects, suggesting that inhibiting the mononuclear phagocyte pathway may provide a novel therapeutic approach for RA.

Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is an incurable and chronic disorder, with worsening prognosis for patients as their disease progresses. We compared the efficacy and safety of the combination of fludarabine and alemtuzumab with fludarabine monotherapy in previously treated patients with relapsed or refractory CLL. METHODS: Patients (aged ≥ 18 years) with CLL Binet stage A, B, or C or Rai stages I-IV were randomly assigned in a 1:1 ratio according to a computer-generated allocation schedule to open-label combination treatment (fludarabine 30 mg/m(2) per day and alemtuzumab 30 mg per day on days 1-3) or monotherapy (fludarabine 25 mg/m(2) on days 1-5) by use of an interactive voice response system. Both regimens were given intravenously for a maximum of six 28-day cycles. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00086580. FINDINGS: Fludarabine plus alemtuzumab (n=168) resulted in better PFS than did fludarabine monotherapy (n=167; median 23·7 months [95% CI 19·2-28·4] vs 16·5 months [12·5-21·2]; hazard ratio 0·61 [95% CI 0·47-0·80]; p=0·0003) and overall survival (median not reached vs 52·9 months [40·9-not reached]; 0·65 [0·45-0·94]; p=0·021) compared with fludarabine alone. All-cause adverse events occurred in 161 (98%) of 164 patients in the combination treatment group and 149 (90%) of 165 in the fludarabine alone group. Patients in the fludarabine plus alemtuzumab group had more cytomegalovirus events (23 [14%] vs one [<1%]) and grade 1 or 2 potentially alemtuzumab infusion-related adverse reactions (102 [62%] vs 22 [13%]). Grade 3 or 4 toxicities in the combination treatment and monotherapy groups were leucopenia (121 [74%] of 164 vs 55 [34%] of 164), lymphopenia (149 [94%] of 158 vs 53 [33%] of 161), neutropenia (93 [59%] of 157 vs 110 [68%] of 161), thrombocytopenia (18 [11%] of 164 vs 27 [17%] of 163), and anaemia (14 [9%] of 163 vs 28 [17%] of 164). The incidence of serious adverse events was higher in the combination treatment group (54 [33%] of 164 vs 41 [25%] of 165); deaths due to adverse events were similar between the two groups (ten [6%] vs 12 [7%]). INTERPRETATION: The combination of fludarabine and alemtuzumab is another treatment option for patients with previously treated CLL. FUNDING: Genzyme.

Influence of pulmonary rehabilitation on clinical characteristics in patients with chronic heart failure and chronic obstructive pulmonary disease / Influência da reabilitação pulmonar nas características clínicas em pacientes com insuficiência cardíaca crônica e doença pulmonar obstrutiva crônica

Background: The improvement of treatment strategies in patients with chronic obstructive pulmonary disease (COPD) and especially with comorbid pathology should provide rational conversion of standard schemes of therapy and rehabilitation in accordance with their clinical, pathogenic, functional and economic feasibility. Objective: To assess the influence of pulmonary rehabilitation on clinical characteristics in patients with chronic heart failure (CHF) and concomitant COPD. Methods: The study included 102 patients with CHF and concomitant COPD (males, 62%; mean age, 68.2 ± 4.5 years). All patients were divided into two groups: control group (CG) (n = 54), received only standard therapy of CHF and COPD; and intervention group (IG) (n = 48) were additionally taught the full yogic breathing as a program of pulmonary rehabilitation. Calculation of points by clinical evaluation scale (CES), assessment of CHF functional class (FC) (NYHA) and 6-minute walk test (6MWT - with the evaluation of dyspnea by the Borg scale) were performed in all patients on admission to the department and at discharge. Significant association was defined by p value < 0.05. Results: At baseline, there were no significant differences in clinical characteristics of the patients and studied parameters between the groups. At discharge both groups showed significant reduction of dyspnea by the Borg scale (in CG: from 7.2 ± 0.8 points to 5.2 ± 0.3; in IG: from 7.4 ± 0.6 points to 3.2 ± 0.4), the number of points by CES (in CG: from 10.8 ± 0.3 points to 7.2 ± 0.4; in IG: from 10.7 ± 0.6 points to 5.9 ± 0.6). Increase in exercise tolerance (by the distance of 6MWT) was observed in both groups (in CG: from 215 ± 24 m to 275 ± 22 m; in IG: from 219 ± 21 m to 308 ± 24 m). The changes were more significant in IG compared to CG. We observed the prominent decrease in CHF FC and length of hospital stay in IG. Conclusions: Application of full yogic breathing as the program of pulmonary rehabilitation in addition to standard therapy of the patients with CHF and COPD is associated with a significant decrease in CHF FC, an increase in exercise tolerance and a reduced length of hospital stay