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Lenalidomide yields sustained RBC-TI in 26.9% of RBC transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes ineligible for or refractory to erythropoiesis-stimulating agents. Response to lenalidomide was associated with improved HRQoL. Treatment-emergent adverse event data were consistent with the known safety profile of lenalidomide.

PURPOSE Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion–dependent anemia and thrombocytopenia. METHODS Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109/L. CONCLUSION CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.

Substantial evidence indicates that triglyceride-rich lipoprotein remnants are atherogenic. Additional research has, however, been limited by available methods for separation and quantification of remnants. We have evaluated an immunoseparation assay developed to measure cholesterol in remnant-like particles (RLP-C). This method uses monoclonal antibodies to human apolipoproteins B-100 and A-I to remove most of the apolipoprotein B-100-containing lipoproteins (namely LDL and nascent VLDL) and apolipoprotein A-I-containing lipoproteins (namely chylomicrons and HDL), leaving behind a fraction of triglyceride-rich lipoproteins, including chylomicron and VLDL remnants, both of which are enriched in apolipoprotein E. Cholesterol in the unbound fraction is measured with a sensitive enzymatic assay. The RLP-C concentration was highly correlated with total triglyceride-rich lipoproteins (sum of VLDL-cholesterol and IDL-cholesterol) separated by ultracentrifugation and by polyacrylamide gel electrophoresis (r = 0.86 and 0.76, respectively). The within-run and run-to-run imprecision (CV) of the assay was ∼6% and 10%, respectively. The assay was not affected by hemoglobin up to 5000 mg/L (500 mg/dL), bilirubin up to 342 mmol/L (20 mg/dL), glucose up to 67 mmol/L (1200 mg/dL), or ascorbic acid up to 170 mmol/L (3.0 mg/dL). In 726 subjects (men, n = 364; women, n = 362) in the US, the 75th percentiles of RLP-C concentration were 0.17 mmol/L (6.6 mg/dL) and 0.23 mmol/L (8.8 mg/dL) in sera obtained after overnight fasting or randomly, respectively. A group of 151 patients from nine US centers and one Canadian center with coronary artery atherosclerosis established by angiography had higher median RLP-C concentrations than 302 gender- and age-matched controls (P <0.05). We conclude that the RLP-C assay compares favorably to ultracentrifugation and electrophoresis and provides a convenient and economical approach to measure triglyceride-rich lipoprotein remnants in routine clinical laboratories.

Objective. OPC-28326 is a selective ␣-adrenergic antagonist with preferential binding to the ␣ 2C -adrenergic receptor (␣ 2C -AR) subtype. This study observed the effect of OPC-28326 on skin temperature and digital blood flow following an acute cold challenge in patients with Raynaud's phenomenon secondary to scleroderma.Methods. The study was designed as a singlecenter, double-blind, placebo-controlled, randomized, 3-period crossover study of OPC-28326 (oral doses of 10 mg or 40 mg) or placebo. The primary outcome measures were the time to recover 50% and 70% of the fall (induced by cold challenge) in baseline digital skin temperature.Results. Twelve of 13 enrolled patients completed the study. The mean time to achieve 50% and 70% recovery of the change in prechallenge digital skin temperature was shorter after the OPC-28326 40-mg dose than after placebo (50% recovery at 5.8 minutes versus 10.0 minutes [P ‫؍‬ 0.02]; 70% recovery at 13.8 minutes versus 19.5 minutes [P ‫؍‬ 0.01]). These recovery times tended to be shorter in the 10 mg OPC-28326 group as well, but the difference versus placebo was not significant (50% recovery at 9.0 minutes versus 10.0 minutes [P ‫؍‬ 0.65]; 70% recovery at 15.3 minutes versus 19.5 minutes [P ‫؍‬ 0.07]). Total digital blood flow tended to be lower prior to the cold challenge and after administration of 40 mg OPC-28326, as compared with that after placebo, but the difference was not significant. Symptoms that were potentially drug-related were reported more frequently with 40 mg OPC-28326 than with 10 mg OPC-28326 or with placebo, but none were serious or sustained.Conclusion. OPC-28326 at doses of 10 mg and 40 mg was well tolerated during this study. The shorter time to skin temperature recovery after 40 mg OPC-28326 suggests that selective ␣ 2C -AR blockade improves digital skin perfusion during recovery from cooling in patients with Raynaud's phenomenon secondary to scleroderma.