Arlene S. Swern

Montelukast, Compared With Fluticasone, for Control of Asthma Among 6- to 14-Year-Old Patients With Mild Asthma: The MOSAIC Study

Background. Guidelines recommend daily controller therapy for mild persistent asthma. Montelukast has demonstrated consistent benefit in controlling symptoms of asthma and may be an alternative, orally administered, nonsteroidal agent for treating mild asthma. Methods. The Montelukast Study of Asthma in Children (MOSAIC study) was a 12-month, multicenter, randomized, double-blind, noninferiority trial to determine the effect of once-daily, orally administered montelukast (5 mg) (n = 495), compared with twice-daily, inhaled fluticasone (100 μg) (n = 499), on the percentage of asthma rescue-free days (RFDs) (any day without asthma rescue medication and with no asthma-related resource use). Patients 6 to 14 years of age had mild persistent asthma (average percentage of predicted forced expiratory volume in 1 second: 87.2%; RFDs at baseline: 64%). Montelukast would be considered not inferior to fluticasone if the upper limit of the 95% confidence interval for the difference in mean percentages of RFDs (fluticasone minus montelukast) was above −7% (a difference of ∼2 days/month). Results. The mean percentage of RFDs was 84.0% in the montelukast group and 86.7% in the fluticasone group. The least-squares mean difference was −2.8% (95% confidence interval: −4.7% to −0.9%), within the noninferiority limit of −7%. The proportion of patients requiring systemic corticosteroids and the number of patients with an asthma attack were greater in the montelukast group. Both montelukast and fluticasone were well tolerated. Conclusions. Montelukast was demonstrated to be not inferior to fluticasone in increasing the percentage of RFDs among 6- to 14-year-old patients with mild asthma. Secondary end points, including percentage of predicted forced expiratory volume in 1 second value, days with β-receptor agonist use, and quality of life, improved in both groups but were significantly better in the fluticasone treatment group.

A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial

The phase III AZA-001 study established that azacitidine significantly improves overall survival compared with conventional care regimens (hazard ratio 0.58 [95% confidence interval 0.43–0.77], P<0.001). This analysis was conducted to investigate the relationship between treatment response and overall survival. AZA-001 data were analyzed in a multivariate Cox regression analysis with response as a time-varying covariate. Response categories were “Overall Response” (defined as complete remission, partial remission, or any hematologic improvement) and “Stable Disease” (no complete or partial remission, hematologic improvement, or progression) or “Other” (e.g. disease progression). Achieving an Overall Response with azacitidine reduced risk of death by 95% compared with achieving an Overall Response with the conventional care regimens (hazard ratio 0.05 [95%CI: 0.01–0.43], P=0.006). Sensitivity analyses indicated that significantly improved overall survival remained manifest for patients with a hematologic improvement who had never achieved complete or partial remission (hazard ratio 0.19 [95%CI: 0.08–0.46], P<0.001). Stable Disease in both azacitidine-treated and conventional care-treated patients was also associated with a significantly reduced risk of death (hazard ratio 0.09, [95%CI: 0.06–0.15]; P<0.001). These results demonstrate azacitidine benefit on overall survival compared with conventional care regimens in patients with higher-risk myelodysplastic syndromes who achieve hematologic response but never attain complete or partial remission, in addition to the survival advantage conferred by achievement of complete or partial remission. This study was registered with clinicaltrials.gov (NCT00071799).

Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome

The erythropoietic effects of lenalidomide are cytokine dependent, suggesting that the erythroid hematologic improvement (HI-E) rate may be augmented by combined treatment (CT) with recombinant human erythropoietin (rhu-EPO) in myelodysplastic syndrome (MDS). In the present study, we explored the benefits of CT and the relationship between lenalidomide pharmacokinetics and hematologic toxicity in transfusion-dependent patients with low- to intermediate-1-risk MDS who failed prior rhu-EPO. In stage I, patients received 10 or 15 mg/d of lenalidomide monotherapy. At week 16, erythroid nonresponders (NRs) were eligible for CT with rhu-EPO 40 000 U/wk. Among 39 patients, HI-E response rate to monotherapy was 86% (6 of 7) in del(5q) and 25% (8 of 32) in non-del(5q) patients (10 mg, 17.7%; 15 mg, 33.3%). Twenty-three patients proceeded to CT, with 6 (26.0%) achieving HI-E. In 19 non-del(5q) patients, 4 (21.1%) showed HI-E. Mean baseline serum EPO in non-del(5q) patients was lower in monotherapy and CT responders than in NR (not statistically significant). Thrombocytopenia was significantly correlated with lenalidomide area under the plasma concentration-time curve (P = .0015), but severity of myelosuppression did not. The benefits of lenalidomide plus rhu-EPO are currently under investigation in a phase 3 Eastern Cooperative Oncology Group (ECOG)-sponsored intergroup study. This study is registered at www.clinicaltrials.gov as NCT00910858.

Perceptions of Disease State, Treatment Outcomes, and Prognosis Among Patients with Myelodysplastic Syndromes: Results from an Internet-Based Survey

PURPOSE Myelodysplastic syndromes (MDSs) are a heterogenous group of clonal hematopoietic disorders affecting approximately 60,000 people in the U.S. Little information is available regarding how aware MDS patients are of their disease severity, prognosis, and treatment outcomes. METHODS This Internet-based survey assessed patient perceptions regarding these factors, determined differences between patients with higher- and lower-risk disease and between those receiving active treatment and supportive care, and assessed patient-reported outcomes. RESULTS Among 358 patients (median age, 65 years), the median time since MDS diagnosis was 3 years and time from initial hematologic abnormality detection was 6 years. Many patients (55%) did not know their International Prognostic Scoring System score, 42% were unaware of their blast percentage, and 28% were unaware of their cytogenetics. Patients were unlikely to recall having their MDS described as cancer (7%), 37% felt their treatment would improve survival, and 16% felt treatment would be curative. Patients receiving active treatment were more likely to believe their therapy would prolong survival than those receiving supportive care (52% versus 31%; p < .001) or be curative (23% versus 14%; p = .03). Patients with higher-risk disease were more likely to think their therapy would be curative than those with lower-risk disease (26% versus 11%; p = .01). Patients with MDS reported poor physical or mental health on two to three times more days per month than population norms. CONCLUSION Patients with MDS have a limited understanding of their disease characteristics, prognosis, and treatment goals. These results may help improve physician-patient communication and identify factors to consider when making treatment decisions.

Efficacy and safety of long-term treatment with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma

Data from two randomized pivotal, phase 3 trials evaluating the combination of lenalidomide and dexamethasone in relapsed/refractory multiple myeloma (RRMM) were pooled to characterize the subset of patients who achieved long-term benefit of therapy (progression-free survival ⩾3 years). Patients with long-term benefit of therapy (n=45) had a median duration of treatment of 48.1 months and a response rate of 100%. Humoral improvement (uninvolved immunoglobulin A) was more common in patients with long-term benefit of therapy (79% vs 55% P=0.002). Significant predictors of long-term benefit of therapy in multivariate analysis were age<65 years (P=0.03), β2-microglobulin <2.5 mg/l (P=0.002) and fewer prior therapies (P=0.002). The exposure-adjusted incidence rate (EAIR) of grade 3–4 neutropenia was lower in patients with long-term benefit of therapy (13.9 vs 38.2 per 100 patient-years). The EAIR for invasive second primary malignancy was the same in patients with long-term benefit of therapy and other patients (1.7 per 100 patient-years). These findings indicate that patients with RRMM can experience long-term benefit with lenalidomide and dexamethasone treatment with manageable side effects.

Real-world clinical experience in the Connect(®) chronic lymphocytic leukaemia registry: a prospective cohort study of 1494 patients across 199 US centres.

The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real‐world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community‐, 17 academic‐, and 3 government‐based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient‐level observational data that represent real‐world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice.

Impact of lenalidomide dose on progression-free survival in patients with relapsed or refractory multiple myeloma

This analysis assessed the effect of lenalidomide on progression-free survival (PFS). Patients with relapsed or refractory multiple myeloma (RRMM) who received lenalidomide plus dexamethasone in the MM-009 and MM-010 trials were pooled and those who had not progressed and were still receiving lenalidomide at 12 months were included. The median follow-up of surviving patients was 48 months. Of 353 patients who received lenalidomide plus dexamethasone, 116 (33%) had not progressed. Overall, 52 patients (45%) had no dose reductions, 25 (22%) had dose reductions ⩾12 months and 39 (34%) had dose reductions before 12 months. Patients who had dose reductions ⩾12 months had a significantly longer median PFS than those who had reductions before 12 months (P=0.007) or no dose reductions (P=0.039) (not reached vs 28.0 vs 36.8 months, respectively). In a multivariate Cox regression model, dose reduction ⩾12 months was an independent predictor of improved PFS (hazard ratio, 0.47; 95% confidence interval, 0.23–0.98) after adjusting for patient characteristics. The data suggest that to achieve maximum PFS benefit, patients with RRMM should be treated for ⩾12 months with full-dose lenalidomide plus dexamethasone. Thereafter, patients may benefit from lower-dose continued therapy; prospective studies are needed to confirm these findings.

Patients with myelodysplastic syndromes treated with azacitidine in clinical practice: the AVIDA® registry

Abstract The AVIDA registry evaluated azacitidine usage and effectiveness in unselected patients with myelodysplastic syndromes (MDS) in community practice. Treating physicians made all treatment decisions. Hematologic improvement (HI) and transfusion independence (TI) assessments used International Working Group (IWG) 2000 criteria. Enrolled were 421 patients with MDS (n = 228 International Prognostic Scoring System [IPSS] lower-risk, n = 106 higher-risk, 86 patients unclassified) from 105 US sites. Median follow-up was 7.6 months (range: 0.1–27.6). HI and red blood cell TI rates were similar regardless of administration route or dosing schedule. Safety and tolerability were consistent with previous reports. The AVIDA registry data support azacitidine effectiveness and safety in patients with lower- or higher-risk MDS treated in community practice.

Montelukast in asthmatic patients 6 years–14 years old with an FEV1 > 75%

SUMMARY Objectives: Montelukast is a potent leukotriene receptor antagonist effective for treating asthma symptoms in adult and pediatric patients. The purpose of this analysis was to assess the clinical efficacy of montelukast, a potent leukotriene-receptor antagonist, in a subgroup analysis of patients aged 6 years–14 years with milder asthma, defined as a percentage predicted forced expiratory volume in 1 s (FEV1) > 75% using data from a clinical trial of pediatric patients with a broad range of asthma severities. Research design and methods: The original previously published clinical trial was an 8-week multi-center, randomized, double-blind, parallel-group study conducted in 47 centers in the United States and Canada. The study compared the efficacy of once daily montelukast 5 mg to placebo in patients 6 years–14 years old with persistent asthma and an FEV1 ranging from 50% to 85% of predicted. A total of 87 patients in the montelukast group and 51 patients in the placebo group were selected from the original cohort of 336 patients based on percentage predicted FEV1 of > 75%. The primary endpoint was percentage change in FEV1 from baseline compared with placebo over 8 weeks of active treatment. Results: Montelukast significantly improved the primary endpoint of percentage change in FEV1 compared with placebo ( p = 0.005). Other efficacy endpoints were significantly improved on montelukast similar to efficacy in the original study. Conclusion: Montelukast significantly improved FEV1, clinic measured peak expiratory flow (PEF), reduced nocturnal awakenings, and improved quality of life in children with milder persistent asthma defined as an FEV1 > 75% of predicted.

Validation of the IPSS-R in lenalidomide-treated, lower-risk myelodysplastic syndrome patients with del(5q).

Validation of the IPSS-R in lenalidomide-treated, lower-risk myelodysplastic syndrome patients with del(5q)