Systematic review and pooled analysis of survival outcomes in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia who have undergone haematopoietic stem cell transplant.

OBJECTIVE: Information about the long-term survival impact of hematopoietic stem cell transplant (HSCT) in adults with relapsed/refractory B-cell acute lymphoblastic leukaemia is limited. The objective was to conduct a systematic review identifying studies reporting survival in HSCT-receiving patients and apply parametric analyses to predict long-term survival. MATERIALS AND METHODS: Twenty-five relevant studies were identified. Analyses were conducted in 10 studies (n=503; "global" analysis) reporting overall survival (OS) data as Kaplan-Meier curves or at patient level. Four studies (n=217; "subgroup" analysis) measured OS from the point of HSCT. Patient-level data were recreated from Kaplan-Meier curves and pooled, with six models tested for longer-term extrapolation. Additionally, a sensitivity analysis was undertaken involving removal of data from the oldest study cohort (recruited between 1981-1997) to determine if the year which patients received HSCT impacted survival compared to post-2009 data. RESULTS: Median OS and five-year survival probability were 11.4 months and 24.4% (95% CI, 20.5-28.5%) in the global analysis, and 12.0 months and 28.4% (95% CI, 22.1-34.9%) in the subgroup analysis. The generalised gamma and Gompertz models fit longer-term extrapolation criteria. The generalised gamma model predicted survival at 10.4% vs. 14.8% (15 years), 8.3% vs. 12.8% (20 years), and 6.9% vs. 11.4% (25 years) for the global and subgroup analysis, respectively. The Gompertz model predicted survival to plateau at 23% vs. 25.6% just before 10 years. The sensitivity analysis excluding older data found median survival increased two-fold (25.3 vs. 12 months). CONCLUSIONS: Results synthesize long-term evidence of outcomes for HSCT-receiving patients, providing a basis for treatment comparison. Risk of death is low beyond four years and newer data appears correlated with improved outcomes.

Efficacy of pallidal stimulation in isolated dystonia: a systematic review and meta-analysis.

The aim of this review was to provide strong clinical evidence of the efficacy of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in isolated inherited or idiopathic dystonia. Eligible studies were identified after a systematic literature review of the effects of bilateral GPi-DBS in isolated dystonia. Absolute and percentage changes from baseline in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor and disability scores were pooled, and associations between treatment effect and patient characteristics were explored using meta-regression. In total, 24 studies were included in the meta-analysis, comprising 523 patients. The mean absolute and percentage improvements in BFMDRS motor score at the last follow-up (mean 32.5 months; 24 studies) were 26.6 points [95% confidence interval (CI), 22.4-30.8] and 65.2% (95% CI, 59.6-70.7), respectively. The corresponding changes in disability score at the last follow-up (mean 32.9 months; 14 studies) were 6.4 points (95% CI, 5.0-7.8) and 58.6% (95% CI, 50.3-66.9). Multivariate meta-regression of absolute scores indicated that higher BFMDRS motor and disability scores before surgery, together with younger age at time of surgery, were the main factors associated with significantly better DBS outcomes at the latest follow-up. Reporting of safety data was frequently inconsistent and could not be included in the meta-analysis. In conclusion, patients with isolated inherited or idiopathic dystonia significantly improved after GPi-DBS. Better outcomes were associated with greater dystonia severity at baseline. These findings should be taken into consideration for improving patient selection for DBS.

A Cost-Effectiveness Analysis of Nintedanib in Idiopathic Pulmonary Fibrosis in the UK.

BACKGROUND: International guidelines recommend nintedanib (OFEV®) as an option for the treatment of idiopathic pulmonary fibrosis (IPF). OBJECTIVE: The objective of this study was to assess the cost effectiveness of nintedanib versus pirfenidone, N-acetylcysteine and best supportive care (BSC) for the treatment of IPF from a UK payer's perspective. METHODS: A Markov model was designed to capture the changes in the condition of adults with IPF. Efficacy outcomes included mortality, lung function decline and acute exacerbations. Treatment safety (serious adverse events) and tolerability (overall discontinuation) were also considered. The baseline risk of these events was derived from patient-level data from the placebo arms of nintedanib clinical trials (TOMORROW, INPULSIS-1, INPULSIS-2). A network meta-analysis (NMA) was conducted to estimate the relative effectiveness of the comparator treatments. Quality of life and healthcare resource use data from the clinical trials were also incorporated in the economic model. RESULTS: Nintedanib showed statistically significant differences against placebo on acute exacerbation events avoided and lung function decline. In the cost-effectiveness analysis, the results were split between two treatments with relative low costs and modest effectiveness (BSC and N-acetylcysteine) and two that showed improved effectiveness (lung function) and higher costs (nintedanib and pirfenidone). All comparators were assumed to have similar projected survival and the difference in quality-adjusted life-years (QALYs) was driven by the acute exacerbations and lung function estimates. In the base-case deterministic pairwise comparison with pirfenidone, nintedanib was found to have fewer acute exacerbations and resulted in less costs and more QALYs gained. CONCLUSIONS: Compared with BSC (placebo), nintedanib and pirfenidone were the only treatments to show statistical significance in the efficacy parameters. We found substantial uncertainty in the overall cost-effectiveness results between nintedanib and pirfenidone. N-Acetylcysteine was largely similar to BSC but with a worse survival profile. INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.

Comparative efficacy of biological treatments for moderate-to-severe psoriasis: a network meta-analysis adjusting for cross-trial differences in reference arm response.

BACKGROUND: Multiple biological therapies are approved for the treatment of moderate-to-severe psoriasis. OBJECTIVES: To assess the short-term efficacy of biological treatments for moderate-to-severe psoriasis via a network meta-analysis that adjusts for reference arm response rates. METHODS: Fifteen randomized trials of biological treatments for moderate-to-severe psoriasis were identified. Rates of response, assessed as 50%, 75% and 90% reductions in the Psoriasis Area and Severity Index (PASI), were compared using a network meta-analysis. To account for variation across trials, the model was adjusted for placebo responses, the relevance of which was assessed by testing its statistical significance, impact on model fit, and extent to which lack of adjustment confounded the efficacy estimates for biologics. RESULTS: Psoriasis Area and Severity Index 75 response rates for placebo arms ranged from 1·8% to 18·9%. The probability of achieving a PASI 75 response was 80·5% [95% credible interval (CrI) 74·8-85·7] with infliximab 5 mg kg(-1) ; 72·5% (95% CI 66·1-78·3) with ustekinumab 90 mg; 67·5% (95% CI 60·7-73·9) with ustekinumab 45 mg; 66·2% (95% CI 57·3-73·3) with adalimumab 40 mg; 51·9% (95% CI 45·7-58·4) with etanercept 50 mg; and 38·0% (95% CI 31·6-45·1) with etanercept 25 mg. Infliximab had the highest PASI 75 response. Adalimumab and both ustekinumab doses had significantly higher PASI 75 responses than both etanercept doses. There were no significant differences among adalimumab and ustekinumab doses. CONCLUSIONS: A model adjusted for reference arm response rates was found to fit clinical trial data significantly better than unadjusted models.

A retrospective cohort study of the impact of biologic therapy initiation on medical resource use and costs in patients with moderate to severe psoriasis.

BACKGROUND: Biologic therapy has become established as an important treatment option in patients with severe psoriasis, but is significantly more expensive in terms of drug costs than traditional treatment options. Relatively little is known about the total healthcare cost of treating severe psoriasis in daily clinical practice and what the budgetary impacts of such high-cost drugs are when compared with standard systemic therapy. OBJECTIVES: To describe the impact of biologic therapy introduction on the use of medical resources, costs and where available, outcomes in patients with moderate to severe psoriasis. METHODS: Data were extracted from case notes of a sequential patient cohort with psoriasis attending a tertiary referral severe psoriasis service and initiated on biologics (adalimumab, efalizumab, etanercept or infliximab) for treatment of their psoriasis. Data on hospital resource use (inpatient, outpatient, day ward, accident and emergency visits and phototherapy sessions) and drug usage (systemic nonbiologic and biologic psoriasis therapies and supportive drugs) were collected for 12 months prior to, and at least 6 months following initiation of biologic therapy. Outcome was measured using the Psoriasis Area and Severity Index (PASI). Differences in resource use and associated costs and outcomes, between 12 months before and after initiation of biologic therapy, were tested using Wilcoxon paired sign tests for continuous data and the McNemar test for categorical data. Confidence intervals (CI) around treatment costs were constructed using a 5000-sample bootstrap analysis. RESULTS: The primary analysis population comprised 76 patients completing 12 months of biologic therapy: 71% males; mean age at time of study 47·3 years (range 23-74); mean duration of psoriasis 24·7 years (range 5·3-45·5). Significant reductions (P < 0·05) in the year following initiation of biologic therapy were observed for all hospital resource use categories, with mean annual costs reduced by £1682 (95% CI -3182 to -182·2; P = 0·05). Mean annual drug costs increased by £9456 (95% CI 8732-10,182; P < 0·001). Mean PASI fell by 8·9 points from 18·7 to 9·8 (95% CI -10·8 to -7·1; P < 0·001). CONCLUSIONS: Total healthcare costs associated with treatment of severe psoriasis with biologic therapy are significantly greater than with traditional systemic therapy. However, some of these are offset by substantial reductions in the number and length of hospital admissions and use of photo- and systemic therapy, and result in significantly improved patient outcome (as inferred by improvement in PASI).