Validity of event-free survival as a surrogate endpoint in haematological malignancy: Review of the literature and health technology assessments.

OBJECTIVE: Event-free survival (EFS) is increasingly used as a primary endpoint in trials of haematological malignancies (HMs). A key consideration is whether EFS can reliably predict survival. METHODS: We conducted a review of the scientific literature and health technology assessments to evaluate evidence for EFS-OS surrogacy in HMs and acceptability of EFS by payers. RESULTS: Evidence of surrogacy varies by indication and line of therapy. In first-line AML, EFS is highly correlated with OS at the trial-level supporting its use as an early endpoint for traditional approval of treatments with curative intent. Surrogacy was also demonstrated in first-line DLBCL but remains unexplored in relapsed/refractory setting where post-transplant EFS24 was not prognostic of survival. In first-line FL, PTCL, T-LBL, and MCL, EFS24 is prognostic of survival but trial-level surrogacy has not yet been evaluated. CONCLUSION: Strong EFS-OS correlation required for surrogacy may only be achievable in HMs with treatments characterised by high rates of durable remissions. Nevertheless, EFS24 is associated with favourable outcomes and remains a clinically meaningful endpoint in HMs.

Croatian Version of the Short Assessment of Health Literacy for Spanish Adults (SAHLSA-50): Cross-Cultural Adaptation and Psychometric Evaluation.

(1) Background: Short Assessment of Health Literacy for Spanish Adults (SAHLSA-50) was originally designed for Spanish-speaking regions, and translations validated for several languages. The aim of the study was to adapt and verify the psychometric characteristics of SAHLSA-50 in the Croatian context; (2) Methods: The cross-sectional study included 590 respondents from the general population older than 18 years of age. Health literacy was measured by two scales: SAHLCA-50 and the Croatian version of the Newest Vital Sign screening test (NVS-HR), which was used as a measure of concurrent validity. Subjective Health Complaints (SHC) and Satisfaction with Life Scale (SWLS) questionnaires were also used to assess convergent validity; (3) Results: Internal consistency reliability of SAHLCA-50 was high and corresponds to the findings of the authors of the original research. The Cronbach alpha coefficient for SAHLCA-50 version was 0.91. The correlation of SAHLCA-50 with the NVS-HR test speaks in favor of concurrent validity. Correlation between health literacy and SHC speaks for convergent validity, just as was expected, while correlation with life satisfaction was not observed; (4) Conclusions: The SAHLCA-50 test can be a good and quick tool to assess health literacy of the adult population in the Croatian language. HL can affect the health and quality of life of the individual and the wider community.

Risk assessment of dietary exposure to aflatoxin B1 in Serbia.

Classified as Group 1 carcinogens aflatoxins (AFs) are of major concern for food safety and public health. Within the AFs group, aflatoxin B1 (AFB1) occurs at the highest levels in different food products and is considered as the most potent representative. A total of 463 samples of products susceptible to contamination with AFB1 and commonly consumed in Serbia were collected and analyzed. Consumption surveys were performed using a food frequency questionnaire (FFQ) and 24-h recall-based method. Monte Carlo simulation of 100,000 iterations was performed to estimate the intake of AFB1 through each food category, while a simple distribution approach was performed to estimate overall exposure of tested population groups. Risk characterization was performed by calculation of the Margin of Exposure (MOE) and by calculation of the number of possible hepatocellular carcinoma (HCC) cases. The highest exposure was observed in children with the mean overall estimated daily intake (EDI) in the range of 0.79-1.10 and 1.20-1.66 ng kg-1 bw day-1, followed by adolescents 0.56-0.81 and 0.94-1.32 ng kg-1 bw day-1, adult females 0.52-0.72 and 0.56-0.76 ng kg-1 bw day-1 and adult males with the mean overall EDI in the range of 0.39-0.56 and 0.47-0.66 ng kg-1 bw day-1 depending on consumption survey method and for the lower (LB) and upper bound (UB) scenario. MOE values that resulted from the mean values of the overall EDI of AFB1 were low, indicating high concern for all population groups. Based on obtained mean values of the overall EDI higher estimates of possible HCC cases caused by exposure to AFB1 were in the range of 0.01-0.02 cases/year/105 individuals, depending on the population group.

Cost-utility analysis of life-long prophylaxis with recombinant factor VIIIFc vs recombinant factor VIII for the management of severe hemophilia A in Sweden.

AIMS: Prophylaxis with recombinant factor VIII (rFVIII) is the standard of care for severe hemophilia A in Sweden. The need for frequent injections with existing rFVIII products may, however, result in poor adherence to prophylaxis, leading to increased bleeding and long-term joint damage. Recombinant FVIIIFc (rFVIIIFc) is an extended half-life fusion protein which can offer prolonged protection and reduced dosing frequency. The objective of this study was to evaluate the cost-utility of prophylaxis with rFVIIIFc in severe hemophilia A from the perspective of the Swedish health system. METHODS: A Markov model was built to estimate lifetime costs and benefits of prophylaxis with rFVIIIFc vs rFVIII products. Clinical outcomes were represented by annualized bleeding rate (ABR) and quality of life via disutility applied to bleeding events and injection frequency. Costs included the cost of FVIII for routine prophylaxis and bleed resolution. The pooled comparator was costed by weighting the cost of individual products by their market share. RESULTS: In the base case, rFVIIIFc was dominant vs the pooled comparator. Savings of SEK 9.0 million per patient resulted from lower factor consumption for prophylaxis and bleed resolution. Fewer bleeds and reduced injection frequency yielded an estimated 0.59 quality-adjusted life years (QALYs). Results were sensitive to drug dosage and robust to variation in other parameters. Probabilistic sensitivity analysis suggested a greater than 85% probability of rFVIIIFc being cost-effective at a willingness-to-pay threshold of 500,000 SEK/QALY. LIMITATIONS: Due to unavailibilty of patient-level data, treatment benefit was based on a non-adjusted indirect comparison. Dosing and treatment outcomes were assumed to persist over the model duration in the absence of long-term outcome data. CONCLUSION: The results suggest that rFVIIIFc may be a cost-effective option for hemophilia A prophylaxis, generating greater quality of life and reduced costs for the Swedish payer compared to more frequently administered rFVIII alternatives.

Serbian Language version of the Modified Checklist for Autism in Toddlers, Revised, with Follow-Up: Cross-Cultural Adaptation and Assessment of Reliability.

Early detection of Autism Spectrum Disorder (ASD) has proven to be of high significance, however there is a limited availability of ASD screening tools in Serbian language. In this study we aim to translate, assess reliability and, in part, test the applicability of Modified Checklist for Autism in Toddlers, Revised, with Follow-Up (M-CHAT R/F) in Serbian Healthcare environment. We screened 128 children in three primary healthcare centres and 20 children in a tertiary psychiatric center, using M-CHAT R/F translated into Serbian language, between December 2014 and October 2015. At the end of the screening process 80% of participants in the risk group screened positive for ASD, while in the control group 4 (3.1%) participants screened positive, with a mean total scores of 8.25 and 0.66 respectively. The Cronbach's α coefficient was 0.91 and Guttman's λ6 was 0.93. Test - retest reliability was deemed as acceptable, and no significant correlation was found between M-CHAT-R/F scores and Epworth Sleepiness Scale for children scores. The Serbian version of the M-CHAT-R/F has shown satisfactory reliability. We can therefore assert that it is a reliable tool for identifying ASD and it can be used in clinical practice to improve early detection, assessment and treatment.

Assessment of Minimal Residual Disease in Standard-Risk AML.

BACKGROUND: Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. METHODS: We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. RESULTS: Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status. CONCLUSIONS: The presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors. (Funded by Bloodwise and the National Institute for Health Research; Current Controlled Trials number, ISRCTN55675535.).