Treatments for relapsed-refractory diffuse large B-cell lymphoma: comparison of overall survival outcomes observed with four novel agents.

OBJECTIVE: Tafasitamab, loncastuximab, tesirine, polatuzumab, and selinexor have been proposed for the treatment of relapsed/refractory B-cell lymphomas. We studied the patterns of overall survival (OS) for these four agents. PATIENTS  AND METHODS: We reconstructed patient-level data from the published Kaplan-Meier OS graphs. For this purpose, we used an artificial intelligence technique (the Shiny method). Reconstructed survival curves were then subjected to standard statistics to perform between-treatment comparisons, and hazard ratios (HRs) and 95% confidence intervals (CI) were estimated. RESULTS: Using tafasitamab plus lenalidomide as a common comparator, our analysis of OS yielded the following results: a) Polatuzumab vedotin vs. tafasitamab + lenalidomide: HR=1.60 (95%CI, 0.94-2.74, p=0.0831); b) Selinexor vs. tafasitamab + lenalidomide: HR=2.28 (95%CI, 1.54-3.38, p<0.001); c) Loncastuximab tesirine vs. tafasitamab + lenalidomide: HR=2.35 (95%CI, 1.55-3.56, p<0.001). All three values favored tafasitamab + lenalidomide. CONCLUSIONS: These comparative OS results represent the original findings. Although these comparisons were indirect, our analysis offered a useful synthesis of the outcomes reported thus far for these four treatments.

Restricted mean survival time in advanced non-small cell lung cancer treated with immune checkpoint inhibitors.

OBJECTIVE: The purpose of this study was to review the effectiveness of immune checkpoint inhibitors (ICIs) in the first-line treatment of advanced non-small cell lung carcinoma with wild-type epidermal grow factor receptor (EGFR) or anaplastic lymphoma kinase. MATERIALS AND METHODS: After a standard literature search, we identified all randomized studies published on this issue. Our first inclusion criterion was the use of pembrolizumab, nivolumab, atezolizumab or durvalumab in the treatment arm versus chemotherapy in the control arm. The second criterion was the availability of information on overall survival at 2 years. The restricted mean survival time (RMST) was used to analyze the survival curves and rank the treatments. RESULTS: From the eligible studies, we selected 5 randomized trials that met our inclusion criteria. These trials studied a total of 11 cohorts of patients in whom the treatment arm received ICI as monotherapy (n=3) or in combination with either chemotherapy (n=2) or other monoclonal antibodies (n=1). All the control groups (n=5) received chemotherapy. Pembrolizumab (alone or in combination) showed improvement in overall survival compared with controls, but with borderline statistical significance. Nivolumab, atezolizumab and durvalumab failed to demonstrate any survival advantage. Overall, the RMSTs provided more conservative results than those previously reported using the hazard ratio. In comparing the values of RMST across treatments, pembrolizumab combined with chemotherapy ranked first. CONCLUSIONS: Our results summarized the efficacy of these treatments and showed that only pembrolizumab can have a role as the first-line treatment of NSCLC. These findings are at variance with those previously reported using the hazard ratio as the outcome measure.

Incidence of low-titre factor VIII inhibitors in patients with haemophilia A: meta-analysis of observational studies.

INTRODUCTION: A few studies have been focused on low-titre inhibitors in patients with haemophilia A. Although several putative factors have been implicated in the development of these inhibitors, solid data are still lacking. AIM: The aim of this study was to perform a proportion meta-analysis on the incidence of low-titre inhibitors in haemophilia A. METHODS: We surveyed the PubMed database to identify studies on de novo development of low-titre inhibitors in haemophilia A patients. On the basis of these data, we carried out a proportion meta-analysis to summarize information on incidence and between-study variability. Furthermore, the following three covariates were assessed by meta-regression: (i) mild disease vs. severe haemophilia; (ii) status of previously untreated patient (PUP) as opposed to multi-transfused and (iii) type of factor VIII. RESULTS: Our literature search on PubMed extracted 340 eligible articles. From these, we selected 33 patient cohorts that were included in our meta-analysis (19 cohorts for PUPs and 14 cohorts for multi-transfused or unselected patients). The pooled incidence of low-titre inhibitors was 10.3% (95%CI: 8.3-12.5%) for studies including PUPs and 5.8% (95%CI: 2.5-10.4%) for the other studies; the difference was statistically significant (P = 0.003). Meta-regression of 31 patient cohorts found that mild disease and type of factor VIII were not associated with an increased incidence of low-titre inhibitors. CONCLUSIONS: Our results confirmed that PUPs show a higher incidence of low-titre inhibitors than the other patients. Furthermore, our data showed that mild haemophilia was not associated with an increased incidence of low-titre inhibitors.

Gastrointestinal and renal side effects of bisphosphonates: differentiating between no proof of difference and proof of no difference.

BACKGROUND: This study was aimed at comparing the safety of bisphosphonates in women with osteoporosis by application of equivalence testing. METHODS: Gastrointestinal and renal side effects were evaluated based on information published in randomized controlled trials. RESULTS: The data on gastrointestinal side effects (47 trials) indicated that alendronate, risedronate etidronate, and zolendronate have similar rates of the adverse effects; application of Bayesian network meta-analysis showed that equivalence was demonstrated according to margins around ±10%. The data on renal safety were more sparse and suffered from the use of different outcome measures; hence, a single trial could be evaluated. This trial showed a similar effect of alendronate and risedronate on renal function at 12 months; equivalence was based on differences between the two agents in renal function with margins of less than ±10.4 ml/min. CONCLUSION: Our study provided quantitative information to determine to what extent bisphosphonates can be considered equivalent in terms of gastrointestinal and renal side effects.

A uniform procedure for reimbursing the off-label use of antineoplastic drugs according to the value-for-money approach.

National healthcare systems as well as local institutions generally reimburse numerous off-label uses of anticancer drugs, but an explicit framework for managing these payments is still lacking. As in the case of on-label uses, an optimal management of off-label uses should be aimed at a direct proportionality between cost and clinical benefit. Within this framework, assessing the incremental cost/effectiveness ratio becomes mandatory, and measuring the magnitude of the clinical benefit (e.g. gain in overall survival or progression-free survival) is essential.This paper discusses how the standard principles of cost-effectiveness and value-for-money can be applied to manage the reimbursement of off-label treatments in oncology. It also describes a detailed operational scheme to appropriately implement this aim. Two separate approaches are considered: a) a trial-based approach, which is designed for situations where enough information is available from clinical studies about the expected effectiveness of the off-label treatment; b) an individualized payment-by-results approach, which is designed for situations in which adequate information on effectiveness is lacking; this latter approach requires that each patient receiving off-label treatment is followed-up to determine individual outcomes and tailor the extent of payment to individual results.Some examples of application of both approaches are presented in detail, which have been extracted from a list of 184 off-label indications approved in 2010 by the Region of tuscany in italy. these examples support the feasibility of the two methods proposed.In conclusion, the scheme described in this paper represents an operational solution to an unsettled problem in the area of oncology drugs.

Event-free survival and cost-effectiveness in adult acute lymphoblastic leukaemia in first remission treated with allogeneic transplantation.

Allogeneic transplantation in patients with acute lymphoblastic leukaemia in first remission (ALL-CR1) has been studied in several clinical trials. However, no pooled survival analysis has yet been done. We conducted a survival meta-analysis to compare allogeneic transplantation vs chemotherapy or autologous transplantation using an intention-to-treat approach. Our study included the controlled clinical trials, wherein allocation to allogeneic transplant was based on donor availability. The event-free individual survival data were reconstructed on the basis of published information and Kaplan-Meier graphs. We then generated the meta-analytic event-free survival curves for the two treatments. The mean survival gain per patient was estimated and a simplified cost-effectiveness assessment was carried out. In the allogeneic transplantation group, 293 patients were examined and 479 as controls (four trials). The event-free survival difference was statistically significant (P=0.011). The relative risk for event occurrence was 0.79 for the experimental group vs the controls (95% CI: 0.66-0.96; P=0.017). The mean survival gain was 1 year per patient. The cost per life-year gained was less than the conventional threshold of 50,000 euros. Allogeneic transplantation in ALL-CR1 improves event-free survival as compared to chemotherapy or autologous transplantation. Its cost-effectiveness profile is acceptable.

Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from long-term studies?

OBJECTIVE: A review of long-term open-label studies was performed with the aim of detecting differences in efficacy and/or tolerability of new antiepileptic drugs (AEDs). METHODS: From more than 500 open studies conducted to evaluate the efficacy and tolerability of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), pregabalin (PGB), tiagabine (TGB), topiramate (TPM) or zonisamide (ZNS), we selected all studies that reported or allowed us to calculate the number of patients who achieved seizure freedom for 6 months and/or the number of patients withdrawing for adverse effects and/or the number or percentage of patients continuing treatment after 1 year. RESULTS: No studies were found in which this information was available for OXC, PGB, TGB or ZNS. The number of patients who achieved seizure freedom for 6 months was reported in four studies each for GBP and TPM, five studies for LTG, and eight studies for LEV. The best efficacy profile using this end point was found for LEV, followed by TPM, LTG, and GBP. Twenty-two studies reported the number of patients withdrawing due to adverse effects. LEV was the best-tolerated AED, a little ahead of LTG, and significantly better than GBP or TPM . TPM was by far the least well-tolerated drug. Information concerning patients continuing treatment after 1 year was reported in two GBP studies, two TPM studies, six LEV studies and five LTG studies. GBP had a very low retention rate (between 20% and 25% of patients continued the drug), while TPM and LTG had a retention rate of 40-60% and LEV had a retention rate of 60-75%. CONCLUSION: One limitation of these rankings is that their statistical value is limited because of the indirect nature of the comparisons. Anyhow, this review covers the main studies published thus far on this subject and provides full updated information on the current literature about these drugs.

Effects of ionic and non-ionic paramagnetic contrast media on brain bio-electric activity.

The potential neurotoxic effects of gadolinium (Gd)-based compounds for enhanced MRI are not completely understood. We investigated electroencephalography changes induced by ionic and non-ionic Gd-based compounds administered intravenously in patients affected by lesions of the central nervous system (CNS) characterized by breakdown of the blood-brain barrier. This double-blind, randomized, study of two parallel groups involved 40 patients scheduled for an MRI examination with contrast medium for known CNS lesions. Twenty patients were randomly allocated to receive non-ionic Gd-DTPA-BMA/gadodiamide and 20 patients were randomly allocated to receive ionic Gd-DTPA/gadopentetate. For both groups the intravenous dose was 0.1 mmol/kg body weight. Three electroencephalography recordings were performed: immediately before, during, and 15 min after contrast medium injection. Mean and peak frequencies of the beta band and absolute power of the delta and/or theta bands of the electroencephalograms (EEGs) were noted. Each EEG was also evaluated to detect any alterations. The values of the 8-12 Hz band showed a significant increase during and after injection versus baseline in the gadopentetate group (P<0.05) and a significant decrease during injection in the gadodiamide group (P<0.05). The values of the 12-16 Hz band showed a significant increase versus baseline during and after injection in the gadopentetate group (P<0.05). The electrophysiological method based on computerised spectral analysis is a sensitive tool for evaluating effects of contrast media on brain bio-electric activity. EEG changes are detectable, even in the absence of any clinical evidence. It would appear that there might be clinical advantages in the use of non-ionic compounds.

Audit of a shared-care program for persons with diabetes: baseline and 3 annual follow-ups.

In Italy, data on shared-care programs for diabetes are lacking. We described the characteristics of type 2 diabetic population assisted in general practice and evaluated 3 years of follow-up outcomes and performance indicators in a shared-care program in Modena, Italy (1998-2001); only well-controlled diabetic patients were considered. Forty-nine percent of territorial GPs adhered to the project (257 out of 521) and 77% of them sent 6409 paired baseline and follow-up datasheets. Altogether, 97.8% patients had type 2 diabetes, mean age 68.6+/-11.7 years, disease duration 9.6+/-7.5 years, BMI 28.6+/-4.8 kg/m2, HbA(1c) 7.6%+/-1.6%, 16.1% of them were disabled. Among the non-disabled patients, 23.6% had optimal glycemic control (HbA(1c) < or =6.5%); at baseline the prevalence of micro- and macrovascular diabetic complications was: 8.2% microalbuminuria and 2.4% macroalbuminuria plus nephropathy, 11.0% nonproliferative and 3.0% preproliferative retinopathy, 7.0% neuropathy, 1.8% diabetic foot; 8.5% angina, 6.9% TIA or stroke, 6.3% infarction, 5.2% intermittent claudication, 4.1% heart failure. Among the disabled patients 27.9% had optimal glycemic control, but they had more diabetic complications. The performance indicators significantly improved over the 3-year study period: glycemic control indicators increased from 66%-75% to 83%-90% and micro- and macrovascular indicators from 59%-65% to 75%-81%. The outcome indicators also improved: mean HbA(1c) value changed from 7.6%+/-1.6% to 7.3%+/-1.3% and the percentage of people with HbA(1c)< or =6.5% significantly improved over time. Similar trends were observed in both disabled and non-disabled diabetic patients.

Iron lung versus conventional mechanical ventilation in acute exacerbation of COPD.

The aim of this randomised study was to compare the effects of iron lung ventilation (ILV) with invasive mechanical ventilation (IMV) in patients with acute respiratory failure (ARF) due to exacerbation of chronic obstructive pulmonary disease. Forty-four patients with ARF were assigned either to ILV (22 patients) or IMV (22 patients). Primary end-points were the improvement in gas exchange and complications related to mechanical ventilation. On admission ILV and IMV groups did not differ in age, simplified acute physiology score II, arterial oxygen tension (Pa,O2)/inspiratory oxygen fraction (FI,O2), arterial carbon dioxide tension (Pa,CO2) and pH. Compared with baseline, ILV and IMV induced a similar and significant improvement in Pa,O2/FI,O2, Pa,CO2 and pH after 1 h of treatment and at discontinuation of mechanical ventilation. Major complications tended to be more frequent in patients treated with IMV than in those treated with ILV (27.3% versus 4.5%), whereas mortality rate was similar (27.3% versus 18.2%). The ventilator-free days and the length of hospital stay were significantly lower in the ILV than in the IMV group. This study suggests that iron lung ventilation is as effective as invasive mechanical ventilation in improving gas exchange in chronic obstructive pulmonary disease patients with acute respiratory failure, and is associated with a tendency towards a lower rate of major complications.