Tea Reljic

Antithymocyte globulin for acute-graft-versus-host-disease prophylaxis in patients undergoing allogeneic hematopoietic cell transplantation: a systematic review.

Graft-versus-host-disease (GVHD) is a major complication associated with allogeneic hematopoietic cell transplantation (allo-HCT). Antithymocyte globulin (ATG) is recommended for GVHD prophylaxis following allo-HCT, however, evidence on efficacy of ATG is conflicting. Accordingly, we undertook a systematic review. All phase III randomized controlled trials (RCTs) comparing ATG versus control for prevention of GVHD in patients undergoing allo-HCT were eligible. Medline and Cochrane databases were searched. Data on methodological quality, benefits and harms were extracted for each trial and pooled under a random effects model. Seven RCTs enrolling 733 patients met inclusion criteria. Pooled results showed no difference for overall survival with use of ATG (hazard ratio was 0.91; 95% confidence intervals (CI), 0.75–1.10; P=0.32). There was a significant benefit for prevention of grade III/IV acute GVHD (risk ratio (RR)=0.51; 95% CI, 0.27–0.94; P=0.03). There was no benefit associated with ATG use for prevention of either grade II (RR=0.79; 95% CI, 0.48–1.30; P=0.35) or grade I acute GVHD (RR=1.42; 95% CI, 0.75–2.69; P=0.28). Use of ATG was not associated with significant reduction in non-relapse mortality (RR=0.74; 95% CI, 0.53–1.03; P=0.08). Future trials with adequate sample size are required to provide more definitive answers.

Extracorporeal Photopheresis in Steroid-Refractory Acute or Chronic Graft-versus-Host Disease: Results of a Systematic Review of Prospective Studies

Acute and chronic graft-versus-host disease (GVHD) remain major obstacles for successful allogeneic hematopoietic cell transplantation. Extracorporeal photopheresis (ECP) modulates immune cells, such as alloreactive T cells and dendritic cells, and improves GVHD target organ function(s) in steroid-refractory GVHD patients. We performed a systematic review to evaluate the totality of evidence regarding the efficacy of ECP for treatment of acute and chronic steroid-refractory or steroid-dependent GVHD. Nine studies, including 1 randomized controlled trial, met inclusion criteria, with a total of 323 subjects. In pooled analyses, overall response rates (ORR) were .69 (95% confidence interval [CI], .34 to .95) and .64 (95% CI, .47 to .79) for acute and chronic GVHD, respectively. In acute GVHD organ-specific responses, ECP resulted in the highest ORR for cutaneous, with .84 (95% CI, .75 to .92), followed by gastrointestinal with .65 (95% CI, .52 to .78). Similar response rates were seen in chronic GVHD involving the skin and gastrointestinal tract. Conversely, ORR for chronic GVHD involving the lungs was only .15 (95% CI, 0 to .5). In chronic GVHD, grades 3 to 4 adverse events were reported at .38 (95% CI, .06 to .78). ECP-related mortality rates were extremely low. Rates of immunosuppression discontinuation were .55 (95% CI, .40 to .70) and .23 (95% CI, .07 to .44) for acute and chronic GVHD, respectively. In summary, albeit limited by numbers of available studies, pooled analyses of prospective studies demonstrate encouraging responses after ECP treatment in acute and chronic GVHD after failing corticosteroids. Further research efforts are needed to improve organ-specific responses.

Comparative efficacy of tandem autologous versus autologous followed by allogeneic hematopoietic cell transplantation in patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials

BackgroundDespite advances in understanding of clinical, genetic, and molecular aspects of multiple myeloma (MM) and availability of more effective therapies, MM remains incurable. The autologous-allogeneic (auto-allo) hematopoietic cell transplantation (HCT) strategy is based on combining cytoreduction from high-dose (chemo- or chemoradio)-therapy with adoptive immunotherapy. However, conflicting results have been reported when an auto-allo HCT approach is compared to tandem autologous (auto-auto) HCT. A previously published meta-analysis has been reported; however, it suffers from serious methodological flaws.MethodsA systematic search identified 152 publications, of which five studies (enrolling 1538 patients) met inclusion criteria. All studies eligible for inclusion utilized biologic randomization.ResultsAssessing response rates by achievement of at least a very good partial response did not differ among the treatment arms [risk ratio (RR) (95% CI) = 0.97 (0.87-1.09), p = 0.66]; but complete remission was higher in the auto-allo HCT arm [RR = 1.65 (1.25-2.19), p = 0.0005]. Event-free survival did not differ between auto-allo HCT group versus auto-auto HCT group using per-protocol analysis [hazard ratio (HR) = 0.78 (0.58-1.05)), p = 0.11] or using intention-to-treat analysis [HR = 0.83 (0.60-1.15), p = 0.26]. Overall survival (OS) did not differ among these treatment arms whether analyzed on per-protocol [HR = 0.88 (0.33-2.35), p = 0.79], or by intention-to-treat [HR = 0.80 (0.48-1.32), p = 0.39] analysis. Non-relapse mortality (NRM) was significantly worse with auto-allo HCT [RR (95%CI) = 3.55 (2.17-5.80), p < 0.00001].ConclusionDespite higher complete remission rates, there is no improvement in OS with auto-allo HCT; but this approach results in higher NRM in patients with newly diagnosed MM. At present, totality of evidence suggests that an auto-allo HCT approach for patients with newly diagnosed myeloma should not be offered outside the setting of a clinical trial.

Treatment Success in Cancer: Industry Compared to Publicly Sponsored Randomized Controlled Trials

Objective To assess if commercially sponsored trials are associated with higher success rates than publicly-sponsored trials. Study Design and Settings We undertook a systematic review of all consecutive, published and unpublished phase III cancer randomized controlled trials (RCTs) conducted by GlaxoSmithKline (GSK) and the NCIC Clinical Trials Group (CTG). We included all phase III cancer RCTs assessing treatment superiority from 1980 to 2010. Three metrics were assessed to determine treatment successes: (1) the proportion of statistically significant trials favouring the experimental treatment, (2) the proportion of the trials in which new treatments were considered superior according to the investigators, and (3) quantitative synthesis of data for primary outcomes as defined in each trial. Results GSK conducted 40 cancer RCTs accruing 19,889 patients and CTG conducted 77 trials enrolling 33,260 patients. 42% (99%CI 24 to 60) of the results were statistically significant favouring experimental treatments in GSK compared to 25% (99%CI 13 to 37) in the CTG cohort (RR = 1.68; p = 0.04). Investigators concluded that new treatments were superior to standard treatments in 80% of GSK compared to 44% of CTG trials (RR = 1.81; p<0.001). Meta-analysis of the primary outcome indicated larger effects in GSK trials (odds ratio = 0.61 [99%CI 0.47–0.78] compared to 0.86 [0.74–1.00]; p = 0.003). However, testing for the effect of treatment over time indicated that treatment success has become comparable in the last decade. Conclusions While overall industry sponsorship is associated with higher success rates than publicly-sponsored trials, the difference seems to have disappeared over time.

Gemtuzumab ozogamicin for treatment of newly diagnosed acute myeloid leukaemia: a systematic review and meta-analysis

Evidence regarding the efficacy of gemtuzumab ozogamicin (GO) addition to standard induction chemotherapy in newly diagnosed acute myeloid leukaemia (AML) is conflicting. This systematic review aimed to identify and summarize all evidence regarding the benefits and harms of adding GO to conventional chemotherapy for induction treatment of AML. A comprehensive literature search of two databases (PUBMED and Cochrane) from inception up to November 22, 2012, and 4 years of proceedings from four major haematology/oncology conferences was undertaken. Endpoints included benefits (complete remission, relapse‐free, event‐free, and overall survival), and harms (early mortality and incidence of hepatic veno‐occlusive disease/sinusoidal obstructive syndrome). Seven trials (3942 patients) met all inclusion criteria. Addition of GO showed improved relapse‐free [Hazard Ratio (HR) = 0·84 (95% confidence interval (CI) 0·71–0·99)] and event‐free survival [HR = 0·59 (95%CI 0·48–0·74)] but not overall survival [HR = 0·95 (95%CI 0·83–1·08)]. Addition of GO resulted in higher rate of early mortality [Risk Ratio = 1·60 (95%CI 1·07–2·39)]. Improved overall survival was observed in studies using a lower cumulative GO dose (<6 mg/m2) [HR = 0·89 (95%CI 0·81–0·99)]. Addition of GO to conventional chemotherapy as induction therapy may improve relapse‐free and event‐free survival, but does not impact overall survival and significantly increases early mortality in AML.

Efficacy of adoptive immunotherapy with donor lymphocyte infusion in relapsed lymphoid malignancies

AIMS There is a perceived benefit associated with the administration of donor lymphocyte infusion (DLI) in patients with lymphoid malignancies relapsing after allogeneic hematopoietic cell transplantation. However, it is unclear if and how this benefit varies according to specific diseases. Because administration of DLI is not universally effective and could be associated with significant toxicities resulting in morbidity and mortality, it is imperative to identify cases where benefits outweigh harms of the procedure. MATERIALS & METHODS We conducted a systematic review of the published literature and extracted and pooled data independently for each disease cohort: acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), non-Hodgkins lymphoma (NHL) and Hodgkins lymphoma (HL). RESULTS In summary, 39 studies met inclusion criteria. The pooled proportion (95% CI) for complete response was 27% (16-40) in ALL, 55% (15-92) in CLL, 26% (19-33) in MM, 52% (33-71) in NHL and 37% (20-56) in HL. CONCLUSION Complete response rates appear higher when DLI is used for relapsed CLL and lymphomas (NHL and HL), and less pronounced in ALL or MM. Absence of data pertaining to disease-specific prognostic determinants, such as adverse genetic or molecular abnormalities, or quantitative disease burden when applicable, limit our ability to identify cases in whom benefits from DLI outweigh risks associated with the procedure within a particular disease.

Poor Outcome of Patients With Myelodysplastic Syndrome After Azacitidine Treatment Failure

BACKGROUND Limited data have been reported describing the outcome and prognosis of patients with MDS in whom treatment with azanucleosides has failed. We report our single-institutional experience of patients with higher-risk MDS in whom therapy with azacitidine has failed. PATIENTS AND METHODS This was a retrospective study of MDS patients treated at the Moffitt Cancer Center in whom azacitidine treatment regimens had failed. Patients were identified through the Moffitt database, and clinical data were extracted. Azacitidine failure was defined as failure to achieve hematologic improvement or better after at least 4 cycles of therapy, loss of response, or disease progression during therapy. The objectives were to characterize response to salvage therapies after azacitidine failure and to estimate the overall survival. All responses were defined according to the International Working Group 2006 criteria, and survival was estimated using the Kaplan-Meier method. RESULTS A total of 59 patients in whom azacitidine treatment had failed were identified. The median age at treatment failure was 68 years, and most were Caucasian male patients. Thirteen patients received intensive chemotherapy with an overall response rate of 31%. Six patients were treated with decitabine, and none responded. Median overall survival of the entire cohort after azacitidine failure was 5.8 months (95% confidence interval, 1.3-10.3 months), with an estimated 12-month survival of 17%. CONCLUSION Patients with higher-risk MDS in whom azacitidine treatment has failed have a poor prognosis and low probability of response to salvage treatments. The standard of care after azanucleoside failure should be enrollment in clinical trials.

How do physicians decide to treat: an empirical evaluation of the threshold model

BackgroundAccording to the threshold model, when faced with a decision under diagnostic uncertainty, physicians should administer treatment if the probability of disease is above a specified threshold and withhold treatment otherwise. The objectives of the present study are to a) evaluate if physicians act according to a threshold model, b) examine which of the existing threshold models [expected utility theory model (EUT), regret-based threshold model, or dual-processing theory] explains the physicians’ decision-making best.MethodsA survey employing realistic clinical treatment vignettes for patients with pulmonary embolism and acute myeloid leukemia was administered to forty-one practicing physicians across different medical specialties. Participants were randomly assigned to the order of presentation of the case vignettes and re-randomized to the order of “high” versus “low” threshold case. The main outcome measure was the proportion of physicians who would or would not prescribe treatment in relation to perceived changes in threshold probability.ResultsFewer physicians choose to treat as the benefit/harms ratio decreased (i.e. the threshold increased) and more physicians administered treatment as the benefit/harms ratio increased (and the threshold decreased). When compared to the actual treatment recommendations, we found that the regret model was marginally superior to the EUT model [Odds ratio (OR) = 1.49; 95% confidence interval (CI) 1.00 to 2.23; p = 0.056]. The dual-processing model was statistically significantly superior to both EUT model [OR = 1.75, 95% CI 1.67 to 4.08; p < 0.001] and regret model [OR = 2.61, 95% CI 1.11 to 2.77; p = 0.018].ConclusionsWe provide the first empirical evidence that physicians’ decision-making can be explained by the threshold model. Of the threshold models tested, the dual-processing theory of decision-making provides the best explanation for the observed empirical results.

Thinking Styles and Regret in Physicians

Background Decision-making relies on both analytical and emotional thinking. Cognitive reasoning styles (e.g. maximizing and satisficing tendencies) heavily influence analytical processes, while affective processes are often dependent on regret. The relationship between regret and cognitive reasoning styles has not been well studied in physicians, and is the focus of this paper. Methods A regret questionnaire and 6 scales measuring individual differences in cognitive styles (maximizing-satisficing tendencies; analytical vs. intuitive reasoning; need for cognition; intolerance toward ambiguity; objectivism; and cognitive reflection) were administered through a web-based survey to physicians of the University of South Florida. Bonferroni’s adjustment was applied to the overall correlation analysis. The correlation analysis was also performed without Bonferroni’s correction, given the strong theoretical rationale indicating the need for a separate hypothesis. We also conducted a multivariate regression analysis to identify the unique influence of predictors on regret. Results 165 trainees and 56 attending physicians (age range 25 to 69) participated in the survey. After bivariate analysis we found that maximizing tendency positively correlated with regret with respect to both decision difficulty (r=0.673; p<0.001) and alternate search strategy (r=0.239; p=0.002). When Bonferroni’s correction was not applied, we also found a negative relationship between satisficing tendency and regret (r=-0.156; p=0.021). In trainees, but not faculty, regret negatively correlated with rational-analytical thinking (r=-0.422; p<0.001), need for cognition (r=-0.340; p<0.001), and objectivism (r=-0.309; p=0.003) and positively correlated with ambiguity intolerance (r=0.285; p=0.012). However, after conducting a multivariate regression analysis, we found that regret was positively associated with maximizing only with respect to decision difficulty (r=0.791; p<0.001), while it was negatively associated with satisficing (r=-0.257; p=0.020) and objectivism (r=-0.267; p=0.034). We found no statistically significant relationship between regret and overall accuracy on conditional inferential tasks. Conclusion Regret in physicians is strongly associated with their tendency to maximize; i.e. the tendency to consider more choices among abundant options leads to more regret. However, physicians who exhibit satisficing tendency – the inclination to accept a “good enough” solution – feel less regret. Our observation that objectivism is a negative predictor of regret indicates that the tendency to seek and use empirical data in decision-making leads to less regret. Therefore, promotion of evidence-based reasoning may lead to lower regret.

Evaluation of Physicians' Cognitive Styles.

Background. Patient outcomes critically depend on accuracy of physicians’ judgment, yet little is known about individual differences in cognitive styles that underlie physicians’ judgments. The objective of this study was to assess physicians’ individual differences in cognitive styles relative to age, experience, and degree and type of training. Methods. Physicians at different levels of training and career completed a web-based survey of 6 scales measuring individual differences in cognitive styles (maximizing v. satisficing, analytical v. intuitive reasoning, need for cognition, intolerance toward ambiguity, objectivism, and cognitive reflection). We measured psychometric properties (Cronbach’s α) of scales; relationship of age, experience, degree, and type of training; responses to scales; and accuracy on conditional inference task. Results. The study included 165 trainees and 56 attending physicians (median age 31 years; range 25–69 years). All 6 constructs showed acceptable psychometric properties. Surprisingly, we found significant negative correlation between age and satisficing (r = −0.239; P = 0.017). Maximizing (willingness to engage in alternative search strategy) also decreased with age (r = −0.220; P = 0.047). Number of incorrect inferences negatively correlated with satisficing (r = −0.246; P = 0.014). Disposition to suppress intuitive responses was associated with correct responses on 3 of 4 inferential tasks. Trainees showed a tendency to engage in analytical thinking (r = 0.265; P = 0.025), while attendings displayed inclination toward intuitive-experiential thinking (r = 0.427; P = 0.046). However, trainees performed worse on conditional inference task. Conclusion. Physicians capable of suppressing an immediate intuitive response to questions and those scoring higher on rational thinking made fewer inferential mistakes. We found a negative correlation between age and maximizing: Physicians who were more advanced in their careers were less willing to spend time and effort in an exhaustive search for solutions. However, they appeared to have maintained their “mindware” for effective problem solving.