ALBERT

Description: Abstract 1419 Poster Board I-442 For more than 20 years high dose chemotherapy followed by allogeneic stem cell transplantation (SCT) has been considered as a reasonable approach for the treatment of patients with AML. Moreover, during the last decade new scientific and technical developments results in major changes of clinical practice of transplantation. Enhanced donor availabilities and new strategies, e.g. dose-reduced conditioning, now make allogeneic stem cell transplantation available to patients who do not have a related donor or would not tolerate high-dose chemotherapy due to age or comorbidities. Usually, the decision to start the work-up process for allogeneic transplantation in AML patients is based on the availability of a donor, the assignment to the cytogenetic risk group, and the response to induction therapy, as well as patient factors. However, there would be greater confidence in defining who should, or should not, receive an allograft if the available recommendations given in guidelines are consistent and similar. In this analysis, a comprehensive systematic literature search for best available evidence from controlled clinical trials was performed in the bibliographic databases MEDLINE, EMBASE and Cochrane Central. In addition, the websites of major organizations in Europe and the US (European Group for Blood and Marrow Transplantation, EBMT; European Society for Medical Oncology, ESMO; British Committee for Standards in Hematology, BCSH; American Society for Blood and Marrow Transplantation, ASBMT; National Comprehensive Cancer Network, NCCN) were screened and the specific databases of the National Guideline Clearinghouse and the Guideline International Network Database were also searched to identify the latest recommendations and guidelines. The following points were selected for systematic comparison of the best available evidence: Factors for risk assessment and categorization of AML, donor categories for allogeneic SCT (sibling donors / matched unrelated donors), allogeneic transplantation in first CR, allogeneic transplantation in relapse/progressive disease or second CR, and allogeneic transplants with reduced intensity conditioning regimen. Several interesting findings emerge from this analysis: 1) For patients with relapse or refractory disease donor availability should be explored and discussed, though this is not based on reliable evidence from randomized studies; 2) Patients in CR1 with intermediate or high risk disease who have a matched related donor available should receive allogeneic stem cell transplantation (intermediate risk; ASBMT: reasonable, NCCN: option); 3) For patients who lack a family donor the recommendations are not consistent; 4) Allogeneic transplantation with reduced conditioning in AML patients is feasible, but the superiority over standard therapeutic regimens has not been proven yet. In summary, current guidelines differ in critical points in the recommendation for allogeneic stem cell transplantation. Furthermore, it is likely that only well-defined subgroups of AML patients will benefit from stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4632 Introduction: Chronic lymphocytic leukemia (CLL) accounts for 25% of all leukemias and remains incurable with conventional chemotherapy (CX). Rituximab (R) may be an effective treatment option for CLL patients with the potential to improve overall survival (OS) when given in combination with CX but there is also a risk of more side effects such as infections. This review aims to summarize the evidence for this new treatment option by evaluating the effects on OS, progression-free survival (PFS) and side effects. Methods: MEDLINE and CENTRAL were systematically searched for randomized controlled trials up to April 2010. Trials of patients with CLL comparing CX including R and treatment with CX alone (CX identical in both groups) were included. Clinical trials with previously untreated and pre-treated patients were explored in the main meta-analyses. Trial selection, quality assessment and data extraction were done independently by two review authors. Dichotomous data were analyzed as relative effect measures (i.e. relative risk, RR) with 95% confidence intervals (CI). Time-to-event outcomes were analyzed with hazard ratios (HR) and 95% CI in a random effects model. Results: A total of 992 records were screened. Two eligible trials with 921 untreated (GCLLSG CLL 8 trial (CLL8) and CALGB 9712 trial (CALGB 9712)) and two eligible trials with 604 pre-treated patients (REACH trial (REACH) and NCRI CLL 201 trial) that were fitting the inclusion criteria were identified. The NCLRI CLL 201 trial provided response data only. CALGB 9721 did not report HRs or P-values on OS or PFS and the survival curves for PFS and OS were of low quality, so the provided data were not included in the meta-analysis. Both, CLL8 and REACH examined patients receiving fludarabine (F) and cyclophosphamide (C) with or without R and were meta-analyzed with regard to PFS and OS. PFS (1342 patients) was significantly longer for FCR (HR 0.65, 95% CI [0.48, 0.88]). Analysis of OS (1368 patients) also showed a significantly longer survival for FCR (HR 0.73 (95% CI [0.58, 0.93]). CLL8 provided HRs for the different disease stages and showed significantly improved OS after FCR for Binet B patients only [Binet A: HR 0,19, 95% CI [0.23, 1.613]; Binet B: HR 0.45, 95% CI [0.295, 0.689]; Binet C: HR 1.4, 95% CI [0.843, 2.620]). REACH had not been significant regarding OS (HR 0.83, 95% CI [0.59, 1.17]). With regard to severe hematologic toxicity, meta-analysis of CLL8, REACH and CALGB 9721 showed a significantly higher risk of neutropenia (RR 1.46, CI 95% [1.03, 2.08]) for regimens including R, but there was no statistical difference for thrombocytopenia (RR 1.06, CI 95% [0.60, 1.87]), anemia (RR 0.89 [0.63, 1.26]) or the incidence of severe infections (RR 1.08 CI 95% [0.86, 1.35]). REACH reported a higher rate of secondary malignancies in the FCR-arm (FCR (7%), FC (5%)). Conclusions: This systematic review demonstrates significantly longer OS for CLL patients that received FCR compared to FC (HR 0.65, 95% CI [0.48, 0.88]) and confirms better PFS for patients receiving FCR (HR 0.73 (95% CI [0.58, 0.93]). Adverse events (particularly neutropenia) occurred more often when patients were treated with CX plus R but did not result in an increased infection rate. However, data of CLL8 were only available from the abstract and need to be subsequently confirmed. Disclosures: Hallek: Roche: Consultancy, Honoraria, Research Funding.

Description: Background: Erythropoiesis-stimulating agents (ESAs) reduce anemia in cancer patients; however, there are concerns that ESAs increase mortality in some patients. Within the framework of an international collaboration we thus conducted a patient-level meta-analysis to assess the effects of ESAs on mortality in cancer patients. Methods: We performed a meta-analysis, based on the intention-to-treat principle, of cancer patients enrolled in randomized controlled trials comparing epoetin alfa, epoetin beta or darbepoetin alfa plus red blood cell transfusions as needed versus transfusion alone, for prophylaxis or treatment of anemia while or after receiving anticancer therapy. Patient-level data were obtained and analyzed by independent statisticians at two academic departments. Primary endpoints were on-study mortality and overall survival in patients receiving chemotherapy, defined as all patients from studies in which =/〉 70% of study population received chemotherapy, and in all cancer patients regardless of anticancer therapy. On-study mortality was defined as death from any cause between date of randomization and 28 days after end of active study phase. Overall survival was defined as death from any cause between date of randomization and longest follow up available. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated per study and meta-analyzed with fixed-effects and random-effects models. Stratified multivariable Cox-regression analyses were conducted to assess the impact of baseline imbalances. Tests for interactions were used to identify differences in effect across pre-specified subgroups. All analyses were pre-specified in a peer-reviewed protocol (Bohlius et al. 2008). An independent steering committee consisting of clinicians and methodologists agreed on all analyses and interpretations. Independent investigators and representatives from manufacturers contributing data offered advice, but had no decision-making authority. Results: Data from 13,933 cancer patients enrolled in 53 studies were included in the analysis; 38 trials including 10,441 patients used mainly chemotherapy. Including all cancer patients ESAs increased on-study mortality by 17% (HR 1.17; 95% CI 1.06–1.30), with little evidence for a difference between chemotherapy and other trials (p for interaction=0.42), and worsened overall survival by 6% (HR 1.06; 95% CI 1.00–1.12). In the chemotherapy population on-study mortality was increased by 10% (HR 1.10, 95% CI 0.98–1.24) and overall survival was worsened by 4% (HR 1.04; 95% CI 0.97–1.11). Adjusting for known prognostic factors had little effect on the overall estimates. There was no conclusive evidence for effect modification by patient level characteristics such as age, sex, Hb and Hct at baseline, Hb ceiling, type and stage of tumor or study level characteristics (anticancer treatment, ESA treatment schedules, study design and quality) for the outcomes tested. Conclusion: ESA treatment in cancer patients increased on-study mortality by 17% and worsened overall survival by 6%. For patients undergoing chemotherapy the increase was less pronounced, but could not be excluded. In clinical practice, risks of ESAs must be balanced against benefits of ESAs depending on the clinical circumstances of the individual patient.

Description: Background: Epoetin (EPO), darbepoetin (DARB) and red blood cell transfusions (RBCT) are therapeutic alternatives to treat anemia associated with cancer and cancer therapy. Results of randomized controlled trials (RCTs) conflict, and some question the safety of EPO and DARB. Previously, we systematically reviewed this topic (Bohlius et al, JNCI 2005). Since then many new studies became available necessitating an update the prior systematic review. Objectives: To determine the effectiveness and safety of recombinant human erythropoietin and darbepoetin to prevent or alleviate anemia in cancer patients (pts), and to compare current and previous results of systematic review. Methods: Included RCTs compared EPO or DARB plus RBCT if needed with observation plus RBCT for prophylaxis or treatment of anemia in cancer patients receiving or not receiving antineoplastic therapy. Patients had solid tumors or hematological malignancies including MDS. Endpoints were rates of RBCT, hematological response (defined as transfusion free Hb increase of 2 g/dL), tumor response, overall survival and thrombo embolic events. Medical databases (Cochrane Library, MEDLINE, EMBASE) and conference proceedings were searched (first review:1985–2001, update up to 04/2005). We included full-text and abstract publications plus unpublished data. Data extraction and quality assessment were in duplicate. Results: The update included 57 trials with 9,353 patients. Use of EPO or DARB significantly reduced the relative risk (RR) of RBCTs (RR 0.64; 95%-CI 0.60–0.68; 42 trials, n = 6,510). On average, participants in the EPO/DARB groups received one unit of blood less than controls (weighted mean difference −1.05; 95% CI− 1.32 −0.78; 14 trials, n = 2,353). Hb response (baseline Hb 〈 12 g/dL) was more likely in the EPO/DARB group (RR 3.43; 95%-CI 3.07–3.84; 22 trials, n = 4,307). Thrombo embolic complications were more frequent in patients receiving EPO/DARB: RR 1.67 (95%-CI 1.35–2.06; 35 trials, n = 6,769). Uncertainties remain whether and how EPO/DARB affects tumor response (fixed effect RR 1.12; 95%-CI 1.01–1.23; random effects: RR 1.09; 95%-CI 0.94–1.26; 13 trials, n = 2,833) or overall survival (HR 1.08; 95%-CI 0.99–1.18; 42 trials, n = 8,167). Subgroup analyses comparing EPO and DARB did not identify clinically or statistically significant differences. This update confirms previous findings for transfusion rates and hematological response. In contrast, the update suggests EPO/DARB may reduce survival whereas the first review suggested possible benefits (HR 0.81; 95%-CI 0.67–0.99; 19 trials, n = 2,865). Factors possibly contributing to these conflicting results include mortality due to thrombo embolic complications and tumor progression but also methodological limitations such as baseline imbalances. Conclusion: EPO or DARB given to cancer pts reduces the relative risk for red blood cell transfusion and increases likelihood of hematological response. However, EPO/DARB also increases the risk of thrombo embolic complications. The impact on tumor response and survival is uncertain.

Description: Background: Erythropoiesis stimulating agents (ESAs) consistently have been shown to decrease transfusions in anemic oncology patients. However, whether they increase mortality in cancer patients is under debate. Results from individual studies conflict, and results from literature based meta-analyses are inconclusive. We conducted a meta-analysis based on individual patient data (IPD) from all available randomized controlled trials (RCTs). Meta-analyses with individual patient data offer several advantages over study-level analysis, including the ability to gain statistical power and increase validity using time-to-event analyses, to adjust for prognostic variables that may have confounded the original treatment comparisons and to investigate subgroups in which treatment may be either more or less effective or harmful. Methods: An international collaboration conducted an individual patent data meta-analysis of ESA effects on mortality in cancer patients. With guidance from an independent steering committee of international experts in hematology, oncology, radiotherapy, epidemiology, medical statistics and a consumer representative, we developed a detailed protocol and statistical analysis plan. Independent RCT investigators and representatives from pharmaceutical companies who submitted data provided additional input through the project’s advisory board. IPD from RCTs of ESA plus red blood cell transfusion (RBCT) (as needed) versus placebo or no ESA plus RBCT (as needed), for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy, were included. Hazard ratios and 95% confidence intervals (CIs) were calculated per study and meta-analyzed with fixed-effects and random-effects models. Primary endpoints were overall survival (during active study phase and for the longest follow-up available) for patients receiving chemotherapy, and for all cancer patients regardless of anticancer treatment. Stratified multivariable Cox-regression analyses were conducted to assess the impact of baseline imbalances and to identify potential effect modifiers. Duplicate main statistical analyses were conducted independently at two academic statistical departments. Results: Data on 13933 patients enrolled in 53 studies were included in the analysis. Data were provided by the companies Amgen Inc., Johnson & Johnson Pharmaceutical Research & Development, L.L.C., and F. Hoffmann-La Roche Ltd.; and by five independent investigators. Results are currently undergoing internal verification and final evaluation and will be presented at the meeting. Conclusion: Final conclusions will be presented at the meeting. Future analyses using IPD will be conducted to estimate the risks (clots, tumor progression) and potential benefits (transfusion needs and quality of life/fatigue) from other outcomes.