Ibrutinib for Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: A Meta-Analysis of Randomized Controlled Trials

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5596-5596
Author(s):  
Shijia Zhang ◽  
Larysa Sanchez ◽  
Jieqi Liu ◽  
Victor Chang ◽  
Stuart L. Goldberg
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Controlled Trials ◽  
Small Lymphocytic Lymphoma ◽  
Bulky Disease ◽  
Free Survival ◽  
Randomized Controlled

Background: Ibrutinib, a Bruton's tyrosine kinase inhibitor, was approved by FDA for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This study aims to evaluate the efficacy and safety data from randomized controlled trials (RCT) of ibrutinib-based therapy in patients with CLL or SLL. Methods: PubMed, ASH, and ASCO databases (2008-2016) were searched for randomized control trials of ibrutinib therapy (either single-agent or combination) for chronic lymphocytic leukemia or small lymphocytic lymphoma through June 30, 2016. Study endpoints included overall survival (OS), progression-free survival (PFS), and adverse events (AE). Pooled hazard ratios (HR) for survival outcomes and relative risks (RR) for dichotomous data with 95% confidence interval (CI) were calculated with a random effect model using MedCalc. Results: Four randomized controlled trials (RESONATE-1, RESONATE-2, HELIOS, and CLL12) were identified, but CLL12 trial was excluded from this study since the efficacy data were not available at the time of this meta-analysis. Pooled data from the 3 RCTs (1238 patients) showed that ibrutinib-based therapy improved overall survival (HR 0.419; 95% CI 0.242-0.725, P = 0.002) and progression-free survival (HR 0.201; 95% CI 0.162-0.251, P < 0.001) compared to regimens without ibrutinib. Subgroup analysis showed that the PFS benefits were independent of sex (male: HR 0.188, 95% CI 0.143-0.249, P < 0.001; female: HR 0.225, 95% CI 0.154-0.331, P < 0.001), Rai stage (0-II: HR 0.154, 95% CI 0.109-0.217, P < 0.001; III-IV: HR 0.235, 95% CI 0.167-0.333, P < 0.001), bulky disease (<5 cm: HR 0.219, 95% CI 0.155-0.309, P < 0.001; ≥5 cm: HR 0.179, 95% CI 0.135-0.238, P < 0.001) or chromosome 11q deletion (positive: HR 0.099, 95% CI 0.060-0.163, P < 0.001; negative: HR 0.261, 95% CI 0.212-0.322, P < 0.001). Ibrutinib-based therapy significantly increased the risk of developing all-grade diarrhea (RR = 2.135, 95% CI = 1.437-3.174, p < 0.001), pyrexia (RR = 1.265, 95% CI = 1.011-1.583, p = 0.040), and arthralgia (RR = 1.863, 95% CI = 1.101-3.152, p = 0.020), but not anemia (RR = 0.955, 95% CI = 0.694-1.313, p = 0.777), neutropenia (RR = 1.048, 95% CI = 0.760-1.446, p = 0.774), fatigue (RR = 0.897, 95% CI = 0.746-1.078, p = 0.247), or nausea (RR = 0.951, 95% CI = 0.600-1.506, p = 0.829). Conclusions: Ibrutinib-based therapy significantly improves OS and PFS (independent of sex, Rai stage, bulky disease or chromosome 11q deletion) in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, but increases the risks of all-grade adverse events including diarrhea, pyrexia, and arthralgia. Disclosures Chang: Johnson and Johnson: Other: Stock; Amgen: Other: Research; Boehringer Ingelheim: Other: Research. Goldberg:Neostem: Equity Ownership; Bristol Myers Squibb, Novartis: Speakers Bureau; COTA Inc: Employment; Pfizer: Honoraria; Novartis: Consultancy.

scholarly journals Efficacy of front-line immunochemotherapy for follicular lymphoma: a network meta-analysis of randomized controlled trials

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Yucai Wang ◽  
Shouhao Zhou ◽  
Xinyue Qi ◽  
Fang Yang ◽  
Matthew J. Maurer ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Follicular Lymphoma ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Similar Efficacy ◽  
Controlled Trials ◽  
Front Line ◽  
Free Survival ◽  
Randomized Controlled

Abstract Front-line treatment for follicular lymphoma has evolved with the introduction of maintenance therapy, bendamustine (Benda), obinutuzumab (G), and lenalidomide (Len). We conducted a random-effects Bayesian network meta-analysis (NMA) of phase 3 randomized controlled trials (RCTs) to identify the regimens with superior efficacy. Progression-free survival (PFS) was compared between 11 modern regimens with different immunochemotherapy and maintenance strategies. G-Benda-G resulted in with the best PFS, with an HR of 0.41 compared to R-Benda, a surface under the cumulative ranking curve (SUCRA) of 0.97, a probability of being the best treatment (PbBT) of 72%, and a posterior ranking distribution (PoRa) of 1 (95% BCI 1–3). This was followed by R-Benda-R4 (HR = 0.49, PbBT = 25%, PoRa = 2) and R-Benda-R (HR = 0.60, PbBT = 3%, PoRa = 3). R-CHOP-R (HR = 0.96) and R-Len-R (HR = 0.97) had similar efficacy to R-Benda. Bendamustine was a better chemotherapy backbone than CHOP either with maintenance (R-Benda-R vs R-CHOP-R, HR = 0.62; G-Benda-G vs G-CHOP-G, HR = 0.55) or without maintenance therapy (R-Benda vs R-CHOP, HR = 0.68). Rituximab maintenance improved PFS following R-CHOP (R-CHOP-R vs R-CHOP, HR = 0.65) or R-Benda (R-Benda-R vs R-Benda, HR = 0.60; R-Benda-R4 vs R-Benda, HR = 0.49). In the absence of multi-arm RCTs that include all common regimens, this NMA provides an important and useful guide to inform treatment decisions.

scholarly journals Progression-free survival as a surrogate endpoint for overall survival in modern ovarian cancer trials: a meta-analysis

2018 ◽  
Vol 10 ◽  
pp. 175883591878850 ◽  
Author(s):  
Katrin M. Sjoquist ◽  
Sarah J. Lord ◽  
Michael L. Friedlander ◽  
Robert John Simes ◽  
Ian C. Marschner ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Surrogate Endpoint ◽  
Controlled Trials ◽  
First Line ◽  
Free Survival ◽  
Randomized Controlled ◽  
The Difference

Background: Progression-free survival (PFS) has been adopted as the primary endpoint in many randomized controlled trials, and can be determined much earlier than overall survival (OS). We investigated whether PFS is a good surrogate endpoint for OS in trials of first-line treatment for epithelial ovarian cancer (EOC), and whether this relationship has changed with the introduction of new treatment types. Methods: In a meta-analysis, we identified summary data [hazard ratio (HR) and median time] from published randomized controlled trials. Linear regression was used to assess the association between treatment effects on PFS and OS overall, and for subgroups defined by treatment type, postprogression survival (PPS) and established prognostic factors. Results: Correlation between HRs for PFS and OS, in 26 trials with 30 treatment comparisons comprising 24,870 patients, was modest ( r2 = 0.52, weighted by trial sample size). The correlation diminished with recency: preplatinum/paclitaxel era, r2 = 0.66; platinum/paclitaxel, r2 = 0.44; triplet combinations, r2 = 0.22; biologicals, r2 = 0.30. The median PPS increased over time for the experimental ( Ptrend = 0.03) and control arms ( Ptrend = 0.003). The difference in median PPS between treatment arms strongly correlated with the difference in median OS ( r2 = 0.83). In trials where the control therapy had median PPS of less than 18 months, correlation between PFS and OS was stronger ( r2 = 0.64) than where the median PPS was longer ( r2 = 0.48). Conclusions: In EOC, correlation in the relative treatment effect between PFS and OS in first-line platinum-based chemotherapy randomized controlled trials is moderate and has weakened with increasing availability of effective salvage therapies.

Forest Plot to Compare Therapies in a Network Meta-Analysis in First Line Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4596-4596
Author(s):  
Alfonso Piciocchi ◽  
Katia Bontempi ◽  
Paola Fazi ◽  
Marco Vignetti ◽  
Franco Mandelli
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Randomized Controlled Trials ◽  
Disease Progression ◽  
Meta Analysis ◽  
Lymphocytic Leukemia ◽  
Forest Plot ◽  
Controlled Trials ◽  
First Line ◽  
Early Stage Disease ◽  
Randomized Controlled

Abstract Abstract 4596 Several therapies, composed by single agent or combinations, are available for untreated patients in chronic lymphocytic leukemia and it is difficult to rank treatments according to their effect size when not all treatments have been compared directly. Direct randomized comparison is the most reliable way of comparing treatments but when the number of available treatments increases the number of possible pairwise comparisons increases quadratically, so it is common for only a small fraction of the possible comparisons to be performed. Network meta-analysis permits to add indirect estimates for assessing the relative effectiveness of two treatments when they have not been compared directly in a randomized trial but have each been compared to other treatments. Network meta-analysis of randomized controlled trials was used to combine direct and indirect estimates of the effect of four drugs and their combinations from five randomized controlled trials (Fig. IA) in CLL patients based on a systematic review conducted by M.M. Cheng et al. (Cancer Treatment Review 2012) on 2625 patients where Chorambucil, Fludarabine, Rituximab, Alemtuzumab, Bendamustine, Cladribine and Pentostatin have been considered as primary first-line agents for CLL. Patients were younger (59–65 years), had good performance status (ECOG: 0–1) and early stage disease (Rai 0-II, Binet A or B). We carried out an analysis based on the endpoint of PFS, described as the duration of the time from randomization until disease progression or death from any cause and to consider the heterogeneity among the studies a random effects model was performed. The differences in PFS of all therapies considered in the analysis were compared with combination of Fludarabine and Chorambucil (FC). The results were summarized by forest plot (Fig IB) in terms of reduction or increase of Hazard Ratio. As the forest plot shows, FCR has relatively higher potential of preventing disease progression in younger patients affected by chronic lymphocytic leukemia. Respect to a traditional meta-analysis, which usually compares only two treatments, network meta-analysis is a useful method to combine direct and indirect comparisons of treatments from RCTs and to analyze the hierarchy in treatment effects and tests for consistency of the relations of the network. Disclosures: No relevant conflicts of interest to declare.

Sex Is an Independent Prognostic Indicator for Survival and Relapse/Progression-Free Survival in Metastasized Stage III to IV Melanoma: A Pooled Analysis of Five European Organisation for Research and Treatment of Cancer Randomized Controlled Trials

2013 ◽  
Vol 31 (18) ◽  
pp. 2337-2346 ◽  
Author(s):  
Arjen Joosse ◽  
Sandra Collette ◽  
Stefan Suciu ◽  
Tamar Nijsten ◽  
Poulam M. Patel ◽  
...  
Keyword(s):  
Randomized Controlled Trials ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Metastatic Tumor ◽  
Stage Iii ◽  
Controlled Trials ◽  
Free Survival ◽  
European Organisation ◽  
Randomized Controlled ◽  
Female Advantage

Purpose To study sex differences in survival and progression in patients with stage III or IV metastatic melanoma and to compare our results with published literature. Patients and Methods Data were retrieved from three large, randomized, controlled trials of the European Organisation for Research and Treatment of Cancer in patients with stage III and two trials in patients with stage IV melanoma. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for females compared with males, adjusted for different sets of confounders for stage III and stage IV, respectively. Results In 2,734 stage III patients, females had a superior 5-year disease-specific survival (DSS) rate compared with males (51.5% v 43.3%), an adjusted HR for DSS of 0.85 (95% CI, 0.76 to 0.95), and an adjusted HR for relapse-free survival of 0.86 (95% CI, 0.77 to 0.95). In 1,306 stage IV patients, females also exhibited an advantage in DSS (2-year survival rate, 14.1% v 19.0%; adjusted HR, 0.81; 95% CI, 0.72 to 0.92) as well as for progression-free survival (adjusted HR, 0.79; 95% CI, 0.70 to 0.88). This female advantage was consistent across pre- and postmenopausal age categories and across different prognostic subgroups. However, the female advantage seems to become smaller in patients with higher metastatic tumor load. Conclusion The persistent independent female advantage, even after metastasis to lymph nodes and distant sites, contradicts theories about sex behavioral differences as an explanation for this phenomenon. A biologic sex trait seems to profoundly influence melanoma progression and survival, even in advanced disease.

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