Rituximab (R) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the current standard therapy for diffuse large B cell lymphoma (DLBCL). Obinutuzumab (G), a glycoengineered, ...type II anti-CD20 monoclonal antibody, has shown activity and an acceptable safety profile when combined with CHOP (G-CHOP) in patients with advanced DLBCL. We present the final analysis results of the Phase III GOYA study (NCT01287741), which compared the efficacy and safety of G-CHOP versus R-CHOP in patients with previously untreated DLBCL.
Patients aged ≥ 18 years with previously untreated advanced DLBCL were randomly assigned to receive eight 21-day cycles of R or G, plus six or eight cycles of CHOP. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival, other time-to-event endpoints, and safety; investigator-assessed PFS by cell of origin subgroup was an exploratory endpoint.
A total of 1418 patients were randomized, with 1414 included in this final analysis (G-CHOP, N = 704; R-CHOP, N = 710). Five-year PFS rates were 63.8% and 62.6% for G-CHOP and R-CHOP, respectively (stratified hazard ratio 0.94, 95% CI 0.78-1.12; p = 0.48). The results of the secondary efficacy endpoints did not show a benefit of G-CHOP over R-CHOP. In the exploratory analysis, a trend towards benefit with G-CHOP over R-CHOP was apparent in the patients with germinal center B cell DLBCL. The safety profile of G-CHOP was as expected, and no new safety signals were observed. More grade 3-5 (75.1% vs 65.8%), serious (44.4% vs 38.4%), and fatal (6.1% vs 4.4%) adverse events (AEs) were observed in the G-CHOP arm compared with the R-CHOP arm, respectively, with the most common fatal AEs being infections. A higher incidence of late-onset neutropenia occurred in the G-CHOP arm (8.7%) versus the R-CHOP arm (4.9%).
The final analysis, similar to the primary analysis, did not show a PFS benefit of G-CHOP over R-CHOP in previously untreated patients with DLBCL. The results of the secondary endpoints were consistent with the primary endpoint. Further exploratory analyses and investigation of biomarkers are ongoing.
This retrospective analysis of the phase III GOYA study investigated the prognostic value of baseline metabolic tumor volume parameters and maximum standardized uptake values for overall and ...progression-free survival (PFS) in treatment-naïve diffuse large B-cell lymphoma. Baseline total metabolic tumor volume (determined for tumors >1 mL using a threshold of 1.5 times the mean liver standardized uptake value +2 standard deviations), total lesion glycolysis, and maximum standardized uptake value positron emission tomography data were dichotomized based on receiver operating characteristic analysis and divided into quartiles by baseline population distribution. Of 1,418 enrolled patients, 1,305 had a baseline positron emission tomography scan with detectable lesions. Optimal cut-offs were 366 cm3 for total metabolic tumor volume and 3,004 g for total lesion glycolysis. High total metabolic tumor volume and total lesion glycolysis predicted poorer PFS, with associations retained after adjustment for baseline and disease characteristics (high total metabolic tumor volume hazard ratio: 1.71, 95% confidence interval CI: 1.35– 2.18; total lesion glycolysis hazard ratio: 1.46; 95% CI: 1.15–1.86). Total metabolic tumor volume was prognostic for PFS in subgroups with International Prognostic Index scores 0–2 and 3–5, and those with different cell-of-origin subtypes. Maximum standardized uptake value had no prognostic value in this setting. High total metabolic tumor volume associated with high International Prognostic Index or non-germinal center B-cell classification identified the highest-risk cohort for unfavorable prognosis. In conclusion, baseline total metabolic tumor volume and total lesion glycolysis are independent predictors of PFS in patients with diffuse large B-cell lymphoma after first-line immunochemotherapy.
Understanding interrupted speech requires top-down linguistic and cognitive restoration mechanisms. To investigate the relation between working memory (WM) and perception of interrupted speech, 20 ...young adults were asked to recognize sentences interrupted at 2 Hz, 8 Hz, and a combination of 2 and 8 Hz. WM was measured using automated reading and operation span tasks. Interestingly, the results presented here revealed no statistical relation between any of the interrupted speech recognition scores and WM scores. This finding is in agreement with previous findings that suggest greater reliance on linguistic factors relative to cognitive factors during perception of interrupted speech.
Since the end of the Cold War, the protection of civilians has increased its weight on the United Nations (UN) agenda. This article (1) maps the evolution of civilian protection within the UN ...framework as an indicator of its shifting priorities, (2) identifies breakpoints in the prevalence and character of the protection discourse, and (3) explores how internal processes of policy development and real-world triggers (namely conflicts and peacekeeping operations) shaped this transformation. The article uses Structural Topic Modeling (STM) to analyze an original corpus of Security Council and General Assembly resolutions on complex humanitarian emergencies since 1990. The analysis uncovers two distinct forms of protection, labeled as "Ground protection" and "Political-legal protection," which are characterized by contrasting temporal and geographic trajectories. Moreover, critical junctures in the protection rhetoric (during the years 2000, 2005, and 2008) coincide with policy watersheds rather than conflict outbreaks or trends in peacekeeping deployment. This article offers a comprehensive analysis of the intricate evolution of civilian protection using text-as-data methods, which uses its theory-building design to encourage further explorations on the interplay between internal and external factors in shaping its progression within the UN framework.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined using a number of well-established molecular subsets. Application of non-negative matrix factorization (NMF) to whole exome ...sequence data has previously been used to identify six distinct molecular clusters in DLBCL with potential clinical relevance. In this study, we applied NMF-clustering to targeted sequencing data utilizing the FoundationOne Heme® panel from the Phase III GOYA (NCT01287741) and Phase Ib/II CAVALLI studies (NCT02055820) in de novo DLBCL. Biopsy samples, survival outcomes, RNA-Seq and targeted exome-sequencing data were available for 423 patients in GOYA (obinutuzumab G-cyclophosphamide, doxorubicin, vincristine, and prednisone CHOP vs rituximab R-CHOP) and 86 patients in CAVALLI (venetoclax+G/R-CHOP).
When the NMF algorithm was applied to samples from the GOYA study analyzed using a comprehensive genomic profiling platform, four of the six groups previously reported were observed: MYD88/CD79B, BCL2/EZH2, NOTCH2/TNFAIP3, and no mutations. Mutation profiles, cell-of-origin subset distributions and clinical associations of MYD88/CD79B and BCL2/EZH2 groups were similar to those described in previous NMF studies. In contrast, application of NMF to the CAVALLI study yielded only three; MYD88/CD79B-, BCL2/EZH2-like clusters, and a no mutations group, and there was a trend towards improved outcomes for BCL2/EZH2 over MYD88/CD79B.
This analysis supports the utility of NMF used in conjunction with targeted sequencing platforms for identifying patients with different prognostic subsets. The observed trend for improved overall survival in the BCL2/EZH2 group is consistent with the mechanism of action of venetoclax, suggesting that targeting sequencing and NMF has potential for identifying patients who are more likely to gain benefit from venetoclax therapy.
The GAUDI study assessed safety and preliminary efficacy of induction therapy with obinutuzumab plus chemotherapy, followed by maintenance therapy with obinutuzumab alone, in previously untreated ...patients with follicular lymphoma. Assignment to chemotherapy was decided on a per-center basis before the patients' enrollment. Patients (n=81) received four to six cycles of obinutuzumab plus bendamustine every 4 weeks or six to eight cycles of obinutuzumab plus CHOP every 3 weeks. Patients with an end-of-treatment response were eligible for obinutuzumab maintenance therapy every 3 months for 2 years or until disease progression. Induction treatment was completed by 90% of patients in the obinutuzumab plus bendamustine group and 95% in the obinutuzumab plus CHOP group, while maintenance was completed by 81% and 72% of patients, respectively. All patients experienced at least one adverse event during induction, most commonly infusion-related reactions (58%), the majority of which were grade 1/2. The most common hematologic adverse event was grade 3/4 neutropenia (36% during induction and 7% during maintenance). One treatment-related death occurred during the maintenance phase. At the end of induction, 94% of patients had achieved an overall response, with complete response based on computed tomography in 36%. The progression-free survival rate at 36 months was 90% in the obinutuzumab plus bendamustine group and 84% in the obinutuzumab plus CHOP group. These results demonstrate that induction therapy with obinutuzumab plus bendamustine or obinutuzumab plus CHOP, followed by obinutuzumab maintenance, is associated with tolerable safety and promising efficacy. This study is registered at ClinicalTrials.gov as NCT00825149.
GALLIUM is a global phase III study that demonstrated significant improvements in progression-free survival (PFS) for obinutuzumab plus chemotherapy (G-chemo) vs. rituximab plus chemotherapy ...(R-chemo) in previously untreated patients with follicular lymphoma (FL). This study aimed to report the results of a subgroup of patients in China.
Patients were randomized to G-chemo or R-chemo. Responders received maintenance therapy for 2 years or until disease progression. The primary endpoint was investigator (INV)-assessed PFS. Secondary endpoints included the overall response rate (ORR) and complete response rate (CRR) at the end of induction chemotherapy, overall survival (OS), and safety.
Overall, 58 patients with FL were randomized to the G-chemo (n = 25) and R-chemo arms (n = 33). The INV-assessed PFS rate at 3 years was 81.8% in the G-chemo arm, vs. 70.2% in the R-chemo arm (hazard ratio 0.35; 95% confidence interval: 0.09-1.34; P = 0.1120). The INV-assessed CRRs (without positron emission tomography PET) in these arms were 24.0% and 21.2%, respectively, whereas the ORRs were 80.0% and 90.9%, respectively. INV-assessed CRR-PET was 52.6% in the G-chemo, vs. 60.9% in the R-chemo. Median OS was not reached in either arm. Grade 3 to 5 adverse events were more frequent in the R-chemo arm (97.0% vs. 88.0%).
The results of this subgroup analysis were consistent with those of the global population, and they suggest that G-chemo has a positive benefit-risk profile in patients from China with FL.
ClinicalTrials.gov, No. NCT01332968.
Purpose
We investigated the prognostic value of pretreatment patient‐reported outcomes (PROs) in patients with diffuse large B‐cell lymphoma (DLBCL) receiving obinutuzumab/rituximab plus chemotherapy ...in the GOYA phase III study.
Methods
Patients completed the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ‐C30) and the Functional assessment of chronic illness therapy‐Lymphoma (FACT–Lym) lymphoma subscale (LYMS) during the study. PRO scales with high prognostic value were identified through Cox regression analyses of overall survival (OS) and progression‐free survival (PFS). These scales were evaluated in terms of their additional prognostic value beyond the International Prognostic Index (IPI). A preliminary assessment was performed to evaluate whether the scales provided improved patient‐risk stratification beyond IPI.
Results
One thousand two hundred and fifty‐nine patients with valid pretreatment PRO scales were included in the analyses, and complete pretreatment data were available for 1239/1414 patients (87.6%). Four PRO scales with high prognostic value were identified: FACT–Lym LYMS and EORTC QLQ‐C30 physical functioning, global health status/quality of life (QoL), and fatigue. All four scales retained significant prognostic value for OS and PFS after IPI adjustment (all p < 0.05). After adjusting for multiple clinical variables (IPI, cell of origin, BCL2 status, and total metabolic tumor volume), all four scales retained significant prognostic value (all p < 0.05) for OS. Only the EORTC QLQ‐C30 physical functioning scale was significant (p < 0.05) for PFS after adjustment for multiple clinical variables.
Conclusions
In this large population of patients with DLBCL, pretreatment PROs provided prognostic information for OS and PFS beyond the well‐established IPI.
Patient reported outcomes were exhaustively reviewed for prognostic signal in GOYA ‐ the largest trial to date for DLBCL ‐ and multiple scales at baseline were prognostic even after multiple testing correction. The prognostic value was often orthogonal and additionally prognostic on top of the International Prognostic Index (IPI) clinical score used in DLBCL.
We evaluated the triplet regimen obinutuzumab-atezolizumab-lenalidomide (G-atezo-len) for patients with relapsed/refractory (R/R) follicular lymphoma (FL) in an open-label, multicenter phase Ib/II ...study (BO29562; NCT02631577). An initial 3 + 3 dose-escalation phase to define the recommended phase II dose of lenalidomide was followed by an expansion phase with G-atezo-len induction and maintenance. At final analysis, 38 patients (lenalidomide 15 mg, n = 4; 20 mg, n = 34) had completed the trial. Complete response rate for the efficacy population (lenalidomide 20 mg, n = 32) at end-of-induction was 71.9% (66.7% in double-refractory patients refractory to rituximab and alkylator n = 12; 50.0% in patients with progressive disease within 24 months of first-line therapy n = 12). The 36-month progression-free survival rate was 68.4%. All treated patients had ≥1 adverse event (AE; grade 3-5 AE, 32 patients 84%; serious AE, 18 patients 47%; AEs leading to discontinuation of any study drug, 11 patients 29%). There were 2 fatal AEs (1 merkel carcinoma, 1 sarcomatoid carcinoma; both unrelated to any study drug). The G-atezo-len regimen is effective and tolerable in patients with R/R FL. AEs were consistent with the known safety profile of the individual drugs.
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