Evaluation of the effect of prospective biomarker testing on progression-free survival in diffuse large B-cell lymphoma.

Novel treatment regimens combining chemotherapy with targeted agents are being developed for diffuse large B-cell lymphoma (DLBCL). These regimens are expected to show efficacy in biomarker-defined..

Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL

Central nervous system (CNS) relapse carries a poor prognosis in diffuse large B-cell lymphoma (DLBCL). Integrating biomarkers into the CNS-International Prognostic Index (CNS-IPI) risk model may improve identification of patients at high risk for developing secondary CNS disease. CNS relapse was analyzed in 1418 DLBCL patients treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy in the phase 3 GOYA study. Cell of origin (COO) was assessed using gene-expression profiling. BCL2 and MYC protein expression was analyzed by immunohistochemistry. The impact of CNS-IPI, COO, and BCL2/MYC dual-expression status on CNS relapse was assessed using a multivariate Cox regression model (data available in n = 1418, n = 933, and n = 688, respectively). High CNS-IPI score (hazard ratio [HR], 4.0; 95% confidence interval [CI], 1.3-12.3; P = .02) and activated B-cell\u2012like (ABC) (HR, 5.2; 95% CI, 2.1-12.9; P = .0004) or unclassified COO subtypes (HR, 4.2; 95% CI, 1.5-11.7; P = .006) were independently associated with CNS relapse. BCL2/MYC dual-expression status did not impact CNS relapse risk. Three risk subgroups were identified based on the presence of high CNS-IPI score and/or ABC/unclassified COO (CNS-IPI-C model): low risk (no risk factors, n = 450 [48.2%]), intermediate risk (1 factor, n = 408 [43.7%]), and high risk (both factors, n = 75 [8.0%]). Two-year CNS relapse rates were 0.5%, 4.4%, and 15.2% in the respective risk subgroups. Combining high CNS-IPI and ABC/unclassified COO improved CNS relapse prediction and identified a patient subgroup at high risk for developing CNS relapse. The study was registered at www.clinicaltrials.gov as #NCT01287741

Interactions between genes involved in the antioxidant defence system and breast cancer risk

The aim of the study is to examine the association between multilocus genotypes across 10 genes encoding proteins in the antioxidant defence system and breast cancer. The 10 genes are SOD1, SOD2, GPX1, GPX4, GSR, CAT, TXN, TXN2, TXNRD1 and TXNRD2. In all, 2271 cases and 2280 controls were used to examine gene–gene interactions between 52 single nucleotide polymorphisms (SNPs) that are hypothesised to tag all common variants in the 10 genes. The statistical analysis is based on three methods: unconditional logistic regression, multifactor dimensionality reduction and hierarchical cluster analysis. We examined all two- and three-way combinations with unconditional logistic regression and multifactor dimensionality reduction, and used a global approach with all SNPs in the hierarchical cluster analysis. Single-locus studies of an association of genetic variants in the antioxidant defence genes and breast cancer have been contradictory and inconclusive. It is the first time, to our knowledge, the association between multilocus genotypes across genes coding for antioxidant defence enzymes and breast cancer is investigated. We found no evidence of an association with breast cancer with our multilocus approach. The search for two-way interactions gave experiment-wise significance levels of P=0.24 (TXN [t2715c] and TXNRD2 [g23524a]) and P=0.58 (GSR [c39396t] and TXNRD2 [a442g]), for the unconditional logistic regression and multifactor dimensionality reduction, respectively. The experiment-wise significance levels for the three-way interactions were P=0.94 (GPX4 [t2572c], TXN [t2715c] and TXNRD2 [g23524a]) and P=0.29 (GSR [c39396t], TXN [t2715c] and TXNRD2 [a442g]) for the unconditional logistic regression and multifactor dimensionality reduction, respectively. In the hierarchical cluster analysis neither the average across four rounds with replacement of missing values at random (P=0.12) nor a fifth round with more balanced proportion of missing values between cases and controls (P=0.17) was significant

Evaluating rehabilitation following lumbar fusion surgery (REFS): study protocol for a randomised controlled trial

BACKGROUND: The rate of lumbar fusion surgery (LFS) is increasing. Clinical recovery often lags technical outcome. Approximately 40% of patients undergoing LFS rate themselves as symptomatically unchanged or worse following surgery. There is little research describing rehabilitation following LFS with no clear consensus as to what constitutes the optimum strategy. It is important to develop appropriate rehabilitation strategies to help patients manage pain and recover lost function following LFS. METHODS/DESIGN: The study design is a randomised controlled feasibility trial exploring the feasibility of providing a complex multi-method rehabilitation intervention 3 months following LFS. The rehabilitation protocol that we have developed involves small participant groups of therapist led structured education utilising principles of cognitive behavioral therapy (CBT), progressive, individualised exercise and peer support. Participants will be randomly allocated to either usual care (UC) or the rehabilitation group (RG). We will recruit 50 subjects, planning to undergo LFS, over 30 months. Following LFS all participants will experience normal care for the first 3 months. Subsequent to a satisfactory 3 month surgical review they will commence their allocated post-operative treatment (RG or UC). Data collection will occur at baseline (pre-operatively), 3, 6 and 12 months post-operatively. Primary outcomes will include an assessment of feasibility factors (including recruitment and compliance). Secondary outcomes will evaluate the acceptability and characteristics of a limited cluster of quantitative measures including the Oswestry Disability Index (ODI) and an aggregated assessment of physical function (walking 50 yards, ascend/descend a flight of stairs). A nested qualitative study will evaluate participants' experiences. DISCUSSION: This study will evaluate the feasibility of providing complex, structured rehabilitation in small groups 3 months following technically successful LFS. We will identify strengths and weakness of the proposed protocol and the usefulness and characteristics of the planned outcome measures. This will help shape the development of rehabilitation strategies and inform future work aimed at evaluating clinical efficacy. TRIAL REGISTRATION: ISRCTN60891364, 10/07/2014

Safety and Efficacy of Atezolizumab in Combination with Rituximab Plus CHOP in Previously Untreated Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Primary Analysis of a Phase I/II Study

Abstract Introduction: Rituximab (R) plus CHOP (R-CHOP) is standard of care for patients (pts) with previously untreated DLBCL. Although most pts have long-term responses, up to 40% of pts fail to achieve a remission or relapse. Atezolizumab (atezo) is a fully humanized anti-programmed death-ligand 1 (PD-L1) antibody with a complementary mechanism of action to R. An ongoing Phase I/II study (NCT02596971) is evaluating the safety and efficacy of atezo in combination with R-CHOP (R-CHOP-atezo) in DLBCL pts. Results from the primary analysis are reported. Methods: This open-label, multicenter study enrolled pts (≥18 years; ECOG PS 0-2) with previously untreated advanced DLBCL (Ann Arbor Stage III/IV, International Prognostic Index [IPI] score ≥2 or Stage II with bulky disease [at least 1 lesion ≥7cm]). Pts received induction treatment with R-CHOP-atezo (8 cycles [each 21 days] of R [375mg/m2 IV on Day 1 (Cycles 1-8)] and atezo [1200mg IV on Day 1 (Cycles 2−8)], and 6 or 8 cycles of CHOP [as determined by the investigator (INV)]). Pts who achieved a complete response (CR) at end of induction (EOI) received consolidation treatment with atezo 1200mg IV on Day 1 of Cycles 9─25, every 21 days for 12 months (mo). Primary endpoints were safety, and efficacy as determined by CR rate at EOI by independent review committee (IRC) using modified Lugano 2014 criteria (if bone marrow [BM] involvement at baseline [BL], CR was confirmed with a negative BM biopsy at EOI; designation of partial response [PR] on PET required that CR or PR on CT scan were met). Secondary endpoints included CR at EOI assessed by INV (modified Lugano 2014 criteria) and by IRC and INV (Cheson et al. J Clin Oncol 2007). Minimal residual disease (MRD) was evaluated at EOI using the Adaptive ImmunoSEQ® NGS platform (v2). Results: At the data cut-off (April 11, 2018), 42 pts were enrolled and received treatment (safety population); 7 pts discontinued during the induction phase (1 protocol violation, 1 withdrawal of consent [these 2 pts discontinued after Cycle 1, Day 1 and were not treated with atezo, and were not included in the efficacy analysis], 4 adverse events [AEs], 1 progressive disease [PD]). Of 35 pts completing induction, 30 entered the consolidation phase; 5 pts discontinued at EOI (2 PD, 3 PR). Pt demographics and disease characteristics are shown in Table 1. Among 40 pts evaluable for response (efficacy population), 31 pts (77.5%) had a CR and 4 pts (10%) had a PR by IRC (modified Lugano 2014 criteria); PD occurred in 2 pts (5%), and 3 pts (7.5%) were not evaluable. Response assessments by Cheson et al. (J Clin Oncol 2007) were similar by IRC and INV; IRC assessment showed 31 (77.5%) CRs, 5 (12.5%) PRs, 2 (5%) pts with PD and 1 with SD (Table 2). MRD was evaluable in 26 pts at BL: 10 pts were MRD negative and 16 pts were MRD positive. Of the 16 MRD positive pts at BL, MRD data were available for 14 at EOI: 13 pts were negative and 1 pt was positive (PR by INV and IRC). Median dose intensity was >99% for the induction phase (median exposure 6.7 mo [range 1.5-7.3]) and 100% for the consolidation phase (median exposure 3.7 mo [range 0.7-9.3]). During induction, all 42 pts (100%) had ≥1 AE, 29 (69%) had a grade (Gr) 3-4 AE and 12 (29%) had a serious AE. No fatal AEs were reported. AEs led to any treatment discontinuation in 6 pts (14%) (Gr 3 neutropenia and Gr 3 transaminase increase, Gr 2 hyperthyroidism, Gr 3 lipase increase, Gr 1-2 peripheral neuropathy, Gr 4 thrombocytopenia), dose reduction (CHOP) in 9 pts (21%) (Gr 4 anemia, Gr 3 pancytopenia, Gr 2 paresthesia, Gr 4 neutropenia and Gr 1-2 peripheral neuropathy) and dose interruption (missed doses and dose delays) in 15 pts (36%). Five pts had AEs of interest to atezo (Gr 3 increased lipase, Gr 2 hyperthyroidism, and Gr 1 infusion-related reaction). Common Gr 3-4 AEs during induction were: neutropenia (45%), febrile neutropenia (9.5%), leukopenia (5%), anemia (5%), increased lipase (5%), and fatigue (5%), and during consolidation were: neutropenia (10%), febrile neutropenia (3%), increased lipase (14%), and syncope (7%). Conclusions: The PET-CR rate with R-CHOP-atezo at EOI is encouraging and compares favorably with that previously reported with R-CHOP. The overall safety profile of R-CHOP-atezo is manageable, with no new safety signals reported. Preliminary MRD data at EOI are encouraging and support activity. Biomarker data and duration of response will be presented. Disclosures Younes: Sanofi: Honoraria; Roche: Honoraria, Research Funding; Takeda: Honoraria; Bayer: Honoraria; J&J: Research Funding; BMS: Honoraria, Research Funding; Astra Zeneca: Research Funding; Celgene: Honoraria; Novartis: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Honoraria; Janssen: Honoraria, Research Funding; Abbvie: Honoraria; Genentech: Research Funding; Incyte: Honoraria; Merck: Honoraria; Curis: Research Funding. Burke:Tempus Labs: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Diefenbach:Genentech: Consultancy; Trillium: Research Funding; Millenium/Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Denovo: Research Funding; Acerta: Research Funding. Hawkes:Celgene: Other: Advisory board, Research Funding; Astra Zeneca: Research Funding; Merck: Other: Advisory board; Takeda: Other: Speaker fee; Roche: Other: Speaker fee; advisory board; Bristol Myers Squibb: Other: Speaker fee, Research Funding; Merck Sharpe Dohme: Research Funding; Merck KGA: Research Funding. Khan:Roche: Honoraria; AbbVie: Honoraria. Lossos:Affimed: Research Funding. Vitolo:Takeda: Speakers Bureau; Gilead: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sandoz: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yuen:Seattle Genetics: Research Funding. Oestergaard:Roche: Employment, Other: Ownership interests PLC. Chitra:Genentech/Roche: Employment. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Sellam:Roche: Employment. Sharman:Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Acerta: Consultancy, Research Funding