scholarly journals Neoantigens in Patients with De Novo Follicular Lymphoma: Results from the PRIMA Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Carsten Henneges ◽  
Dexter X Jin ◽  
Jeffrey M Venstrom ◽  
Sally E Trabucco ◽  
Tina G Nielsen ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Clinical Outcomes ◽  
Prognostic Value ◽  
De Novo ◽  
Null Model ◽  
B Cell Lymphoma ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Publicly Traded ◽  
The Past

Introduction: Follicular lymphoma (FL) is a slow growing lymphatic cancer characterized by translocations in and overexpression of BCL-2, which inhibits apoptosis. This pathogenesis may generate neoantigens (NAs) that are recognizable by T-cells as part of a patients' immune surveillance and are unique to specific FL mutations. Tumor mutation burden (TMB), and NA prevalence and prognostic nature, have previously been characterized for diffuse large B-cell lymphoma (DLBCL), identifying that TMB correlated with NA burden (NAB). While TMB did not correlate with outcomes, the presence of a NA, especially BCL2 NA, correlated with outcomes in de novo DLBCL. In addition, the majority of patients were predicted to have ≥1 NA (Paulson, EHA 2019). However, to date, the prevalence of NAs in FL, and their association with clinical outcomes, have not been characterized. The aim of our study was to characterize NA prevalence and evaluate the prognostic value of NA biomarkers, assessed by a targeted, comprehensive genomic profiling (CGP) platform, on progression-free survival (PFS) for patients with de novo FL. Methods: CGP data on 465 genes were available from patients with FL who provided biopsy samples at screening for the Phase III PRIMA trial (NCT00140582; intent-to-treat [ITT] population =1018; patients received rituximab [R] maintenance vs observation after response to initial first-line treatment with R-CVP [cyclophosphamide, vincristine, prednisone], R-CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] or R-FCM [fludarabine, cyclophosphamide, mitoxantrone]). CGP was used to calculate TMB, HLA type (OptiType) and NA prediction (NetMHCpan). The prevalence of NAs at time of screening was analyzed by the number and proportion of patients. The prognostic value of NAs were evaluated against the Cox Proportional Hazards null model for PFS including terms for treatment, country and response to induction treatment. The Akaike Information Criterion (AIC), a likelihood ratio test (LRT) p-value vs the null when including an additional NA term and its associated hazard ratio (95% CI), were calculated. A visualization of the genetic mutational landscape was generated using dimension reduction methods. Results: In total, 247 of the 1202 enrolled patients were assayed with CGP. Baseline characteristics and survival in the biomarker evaluable population (BEP) were consistent with the ITT population. We calculated a median TMB of 6.7 mutations per megabase for the PRIMA cohorts with a median of two predicted NAs per patient. The majority of patients (83%) were predicted to have ≥1 NA. TMB moderately correlated with NAB (0.42 pearson coefficient), Figure A. TMB was not associated with outcomes (hazard ratio [HR] 95% CI: 0.98 [0.94-1.02]) and similarly the presence of a NA was not associated with PFS (HR [95% CI]: 0.90 [0.56-1.44]). The most prevalent predicted NAs (n [patients]; %) were in BCL2 (54; 21.9%), CREBBP (49; 19.8%), EZH2 (14; 5.7%), KMT2D (13; 5.3%), and CARD11 (10; 4.0%). In a pooled analysis of patients from both arms, only presence of EZH2 NA improved the AIC of the null model (AIC=1135.6) to 1134.7 (LRT p=0.09 better than 0.1), Table. The HR (95% CI) of EZH2 NA in this model was 0.46 (0.17-1.25), indicating better survival for the EZH2 NA-negative group. Within each treatment group, HR (95% CI) for EZH2 was 0.27 (0.07-1.13) in the observation group and 1.05 (0.25-4.44) in the R group, Figure B. Inspecting the tSNE mutations by gene, a neighborhood pattern could be seen between EZH2 and BCL2 connected by KMT2D and flanked by CARD11 and CREBBP, Figure C. Conclusions: We observed that similarly to de novo DLBCL, TMB and NAB were also correlated in patients with de novo FL. While NAB was associated with clinical outcomes in de novo DLBCL, we did not observe these associations in FL. In patients with de novo FL,who discontinued R after initial treatment response, the absence of EZH2 predicted neoantigens were associated with PFS. This is consistent with results on EZH2 mutation status reported by Huet, et al.(Blood Cancer J 2017). A caveat to this hypothesis generating analysis is the small number of PFS events in the EZH2 neoantigen group. These insights may inform future personalized strategies in FL. Disclosures Henneges: Genentech (via Syneos Health): Current Employment; University of Wurzburg: Ended employment in the past 24 months. Jin:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Foundation Medicine Inc: Current Employment. Venstrom:Foundation Medicine, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Trabucco:F. Hoffmann-La Roche, Bristol-Myers Squibb Co., BioNTech: Current equity holder in publicly-traded company; Bristol-Myers Squibb Co: Current equity holder in publicly-traded company; BioNTech: Current equity holder in publicly-traded company; Loxo Oncology: Divested equity in a private or publicly-traded company in the past 24 months; Foundation Medicine, Inc.: Current Employment; Patent pending with Foundation Medicine and Genentech: Patents & Royalties: Patent pending. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Penuel:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Salles:Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, Roche, Takeda: Other: Participation to educational events; Abbvie, Autolus, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Epizyme, Janssen, Karyopharm, Morphosys, Novartis, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, F. Hoffmann-La Roche, Takeda: Honoraria; Abbvie, Autolus, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Epizyme, Janssen, Karyopharm, Morphosys, Novartis, F. Hoffmann-La Roche, Takeda: Consultancy. Paulson:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in private company, Current equity holder in publicly-traded company.

scholarly journals Recil 2017 Criteria Demonstrated Similar Prognostic Value and Detected a Comparable Treatment Difference between Obinutuzumab- and Rituximab-Chemotherapy Compared with Cheson 2007 and Lugano 2014 Criteria in Patients with Previously Untreated Advanced-Stage Follicular Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Lale Kostakoglu ◽  
Andrew Davies ◽  
Michael Herold ◽  
Wolfgang Hiddemann ◽  
Robert Marcus ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Value ◽  
Response Assessment ◽  
Phase Iii ◽  
Publicly Traded ◽  
Advisory Committees ◽  
High Concordance ◽  
Dimensional Assessment

Introduction: Lugano 2014 criteria are the current standard for response assessment in lymphoma and incorporate 18F fludeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) into standard staging of FDG-avid lymphomas (Cheson, et al. J Clin Oncol 2014); bi-dimensional tumor measurements of up to six CT target lesions are used for non-FDG avid lymphomas, and when PET is unavailable. The Response Evaluation Criteria in Lymphoma (RECIL), developed more recently, showed that uni-dimensional measurements of up to three target lesions could provide response assessment at a similar accuracy to the Lugano criteria (Younes, et al. Annals Oncol 2017). In the Phase III GOYA trial (NCT01287741), complete response (CR) status by RECIL criteria showed high concordance with Lugano criteria and was highly prognostic for survival outcome in previously untreated patients (pts) with CD20-positive diffuse large B-cell lymphoma treated with obinutuzumab (G) plus chemotherapy (G-chemo) or rituximab (R)-chemo. Here, we compared the prognostic and predictive performance of the Lugano and RECIL criteria in pts from the Phase III GALLIUM trial (NCT01332968). Methods: Pts were randomized 1:1 to receive G or R plus CHOP, CVP, or bendamustine (stratification factors: chemotherapy regimen, Follicular Lymphoma International Prognostic Index and geographic region). FDG-PET scans were mandatory in the first 170 pts where a PET scanner was available, and optional thereafter, and were performed at screening and end of induction (EOI). Response was assessed by the investigator (INV) and an independent review committee (IRC) using Cheson 2007 criteria, the IRC also assessed EOI response using Lugano 2014 criteria. Response and progression-free survival (PFS) by RECIL 2017 criteria were retrospectively evaluated via a programming algorithm based on IRC-assessed 5PS scores and the individual lesion measurements from INV assessment. Response categories at EOI by RECIL criteria were cross-tabulated against those by Lugano criteria. Estimates of the treatment effect for PFS were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) using stratified log-rank tests. Landmark analyses of PFS and overall survival (OS) from EOI, by EOI CR/non-CR status were performed. The impact of covariates on the prognostic value for PFS and OS were analyzed using multivariable Cox models. Results: In GALLIUM, 1202 pts with follicular lymphoma (FL) were enrolled (601 per treatment arm), of which 595 had PET evaluable data (R-chemo, n=298; G-chemo, n=297). High concordance between Lugano and RECIL criteria for EOI CR was observed regardless of antibody received, with 416 pts classified as CR by RECIL among the 450 pts achieving complete metabolic response (CMR) by Lugano (416/450 [92.4%]; R-chemo, 199/216 [92.1%]; G-chemo, 217/234 [92.7%]) (Table). However, poor concordance was seen for progressive disease (PD), with 18/21 (85.7%) pts with progressive metabolic disease by Lugano classified as partial/minimal responders by RECIL. A strong correlation was observed between Cheson 2007 and RECIL PFS definitions, with a kappa estimate of 0.63 (95% CI: 0.58-0.69). EOI CR status by RECIL showed prognostic value by Cox multivariable regression analysis adjusted for stratification factors for PFS and OS; this prognostic value was similar with Lugano criteria (Figure). PFS rate by treatment arm for pts with a CR/CMR was higher by RECIL versus Lugano for both R-chemo and G-chemo (PFS rate at 3 years from EOI: RECIL: 86.0% and 89.7%; Lugano: 76.4% and 85.0%, respectively); similar results were seen with OS. G-chemo was associated with improved RECIL-PFS (from randomization) compared with R-chemo (HR, 0.72; 95% CI: 0.57-0.91; p=0.0069), similar to the GALLIUM 5-year updated analysis results by Cheson 2007 (HR, 0.76; 95% CI: 0.62-0.92; p=0.0043) (Townsend, et al. ASCO 2020). Conclusions: RECIL 2017 criteria showed high concordance with Lugano 2014 criteria with EOI CR strongly prognostic for improved outcomes versus non-CR; however, a discordance was observed for PD. A similar treatment difference between arms for PFS was detected with RECIL and Cheson 2007 criteria. RECIL criteria (uni-dimensional assessment of up to three target lesions) may be a suitable alternative to Lugano criteria (bi-dimensional assessment of up to six target lesions) in pts with previously untreated advanced-stage FL. Disclosures Kostakoglu: F. Hoffmann-La Roche: Consultancy. Davies:Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Celegene, Roche, Kite Pharma, Celegene: Honoraria; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Herold:Helios Klinikum Erfurt: Current Employment; F. Hoffmann-La Roche: Research Funding. Hiddemann:F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Marcus:Gilead: Consultancy; F. Hoffmann-La Roche: Honoraria; Janssen: Honoraria, Speakers Bureau. Trotman:Celgene: Research Funding; F. Hoffmann-La Roche: Research Funding; BeiGene: Research Funding; Takeda: Research Funding; PCYC: Research Funding. Knapp:F. Hoffmann-La Roche: Current Employment. Mattiello:F. Hoffmann-La Roche: Current Employment. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Sahin:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Ward:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Younes:AstraZeneca: Current Employment; MSKCC: Ended employment in the past 24 months; Janssen, Curis, Merck, Bristol-Myers Squibb, Syndax Pharmaceuticals, F. Hoffmann-La Roche, Curis (Inst), Johnson & Johnson (Inst), Novartis (Inst): Research Funding; Janssen, AbbVie, Merck, Curis, Epizyme, F. Hoffmann-La Roche, Takeda, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Celgene, Incyte, Janssen Pharmaceuticals, Merck, Sanofi, Seattle Genetics, Takeda Millennium: Honoraria; BioPath, Xynomic, Epizyme, and F. Hoffmann-La Roche: Consultancy.

scholarly journals Automated Baseline Fluorodeoxyglucose-Positron Emission Tomography Imaging and High BCL2 Expression Provide Orthogonal Prognostic Value in Predicting High-Risk De Novo Diffuse Large B-Cell Lymphoma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Skander Jemaa ◽  
Samuel Tracy ◽  
Alessia Bottos ◽  
Alex de Crespigny ◽  
Thomas Bengtsson ◽  
...  
Keyword(s):  
High Risk ◽  
Prognostic Value ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Prognostic Models ◽  
Imaging Features ◽  
Publicly Traded ◽  
Private Company ◽  
Positron Emission ◽  
Bcl2 Expression

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for 30─40% of cases (Li, et al. Pathology 2017). Although rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) cures approximately 50─60% of patients, clinical outcomes remain poor for those with relapsed or refractory (R/R) disease (Liu and Barta. Am J Hematol 2019). Current prognostic models such as the International Prognostic Index (IPI) have suboptimal sensitivity and specificity to identify these patients at diagnosis. Models that combine biological, clinical and imaging markers may improve prognostication in DLBCL. Methods: We evaluated fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging features alongside clinical and biomarker data in modeling disease prognosis with a primary endpoint of investigator-assessed progression-free survival (PFS) for de novo DLBCL patients from the randomized phase III GOYA study (NCT01287741) comparing R-CHOP versus obinutuzumab (G)-CHOP. Imaging features were derived using a computer-vision modeling algorithm (Jemaa, et al. J Digit Imaging 2020), and included total and by-organ number and volume of lesions. The evaluable population (n=1286) was split into pre-defined training (n=964; PFS events=307) and holdout populations (n=322; PFS events=96). Baseline clinical and imaging features were dichotomized by median or a clinically relevant threshold, and screened with univariate Cox proportional hazard (PH) models (Figure A). Screened variables were further selected to construct a multivariate Cox PH model for risk prognosis utilizing a regularized LASSO Cox regression (Simon, et al. J Statistical Software 2011). Model performance was evaluated by area under the receiver operating characteristic curve (AUC) and C-index on the holdout population. Additional biomarker features were evaluated, including, BCL2 protein expression as determined by Ventana investigational-use only immunohistochemistry (IHC) assay, gene expression quantified by TruSeq® (Illumina) RNAseq, next generation sequencing-based genomic profiling using the FoundationOne HemeTM platform (F1H, Foundation Medicine Inc. [FMI]) and cell of origin (COO) by the Nanostring assay. Results: Total metabolic tumor volume (TMTV), total number of lesions, longest diameter of any lesion, number of kidney lesions, and number of liver lesions were selected as prognostic imaging factors for PFS in de novo DLBCL patients. Strong correlation was observed between corresponding volume and lesion number features, as expected, though collinearity appeared to otherwise be minimal (Figure B). Performance of the resulting model composed of these imaging variables alongside standard clinical features and treatment (AUC=0.66; C-Index=0.64) improved upon a model composed of IPI categories (AUC=0.60; C-Index=0.60). High risk, defined by log-hazard >0 was associated with reduced PFS (Figure C). High BCL2 expression by IHC (score >1) was prognostic for PFS independent of clinical and imaging features (HR, 2.02; CI: 1.36─2.98). High BCL2 was predictive of PFS in patients treated with G-CHOP over R-CHOP in de novo DLBCL patients (HR, 0.55; CI: 0.32─0.97) (Figure D). This trend held when adjusting for COO separate to imaging features. Mutational analysis using the FMI panel also indicated the additional prognostic value of BCL2 and TP53 single-nucleotide variants through selection by LASSO. Conclusions: Automated baseline imaging features and high BCL2 expression demonstrated prognostic value orthogonal to standard clinical features in predicting high-risk de novo DLBCL despite limitations imposed by sample size and multicollinearity among features. These findings support the integration of imaging, genomic and clinical factors in prognostic models to improve the identification of high-risk de novo DLBCL patients. Disclosures Jemaa: F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Tracy:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Bottos:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. de Crespigny:Genentech, Inc.: Current Employment; F Hoffmann-La Roche: Current equity holder in publicly-traded company. Bengtsson:Genentech, Inc.: Current Employment; F Hoffmann-La Roche: Current equity holder in publicly-traded company. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Paulson:Genentech, Inc.: Current Employment; F. Hoffmann-Roche: Current equity holder in private company, Current equity holder in publicly-traded company.

scholarly journals Healthcare Resource Utilization and Costs Associated with Obinutuzumab Plus Bendamustine Versus Rituximab Plus Bendamustine for First-Line Treatment of Follicular Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3004-3004
Author(s):  
Tu My To ◽  
Jamie T. Ta ◽  
Arpamas Seetasith ◽  
Rongrong Wang ◽  
Dominic Lai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Follicular Lymphoma ◽  
Real World ◽  
Index Date ◽  
Healthcare Resource ◽  
Phase Iii ◽  
Publicly Traded ◽  
First Line ◽  
The Past

Abstract Background: Obinutuzumab (G) is an anti-CD20 monoclonal antibody approved in the US for the first-line (1L) treatment of follicular lymphoma (FL), relapsed or refractory FL, and 1L chronic lymphocytic leukemia. G plus chemotherapy (G-chemo) demonstrated superior progression-free survival versus (vs) rituximab (R) plus chemotherapy (R-chemo) in patients with previously untreated FL in the Phase III, randomized GALLIUM study (NCT01332968; Marcus et al. N Engl J Med 2017). R-bendamustine (R-benda) and G-bendamustine (G-benda) are among the most commonly used chemoimmunotherapy (CIT) regimens for FL (Ta et al. J Clin Oncol 2021), and information on comparative healthcare resource use (HRU) and real-world costs associated with G-chemo vs R-chemo in previously untreated FL patients is limited. The aim of this study was to compare HRU and costs for G-benda and R-benda for the 1L treatment of FL using US claims databases. Methods: This was a retrospective cohort study using administrative claims data from the IQVIA PharMetrics® Plus and IBM® MarketScan Commercial and Medicare Supplemental databases. We identified patients aged ≥18 years, who had ≥1 inpatient claim or ≥2 outpatient claims with a diagnosis of FL from February 1, 2015 to September 30, 2020, and received 1L R-benda or G-benda between February 1, 2016 and March 31, 2020. The first claim for FL treatment was the index date. All patients had ≥12 months of pre- and ≥6 months of post-index continuous enrollment in medical and pharmacy benefits. Patients with other primary cancers, FL treatment, diffuse large B-cell lymphoma (DLBCL), or stem cell transplant during the pre-index period, or clinical trial participation or end-stage renal disease during the study period were excluded. Patients initiating 1L G-benda were propensity score matched 1:2 with patients initiating 1L R-benda based on age, sex, Charlson Comorbidity Index (CCI), region, and insurance type. All-cause and FL-related (i.e. claim with a FL diagnosis in any position) HRU and costs (2020 USD) per patient per month (PPPM) during the follow-up period were reported. Patients were followed until the earliest of initiation of second-line therapy, end of continuous follow-up, or end of data availability. Results: Overall, 270 patients were included; of these, 90 (33.3%) patients receiving G-benda were matched to 180 (66.7%) patients receiving R-benda for 1L treatment of FL. 45.2% were male, and the mean (standard deviation [SD]) age and CCI at index date were 59.1 (9.9) years and 1.7 (1.1), respectively. Median follow-up was 7.4 months. After matching, baseline characteristics were well-balanced between R-benda and G-benda patients (standardized mean difference [SMD] <0.1). Both all-cause and FL-related HRU were similar between R-benda and G-benda treated patients across all service categories (Figure 1). Total all-cause mean [SD] PPPM costs were also similar in G-benda vs R-benda patients ($21,378 [$15,242] vs $21,352 [$14,145]; p=0.77) (Figure 2). The majority of the total costs were FL-related and comparable across both patient groups: $17,353 ($11,370) for G-benda vs $17,724 ($13,530) for R-benda (p=0.71). Specifically, FL-treatment related costs PPPM were $17,070 ($14,064) for G-benda; this is comparable to $16,138 ($11,828) PPPM for R-benda (p=0.39). Conclusions: Our study found similar total costs of care and HRU among patients receiving 1L G-benda versus those receiving R-benda, providing real-world economic evidence that complements clinical trial data supporting the use of G-chemo for 1L treatment of FL. Figure 1 Figure 1. Disclosures To: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Ta: Genentech, Inc.: Current Employment. Seetasith: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Wang: The SPHERE Institute: Ended employment in the past 24 months; Aurinia Pharmaceuticals Inc.: Current equity holder in publicly-traded company; Novavax, Inc.: Current equity holder in publicly-traded company; Oragenics, Inc.: Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment; TG Therapeutics, Inc.: Current equity holder in publicly-traded company. Lai: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Shapouri: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company.

scholarly journals A Prognostic Model Incorporating Tumor Lesion Morphology and Texture Features Identifies High-Risk Patient Subpopulations in De Novo DLBCL and FL

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-28
Author(s):  
Xiao Li ◽  
Skander Jemaa ◽  
Richard AD Carano ◽  
Thomas Bengtsson ◽  
Joseph N Paulson ◽  
...  
Keyword(s):  
High Risk ◽  
Fdg Pet ◽  
De Novo ◽  
Risk Group ◽  
Low Risk ◽  
Phase Iii ◽  
Publicly Traded ◽  
Prognostic Performance ◽  
Pet Scans ◽  
Worse Prognosis

Background: Despite effective first-line (1L) treatment options for patients with NHL almost 40% of patients with diffuse large B cell lymphoma (DLBCL) will have a poor response or disease progression after 1L treatment. In follicular lymphoma (FL) 15-20% of patients experience early relapse, and almost 8% may develop transformation to more aggressive forms of the disease (such as DLBCL) after 1L treatment. More accurate identification of patients at high-risk for a poor prognosis with the standard of care could lead to improved outcomes. Although the International Prognostic Index (IPI) and its FL extension (FLIPI) are often used to stratify patients by prognosis, they have relatively modest sensitivity and specificity for predicting individualized risk. Radiomics is a promising approach to improve upon existing prognostic models because it provides a comprehensive quantification of tumor lesion morphology and texture derived from FDG-PET scans and may provide new and important information about disease biology and progression risk on an individual level. Methods: A collection of 107 radiomics features [pyradiomics v2.20] that describe shape, size or volume and texture of tumor lesions, including complex features that are believed to reflect the underlying biological tumor phenotype and microenvironment, were derived for n=1093 de novo DLBCL patients with available baseline FDG-PET scans from the Phase III GOYA study (NCT01287741) evaluating obinutuzumab plus CHOP chemotherapy (G-CHOP) versus rituximab plus CHOP chemotherapy (R-CHOP) (Vitolo, et al. J Clin Oncol 2017). The same set of features were also extracted from n=451 de novo FL patients with available baseline FDG-PET scans from the Phase III GALLIUM study (NCT01332968) comparing obinutuzumab plus chemotherapy with rituximab plus chemotherapy [Marcus, et al. N Engl J Med 2017]. To investigate the association between the derived radiomics features along with baseline clinical variables and progression-free survival (PFS), a Cox proportional hazard model with L1 regularization was trained and internally validated using the GOYA study. We used a nested Monte Carlo Cross Validation (nMCCV) strategy to train our model and provide high- and low-risk group predictions on held-out samples of data. This modeling strategy allows us to make a group prediction on all GOYA patients while reducing overfitting. To evaluate prognostic performance, we ported the final model trained using the GOYA study (called the Li prognostic model) to the fully independent GALLIUM study. Results: Using our nMCCV approach we identified 11 factors, with an inclusion probability of >50%, that are associated with PFS of DLBCL patients (Figure A). Included within the top features are several image-derived morphometric (i.e. metabolic tumor volume, surface area) and radiomics features (i.e. tumor elongation, NGTDM contrast, GLCM inverse variance). When stratifying patients on the predicted (via majority vote) low-risk vs high-risk groupings we found that our high-risk group had significantly worse prognosis vs the low-risk group (Figure B). In comparison, the high-risk group from the IPI model (defined as IPI > 2) had significantly worse prognosis vs the low-risk group, but the performance was slightly worse than our model (Figure C). PFS probability estimates at 2 and 5 years for predicted high-risk patients was 72.7% [70.0-76.6] and 59.8% [54.8-65.2] (vs 74% [70.0-78.2] and 60.4% [55.1-66.2] for the IPI model). After training and testing in the DLBCL population, we evaluated the prognostic performance of our model in an independent set of FL patients. We found that high-risk FL patients had a significantly worse prognosis than the low-risk group (Figure D). PFS probability estimates at 2 and 5 years for predicted high-risk patients was 77.4% [69.8-85.8] and 48.9% [39.5-60.5] (vs. 80% [0.748-0.856] and 58.3% [51.6-65.9] in the full group). Conclusions: Radiomics features are prognostic in DLBCL and provide a modest improvement in prognostic performance when combined with traditional IPI scores, clinical features, and lab values (vs IPI alone). Our prognostic signature, developed in DLBCL, has significant prognostic performance in an independent dataset of patients with FL. While these results are promising, our FL validation dataset was relatively small and further evidence is required to confirm our findings. Disclosures Li: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Jemaa:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Carano:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Bengtsson:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Paulson:F. Hoffmann-La Roche: Current equity holder in private company, Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Jansen:F. Hoffmann-La Roche: Current Employment; Molecular Health GmbH: Ended employment in the past 24 months; F. Hoffmann-La Roche, Abbvie, Alphabet, other (non-healthcare), indexed funds and ETFs: Current equity holder in publicly-traded company. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Hibar:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company.

Multi-institutional evaluation of the clinical outcomes and genomic correlates of African Americans with metastatic castration-sensitive prostate cancer (mCSPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 17-17
Author(s):  
Meredith MI Freeman ◽  
Ellen Jaeger ◽  
Jason Zhu ◽  
Audrey Phone ◽  
Roberto Nussenzveig ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Retrospective Analysis ◽  
Clinical Outcomes ◽  
De Novo ◽  
High Volume ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Treatment Intensification ◽  
Radium 223 ◽  
Incidence And Mortality

17 Background: Prostate cancer incidence and mortality is higher in African American (AA) as compared with non-AA men. The outcomes of mCSPC have significantly improved through treatment intensification yet, AA representation in those studies was suboptimal. We aimed to report the clinical, treatment outcomes and genomic data of AA men with mCSPC. Methods: Retrospective analysis of consecutive AA men with mCSPC at six Academic Institutions. The primary objective was to report the baseline characteristics and treatment patterns of mCSPC AA patients. The secondary objectives included the germline and somatic data and the clinical outcomes including PSA response, progression-free survival and subsequent treatments. Results: A total of 71 patients, median age 63 years (range, 41-84) with 58% Gleason 8-10, initial PSA of 69.8 ng/mL (0.02-7650), 59% with de-novo and 55% with high-volume (CHAARTED criteria; 20% visceral) disease, were included in this analysis. Twenty-two patients (31%) were treated with androgen deprivation therapy (ADT; 67% prior to year 2017), while 24%, 45% and 3% received docetaxel (median 6 cycles), abiraterone acetate and enzalutamide, respectively. Two patients received triplet therapy with ADT/docetaxel plus abiraterone or enzalutamide. Undetectable PSA was achieved in 35% after a median of 8.9 months (1.8-22.3). Among patients with mCSPC who received radiation therapy to prostate (n = 8), 89% had low volume disease. At time of cut off, thirty-two patients developed CRPC and the estimated median time to CRPC was 2.9 years (95% CI, 1.6-4.2). Subsequent therapies (n = 29) included abiraterone acetate (41%), enzalutamide (24%), bicalutamide (10%), radium-223 (7%), chemotherapy (7%), sipuleucel-T (3%) and others (7%). Five patients (8%) had pathogenic germline alterations (n = 2 BRCA1; n = 1 HOXB13, PALB2 and PMS2). Additionally, the most common somatic alterations among tested patients (n = 27) included CDK12, SPOP, TMPRSS2-ERG fusion, and TP53, all in 11% frequency. Of note, n = 2 BRCA1 and n = 1 high MSI/TMB. Conclusions: In one of the largest reported cohorts to our knowledge, mCSPC AA presented with a high number of de-novo and high-volume disease and might harbor a different germline and somatic genomic profile. The outcomes were comparable to contemporary phase III trials with treatment intensification, yet 31% were treated with ADT. Despite the known limitations associated with retrospective analysis, these data support prior observations where AA might have better initial PSA responses to ADT-based strategies compared with Caucasians, requiring further validation.

Tissue Microarray Is a Useful Tool in the Evaluation of Genes Implicated in Transformation of Follicular Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2267-2267 ◽  
Author(s):  
Abigail Lee ◽  
Andrew Davies ◽  
Andrew Clear ◽  
Maria Calaminici ◽  
Janet Matthews ◽  
...  
Keyword(s):  
Gene Expression ◽  
Follicular Lymphoma ◽  
Tissue Microarray ◽  
Molecular Mechanisms ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Follicular Dendritic Cell ◽  
Response To Therapy ◽  
Aurora Kinase B ◽  
General Response

Abstract A subset of patients (pts.) with follicular lymphoma (FL) will transform to a more aggressive histological sub-type, most typically diffuse large B-cell lymphoma (DLBCL). In general response to therapy is poor and survival short. Paired analysis of samples pre- and post transformation suggest that the molecular mechanisms underlying transformation (Tx) are heterogeneous. In order to independently validate recurring changes in gene/protein expression at transformation (GC phenotype of TxDLBCL, Davies et al., 2002; loss of follicular dendritic Cell (FDC) markers, Shiozawa et al., 2003) a Tx-tissue microarray (Tx-TMA) was created comprising serial samples from 35 pts. (median age 54yrs (22–81) at the time of transformation). In these pts. transformation occurred a median of 3.1years from diagnosis (range 0–15.4) and for each pt. ‘set’ at least 1 pre-Tx FL sample (1–3; n=56), and 1 (1–4; n=44) post transformation sample were represented on the array. To ensure that the Tx-TMA cores accurately represented the corresponding full tissue sections a panel of routine immunohistochemical (IHC) diagnostic markers (n=9) were scored. The concordance between Tx-TMA and full sections (n=10) was >90%. The Tx-TMA was then used to investigate the phenotype of transformed DLBCL, according to the germinal centre (GC)/non-GC like model of de novo DLBCL. Using CD10, BCL6 and MUM1 expression to discriminate between the two subclasses of DLBCL the methodology was first validated on a de novo DLBCL TMA (n=31; 20/31 (65%) non-GC, 11/31 (35%) GC phenotype; 5-yr survival for non-GC pts. 51% and for GC pts., 73%). IHC confirmed the results of gene expression profiling indicating that in 31/35 (89%) pts. transformed DLBCL was of GC phenotype (28/35 (80%) CD10+ and 3/35 (9%) CD10-, BCL6+, MUM1-). Of the remainder, 4/35 were CD10-, BCL6+, of which 3/4 were MUM1+ (3/35 (9%) non-GC phenotype; 1/4 MUM1 was not assessable). Similarly the Tx-TMA confirmed loss of FDC markers (CD21 and CD23) on transformation. Samples from 28 pts were evaluable for CD21 and CD23 IHC expression. In 71% (20/28) of pts. the FDC meshwork was lost or became more sparse on transformation (CD21 loss 15/28 (54%); CD23 loss 17/28 (61%)). The most discriminating changes in gene expression on transformation are now being assessed by IHC. Aurora kinase B (ARKB) is an attractive therapeutic target given that disruption of ARK function results in the induction of apoptosis in RL, a t(14:18) positive DLBCL cell line (Harrington et al. 2004). The observed elevation in ARKB transcription on transformation was confirmed by IHC in this series. The Tx-TMA showed ARKB expression increased on Tx in 13/33 (40%) pts., potentially defining a subset of pts. who might be considered for ARKB directed therapies. Expression of ARKB was low throughout in 18/33 (55%) pts and decreased in 2/33 (6%) pts.; difference in ARKB expression was not significantly associated with survival. These preliminary studies suggest that the availability of TMA of serial biopsies from pts. with transformed FL will provide a powerful means of assessing the relevance of gene expression, both within the tumour and the microenvironment while facilitating the selection of patients most likely to benefit from directed therapeutic approaches.

Prognostic value of the 3q27 and 18q21 translocations for diffuse large B-cell lymphoma and follicular lymphoma in the rituximab era.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. e18513-e18513
Author(s):  
R. Watanabe ◽  
N. Tomita ◽  
C. Matsumoto ◽  
Y. Hattori ◽  
S. Matsuura ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Prognostic Value ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Transformation of Follicular Lymphoma to Double Hit B-Cell Lymphoma Causing Hypercalcemia in a 69-Year-Old Female: A Case Report and Review of the Literature

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Sakshi Kapur ◽  
Miles B. Levin
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
De Novo ◽  
Cell Lymphoma ◽  
Care Center ◽  
Tertiary Care ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
Severe Hypercalcemia ◽  
Double Hit

Double hit B-cell lymphomas are rare tumors that are defined by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, mainly a t(14;18)(q32;q21) involving BCL2. These tumors mostly occur in adults and carry a very poor prognosis. Double hit lymphomas can occur de novo, or arise from transformation of follicular lymphoma. We report a case of a 69-year-old female with abdominal distention and progressively worsening weakness over six months. Patient presented with severe hypercalcemia and multiple intra-abdominal/pelvic masses. Histopathology results of the abdominal mass were compatible with a double hit B-cell lymphoma. However, bone marrow biopsy results showed a low grade follicular lymphoma, thus suggesting peripheral transformation of follicular lymphoma to double hit B-cell lymphoma. Patient was transferred to a tertiary care center and was started on combination chemotherapy (EPOCH: doxorubicin, etoposide, vincristine, cyclophosphamide, and prednisone). Our paper highlights not only transformation of follicular lymphoma to double hit B-cell lymphoma and the challenges encountered in diagnosing and treating these aggressive tumors, but also the association of new onset/worsening hypercalcemia in such patients.

Sign in / Sign up

Export Citation Format

Share Document