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This study's focus is the association of end-of-therapy (EOT) PET results with progression-free (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma receiving first-line chemoimmunotherapy. We develop a Bayesian hierarchical model for predicting PFS and OS from EOT PET-complete response (PET-CR) using a literature-based meta-analysis of 20 treatment arms and a substudy of 4 treatment arms in 3 clinical trials for which we have patient-level data. The PET-CR rate in our substudy was 72%. The modeled estimates for hazard ratio (PET-CR/non-PET-CR) were 0.13 for PFS (95% CI 0.10, 0.16) and 0.10 for OS (CI 0.07, 0.12). Hazard ratios varied little by patient subtype and were confirmed by the overall meta-analysis. We link these findings to designing future clinical trials and show how our model can be used in adapting the sample size of a trial to accumulating results regarding treatment benefits on PET-CR and a survival endpoint.

Purpose:Natural killer (NK) cells are key effector cells for anti-CD20 monoclonal antibodies (mAb), such as obinutuzumab and rituximab. We assessed whether low pretreatment NK-cell count (NKCC) in peripheral blood or tumor tissue was associated with worse outcome in patients receiving antibody-based therapy.Patients and Methods:Baseline peripheral blood NKCC was assessed by flow cytometry (CD3−CD56+ and/or CD16+ cells) in 1,064 of 1,202 patients with follicular lymphoma treated with obinutuzumab or rituximab plus chemotherapy in the phase III GALLIUM trial (NCT01332968) and 1,287 of 1,418 patients with diffuse large B-cell lymphoma (DLBCL) treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP or R-CHOP) in the phase III GOYA trial (NCT01287741). The prognostic value of tumor NK-cell gene expression, as assessed by whole-transcriptome gene expression using TruSeq RNA sequencing, was also analyzed. The association of baseline variables, such as treatment arm, was evaluated using multivariate Cox regression models using a stepwise approach.Results:In this exploratory analysis, low baseline peripheral blood NKCC was associated with shorter progression-free survival (PFS) in both follicular lymphoma [hazard ratio (HR), 1.48; 95% confidence interval (CI), 1.02–2.14; P = 0.04] and DLBCL (HR, 1.36; 95% CI, 1.01–1.83; P = 0.04), and overall survival in follicular lymphoma (HR, 2.20; 95% CI, 1.26–3.86; P = 0.0058). Low tumor NK-cell gene expression was associated with shorter PFS in G-CHOP–treated patients with DLBCL (HR, 1.95; 95% CI, 1.22–3.15; P < 0.01).Conclusions:These findings indicate that the number of NK cells in peripheral blood may affect the outcome of patients with B-cell non-Hodgkin lymphoma receiving anti-CD20–based immunochemotherapy.

Baseline patient and disease characteristics in FL and DLBCL patients with NKCCs available (analysis population) and in the GALLIUM and GOYA ITT populations.

Association between baseline peripheral blood NKCC and tumor NK cell gene expression in FL (A) and DLBCL (B)

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.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.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.In this large population of patients with DLBCL, pretreatment PROs provided prognostic information for OS and PFS beyond the well-established IPI.

Complete metabolic response (CMR) on positron emission tomography-computed tomography (PET-CT) was the sole independent predictor of overall survival in the PET sub-study of the phase III GALLIUM trial (NCT01332968) in first-line treatment of high tumour burden follicular lymphoma (FL). The aim of this analysis was to investigate further the outcome of patients not achieving CMR. Methods: Two international experts re-reviewed PET-CT scans from patients failing to achieve CMR assessed by the Independent Review Committee (IRC) blinded otherwise to IRC results. Metabolic response category and Deauville score (DS) were assigned. Progression-free survival (PFS) was investigator assessed with contrast-enhanced CT (ceCT). Kaplan–Meier methodology was used to estimate landmark PFS and time-to-next treatment (TTNT) from end-of-induction by DS. Patients who experienced CT-based progressive disease at end-of-induction were excluded. Results: Fifty-four patients were reviewed. Six had CMR, 37 partial metabolic response, two no metabolic response and nine progressive metabolic disease. Patients were reassigned to CMR because fluorodeoxyglucose uptake was considered as i) inflammatory (n = 2), ii) incidental neoplasia (n = 2) or iii) where fluorodeoxyglucose uptake was visually close to liver uptake but quantitatively lower (n = 2). There was a trend for shorter PFS and TTNT for patients with DS-5 than DS-4. High-grade mesenteric uptake at end-of-induction was common, occurring in 20 patients with non-CMR, fourteen of whom achieved CMR at all other sites. Only 3/14 (21%) patients with mesenteric uptake as the only site of disease experienced progression or death within 24 months (PFS24) whereas 4/6 patients (67%) with mesenteric and additional sites of fluorodeoxyglucose-avid disease had a PFS24 event. All patients with early progression had measurable disease on ceCT at fluorodeoxyglucose-avid sites at end-of-induction. Conclusion: After induction immunochemotherapy, CMR was assigned after reassessment in some patients, where increased fluorodeoxyglucose uptake was considered due to inflammation/incidental neoplasia rather than lymphoma. Quantitative assessment to confirm the visual impression of residual uptake in lesions is suggested. Isolated mesenteric fluorodeoxyglucose uptake is likely a common false-positive finding at end-of-induction and does not warrant changes in clinical management nor disease surveillance unless there is measurable disease on ceCT or clinical suspicion of active disease.

Aggressive large B-cell lymphoma (LBCL) has variable outcomes. Current prognostic tools use factors for risk stratification that inadequately identify patients at high risk of refractory disease or relapse before initial treatment. A model associating 2 risk factors, total metabolic tumor volume (TMTV) >220 cm3 (determined by fluorine-18 fluorodeoxyglucose positron emission tomography coupled with computed tomography) and performance status (PS) ≥2, identified as prognostic in 301 older patients in the REMARC trial (#NCT01122472), was validated in 2174 patients of all ages treated in 2 clinical trials, PETAL (Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas; N = 510) and GOYA (N = 1315), and in real-world clinics (N = 349) across Europe and the United States. Three risk categories, low (no factors), intermediate (1 risk factor), and high (2 risk factors), significantly discriminated outcome in most of the series. Patients with 2 risk factors had worse outcomes than patients with no risk factors in the PETAL, GOYA, and real-world series. Patients with intermediate risk also had significantly worse outcomes than patients with no risk factors. The TMTV/Eastern Cooperative Oncology Group-PS combination outperformed the International Prognostic Index with a positive C-index for progression-free survival and overall survival in most series. The combination of high TMTV > 220 cm3 and ECOG-PS ≥ 2 is a simple clinical model to identify aggressive LBCL risk categories before treatment. This combination addresses the unmet need to better predict before treatment initiation for aggressive LBCL the patients likely to benefit the most or not at all from therapy.

Follicular lymphoma (FL) is one of the most common subtypes of non-Hodgkin lymphoma worldwide. Improved survival outcomes with rituximab-based therapy in clinical trials led to the establishment of rituximab-based immunochemotherapy as standard of care for first-line (1L) treatment of FL. In the GALLIUM trial, obinutuzumab-based immunochemotherapy demonstrated improved progression-free survival (PFS), prolonged time-to-next antilymphoma treatment (TTNT) and comparable overall survival (OS) compared with rituximab-based immunochemotherapy as 1L treatment for FL. Using GALLIUM as an example, this article aims to explain how improved outcomes in 1L treatment of FL have changed the landscape for the design and interpretation of future trials. As approved therapies for 1L FL already achieve good responses, it is becoming more difficult to design trials that demonstrate further treatment benefits with the currently accepted primary endpoints. New endpoints are needed to reflect the long remission times, low relapse rates, and impact of subsequent therapies in FL. PFS is used as a primary efficacy endpoint in registrational clinical trials for indolent malignancies like FL, where improvement in OS is not always observed due to the large number of patients and long study duration required to demonstrate a clear survival benefit. However, there are limitations to using PFS as the primary endpoint. Other potential endpoints, including TTNT, progression of disease within 2 years, response rate, and minimal residual disease status are explored.

Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs >70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (>70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age >70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin 70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients >70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P < .001). Age >70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients >70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs.

International audience; Progression-free survival (PFS) has been the regulatory primary end-point for recent phase III trials in first-line follicular lymphoma (FL), but requires prolonged follow-up. Complete response (CR) at 30 months after initiation of induction treatment was validated as surrogate end-point for PFS. Our objective was to further evaluate surrogacy of CR measured by [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at the end of induction (EoI). Individual patient data were analysed from 1505 patients from five randomized trials. Trial-level surrogacy examining the association between treatment effects on EoI-PET-CR and PFS was evaluated using linear regression () and bivariate Copula () models. Although EoI-PET-CR strongly predicted PFS at a prognostic level, the trial-level assessment did not show strong correlation (, confidence interval [CI]: 0.20–0.88;, CI: 0.0–0.82). The high uncertainty in estimation was possibly due to the small number of trials and the population of patients with available PET data. Maintenance therapy affecting PFS beyond induction treatment, but not EoI-PET-CR end-point, may have distorted the association between treatment effects. However, there will probably be a number of additional trials approaching completion with available PET response data. Refined evaluation of PET-CR based surrogate end-points is still warranted.

Leveraging the Follicular Lymphoma Analysis of Surrogacy Hypothesis database of individual patient data from first-line clinical trials, we studied the clinical course of follicular lymphoma (FL) and investigated clinical factors associated with FL outcomes.We examined 2428 patients from 8 randomized trials using multistate survival models with 4 states: induction treatment, progression, death from FL, and death from other causes. We utilized Aalen-Johansen estimator and Cox models to assess the likelihood of FL outcomes and quantify predictors' effects.Two-year progression, FL-related death, and death from other causes estimates were 26.5%, 3.4% and 1.4%, respectively. FL-associated deaths were the primary cause of mortality within 10 years of follow-up. Male sex (hazard ratio: 1.25; 95% confidence interval: 1.05-1.47),4 involved nodal areas (1.51; 1.23-1.86), elevated LDH (1.20; 1.01-1.43), low hemoglobin (1.44; 1.15-1.81), and elevated β-2 levels (1.23; 1.02-1.47) increased risk of progression. CD20-targeting agents reduced risks for progression (0.29; 0.22-0.39), death from FL (0.05; 0.01-0.20), and death from other causes without progression (0.13; 0.05-0.33) and following progression (0.52; 0.30-0.92). Estimated 2-year progression rates were 22.3% and 43.5% with or without CD20-targeting agents, respectively. Two-year FL-associated mortality rate was 8.3% among patients without CD20-targeting agents, 5.4% with B-symptoms, 4.9% with elevated LDH, and 9.1% with low hemoglobin.This study identified independent contributions of baseline clinical factors to distinct outcomes for patients with FL following first-line therapy on a clinical trial. Similar analytical approaches are needed to increase understanding of factors that influence FL outcomes in other settings.

18F-Fluorodeoxyglucose-positron emission tomography (FDG-PET) is commonly used in clinical practice and clinical drug development to identify and quantify metabolically active tumors. Manual or computer-assisted tumor segmentation in FDG-PET images is a common way to assess tumor burden, such approaches are both labor intensive and may suffer from high inter-reader variability. We propose an end-to-end method leveraging 2D and 3D convolutional neural networks to rapidly identify and segment tumors and to extract metabolic information in eyes to thighs (whole body) FDG-PET/CT scans. The developed architecture is computationally efficient and devised to accommodate the size of whole-body scans, the extreme imbalance between tumor burden and the volume of healthy tissue, and the heterogeneous nature of the input images. Our dataset consists of a total of 3664 eyes to thighs FDG-PET/CT scans, from multi-site clinical trials in patients with non-Hodgkin’s lymphoma (NHL) and advanced non-small cell lung cancer (NSCLC). Tumors were segmented and reviewed by board-certified radiologists. We report a mean 3D Dice score of 88.6% on an NHL hold-out set of 1124 scans and a 93% sensitivity on 274 NSCLC hold-out scans. The method is a potential tool for radiologists to rapidly assess eyes to thighs FDG-avid tumor burden.

The utility of posttreatment bone marrow biopsy (BMB) histology to confirm complete response (CR) in lymphoma clinical trials is in question. We retrospectively evaluated the impact of BMB on response assessment in immunochemotherapy-treated patients with previously untreated follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the phase 3 Study of Obinutuzumab (RO5072759) Plus Chemotherapy in Comparison With Rituximab Plus Chemotherapy Followed by Obinutuzumab or Rituximab Maintenance in Patients With Untreated Advanced Indolent Non-Hodgkin's Lymphoma (GALLIUM; NCT01332968) and A Study of Obinutuzumab in Combination With CHOP Chemotherapy Versus Rituximab With CHOP in Participants With CD20-Positive Diffuse Large B-Cell Lymphoma (GOYA; NCT01287741) trials, respectively. Baseline BMB was performed in all patients, with repeat BMBs in patients with a CR by computed tomography (CT) at end of induction (EOI) and a positive BMB at baseline, to confirm response. Positron emission tomography imaging was also used in some patients to assess EOI response (Lugano 2014 criteria). Among patients with an EOI CR by CT in GALLIUM and GOYA, 2.8% and 4.1%, respectively, had a BMB-altered response. These results suggest that postinduction BMB histology has minimal impact on radiographically (CT)-defined responses in both FL and DLBCL patients. In GALLIUM and GOYA, respectively, 4.7% of FL patients and 7.1% of DLBCL patients had a repeat BMB result that altered response assessment when applying Lugano 2014 criteria, indicating that bone marrow evaluation appears to add little value to response assessment in FL; however, its evaluation may still have merit in DLBCL.

A minority of patients with follicular lymphoma (FL) undergo histological transformation (HT). This retrospective analysis of 549 patients from the phase 3 GALLIUM study (NCT01332968) assessed the relationship between maximum standardized uptake value (SUVmax) at baseline on positron emission tomography (PET) and HT risk. Previously untreated patients with high tumor burden grade 1-3a FL received obinutuzumab- or rituximab-based chemotherapy induction. The relationship between baseline SUVmax (bSUVmax) and HT risk was assessed using cutoff values for SUVmax >10 and >20. Overall, 15 of 549 (2.7%) patients with baseline PET scans experienced biopsy-confirmed HT (median follow-up, 59 months). More than 65% of patients had bSUVmax > 10, with 3.3% of these experiencing HT. Only 1 of 74 (1.4%) patients with bSUVmax > 20 underwent HT. Median bSUVmax in patients with HT vs without HT was 12.4 (range, 8.1-28.0) vs 11.8 (range, 3.1-64.4), respectively; median bSUVrange (the difference between bSUVmax of the most and least 18F-fluorodeoxyglucose–avid lymphoma sites) was 8.0 (range, 1.1-23.9) vs 7.1 (range, 0.0-59.8), respectively. There was no temporal relationship between bSUVmax and HT. Neither bSUVmax nor bSUVrange predicted HT in GALLIUM, suggesting that there may be little benefit in rebiopsy of lesions to exclude HT based on SUVmax alone before initiating therapy in patients with high tumor burden FL.

Observational studies and stand-alone trials indicate that patients with follicular lymphoma (FL) who experience disease progression within 24 months of front-line chemoimmunotherapy (POD24), have poor outcomes. We performed a pooled analysis of 13 randomized clinical trials of patients with FL in the pre- and postrituximab eras to identify clinical factors that predict POD24. Logistic regression models evaluated the association between clinical factors and POD24. Cox regression evaluated the association between POD24 as a time-dependent factor and subsequent overall survival (OS). A landmark analysis evaluated the association of POD24 with OS for the subset of patients who were alive at 24 months after trial registration. Patients without progression at 24 months at baseline had favorable performance status (PS), limited-stage (I/II) disease, low-risk FL International Prognostic Index (FLIPI) score, normal baseline hemoglobin, and normal baseline β2 microglobulin (B2M) level. In a multivariable logistic regression model, male sex (odds ratio [OR], 1.30), PS ≥2 (OR, 1.63), B2M (≥3 mg/L; OR, 1.43), and high-risk FLIPI score (3-5; OR, 3.14) were associated with increased risk of progression before 24 months. In the time-dependent Cox model and the 24-month landmark analysis, POD24 was associated with poor subsequent OS (hazard ratio, 4.85 and 3.06, respectively). This is the largest pooled analysis of clinical trials data validating POD24 as a robust indicator of poor FL survival and identified clinical predictors of early death and progression that can aid in building comprehensive prognostic models incorporating clinical and molecular predictors of POD24.

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.

Summary: Obesity is associated with increased risk for fragility fractures. However, the cellular mechanisms are unknown. Using a translational approach combining RNA sequencing and cellular analyses, we investigated bone marrow stromal stem cells (BM-MSCs) of 54 men divided into lean, overweight, and obese groups on the basis of BMI. Compared with BM-MSCs obtained from lean, obese BM-MSCs exhibited a shift of molecular phenotype toward committed adipocytic progenitors and increased expression of metabolic genes involved in glycolytic and oxidoreductase activity. Interestingly, compared with paired samples of peripheral adipose tissue-derived stromal cells (AT-MSCs), insulin signaling of obese BM-MSCs was enhanced and accompanied by increased abundance of insulin receptor positive (IR+) and leptin receptor positive (LEPR+) cells in BM-MSC cultures. Their hyper-activated metabolic state was accompanied by an accelerated senescence phenotype. Our data provide a plausible explanation for the bone fragility in obesity caused by enhanced insulin signaling leading to accelerated metabolic senescence of BM-MSCs. : Tencerova et al. show that in human obesity, BM-MSCs exhibit a hypermetabolic state defined by upregulation of insulin signaling with enhanced adipogenesis and increased intracellular reactive oxygen species (ROS), leading to a senescence bone microenvironment contributing to bone fragility. Moreover, increased abundance of IR+ and LEPR+ BM-MSCs is characteristic of this phenotype, with an activated metabolic rate in obese subjects. Keywords: obesity, skeletal fragility, bone marrow skeletal stem cells, adipose-derived stem cells, differentiation potential, adipogenesis, insulin signaling

Risk of hepatitis B virus (HBV) reactivation was assessed in B-cell non-Hodgkin lymphoma (NHL) patients with resolved HBV infection (hepatitis B surface antigen negative, hepatitis B core antibody positive) who received obinutuzumab- or rituximab-containing immunochemotherapy in the phase 3 GOYA and GALLIUM studies. HBV DNA monitoring was undertaken monthly to 1 year after the last dose of study drug. In case of HBV reactivation (confirmed, HBV DNA ≥29 IU/mL), immunochemotherapy was withheld and nucleos(t)ide analog treatment (preemptive NAT) started. Immunochemotherapy was restarted if HBV DNA became undetectable or reactivation was not confirmed, and discontinued if HBV DNA exceeded 100 IU/mL on NAT. Prophylactic NAT was allowed by investigator discretion. Among 326 patients with resolved HBV infection, 27 (8.2%) had HBV reactivation, occurring a median of 125 days (interquartile range, 85-331 days) after the first dose. In 232 patients without prophylactic NAT, 25 (10.8%) had HBV reactivation; all received preemptive NAT. Ninety-four patients received prophylactic NAT; 2 (2.1%) had HBV reactivation. No patients developed HBV-related hepatitis. On multivariate Cox analysis, detectable HBV DNA at baseline was strongly associated with an increased risk of reactivation (adjusted hazard ratio [HR], 18.22; 95% confidence interval [CI], 6.04-54.93; P < .0001). Prophylactic NAT was strongly associated with a reduced risk (adjusted HR, 0.09; 95% CI, 0.02-0.41; P = .0018). HBV DNA monitoring–guided preemptive NAT was effective in preventing HBV-related hepatitis during anti–CD20-containing immunochemotherapy in B-cell NHL patients with resolved HBV infection. Antiviral prophylaxis was also effective and may be appropriate for high-risk patients. These trials were registered at www.clinicaltrials.gov as NCT01287741 (GOYA) and NCT01332968 (GALLIUM).

GOYA was a randomized phase 3 study comparing obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs standard-of-care rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This retrospective analysis of GOYA aimed to assess the association between progression-free survival (PFS) and overall survival (OS) with positron emission tomography (PET)–based complete response (CR) status. Overall, 1418 patients were randomly assigned to receive 8 21-day cycles of obinutuzumab (n = 706) or rituximab (n = 712) plus 6 or 8 cycles of CHOP. Patients received a mandatory fluoro-2-deoxy-d-glucose–PET/computed tomography scan at baseline and end of treatment. After a median follow-up of 29 months, the numbers of independent review committee–assessed PFS and OS events in the entire cohort were 416 (29.3%) and 252 (17.8%), respectively. End-of-treatment PET CR was highly prognostic for PFS and OS according to Lugano 2014 criteria (PFS: hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.19-0.38; P < .0001; OS: HR, 0.12; 95% CI, 0.08-0.17; P < .0001), irrespective of international prognostic index score and cell of origin. In conclusion, the results from this prospectively acquired large cohort corroborated previously published data from smaller sample sizes showing that end-of-treatment PET CR is an independent predictor of PFS and OS and a promising prognostic marker in DLBCL. Long-term survival analysis confirmed the robustness of these data over time. Additional meta-analyses including other prospective studies are necessary to support the substitution of PET CR for PFS as an effective and practical surrogate end point. This trial was registered at www.clinicaltrials.gov as #NCT01287741.

Global collaboration, or the ability to collaborate with people different from ourselves or even across species, becomes increasingly important in our interconnected world to engage constructively with and across difference. As we face more complex challenges, both locally and globally, the need for the creativity and innovation made possible by diverse perspectives is only amplified. Through five stories from our work as consultants and practitioners helping organizations to collaborate, we explore the role of global leadership in collaboration during times of crisis in various sectors. We began by asking ourselves a series of questions about global collaboration that could also serve as future research directions for scholars. We argue that new forms of leadership are required in the global context where both tasks and relationship domains are characterized by high complexity. We conclude by providing insights and recommendations for global leaders to address those complexities through collaboration and help their organizations learn from their experiences in crises and beyond.

The introduction of anti-CD20 monoclonal antibody therapy with rituximab in the 1990s greatly improved outcomes for patients with B-cell malignancies. Disease resistance or relapse after successful initial therapy and declining efficacy of subsequent rounds of treatment were the basis for the development of alternative anti-CD20-based antibody therapies. The novel anti-CD20 antibodies of atumumab, ublituximab, and obinutuzumab were developed to be differentiated via structural and mechanistic features over rituximab. We provide an overview of preclinical and clinical data, and demonstrate ways in which the pharmacodynamic properties of these novel agents translate into clinical benefit for patients. Of the novel anti-CD20 antibodies, only obinutuzumab has shown consistently improved efficacy over rituximab in randomized pivotal trials in indolent non-Hodgkin lymphoma and chronic lymphocytic leukemia. The Phase 3 GALLIUM trial demonstrated significant improvements in progression-free survival with obinutuzumab-based immunochemotherapy over rituximab-based immunochemotherapy. Novel combinations of obinutuzumab, including with chemotherapy-free options are being explored, such as with the newly approved combinations of obinutuzumab with venetoclax, ibrutinib, or acalabrutinib. The biggest unmet need remains in the treatment of diffuse large B-cell lymphoma; emerging options in this field include the use of CAR-T cells and T-cell bispecific antibodies.

Diffuse large B-cell lymphoma represents a biologically and clinically heterogeneous diagnostic category with well-defined cell-of-origin subtypes. Using data from the GOYA study (NCT01287741), we characterized the mutational profile of diffuse large B-cell lymphoma and evaluated the prognostic impact of somatic mutations in relation to cell-of-origin. Targeted DNA next-generation sequencing was performed in 499 formalin-fixed paraffin-embedded tissue biopsies from previously untreated patients. Prevalence of genetic alterations/mutations was examined. Multivariate Cox regression was used to evaluate the prognostic effect of individual genomic alterations. Of 465 genes analyzed, 59 were identified with mutations occurring in at least 10 of 499 patients (≥2% prevalence); 334 additional genes had mutations occurring in ≥1 patient. Single nucleotide variants were the most common mutation type. On multivariate analysis, BCL2 alterations were most strongly associated with shorter progression-free survival (multivariate hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2). BCL2 alterations were detected in 102 of 499 patients; 92 had BCL2 translocations, 90% of whom had germinal center B-cell-like diffuse large B-cell lymphoma. BCL2 alterations were also significantly correlated with BCL2 gene and protein expression levels. Validation of published mutational subsets revealed consistent patterns of co-occurrence, but no consistent prognostic differences between subsets. Our data confirm the molecular heterogeneity of diffuse large B-cell lymphoma, with potential treatment targets occurring in distinct cell-of-origin subtypes. clinicaltrials.gov identifier: NCT01287741.

Patients with advanced‐stage follicular lymphoma (FL) who progress early after receiving first‐line therapy have poor overall survival (OS). Currently applied clinical prognostic models such as FL International Prognostic Index [FLIPI], FLIPI‐2 and PRIMA‐Prognostic Index [PRIMA‐PI] have suboptimal sensitivity and specificity to predict this poor prognosis subgroup. The primary objective was to develop a novel prognostic model, the FL Evaluation Index (FLEX) score, to identify high‐risk patients and compare its performance with FLIPI, FLIPI‐2 and PRIMA‐PI. Progression‐free survival (PFS) after first‐line immunochemotherapy was the key endpoint, while OS and progression of disease within 24 months (POD24) were also assessed. The model, which includes nine clinical variables, was developed using a cohort of patients with previously untreated advanced‐stage FL from the phase 3 GALLIUM trial ({"type":"clinical-trial","attrs":{"text":"NCT01332968","term_id":"NCT01332968"}}NCT01332968). The performance of the model was validated using data from the SABRINA trial ({"type":"clinical-trial","attrs":{"text":"NCT01200758","term_id":"NCT01200758"}}NCT01200758). In GALLIUM (n = 1004; 127 with and 877 without POD24), FLEX increased the intergroup (low‐risk/high‐risk) difference in 2‐year and 3‐year PFS rates and demonstrated superior intergroup differences in 2‐year and 3‐year OS rates compared with FLIPI, FLIPI‐2 and PRIMA‐PI. Sensitivity for a high‐risk score to predict POD24 was 60% using FLEX compared with 53% for FLIPI and FLIPI‐2, and 69% for PRIMA‐PI, while specificity was 68% for FLEX compared with 58% for FLIPI, 59% for FLIPI‐2 and 48% for PRIMA‐PI. The prognostic value of FLEX in SABRINA was similar to FLIPI. Therefore, FLEX appears to perform better than existing prognostic models in previously untreated FL, in particular for the newer treatment regimens.

Obesity represents a risk factor for development of insulin resistance and type 2 diabetes. In addition, it has been associated with increased adipocyte formation in the bone marrow (BM) along with increased risk for bone fragility fractures. However, little is known on the cellular mechanisms that link obesity, BM adiposity, and bone fragility. Thus, in an obesity intervention study in C57BL/6J mice fed with a high-fat diet (HFD) for 12 weeks, we investigated the molecular and cellular phenotype of bone marrow adipose tissue (BMAT), BM progenitor cells, and BM microenvironment in comparison to peripheral adipose tissue (AT). HFD decreased trabecular bone mass by 29%, cortical thickness by 5%, and increased BM adiposity by 184%. In contrast to peripheral AT, BMAT did not exhibit pro-inflammatory phenotype. BM progenitor cells isolated from HFD mice exhibited decreased mRNA levels of inflammatory genes (Tnfα, IL1β, Lcn2) and did not manifest an insulin resistant phenotype evidenced by normal levels of pAKT after insulin stimulation as well as normal levels of insulin signaling genes. In addition, BM progenitor cells manifested enhanced adipocyte differentiation in HFD condition. Thus, our data demonstrate that BMAT expansion in response to HFD exerts a deleterious effect on the skeleton. Continuous recruitment of progenitor cells to adipogenesis leads to progenitor cell exhaustion, decreased recruitment to osteoblastic cells, and decreased bone formation. In addition, the absence of insulin resistance and inflammation in the BM suggest that BMAT buffers extra energy in the form of triglycerides and thus plays a role in whole-body energy homeostasis. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Background: Cytokine release syndrome (CRS) is a potentially life-threatening toxicity caused by immune activation. CRS can be triggered non-specifically by T-cell engaging therapies. Risk factors for CRS are expected to be disease-specific and prediction of an individual patient's CRS risk is not currently possible. Glofitamab is a T-cell engaging bispecific antibody targeting CD20 and CD3 with a novel 2:1 format that has shown promising efficacy with a manageable safety profile in NP30179 (NCT03075696), an ongoing Phase I/II dose finding study evaluating glofitamab in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). While CRS is observed with glofitamab, cases typically occur with grade 1/2 severity (per ASTCT, Lee et al 2019) with most occurrences confined to the first cycle of therapy. Data from NP30179 were used to develop a model to predict the occurrence of Grade ≥ 2 CRS after the first glofitamab dose to enable stratification of patients according to risk of CRS with possible future implications for intensity of monitoring for those at low risk. Methods: Glofitamab was administered intravenously over 4 to 8 hours as a fixed or step-up dosing regimen, as previously described (Hutchings, et al JCO 2021). Non-overlapping training and validation data sets were defined; the training data set included patients with aggressive (n=165) or indolent NHL (n=31) who received a first dose of 0.6-25 mg, and the model validation data set (n=51; 35 aggressive NHL) included patients who received a 2.5mg first dose. The primary outcome was defined as Grade ≥2 CRS in the week after the first glofitamab dose, and included 65 events (n=58 training, n=7 validation). In the training data set we evaluated the association between the dose, putative risk factors (including demographics, medical history, disease characteristic variables, baseline laboratory values) and the occurrence of CRS. Univariate and multivariate models were applied in a stratified cross-validation setting to assess the most predictive and stable combination of risk factors. Baseline and on-treatment cytokine levels were analyzed via ELISA in a subset of patients (n=89). Results: The temporal pattern of CRS occurrences revealed that the vast majority of first CRS events occur after the first dose of glofitamab. To predict the occurrence of Grade ≥ 2 CRS after the first glofitamab dose, a multivariate model was developed to include glofitamab first dose and a combined risk score, termed the "CRS risk score" (CRSRS), which is the weighted sum of binarized risk factor values at baseline (Figure). The predictive ability was tested in the validation data set in which the incidence of Grade ≥ 2 CRS was 14% (7/51). A low risk group (CRSRS Induction of cytokines, including IL-6 and TNFα, was observed upon treatment with glofitamab and peak magnitude of cytokine induction was associated with CRS incidence and severity. Cytokine induction was evident by end of glofitamab infusion and peak levels of TNFα were observed by mid-infusion. CRSRS and TNFα induction were evaluated together for the subset of patients with cytokine data available to determine whether risk classification incorporating both metrics could refine the risk stratification of patients. Early TNFα changes were layered on top of CRSRS (at the cutoff of 5.0) such that patients with less than 1.5-fold induction were classified as low risk, and patients with more than 8-fold induction were classified as high risk. In the training data set, this decision tree approach improved the performance of prediction compared to CRSRS alone. Conclusions: A model based on 8 baseline factors allowed an accurate classification of risk for Grade ≥2 CRS upon treatment with glofitamab. Addition of TNFα induction may improve the predictive value. The predictive performance was confirmed in a separate validation data set with additional analyses in independent cohorts ongoing. The CRSRS, alone or in combination with cytokine induction, represents a tool to predict the occurrence of Grade ≥2 CRS after the first glofitamab dose to enable stratification of patients according to risk of CRS with possible future implications for the intensity of monitoring for those at low risk. K.V.K. and A.B. have contributed equally. Disclosures Belousov: F. Hoffmann-La Roche Ltd: Current Employment. Byrtek: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Kwan: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Perez-Callejo: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Li: Genentech, Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Carlile: AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. McCall: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Nielsen: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Piccione: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. OffLabel Disclosure: Glofitamab is a full-length, humanized, immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent.

Background: Chemotherapy combined with anti-CD20 antibodies is the current standard treatment for patients with symptomatic advanced stage follicular lymphoma (FL). We have previously shown that the EZH2 gene mutation status was predictive of differential efficacy of the chemotherapy backbone within the GALLIUM trial. Specifically, EZH2 mutations, found in 22% of cases (93/418), were associated with longer progression-free survival (PFS) in patients who received CHOP/CVP regimens (with either Rituximab (R) or Obinutuzumab (G)), but were not predictive in patients who received Bendamustine-based regimens (Jurinovic, ASH 2019). In an earlier study, we defined a gene expression profile (GEP) signature which was significantly associated with EZH2 gene mutation status (Pastore, Lancet Oncol 2015). Here, we wanted to explore the predictive utility of this EZH2 GEP signature within the GALLIUM trial. Methods: GALLIUM (NCT01332968) enrolled 1202 patients with FL randomized to either receive R- or G-based therapy (Marcus, NEJM 2017). The chemotherapy consisted either of CHOP, CVP or Bendamustine according to a center-level decision. Inclusion criteria comprised previously untreated FL, advanced stage or stage II with bulky disease, and ECOG performance status 0-2. All patients required treatment according to the GELF criteria. Here, we analyzed all 134 cases with available DNA and transcriptome sequencing data. Results: Of the 129 genes from the original EZH2 GEP signature, 96 (74%) were evaluable in our transcriptome data. We used the unsupervised k-means algorithm to identify 2 GEP clusters, EZH2_mut and EZH2_WT, comprising 67 patients each (Fig A). Patients in the EZH2_mut cluster had significantly longer PFS with CHOP/CVP-based regimens (HR = 4.99, P = 0.002), while the EZH2 GEP signature was not predictive in patients receiving Bendamustine-based treatment (Fig B). As expected, EZH2 mutations were significantly enriched in the EZH2_mut cluster (30% vs 13%; P = 0.034). Of note, 47 cases in the EZH2_mut cluster had no detectable EZH2 mutation. We wanted to test, whether the predictive utility of the EZH2 GEP signature was maintained in cases without EZH2 mutations. Indeed, patients without EZH2 mutations grouped into the EZH2_mut cluster also had longer PFS with CHOP/CVP-based regimens (HR = 4.74, P = 0.007), whereas the ones grouped into the EZH2_WT cluster had longer PFS with Bendamustine-based regimens (HR = 0.36, P = 0. 03) (Fig. C). To explore the genetic determinants of the EZH2 GEP signature in cases without EZH2 mutations, we analyzed the available DNA sequencing data, considering recurrent non-silent gene mutations and copy-number alterations (CNA) with frequencies of 10% in either cluster. As expected, gain of chromosome 7 (chr7), which contains the EZH2 gene, was enriched in the EZH2_mut cluster (21% vs 7%, P = 0.04). Cases with chr7 gain had significantly increased EZH2 mRNA expression levels as compared to cases without EZH2 CNA or mutations (P < 0.0001). Furthermore, univariate analysis revealed enrichment of mutations in TNFRSF14 (49% vs 24%), BCL7A (28% vs 8%), GNA13 (15 vs 7%), SOCS1(19 vs 8%), and HVCN1 (13 vs 7%) in the EZH2_mut cluster, but none of these associations were significant after correction for multiple testing. Finally, we wanted to better delineate the transcriptional phenotype of the EZH2 GEP signature in cases that lack EZH2 mutations. GSEA analysis revealed that the EZH2_mut cluster was strongly enriched for the hallmark signatures mTORC1 signaling, MYC and E2F target genes. Furthermore, we used CIBERSORT to estimate the immune cell composition of the tumor microenvironment (TME). The TME compositions of FL in the EZH2_mut cluster lacking EZH2 mutations more closely resembled FL with EZH2 mutations, most notably for higher T follicular helper (TFH) cell (P = 0.003) and macrophage M0 scores (P < 0.001) as compared to FL in the EZH2_WT cluster lacking EZH2 mutations. In conclusion we show that an EZH2 GEP signature is (i) significantly associated with EZH2 gene mutation status, (ii) also observed in a subset (47/105, 45%) of cases that lack EZH2 mutations but harbor other genetic alterations (including chr7 gain/EZH2 overexpression), (iii) associated with a distinct TME composition enriched for TFH cells and M0 macrophages, and (iv) predictive of differential efficacy of chemotherapy-backbones in combination with Rituximab or Obinutuzumab. Figure 1 Figure 1. Disclosures Bolen: F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech: Current Employment. Knapp: F. Hoffmann-La Roche Ltd: Current Employment. Bottos: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Richter: HTG Molecular Diagnostics, Inc.: Current Employment, Research Funding. Fitzgibbon: Epizyme: Research Funding. Klapper: Takeda: Consultancy, Research Funding; Amgen: Research Funding; Regeneron: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Davies: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma/AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; BioInvent: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. von Bergwelt: MSD Sharpe & Dohme: Honoraria, Research Funding, Speakers Bureau; Mologen: Honoraria, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Miltenyi: Honoraria, Research Funding, Speakers Bureau. Nielsen: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Dreyling: Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; BeiGene: Consultancy; Novartis: Consultancy, Speakers Bureau; Genmab: Consultancy; Amgen: Speakers Bureau; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding. Hiddemann: Janssen: Research Funding; F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Unterhalt: Roche: Research Funding. Weigert: Janssen: Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding.

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.

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.

Introduction: R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisolone) remains the standard of care for first-line (1L) treatment of diffuse large B-cell lymphoma (DLBCL), with a long-term event free survival of 60-70% in patients (pts) who complete the recommended treatment course of 6-8 cycles (Coiffier, et al. Blood 2010). However, significant numbers of pts are unable to tolerate R-CHOP due to comorbidity or frailty, which confers susceptibility to consequences of treatment-related toxicities. These pts are less likely to achieve complete remission and are at higher risk of relapse as they receive a lower chemotherapy dose intensity due to treatment discontinuation, interruptions, or reductions (Długosz-Danecka, et al. Cancer Med 2019). Identifying these pts upfront could facilitate recruitment into studies of alternate therapies, thereby sparing them the unfavorable risk/benefit profile of R-CHOP treatment. The aim of this study was to develop a predictive tool to identify pts newly diagnosed with DLBCL who are unlikely to tolerate anti-CD20 with CHOP. Methods: We performed an exploratory analysis based on 1,407 newly diagnosed DLBCL pts from the Phase III GOYA trial [NCT01287741] who were treated with R-CHOP or obinutuzumab in combination with CHOP (G-CHOP). To identify pts who did not tolerate anti-CD20 + CHOP, we selected a hybrid binary endpoint: 1) adverse events (AEs) leading to withdrawal of cyclophosphamide and/or doxorubicin; 2) average relative dose intensity of cyclophosphamide and doxorubicin We separated data into 5-folds with a training (n=1051) and a hold-out test set (n=355) to be evaluated in the future. Candidate predictive variables were selected on the basis of known baseline characteristics, which contribute to patient frailty, comorbidity and chemotherapy toxicity. Prediction performance was evaluated by 4-fold cross validation (CV) on the training set. We first associated variables with clinical outcomes to estimate variable importance. We combined highly informative variables to fit a logistic regression model that maximized prediction and evaluated robustness. Results: Of 1,407 evaluable pts that initiated anti-CD20 + CHOP, the hybrid tolerability binary endpoint occurred in 188 (13.4%) (Figure A). There were 104 (7.4%) pts with AEs leading to withdrawal of cyclophosphamide and/or doxorubicin; 162 (11.5%) instances of reduced average relative dose intensity of cyclophosphamide and doxorubicin We identified a model including: albumin, percentage of bone marrow lymphocytes, CCI, creatinine clearance and previous history of heart, vascular or diabetes comorbidities (Table). Our TRAIL model was trained on 742 pts with complete data. We achieved an area under the receiver operating characteristic curve (AUC) of 75.5% and a CV AUC of 74.9% (sensitivity = 75%, specificity = 69.6%) (Figure B). To create a simpler model using information available in the routine clinical setting, we removed bone marrow lymphocytes and trained a model on 1022 pts with complete data achieving a CV AUC of 70.1% (sensitivity = 68.1%, specificity = 67.2%). Other top ranking models with complete data on all pts achieved AUCs >70% and included age, hemoglobin, T-cell counts, proportion of TH cells, and lactate dehydrogenase (LDH). Implementations of CCI alone performed less well with a CV AUC of 62.9%. Conclusions: Future analyses will evaluate TRAIL on the hold-out test set to estimate a final unbiased measure of performance as well as an evaluation in an independent clinical trial. This model has the potential to be used as clinical decision support to guide physician judgement and enable patient enrollment into future clinical trials for alternate therapies, as well as alleviate anti-CD20 or R-CHOP associated toxicities for 1L DLBCL patients who are unlikely to derive the full benefit of this treatment. Disclosures Bataillard: Imperial College Healthcare NHS Trust: Ended employment in the past 24 months; Roche Products Limited (temporary clinical fellowship as a fixed-term sabbatical from Hematology specialty training fellowship at Imperial College Healthcare NHS Trust): Current Employment. Harris:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Kwan:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Henneges:Genentech, Inc. (via Syneos Health): Current Employment; University of Wurzburg: Ended employment in the past 24 months. Paulson:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in private company, Current equity holder in publicly-traded company. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company.

Introduction: The lymphoma microenvironment is increasingly recognized as crucial to sustaining lymphoma cell growth and an important contributor to treatment outcome, especially in the context of immunotherapies. CD20-targeted monoclonal antibodies (e.g. obinutuzumab [G] and rituximab [R]) function by several mechanisms, including antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). Immune effector cells, such as natural killer (NK) cells and phagocytes (i.e. macrophages and dendritic cells), and the Fc gamma receptor (FcγR) found on the surface of these cells, are critical to antibody treatment efficacy. Here we evaluated how the lymphoma microenvironment may affect clinical outcome in patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL) receiving immunochemotherapy. Methods: We leveraged two large Phase III clinical trials of pts with previously untreated DLBCL (GOYA [NCT01287741] and MAIN [NCT00486759]) to produce comprehensive lymphoma immune microenvironment profiles from 604 tissue biopsies from pts treated with R plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or G plus CHOP (G-CHOP) using the RNA-Seq deconvolution and marker gene methods: quanTIseq and xCell. The infiltration scores in each pt for various immune and stromal cell types were assessed, and their contribution to disease biology and treatment outcome was examined. Results: The extent of lymphoma microenvironment heterogeneity highlighted by the deconvolution analyses was consistent with previous studies (Figure A). Of the infiltrating cell types analyzed, the M1 macrophage signature quantified by either quanTIseq or xCell was most strongly associated with lower risk of progression (progression-free survival [PFS]; quanTIseq: HR, 0.596; 95% CI: 0.441-0.805; 24-month PFS: 82% [M1 high] vs 68% [M1 low] and xCell: HR, 0.627; 95% CI: 0.465-0.844; 24-month PFS: 80% [M1 high] vs 70% [M1 Low]; Figure B, C, D) and improved overall survival (OS; quanTIseq: HR, 0.465; 95% CI: 0.318-0.679; and xCell: HR, 0.527; 95% CI: 0.365-0.762). This finding was confirmed by both algorithms. This prognostic trend was stronger amongst G-treated pts than R-treated pts, consistent with the previous finding that G exhibits higher ADCC versus R (Mössner, et al. Blood 2010). Pts with PFS >24 months had significantly higher levels of M1 macrophage scores than pts with PFS Conclusions: Data suggest macrophage polarization may be an important contributor to immunochemotherapy outcome in DLBCL. Previous studies aiming to link tumor-associated macrophages to R-CHOP outcome have yielded conflicting results, perhaps as most relied on CD68/CD163 staining alone as markers. Although R and G are thought to function via NK cell-mediated ADCC, FcγR-dependent stimulation of M1 macrophage-mediated ADCP may be key to sustaining their anti-lymphoma activity. Strategies facilitating the recruitment of M1 macrophages or macrophage repolarization may augment responses to immunochemotherapy in DLBCL. Disclosures Yan: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Chang:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Raghavan:F. Hoffmann-La Roche: Current Employment. Dong:In graduate school: University of Toronto, MSc Biostatistics: Ended employment in the past 24 months; F. Hoffmann-La Roche, Mississauga, Biometrics: Current Employment. Klein:Roche: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Paulson:Genentech, Inc: Current Employment; F. Hoffmann-La Roche: Current equity holder in private company, Current equity holder in publicly-traded company. Hatzi:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment.

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.

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‒like (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 #{"type":"clinical-trial","attrs":{"text":"NCT01287741","term_id":"NCT01287741"}}NCT01287741.

7511 Background: G-len has promising activity and manageable toxicity in R/R FL (Morschhauser et al. 2019). We report the final analysis of an open-label, multicenter, Phase Ib/II trial (NCT02631577) that evaluated the immunomodulatory triplet G-atezo-len in pts with R/R FL. Methods: An initial 3+3 dose‐escalation to identify the Phase II len dose was followed by an expansion phase with G-atezo-len. Enrolled pts (aged ≥18 years) received induction with 6, 28-day cycles of G 1000 mg IV on Day [D] 1, 8, and 15 of Cycle [C] 1 and D1 of C2–6, atezo 840 mg IV on D1 and 15 of C2–6, and len 15/20 mg (dose escalation) or 20 mg (expansion) orally on D1–21 of C1–6. Responders received 24 months (mos) of maintenance with G 1000 mg D1 every 2 mos, atezo 840 mg D1–2 every mo, and len 10 mg D1–21 mos 1–12. The primary endpoint was complete response at end of induction by PET-CT assessed by Independent Review Committee (modified Lugano 2014 criteria; Morschhauser et al. ICML 2019). Exploratory endpoints described herein included progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Adverse events (AEs) were also assessed. Results: At the final analysis (October 7, 2020), 38 pts had completed the trial. Median age was 62 years, 26% had a high-risk FLIPI score, 45% were refractory to their last line of therapy, and 37% had progression of disease within 24 mos of their first-line of therapy (POD24). Median treatment duration was 26 mos (range: 0.4‒30). The 36-mo PFS rate for the overall population (median observation time, 35.9 mos; range: 3‒47) was 64% (95% CI, 45‒79), OS was 85% (95% CI, 70‒93), and median DOR was 38 mos (95% CI, 35‒NE). 36-mo PFS rates for the following subgroups are provided in the table: double refractory (rituximab and an alkylator); with/without POD24; minimal residual disease (MRD) +/-. In total, 32 pts (84%) had a Grade 3/4 AE (majority hematologic), and 18 (47%) had a serious AE. Five pts (13%) during induction and six pts (16%) during maintenance had an AE that led to discontinuation of any drug. Two fatal AEs were reported (1 merkel carcinoma, 1 sarcomatoid carcinoma; both unrelated to any study drug). The most common atezo AEs of special interest were hyperthyroidism (13%), hypothyroidism (11%), increased ALT and AST (both 8%), increased lipase (8%), and hepatocellular injury (5%). Conclusions: G-atezo-len is efficacious in pts with R/R FL, with data from the final analysis suggesting a potential for improved outcomes versus the G-len doublet. AEs were consistent with the safety profile of the individual drugs. Clinical trial information: NCT02631577. [Table: see text]

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.