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Although advanced‑stage follicular lymphoma (FL) is considered incurable, survival has improved with the introduction of the anti-CD20 antibodies, rituximab (R) and obinutuzumab (G). However, FL can undergo histological transformation (HT) to a more aggressive disease, and a validated model for predicting HT risk is not yet available.We assessed HT incidence, risk factors and outcomes in the phase III, GALLIUM study evaluating R- or G-chemotherapy in patients with previously untreated, advanced-stage FL (ClinicalTrials.gov NCT01332968). HT rates were assessed by repeat tumour biopsy at disease progression or relapse, at the investigator's discretion.Of 1202 patients enrolled, 315 (26.2%) experienced progressive disease; 46 (14.6%) had a biopsy at first progression, 40 of whom had biopsy-confirmed HT. HT risk factors were male sex (subdistribution hazard ratio [sHR], 2.21; 95% confidence interval [CI], 1.16-4.20), elevated baseline serum lactate dehydrogenase (sHR, 3.97; 95% CI, 2.03-7.76), and elevated baseline serum βHT was a low-frequency event associated with poor survival outcomes in the GALLIUM study. Male sex and elevated baseline levels of serum LDH and B2M were significant risk factors for HT. Further research is required to develop validated prognostic indices for HT risk and guide treatment decisions.

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.

Fc γ receptor IIB (FcγRIIB) is an inhibitory molecule capable of reducing antibody immunotherapy efficacy. We hypothesized its expression could confer resistance in patients with diffuse large B-cell lymphoma (DLBCL) treated with anti-CD20 monoclonal antibody (mAb) chemoimmunotherapy, with outcomes varying depending on mAb (rituximab [R]/obinutuzumab [G]) because of different mechanisms of action. We evaluated correlates between FCGR2B messenger RNA and/or FcγRIIB protein expression and outcomes in 3 de novo DLBCL discovery cohorts treated with R plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) reported by Arthur, Schmitz, and Reddy, and R-CHOP/G-CHOP-treated patients in the GOYA trial (NCT01287741). In the discovery cohorts, higher FCGR2B expression was associated with significantly shorter progression-free survival (PFS; Arthur: hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01-1.19; P = .0360; Schmitz: HR, 1.13; 95% CI, 1.02-1.26; P = .0243). Similar results were observed in GOYA with R-CHOP (HR, 1.26; 95% CI, 1.00-1.58; P = .0455), but not G-CHOP (HR, 0.91; 95% CI, 0.69-1.20; P = .50). A nonsignificant trend that high FCGR2B expression favored G-CHOP over R-CHOP was observed (HR, 0.67; 95% CI, 0.44-1.02; P = .0622); however, low FCGR2B expression favored R-CHOP (HR, 1.58; 95% CI, 1.00-2.50; P = .0503). In Arthur and GOYA, FCGR2B expression was associated with tumor FcγRIIB expression; correlating with shorter PFS for R-CHOP (HR, 2.17; 95% CI, 1.04-4.50; P = .0378), but not G-CHOP (HR, 1.37; 95% CI, 0.66-2.87; P = .3997). This effect was independent of established prognostic biomarkers. High FcγRIIB/FCGR2B expression has prognostic value in R-treated patients with DLBCL and may confer differential responsiveness to R-CHOP/G-CHOP.

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.

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.

Background: The anti-CD20 monoclonal antibody (mAb), obinutuzumab (G), has shown improved outcomes versus rituximab (R) in indolent lymphomas; however, no improvement was seen in diffuse large B-cell lymphoma (DLBCL), and the molecular basis is unclear. The inhibitory Fc gamma receptor IIB (Fc γRIIB), expressed on lymphoma cells, can impair the effects of direct targeting mAbs, such as R, by binding and internalizing them, reducing opsonization and limiting FcγR-mediated killing. We hypothesized that FcγRIIB expression on cellular effectors and/or the lymphoma confers treatment resistance in some patients (pts) and evaluated if outcomes differ for therapies involving a non-internalized mAb (G). Methods: We evaluated correlates between FCGR2B mRNA and/or FcγRIIB protein expression and pt outcomes in two discovery cohorts of de novo DLBCL treated with R-CHOP (Arthur et al. 2018, n=372; Schmitz et al. 2018, n=234), and the phase III GOYA trial (NCT01287741; n=552), which compared R-CHOP with G-CHOP in pts with previously untreated DLBCL. FCGR2B mRNA expression was assessed by RNA-Seq, and protein expression was assessed in evaluable cohorts by immunohistochemistry, using tissue microarrays with macrophages identified by CD68. FCGR2B expression was also measured by a NanoString assay (Arthur cohort). Cox regression analyzed the impact of FcγRIIB/FCGR2B expression on progression-free survival (PFS), with univariate and multivariate models adjusted for International Prognostic Index (IPI), cell of origin (COO), and BCL2 protein expression. Results: In the discovery cohorts, a higher FCGR2B expression was significantly associated with shorter PFS (Arthur: HR 1.09 [95% CI: 1.01–1.19], P=0.036; Schmitz: HR 1.13 [95% CI: 1.02–1.26], P=0.0243). Expression by NanoString strongly correlated with RNA-Seq, confirming the association with shorter PFS (HR 1.13 [95% CI: 1.04–1.23], P=0.0048). In GOYA, a significant association between PFS and FCGR2B was observed in the R arm (HR 1.26 [95% CI: 1.00–1.58], P=0.0455), with no prognostic effect observed for G (HR 0.91 [95% CI: 0.69–1.20], P=0.5). Pts with high FCGR2B expression appeared to benefit more from G than R (HR 0.67 [95% CI: 0.44–1.02], P=0.0622), in contrast to pts with low FCGR2B expression (HR 1.58 [95% CI: 1.00–2.50], P=0.0503). In both Arthur and GOYA cohorts, FCGR2B expression by RNA-Seq was associated with FcγRIIB on the tumor, which correlated with a shorter PFS for R (HR 2.17 [95% CI: 1.04–4.50], P=0.03), but not G (HR 1.37 [95% CI: 0.66–2.87], P=0.4). This prognostic effect on PFS was independent of established prognostic biomarkers, IPI, COO and BCL2. Conclusion: High FcγRIIB/FCGR2B expression in pts with DLBCL has prognostic value in those treated with R and may confer differential responsiveness to R or G. Citation Format: Laura K. Hilton, Malgorzata Nowicka, Margaret Ashton-Key, Chantal E. Hargreaves, Chern Lee, Russell Foxall, Matthew J. Carter, Stephen A. Beers, Kathleen N. Potter, Christopher R. Bolen, Christian Klein, Andrea Knapp, Farheen Mir, Matthew Rose-Zerilli, Cathy Burton, Wolfram Klapper, David W. Scott, Laurie H. Sehn, Umberto Vitolo, Maurizio Martelli, Marek Trneny, Graham W. Slack, Pedro Farinha, Jonathan C. Strefford, Mikkel Z. Oestergaard, Ryan D. Morin, Mark S. Cragg. Prognostic significance of Fc gamma receptor IIB expression in the response of previously untreated diffuse large B-cell lymphomas to anti-CD20 monoclonal antibodies: Differing impact of rituximab and obinutuzumab [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-26.

Introduction: Predicting the risk of histologic transformation (HT) from indolent follicular lymphoma (FL) to a more aggressive form of lymphoma represents a major challenge in managing patients with FL. We assessed the incidence of HT in the GALLIUM study (NCT01332968) and determined risk factors for transformation and impact on clinical outcomes. Methods: In the Phase III GALLIUM study, patients with previously untreated FL were randomized to receive either the anti-CD20 antibody rituximab (R; 375mg/m² on Day (D) 1 of each cycle) or obinutuzumab (G; 1000mg on D1, 8, and 15 of Cycle 1 and D1 of subsequent cycles) in combination with chemotherapy (CHOP, CVP or bendamustine). Patients who achieved at least a partial response at the end of induction therapy proceeded to maintenance therapy with the same antibody, every 2 months for 2 years, or until progression of disease. Repeat biopsies at progression were not mandatory but carried out in case of clinical suspicion of HT. The rate of HT, as assessed by the local pathologist, in patients with a repeat biopsy at the time of disease progression/relapse was an exploratory endpoint. Results: 1202 patients were enrolled. After a median follow up of 57.3 months, 315 (26.2%) patients progressed (median time to relapse, 25.3 months); of these 315 patients, 46 (14.6%) had a biopsy at first progression due to a clinical suspicion of transformation. Forty patients, corresponding to 3.3% of all patients enrolled in GALLIUM and 12.7% of those that progressed, had biopsy-confirmed HT. Among 153 patients with disease progression within 24 months (POD24), 31/153 (20.3%) had HT. Fewer patients transformed in the G-chemo arm (16/40; 40%) compared with R-chemo (24/40; 60%). In total, 116 patients relapsed in the G-chemo arm versus 159 in the R-chemo arm. Compared with no HT, patients with HT were more likely to be male and have bone marrow involvement, stage 3A FL, high FL International Prognostic Index risk, low hemoglobin (Hb), elevated serum lactate dehydrogenase (LDH), elevated beta-2-microglobulin, and high total metabolic tumor volume (Table). A comparison of chemotherapy backbones showed a trend towards higher HT incidence with bendamustine (5.8% [26/686]) compared with CVP, 4.3% (5/117) and CHOP, 2.3% (9/399). A multivariate cause-specific cox model identified several risk factors for HT, including elevated LDH levels (hazard ratio [HR], 4.27 [95% CI: 2.08─8.78]; p Conclusions: In GALLIUM, a low rate of HT was observed over 5 years, with the majority occurring within the first 2 years. Patients with POD12 had poor OS regardless of whether transformation occurred or not. Risk factors for HT included elevated LDH, anemia, and male gender. Patients with HT, especially those with progression of disease within 24 months, had poor OS compared to patients who relapsed with persistent FL. Disclosures Casulo: Celgene: Research Funding; Gilead: Honoraria, Other: Travel, accommodation, expenses; Roche: Other: Travel, accommodation, expenses. Herold:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; GILEAD: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Hiddemann:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Bayer: Research Funding; Vector Therapeutics: Consultancy, Honoraria. Iyengar:Roche: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Marcus:Roche / Genentech: Honoraria, Speakers Bureau; Gilead: Consultancy. Seymour:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy; Acerta: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding. Launonen:F. Hoffmann-La Roche Ltd: Employment. Knapp:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mir:Roche: Other: Previous employment.

Introduction: Fc gamma receptors (FCGR) are critical mediators of anti-CD20 monoclonal antibody-mediated cell-killing in lymphoma patients (pts). Previous studies have investigated the impact of FCGR genetics on pts' responses to treatment with rituximab (R). In particular, Single Nucleotide Polymorphisms (SNPs) in FCGR2A H131R (rs1801274), FCGR3A F158V (rs396991), and FCGR2B I232T (rs1050501) have been shown to affect either affinity for IgG (H131R; F158V) or receptor activity (I232T) (reviewed in Hargreaves et al. Immunol Rev 2015). Although the impact of these SNPs on effector function has been demonstrated in vitro, their influence on overall pt response is less clear, with multiple small cohort studies reporting inconsistent effects, likely due to their limited size. Therefore, we assessed the clinical importance of FCGR genotypes in two large, international, randomized Phase III clinical trials, assessing their potential impact on the efficacy of R or obinutuzumab (GA101; G) in combination with chemotherapy in pts with untreated advanced follicular lymphoma (FL) (GALLIUM; NCT01332968) and untreated diffuse large B-cell lymphoma (DLBCL) (GOYA; NCT01287741). Methods: Genomic DNA was extracted from peripheral blood mononuclear cells in 2465 pts enrolled in GALLIUM (R-chemo vs G-chemo; n=1144 of 1202 enrolled) and GOYA (R-CHOP vs G-CHOP; n=1321 of 1418 enrolled). The key SNPs, FCGR2A H131R (rs1801274), FCGR3A F158V (rs396991), and FCGR2B I232T (rs1050501), were genotyped in all samples using TaqMan™ discrimination assays, with confirmatory Sanger sequencing employing FCGR-gene-specific polymerase chain reaction primers in 10% of cases. For both trials, our analysis of progression-free survival (PFS) included a univariate Cox regression analysis adjusted for treatment arm, and multivariate Cox regression analysis adjusted for stratification factors (GALLIUM: FLIPI and chemotherapy regimen; GOYA: IPI, cell of origin [COO], number of CHOP cycles, and BCL2;). In GOYA, we also adjusted for COO and BCL2 protein expression as we have previously shown these to be prognostically significant (Vitolo et al. J Clin Oncol 2017; McCord et al. Blood 2017). Multiple test correction was performed using Benjamini and Hochberg methodology. Results: The demographic and clinical characteristics of the FL and DLBCL pts included were comparable to those previously reported for the entire GALLIUM and GOYA trials, respectively. The prevalence of each FCGR genotype was comparable across trials, observed in both cohorts as: FCGR2A: R131R, 21.2% (523/2465 pts); H131R, 46.5% (1146/2465 pts); and H131H, 32.3% (796/2465 pts); FCGR3A: F158F, 43.6% (1073/2462); V158F, 44.5% (1096/2462); and V158V, 11.9% (293/2462); FCGR2B: I232I, 74.5% (1596/2143); I232T, 23.5% (503/2143); and T232T, 2.1% (44/2143). In FL, only FCGR2B was associated with PFS in univariate analyses comparing I232T to I232I genotype (Figure), with a more modest association for R treated pts (hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.54─1.14; p=0.21) compared to G treated pts (HR 0.56; 95% CI 0.34─0.91; p=0.02). However, neither observation retained statistical significance in stratified analyses. In DLBCL, there was no evidence of a univariate prognostic effect of FCGR genotype. However, in multivariate analysis, we observed an association in the R treatment arm of GOYA with the FCGR2B T232T SNP (HR 4.37; 95% CI: 1.69-11.30; p=0.002 and multiple testing adjusted p=0.03) compared to the I232I pts. However, this observation should be interpreted with caution, given the low prevalence of this genotype (n=13) and limited number of PFS events (n=6). Conclusions: We analyzed FCGR genotype status in 2465 pts with indolent and aggressive lymphoma treated with chemotherapy in combination with R or G and identified no clear prognostic impact of the three key FCGR SNPs. In conclusion, this study, the largest performed to date, provides further conclusive evidence that FCGR genotype does not confer differential responsiveness to R or G in treatment naive pts with advanced FL or aggressive DLBCL. JCS, MN and CH share first authorship, MCC and MZO share senior authorship. Disclosures Strefford: University of Southampton: Employment; F.Hoffman-La Roche: Research Funding. Nowicka:F.Hoffman-La Roche: Employment. Parker:Kay Kendall Leukaemia Fund: Research Funding; University of Southampton: Employment. Knapp:Roche: Employment. Mir:F.Hoffman-La Roche Ltd: Employment. Rose-Zerilli:Leuka Charity: Research Funding. Burton:NHS: Employment; Takeda: Honoraria; Roche: Honoraria; Takeda: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Consultancy. Hiddemann:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Klapper:HTG Molecular Diagnostics, Inc.: Research Funding; Regeneron: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; F.Hoffman-La Roche: Honoraria, Research Funding. Sehn:Morphosys: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martelli:Celgene: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Trněný:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Davies:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Kite: Consultancy; GSK: Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cragg:Bioinvent: Consultancy, Patents & Royalties: Patent licenced to Bioinvent around CD32b blockade; Boehringer Ingleheim: Consultancy. Oestergaard:Roche: Employment, Other: Ownership interests PLC.

Introduction: Progression of disease within 24 months of initial therapy (POD24) is associated with poor survival in patients with follicular lymphoma (FL). Existing prognostic models, such as FLIPI-1 and FLIPI-2, show poor sensitivity for POD24, and are derived from cohorts lacking bendamustine-treated patients. More accurate predictive models based on current standard therapies are needed to identify patients with high-risk disease. The Phase III GALLIUM trial (NCT01332968) compared the safety and efficacy of standard chemotherapy regimens plus rituximab (R) or obinutuzumab (G) in patients with previously untreated FL. Using GALLIUM data, we developed a novel risk stratification model to predict both PFS and POD24 in FL patients after first-line immunochemotherapy. Methods: Enrolled patients were aged ≥18 years with previously untreated FL (grades 1-3a), Stage III/IV disease (or Stage II with bulk), and ECOG PS ≤2, and required treatment by GELF criteria. Patients were randomized to receive either G- or R-based immunochemotherapy, followed by maintenance with the same antibody in responders. The chemotherapy arm (CHOP, CVP, or bendamustine) was selected by each study center. POD24 was defined as progressive disease or death due to disease within 24 months of randomization (noPOD24 = no progression or lymphoma-related death in that period). The most strongly prognostic variables, based on PFS hazard ratios, were estimated using penalized multivariate Cox regression methodology via an Elastic Net model. Selected variables were given equal weights, and a clinical score was formed by summating the number of risk factors for each patient. Low- and high-risk categories were determined using a cut-off that provided the best balance between true- and false-positives for PFS. PFS correlation and sensitivity to predict POD24 were assessed. The data used are from an updated GALLIUM efficacy analysis (data cut-off: April 2018; median follow-up: 57 months). Results: 1202 FL patients were enrolled. Based on data availability and biological plausibility (i.e. could reasonably be linked with high-risk disease), 25 potential clinical and treatment-related prognostic variables were entered into the Elastic Net model (Table). A model containing 11 factors was retained by the methodology and chosen as the best model (Table). Patients were categorized as 'low risk' if they scored between 0 and 3 (n=521/1000 patients with complete data) and as 'high risk' if they scored between 4 and 11 (n=479/1000 patients). At 2 years, the PFS rate was 84.5% in the whole FL population. Using our model, 2-year PFS for high-risk patients was 77% compared with 79.9% for FLIPI-1 and FLIPI-2. In low-risk patients, 2-year PFS was 92% compared with 87.9% for FLIPI-1 and 87.6% for FLIPI-2 (low-intermediate-risk patients). Our model increased the inter-group difference in 2-year PFS rate from 8% (FLIPI-1) and 7.7% (FLIPI-2) to 15%. At 3 years, the inter-group difference increased from 6.9% (FLIPI-1) and 9% (FLIPI-2) to 17% (Figure). Sensitivity for a high-risk score to predict POD24 was 73% using our model compared with 55% for FLIPI-1 and 52% for FLIPI-2 (based on 127 POD24 and 873 noPOD24 patients with complete data). Excluding patients who received CVP, which is now rarely used, resulted in an inter-group difference in PFS of 15% at 2 years and 16.8% at 3 years. A sensitivity analysis showed that inclusion of the 9 clinical factors only (i.e. removal of CVP and R treatment as variables) formed a more basic scoring system (low-risk patients, 1-3; high-risk patients, 4-9); the inter-group difference in PFS was 16.5% at 2 years and 17.6% at 3 years. However, sensitivity for POD24 decreased to 56%. Conclusion: Our clinical prognostic model was more accurate at discriminating patients likely to have poor PFS than either FLIPI-1 or FLIPI-2, and its prognostic value was sustained over time. Our model also identified the FL population at risk of POD24 with greater sensitivity. Variables such as age and bone marrow involvement were not retained by our model, and thus may not have a major impact in the current era of therapy. Factors such as sum of the products of lesion diameters were included, as this captures tumor burden more accurately than presence of bulk disease. Future studies will aim to improve the accuracy of the model by considering gene expression-based prognostic markers and DNA sequencing to form a combined clinico-genomic model. Disclosures Mir: F. Hoffmann-La Roche: Employment. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Marcus:F. Hoffman-La Roche: Other: Travel support and lecture fees; Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy. Seymour:Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bolen:Roche: Other: Ownership interests PLC*. Knapp:Roche: Employment. Launonen:Launonen: Other: Ownership interests none PLC; Travel, accommodation, expenses; Novartis: Consultancy, Equity Ownership, Other: Ownership interests none PLC; Travel. accommodation, expenses; Roche: Employment, Other: Travel, accommodation, expenses. Mattiello:Roche: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Oestergaard:Roche: Employment, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Casulo:Gilead: Honoraria; Celgene: Research Funding.

Introduction: Follicular lymphoma (FL) generally has an indolent clinical course, but there is a 1-2% annual rate of histological transformation (HT) into aggressive lymphoma. Nodal HT sites have a higher maximum standardized uptake value (SUVmax) than non-transformed sites, and patients with HT typically show greater variation in SUVmax between sites. Upfront identification of patients at high risk of HT would allow physicians to consider treatment intensification. The objective of this analysis was to assess the relationship between baseline SUVmax (bSUVmax) and HT in the GALLIUM study (NCT01332968). Methods In the randomized, phase III GALLIUM study, 1202 previously untreated patients with grade 1-3a FL were randomized to receive induction with either obinutuzumab (GA101; G)- or rituximab (R)-based immunochemotherapy. Patients who responded received maintenance therapy with the same antibody. The primary endpoint of investigator-assessed progression-free survival was significantly improved in the G arm relative to the R arm (hazard ratio 0.66; p=0.001). As an exploratory endpoint, the degree of 18-fluorodeoxyglucose (FDG)-avidity expressed by SUVmax was assessed in patients with baseline FDG positron emission tomography (FDG-PET) scans by an independent review committee. Results: Among 522 patients with available bSUVmax data, 13 (2.5%) experienced biopsy-confirmed HT to diffuse large B-cell lymphoma or Grade 3b FL after a median follow-up of 59 months. Patients with HT were older (median age 61 vs 56 years), and were more likely to have a poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status 2: 15.4% vs 2.6%), present with high-risk Follicular Lymphoma International Prognostic Index (FLIPI; 61.5% vs 40.3%), and have bone marrow involvement (76.9% vs 52.9%) than those without. More than 65% of patients showed bSUVmax >10, but only a minority of these experienced HT. Median (range) bSUVmax in patients with versus without HT was 12.4 (8.14, 27.95) versus 11.8 (3.05, 64.43), respectively. Median (range) baseline SUVrange (bSUVrange), defined as the difference between bSUVmax of the most and least FDG-avid lymphoma sites, was 6.6 (1.08, 23.91) versus 7.14 (0.00, 59.81), respectively (Figure). Conclusions: bSUVmax >10 is common in patients with previously untreated FL and is rarely associated with early HT. Neither bSUVmax nor bSUVrange predicted HT in GALLIUM, suggesting there may be little benefit in re-biopsy of lesions to exclude HT before commencing therapy. Better markers for identification of FL patients at risk of transformation are needed. Disclosures Mir: F. Hoffmann-La Roche: Employment. Barrington:F.Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees; Department of Health (England): Research Funding; MRC: Research Funding; CRUK: Research Funding; EPSRC: Research Funding; National Institute of Health Research: Research Funding. Meignan:F. Hoffman-La Roche Ltd: Honoraria. Brown:PAREXEL, external business partner with Roche Products Ltd, Welwyn, UK: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Sahin:F. Hoffman-La Roche Ltd: Other: Ownership interests PLC. Trotman:F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Janssen: Other: Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding; Takeda: Other: Unremunerated member of Ad Board; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding.

Introduction: BCL2 overexpression leading to evasion of apoptosis is common in hematologic malignancies. In DLBCL, 50% of patients (pts) overexpress BCL2 protein, 30% overexpress BCL2 and MYC (double-expressor [DE]) and 5-10% have translocations of BCL2 and MYC (double-hit [DH]), all of which are associated with a poor prognosis. We hypothesized that combination of the BCL2 inhibitor venetoclax (Ven) with chemotherapy would improve DLBCL outcomes based on pre-clinical and early clinical data. The Phase Ib part of the CAVALLI (NCT02055820) study assessed the maximum tolerated dose (MTD) of CHOP + rituximab (R) or obinutuzumab (G) with Ven (200-800mg) in non-Hodgkin lymphoma, recommending 800mg of Ven + R-CHOP for Phase II. The single-arm, multicenter Phase II part of CAVALLI investigated the efficacy of Ven + R-CHOP in all first-line (1L) DLBCL pts, by BCL2 immunohistochemistry (IHC) status within cell-of-origin (COO) subtypes, by BCL2 fluorescence in situ hybridization (FISH) and in DE and DH pts, with the intent to compare against a matched pt population in the R-CHOP arm of the GOYA Phase III study. Here we report the first safety, efficacy and biomarker analyses in all pts from this ongoing Phase II study. Methods: Eligible pts (age ≥18 yrs; Eastern Cooperative Oncology Group performance status ≤2; 1L DLBCL; International Prognostic Index score 2-5; ≥1 measurable lesion >1.5cm) were assigned to receive six 3-weekly cycles of R-CHOP + 800mg Ven daily for 10 days (Days 1-10, except Cycle 1: Days 4-10), followed by two 3-weekly cycles of 800mg Ven on Days 1-10 + R on Day 1. The primary endpoint was PET-CT response 6-8 weeks after the last R dose (EoT), according to a modified version of Lugano 2014 criteria. Secondary endpoints were progression-free survival (PFS) and safety. Biomarker analyses in CAVALLI and GOYA were performed in pre-treatment tumor samples including a BCL2 IHC assay (cutoff: 50% medium/high expression), MYC IHC assay (cutoff 40% signal), BCL2 and MYC FISH, and COO assay (Nanostring). Results: 211 pts were enrolled; 208 received any treatment and were included in efficacy and safety analyses. Overall, pt characteristics were similar for CAVALLI and GOYA, except CAVALLI enrolled more Ann Arbor Stage IV (65.4% vs 47.1%) and BCL2 IHC-positive pts (57.7% vs 50.0%). The EoT complete response rate in all pts did not differ significantly between CAVALLI and GOYA (69.2% vs 62.8%, respectively; Table 1), but was improved in BCL2-positive subgroups, specifically in BCL2 FISH-positive (70.0% vs 47.5%) and DH (71.4% vs 25.0%) pts. With 20 months' median follow-up in CAVALLI, disease progression and death had occurred in 29 and 6 pts, respectively. When compared with GOYA and adjusted for baseline covariates by Cox methodology, PFS improvement was observed in BCL2 IHC-positive pts (HR, 0.53; 95% CI: 0.30-0.93), including within both activated B-cell (ABC; HR, 0.43; 95% CI: 0.19-0.94) and germinal center B-cell (GCB; HR, 0.41; 95% CI: 0.17-0.95) COO subgroups. No PFS benefit was observed in BCL2 IHC-negative GCB pts; the BCL2 IHC-negative ABC subgroup was too small for evaluation (Figure 1). Grade 3-4 adverse events (AEs) occurred in 85% (176/208) of pts in CAVALLI versus 66% (373/574) in GOYA; the majority were cytopenias, infections and febrile neutropenia (Table 2). In CAVALLI, 1% (3/208) of AEs were fatal versus 5% (30/564) in GOYA but follow-up was longer in GOYA (57 vs 20 months). The higher rate of AEs in CAVALLI led to dose interruptions/discontinuations of both Ven and R-CHOP; 61% of pts had >90% relative dose intensity (RDI) of Ven; 73.2% of CAVALLI pts had >90% RDI of each of doxorubicin and cyclophosphamide versus 76.4% for doxorubicin and 77.6% for cyclophosphamide in GOYA. There were no major differences in grade 3-4 AEs or the RDI of R-CHOP across intention-to-treat and BCL2-positive subgroups. GCSF prophylaxis was recommended, but not uniformly delivered. Conclusions: The addition of Ven to R-CHOP in 1L DLBCL treatment resulted in improved efficacy in BCL2 IHC-positive pts compared with matched GOYA controls. Higher rates of cytopenia, infection and febrile neutropenia were observed in CAVALLI versus the R-CHOP arm in GOYA. These data further support exploration of Ven + R-CHOP in a high-risk population of BCL2-positive 1L DLBCL, including DH pts. Disclosures Morschhauser: Epizyme: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feugier:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Agios: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; ArQule: Research Funding; Constellation: Research Funding; Curis: Research Funding; Genentech: Research Funding; Forma: Research Funding; Novartis: Research Funding; BeiGene: Research Funding; Pfizer: Research Funding; Forty Seven: Research Funding; TG Therapeutics: Research Funding; Portola: Research Funding; Calithera: Research Funding; Seattle Genetics: Research Funding; Verastem: Consultancy, Research Funding; Trillium: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Janssen: Research Funding; Kite: Research Funding; Takeda: Research Funding. Gasiorowski:Novartis: Honoraria; MSD: Honoraria. Greil:Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Illés:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Johnson:Merck: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Seattle Genetics: Honoraria; Lundbeck: Consultancy, Honoraria, Other: travel, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding. Lugtenburg:Genmab: Consultancy; Squibb: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Sandoz: Consultancy; Bristol-Meyers: Consultancy; Servier: Consultancy, Research Funding; Roche: Consultancy. Salles:BMS: Honoraria, Other: Advisory Board; Servier: Honoraria, Other: Advisory Board; Servier: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Epizyme: Honoraria; Morphosys: Honoraria; Abbvie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Honoraria; Merck: Honoraria; Pfizer: Honoraria; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board. Trněný:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding. Mir:F. Hoffmann-La Roche: Employment. Kornacker:F. Hoffmann-La Roche Ltd: Employment. Punnoose:Roche: Equity Ownership; Genentech Inc: Employment. Samineni:Genentech Inc: Employment, Other: Ownership interests non-PLC. Szafer-Glusman:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Petrich:Abbvie: Employment, Other: Ownership interests PLC. Sinha:F. Hoffmann-La Roche Ltd: Employment. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Zelenetz:Celgene: Consultancy; Abbvie: Research Funding; Gilead: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech/Roche: Consultancy, Research Funding; Novartis/Sandoz: Consultancy; Amgen: Consultancy.

Maternally inherited diabetes with deafness is rare diabetes caused by a mitochondrial DNA defect. 85% of cases are associated with m.3243A>G mutation. It is important to diagnose this form of diabetes because of the unique management issues and associated comorbidities. A very strong family history of diabetes, deafness and presence of retinal dystrophy should prompt an investigation for MIDD. Microvascular complications out of keeping with duration of diabetes are another clue to the diagnosis. Retinal and renal manifestations of mitochondrial disease may be confused for diabetic complications. Glutamic acid decarboxylase (GAD) autoantibody negativity in a nonobese diabetic is another clue. Cardiac conduction defects and GDM may also raise suspicion as to the diagnosis. Recognizing this etiology of DM should promote family screening, genetic counseling, screening of associated comorbidities, avoidance of metformin, and cautious use of statins. We report a 77 years old lady with MIDD who was being followed up as insulin requiring type 2 diabetes. We then identified 5 more patients with MIDD in the same clinic. They all had A3243 mutation with characteristic clinical presentation. The pharmacological approaches discussed in the paper are unlikely to work in these patients as they were diagnosed late.

A 64-year-old male presented with neurofibromatosis 1 and Cushing's syndrome. Clinically he was over weight, depressed with extensive skin bruising and hypertension. His 24 hours urinary metanephrines, urinary 5HIAA, gut peptides and chromgranin levels were normal. His renal function and renal MRI scan was also normal. His cortisol failed to suppress on overnight dexamethsone suppression test. His low dose dexamethasone suppression with CRH stimulation showed failure of suppression of cortisol to < 50 nmol/L and ACTH was measurable at 10 ng/L on day 3. There was no response of ACTH or cortisol to CRH stimulation. His ACTH precursors were high at 126 pmol/L consistent with defective pro-opiomelanocortin (POMC) processing suggesting an ectopic source of ACTH production. The MRI scan of his pituitary and CT scan of the adrenal glands was normal. His octreotide scan was negative. The source of his ectopic ACTH was most likely a large retroperitoneal plexiform neurofibroma seen on CT abdomen that had undergone malignant peripheral nerve sheath tumour transformation on histology. He was a poor surgical risk for tumour debulking procedure. In view of the available literature and role of c-kit signalling in neurofibromatosis, he was treated with Imitinib. Four months after the treatment his Cushings had resolved on biochemical testing. After a year his plexiform neurofibroma has not increased in size. To our knowledge, this is the first case of NF1 associated with clinical and biochemical features of Cushing's secondary to ectopic ACTH due to MPNST in a plexiform neurofibroma and its resolution on treatment with imatinib.