Background: Immunochemotherapy with rituximab plus chemotherapy (R-chemo) has significantly improved outcomes for patients (pts) with previously untreated follicular lymphoma (FL). However, most pts still experience disease relapse, progression, or death. Obinutuzumab (G) is a type II anti-CD20 monoclonal antibody with enhanced direct cell killing, antibody-dependent cellular cytotoxicity and antibody-dependent phagocytosis versus R. The safety and efficacy of G-chemo versus R-chemo was assessed in pts with previously untreated, advanced stage FL in the randomized, Phase III GALLIUM (NCT01332968) study. In the primary analysis, G-chemo demonstrated a significant improvement in progression-free survival (PFS) versus R-chemo, with a manageable safety profile (Marcus, et al. 2017); this efficacy benefit was maintained after 5 years of observation (Townsend, et al. 2020). Aims: To report the final analysis of the GALLIUM study after a median observation time of 8 years. Methods: Pts aged ≥18 years with previously untreated histologic Grade 1–3a FL requiring treatment were enrolled. Pts were randomized 1:1 to receive G 1000mg intravenously (IV; Days [D]1, 8 and 15 of Cycle 1 and D1 of subsequent cycles) or R 375mg/m2 IV (D1 of each cycle) plus chemo for 6 or 8 cycles depending on the chemo backbone selected at each institution (cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP]; cyclophosphamide, vincristine, and prednisolone [CVP]; or bendamustine). Pts attaining a complete or partial response received maintenance with the same antibody every 2 months for 2 years or until disease progression (PD). The primary endpoint was investigator-assessed PFS; secondary endpoints included time-to-next anti-lymphoma treatment (TTNLT), overall survival (OS) and incidence of adverse events (AEs). All pts provided written informed consent. Results: 1202 pts with FL were enrolled (G-chemo, n=601; R-chemo, n=601). As of July 30, 2021, median observation time was 8 years. Seven-year PFS was improved with G-chemo (63.4%) versus R-chemo (55.7%; hazard ratio [HR], 0.77; 95% confidence interval [CI]: 0.64–0.93; p=0.006; Figure). TTNLT was also improved with G-chemo versus R-chemo (HR, 0.71; 95% CI: 0.58–0.87; p=0.001); the proportion of pts who had not started their next treatment at 7 years was 74.1% and 65.4%, respectively. Disease transformation was observed in 4.2% of pts with G-chemo and 5.0% of pts with R-chemo. Seven-year OS was similar in both arms, 88.5% with G-chemo versus 87.2% with R-chemo (HR, 0.86; 95% CI: 0.63–1.18; p=0.36). Seventy-five pts in the G-chemo arm and 86 pts in the R-chemo arm had died, most commonly due to PD (4.2% and 6.0%, respectively). The incidence of serious AEs (SAEs) was 48.9% with G-chemo (28.2% and 24.4% during induction and maintenance, respectively) and 43.4% with R-chemo (24.6% and 21.7%, respectively). Rates of fatal AEs were similar with G-chemo (4.4%) and R-chemo (4.5%); pneumonia was the most common fatal AE (0.8% [n=5] and 0.2% [n=1], respectively) and SAE (5.9% [n=35] and 6.2% [n=37], respectively). Second malignancies occurred in 13.1% of pts in the G-chemo arm and 9.9% of pts in the R-chemo arm. After adjusting for observation time, rates were similar between arms. These safety findings are consistent with previous analyses. Image:Summary/Conclusion: After a median observation time of 8 years, a meaningful improvement in PFS was maintained with G-chemo versus R-chemo in pts with previously untreated FL, confirming the role of G-chemo as a standard of care for the first-line treatment of pts with FL.

Background: Limited evidence-based management guidelines for resectable intrahepatic cholangiocarcinoma (ICC) exist. We evaluated utilization rates and outcomes of ICC treated with neoadjuvant chemotherapy, in relation to other treatment strategies. Methods: Patients ≥18 years with clinical stage I-III ICC undergoing curative-intent surgery from 2006-2016 were identified from the NCDB. Patients were stratified by year of diagnosis and treatment regimen: surgery alone, neoadjuvant therapy followed by surgery (NAT), or surgery followed by adjuvant therapy (AT). Predictors of treatment regimen utilization were identified, and oncologic outcomes were compared. Results: 2,736 patients with resectable ICC were identified. Although chemotherapy utilization was low, NAT use increased from 4.3% to 7.2% (p=0.011). With regard to treatment regimen utilization, higher clinical stage was predictive of use of NAT. Higher pathologic stage and positive resection margins were predictive of use of AT. The risk of death from ICC decreased over the study period (2013-2016 vs. 2006-2008: aHR 0.70, 95%CI 0.60-0.81; 2009-2012 vs. 2006-2008: aHR 0.72, 95%CI 0.62-0.82). Neither receipt of NAT nor AT was associated with decreased risk of death; however, patients receiving NAT were more likely to undergo margin-negative resections (72.5% vs 62.6%, p=0.027). Margin-positive resections resulted in increased risk of death (aHR 1.74, 95%CI 1.52-1.99). Conclusion: Utilization of NAT for treatment of ICC has increased, and the risk of death from ICC has decreased. NAT is more likely to result in margin-negative resections, which are associated with decreased risk of death. Prospective studies evaluating NAT as first-line treatment for patients with high-risk resectable ICC are needed.

Zanubrutinib is a potent, specific next-generation BTK inhibitor with high selectivity for BTK vs the TEC- and EGFR-family kinases, which may be related to off-target toxicities. This is a single-arm, multicenter study of adults with R/R MZL who previously received ≥1 prior therapy including ≥1 CD20 antibody regimen. All received zanubrutinib 160 mg bid until disease progression/unacceptable toxicity. Primary endpoint was overall response rate (ORR) by independent review committee (IRC). Secondary endpoints include investigator-assessed (INV) ORR, duration of response (DOR), progression-free survival (PFS), and safety. By January 11, 2021, 68 patients (pts) were enrolled and treated. Median age was 70 years (range, 37-95). Subtypes included extranodal (38%), nodal (38%), splenic (18%), and indeterminate in 6% of pts. Median number of prior therapies was 2 (range, 1-6), and 32% had disease refractory to last therapy. Median duration of drug exposure was 59.1 weeks (range, 3.7-84.1). At a median follow-up of 15.5 months (range, 1.6-21.7), INV ORR was 74% with a CR rate of 24%. Responses were observed in all subtypes. Median DOR and PFS were not reached. IRC review is ongoing. Twenty-eight (41%) pts discontinued treatment. The most common treatment-emergent AEs reported in ≥10% of pts were diarrhea (22%), bruising (21%), and constipation (15%). Neutropenia was the most common grade ≥3 AE (10%). All-grade AEs of interest included neutropenia (13%), thrombocytopenia (13%), atrial fibrillation/flutter (3%), and hypertension (3%). No major/serious hemorrhage was reported. No AEs led to dose reductions. Zanubrutinib demonstrated high response rates and durable disease control with a favorable safety profile in pts with R/R MZL. EA – previously submitted to EHA 2021. The research was funded by: BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc., San Mateo, CA, USA Conflicts of interests pertinent to the abstract Research funding: BeiGene, Celgene, Roche, Takeda, PCYC, Janssen Consultant or advisory role AbbVie, AstraZeneca, Janssen, BeiGene Other remuneration: Speakers' Bureau: AbbVie, AstraZeneca, Janssen, BeiGene Consultant or advisory role BeiGene, Celgene, Gilead, Karyopharm, Roche, Takeda Honoraria: Roche Research funding: Genmab, BeiGene, Pharmacyclics, Roche Educational grants: Bristol Meyers Squibb, Roche, Janssen, Celgene Consultant or advisory role Celgene, Janssen, BeiGene, Kite Honoraria: Roche, Recordati Consultant or advisory role Kite, Cellectar Research funding: Roche/Genetech, Celgene, BeiGene Consultant or advisory role Eusa, AbbVie, Janssen Research funding: Janssen Consultant or advisory role Verastem, Celltrion, Gilead, Janssen-Cilag, Bristol Meyers Squibb, Sanofi, Servier, Sandoz, MSD, TG Therapeutics, Takeda, Roche, Eusapharma, Kyowa Kirin, ADC Therapeutics Other remuneration: Speakers' Bureau: Verastem, Celltrion, Gilead, Janssen-Cilag, Bristol Meyers Squibb, Servier, MSD, TG Therapeutics, Takeda, Roche, Eusapharma, Kyowa Kirin Research funding: AbbVie, Pharmacyclics, AstraZeneca, Bristol Meyers Squibb, Celgene Employment or leadership position: University of Auckland Consultant or advisory role Janssen, Roche Honoraria: Janssen, Roche Research funding: BeiGene, Roche, Shire Educational grants: Roche Consultant or advisory role MEI Pharma Consultant or advisory role BeiGene, Genentech, Janssen, Kite/Gilead, Morphosys, Pharmacyclics Research funding: AbbVie, Genentech, Xencor, Infinity, TG Therapeutics, Acerta, Kite, AstraZeneca, SeaGen, VelosBio Consultant or advisory role Janssen, Novartis, Gilead, Roche, Celgene/Bristol Myers Squibb Honoraria: Janssen, Novartis, Gilead, Roche, Celgene/Bristol Myers Squibb Educational grants: Roche, Gilead, Celgene, Bristol Myers Squibb, Novartis Consultant or advisory role Amgen, Servier, Celgene Research funding: Novartis, Janssen, AbbVie, Roche, Amgen, Celgene, Bristol Meyers Squibb, Takeda, Incyte, Pfizer, BeiGene, Oncopeptides, AB, Verastem, Karyopharm, Archiegn, CTI Biopharma Corp, Debiopharm International, Morphosys, Fribrogen, Onconova Therapeutics Inc. Educational grants: Roche, Takeda, AbbVie, Novartis, Sanophy Genzyme, Verastem, Bristol Meyers Squibb Consultant or advisory role Roche Honoraria: Janssen, Celgene, Gilead Educational grants: Amgen Consultant or advisory role Takeda, Gilead, BeiGene Educational grants: Takeda, Janssen Other remuneration: Speakers' Bureau: Takeda, Gilead, AbbVie, Janssen Honoraria: AbbVie Consultant or advisory role Roche, EUSA pharma, George Clinical Research funding: Roche Educational grants: Roche Other remuneration: Speakers' Bureau: Roche Employment or leadership position: BeiGene Stock ownership: BeiGene Employment or leadership position: BeiGene Stock ownership: BeiGene Employment or leadership position: BeiGene Stock ownership: BeiGene Educational grants: BeiGene Other remuneration: Patents, Royalties, OtherIntellectual Property: BeiGene Consultant or advisory role Roche, Janssen, AbbVie, Celgene, Takeda, Merck, Gilead, Mundipharma, AstraZeneca, CSL Honoraria: Roche, Janssen, AbbVie, Celgene, Takeda, Merck, Gilead, AstraZeneca Research funding: BeiGene, Roche, Janssen, AbbVie, Takeda, Merck, Gilead, Epizyme, AstraZeneca Educational grants: Roche

Introduction: The Phase III GALLIUM study (NCT01332968) showed that obinutuzumab (GA101; G) significantly prolonged PFS in previously untreated follicular lymphoma (FL) pts relative to rituximab (R) when combined with chemotherapy (chemo; CHOP, CVP or bendamustine [B]). Grade 3–5 AEs and SAEs were more common with G-chemo. Updated results for each immunochemotherapy regimen are reported here. Methods: Pts were aged ≥18 years with documented, previously untreated FL (grades 1–3a), advanced disease (stage III/IV or stage II with tumour diameter ≥ 7 cm), ECOG PS 0–2, and requiring treatment according to GELF criteria. Chemo regimen was allocated by centre. Pts were randomised 1:1 (stratified by chemo, FLIPI-1 group and geographical region) to R 375 mg/m2 on day (D) 1 of each cycle (C) or G 1000 mg on D1, 8 and 15 of C1 and D1 of C2–8, for 6 or 8 cycles depending on chemo. Pts with CR or PR at end of induction (per Cheson 2007) continued to receive R or G every 2 months for 2 years or until progression. The cut-off date for this analysis was 10 September 2016. All pts gave informed consent. Conclusions: In treatment-naive FL pts, PFS was superior with G-chemo relative to R-chemo with consistent effects across chemo regimens. Some differences were seen in safety profiles between chemo regimens, but comparisons may be confounded by the lack of randomisation. Keywords: follicular lymphoma (FL); obinutuzumab; rituximab.

Introduction: Although advanced age is a well-known adverse prognosis factor in first-line FL, with age >60 being one of the five adverse prognosis factor retained in the FLIPI score, little is known about characteristics and treatment outcomes for young patients. The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group conducted a pooled analysis to compare characteristics and treatment outcomes of young patients aged <40 to patients aged 40–60. Method: Individual patient data from 18 randomized first-line trials included in the FLASH database were obtained for 4249 patients aged <60. Early disease outcomes were evaluated by complete response rate at 24 and 30 months after enrollment (i.e., initiation of induction treatment; CR24 and CR30). Time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were defined in the primary FLASH study (Shi Q et al., JCO 2016). Multivariable stratified Cox models and logistic regression with generalized estimating equation were used to assess the associations between age <40 and outcomes. Variables adjusted were FLIPI risk group, rituximab use and performance status (PS). Results: Among 4249 patients included in 18 trials, 673 (16%) were <40 and 3576 (84%) 40–60. The two groups were similar in Ann Arbor stage, FLIPI risk group, use of rituximab, ECOG PS group (0–1 or ≥2), LDH value, Hb and B2-microglobulin at baseline. Young patients differed significantly only in the number of involved nodal areas (≥5 in 73% of young patients vs 66%, p = 0.0021). The two groups had similar CR24 (32% vs 29%, p = 0.32), CR30 (31% vs 30%, p = 0.57), 5-year estimates for PFS of 44% (95% CI = 41–49 for young patients and 43–46 for patients 40–60) (p = 0.30) and TTP (median TTP 3.9 y vs 4.0 y, HR = 0.96, 95% CI = 0.86–1.08, p = 0.52). OS was significantly higher for young patients with 5-year estimates of 88% (95% CI = 85–90) versus 84% (95% CI = 83–86) (p = 0.003). After adjusting with FLIPI risk group, rituximab use and PS, age <40 was a significant predictor of OS, but not of PFS, TTP or achievement of CR30. Of note, for patients having received rituximab in their first line treatment (n = 1846), patients <40 (n = 265) and patients aged 40–60 (n = 1581) had respective 5-year estimates for PFS of 54% (95% CI = 48–62) and 54% (95% CI = 51–57) (p = 0.70) and for OS of 96% (95% CI = 94–99) versus 90% (95% CI = 88–91) (p = 0.0004) (Figure). No significant difference in OS was observed between the 2 groups for patients not having received rituximab in first line. These data suggest that among patients treated with rituximab, despite an identical PFS, survival outcomes were statistically higher in the <40 group compared to 40–60. Keywords: follicular lymphoma (FL); prognostic indices.

The prognosis of patients with primary central nervous system lymphoma (PCNSL) has improved in recent years. This has partly been achieved by remission induction protocols incorporating high-dose methotrexate (HD-MTX) and rituximab. Given the high rates of relapse, consolidation therapy is usually considered in first response. Whole brain radiotherapy may prolong PFS but appears to confer no long-term survival advantage and is associated with significant neurocognitive dysfunction. Attempts to improve efficacy and reduce neurotoxicity of consolidation therapy have included thiotepa-based high-dose chemotherapy and autologous stem cell transplant (HDC-ASCT). This multi-centre, retrospective study reports the outcome of 70 patients undergoing HDC-ASCT for PCNSL in the United Kingdom. The median age at diagnosis was 56 years and all patients received HD-MTX-containing induction regimens. All patients underwent HDC-ASCT in first response. The rate of complete response increased from 50% before HDC-ASCT to 77% following HDC-ASCT. Treatment-related mortality was 6%. At a median follow-up of 12 months from HDC-ASCT, the estimated 1- and 2-year PFS rates were 71.5% and overall survival 86.4% and 83.3%, respectively. These data are comparable to published studies of HDC-ASCT for PCNSL, supporting its feasibility and efficacy.

Introduction: In previously untreated patients (pts) with FL in the National Lymphocare Study who received immunochemotherapy, progression of disease (POD) in the first 24 months (POD24) predicted poor overall survival (OS) (Casulo et al. J Clin Oncol 2015). In the GALLIUM study (NCT01332968) in previously untreated FL pts, the primary endpoint of investigator (INV)-assessed progression-free survival (PFS) was significantly improved with obinutuzumab (GA101; G)-based vs rituximab (R)-based immunochemotherapy (Marcus et al. Blood 2016). This exploratory analysis aimed to assess whether POD24, and POD at time points other than 24 months, predicted OS in GALLIUM.