Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1,384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n=749) or at the end (n=635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT; 5.7% vs 5.8%, p=0.98, 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n=1,253). In patients with high CNS international prognostic index (n=600), 3-year CNS relapse rate was 9.1% with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX versus EOT, with 308/1573 (19.6%) i-HD-MTX treatments resulting in delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk versus i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Summary Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression‐free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8–16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.

This experimental study compares the effects of early postoperative administration of three enteral diets of different compositions on the healing of colonic anastomoses. Sixty Wistar rats were subjected to colonic anastomoses. Following surgery, the rats were randomly allocated to four groups of 15 each. The rats in control group A received an electrolyte and glucose solution, the rats in group B received a complete balanced nutrition, in group C a complete balanced nutrition supplemented with fiber and in group D an isocaloric specialized elemental nutrition enriched with glutamine. The rats were sacrificed on day 7 following operation. Rupture of the anastomosis was higher in rats of the control group compared to the other three groups. Adhesion formation was more extensive in group A in comparison to the other three groups. The anastomotic bursting pressures were statistically significantly higher in groups C and D compared to the other two groups (p < 0.05). There was no statistically significant difference between group C and D (p > 0.05) while a statistically significant difference was noted between group B and group A (p < 0.05). Histological examination showed more profound inflammatory reaction in group A compared to the other three groups. There was also a statistically significant difference between group B and groups C and D while inflammatory reaction was of no statistically significant difference between group C and group D. Healing of the anastomoses was statistically significantly impaired in group A compared to the other three groups. There was no statistically significant difference between group C and group D while a statistically significant difference was found between group B and groups C and D. In conclusion, early postoperative enteral feeding improves healing of experimental colonic anastomoses in rats. This effect was more evident when fiber-supplemented diets or diets enriched with glutamine were administered.

Introduction Central nervous system relapse (secondary central nervous system lymphoma -SCNS) is an uncommon but devastating complication of aggressive B-cell lymphoma. Patients (Pts) with CNS-IPI 4-6 are at greatest risk (10.2% at 2 years). Intravenous high-dose methotrexate (HD-MTX) is widely used to mitigate SCNS risk but data supporting this practice are limited. Methods We performed a multicentre, retrospective study at 21 sites in Australia, Asia, North America and Europe. Chart or registry review was performed for consecutively diagnosed pts with diffuse large B-cell lymphoma (DLBCL) and CNS-IPI 4-6, high grade B-cell lymphoma (HGBL) with rearrangements of MYC+BCL2 and/or BCL6 and primary breast/testicular DLBCL irrespective of CNS-IPI. Pts were diagnosed between 2000-2020, 18-80 years at diagnosis, and treated with curative intent anti-CD20 based chemo-immunotherapy. Pts with CNS involvement at diagnosis were excluded. HD-MTX was defined as at least one cycle of intravenous MTX at any dose. Time to SCNS was calculated from date of diagnosis (all-pts), and from the end of frontline systemic lymphoma therapy, defined as 6x21 days from diagnosis (complete response (CR-pts)), until SCNS, systemic relapse, death, or censoring, whichever came first. Cumulative risk of SCNS was computed using the Aalen-Johansen estimator treating death and systemic relapses as competing events. Adjusted cumulative risks were obtained by using an inverse probability of treatment weighting approach. The average treatment effect was computed as the difference in adjusted 5-year risk of SCNS. Results - 2300 and 1455 pts were included in the all-pts and CR-pts analyses, respectively. Baseline demographics and details of therapy are summarised in Table 1. Except for a predominance of males, pts ≤60 years and pts with ECOG 0-1 in the HD-MTX vs no HD-MTX groups, the demographics and treatments were well balanced. At a median follow up of 5.9 years (range 0.0-19.1) and 5.5 years from diagnosis (range 0.0-18.7), 201/2300 and 84/1455 pts experienced CNS events in the all-pts and CR-pts analyses respectively. For all-pts(n=2300), CNS-IPI was 4-6 in 2052(89.2%), with R-CHOP-like therapy given to 93.8%. 410 pts (17.8%) received HD-MTX (265 HD-MTX alone, 145 in combination with intrathecal methotrexate (IT-MTX);435 received IT-MTX alone;1455 received neither. There were 32/410 and 169/1890 SCNS events, with median time from diagnosis to SCNS of 8.8 and 6.7 months in the HD-MTX and no HD-MTX groups respectively. 5-year OS was 70% (95% CI, 65-76%) and 55% (95% CI 53-57%) in HD-MTX and no HD-MTX groups respectively. There was no difference in the adjusted 5-year risk of SCNS between the HD-MTX and no HD-MTX groups (8.4% vs 9.1%, adjusted hazard ratio [HR] 0.71, p=0.100) (Figure 1). For CR-pts(n=1455), CNS-IPI was 4-6 in 1267(87.0%), with R-CHOP-like therapy given to 93.3%. 284 pts (19.5%) received HD-MTX (170 HD-MTX alone, 114 with IT-MTX);298 received IT-MTX alone;873 received neither. There were 16/284 and 68/1171 SCNS events, with median time from diagnosis to SCNS of 11.0 and 10.3 months in the HD-MTX and no HD-MTX groups respectively. 5-year OS was 74%(95% CI 67-81%) and 75%(95% CI 72-78%) in the HD-MTX groups and no HD-MTX groups respectively (adjusted HR 1.08, p=0.622). There was no difference in the 5-year risk of CNS relapse between the HD-MTX and no HD-MTX groups 5.0% vs 6.0% (adjusted HR 1.03, p=0.903) (Figure 2). Exploratory analysis of the impact of HD-MTX among the highest risk groups CNS IPI 5 (n=368), CNS-IPI 6 (n=59) and CNS-IPI 6 plus all pts with testicular, renal or adrenal involvement (n=349) did not reveal differences in SCNS rates in HD-MTX treated pts. Additional subgroup analyses will be presented at the meeting. Conclusions To our knowledge, this is the largest study of the efficacy of HD-MTX in reducing SCNS events focusing exclusively on high-risk pts. The overall incidence of CNS relapse observed was consistent with previous reports in similar patient cohorts at 9%. The use of HD-MTX did not lower SCNS rates overall or when analysis was confined to CR pts at completion of curative intent therapy to compensate for potential immortal bias associated with HD-MTX therapy. Despite the limitations of the non-randomized and retrospective design, it appears unlikely that HD-MTX is associated with a clinically meaningful reduction in SCNS rates in pts with high risk for SCNS. Figure 1 Figure 1. Disclosures Lewis: AstraZeneca: Consultancy, Honoraria; Novartis: Patents & Royalties: Conference attendance; Janssen: Honoraria, Patents & Royalties: Conference attendance; Roche: Consultancy, Honoraria. Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Bobillo: F. Hoffmann-La Roche Ltd: Consultancy, Speakers Bureau; Gilead: Speakers Bureau. Ekstroem Smedby: Takeda: Consultancy; Janssen Cilag: Research Funding. Savage: Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; Roche: Research Funding; Takeda: Other: Institutional clinical trial funding; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Eyre: Beigene: Honoraria, Research Funding; Incyte: Consultancy; Secura Bio: Consultancy, Honoraria; Janssen: Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Roche: Consultancy, Honoraria. Cwynarski: Incyte: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Atara: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences. Stewart: Teva: Honoraria; Sandoz: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria. Bishton: Gilead: Honoraria, Other: Travel grants; AbbVie: Honoraria, Other: Travel grants; Celgene/BMS: Honoraria, Other: travel grants; Celltrion: Honoraria, Other: Travel grants; Takeda.: Honoraria, Other: Travel grants . Fox: F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Eloranta: Janssen Pharmaceutical NV: Other: NV. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Manos: Bristol-Myers Squibb: Other: Travel and meetings. Hawkes: Specialised Therapeutics: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Antigene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Minson: Novartis: Research Funding; Hoffman La Roche: Research Funding. Dickinson: Celgene: Research Funding; Amgen: Honoraria; Takeda: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Øvlisen: Abbvie: Other: Travel expenses. Gregory: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Talaulikar: Roche: Honoraria, Research Funding; Jansenn: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; EUSA Pharma: Honoraria, Research Funding. Maurer: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genentech: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding. El-Galaly: Abbvie: Other: Speakers fee; ROCHE Ltd: Ended employment in the past 24 months. Cheah: Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Beigene: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory.

Background: Novel strategies are needed to improve upon the 60% cure rate of upfront R-CHOP in advanced DLBCL. Single-agent immune checkpoint inhibition (ICI) has limited efficacy in heavily pre-treated DLBCL (response rate &lt;10%, Ansell JCO 2019), potentially due to residual immunocompromise from prior therapy. Frontline ICI, given when host immunity is relatively intact, may improve these outcomes. Concurrent ICI with R-CHOP is safe (Smith BJH 2020) but corticosteroid-related immunosuppression may negate ICI efficacy. These factors, along with evidence that ICI sensitises non-Hodgkin lymphoma to subsequent chemotherapy (Carreau BJH 2020), support a sequential treatment strategy. Avelumab (Av) is an anti-PDL1 monoclonal antibody with antibody dependent cell cytotoxicity (ADCC) activity which acts synergistically with rituximab (R) in vitro. We report the results of a phase II single arm study assessing safety of 1st line sequential AvR induction, R-CHOP & Av maintenance for DLBCL. Methods: Patients aged ≥18 years, ECOG 0-2 with untreated stage II-IV DLBCL and no active autoimmune disease were treated with AvR induction x2 cycles q2-weekly (Av 10mg/kg IV + R 375mg/m2 IV), followed by R-CHOP21 x 6 cycles then Av 10mg/kg x 6 cycles q2-weekly if in complete metabolic response (CMR) post R-CHOP. The primary endpoint was the rate of grade 3/4 immune-related adverse events (irAE). Secondary endpoints included overall response rate (ORR), failure free survival (FFS), overall survival (OS) and overall toxicity. Response was determined centrally by PET-CT (Lugano 2014 criteria). CMR rates by PET-CT post AvR induction and post C2 R-CHOP were exploratory endpoints. Genomic analysis was performed including next generation sequencing (NGS) based sequence variant detection, copy number analysis and structural variant detection. Results: 28 pts were enrolled from Dec 2017 to Oct 2019. Key baseline characteristics included median age 54 yrs (range 20-79); stage III/IV disease 68%; elevated LDH 61%; IPI ≥2 25%. Histology included 21 DLBCL NOS (75%; 14 GCB, 7 non-GCB by Hans algorithm), 6 primary mediastinal B-cell lymphoma (PMBCL; 21%) and 1 EBV positive DLBCL (4%). The study met its pre-specified primary endpoint of G3/4 irAE &lt;30%. Grade 3/4 irAEs included hepatitis (n=1) and rash (n=2). G1/2 irAEs occurred in 71% (20/28) as follows: rash 53%, liver dysfunction 26%, hyper/hypothyroidism 29% and diarrhoea 21%. 79% had G3/4 toxicity, predominantly haematological, related to RCHOP with febrile neutropenia/infection in 28% of pts. ORR post R-CHOP was 89% (all CR) (Figure 1). The ORR to 2 cycles of induction AvR was 60%, including 6 CMR (21%) across all diagnostic/histologic subgroups (n=1 PMBCL, n=2 non-GCB DLBCL, n=3 GCB DLBCL; Figures 1 and 2). Six pts (21%) progressed during AvR induction (with 1 pt completing only 1 x AvR cycle); all subsequently responded to R-CHOP. With a median follow-up of 16 months, 1-year FFS was 76% and OS 89%. Treatment was discontinued early in 5 pts; 2 during R-CHOP due to progressive disease and 3 during Av maintenance (n=1 immune hepatitis; n=1 pulmonary embolism initially reported as pneumonitis; n=1 progressive disease). Alterations in the CD274/PDCDLG2 locus were identified by NGS in 3 of 27 evaluable pts (n=2 PMBCL, n=1 EBV+ DLBCL). Full genomic analysis to identify factors associated with response will be presented. Conclusion: Sequential AvR induction, R-CHOP and Av maintenance in pts with newly diagnosed DLBCL is feasible with a manageable toxicity profile and a high CR rate. Responses to AvR alone were higher than expected based on the relapsed/refractory population and may suggest superior efficacy of ICI in the frontline setting. These results support ongoing sequential studies of immune priming with PD1/PDL1 inhibition prior to R-CHOP in DLBCL. Acknowledgements: Merck KgA for avelumab plus funding. Tour de Cure Scott Canning Early Career Grant (E Hawkes) and Wilson Centre for Lymphoma Genomics for biomarker testing. Disclosures Hawkes: Astra Zeneca: 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; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding, Speakers Bureau; BMS celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Merck Sharpe &Dohme: Membership on an entity's Board of Directors or advisory committees, Research Funding; takeda: Speakers Bureau; Merck KgA: Research Funding. Chong:Merck Serono: Research Funding; Bristol-Myers Squibb: Research Funding; Hutchison Medipharma: Research Funding; Bayer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Servier: Research Funding; Isofol: Research Funding. Blombery:Novartis: Consultancy; Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria. Barraclough:Roche: Other: Conference sponsorship. Keane:Celgene: Honoraria, Other: Travel; BMS: Research Funding; Roche: Honoraria, Other: Travel, Speakers Bureau; MSD Oncology: Honoraria, Other: Travel; Gilead: Honoraria, Other: Travel, Speakers Bureau. Fong:Pfizer: Honoraria; Astellas: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria; AbbVie: Honoraria. Manos:Bristol-Myers Squibb: Other: Conference sponsorship. OffLabel Disclosure: Avelumab is an anti-PDL1 monoclonal antibody. Inhibition of the PD1/PDL1 pathway stimulates anti-tumour immunity.