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Introduction Following completion of chemotherapy with curative intent for DLBCL, for those in remission (CR), numerous national and international guidelines suggest on-going follow-up primarily to detect relapse of disease. For example, the NCCN guidelines suggest that clinical history, examination and blood investigations should be performed every 3-6 months for 5 years and as clinically indicated thereafter. This is essentially a "screening programme" for an at-risk population that continues based on historical routine rather than due to evidence it is of benefit to the patient. Numerous papers have been published suggesting that routine surveillance scans or bloods such as LDH are not useful in this setting. We sought to analyse whether the screening procedures that are performed in the follow-up setting are useful in the detection of relapse in patients followed up in a single centre. Uniquely, we examined each time point separately rather than group all follow-up events together. Methods Data was obtained retrospectively from electronic patient records for all patients in remission following treatment with frontline chemotherapy for DLBCL at the Royal Marsden Hospital between 2005-2016. Screening assessments analysed were symptoms check, clinical examination, LDH >upper limit of normal, lymphocyte: monocyte ratio (LMR) Results Complete data from 262 patients who achieved a CR and were followed up was available. Median age was 63 years (17-94) with 59 patients with stage 1 disease, and 100 with stage 4 disease. The relapse rate was 59/261 (23%), with a median time to relapse of 13 months (2-120). Of the 59, 52 had symptoms they had noted prior to clinic, of whom 28 requested an early appointment to clinic and 22 waited until their routine clinic appointment or sought advice from other health professionals initially. Only 7 patients were picked up only on investigations performed at the hospital, 1 with hypercalcemia and 6 on routine scan with no symptoms, 3 at 3-6months, 2 and 9-12months and 1 at 12-18 months. Of these, 4/7 patients achieved a CR with subsequent therapy. The remaining 202 patients had 2853 clinic appointments, median number per patient 13 (1-44). The negative predictive value of clinical history, examination, LDH, LMR and CT scan was consistently very high (>90%) at all time points. However, the positive predictive value was low for symptoms, 0-35% with the higher values being in the first year. Clinical examination had better PPV due to fewer positive results, including both true and false. LDH and LMR were associated with a poor PPV at all time points. PPV for CT scans was variable (Table 1). Conclusions The "screening" of patients who are in remission from DLBCL requires considerable health resources and cost and also leads to increased exposure of the patient to hospitals which during the COVID-19 pandemic is being discouraged. Likelihood of relapse (which decreases with time) has an impact on the effectiveness of a screening programme, the relapse rate in this cohort was 23% in keeping with other published data. Importantly, the majority of patients had symptoms suggestive of relapse and so the screening was not required. In the few that were asymptomatic when relapse was diagnosed, there was insufficient data to know whether this earlier detection led to a better outcome, however this has not been seen in other published cohorts. Finally the effectiveness of the screening is dependent on the predictive value of the "tests" being used and this dataset shows that whilst the negative predictive value is high, the positive predictive value is very variable and generally poor for all tools used. We propose that educating the patient regarding symptoms of relapse and having patient directed clinical follow-up rather than routine appointments would lead to marked savings in health resources, reduce hospital exposure of patients by eliminating unnecessary visits without compromising the outcome of the patients. Disclosures Cunningham: Lilly: Research Funding; MedImmune: Research Funding; Merck: Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Bayer: Research Funding; Janssen: Research Funding; Merrimack: Research Funding; Amgen: Research Funding; 4SC: Research Funding; Clovis Oncology: Research Funding; Sanofi: Research Funding; OVIBIO: Membership on an entity's Board of Directors or advisory committees. Iyengar:Beigene: Consultancy; Janssen: Honoraria; Abbvie: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau. El-Sharkawi:Abbvie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Innate: Consultancy.

BACKGROUND Outcomes for patients (pts) with primary CNS diffuse large B cell lymphoma (PCNSL) have improved over recent years, largely through optimisation of first-line methotrexate (MTX)-containing protocols and dose-intensive chemotherapy consolidation. However, 30-50% of pts experience refractory or relapsed (r/r) disease, which confers very poor outcomes and short survival. By contrast to systemic DLCBL, there is no accepted standard approach for r/r PCNSL. Thiotepa is an alkylating agent highly efficient at crossing the BBB and widely incorporated within high-dose therapy and autologous stem cell transplantation (HDT-ASCT) protocols for PCNSL, but has not undergone dose-finding studies nor been incorporated within salvage regimens for PCNSL. The TIER study investigates the safety and efficacy of adding thiotepa, in a dose-escalation design, to the Rituximab, Ifosphamide and Etoposide (R-IE) salvage regimen1. METHODS TIER is an open label, phase I/II UK NCRI TAP study for pts with r/r PCNSL, previously treated with a high-dose MTX-based regimen. In phase I, the RP2D of thiotepa within the TIER combination was established using a 3+3 design, with dose escalations of 30, 40 and 50mg/m2 (dose level 2 (n=4), 3 (n=5) and 4 (n=27) respectively), given on day 5 of R-IE cycle1. The Phase II primary endpoint was overall response rate (ORR) after cycle 2 of TIER (C2) by centrally reviewed contrast-enhanced MRI2, on an intention-to-treat (ITT) basis. Further treatment and consolidation after the primary endpoint MRI was at the discretion of investigators. Key secondary end-points were 2-year PFS, EFS and OS. RESULTS Thirty-six pts were recruited from Jun 2015-Apr 2019 at 13 centres (characteristics: Table 1). The median number of prior lines was 2 (range 1-4) with 44% of patients deemed refractory to their previous line of therapy. During phase I (n=10) no dose limiting toxicities (DLTs) were observed up to and including 50mg/m2 thiotepa, constituting the RP2D (n=27). 56 cycles of TIER were administered across both phases; 5 pts had >1 dose reductions. Median time between C1D1 and C2D1 was 24.7 days (range 22-38). Relative mean dose intensity of thiotepa, ifosphamide and etoposide was 71.8 (SD 44.9), 76.4 (SD 41.6), and 76.8 (SD 41.8) respectively. Further therapy after 2 cycles of TIER was delivered to 41.7% of pts (16.7% ASCT, 22.2% TIE, and 2.8% WBRT). The most common grade 3 / 4 adverse events were thrombocytopenia and neutropenia (47.2 and 55.6% occurring in 15 and 18 pts respectively). 17 serious adverse events (SAEs) were reported in 12 pts, of which 4 were haematological. Of these, 13 were considered related to TIER. Commonly occurring non-haematological SAEs were respiratory tract infections (23.5%) and seizures (11.8%). At data lock, 10/27 pts had responded to treatment as assessed by local investigators (ORR 37%, CR rate 15%). 13 pts were non-evaluable (7 progressed prior to C2 scan, 2 withdrew consent, and 4 awaiting scans) and classed as non-responders. Following data lock, responses were reported for 3 further pts (2 by local investigators and 1 by central review), resulting in a provisional ORR of 13/27 (48%). For the ITT population, median OS time was 3.52 months (95% CI 2.50, 14.17), and median PFS 2.86 months (95%CI 2.34, 6.05) (Figure 1). 6 pts underwent ASCT consolidation after TIER, of whom 2 have relapsed. CONCLUSIONS This is an early analysis of data from the phase I/II TIER study for a heavily pre-treated group of r/r PCNSL; the first such dose-escalation study for this patient group. Phase I determined a RP2D of 50mg/m2 of thiotepa incorporated in the R-IE regimen. There were no DLTs and toxicities, consistent with an intensive ifosphamide-based regimen. ORR was 10 pts (37%) with 3 further responses reported after data lock. If confirmed by central review, the primary endpoint of activity (ORR 40%) will have been reached. However, notwithstanding the response endpoint, most pts experienced very poor survival outcomes. These data describe the feasibility of TIER as a salvage regimen for r/r PCNSL but question the utility of this approach as a standard option, given the short PFS and OS times, except for the minority of pts who received ASCT. Biological and imaging sub studies are underway to identify predictors of outcome. In the modern era of effective first line immunochemotherapy approaches, pts with r/r PCNSL remain a major area of unmet need for whom novel experimental approaches are urgently required. Disclosures Fox: Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Martinez-Calle:ABBVIE: Other: Travel support. Collins:Gilead: Consultancy, Honoraria. Ferreri:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Roche: Research Funding; Kite: Consultancy. Davies:BioInvent: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Bayer: Research Funding; ADCT Therapeutics: Honoraria, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Johnson:Roche: Consultancy, Honoraria, Speakers Bureau; Takeda: Other: Travel, accomodations, expenses. Cwynarski:Adienne: Consultancy; Takeda: Consultancy, Other: conference and travel support , Speakers Bureau; Roche,: Consultancy, Other: conference and travel support, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy; Gilead: Consultancy, Other: conference and travel support, Speakers Bureau; Celgene: Consultancy; Atara: Consultancy; Janssen: Other: conference and travel support, Speakers Bureau.

Background: Despite numerous treatment (Tx) options, follicular lymphoma (FL) remains incurable, and established common treatments such as chemoimmunotherapy combinations and kinase inhibitors can have significant morbidity, especially in older patients or in those with comorbidities. G100 is a TLR4 (toll-like receptor 4) agonist that activates both the innate and adaptive arms of the immune system. When given intratumorally (IT), G100 triggers an anti-tumor immune response that leads to systemic tumor shrinkage (Flowers ASCO 2017). Initial data from a randomized study of the combination of G100 and pembrolizumab (P) demonstrated that the addition of P resulted in more PRs, abscopal tumor shrinkage, and a trend to a better PFS than G100 alone. In addition, an association between baseline tumor TLR4 expression by immunohistochemistry (IHC) and clinical response was observed (Flowers ASH 2017). We now present updated response data and long-term follow-up of this randomized study. Methods: Previously treated or Tx naïve FL pts with ≥2 tumor sites were eligible. Pts received 6-9 doses of IT G100 (G) weekly to a site treated with low dose radiation (RT, 2 Gy x2 doses). A 2nd course of G could be given without additional RT to an additional site. Pts were randomized to IT G (10 µg/dose) or IT G + P 200mg IV on Day 14 then q3wks for up to 2 years. Responses were evaluated by IrRC criteria based on bidimensional measurements (Wolchok ClCanRes 2009). Untreated sites were followed for abscopal response. Results: As of 3July2018, 26 FL pts were treated (13, G vs. 13, G + P). 7 and 5 pts were Relapsed/Refractory (R/R) in G and G+P, respectively. Median number of prior therapies were 3 for G and 4 for G+P and included 5pts previously Tx with auto-SCT. Median duration of observation was 14.3 and 16.6 mos for the G and G+P, respectively. G was well tolerated; related AEs were all grade (Gr) 1/ 2 with no G-related DLTs or SAEs. For G+P, 1 pt experienced Gr 2 hypothyroidism and 1pt, Gr 3 colitis/lab abnormalities/adrenal insufficiency (SAE). No deaths were reported. Overall best responses (PRs) were: 23% in pts on G and 54% in pts on G+P. In the R/R population, PRs occurred in 29% of pts on G and in 80% of pts on G+P. Median time to response was 2.3 mos (range 1.7-18.1) for G and 3.7 mos (range 2.2-17.1) for G+P, and included delayed responses at ≥18mos. Among pts with baseline TLR4high (≥50%) tumor expression, ORR was 17% for G (n=6) vs 75% for G+P (n=8). Within the GELF high tumor burden pts, PRs occurred in 0% of pts in G and in 33% of pts in G+P. Likewise, in pts failing R-Chemo Conclusions: Longer term follow-up of this Phase 2 study demonstrates that additional responses related to G100 continue to develop over time and they are durable. The combination with pembrolizumab is well tolerated and yields an increased clinical benefit both in the percentage of patients responding and its durability, including in patients at high risk with R/R FL. G100 may be an attractive option for R/R FL pts in combination with anti-PD-1 inhibitors or other therapies. Disclosures Flowers: Pharmacyclics: Research Funding; Pharmacyclics/ Janssen: Consultancy; Burroughs Wellcome Fund: Research Funding; Bayer: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; BeiGene: Research Funding; Denovo Biopharma: Consultancy; OptumRx: Consultancy; Gilead: Consultancy; Spectrum: Consultancy; V Foundation: Research Funding; Millennium/Takeda: Research Funding; Janssen Pharmaceutical: Research Funding; National Cancer Institute: Research Funding; Acerta: Research Funding; Abbvie: Consultancy, Research Funding; TG Therapeutics: Research Funding; Celgene: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Consultancy; Karyopharm: Consultancy. Panizo:Roche: Consultancy, Speakers Bureau; Acerta Pharma: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees. Isufi:Genentech: Consultancy; Novartis: Consultancy. Herrera:Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Research Funding; Immune Design: Research Funding; Merck, Inc.: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding. Cull:Celgene: Speakers Bureau. Bartlett:Acerta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Janssen: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImaginAB: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Millennium: Research Funding. de la Cruz-Merino:Roche: Consultancy, Other: travel, Speakers Bureau; Novartis: Consultancy, Other: travel, Speakers Bureau; BMS: Consultancy, Other: travel, Speakers Bureau; Merck: Consultancy, Other: travel, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: travel, Research Funding, Speakers Bureau. Houot:Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Chau:Five Prime Therapeutics: Other: Advisory Board; Bristol Meyers Squibb: Other: Advisory Board; Janssen-Cilag: Research Funding; Eli-Lilly: Honoraria, Other: Advisory Board, Research Funding; Roche: Other: Advisory Board; Merck Serono: Other: Advisory Board, Research Funding; MSD: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Sanofi Oncology: Research Funding; Bayer: Other: Advisory Board. von Keudell:Genentech: Consultancy; Bayer: Consultancy. Lu:Immune Design: Employment. Hsu:Immune Design: Employment. Halwani:Abbvie: Research Funding; Amgen: Research Funding; Bristol-Myers Squibb: Research Funding; Genentech, Inc.: Research Funding; Immune Design: Research Funding; Kyowa Hakko Kirin: Research Funding; Miragen: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding.

Introduction: Primary mediastinal B Cell Lymphoma (PMBL) is a high-grade non-hodgkin lymphoma with distinct clinical and biological features. Optimal chemotherapy for this lymphoma is not established but some centres favour more intensive regimes such as DA EPOCH-R over R-CHOP. The role of consolidation radiotherapy is yet to be clarified and whether it can be omitted in those patients with a negative end-of-treatment PET scan (EOT PET) regardless of induction chemotherapy. Furthermore, the occurrence of false positive EOT PET scans may lead to overtreatment. The aim of this study was to establish the outcomes of patients (pts) with PMBL who had been treated in a single centre. Methods: Pts diagnosed with PMBL between 2003 and 2015 in Royal Marsden Hospital were included. Data was collected from electronic patient records and PET CT images review. Survival was defined from date of diagnosis until date of death or date of last follow up. Results: Thirty-four pts were identified with characteristics as shown in the table. Median diameter of the mediastinal mass was 12cm (range 5.5 - 24cm); 25 (74%) pts had a mass of ≥ 10cm. The majority of pts received R-CHOP chemotherapy (2 had 14 day cycles, 30 had 21 day cycles), 1 R-GCVP and another R-PACEBOM. Median number of cycles of chemotherapy was 6 (range 1-8). Seven out of 32 (22%) pts received involved field radiotherapy (IFRT). EOT PET was available for 30 pts. Median time to obtaining EOT PET from completion of chemotherapy was 31 days (20-81). Twenty-three out of 30 pts had EOT PET negative disease with a Deauville score (DS) of 1-3. Twenty-one of these 23 pts did not receive IFRT. Two of these 21 pts relapsed in the mediastinum and were treated with salvage chemotherapy followed by autologous stem cell transplant (ASCT) of whom 1 died due to their lymphoma. The 2 patients who received consolidation radiotherapy remain in remission. Seven out of 30 pts had a positive EOT PET (DS 4-5); of whom 5 received IFRT. Two out of 5 patients relapsed and proceeded with further chemotherapy of whom 1 died due to treatment-related causes while the other 4 patients were alive at time of last follow-up. Two pts with a positive EOT PET did not have IFRT, 1 proceeded with salvage chemotherapy but died due to lymphoma and the other patient was followed up with serial PET scans and ultimately the residual avidity was considered to be due to thymic hyperplasia. Conclusion: Our analysis demonstrates that for the 23 patients who achieved a complete metabolic response on EOT PET the risk of relapse was low (9%) (despite that only 2 patients received consolidation radiotherapy) and only one patient (4%) died of lymphoma. Thus the majority of patients with a negative EOT PET scan following R-CHOP chemotherapy may not need consolidation radiotherapy. This finding should be taken into account when considering the risk/benefit of adding radiotherapy treatment to patients who are already in metabolic CR after chemotherapy. Consolidation radiotherapy is currently being investigated in a prospective IELSG37 trial, NCT01599559. Table. Table. Disclosures Chau: Eli-Lilly: Honoraria, Other: Advisory Board, Research Funding; Bristol Meyers Squibb: Other: Advisory Board; MSD: Other: Advisory Board; Bayer: Other: Advisory Board; Roche: Other: Advisory Board; Merck Serono: Other: Advisory Board, Research Funding; Five Prime Therapeutics: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Janssen-Cilag: Research Funding; Sanofi Oncology: Research Funding. Cunningham:Roche pharmaceuticals: Research Funding.

Background Spleen tyrosine kinase (SYK), a nonreceptor kinase with a key role in B-cell receptor signaling-driven tumorigenesis, is a viable target for inhibition in B-cell malignancies. SYK is also a key regulator of FMS-like tyrosine kinase 3 (FLT-3), which is mutated in 30% of pts with acute myeloid leukemia (AML; Puissant et al. Cancer Cell 2014;25:226-42). TAK-659, a selective, reversible, potent SYK/FLT-3 inhibitor demonstrated inhibition of SYK activity and cell proliferation in vitro and inhibited dose-dependent tumor growth in vivo in lymphoma xenograft models. The TAK-659 maximum tolerated dose (MTD) is 100 mg daily (QD) based on phase 1 data (NCT02000934; Petrich et al. Blood 2015;123:2693). Here we present updated safety and efficacy data from the expansion phase of this study. Methods Adult pts with advanced solid tumors/lymphoma, with no standard effective treatment available, received oral TAK-659 QD in 28-d cycles: 60-120 mg during dose escalation or 100 mg during dose expansion. AEs were assessed per NCI-CTCAE v4.03. Responses per RECIST v1.1 (solid tumors) or IWG modified criteria (lymphoma) were assessed between d22 and d29 (predose) of C2 (both phases), then during C4, C6, and every 3 cycles (escalation) or every even numbered cycle until C12, then every 4 cycles (expansion). During dose escalation, blood samples for plasma PK were collected predose and at multiple times postdose on d1 and d15 of C1; urine samples were collected on d15 of C1, 0-8 hrs postdose. Next-generation sequencing and NanoString analyses are planned to identify mutations correlating with clinical response and to classify lymphoma pts by cell of origin using Lymph2Cx signature. Results At data cut-off (April 27, 2016), 54 pts had received TAK-659. During dose escalation, 35 pts (18 solid tumor; 17 lymphoma [12 DLBCL; 4 FL, 1 MCL]) received TAK-659 QD at 4 dose levels: 60 mg (n=10), 80 mg (n=4), 100 mg (n=14), and 120 mg (n=7). During expansion, 19 lymphoma pts (18 DLBCL; 1 CLL) received TAK-659 QD at 100 mg (MTD). Median age for the overall population was 60.5 years (range, 23-82); 70% were male. Baseline characteristics for the 36 lymphoma pts are shown in Table 1. Of 30 DLBCL and 4 FL pts, 24 and 3, respectively, were response-evaluable as of June 9, 2016 (received ≥1 dose of TAK-659; had ≥1 post-treatment response assessment). By local assessment, 14 pts were de novo (7 GCB, 4 non-GCB, 3 unknown) and 10 were transformed (8 GCB, 2 non-GCB). There were 5 dose-limiting toxicities (DLTs): at 120 mg, 2 pts had increased lipase levels (1 gr 3; 1 gr 4), 1 pt had gr 3 generalized edema, and 1 had gr 3 mucositis; 1 pt at 60 mg had gr 3 increased AST. DLTs related to laboratory changes were asymptomatic. LDH levels were increased from baseline in most pts (significance unknown). Drug-related AEs are shown in Table 2. Drug-related serious AEs (per investigator) were reported for 17 (31%) pts; most common were pneumonia (5 [9%]), pyrexia (3 [6%]), and pneumonitis (2 [4%]). Dose reductions due to AEs occurred in 4 pts (3 from 100 to 80 mg; 1 from 120 to 60 mg). Nine pts discontinued due to AEs; 3 were considered related to TAK-659 (1 sepsis, 2 pneumonitis). There were 10 on-study deaths; 1 was considered possibly related to TAK-659 (sepsis). Preliminary plasma and urine PK data showed that TAK-659 was absorbed quickly (median Tmax 2-3 hrs), with moderate variability in steady-state exposures (40-50% CV for DN-AUCtau), mean peak/trough ratio of 3.2-4.2, and mean accumulation of 2.1- to 2.6-fold after 15 d QD dosing. Renal clearance (CLr) of unchanged drug accounted for 30-34% of apparent oral clearance, suggesting a CLr contribution of ≥30-34% to TAK-659 systemic clearance. Of 24 response-evaluable DLBCL pts, 11 (46%) achieved an objective response; (7 [29%] CR, 4 PR); all 3 response-evaluable FL pts achieved PR; 10/14 responders are ongoing on the study (Figure). Median treatment duration for responders was 138 days for DLBCL (range 54-688) and 237 days for FL (range 185-464). Responses were seen in both de novo and transformed DLBCL pts and appeared to be independent of cell-of-origin classification. No solid tumor pts achieved an objective response. Conclusions Oral TAK-659 has an acceptable PK and safety profile in pts with solid tumors or lymphoma, supporting continuous oral QD dosing. There are early signs of clinical activity in DLBCL and FL pts. Enrollment of pts with additional lymphoma subtypes is ongoing; safety and efficacy will be further investigated. Disclosures Kaplan: Janssen: Research Funding; Seattle Genetics: Research Funding. Gordon:Northwestern University: Patents & Royalties: Patent for gold nanoparticles pending. Infante:Millennium: Research Funding. Popat:Takeda: Honoraria. Madan:Onyx: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Radford:Novartis: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; GSK: Equity Ownership; Astra-Zeneca: Equity Ownership; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. de Oteyza:Takeda: Research Funding. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: 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; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Faucette:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Sheldon-Waniga:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Williams:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Stumpo:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shou:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Bosch:Hoffman La Roche: Consultancy, Honoraria, Research Funding; Millennium: Research Funding.

Background: ECD and LCH are rare disorders for which no approved therapies are available. BRAFV600E mutations have been observed in 50% of patients with LCH and in 50-60% of patients with ECD. Here we present data from a planned Week 16 analysis of patients with ECD/LCH who were enrolled in the VE-BASKET study (ClinicalTrials.gov identifier NCT01524978). Methods: This open-label, Simon 2-stage adaptive-design, phase 2 study included patients with BRAFV600E-mutant ECD and LCH. Patients received vemurafenib (960 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed response rate at Week 8; secondary endpoints included best overall response rate, clinical benefit rate, progression-free survival (PFS), and overall survival (OS). For a subset of patients (n=15), metabolic response by 18F-FDG-PET was assessed; five target lesions were selected and their maximal standardized uptake value (SUVmax), normalized for body weight (BW), was compared with background (liver) SUV. Data cut-off was 2 October 2015. Results: 26 patients (22 with ECD and 4 with LCH; median age 61y) were enrolled. Seven patients (27%) had one prior therapy, six (23%) had two prior therapies, four (15%) had ≥3 prior therapies, and nine (35%) had no prior systemic therapy. Six patients were in follow-up at data cut-off; 16 were on treatment. Best overall response (according to RECIST v1.1) in 25 patients with measurable disease at baseline was 60% (95% CI 38.7-78.9%) with complete response (CR) in two patients (8%) and partial response (PR) in 13 patients (52%) (Figure). Responses were seen in patients with ECD (1 CR, 10 PRs) and LCH (1 CR, 3 PRs). After a median treatment exposure of 14.2 months (range 4.2-22.5 months), median OS and PFS have not been reached. All of the 15 patients assessed by 18F-FDG-PET showed a response: 12 patients had a complete metabolic response (normalization of all lesions' SUVmax-BW to background SUV) and three had a partial metabolic response (>50% decrease in sum of baseline SUVmax of all target lesions) (Figure). Overall, safety data were consistent with prior studies of vemurafenib. Arthralgia (n=17; 65%), fatigue (n=15; 58%), rash macropapular (n=14; 54%), alopecia (n=14; 54%), skin papilloma (n=14; 54%), prolonged QT (n=12; 46%), and palmar-plantar erythrodysesthesia syndrome (n=12; 46%) were the most common all-grade adverse events (AEs). Seventeen patients had serious AEs, including 10 with squamous cell carcinoma of the skin. Seven patients discontinued vemurafenib due to AEs. Conclusion: These data, which represent the only prospective clinical trial data of BRAF inhibition in histiocytosis to date, reveal that vemurafenib has potent single-agent activity in patients with ECD/LCH. Moreover, vemurafenib treatment had remarkable durability of response in histiocytosis, such that no evidence of resistance has been encountered following a median of 14.2 months of treatment. These results are distinct from vemurafenib use in other solid or hematologic malignancies. Figure Figure. Disclosures Subbiah: Abbvie: Research Funding; Nanocarrier: Research Funding; GlaxoSmithKline: Research Funding; Roche/Genentech: Research Funding; Bayer: Research Funding; Novartis: Research Funding. Blay:F. Hoffmann-La Roche: Consultancy, Research Funding; MDS: Research Funding; Lilly: Research Funding; Bayer: Consultancy, Research Funding; Pharmamar: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Puzanov:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunocore: Consultancy. Wolf:F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Clovis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ulaner:GE Healthcare: Research Funding; Genentech: Research Funding; Blue Earth Diagnostics: Research Funding; Susan Komen Foundation: Research Funding; Department of Defense: Research Funding; National Institutes of Health: Research Funding; Zevacor: Honoraria. Lacouture:Quintiles: Consultancy; Boehringer Ingelheim: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Foamix: Consultancy; Infinity: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Berg: Research Funding; Bristol Myers Squibb: Research Funding. Robson:F. Hoffmann-La Roche Ltd: Employment. Makrutzki:F. Hoffmann-La Roche Ltd: Employment.

Introduction: PTCL is a rare and heterogeneous group of non-Hodgkin lymphoma (NHL) comprising ~10% of cases. CHOP is frequently used first-line, but with the exception of ALK+ anaplastic large-cell lymphoma (ALCL), long term outcomes are historically poor with reported 5-yr overall survival (OS) rates of 36%. We retrospectively evaluated the outcomes following first-line chemotherapy for patients with PTCL treated at the Royal Marsden (RM) and Christie (CH) hospitals over a 10-year period. Methods: All eligible patients with PTCL aged ≥18 years and treated at the RM and CH between 1st January 2002 and 31st January 2012 were included. The study was approved by our institutional review boards. Patients were identified from hospital databases and included if they had received at least 1 cycle of first-line chemotherapy. Precursor T-cell malignancies, mycosis fungoides and adult T-cell leukaemia/lymphoma were excluded, as was cutaneous T-cell lymphoma not requiring combination chemotherapy. Clinical data were collated from electronic patient records and the diagnosis of PTCL was confirmed in all cases by an expert haematopathologist. Response was assessed using the IWG 1999 criteria. OS and progression free survival (PFS) were calculated from date of start of 1st line treatment and analysed using Kaplan Meier methods and Cox regression model. The impact of clinical factors on survival was assessed using Cox regression analysis. Results: A total of 143 (RM n=69, CH n=74)patients were evaluable and the median follow-up was 63.4 months. The median age at diagnosis was 59 yrs (range 18-89 yrs). PTCL subtypes were: PTCL not otherwise specified (NOS) (n=48), angioimmunoblastic T-cell lymphoma (AITL) (n=37), ALCL ALK- (n=24), ALCL ALK+ (n=14) and other (n=20). First-line chemotherapy included CHOP (n=97), GEM-P (gemcitabine, cisplatin and methylprednisolone) (n=16), other gemcitabine containing regimen (n=7), asparaginase (n=2) or other (n=21). OS by PTCL subtype is shown in Figure 1. Response was evaluable for 125/143 patients. Overall response (ORR) to first-line chemotherapy was 81.4% with complete response (CR) seen in 42.4%. For the entire cohort (n=143) 5-yr PFS was 20.6% and 5-yr OS was 39.6%. For CHOP treated patients ORR was 80.5% with CR in 43.7%, 5-yr PFS was 25.5% and 5-yr OS was 41.2%. ORR with GEM-P was 78.6% with CR in 50%, 5-yr PFS was 13.6% and 5-yr OS was 39.1%. No statistically significant difference between CHOP and GEM-P was seen in terms of response, OS or PFS. Autologous stem cell transplantation (autoSCT) was performed post first-line induction in 15% (n=22). For patients in CR post induction (CR1) (n=41), we compared survival for those treated with (n=12) and without (n=29) subsequent autoSCT. AutoSCT in CR1 was associated with a trend towards better PFS (HR 0.36, 95%CI 0.13-1.02; p=0.056) but not OS (HR 0.72, 95% CI 0.21-2.47; p=0.599). Uni- (UVA) and multivariate analyses (MVA) were performed to determine the impact of the following on OS and PFS: age (≤60 vs > 60yrs), gender, stage (I-III vs IV), performance status (PS, 0-1 vs 2), B symptoms (present vs absent), ethnicity (white vs other), LDH (normal vs elevated), IPI (low vs intermediate vs high), PTCL subtype, number of extranodal sites (0-1 vs >1), chemotherapy (CHOP vs gemcitabine based vs other), CR post induction (present vs absent) and autoSCT (performed vs not). Factors with a p-value of Conclusion: With the exception of ALK+ ALCL, outcomes for PTCL following first-line chemotherapy remain disappointing and a more effective induction regimen is urgently required. Our data indicates that achieving a CR with first-line induction is a key factor for optimising OS and PFS. To this end, the currently accruing UK NCRI randomised phase II CHEMO-T study is comparing CHOP with GEM-P as first-line regimens in PTCL. AutoSCT in CR1 may offer a PFS benefit and should be considered in eligible patients. Table 1. MVA for OS and PFS (n=104) Risk Factor HR 95% CI p-value OS Intermediate risk IPI 4.56 1.79-11.6 0.001 High risk IPI 12.0 4.32-33.1 Figure 1. OS according to PTCL subtype Figure 1. OS according to PTCL subtype Disclosures Chau: Roche: Research Funding. Cunningham:Merrimack: Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; Medimmune: Research Funding; Astra Zeneca: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Merck Serono: Research Funding; Sanofi: Research Funding.

Introduction The prognostic value of positron emission tomography using 18-fluorodeoxyglucose ([18F]FDG-PET) prior to autologous hematopoietic stem cell transplantation (HSCT) has become more established in recent years. We investigated the utility of pre-HSCT [18F]FDG-PET in patients undergoing autologous HSCT for lymphoma at our centre. Methods 104 patients were identified as having undergone autologous HSCT for lymphoma between 2004 and 2013, who also had pre-transplant PET assessment. Patient demographic and disease-related data was collected retrospectively from electronic patient records. Contemporaneous PET-CT reports were used to document disease status prior to HSCT. Kaplan-Meier and Cox regression analyses assessed univariate and multivariate analysis of disease outcomes. Results The median age was 51 years (range 10-73), and 55.8% were male. 33 patients (31.7%) had Hodgkin lymphoma, the remainder non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (29.8%), mantle cell lymphoma (10.6%), follicular lymphoma (6.7%) and others (21.2%). The majority (81.7%) had advanced stage disease (III-IV). 14.4% had received four or more lines of prior therapy. At pre-transplant PET, 65 patients (62.5%) were documented to have a complete response (CR), 24 (23.1%) had a very good partial response (VGPR) and 15 (14.4%) had a partial response (PR). No patients were shown to have stable or progressive disease at the time of transplantation. All but 5 patients received pre-transplant conditioning consisting of carmustine/lomustine, etoposide, cytarabine and melphalan (BEAM). Progression-free survival (PFS) at 5 years was 43.9%, and overall survival 60.8% at 5 years. There was no difference in PFS or OS in patients with CR or VGPR on pre-transplant PET (see chart). Predictors of inferior PFS on multivariate analysis included 4 or more lines of prior therapy (hazard ratio (HR) 3.36, p=0.009), and those patients with only PR on pre-transplant PET (HR 2.93, p=0.007). Predictors of inferior OS on multivariate analysis included female gender (HR 2.51, p=0.024) and 4 or more lines of prior therapy (HR 3.36, p=0.009), with a trend towards inferior OS in those with age greater than the median (HR 2.10, p=0.081) and with PR on pre-transplant PET (HR 2.55, p=0.055). Day 100 transplant-related mortality was 2.9%. Conclusion In our large single-centre cohort, patients with either CR of VGPR on pre-transplant PET scan showed no difference in either PFS or OS. By contrast, those patients with less than VGPR and those who had undergone four or more prior lines of chemotherapy or radiotherapy had significantly poorer outcomes. Whether eligible patients who fail to achieve at least a VGPR prior to autograft might fare better with allogeneic transplantation remains to be proven. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction Allogeneic hematopoietic stem cell transplant (HSCT) is an option in patients with lymphoma with refractory or multiply relapsed disease. Consensus remains to be reached on the prognostic value of positron emission tomography using 18-fluorodeoxyglucose ([18F]FDG-PET) prior to allogeneic HSCT. Methods Patients having undergone allogeneic HSCT for lymphoma between 2004 and 2013, who also had pre-transplant PET assessment, were identified. Patient demographic and disease-related data was collected retrospectively from electronic patient records. Contemporaneous PET-CT reports were used to document disease status prior to HSCT. Kaplan-Meier analysis was used to assess the impact of categorical variable on patient outcome. Results 44 eligible patients were identified. 30 (68.2%) were male, with a median age of 38 years (range 14-68). 23 (52.3%) had Hodgkin lymphoma, six (13.6%) follicular lymphoma, five (11.4%) mantle cell lymphoma, and three had (6.8%) diffuse large B-cell lymphoma; other B and T-cell lymphomas accounted for the remainder. 39 patients (88.6%) had advanced stage disease, and 32 (72.7%) had received at least four prior lines of chemotherapy or radiotherapy. 20 (45.5%) had had a prior autograft. At pre-transplant staging using PET, 18 (40.9%) achieved a complete response (CR), seven (15.9%) a very good partial response, and 12 (27.3%) a partial response (PR). Two patients (4.5%) had stable disease and five (11.4%) had progressive disease going into transplant. Overall survival (OS) at five years was 38.9%, and progression-free survival (PFS) 35.7%. There was no significant impact of patient age, gender, disease, disease stage or number of lines of previous therapy on OS or PFS. Overall, patients with less than CR on pre-transplant PET showed a trend towards an inferior PFS (48% vs 24% at 3 years, p=0.092), but there was no impact on OS. In particular, patients with PR going into allograft showed OS (55% at three years) and PFS (42% at three years) comparable with those in CR (51% and 48% at three years respectively). However, analysis of disease progression (treating death in remission as a competing risk) showed that those with less that CR on pre-transplant PET had a significantly higher risk of disease progression than those in CR (46% vs 8%, p=0.0068). Non-relapse mortality was 19.5% at 1 year and 39% at 3 years. Conclusion Although a complete response is highly desirable prior to allogeneic transplant in any patient with lymphoma, our study shows that those showing only a partial response to prior therapies may still have a successful long-term outcome. Considering that such patients invariably relapse following autologous transplant, PET may have a role in deciding between autologous and allogeneic transplant in patients who fail to achieve either a CR or VGPR. However, such a question needs to be answered with prospective data. Disclosures No relevant conflicts of interest to declare.

Background: High-grade transformation (HT) of follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL) occurs at a rate of 3% per year and has been associated with a very poor prognosis, with a median overall survival (OS) of 1 year reported by Montoto et al in the pre-rituximab era. Treatment often includes upfront autologous or allogeneic stem cell transplantation (SCT) due to the poor prognosis, but rarely maintenance rituximab despite evidence in FL. These patients are excluded from the majority of clinical trials and hence the role of SCT in the rituximab era and maintenance rituximab are not well evaluated. Methods: We performed a retrospective analysis of all patients aged ≥18 years with histologically proven transformed follicular lymphoma (TFL) diagnosed and treated (≥1 cycle of chemotherapy) at our institute in the 10-year period 2003-2013. Histopathology databases were searched to identify patients diagnosed with DLBCL and FL (grade 1-3a). Clinical data were collated from electronic patient records. Patients with grade 3b FL were excluded. A minimum interval of 6 months between the diagnosis of FL and development of HT was required for inclusion to outrule a discordant lymphoma. All histological specimens were reviewed by an expert haematopathologist. The study was approved by our institutional review board. Results: Between March 2003 and May 2013, a total of 56 patients were diagnosed with TFL (to DLBCL) and received first-line induction treatment +/- autologous/allogeneic SCT. The median follow-up was 5.6 years. The median time from diagnosis of FL to HT was 5.3 (range 0.6-29.3) years with a median age at diagnosis of TFL of 61 years (range 34-85). 59% (n=33) had received prior chemotherapy for FL. At diagnosis of TFL 89% (n=50/56) of patients received chemotherapy +/- radiotherapy (IFRT) without subsequent SCT. Upfront autologous or allogeneic SCT post induction was performed for 4 (7%) and 2 (3.5%) patients respectively. 91% of patients (n=51/56) received rituximab containing (R) chemotherapy and 68% (n=38/56) were treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). 16.1% (9/56) received IFRT post induction. 14.3% (8/56) patients received R-maintenance following first-line treatment for TFL. For patients treated with R-chemotherapy alone (n=46) the 2 and 5-year OS and PFS (for TFL) were 84.5% and 70.9% and 58.7% and 49.3% respectively. In patients aged >65 years (n=17) 5-year OS was similarly 71.6%. Patients treated with R-CHOP had 2 and 5-year OS of 89% and 76% and PFS (TFL) rates of 59.5% and 51.7% respectively. Patients who received R-chemotherapy induction followed by R-maintenance (n=8) had both 2-year OS and PFS (TFL) of 100%. 82% of all patients (46/56) underwent FDG-PET on completion of induction treatment +/- SCT. A negative PET (n=30) was associated with 2 and 5-year OS rates of 90% and 74.1% and PFS (TFL) of 60% and 49.2%. Conclusion: The outcome for TFL has significantly improved with the advent of rituximab. In our analysis the 2 and 5-year OS rates of 84.5% and 70.9% with R-chemotherapy alone are superior to reported OS for patients undergoing upfront autologous/allogeneic SCT, while PFS rates are comparable to those quoted for upfront autologous SCT. Although the numbers are small (n=8) and follow-up shorter, the outcomes for patients treated with R-chemotherapy followed by R-maintenance (2-yr OS and PFS of 100% and 100%) are particularly encouraging while offering minimal additional toxicity. In conclusion our data indicate that upfront SCT may no longer be required for TFL in the rituximab era. Rituximab maintenance should be considered in the management of these patients. Disclosures Hawkes: Roche: Travel grant Other. Peckitt:Sanofi: Membership on an entity's Board of Directors or advisory committees. Dearden:Roche: Membership on an entity's Board of Directors or advisory committees. Cunningham:Astra Zeneca: Research Funding; Novartis: Research Funding; Merck Serono: Research Funding; Sanofi: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Roche: Research Funding.