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The treatment of patients with Bing-Neel syndrome (BNS) is not standardized. We included patients with Waldenström macroglobulinemia (WM) and a radiologic and/or cytologic diagnosis of BNS treated with ibrutinib monotherapy. Response assessment was based on criteria for BNS from the 8th International Workshop for WM. Survival from BNS diagnosis (BNS survival), survival from ibrutinib initiation to last follow-up or death (ibrutinib survival), and time from ibrutinib initiation to ibrutinib discontinuation for toxicity, progression, or death (event-free survival [EFS]) were estimated. Twenty-eight patients were included in our study. The median age at BNS diagnosis was 65 years. Ibrutinib was the first line of treatment for BNS in 39% of patients. Ibrutinib was administered orally at a dose of 560 and 420 mg once daily in 46% and 54% of patients, respectively; symptomatic and radiologic improvements were seen in 85% and 60% of patients within 3 months of therapy. At best response, 85% of patients had improvement or resolution of BNS symptoms, 83% had improvement or resolution of radiologic abnormalities, and 47% had cleared the disease in the cerebrospinal fluid. The 2-year EFS rate with ibrutinib was 80% (95% confidence interval [CI], 58%-91%), the 2-year ibrutinib survival rate was 81% (95% CI, 49%-94%), and the 5-year BNS survival rate was 86% (95% CI, 63%-95%). Ibrutinib therapy is effective in patients with BNS and should be considered as a treatment option in these patients.

AimsRichter's syndrome (RS) refers to high-grade transformation of B-cell chronic lymphocytic leukaemia (CLL), usually to diffuse large B-cell lymphoma, as assessed according to strict World Health Organization (WHO)-defined histological criteria. Although this is a relatively evidence-poor area, the recommended clinical management of high-grade transformation differs considerably from that of relapsed CLL. The CHOP-OR' trial was a single-arm, multicentre, non-randomized phase II National Cancer Research Institute trial in patients with newly diagnosed RS, recruited from across the UK from April 2011 to December 2014. Forty-three patients were enrolled, of whom 37 were ultimately evaluable for response. The aim was to verify the presence of RS in the trial patients and identify pitfalls in the diagnosis of RS. Methods and resultsTwo independent, specialist haematopathologists reviewed histological material from 40 available cases enrolled in the CHOP-OR trial to determine whether the submitted diagnosis of RS was correct. Three cases were unavailable for central review. This series represents the largest central review of RS within a prospective trial in the literature to date. Thirty-three of the 40 (82.5%) submitted cases showed features consistent with WHO-defined RS. Reasons for diagnostic uncertainty in discrepant cases included large proliferation centres, variably confluent and serpiginous proliferation centres, and an apparently high proliferation index, sometimes attributable to a thick section or associated normal bone marrow proliferation. ConclusionsWe discuss the importance of high-quality histological and immunohistochemical sections and strict adherence to WHO criteria in the diagnosis of RS. This study further reinforces the importance of centralized review of cases of haematological malignancy.

Introduction: Venetoclax (VEN) based therapy has become a standard of care in front line and relapsed-refractory (R/R) CLL based on favorable efficacy and toxicity. Whereas prospective data regarding activity of therapies following ibrutinib (IBR) or idelalisib (IDE) are available in the settings of progression (VEN, non-covalent BTKi) and intolerance (acalabrutinib), how best to manage patients (pts) who discontinue (dc) VEN remains a key unanswered question. With the increased use of VEN in early lines of therapy (LOT; CLL 14, MURANO), the activity of BTK inhibitors (BTKi) and cellular therapies following VEN becomes a critical issue. No prospective study has addressed this question, and currently reported VEN clinical trials have limited information about subsequent treatments. While recent data describe VEN resistance mechanisms (Guieze 2018, Blombery 2019), the impact of VEN resistance on efficacy of post VEN therapies is unknown. To address this gap, we conducted an international study to identify a large cohort of pts who dc VEN and have been subsequently treated. Methods: We conducted an IRB approved multicenter (31 US, EU, South American sites, in partnership with UK CLL Forum and CORE registry), retrospective cohort study of CLL pts who dc VEN for any reason. We examined demographics, dc reasons, responses, survival, adverse events (AEs) and activity of post VEN therapies. Primary endpoints were overall response rate (ORR) and progression free survival (PFS) for the post VEN treatments stratified by treatment type (BTKi, PI3Ki and cellular therapy: CAR-T or alloHSCT). ORR was defined by iwCLL criteria and PFS was defined from VEN dc to disease progression (PD), death, or last follow up for next treatment. Pts were further stratified by BTKi (resistant / intolerant) and PI3Ki exposure prior to VEN. PFS-2 was defined as time from VEN start to tumor progression on IBR or death from any cause. Results: 326 CLL pts who dc VEN in the front line (4%) and R/R settings (96%) were identified. The cohort was 69% male, 87% white, median (med) age 66 (38-91) at VEN start, 27% treated with VEN based combinations (n=88, med 6 cycles anti-CD20 abs). Pre VEN prognostic features: 82% IGHV unmutated (n tested=166), 47% del17p (n=306), 45% TP53 mut (n=217), 39% complex karyotype (n=273), 23% BTK mut (n=79), 18% NOTCH1 mut (n=103), 10% PLCγ2 mut (n=74). Pts received med 3 therapies (0-11) prior to VEN; 40% were BTKi naïve (n=130), 60% were BTKi exposed (196) and 81% were IDE naïve (n=263). Most common reasons for VEN dc were PD (38%), AE (20%), Richter's transformation (RT, 14%), 8% pt preference, and HSCT 5%. Of 326 pts who dc VEN, 188 (58%) were treated with a subsequent LOT, 61 are alive and untreated and 77 died prior to a subsequent LOT. Post VEN sequencing analyses focused on BTKi, PI3Ki and cellular therapy (CAR-T or alloHSCT) activities following VEN dc (Table1). ORR to BTKi was 84% (n=44) vs. 54% (n=30, p Conclusions: In the largest experience of therapies following VEN dc in CLL, we demonstrated that therapy selection following VEN requires consideration of prior novel agent exposure and reasons for discontinuation. For BTKi naïve pts, selection of a covalently binding BTKi results in high ORR and durable remissions. PFS-2 data provide reassurance for using VEN prior to IBR. For BTKi exposed pts, BTK inhibition is not effective in the setting of BTKi resistance but should be considered if prior BTKi intolerance. PI3K inhibition following VEN does not appear to result in durable remissions even in PI3Ki naïve pts, suggesting possible overlap in resistance mechanisms (BTK or VEN with PI3K). We conclude that BTKi in naïve or previously responsive pts and alloHSCT following VEN appear to be the most effective strategies with durable responses. These data suggest that a number of effective regimens exist for post VEN pts, providing support for VEN use earlier in the course of CLL. Disclosures Mato: Acerta: Consultancy; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Janssen: Consultancy; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Consultancy. Roeker:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Eyre:Gilead: Consultancy, Other: Research support, Speakers Bureau; Roche: Honoraria; Abbvie: Honoraria, Other: Travel to Conferences; Janssen: Honoraria, Other: Travel to Conferences ; Takeda: Other: Travel to Conferences . Jacobs:Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; JUNO: Consultancy; Gilead: Consultancy; TG Therapeutics: Honoraria, Research Funding. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. Lamanna:Celgene: Consultancy; Infinity/ Verastem: Research Funding; Ming: Research Funding; TG Therapeutics: Research Funding; Oncternal: Research Funding. Brander:Tolero: Research Funding; MEI: Research Funding; BeiGene: Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Acerta: Research Funding. Shadman:AbbVie: Consultancy, Research Funding; Astra Zeneca: Consultancy; BeiGene: Research Funding; TG Therapeutic: Research Funding; ADC Therapeutics: Consultancy; Atara Biotherapeutics: Consultancy; Verastem: Consultancy; Acerta Pharma: Research Funding; Sunesis: Research Funding; Mustang Bio: Research Funding; Celgene: Research Funding; Pharmacyclics: Consultancy, Research Funding; Sound Biologics: Consultancy; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Ujjani:AstraZeneca: Consultancy; Genentech: Consultancy; Rigel: Consultancy; Gilead: Consultancy; Abbvie: Research Funding; Pharmacyclics: Research Funding. Perini:Janssen: Other: Advisory Board; Abbvie: Other: Advisory Board; AstraZeneca: Other: Advisory Board. Pinilla Ibarz:Sanofi: Speakers Bureau; Bayer: Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy; TG Therapeutics: Consultancy. Barrientos:Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy; Gilead: Consultancy; Genentech: Consultancy. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Choi:Abbvie: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; Oncternal: Research Funding. Coombs:H3 Biomedicine: Research Funding. Barr:Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Merck: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; AbbVie: Consultancy. Portell:Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding. Schuster:AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Loxo Oncology: Honoraria; Pfizer: Honoraria; Nordic Nanovector: Honoraria; Pharmacyclics: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; Merck: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Martinez-Calle:ABBVIE: Other: Travel support. Munir:AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees. Nabhan:Aptitude Health: Employment. King:Astrazeneca: Other: Advisory board; Genentech: Other: Advisory Board ; Incyte: Other: Advisory Board. Zelenetz:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cheson:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: 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; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding. Fox:Gilead: Consultancy; Janssen: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Allan:Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Consultancy.

Introduction: Prior to effective novel agent (NA) approval for CLL, alloHSCT was recommended for CLL patients (pts) with early relapse/refractory disease after purine-analogs or deletion 17p (del17p) or TP53 mutation (TP53mut) based on expert consensus and retrospectively demonstrated overall survival (OS) advantage. Since 2014, approvals of ibrutinib (ibr), venetoclax (ven), and PI3K inhibitors (PI3Ki) have led to fewer alloHSCT for CLL. While NAs are indisputably effective, many pts will eventually progress through all available NAs. In the absence of data-driven consensus regarding role of alloHSCT for CLL, decision about proceeding to transplant is currently based on disease and transplant risk, response to NAs, and pt preference. This study of CLL pts who underwent alloHSCT following NA therapy (tx) aimed to help define the role of this potentially curative modality in the era of NAs. Methods: This multicenter, retrospective cohort study examined CLL pts who underwent alloHSCT following treatment with ≥ 1 NA, including baseline clinical, prognostic, and transplant characteristics, tx preceding alloHSCT, transplant outcomes, and tx following alloHSCT. Complex karyotype (CK) and CLL status [complete remission (CR), partial remission (PR), stable disease (SD), and progression of disease (POD)] were defined per iwCLL criteria (Hallek, et al. Blood 2018). Univariate analyses utilizing COX regression evaluated association between pre-alloHSCT factors and progression free survival (PFS). PFS, OS, and non-relapse mortality (NRM) were estimated using Kaplan Meier and life table methods. Other statistics were descriptive. Results: 69 pts with CLL underwent alloHSCT following ≥ 1 NA across 14 US and EU centers, including 6 pts with Richter's transformation (RT) prior to alloHSCT. Table 1 describes baseline characteristics. Prior to alloHSCT, 78% received ibr (n=53), 39% ven (n=25), 20% PI3Ki (n=13), and 36% ≥ 2 NAs. 90% (n=62) received a NA immediately preceding alloHSCT [n=32 ibr (16% CR, 75% PR, 9% SD/POD), n=25 ven (52% CR, 40% PR, 8% SD/POD), 4 PI3Ki (75% PR, 25% SD/POD), 1 IMiD]. With a median (med) follow up 28 months (mo; range 1.2 -85), med PFS and OS from alloHSCT for the entire cohort were not reached (Figure 1A, B). PFS and OS for pts with CLL (excluding RT pts) from alloHSCT were 60% and 82% at 24 mo respectively. Poor risk disease characteristics (TP53mut, del17p, CK), prior NA exposure (ibr, ven, PI3Ki, ≥2 NAs), and transplant characteristics (matched (8/8) vs. mismatched ( To guide decision making about timing of alloHSCT, we examined pts who received 1 (n=44) vs. ≥2 (n=25) NAs. These groups were similar in terms of poor risk features (del 17p 48% vs. 38%, TP53mut 44% vs. 40%, del11q 21% vs. 36%, CK 41% vs. 54%), transplant risk (med age 60 for both groups, med HSCT-CI 0 vs. 1, matched donor 86% vs. 71%), and disease status prior to alloHSCT (CR 25% vs. 40%, PR 66% vs. 48%, SD/POD 9% vs. 12%). PFS was similar for those exposed to 1 vs. ≥ 2 NAs (Figure 1C). Disease status at time of alloHSCT and hematopoietic cell transplantation-specific comorbidity index (HCT-CI) significantly impacted PFS (Figure 1D, E). Conclusions: In the largest series of alloHSCT following NAs, data demonstrate that alloHSCT remains a viable curative strategy that can overcome adverse CLL characteristics including TP53 disruption and CK. As many pts treated with ibr and/or ven will progress or be intolerant, alloHSCT should be included in treatment algorithms for appropriate candidates. These data suggest that exposure to 1 vs. ≥2 prior NAs did not impact outcomes, though disease status at time of alloHSCT and HCT-CI are important predictors of PFS. Therefore, decision about proceeding to alloHSCT should consider comorbidities and current depth of response, as well as anticipated depth of response with the therapeutic options remaining. These data may significantly add to development of evidence-based guidelines for alloHSCT in the era of NAs. Figure 1 Disclosures Roeker: AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Brown:TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Dynamo Therapeutics: Consultancy; Sunesis: Consultancy; Juno/Celgene: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Catapult Therapeutics: Consultancy; AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Loxo: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Pharmacyclics: Consultancy. Dreger:AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Neovii, Riemser: Research Funding. Eyre:Roche: Honoraria; Abbvie: Honoraria, Other: Travel to Conferences; Takeda: Other: Travel to Conferences ; Gilead: Consultancy, Other: Research support, Speakers Bureau; Janssen: Honoraria, Other: Travel to Conferences . Brander:AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; Tolero: Research Funding; Acerta: Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Research Funding; DTRM Biopharma: Research Funding; MEI: Research Funding. Skarbnik:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau. Coombs:H3 Biomedicine: Research Funding. Orchard:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Unrestricted educational award for regional meetings ; Incyte: Other: Unrestricted educational award for regional meetings ; Adienne: Other: Unrestricted educational award for regional meetings . Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Genmab: Consultancy; GSK: Consultancy. Giralt:Johnson & Johnson: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Kite: Consultancy; Amgen: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Novartis: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy. Perales:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees. Mato:Celgene: Consultancy; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding.

Background: B-cell receptor signalling pathway plays a key role in CLL pathogenesis. Overexpression of phosphatidylinositol 3-kinase delta isoform (PI3Kδ) is a characteristic of malignant lymphoid cells {Zhang 2014}. Idelalisib is an oral, selective PI3Kδ inhibitor approved for the treatment of CLL {Brown 2014}. Since its approval there has been a paucity of real world clinical effectiveness and safety data on idelalisib-rituximab (IDELA-R). A large U.S.-based national, retrospective series of 682 CLL patients (pts) explored the optimal sequence of targeted agents in this setting, but included only 62 (9%) pts treated with IDELA-R {Mato 2017}. Aims: To evaluate the effectiveness of IDELA-R in pts with CLL in routine clinical practice in the UK through a protocol-led, retrospective cohort study; RETRO-idel (NCT03582098). Methods: Secondary or tertiary care centres (sites) across the UK were invited to participate. Data were collected retrospectively from sites by study personnel from source data-verified medical records using electronic case report forms (eCRFs). Eligible pts included those who initiated IDELA-R as part of routine clinical management of CLL from Sep 2014 (following European approval), up to and including 31 Dec 2017. Primary endpoint was overall response rate (ORR) defined as the proportion of pts who achieved an objective clinical response after the initiation of IDELA-R treatment. Secondary endpoints included overall survival (OS), progression free survival (PFS), time to next treatment (TTNT), duration of response (DOR), and safety (including serious adverse events [SAE] and AEs of special interest [AESI]). Results: A total of 110 pts were included in the study from 16 UK sites, of whom 74 (67.3%) were males and the median age at IDELA-R initiation was 72 years (range 48 - 90) (Fig 1a). Median number of prior therapies was 1 (range 0 - 8; 23.6% 1st line). Seven (6.4%) pts had received prior ibrutinib. Median time since diagnosis was 7 years (range: 0 - 23), and 54 (49.1%) pts tested had TP53 mutated / del (17p) CLL. Median duration of follow-up was 39.1 months (range 0.1 - 51.9), with 65 (59.1%) pts followed >2 years. Ninety-two (83.6%) pts received pneumocystis jirovecii pneumonia (PJP) prophylaxis and 8 (7.3%) pts had received a stem-cell transplant (SCT) [(before IDELA-R; 2 (1.8%) alloSCT; 2 (1.8%) autoSCT); after IDELA-R; 4 (3.6%) alloSCT)]. The median duration of therapy with IDELA was 12 months (range 0 - 41). The ORR was 88.2% (95% CI: 82.2 - 94.2) and median DOR 32.7 months (95% CI 19.7 - NR). Seven (6.4%) pts had no documented response and response data were missing for 6 (5.4%) pts. Median OS was not reached (95% CI: 31.5 - NR) and median PFS was 29.5 months (95% CI: 22.1, NR) (Fig 1b, c). Median TTNT was 29.2 months 95% CI; 25.3 - 42.8). Overall, 108 (98.2%) pts experienced an SAE or AESI. Diarrhoea was reported in 34 (30.9%) pts, followed by lower respiratory tract infection [LRTI] in 24 (21.8%), neutropenia in 23 (20.9%), rash in 18 (16.4%) and pneumonia in 18 (16.4%). Ten (9.1%) pts had colitis, of which Gr 3/4 colitis occurred in 6 (5.5%). A total of 71 (64.5%) pts experienced a Gr 3/4 AEs including pneumonia in 14 (12.7%), LRTI in 10 (9.1%), neutropenia in 7 (6.4%), diarrhoea in 7 (6.4%) and neutropenic sepsis in 7 (6.4%). There were 85 (77.2%) discontinuations; 54 (56.3%) due to toxicity, 18 (18.8%) due to PD, 11 (11.5%) by investigator discretion, and 2 (2.1%) by subject decision. There were 11 (11.5%) deaths reported whilst pts were receiving IDELA-R. Richter's transformation was documented in 1 (0.9%) pt. At the time of analysis, 46 (41.8 %) pts had died. Conclusions: We report to our knowledge the largest cohort of CLL pts treated with IDELA-R outside of the clinical trial setting. Our findings corroborate those from interventional studies of IDELA {Furman 2014, Sharman 2019}. Longer PFS observed in our study versus prospective trials probably reflects the relatively fewer median number of prior therapies. Median TTNT was slightly shorter than median PFS possibly due to certain pts discontinuing IDELA-R without PD and continuing to a subsequent therapy. Safety profile of IDELA-R was consistent with trial experience, and no new safety signals were identified. IDELA-R remains an effective treatment option for CLL pts. Analyses assessing a) response duration and TTNT in pts stopping therapy due toxicity and b) predictors of PFS (univariable and multivariable analysis) are ongoing and will be presented. Disclosures Eyre: Janssen: Honoraria; Roche: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Abbvie: Honoraria. Islam:Gilead: Honoraria, Other: Conference attendance sponosrship. Nicholson:Pfizer: Other: Conference attendance sponosrship; Takeda: Other: Conference attendance sponsorship. Fegan:Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria; Abbvie: Consultancy, Other: Conference attendance sponsorship. Smith:Gilead: Employment, Equity Ownership. Cursley:Gilead: Employment. Ramroth:Gilead Sciences: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment.

Background Effective treatment for relapsed, refractory (R/R) mantle cell lymphoma (MCL) post Bruton's Tyrosine Kinase inhibitor (BTKi) therapy represents an unmet clinical need with studies consistently reporting dismal outcome. No treatment strategy demonstrates superiority and there is currently no consensus on management. R-BAC (Rituximab, Bendamustine and Cytarabine) has demonstrated excellent upfront response rates in phase 2 trials (overall response rate (ORR) 100%, 2-year progression free survival (PFS) 95%, Visco et al 2013), but with durable responses also reported with other combination therapies there is a rationale to reserve R-BAC for post-BTKi relapse. Aims There is currently no data available assessing efficacy of R-BAC in the post BTKi setting. We first adopted this treatment strategy within routine clinical practice in 2015 and in this study have collected and analysed clinical outcomes across 20 centers in the United Kingdom and Italy. Methods 35 R/R MCL patients (pts) with prior BTKi therapy started R-BAC between October 2015 and February 2019. Treatment consisted of rituximab (375 mg/m2 or 500 mg) D1, bendamustine 70 mg/m2 D1 and D2 and cytarabine 500 mg/m2 D1 to D3 in a 28 day cycle. 29 pts were treated in the UK and 6 in Italy. Analysis included one pt with previous alloHSCT. Response to therapy was measured using Lugano classification (Cheson et al, 2014), although assessment of CR with bone marrow biopsy was not always undertaken. Baseline data, including response to previous BTKi, was collected retrospectively by the treating physician. The primary outcome was PFS to R-BAC. Results Median age at time of R-BAC was 66.3 years (range 43 to 81) and 82.9% of pts were male. At initial diagnosis MIPI was 34.5% low risk, 17.2% intermediate risk and 48.3% high risk; histology was 20.6% blastoid. Pts received a median 2 prior lines of systemic therapy (range 1 to 6). Frontline therapy included high dose cytarabine containing regimen (61.7%) plus consolidation AutoSCT (40.0%), R-CHOP (26.4%), R-CVP (2.9%), FC (2.9%) and ibrutinib plus rituximab (5.9%). 7 patients received maintenance rituximab (28.6%). 45.7% of patients commenced second line therapy within 2 years of initial diagnosis. Prior BTKi therapy included: ibrutinib (n=30), acalabrutinib (n=2), tirabrutinib (n=2) and M7583 (n=1). ORR to prior BTKi was 67.6% (CR 35.3%) and median PFS was 9.2 months. All patients stopped BTKi therapy due to progressive disease (94.3%) or failure to respond (5.7%). All but 1 patient received R-BAC directly after relapse on BTKi. Patients received a median of 4 cycles of treatment (range 1 to 6). 9 pts received attenuated doses of chemotherapy at clinician's discretion from start of therapy and 13 additional pts received attenuated doses beyond cycle 1 (62.9% of all patients received some form of dose attenuation). ORR to R-BAC was 82.3% (CR/CRu rate 55.9%), median PFS 9.3 months (see fig. 1) and median OS 12.2 months. Importantly, outcome for 11 pts ≥70 yrs was similar to younger pts (median PFS 10.6 months vs 8.6 months, p=0.83). 53.5% of evaluable patients demonstrated longer duration of response compared with preceding BTKi. 25 pts completed the planned treatment course, 2 stopped early due to excess toxicity (prolonged cytopenias and infection) and 8 stopped early due to progressive disease. 9 pts received subsequent consolidation alloSCT, and 1 DLI. Although follow-up is short only 1 patient to receive alloSCT has relapsed. 13 patients overall remain in remission, including 5 beyond 12 months. 18 patients (51.4%) required admission during R-BAC, including 15 with neutropenic fever (42.8%) and 72.7% patients required transfusion support. There were no treatment related mortalities. Conclusion This high risk population with a short PFS to prior BTKi demonstrated an excellent response rate to R-BAC. Favorable outcomes in the cohort consolidated with alloSCT, and the generally short duration of response in other pts, suggests R-BAC can be primarily used as a bridge to alloSCT in suitable pts. Treatment had notable hematological toxicity but with efficacy maintained in older pts R-BAC remains a valid option in those deemed unsuitable for transplant, although judicious dose attenuation is advised. In an area lacking a clear therapeutic path, the results from our study support R-BAC being considered a new standard of care option for R/R MCL in the post BTK inhibitor setting. Disclosures Frewin: AbbVie: Other: Meeting attendance sponsorship ; Novartis: Consultancy, Other: Meeting attendance sponsorship . Eyre:Roche: Honoraria; Abbvie: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Janssen: Honoraria. Lambert:Takeda Pharmaceuticals: Other: Funding to attend a scientific conference in 2018. Crosbie:Janssen: Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Kite: Consultancy; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy.

BACKGROUND Novel agents have changed the treatment landscape in chronic lymphocytic leukemia (CLL), however little has been reported about real-world treatment sequence patterns and associated outcomes post-introduction of novel agents. Studies have demonstrated that venetoclax is effective for patients (pts) who have discontinued ibrutinib, however treatments and outcomes post-venetoclax discontinuation remain unclear. The objective of this study was to examine real-world treatment sequence patterns post-introduction of novel agents and specifically understand treatment sequencing following venetoclax. METHODS The CLL Collaborative Study of Real-World Evidence (CORE) is a retrospective, multicenter, collaborative observational study of pts with CLL/small lymphocytic leukemia (SLL). For this analysis, adult pts were eligible for inclusion if they started therapy for CLL/SLL in the relapsed/refractory setting after February 12, 2014 (FDA approval date of first novel agent for CLL/SLL). Interim data are presented; data collection for this analysis is ongoing and is expected to be completed by October 31, 2019. Treatment sequences were characterized specifically focusing on treatment sequencing following venetoclax and other novel agents (i.e., BCRi: e.g., ibrutinib, idelalisib or acalabrutinib). Clinical response, as assessed by physician, was also reported from medical charts (iwCLL criteria were provided as a reference only). RESULTS Of the 267 pts available at the time of interim data analysis, 231 pts (87%) received a novel agent in at least one line of therapy (first-line: 35 pts [15%]; second-line: 133 pts [58%]; third-line or later: 63 pts [27%]). Among novel agents, ibrutinib was the most commonly used first novel agent for 198 pts (86%) followed by venetoclax for 18 pts (8%) and idelalisib for 12 pts (5%). Of those 267 pts, 143 pts (54%) received chemotherapy/chemoimmunotherapy (CT/CIT) followed by a novel agent; 63 pts (24%) received a novel agent followed by a novel agent; 17 (7%) received a novel agent followed by CT/CIT; and 47 (18%) received a CT/CIT followed by CT/CIT. At the time of this interim data cut there were 220 pts (82%) who received BCRi-based regimens (first-line: 33 pts [15%]; second-line: 123 pts [56%]; third-line or later: 64 pts [29%]) and 62 pts (23%) who received venetoclax-based regimens (first-line: 2 pts [3%]; second-line: 22 pts [36%]; third-line or later: 38 pts [61%]). Of the 220 pts who received BCRi-based regimens, 50 (23%) achieved complete remission (CR) and 83 (38%) achieved partial remission (PR) (responses based on physician assessment). Of the 220 pts, 88 (40%) went on to receive a subsequent line of therapy. The most common subsequent treatments administered were venetoclax containing regimens (n= 34, 39%). Of the 88 pts who received a subsequent line of therapy after BCRi-based regimens, 22 pts (25%) achieved CR and 24 pts (27%) achieved PR. Of the 62 pts who received venetoclax-based regimens, 20 pts (32%) achieved CR and 14 pts (23%) achieved PR. Of the 62 pts, 15 pts (24%) went on to receive a subsequent line of therapy. The most common subsequent treatment administered were BCRi containing regimens (n= 10, 67%) primarily ibrutinib-based. Of the 15 pts receiving a subsequent line of therapy after venetoclax-based regimens, 3 pts (20%) achieved CR and 4 pts (27%) achieved PR. While preliminary results are encouraging, further data collection efforts are ongoing and will be included for presentation to confirm the results and outcomes associated with different sequencing options. CONCLUSIONS The treatment paradigm is evolving with the introduction of novel agents. Results from this study will provide a baseline description of treatment sequence patterns enabling clinicians to benchmark the impact of the introduction of novel agents and associated outcomes. Early evidence from these results also suggests that novel agents are most commonly introduced during second line treatment and that other novel agents, including ibrutinib, following venetoclax treatment are being utilized in the real-world settings. Table. Disclosures Mato: Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; Acerta: Consultancy; Janssen: Consultancy; Gilead: Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy. Sail:AbbVie: Employment, Other: may hold stock or stock options. Yazdy:Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy; Bayer: Honoraria, Speakers Bureau. Hill:Amgen: Research Funding; Seattle Genetics: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shadman:Bigene: Research Funding; TG Therapeutics: Research Funding; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Atara: Consultancy; Verastem: Consultancy; Mustang Biopharma: Research Funding; Gilead: Research Funding; Merck: Research Funding; Acerta: Research Funding; Emergent: Research Funding; Celgene: Research Funding; Sunesis: Research Funding. Manzoor:AbbVie: Employment, Other: and may hold stock or stock options. Tuncer:Abbvie: Membership on an entity's Board of Directors or advisory committees; 2018 Steering Committee: Other: reimbursement for travel to the steering committee at ASH. Allan:Janssen: Consultancy, Honoraria; Acerta Pharma: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ujjani:PCYC: Research Funding; Pharmacyclics: Honoraria; AbbVie: Honoraria, Research Funding; Genentech: Honoraria; Atara: Consultancy; Astrazeneca: Consultancy; Gilead: Consultancy. Sharmokh:AbbVie: Employment, Other: may hold stock or stock options. Jiang:AbbVie: Employment, Other: and may hold stock or stock options. Pena:AbbVie: Employment, Other: and may hold stock or stock options. Marshall:AbbVie: Employment, Other: and may hold stock or stock options. Nielsen:AbbVie: Employment, Other: and may hold stock or stock options. Barr:Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; AbbVie: Consultancy; Gilead: Consultancy. Brown:Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; Teva: Honoraria; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun: Research Funding; Sun Pharmaceuticals, Inc: Research Funding; Morphosys: Other: Data safety monitoring boards ; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy. Schuh:Pharmacyclics: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Verastem: Speakers Bureau; Kite: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Bristol-Myers Squibb: Research Funding. Eyre:Janssen: Honoraria, Other: travel support; Gilead: Honoraria, Other: travel support; AbbVie: Honoraria, Other: travel support. Wierda:Pharmacyclics LLC: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Miragen: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; GSK/Novartis: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Acerta Pharma Inc: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; AbbVie: Research Funding. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Roeker:Abbott Laboratories: Equity Ownership; AbbVie: Equity Ownership. Bannerji:Gilead: Other: travel support; Celgene: Consultancy; Celgene: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Merck: Other: travel support, Patents & Royalties: IP rights; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Pharmacyclics: Other: travel support; AbbVie, Inc: Consultancy; Pharmacyclics: Other: travel support; Gilead: Other: travel support; AbbVie, Inc: Consultancy, travel support; Merck: Other: travel support, Patents & Royalties: IP rights. Pauff:AbbVie Inc: Employment, Other: may own stock or stock options. Schuster:Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria. Follows:Roche: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau. Cheson:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Gilead: Research Funding; Epizyme: Research Funding. Eichhorst:Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brander:Genentech: Consultancy, Honoraria, Research Funding; DTRM Biopharma: Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Acerta: Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; MEI: Research Funding. Pivneva:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Lamanna:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche-Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction: The FACIT-Fatigue is a 13-item patient-reported outcome instrument (PRO) that was designed to assess fatigue-related symptoms and impacts on daily functioning. This study assessed the content validity of the FACIT-Fatigue in patients with CLL to help determine if it is fit-for-purpose in this population. Methods: Forty adults with first-line (1L) or relapsed or refractory (R/R) CLL took part in an interview study comprising concept elicitation and cognitive debriefing. All participants had experienced CLL-related symptoms (fatigue, weight loss, fever or night sweats) in the past week. For concept elicitation, interviewers used a standardized semi-structured interview guide with open-ended and prompted questions to explore patients' experiences of the signs, symptoms and impacts of CLL and its treatments. Patients were asked to provide a disturbance rating of these concepts on a 0-10 scale of severity. All interviewed patients completed the FACIT-Fatigue. Item scores can range from 0 ("not at all") to 4 ("very much"), and the total score from 0 to 52; lower scores indicate greater fatigue. The recall period for each item is the past 7 days. The general population mean score is 43 (Cella et al. 2002; Montan et al. 2018). During cognitive debriefing, the clarity of the FACIT-Fatigue items, their relevance to the patients, and the comprehensiveness of the response options were assessed. Interviews were carried out by telephone and lasted about 60-75 minutes. De-identified audio-recorded interviews were transcribed, coded and analyzed using qualitative data analysis software. Results: Median age of participants was 58 years (range: 28-73 years), and gender distribution was equal. During concept elicitation, fatigue was identified as the most prominent and impactful concept. It was the only concept mentioned by 100% of patients, and almost all (1L: 95%; R/R: 85%) mentioned it spontaneously without prompting. Fatigue had a high mean disturbance rating (1L: 7.1; R/R: 6.9). Seven fatigue-related sub-components were identified from the way that patients described their fatigue, covering symptoms (tiredness/need for sleep, lack of energy, weakness, cognitive fatigue) and impacts (decreased ability to maintain social/familial/professional role, decreased physical functioning, frustration). Mean (standard deviation) FACIT-Fatigue score was 28.9 (13.6) for patients with 1L CLL and 29.3 (11.5) for those with R/R CLL, indicating greater fatigue than the general population and providing further evidence that fatigue is a core component of CLL. The items that scored highest were: "I feel fatigued" (item 1; mean score: 2.4) and "I feel tired" (item 4; mean score: 2.4). The items that scored lowest were: "I am too tired to eat" (item 10; mean score: 0.4) and "I need help doing my usual activities" (item 11; mean score: 1.0). During cognitive debriefing, 100% of patients confirmed that the FACIT-Fatigue was reflective of their experiences with fatigue resulting from CLL. All patients found the response options provided by the FACIT-Fatigue to be sufficient. Patients confirmed that most of the FACIT-Fatigue terminology was clear. An exception was the item "I feel listless/washed out" (item 3), which was not consistently understood: most patients linked it to an absence of both physical and mental energy, but some interpreted it just as a lack of physical energy. Overall, patients considered the FACIT-Fatigue items to be relevant and distinct from each other, and found that the impact items captured both the mental and physical impacts of fatigue. One item, "I am too tired to eat", was not considered to be highly pertinent because, although respondents could imagine that some patients with CLL might be too tired to eat, they themselves could only recall being too tired to prepare a meal, not being too tired to eat. However, respondents felt that the item was still relevant and that it did not detract from the applicability or clarity of the FACIT-Fatigue. Conceptual relevance of the FACIT-Fatigue was supported by mapping of its items to the 7 fatigue-related sub-components identified during concept elicitation (Table). Conclusions: Results from concept elicitation and cognitive debriefing interviews demonstrated content validity of the FACIT-Fatigue in patients with CLL with 1L or R/R disease, thus providing evidence that it is fit-for-purpose in this population. Disclosures Chung: AstraZeneca: Employment, Equity Ownership. Eek:AstraZeneca: Employment, Equity Ownership. Eyre:Janssen: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Abbvie: Honoraria; Roche: Honoraria.

Background Follicular lymphoma (FL) patients (pts) receiving immunochemotherapy now have a median overall survival (OS) of 15-20 years (y). ~80% of pts demonstrate an age/sex-matched OS compared to the population (Casulo et al, 2015). As such, optimizing therapy and minimizing toxicities are key outcome measures. The GALLIUM trial (Marcus et al, 2017) reported excess toxicity with front line (1L) obinutuzumab (O) compared to rituximab (R) (neutropenic fever, infection) and with bendamustine (B) (treated-related mortality ~4-5%). Methods We performed a single institution retrospective analysis of 132 consecutively 1L FL pts (2009-19) to assess factors associated with progression-free survival (PFS), OS, and morbidity following chemotherapy (R or O with CVP, CHOP, or B) +/- anti-CD20 antibody (ab) maintenance. Transformed FL was excluded. We collected data on all-cause infection over a 3y period, including infective-related admissions and grade (G) 1-2 infections regardless if they received maintenance. Univariable (UVA) and multivariable analyses (MVA) assessed factors for infective complications. Potential factors included were: age, baseline Hb ( Results Across all pts, the median age was 63 y (range 28-90). Time from diagnosis to 1L was 1.6 months (range 0.03-110). Regimens included R-CHOP (n=34), R-CVP (n=53), R-B (n=32), O-B (n=9). B-treated pts were younger (median 57 y) than R-CHOP (median 62 y) and R-CVP (median 71 y). The mean CIRS-G (R-CHOP 1.38 vs R-CVP 2.76 vs B-R 1.1) and CIRS-G severity score (R-CHOP 0.81 vs R-CVP 1.38 vs R-B 0.81) were both higher in R-CVP pts. R-CVP pts had lower FLIPI scores (FLIPI 3-5: B-R/O 71%, R-CHOP 68%, R-CVP 55%). 68% R-CHOP, 51% R-CVP and 76% B-R/O of pts started anti-CD20 ab maintenance. The 3y PFS was 70% (95% confidence interval (CI) 61-78%) (Fig A) and 3y OS 89% (95% CI 82-93%) (Fig B) across all pts. Pts receiving R-CVP had an inferior PFS (Fig C) than RCHOP or B-R/O (3y PFS 52% (95% CI 37-66%) vs R-CHOP 3y PFS: 82% (95% CI 63-92%) vs BR 88% (95% 70-95%) vs B-O 63% (CI 24-87%) p=0.004). This translated to R-CVP pts having an inferior OS (Fig D) compared to RCHOP or B-R/O (3y OS 82% (95% CI 68-90%) vs R-CHOP 100% vs BR 91% (95% 74-97%) vs B-O 88% (95% CI 39-98%) p=0.006); reflecting both pt characteristics and treatment efficacy. Across all pts, the 3y PFS was 81% (95% CI 70-89%) with anti-CD20 ab maintenance versus 53% (95% CI 37-66%) without maintenance (p=0.001) (Fig E). There was an OS difference in favour of maintenance (3y OS 75% vs 97%) (p=0.012) (Fig F). There were 74 documented infective episodes (G1+) across all pts over 3y follow up. There were 43 infective-related admissions (G3+) during induction (n=132) and 16 during maintenance (n=83). The highest numerical risk of any infective episode(s) within 3 y follow up was BR (69% 22/32) and lowest R-CVP (50% 25/50) (p=0.09). G3+ infection during induction was significantly higher with R-CHOP (52% 17/33) compared to BR 6/32 (19% 6/32) (p=0.006). Conversely during maintenance, infective-related admissions were numerically higher in B-treated (R+O) (23% 7/31) compared to RCVP/RCHOP pts (16% 8/50) (p=0.46). Factors associated with an increased risk for all grade infections by UVA included: maintenance (odds ratio (OR): 2.1 (95% CI 1-4.4), p=0.05), CIRS-G* (OR: 1.2 (95% CI 1-4.4), p=0.07), CIRS-G severity* (OR: 1.5 (1.0-2.2) p=0.04). On MVA, the only risk factor for all grade infective episodes (ref: R-CVP) was BR (OR 3.8 (95% CI 1.2-11.6); p=0.02). Factors associated with an increased infective-related admission by UVA included high CIRS-G* (OR:1.15 (95% CI 1-4.4), p=0.09). On MVA, the factors of significance for an increased infective admissions were CIRS-G* (OR 1.34 (95% CI 1.0-1.8) and R-CHOP (ref: R-CVP OR:1.0) OR 3.2 (95% CI 1.1-9.1); p=0.03). Conclusions OS and PFS were superior in pts receiving R-CHOP or B-based treatment compared to R-CVP. Similarly, superior OS and PFS were seen in pts receiving anti-CD20 maintenance. Consistent with GALLIUM, we show the risk of infective-related episodes across 3 y following bendamustine when accounting for other factors. Careful anti-infective measures (anti-viral, anti-PCP) are required following B-based therapy, including on maintenance. Infective-related admissions (G3+) were independently associated with R-CHOP. *continuous variable Disclosures Djebbari: Takeda: Honoraria, Other: support with conference attendance; Novartis: Honoraria; Celgene: Honoraria, Other: support with conference attendance, Research Funding; Amgen: Honoraria. Collins:Gilead: Consultancy, Honoraria. Eyre:Roche: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Janssen: Honoraria; Abbvie: Honoraria.

Introduction Diffuse large B cell lymphoma (DLBCL) and osteoporotic fracture are commoner in older patients (pts). Steroids and chemotherapy are recognised as a risk factor (RF) for fragility-related fracture and its associated morbidity. A small randomised trial (RCT) (Westin 2013) showed bisphosphonates stabilize bone mineral density (including all ages / histologies) in NHL pts. Despite this, there is a lack of data defining the specific incidence and fracture risk in older DLBCL pts post R-CHOP. We aimed to better define this risk in this specific cohort. Methods Data on consecutive DLBCL pts ≥70 years (y) treated with R-CHOP were retrospectively collected across 7 UK centres (2009-2019). Follow up was censored in 07/2019. All pts had untreated, de novo DLBCL or untreated transformed (to DLBCL) indolent B cell NHL. PTLD, HIV and pre-treated NHL pts were excluded. All pts received 1-9 cycles of full or attenuated R-CHOP with curative intent. Pts were excluded if they had progressive disease (PD) or died < 6 months (m) of cycle 1 R-CHOP (RCHOP1). A detailed anonymised database included ECOG performance status (PS), body mass index (BMI), history of osteoporosis / osteopenia, documented steroid pre-phase, vitamin D supplementation, calcium and alkaline phosphatase levels, and sites of bone DLBCL involvement. Fractures at diagnosis (DLBCL-related/unrelated) and pre diagnosis were collected. Fractures (including bone site) occurring during 18m from RCHOP1 were identified from radiology records. Pts were followed for a minimum of 6m and censored at 18m from RCHOP1, or at their last follow up if < 18m or at PD or death if between 6-18m. Baseline pt characteristics were descriptive. Survival analyses were performed using Kaplan Meier methods and Cox regression with comparisons between categories using the log-rank test. Time to event analyses were measured from RCHOP1 until fracture event. Primary end point was 18m cumulative fracture incidence censoring pts at death or relapse. Univariable and multivariable analyses (UVA; MVA) of potential influencing RFs for fracture was assessed by Cox regression (Final stepwise model; p=0.1 for inclusion). Results Of 589 pts identified, 92 pts had PD or died prior to 6m and were excluded. 20 pts were excluded due to short follow up. Across 477 pts, the median age was 77 (range 70-93) y. 66% had an ECOG PS 0-1. The median cycles given was 6 (range 1-9). 27.3% received pre-phase steroids. The median BMI was 25.5 (range 14.2-48.1). 8.1% had a fracture prior to DLBCL, and 9.1% had a history of osteopenia or osteoporosis. 5.7% were current smokers, 3% had rheumatoid arthritis, 13.5% had type (T) 2 diabetes (DM), and 4.5% had a history of excess alcohol. At baseline, 25.2% had PET or CT-assessed cortical bone involvement. Overall, there were 52 fractures, including 50 within 18m follow up. Cumulative fracture incidence was 6.3% (95% confidence interval (CI) 4.4 - 8.9) at 6m, 9.5% (95% CI 7.1 - 12.6) at 12m and 11.5% (95% CI 8.8 - 14.9) at 18m (Fig A). 6 pts had multiple fracture sites (2; n=5, 3; n=1). 32 (62%) had vertebral fracture(s). Thoracic (34% 20/59) and lumbar vertebral (27% 16/59) were dominant sites (Fig C). 7/52 fractures were at the site of DLBCL involvement, 17/52 were at a different site from initial bone DLBCL involvement, 27/52 were in pts without bone involvement and 1/52 was unknown. Univariable RFs included female sex (hazard ratio (HR) 1.89 (95% CI 1.05 - 3.28)), known osteopenia or osteoporosis (HR 2.64 (95% CI 1.32 - 5.29)), DLBCL-related fracture at diagnosis (HR 4.05 (95% CI 2.07 - 7.92) (Fig B). Initial bone involvement was only associated with an increased risk in pts with a DLBCL-related baseline fracture (95% CI HR 4.56 (2.27 - 9.17)) (Table 1). MVA showed that DLBCL-related baseline fracture (HR 4.32 (1.97 - 9.47)) was the only significant independent RF for fracture with low BMI (p=0.051) and smoking history (p=0.052) of borderline significance (Table 2). Conclusions This is the largest series to date to show there is a clinically relevant fracture risk in older DLBCL pts specifically receiving R-CHOP in early follow up. Our data have limitations inherent to a retrospective study including the potential for unknown confounders, missing data, and medical record misinterpretation. Prospective data is required to validate RFs identified which could enable targeting a high-risk population. An RCT is needed to determine the value of prophylactic intervention(s) in high risk pts. Figure Disclosures Gibb: Takeda: Research Funding. Collins:Gilead: Consultancy, Honoraria. Eyre:Janssen: Honoraria; Abbvie: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Roche: Honoraria.

BACKGROUND The recent approval of novel agents (NAs) has changed the treatment landscape in chronic lymphocytic leukemia (CLL), however, there remains uncertainty regarding treatment discontinuation patterns in real-world (RW) settings. This study assessed patterns of and reasons for discontinuation for patients (pts) treated with chemotherapy/chemoimmunotherapy (CT/CIT) and NAs in first (1L) and second (2L) lines of therapy in CLL. METHODS The CLL Collaborative Study of Real-World Evidence (CORE) study is a retrospective, multicenter, observational study. Adult CLL patients (pts) were included if they were diagnosed with CLL, initiated 1L or 2L therapy for CLL on/after 01/01/2012 (excluding lines of therapy received as part of clinical trials). Discontinuation patterns were assessed among CT/CIT and NAs, more specifically in four treatment cohorts: fludarabine+cyclophosphamide+rituximab (FCR), bendamustine+rituximab (BR), B-cell receptor inhibitors (BCRi)-based (e.g., acalabrutinib, ibrutinib, or idelalisib) and venetoclax-based regimens. Treatment discontinuation was operationally defined as ending therapy for reason(s) other than completion of planned duration of therapy. RESULTS Of 671 pts receiving 1L therapy, 81 (12%) received FCR (median age=58, 70% males); 153 (23%) BR (median age=63, 61% males), 255 (38%) BCRi-based (median age=65, 65% males); and 13 (2%) venetoclax-based (median age=59, 54% males). The remaining 169 pts received other regimens (e.g., other CT/CIT). The most common BCRi-based therapy in 1L was ibrutinib-containing regimens (97%). Median duration of follow-up was 24, 27, 11 and 8 months for FCR, BR, BCRi-based and venetoclax-based regimens, respectively. Treatment discontinuation occurred in 18 (22%), 41 (27%), 51 (20%) and 4/13 pts receiving FCR, BR, BCRi-based and venetoclax-based regimens, respectively. The most common reason for discontinuation in FCR (11/18 pts; 61%), BR (15/41 pts; 37%) and BCRi-based (24/51 pts; 47%) cohorts was adverse events (AEs), with >70% being severe AEs in each cohort. Common AEs leading to discontinuations were hematological abnormalities (e.g., neutropenia, thrombocytopenia) in the FCR (6/18 pts; 33%) and BR (6/41 pts; 15%) cohorts. In the BCRi-based cohort the most common AEs leading to discontinuations were cardiac (4/51 pts; 8%), skin and subcutaneous tissue disorders (e.g., rash; 6/51 pts; 12%), hemorrhage/bleeding (3/51; 6%), and musculoskeletal and connective tissue disorders (3/51; pts; 6%). For the relatively small number of pts treated with venetoclax-based regimens and discontinued, disease progression was the common reason for discontinuations (3/4 pts); no pts discontinued venetoclax-based regimens due to adverse events. In the relapsed/refractory setting specifically in 2L, 15 (7%), 113 (56%) and 16 (8%) pts received BR, BCRi-based and venetoclax-based regimen respectively, of which the most common BCRi-based therapy regimen was ibrutinib-based (95%). Treatment discontinuation occurred in 5/15 pts (33%), 27/113 pts (24%) and 4/16 pts (25%) receiving BR, BCRi-based and venetoclax-based regimens, respectively. The most common reason for discontinuations were severe AEs for BR (3/5 pts) and BCRi-based (13/27 pts) cohorts and disease progression for venetoclax-based regimens (2/4). CONCLUSIONS Despite the relatively short follow-up, in both 1L and 2L, similar discontinuation patterns emerge. CT/CIT is often discontinued prior to completion of planned cycles of therapy, suggesting that these regimens are difficult to tolerate. Additionally, treat to progression BCRi-based regimens are also discontinued for severe AEs, discordant to results from clinical trials. With a small cohort and limited information collected, results on venetoclax discontinuation warrants additional studies. Well tolerated chemotherapy-free combinations with finite treatment duration in treatment naïve and relapsed/refractory settings may limit continuous exposure to treatment and prevent discontinuations due to AEs. Table Disclosures Shadman: Atara: Consultancy; Gilead: Research Funding; TG Therapeutics: Research Funding; Bigene: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Emergent: Research Funding; Sunesis: Research Funding; Merck: Research Funding; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Mustang Biopharma: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; ADC Therapeutics: Consultancy. Sail:AbbVie: Employment, Other: and may hold stock or stock options. Manzoor:AbbVie: Employment, Other: and may hold stock or stock options. Yazdy:Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy; Bayer: Honoraria, Speakers Bureau. Hill:AstraZeneca: Consultancy, Honoraria; Pharmacyclics: 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; TG therapeutics: Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; Takeda: Research Funding; Amgen: Research Funding. Tuncer:Abbvie: Membership on an entity's Board of Directors or advisory committees; 2018 Steering Committee: Other: reimbursement for travel to the steering committee at ASH. Allan:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Janssen: Consultancy, Honoraria; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Ujjani:Atara: Consultancy; Gilead: Consultancy; Astrazeneca: Consultancy; Genentech: Honoraria; PCYC: Research Funding; Pharmacyclics: Honoraria; AbbVie: Honoraria, Research Funding. Emechebe:AbbVie: Employment, Other: and may hold stock or stock options. Kamalakar:AbbVie: Employment, Other: and may hold stock or stock options. Sharmokh:AbbVie: Employment, Other: may hold stock or stock options. Jiang:AbbVie: Employment, Other: and may hold stock or stock options. Pena:AbbVie: Employment, Other: and may hold stock or stock options. Marshall:AbbVie: Employment, Other: and may hold stock or stock options. Nielsen:AbbVie: Employment, Other: and may hold stock or stock options. Barr:Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding. Brown:Dynamo Therapeutics: Consultancy; Catapult Therapeutics: Consultancy; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy; Sun: Research Funding; Sun Pharmaceuticals, Inc: Research Funding; Morphosys: Other: Data safety monitoring boards ; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy. Schuh:AbbVie: Consultancy, Speakers Bureau; Kite: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Verastem: Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Eyre:Janssen: Honoraria, Other: travel support; AbbVie: Honoraria, Other: travel support; Gilead: Honoraria, Other: travel support. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche-Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; AbbVie: 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, Research Funding; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Wierda:Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; Loxo Oncology Inc.: Research Funding; KITE pharma: Research Funding; Acerta Pharma Inc: Research Funding; Miragen: Research Funding; Pharmacyclics LLC: Research Funding; Cyclcel: Research Funding. Skarbnik:Jazz Pharmaceuticals: Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Roeker:Abbott Laboratories: Equity Ownership; AbbVie: Equity Ownership. Bannerji:Celgene: Consultancy; Celgene: Consultancy; Pharmacyclics: Other: travel support; Merck: Other: travel support, Patents & Royalties: IP rights; AbbVie, Inc: Consultancy; Gilead: Other: travel support; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Merck: Other: travel support, Patents & Royalties: IP rights; Pharmacyclics: Other: travel support; AbbVie, Inc: Consultancy, travel support; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Gilead: Other: travel support. Pauff:AbbVie: Employment, Other: and may hold stock or stock options. Schuster:Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees. Follows:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Cheson:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Eichhorst:BeiGene: Research Funding; ArQule: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brander:DTRM Biopharma: Research Funding; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; MEI: Research Funding; Tolero: Research Funding; Acerta: Research Funding. Pivneva:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Guerin:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member, Research Funding.

Background: Ibrutinib has transformed the clinical approach to relapsed mantle cell lymphoma (MCL) with those receiving ibrutinib at first relapse obtaining the greatest benefit encouraging use earlier in the treatment algorithm (Rule et al, 2019). However, the general applicability of clinical trial findings is not established and concerns regarding ibrutinib tolerability persist, especially in non-trial populations enriched for frailer patients with multiple co-morbidities. In the United Kingdom, ibrutinib is funded as standard of care at first relapse. This study has analysed the clinical effectiveness and tolerability of this approach in a non-clinical trial real world population. Method: 23 centres across the United Kingdom contributed data from consecutive patients treated with ibrutinib for MCL at first relapse. Patients received standard dose 560 mg OD, unless documented, and commenced treatment between August 2014 and April 2019. Response to therapy was defined as per Lugano classification (Cheson et al, 2014), although CR assessment by bone marrow biopsy was not always undertaken. Data was collected on baseline characteristics, including response to prior therapy, and MIPI at time of relapse. The study primary outcome was PFS. Predictors of progression were determined using univariate Cox regression. Results: 169 patients were included in the study. Median age at start of ibrutinib was 72 years (range 33 to 97) and 122 (72.2%) were male. At diagnosis 13.5% had blastoid histology; 59.3% Ki67 ≥30%; 32.0% received cytarabine based induction and 27.8% HSCT consolidation; 11.2% received low intensity frontline therapy (i.e. not fit for R-CHOP) due to frailty. Median PFS following frontline therapy was 21.4 months (95% CI 14.6 to 28.3) and 52.1% progressed within 2 years. At start of ibrutinib 52.2% were MIPI high risk; 23.9% were ECOG 2 or higher and 2.4% had CNS involvement. Overall response rate (ORR) to ibrutinib was 71.6% with 30.4% achieving CR/CRu. Estimated median PFS from start of ibrutinib was 16.5 months (95% CI 11.5 to 21.5) and estimated OS 23.9 months (95% CI 13.0 to 34.8), with median follow up 26 months. Median PFS for patients with early relapse to frontline therapy (progression of disease 1 were also negative predictors of PFS (see table 1 for univariate analysis). 10 patients (5.9%) received attenuated dose from start of therapy due to frailty and 20 patients (11.8%) underwent dose reductions while on therapy due to drug toxicity. Of 109 patients to discontinue ibrutinib 72 (66.1%) were due to progressive disease, 15 for consolidation alloHSCT (13.8%), 13 due to medical co-morbidities and unrelated death (11.9%), and 9 due to drug toxicity (8.3%), including 1 bleed. Only 5.3% of all patients stopped therapy due to drug toxicity. Patients ≥80 yrs were more likely to stop therapy early for reasons other than progressive disease or alloHSCT (OR 2.92, p=0.02), but frailer patients who received low intensity frontline therapy also showed a trend for more durable response with second-line ibrutinib (PFS 10.0 months versus 4.0 months, p=0.36) justifying use in this patient group. Conclusion: This study population is enriched for several recognised adverse prognostic markers, including older age and poor performance status, which is likely to explain differences in PFS relative to clinical trial data. Despite these features response rates were similar, and it is notable that 46.7% of evaluable pts achieved longer PFS with ibrutinib than preceding front-line therapy. It is reassuring that the proportion of patients stopping ibrutinib due to toxicity was similar to trial data and bleeding events that required alterations to therapy were rare (3 cases, 1.8%). Although ibrutinib represents a significant breakthrough with clear benefit to most patients the results also highlight that outcome for many remains poor. 40% of patients progressed within 1 year of starting ibrutinib and median OS post ibrutinib was only 3.6 months. 35.2% of patients died within 1 month of documented relapse suggesting many, predominantly older patients, were not fit for further therapy. Of the 53 pts surviving beyond 1 month median OS was 7.5 months and 21.9% lived beyond 1 year. Improved treatment strategies in the post-ibrutinib setting remains a priority. Disclosures Rule: Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Kite: Consultancy. Eyre:Gilead: Consultancy, Honoraria, Other: commercial research support; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria. Furtado:Abbvie: Honoraria. Shah:ABBVIE: Consultancy. Campbell:Novartis: Consultancy, Other: Educational support; Takeda: Consultancy, Other: Educational support; Bristol Myers-Squibb: Other: Educational support; Roche: Other: Educational support; Celgene: Other: Educational support. McCarthy:Janssen: Honoraria, Other: Educational grant to attend meetings . Lambert:Takeda Pharmaceuticals: Other: Funding to attend a scientific conference in 2018. McKay:Epizyme: Consultancy, Honoraria. Osborne:Roche: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Gilead: Consultancy; MSD: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Novartis: Other: Travel; Pfizer: Honoraria, Speakers Bureau; Servier: Consultancy. Bishton:Takeda: Other: Travel support, Research Funding; AbbVie: Research Funding; Celltrion: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Other: Travel support, Research Funding. Crosbie:Janssen: Honoraria.

Follicular lymphoma (FL) is an indolent B-cell malignancy with a variable course. Standard immuno-chemotherapy incorporate alkylator and anti-CD20 monoclonal antibody as first line (Rummel et al, 2013) commonly followed by 24 months rituximab maintenance (Salles et al, 2008). Anthracycline, purine analogue, and alkylator combination are used at relapse and younger patients may have remissions consolidated with autologous or allogeneic stem-cell transplantation (alloSCT) (Kothari et al, 2014). Relapsed or refractory (R/R) FL in patients unfit for transplantation or post-transplantation is incurable, and remains an unmet need.

The transformation of chronic lymphocytic leukemia (CLL) to high-grade diffuse large B-cell lymphoma (DLBCL), also called Richter’s Syndrome (RS), is a rare cancer with dismal prognosis. Drug discovery for RS is hampered by the lack of suitable experimental models, and effective therapies remain elusive rendering RS an area of high unmet clinical need. We performed whole genome sequencing (WGS) to interrogate paired CLL and RS samples from 17 patients enrolled in a prospective multicenter Phase 2 clinical trial (CHOP-OR) and we found that subclones affected by mutations in MAPK and PI3K pathways show a high expansion probability during transformation. We also demonstrate for the first time that non-coding mutation clusters in a PAX5 enhancer, situated 330kb upstream from the transcription initiation site, correlate with transformation. Finally, we confirm our findings by employing targeted DNA sequencing (TGS) and RNA expression profiling on an extended cohort of 38 patients. Statement of significance Through integrated analysis of WGS, TGS and RNA expression data, we identified drivers of transformation not previously implicated in RS, which can be targeted therapeutically and tested in the clinic. Our results have informed the design of a new clinical platform study, which is now open to recruitment in the UK.

[This corrects the article DOI: 10.18632/oncotarget.26460.].

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare form of Hodgkin lymphoma that typically presents as early stage, indolent disease in young adult males. The relationship between NLPHL and DLBCL is incompletely understood, and there remains a paucity of data with regard the incidence and management of high-grade transformation. We report the largest study to date describing the incidence, management and long-term outcome of 26 cases of high-grade transformation of NLPHL over a 30-year period. We report a transformation incidence of 17.0%. Bone marrow, splenic, and liver infiltration with DLBCL was frequent. Patients with an aa-IPI 2–3 have poorer OS and PFS (P = 0.034 and P = 0.009, respectively). Although the approach to treatment was somewhat variable, typically young, otherwise fit patients received anthracycline-based induction, platinum-based consolidation with stem cell harvesting, followed by autologous SCT with BEAM conditioning. Long-term (5 year) PFS was over 60% with this approach, and comparable to our de novo DLBCL historical age and time period-matched cohort largely treated with CHOP-like chemotherapy alone. The transformation rate of 17.0% highlights the importance of accurate initial diagnosis, long-term follow-up, and re-biopsy at relapse. Am. J. Hematol. 90:E103–E110, 2015. © 2015 Wiley Periodicals, Inc.

It has long been understood that the immune system has intrinsic anti-tumour activity in humans, and that a key mechanism of tumour progression is the ability of a tumour to escape this immune surveillance. A number of attempts have been made to harness this anti-tumour immunity in both solid tumour oncology and haematological malignancies with variable success. Examples include the use of allogeneic stem cell transplantation and donor lymphocyte infusion in haematological cancer and vaccine studies in solid tumours. Enhanced signalling of the Programmed cell death-1 (PDCD1, PD-1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA4) 'immune checkpoint' pathway has emerged recently as a critical mechanism by which tumours can escape the natural anti-tumour immune response. As such, novel therapies have been developed to help enhance this natural immunity by switching off the PDCD1/CTLA4 immune checkpoint pathway. The following review will discuss the pathobiology of these pathways and the exciting new data now available in lymphoid malignancies.

Relapsed or refractory classical Hodgkin lymphoma (cHL) is associated with a poor outcome when standard chemotherapy fails. Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate licensed for use at relapse after autologous stem cell transplant (ASCT) or following two prior therapies in those unsuitable for ASCT. There are limited data assessing the ability of BV to enable curative SCT. We performed a UK-wide retrospective study of 99 SCT-naïve relapsed/refractory cHL. All had received 2 prior lines and were deemed fit for transplant but had an insufficient remission to proceed. The median age was 32 years. Most had nodular sclerosis subtype, Eastern Cooperative Oncology Group performance status 0-1 and advanced stage disease. The median progression-free survival (PFS) was 5·6 months and median overall survival (OS) was 37·2 months. The overall response rate was 56% (29% complete response; 27% partial response). 61% reached SCT: 34% immediately post-BV and 27% following an inadequate BV response but were salvaged and underwent deferred SCT. Patients consolidated with SCT had a superior PFS and OS to those not receiving SCT (P < 0·001). BV is an effective, non-toxic bridge to immediate SCT in 34% and deferred SCT in 27%. 39% never reached SCT with a PFS of 3·0 months, demonstrating the unmet need to improve outcomes in those unsuitable for SCT post-BV.

[Figure][1] A 31-year-old white man presented with a 6-week history of symptoms of anemia, progressive hearing loss, and periorbital edema. Clinical examination revealed striking periorbital swelling (panels A-B) and periauricular edema with resultant tympanic membrane obstruction. No

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.

Anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma seen in both adults and children. ALCL is associated with a characteristic chromosomal translocation, t(2;5)(p23;35) which fuses the anaplastic lymphoma kinase (ALK) gene on chromosome 2 with the nucleophosmin (NPM) gene on chromosome 5, resulting in a NPM-ALK fusion protein, ALK over-expression and constitutive tyrosine kinase activity. This aggressive lymphoma is more prevalent in males and can present with extranodal involvement (lung, skin and marrow infiltration) and haemophagocytic lymphohistocytosis. The long-term overall survival is approximately 70-90% in children and over 70% in adults. Staging systems and prognostic risk factors are different in both childhood and adult ALCL. Treatment in adults is typically anthracycline-based, with autologous stem cell transplantation (ASCT) salvaging patients in relapsed disease. There is evidence for ALL-like therapy or intensive, pulsed anthracycline-based induction in children. ASCT, allogeneic SCT and vinblastine maintenance are all considered reasonable options in relapsed childhood disease. The anti-CD30 immunoconjugate Brentuximab Vedotin and the specific ALK inhibitor Crizotinib are changing the treatment paradigm in ALCL (ALK-positive or negative) and ALK-positive ALCL respectively. Both agents have shown encouraging responses in relapsed ALCL. It remains to be seen how these novel agents are used, but it is very possible that they may improve overall responses and survival in both children and adults. This review highlights the presentation, histopathological features, prognostic factors, and evidence-based treatment approaches in the first line and relapsed setting in ALK-positive ALCL. The review concludes by discussing the novel approaches using Brentuximab and Crizotinib which are being tested in clinical trials.

Since the discovery of rapamycin in Easter Island soil in 1975, more has been learnt about the relevance and importance of the mammalian target of rapamycin (mTOR) pathway in cell signalling, proliferation and ultimately tumourigenesis. Rapamycin targets the mTORC1 complex alone. Despite initial excitement, rapamycin and its analogues, everolimus and temsirolimus, have displayed limited efficacy in the treatment of lymphoid malignancies. This review highlights the important and well-described aspects of the critical phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT/mTOR pathway and discusses the mechanisms of action of rapamycin, its clinical efficacy in lymphoid malignancies, and the mechanisms of resistance. Renewed interest in targeting the pathway has evolved through the discovery of mTORC2, a protein complex associated with a key mechanism of resistance to first generation mTOR inhibitors. As such, novel dual inhibitors of mTORC1 and mTORC2 have been developed, along with other dual inhibitors of the mTOR pathway. The evolution in the development of dual inhibitors is described herein, along with the burgeoning in vitro, pre-clinical data and the early phase clinical data available. Although historically mTOR inhibitors have been used extensively in haematopoietic and solid organ transplant prophylaxis, this review will focus on developments of their use in lymphoid malignancies.

Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8–10 months. We conducted a phase II trial of standard CHOP-21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2–6: 1000 mg day 1) (CHOP-O) followed by 12 months ofatumumab maintenance (1000 mg given 8-weekly for up to six cycles). Forty-three patients were recruited of whom 37 were evaluable. Seventy-three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide-based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression-free survival was 6·2 months (95% confidence interval [CI] 4·9–14·0 months) and median OS was 11·4 months (95% CI 6·4–25·6 months). Treatment-naïve and TP53-intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non-neutropenic infections were observed. There were no treatment-related deaths. Seven patients received platinum-containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP-O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.

Introduction Very few studies have assessed the incidence and risk factors associated with CNS progressive disease (PD) in elderly DLBCL. The CNS IPI (international prognostic index) uses the standard IPI with an additional point for renal/adrenal (R/A) involvement to define CNS risk in DLBCL patients (pts). The CNS IPI is validated in younger DLBCL pts (Schmitz et al, 2016) but little is known about CNS risk in the elderly. Few data exist outwith a single study of pts >80 years (y) pooled from 2 LYSA mini CHOP trials (Cabannes-Hamy et al 2018). CNS PD risk from 270 pts >80y was 1.8% at 2y and 3% overall. CNS PD risk did not differ according to CNS IPI in this study. No real world data outside of these trials exists. Few studies have assessed the risk of CNS prophylaxis (intrathecal (IT) +/- high dose intravenous (IV) methotrexate (HDMTX)) in the elderly. Methods Data on consecutively treated new DLBCL pts ≥70y were retrospectively collected across 6 UK centres (2009-2018). We compiled a detailed database of CNS-IPI, extranodal disease sites, CNS prophylaxis, adverse events related to IV HDMTX, rate and timing of CNS PD, outcome post CNS PD and associations with CNS PD risk. Results 529 pts received Rituximab (R) chemotherapy with curative intent (513 R-CHOP/attenuated R-CHOP (97.0%), 13 R-PMitCEBO, 3 R-GCVP). 80.7% (427/529) received no CNS prophylaxis, 14.7% (78/529) received intrathecal (IT) MTX prophylaxis, 2.1% (11/529) received HDMTX only, and 2.5% (13/529) received both IV HDMTX and IT MTX. The median age of all pts was 76.7y and median follow up 2.9y (range 0.4 - 10.9y). The CNS IPI was 1 in 11.8% (60/510), 2 in 21.2% (108/510), 3 in 24.3% (124/510), 4 in 26.1% (133/510), 5 in 12.9% (66/510) and 6 in 3.7% (19/510). 19 pts were unclassifiable due to a missing LDH (Table 1). Extranodal sites (ENS) were noted in 64.7% (342/529). Median ENS were 1 (range 0-5). Commonest sites were bone 24.2% (128/529), liver 9.6% (51/529), renal 7.6% (40/529), and gastric/oesophageal 7.0% (37/529). R/A involvement was present in 9.3% (49/529). Pts with higher CNS IPI were more likely to receive CNS prophylaxis (IT and/or MTX); CNS IPI 0-1; 13.3%, 2-3; 10.9%, 4+; 29.9% (p Of 24 pts receiving IV HDMTX, median age was 72.4y, mean CNS IPI 3.6 (median 4), and median eGFR 83 (range 47 - 90) ml/min/1.73m2. 21% (5/24) were readmitted with complications directly post HDMTX (Neutropenic fever (NF) (n=1), non-NF (n=1), mucositis (n=1), pericarditis (n=1), and pneumonia/SIADH (n=1)). A single CNS PD occurred in this cohort (4.2%). When pts that received IT MTX were compared to pts receiving no IT MTX, the readmission rate during R-chemo with all-cause infection was 53.8% (42/78) vs 25.9% (105/405; 22 unknown) (p The overall rate of CNS PD was 2.7% (14/527). These included isolated CNS PD (n=11) and concurrent CNS and systemic PD (n=3). The rate of CNS PD was 2.2% (4/178 including (1 concurrent relapse)) in ≥80y and was not statistically different at 2.9% (10/349 including 2 concurrent PD) in 70-80y (p=0.87). 71% (10/14) CNS PD had a CNS IPI 4-6. 12/14 of CNS PD occurred The rate of CNS PD according to CNS IPI was: CNS IPI 1-3: 1.3% (4/300), CNS IPI 4: 2.3% (3/133), CNS-IPI 5: 4.5% (3/66) and CNS IPI 6: 21.1% (4/19) (CNS IPI 4-6: 4.6% (10/218)). CNS PD risk with R/A involvement was 8.2% (4/49). Significant Univariate risk factors for CNS PD include higher CNS IPI, ECOG 3-4, ≥2 ENS and R/A involvement as higher risk pts (Table 1). The overall survival (OS) post CNS PD (CNS only) was short (median of 2.7 months (m) (range 23 days - 8.6 m)) which was similar to OS of systemic PD (median 3.3 m) (Fig D). Conclusions The rate of CNS PD in elderly pts receiving RCHOP or RCHOP-like treatment is low and consistent with LYSA data. There were no differences in CNS PD incidence in 70-80y vs ≥80y. Increase risk was particularly apparent in CNS IPI 5-6 and R/A involvement. IV HDMTX in ≥70y was associated with a 21% readmission rate and its benefit is unclear. Readmission with infection was statistically higher in those receiving IT MTX although this is confounded by higher IPI in these pts. Prophylaxis requires a careful risk assessment in the elderly, evaluation of individual pt factors and consideration of the risks. On the basis of these data, consideration of prophylaxis should be confined to CNS IPI 5-6 and/or R/A involvement. Disclosures Eyre: Celgene: Other: travel support; Janssen: Consultancy, Other: travel support; Roche: Consultancy; Abbvie: Consultancy, Other: travel support; Gilead: Consultancy, Other: travel support. Djebbari:Celgene: Honoraria, Other: travel support, Research Funding; Takeda: Honoraria, Other: travel support; Pfizer: Other: conference registration. McMillan:Celgene: Honoraria, Other: travel support; BMS: Honoraria; Amgen: Honoraria; Takeda: Other: travel support; Roche: Consultancy, Honoraria, Other: travel support; Pfizer: Research Funding; MSD: Honoraria. Bishton:Abbvie: Research Funding; Roche: Research Funding; Takeda: Other: travel support to ASH; Gilead: Research Funding. Fox:Roche: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: travel support, Speakers Bureau; Sunesis: Consultancy; Gilead: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Abbvie: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: travel support, Speakers Bureau. Collins:ADC Therapeutics: Consultancy, Honoraria, Research Funding; Celgene Corporation: Research Funding; Amgen: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria.

Introduction: Venetoclax (Ven), an oral BCL2 inhibitor, is approved for the treatment (tx) of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Ven is generally well tolerated, and side effects observed in clinical trials have been consistent with other CLL tx. Clinical trials using the approved dose escalation schedule report negligible rates of clinical tumor lysis syndrome (TLS). We aimed to understand rates of select adverse events (AEs) including cytopenias, infections, and TLS in CLL patients (pts) treated with Ven in community and academic settings. To do so, we examined 297 pts with CLL who received Ven, either alone or paired, in this multicenter, international study. Methods: We conducted a retrospective cohort study of Ven treated pts with CLL across at 15 academic (n=169) and 51 community (n=128) centers outside of the clinical trial setting. This study represents a collaboration between US centers, CLL Collaborative Study of Real World Evidence (CORE), and UK CLL Forum. Demographics, baseline disease characteristics, Ven dosing, TLS risk (per FDA Ven label) and prophylaxis, and AEs were collected. Lab vs. clinical TLS was defined by Howard criteria. PFS was estimated by Kaplan Meier methodology. All comparisons were descriptive. Results: Of the 297 pts examined, median age at Ven initiation was 67 (range 37-91). The group was 69% male, 96% had R/R CLL, and 45% had del17p. Baseline characteristics stratified by practice setting are included in Table 1. 80% received Ven as monotherapy while 20% received it paired with another agent (anti-CD20 mAb (75%), ibrutinib (8.5%), other (16.5%)). All pts were treated outside of clinical trials. During dose escalation, 81% achieved a 400 mg dose and 65% maintained 400 mg following escalation (cyp3A4 use unknown). TLS risk was low in 40%, intermediate (int) in 32%, and high risk in 28%. CT scan prior to Ven initiation was performed in 62%. At least one hospitalization occurred for 56% of low, 80% of int, and 88% of high risk pts (63% of the total cohort). Table 1 describes the distribution of TLS risk and frequency of hospitalizations in academic, community centers. TLS prophylactic measures were available for a subset of pts. Allopurinol was used for 91% (n=68/75) of low, 93% (n=52/56) of int, and 94% (n=29/31) of pts at high risk for TLS. Rasburicase was used for 27% (n=28/102) of low, 42% (n=34/81) of int, and 72% (n=57/79) of high risk pts. Normal saline was used in 85% (n=62/73) of low, 88% (n=49/56) of int, and 97% (n=30/31) of high risk pts. TLS occurred in 8.4% of pts (n=25/297). Three lab and 2 clinical events occurred in low risk pts, 7 lab and 3 clinical events in int risk pts, and 7 lab and 3 clinical events in high risk pts. Of pts with TLS, 1 has discontinued Ven. Of pts with clinical TLS, all were hospitalized, received allopurinol and normal saline, and 28% received rasburicase. 72% with TLS had creatinine clearance Select AEs were neutropenia (ANC7 stools/day) 6.9%. For the subset who received Ven paired, AEs were not increased: 35% neutropenia, 29% thrombocytopenia, 22% infection, 6.3% neutropenic fever, and 6.4% diarrhea. TLS was observed in 3.4% of pts who received Ven paired vs. 9.3% who received Ven monotherapy. 29% pts required ≥1 dose reduction and 32% had ≥1 dose interruption. Median length of dose interruption was 7 days (range 1 - 132). 22 pts (7.4%) discontinued Ven due to an AE. PFS was similar in pts with ≥1 dose interruption vs. 0, pts who required dose interruption ≥8 days vs. Conclusions: Ven was well tolerated in this cohort; AE rates were similar to those reported in clinical trials. Both academic and community sites employed TLS prophylaxis consistent with FDA/EMA recommendations resulting in a small proportion of clinical TLS events ( Disclosures Fox: Sunesis: Consultancy; Celgene: Consultancy, Other: Travel support, Speakers Bureau; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau. Eyre:Gilead: Consultancy, Other: travel support; Abbvie: Consultancy, Other: travel support; Roche: Consultancy; Janssen: Consultancy, Other: travel support; Celgene: Other: travel support. Allan:Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees. Schuster:OncLive: Honoraria; Physician's Education Source, LLC: Honoraria; Dava Oncology: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Gilead: 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, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Nabhan:Cardinal Health: Employment, Equity Ownership. Hill:Amgen: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Lentigen Technology: Research Funding; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria; Exelexis: Equity Ownership; Oncosec: Equity Ownership; Geron: Equity Ownership. Lamanna:Jannsen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Coombs:AROG: Other: Travel fees; H3 Biomedicine: Honoraria; Abbvie: Consultancy; DAVA Oncology: Honoraria; Incyte: Other: Travel fees. Barr:AbbVie, Gilead: Consultancy. Skarbnik:Gilead Sciences: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shadman:Pharmacyclics: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy; Celgene: Research Funding; Verastem: Consultancy; Gilead Sciences: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Mustang Biopharma: Research Funding; Beigene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy. Ujjani:AbbVie: Consultancy, Speakers Bureau. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Jacobs:Genentech: Honoraria. Schuh:Giles, Roche, Janssen, AbbVie: Honoraria. Brander:Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria. Mato:Pharmacyclics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Regeneron: Research Funding; Sunesis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Acerta: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Prime Oncology: Speakers Bureau.

Introduction: Venetoclax (Ven) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (Ven mono) or in combination (Ven paired) with rituximab based on clinical trials with selected patients (pts) and limited ibrutinib exposure. Whether Ven paired is superior to Ven mono, patterns of care, and outcomes following Ven discontinuation are unknown. Further, better delineation of adverse events (AEs) when Ven is used outside of clinical trials is needed. To address these gaps, we conducted a multicenter, international study in partnership with CLL Collaborative Study of Real World Evidence (CORE) and UK CLL Study Forum examining the clinical experience of 348 Ven treated CLL pts, representing the largest series of Ven treated pts reported to date. Methods: We conducted a retrospective cohort analysis of CLL pts treated with Ven across 24 US and 42 UK academic and community centers. We examined demographics, baseline disease characteristics, dosing, AEs, TLS risk and outcomes, response rates, outcomes (overall survival (OS) and progression free survival (PFS)), and tx sequencing. TLS events were defined by Howard criteria. PFS and OS were estimated by the Kaplan Meier method. Comparisons of outcomes used the Log Rank test. Univariate and multivariate analyses were performed with COX regression. All other comparisons were descriptive. Results: Of these 348 CLL pts, 94% were R/R, median age 67 years (range:37-91), 69% male, 85% white, and 73% Rai stage ≥2. 19% received Ven on clinical trial. 79% had Ven mono; Ven was paired most commonly with anti-CD20 (n=51) and ibrutinib (n=10). Pts received a median of 3 tx (range 0-15) before Ven; 78% received ibrutinib, 29% received PI3Ki, 20% had ≥2 prior kinase inhibitors, and 68% had chemoimmunotherapy. Median time from most recent tx to Ven start was 1.1 months (range 0-62). Pre-Ven prognostic markers included 43% del17p, 34% TP53 mutated, 24% del11q, 38% complex karyotype (≥ 3 abnormalities), and 84% IGHV unmutated (Table 1). TLS risk was low in 38%, intermediate in 34% and high in 28%. During ramp up, TLS was observed in 10% (22 lab, 9 clinical TLS events, 3 missing data). Following dose escalation, 70% achieved a stable Ven dose of 400 mg, 33% required ≥ 1 dose interruption and 27% required ≥ 1 dose reduction. AEs included grade 3 neutropenia 39%, grade 3 thrombocytopenia 29%, infections 25%, grade ≥ 2 diarrhea 7.8%, and neutropenic fever 7.7%. AEs were similar whether treated on or off clinical trial. The ORR to Ven mono, Ven paired was 81% (34% CR), 86% (29% CR). With a median follow-up of 14.2 months, median PFS and OS were not reached (12 month PFS 74%, OS 82%). Figure 1 depicts PFS stratified by Ven mono vs. paired, clinical trial vs. clinical practice, del17p status, and complex karyotype. Pts who discontinued Ven due to AEs had better OS compared with those who discontinued due to progression or Richter Transformation (RT) (Median OS 47 vs. 15.1 vs. 8.6 months, respectively). In multivariate analyses, complex karyotype was the only independent predictor of PFS (HR 2.8, p Conclusions: In this heavily pretreated, poor risk group, Ven showed favorable outcomes with comparable toxicity and efficacy on or off clinical trial. Similar outcomes were observed for Ven mono and Ven paired; longer follow up is needed from studies of Ven paired to understand depth and durability of response. Complex karyotype independently predicted inferior PFS and OS. Without complex karyotype, del(17p), multiple lines of prior tx, and prior ibrutinib tx were independent predictors of inferior outcomes. Outcomes of retreatment with KI in Ven-failure previously treated with KI were poor. Data on sequencing cellular therapies post Ven is forthcoming. Disclosures Mato: AbbVie: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; AstraZeneca: Consultancy; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Acerta: Research Funding; Prime Oncology: Honoraria; Portola: Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy. Eyre:Abbvie: Consultancy, Other: travel support; Janssen: Consultancy, Other: travel support; Roche: Consultancy; Gilead: Consultancy, Other: travel support; Celgene: Other: travel support. Nabhan:Cardinal Health: Employment, Equity Ownership. Lamanna:Acerta: Research Funding; TG Therapeutics: Research Funding; Jannsen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brander:Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Barr:AbbVie, Gilead: Consultancy. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Shah:Geron: Equity Ownership; Lentigen Technology: Research Funding; Exelexis: Equity Ownership; Oncosec: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria. Allan:AbbVie: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Kennard:AbbVie, Gilead, Verastem: Consultancy. Schuster:Gilead: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: 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, Research Funding; Genentech: Honoraria, Research Funding; Physician's Education Source, LLC: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; OncLive: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau. Coombs:AROG: Other: Travel fees; Abbvie: Consultancy; Incyte: Other: Travel fees; DAVA Oncology: Honoraria; H3 Biomedicine: Honoraria. Ujjani:AbbVie: Consultancy, Speakers Bureau. Jacobs:Genentech: Honoraria. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Schuh:Giles, Roche, Janssen, AbbVie: Honoraria. Shadman:Celgene: Research Funding; Gilead Sciences: Research Funding; Mustang Biopharma: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Consultancy; Pharmacyclics: Research Funding; Genentech: Research Funding; Genentech: Consultancy; Acerta Pharma: Research Funding; Beigene: Research Funding; Verastem: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; AbbVie: Consultancy. Fox:Abbvie: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: travel support, Speakers Bureau; Gilead: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: travel support, Speakers Bureau; Sunesis: Consultancy.

INTRODUCTION Primary central nervous system lymphoma (PCNSL) in patients (pts) over 65 years old have poorer outcome compared to younger cohorts, as comorbidities, baseline performance status and susceptibility to iatrogenic toxicity impede adequate drug delivery (Kasenda et al, Ann Oncol, 2015). Balancing toxicity against treatment benefits remains a challenge in this age group. Recent trials have attempted to rationalize treatment aiming for reduced toxicity whilst maintaining CNS penetration. Efficacy of additional agents, such as oral alkylators (Fritsch et al, Leukemia 2017) has also been demonstrated. Most clinical trial cohorts underrepresent elderly pts and thus analysis of real-world outcomes and therapeutic practice is warranted. METHODS Consecutively diagnosed pts between 01/10/12 and 01/10/17, ≥65 years old in 14 tertiary UK centres were analysed retrospectively. Radiological exclusion of systemic disease and histological diagnosis were mandatory. Pts receiving any form of 1st line treatment including palliative (whole-brain radiotherapy [WBRT]/oral chemotherapy), best supportive care (BSC) or clinical trial were included. Diagnostic and referral pathways were audited. Baseline patient characteristics and treatment received was recorded in order to document current UK practice. Pts. were stratified into 4 treatment groups: single agent MTX; MTX with oral alkylator; high-intensity HI-MTX (MTX/AraC and MATRix) or palliative intent treatment (WBRT/oral alkylator/BSC). The study primary outcome was overall response rate (ORR) after induction. Secondary outcomes were PFS and OS. Additional variables were MTX clearance and the relative dose intensity (RDI) of MTX normalised with a reference of 14mg/m2. UV/MVA for ORR and Cox-regression for PFS and OS were used for identification of baseline predictors of response and survival. RESULTS 244 pts were included in the analysis with median age 71yrs (range 65-91) and 123 (50%) male. LDH (Elevated:104, 42%) and ECOG performance score (PS) (3-4: 87, 36%) were the only prognostic markers recorded. Median time from presenting scan to treatment was 33 days (IQR 22-48). Demographic characteristics are summarised in table 1. 80% of pts (n=192) received MTX based chemotherapy. 68% of pts >70yr and 50% >75yr received >1 cycle of MTX. MTX median cumulative dose delivered was 10.6 g/m2 (range 1.5-21), median number of cycles was 4 (range 1-6). Dose reductions of MTX occurred in 53/176 pts. (30%). Median time to MTX clearance was 3 days (range 1-18) and median RDI was 0.75 (range 0.11-1.5). TRM for MTX treated pts was 7.2%. 112 pts received rituximab (46%; 11% pre-2015 vs. 64% post-2015). 73 pts. (38%) received ORR after induction was 63%. HI-MTX (HR 3.4; CI 95% 1.5 - 7.6; p=0.003) was independently associated with superior ORR compared to HD-MTX alone (Table 1). Median follow up for survival was 25 months. 2-yr PFS and OS were both 39%, median OS after progression was 80 days. MTX RDI (HR 0.18; p 52 pts (21%) received upfront palliative treatment and compared to MTX cohort, were older (median 76y vs. 70y), had a poorer PS (ECOG 3-4: 62% vs. 28%) and higher incidence of impaired renal function (GFR < 60ml/min: 15% vs. 5%). CONCLUSION MTX can be delivered to the majority of pts >70 years with manageable TRM rates. Notably, early treatment discontinuation was relatively frequent with outcomes in this group comparable to palliative care. By contrast, pts who completed >3 cycles of HI-MTX and underwent consolidation experienced comparable outcomes to younger trial cohorts. MTX combination chemotherapy and MTX dose intensity were the strongest predictors of survival whilst rituximab was not a covariate for response or survival despite an increase in its use. Maximising cumulative MTX dose, particularly within more intensive protocols, may translate into improved ORR and survival in older pts with PCNSL. Table. Table. Disclosures Kassam: AbbVie: Equity Ownership. Culligan:Merck Sharp & Dohme (MSD): Honoraria; Celgene: Other: Support to attend conferences; Daiichi-Sankyo: Other: Support to attend conferences; JAZZ: Honoraria; Abbvie: Other: Support to attend conferences; Takeda: Honoraria, Other: Support to attend conferences; Pfizer: Honoraria. McKay:Epizyme: Consultancy, Honoraria. Eyre:Roche: Consultancy; Janssen: Consultancy, Other: travel support; Gilead: Consultancy, Other: travel support; Abbvie: Consultancy, Other: travel support; Celgene: Other: travel support. Osborne:Roche: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Servier: Consultancy; MSD: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Other: Travel to conference. Yallop:Servier: Other: Travel funding; Pfizer: Consultancy. Fox:Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: Travel support, Speakers Bureau; Sunesis: Consultancy; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau. Cwynarski:Roche: Consultancy, Other: Conferences/Travel support, Speakers Bureau; Autolus: Consultancy; Kite: Consultancy; Gilead: Consultancy, Other: Conferences/Travel support, Speakers Bureau; Janssen: Other: Conferences/Travel support.

Introduction The impact of RCHOP dose attenuation in elderly patients (pts) with DLBCL is poorly understood. 1% of DLBCL 1st line pts in trials are ≥80 years (y). Attenuated R-CHOP (25mg/m2 doxorubicin (DOX); 400mg/m2 cyclophosphamide (CYCLO), 1mg vincristine) cure 50-60% in phase II trials (Peyrade et al, 2011, 2017). Full dose RCHOP compared to attenuated RCHOP does not improve outcome in ≥80y (Juul et al, 2018) or may worsen survival via toxicity (Eyre et al, 2016, Carson et al 2015). Methods We systematically collected data on IDI (cycle (C)1 dose) and RDI of CYCLO/DOX in consecutively treated pts ≥70ys across 6 UK centres (2009-18). Untreated de novo DLBCL and untreated transformation (HGT) of indolent NHL (iNHL) receiving ≥C1 were included. RCHOP was given at a minimum interval of 21 days. G-CSF was routine. The following were excluded: HIV+, prior solid organ transplant, isolated leg type DLBCL, pre-treated HGT, central nervous system involvement with DLBCL, and pts unfit for anthracycline. Data were collected on Cumulative Illness Rating Scale for Geriatrics (CIRS-G), CIRS-G severity index (total/no. categories), age-adjusted international prognostic index ((aa)IPI), Hb, albumin, LDH, B symptoms, bulk ≥10cm, major operation at diagnosis, and extranodal sites (ENS). Predictors of progression free (PFS), disease free (DFS), and overall survival (OS), were determined using univariable (UVA) and multivariable (MVA) Cox regression. Factors were analysed as continuous (denoted *); additionally IDI (full dose: ≥80% of weight based dose vs attenuated: Results 511 pts received R-CHOP with curative intent. 49% were male and 51% were female. Median follow up was 1.67y. Median age was 77y. 32% had stage I-II and 68% stage III/IV. 14% had concurrent iNHL, 20% bulk, 33% >1 ENS, and 66% IPI 3-5. 46% had CIRS-G ≥6. When comparing age/IDI categories, in 70-80y, pts with IDI80% (2-4; 30%), higher IPI 3-5 (71% vs 64%), higher CIRS-G≥6 (59% vs 40%), and higher CIRS-G severity index. ≥80y receiving IDI>80% had better ECOG (0-1 67% vs IDI For all pts, median PFS was 5.4y (95% confidence interval (CI) 4.1 - 6.9), median DFS was not reached, and median OS 5.5y (95% CI 4.5 - 6.7). When analysed by 70-80 vs ≥80y: 2y PFS was 71.8% (95% CI 66.4-76.4%) vs 60.3% (95% CI 51.5-68.0%), 2y DFS 79.4% (95% CI 74.3-83.6%) vs 76.7% (95% CI 68.4-83.1%) (p = 0.23) and 2y OS 74.6% (95% CI 69.4-79.1%) vs 60.2% (95% CI 51.2-68.1%). Unlike OS and PFS, DFS was not significantly different when 70-80y vs ≥80y were compared, suggesting >80y have a worse outcome due to toxicity and/or unrelated causes of death. 15 deaths in >80y with IDI>80 were: infection (n=5), systemic progressive disease (PD) (n=7), CVA leading to stopping RCHOP post C1 (subsequent PD) (n=1), unknown (in remission) (n=1), dementia (n=1). In 70-80y, IDI>80% had significantly improved PFS, DFS and OS. In ≥80y, there was no difference in PFS, DFS or OS according to IDI 80% (Fig A-F). UVA Univariable predictors of worse PFS and OS included age*, ECOG PS*, DOX IDI*, CYCLO IDI*, combined IDI*, IPI 3-5, aaIPI 2-3, raised LDH, male gender and B symptoms (all p MVA IDI* remained an independent predictor of PFS, DFS and OS. Using 70-80y IDI>80 (HR 1.0) as the comparator, the following were associated with significantly increased risk of PD and / or death in PFS and OS in MVA: 70-80y IDI80. Compared to 70-80y IDI>80 (HR 1.00), the HR for DFS in ≥80y IDI>80 approached significance (p = 0.07) vs PFS and OS, suggesting that causes other than PD account in part for inferior OS and PFS (Table 1). Conclusions To our knowledge, this is the largest series that has systematically analysed RDI, IDI (DOX, CYCLO and combination) and co-morbidities in consecutive unselected DLBCL ≥70y. Consistent with recent literature (Juul et al, 2018), there is no clear benefit to PFS, DFS or OS in dose intensifying (IDI>80) in ≥80y. IDI is a clear independent predictor of outcome across all pts. Pts 70-80y with IDI Disclosures Eyre: Janssen: Consultancy, Other: travel support; Roche: Consultancy; Abbvie: Consultancy, Other: travel support; Gilead: Consultancy, Other: travel support; Celgene: Other: travel support. Fox:Celgene: Consultancy, Other: Travel, Speakers Bureau; Sunesis: Consultancy; Abbvie: Consultancy, Other: Travel, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel, Speakers Bureau; Gilead: Consultancy, Other: Travel, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel, Research Funding, Speakers Bureau. McMillan:Celgene: Honoraria, Other: travel support; BMS: Honoraria; Amgen: Honoraria; Takeda: Other: travel support; Roche: Consultancy, Honoraria, Other: travel support; Pfizer: Research Funding; MSD: Honoraria. Bishton:Abbvie: Research Funding; Roche: Research Funding; Takeda: Other: travel support to ASH; Gilead: Research Funding. Collins:Celleron: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Celgene Corporation: Research Funding; MSD: Consultancy, Honoraria; Amgen: Research Funding; Pfizer: Consultancy, Honoraria.

We describe a rare case of fatal mumps encephalomyelitis occurring in 19-year old male following matched unrelated donor peripheral blood haematopoietic stem cell transplantation (HSCT). The indication for HSCT was for an undefined form of severe combined immunodeficiency (SCID). Molecular typing of the mumps viral RNA isolated from neural tissue indicated that the infection was acquired at the time of a mumps outbreak in England and Wales that occurred between 2004 and 2006. This case highlights the importance of considering mumps in the differential diagnosis of central nervous system infection in highly immunosuppressed patients.

Diagnosis and management of myeloma in the very elderly patient is challenging. Treatment options have vastly improved for elderly myeloma patients but still require the clinician to personalize therapy. In this paper, we offer evidence-based, pragmatic advice on how to overcome six of the main challenges likely to arise: 1) diagnosis of myeloma in this age group, 2) assessment of the need for treatment, and the fitness for combination chemotherapy, 3) provision of the best quality of supportive care, 4) choice of combination chemotherapy in those fit enough for it, 5) treatment of relapsed myeloma, and 6) provision of end of life care. With an increased burden of comorbidities and a reduced resilience to treatment and its associated toxicities, the management of myeloma in this age group requires a different approach to that in younger patients to maximize both quality and length of life.

Histological features of Epstein-Barr virus (EBV) can rarely mimic lymphoma. A 25-year-old presented with a spontaneous splenic rupture following a short illness. Histopathology assessment of the splenic and marrow tissue was highly suggestive of peripheral T-cell lymphoma not-otherwise-specified (PTCL-NOS). T-cell receptor (TCR) PCR clonality studies revealed a monoclonal T-cell population expressing for both TCRβ and γ, strongly suggestive of a T-cell clonal disease. EBV IgM was positive and IgG negative. EBV PCR was positive (7.02 ×10(4)/mL). Despite the strong suggestion of PTCL-NOS from histopathology and clonality studies, the decision was made to observe the patient and not start multiagent chemotherapy. The patient remained well, with no signs of PTCL and subsequently seroconverted to IgG+ EBV. We highlight the potential pitfall of acute EBV masquerading as PTCL and show the critical role of the multidisciplinary integration of histopathological, serology, molecular and clinical features to avoid misdiagnosis.

Gemcitabine is a nucleoside analogue used widely across haemato-oncology. Side effects are generally predictable, and typically consist of cytopenia, nausea, and infection. As the present case clearly demonstrates, gemcitabine is in rare cases associated with life-threatening large vessel vasculitis, which can involve the aorta. It is important to consider gemcitabine-induced vasculitis in non-specifically unwell patients with raised inflammatory markers and fever of unknown origin, with or without signs of vascular compromise. Early recognition, cessation of gemcitabine therapy, and high-dose steroids are critical for a good outcome. PET CT is valuable to diagnose large vessel vasculitis and monitor treatment response.

The goal of managing classical Hodgkin lymphoma (cHL) in pregnancy is to obtain good long-term outcomes for both the mother and fetus. Given the excellent outcomes outside of pregnancy, the goal of treatment should remain curative. There remains a tension and debate regarding the timing of chemotherapy, the curative nature of such treatment and the timing of delivery. Moreover, the aim during pregnancy should be to minimize fetal toxicity and optimize perinatal outcomes. The management of cHL within pregnancy was covered within the excellent recent British Committee for Standards in Haematology guidelines, but with necessary brevity. By reviewing the literature over the last 30 years, herein we discuss the options for management during each trimester. Critical organogenesis occurs between 2 and 8 weeks post-conception; during which time the immature fetus is vulnerable to cytotoxic exposure. We discuss the evidence for using ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and single agent vinblastine in the first trimester. cHL presenting in pregnancy raises complex and difficult ethical dilemmas that can cause anxiety for patients, families and physicians. Decision-making must be multi-disciplinary and holistic, taking into account the patient's wishes, psycho-social and religious beliefs and personal circumstances. Clear communication between the haemato-oncologist, medical obstetrician, nurse specialists, midwives and neonatologists is paramount to a successful outcome.

We read with great interest the recently published updated British Committee for Standards in Haematology (BCSH) guidelines on the diagnosis and management of Waldenstr€ om macroglobulinaemia (Owen et al, 2014). The authors are to be congratulated for producing an excellent, comprehensive and clear guideline. However, we differ with regard to the statement that ‘Dutcher bodies are intranuclear inclusions of immunoglobulin’. Dutcher bodies certainly appear to be intranuclear; however, they are intracytoplasmic immunoglobulin inclusions that invaginate into or overlie the nucleus. Sometimes the process of invagination can be clearly seen (Bain, 2009a). Dutcher bodies are thought to most probably result from the accumulation of immunoglobulin in the perinuclear cisterna (Brunning & Parkin, 1976). These inclusions have therefore been termed periodic acid-Schiff (PAS)-positive intranuclear ‘pseudoinclusions’ by the World Health Organization 2008 classification (Swerdlow et al, 2008). Indeed, Dutcher bodies were first described as intranuclear inclusions by Dutcher and Fahey (1959) in patients with Waldenstr€ om macroglobulinaemia. These PAS-positive inclusions were initially thought to have originated in the nucleus, only to be subsequently extruded into the cytoplasm via a ruptured nuclear membrane (Dutcher & Fahey, 1959). Russell bodies are also intracytoplasmic. They are typically spherical immunoglobulin inclusions that can expand to fill the cytoplasm of a cell with a single or multiple inclusions. Multiple Russell bodies can fill the cytoplasm and form a so-called Mott cell (Bain, 2009b). Russell bodies were initially described in the British Journal of Medicine in 1890 by the pathologist William Russell (1852–1940) who confidently described an ‘organism’ that caused cancer (Russell, 1890). Dutcher bodies, single or multiple Russell bodies and the inclusions of Mott cells are therefore morphological evidence of the same cytoplasmic inclusion(s) (Zini et al, 2010). Of course, we know now that both Dutcher bodies and Russell bodies are not specific to neoplastic plasma or plasmacytoid cells. Indeed they have been described in a number of reactive conditions (Gray & Schwartz, 2002) and other B-cell neoplasms (Metz et al, 1992). Although Mott cells, Dutcher bodies and Russell bodies are all aspects of the same phenomenon, the correct description of these inclusions helps to avoid confusion.

T cell ProLymphocytic Leukemia (T-PLL) is a rare lymphoid malignancy and is typified by its aggressive presentation and chemo-resistance. Given its rarity, haemato-oncologists are likely to manage only a handful of cases across their career and therefore making the diagnosis is the initial challenge. This diagnosis is critical, as recent data suggests that choosing specific treatment options, such as alemtuzumab, is important in improving outcomes.

Introduction CXD101 is a class I-selective HDAC inhibitor (HDACi)with no demonstrable activity against HDAC class II in non-clinical studies. CXD101 induces specific HDAC inhibition and subsequent to that, enhanced histone acetylation in a time and dose-dependent fashion in cell lines cells in vitro, leucocytes obtained from treated rats and dogs, and human leucocytes treated ex vivo. CXD101 has been tested on several tumor cell lines including non-Hodgkin lymphoma (NHL) and myeloma. We sought to determine the maximal tolerated dose (MTD) of CXD101 in a dose escalation study in patients with advanced solid and haematological cancer.We report the phase 1 first-in-human experience with CXD101 in patients with advanced malignancy. Methods In this phase 1 study we escalated the dose of CXD101 from 1 mgadministered orally twice daily (B.D.)for 5 days in a 21 day cycle, following a 3+3 design. Eligible patients had advanced solid tumours or relapsed, refractory lymphoma. A preliminary assessment of efficacy was performed in a dose expansion cohort after the MTD was found. 39 patients were enrolled, of whom 36 were exposed to CXD101. Lymphoma patients were assessed by Cheson 2007 criteria, and solid tumor patients by RESIST 1.1. A genome-wide loss-of-function screen identified HR23B, a protein that shuttles ubiquitinated cargo proteins to the proteasome, as a sensitivity determinant for HDAC inhibitor-induced cell apoptosis(Fotheringham et al., 2009).HR23B status was assessed in all cases with available archival tumor tissue. Results MTD Thirty patients were enrolled in the dose escalation cohort of whom 29 were evaluable for DLT assessment. The first DLT was noted at 16mg B.D. in cohort 5 (QTc prolongation). Subsequent DLTs were seen at 20mg B.D. (1 of 6; grade 4 neutropenia), and at the non-tolerated dose of 24/25mg B.D. (2 of 5; both neutropenic infection). A formal MTD and recommended phase II dose was established at 20 mg B.D. This dose was taken forward to treat 6 patients within the expansion cohort to date. Lymphoma patients - efficacy The baseline characteristics of 22 lymphoma patients included amedian age was53.5 years (range 21-79 years) and 59% were male. Patients received a median of 4 prior lines of therapy. The international prognostic index was 3-5 in 85%. In the 17 lymphoma patients dosed at 16mg b.d. or above, 3 partial responses (2 Hodgkin lymphoma post allogenic stem cell transplantation, 1 refractory angioimmunoblastic T-cell lymphoma) and 1 complete response (relapsed follicular lymphoma) were noted (overall response rate 23.5%) alongside 7 patients gaining clinical benefit with stable disease. Tumor volume reduction was seen in 56% of lymphoma cases (Figure 1). The median progression free survival in these 17 patients was 113 days (95% confidence interval (CI) 35-162 days). In those with PR (n=3) and CR (n=1), the duration of response was: 203 days, 161 days, 141 days (ongoing), and 176 days (ongoing) respectively.Detailed results on the solid tumor patients are reported separately (ESMO, 2016). Safety CXD101 was typically well tolerated. Across all 36 patients, possibly, probably or definitely IMP-relatedadverse events (AE) occurring in >10% of the total cycles doses regardless of attribution were: thrombocytopenia (28% grade 1-2; 10% grade 3-4), neutropenia (20% grade 1-2; 16% grade 3-4), anaemia (10% grade 1-2), nausea (19% grade 1-2), diarrhoea (11% grade 1-2), vomiting (11% grade 1-2), anorexia (10% grade 1-2), fatigue (25% grade 1-2), QTc prolongation (17% grade 1-2). The most frequent AEs observed were consistent with the known AE prolife of HDACi. All AEs were manageable. Conclusions CXD101 demonstrates a favourable safety profile. The MTD for CXD101 observed was 20 mg B.D. for 5 days in a 3-weekly cycle. Disease activity was seen in T-cell lymphoma, Follicular lymphoma and Hodgkin lymphoma (including post-allogenic stem cell transplantation). Further analysis of HR23B correlated tumor response and durability is ongoing and will be presented alongside pharmacokinetic and pharmacodynamic data. Trial ID: NCT01977638. Disclosures Eyre: Gilead: Honoraria, Other: Travel, Accomodation, Speakers Bureau; Celgene: Other: Travel, Accomodation; GSK: Honoraria; Takeda: Honoraria, Other: Travel, Speakers Bureau. Collins:Takeda: Consultancy, Honoraria, Speakers Bureau. Whittaker:Celleron Therapeutics: Employment, Equity Ownership. La Thangue:Celleron: Employment, Equity Ownership. Kerr:Celleron Therapeutics: Employment, Equity Ownership.

Background:Up to 10% of patients with chronic lymphocytic leukemia (CLL) undergo a high-grade transformation called Richter Syndrome (RS), most commonly of the diffuse large B cell lymphoma type. In ~80% of cases, the lymphoma originates from the CLL clone and is associated with a median survival inferior to 1 year after diagnosis. Prognosis following standard immunochemotherapy remains very poor and new therapeutic targets for RS are urgently needed. Methods:Only samples from patients with newly diagnosed RS recruited into the UK CHOP-OR (CHOP in combination with Ofatumumab, EudraCT number 2009-016459-23) were included (Eyre et al, Br J Haematol. 2016). DNA was extracted from 35 peripheral blood mononuclear cells (leukemic phase) and 21 FFPE-lymph node slides (Richter phase). For 15 patients, paired CLL and RS phase were available. A TruSeq Custom Amplicon panel (TSCA, Illumina) was designed targeting 28 recurrently mutated genes in CLL based on recent publications. Average sequencing depth was 2311x. Single nucleotide variant (SNV) were filtered with a variant allele frequency (VAF) >10%, with a depth >20, with an altered variant read >6 and by excluding synonymous mutation and mutation with a frequency >5% in the general population. Mutation frequencies were compared to those of Landau et al based on a CLL population of 538 patients. Results: Pathogenic mutations were identified in 28/30 CLL phase (93%) and 18/18 (100%) of RS phase. In the majority of paired cases (80%), mutations identified in the CLL phase were confirmed in the RS phase. Additional mutations were acquired in the RS phase compared to the CLL phase (277 versus 82) with a median of 5.5 mutations/RS phase versus 3 mutations/CLL phase (P=0.0003). When compared to the frequency in a general CLL population, we observed a significant increase of mutations in ATM (15%, 57%, 78% for general CLL population, CLL phase of RS, RS phase, respectively), TP53 (7%, 23%, 56%), NOTCH1 (6%, 23%, 50%), CDKN2A (23.1 months vs 6.6 months, P=0.0242). Conclusion: We show that CLL patients developing RS carry a high mutation burden and recurrent driver mutations in the leukemic clone and that additional mutations are acquired in the RS phase. We confirm the association of mutations in TP53, NOTCH1 and CDKN2A with RS and show in addition that SAMHD1 mutations are also frequently seen in RS. Finally, we propose that patients with biopsy findings of classical RS but no mutation in any of the 6 selected genes have an improved PFS and OS whereas patients without the classical RS biopsy features but a high-risk mutation profile fare poorly. Disclosures Eyre: GSK: Honoraria; Celgene: Other: Travel, Accomodation; Gilead: Honoraria, Other: Travel, Accomodation, Speakers Bureau; Takeda: Honoraria, Other: Travel, Speakers Bureau. Schuh:Gilead: Consultancy, Honoraria, Research Funding; Roche, Janssen, Novartis, Celgene, Abbvie: Consultancy, Honoraria.

Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world, with an annual incidence of 4.7 per 100,000 adults. Approximately 5% to 10% of CLL patients develop Richter Transformation (RT), in which CLL transforms into an aggressive lymphoma, most often diffuse large B-cell lymphoma (DLBCL). Prognosis for patients with RT is poor, with median progression-free survival (PFS) of approximately 6 months and median overall survival (OS) of 8 to 10 months (Eyre TA, Br J Haematol 2016). B-cell receptor signaling through Bruton tyrosine kinase (BTK) is one of the essential growth pathways for CLL. Acalabrutinib is a highly selective, potent BTK inhibitor in clinical development for the treatment of hematologic malignancies. Acalabrutinib monotherapy is being evaluated in a Phase 1/2 ACE-CL-001 clinical trial (NCT02029443). Preliminary results are reported for a cohort of patients with RT who were enrolled in ACE-CL-001. Methods: Eligibility criteria for the RT cohort included biopsy-proven RT, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 and age ≥18 years; prior ibrutinib therapy was not an exclusion criterion. Patients with central nervous system involvement of lymphoma were excluded. Patients with RT were treated with acalabrutinib 200 mg twice per day. The primary objective of the study was safety, which was assessed by frequency, severity and attribution of adverse events (AEs). The secondary objective was to determine response rate by investigator assessment. Overall response rate (ORR), PFS, and duration of response (DOR) were calculated. Patients were defined as evaluable for response if they received at least one response assessment after the first dose of study drug and according to established Lugano criteria (Cheson 2014). Results: A heterogeneous group of 29 patients with RT were enrolled. Results are presented through 01 June 2016. The median age was 66 years (range, 43 to 82), including 18 (62%) patients who were ≥60 years. Six (21%) patients had ECOG PS 2. Median time from initial CLL diagnosis was 5.4 years. Baseline disease characteristics included 4 (14%) patients with presence of B symptom(s), 2 of 24 (8%) with bulky lymph nodes ≥10 cm, and 5 of 24 (21%) with 17p deletion. The median number of prior systemic therapies for RT was 4 (range, 0-9). Twelve (41%) patients had received prior treatment with ibrutinib. The median time on treatment (n=29) was 2.1 months (range, 0 to 10.9), with 8 patients (28%) continuing on treatment at the time of data cutoff. The most common adverse events (AEs) (≥15% of patients) were headache [45%, all Grade (Gr) ≤2], diarrhea (28%, all Gr 1), anemia (24%), fatigue (21%), arthralgia (17%) and back pain (17%). Serious AEs (SAEs) occurred in 15 (52%) patients, with hypercalcemia (10%), fatigue (7%), and acute kidney injury (7%) as SAEs that occurred in ≥2 patients. Grade ≥3 AEs occurred in 59%, with Grade 3/4 AEs that occurred in ≥2 patients being neutropenia, anemia, back pain, hypercalcemia (n=3 each), fatigue, asthenia, and acute kidney injury (n=2 each). There were 10 deaths: 6 due to disease progression, 2 due to AEs (a Grade 5 cerebral abscess and a Grade 5 sepsis- both unrelated to study drug), and 2 of unknown cause. Treatment discontinuations occurred in 21 (72%) patients; causes of discontinuation included progressive disease in 15 (52%), withdrawal by patient in 1 (3%), physician decision in 2 (7%), and death due to progressive disease in 3 (10%). In the efficacy evaluable population (n=21), ORR including partial response (PR) or better was 38%, including complete response (CR) in 3 (14%) and PR in 5 (24%) patients. Among 8 responders (PR or better) the median DOR was 5.7 months (95% CI, 0.3 to 7.5). Two patients had a response of CR and went on to transplant. Among 6 efficacy evaluable patients who previously received ibrutinib, 3 responded (PR or better) to acalabrutinib. Median time to PR or better was 1.8 months (95% CI, 1.4 to 2.1). Stable disease was achieved in 5 (24%) patients. Median PFS was 3.2 months (95% CI, 1.8 to 4.0). Conclusions: These preliminary data demonstrate that acalabrutinib has promising single-agent activity in RT patients. These results warrant further investigation of acalabrutinib either as monotherapy or in combination with other targeted therapies in this difficult-to-treat patient population. Disclosures Hillmen: Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Schuh:Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Eyre:Takeda: Honoraria, Other: Travel, Speakers Bureau; Gilead: Honoraria, Other: Travel, Accomodation, Speakers Bureau; Celgene: Other: Travel, Accomodation; GSK: Honoraria. Brown:Infinity: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy; Pfizer: Consultancy; Gilead: Consultancy; Sun BioPharma: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy. Ghia:Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding; Adaptive: Consultancy. Allan:Abbvie: Speakers Bureau; Genentech: Speakers Bureau; Pharmacyclics: Speakers Bureau. Hamdy:Acerta Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Huang:Acerta Pharma: Employment. Izumi:Acerta Pharma: Employment, Equity Ownership. Patel:Acerta Pharma: Employment. Wang:Acerta Pharma: Employment, Equity Ownership.

Background:PQR309 is an oral balanced, pan-PI3K, mTORC1 and mTORC2 inhibitor. It is in clinical development for the treatment of solid tumors and hematologic malignancies. 1st generation mTOR inhibitors inhibit the activity of mTOR within the TORC1 complex only with activation of TORC2 proposed as a putative resistance mechanism. PI3 kinase inhibition may reduce subsequent AKT activation which can bypass some effects of mTOR inhibition. Potent antiproliferative activity of PQR309 was previously demonstrated in lymphoma cell lines in vitro and in vivo. Maximum tolerated dose (MTD) of PQR309 in solid tumours was established at 80 mg using a continuous once daily dosing schedule (OD). Methods:We performeda modified 3+3 DE of PQR309, open label phase 1 trial with expansion, to evaluate safety, pharmacokinetics (PK) and efficacy. Patients with relapsed or refractory lymphoma (any sub-type, ECOG PS of 0-1) were treated in two sequential cohorts with escalating doses of PQR309 administered on an OD dosing schedule to assess the MTD of PQR309. The starting dose of PQR309 was 60mg OD. The dose limiting toxicity (DLT) period was the first cycle of treatment, 21 days (d). PK samples were obtained at predefined time points. Clinical efficacy was evaluated according to revised Cheson criteria. In the expansion phase, patients will be treated at the MTD as defined in the DE phase of the study. Results: 15 patients were enrolled between August 2015 and March 2016 and treated with 60mg (n=8) or 80mg (n=7) of PQR309. Demographics: 5F:10M; median age 60 (range: 34-75), median number of prior systemic treatments 5 (range: 1-8). Lymphoma indications are shown in Table 1. Mean duration on therapy was 39 days (range: 3-160). One patient with follicular lymphoma remains on treatment. Grade (G)3/4 drug-related AE were seen in 3 patients treated with 60mg: 1 G4 rhabdomyolysis, 1 G4 neutropenia, 1 G3 hyperglycemia and one patient who developed G3 anorexia and G4 sepsis. Four patients treated with 80mg developed G3/4 drug-related AEs: two patients developed G3 hyperglycemia, one patient developed G3 fatigue and G3 pneumonitis. No DLT was observed. Preliminary PK showed rapid absorption (Tmax 1-2h), dose proportionality for Cmax and AUC and an estimated T1/2 of around 50 hours, consistent with PQR309 studies in solid tumours that evaluated dose levels from 10 to 150 mg PQR309. Responses observed in each patient are shown in the table below. 4 patients were non-evaluable, 3 due to disease progression requiring cessation of study drug and one requiring steroid doses exceeding protocol defined criteria, all within the 21 day DLT assessment period. Conclusion:The MTD and recommended PQR309 dose for the expansion of the study was 80mg OD, in agreement with earlier dose-finding studies in solid tumours. Adverse event patterns were consistent with those seen in studies involing solid tumours. Hyperglycemia, a predicted on-target effect of PI3K/mTOR inhibition, was observed in the majority of patients, providing evidence of pharmacodynamic effects of PQR309. PK was dose-proportional. Encouraging clinical activity including a CR was observed. The study expansion is ongoing. Disclosures Collins: Takeda: Consultancy, Honoraria, Speakers Bureau. Eyre:GSK: Honoraria; Celgene: Other: Travel, Accomodation; Gilead: Honoraria, Other: Travel, Accomodation, Speakers Bureau; Takeda: Honoraria, Other: Travel, Speakers Bureau. Ivanova:PIQUR: Employment. Schmitz:PIQUR: Employment. Dimitrijevic:PIQUR: Employment. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.