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The phase I/II AU-003 study in patients with treatment-naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.

The influence of early-life growth pattern and body size on follicular lymphoma (FL) risk and survival is unclear. In this study, we aimed to investigate the association between gestational age, growth during childhood, body size, changes in body shape over time, and FL risk and survival.We conducted a population-based family case-control study and included 706 cases and 490 controls. We ascertained gestational age, growth during childhood, body size and body shape using questionnaires and followed-up cases (median=83 months) using record linkage with national death records. We used a group-based trajectory modeling approach to identify body shape trajectories from ages 5-70. We examined associations with FL risk using unconditional logistic regression and used Cox regression to assess the association between body mass index (BMI) and all-cause and FL-specific mortality among cases.We found no association between gestational age, childhood height and FL risk. We observed a modest increase in FL risk with being obese 5 years prior to enrolment (OR=1.43, 95 %CI=0.99-2.06; BMI ≥30 kg/mWe observed a weak association between elevated BMI and FL risk, and no association with all-cause or FL-specific mortality, consistent with previous studies. Future studies incorporating biomarkers are needed to elucidate possible mechanisms underlying the role of body composition in FL etiology.

The association between smoking and alcohol consumption and follicular lymphoma (FL) incidence and clinical outcome is uncertain. We conducted a population-based family case-control study (709 cases: 490 controls) in Australia. We assessed lifetime history of smoking and recent alcohol consumption and followed-up cases (median = 83 months). We examined associations with FL risk using unconditional logistic regression and with all-cause and FL-specific mortality of cases using Cox regression. FL risk was associated with ever smoking (OR = 1.38, 95%CI = 1.08–1.74), former smoking (OR = 1.36, 95%CI = 1.05–1.77), smoking initiation before age 17 (OR = 1.47, 95%CI = 1.06–2.05), the highest categories of cigarettes smoked per day (OR = 1.44, 95%CI = 1.04–2.01), smoking duration (OR = 1.53, 95%CI = 1.07–2.18) and pack-years (OR = 1.56, 95%CI = 1.10–2.22). For never smokers, FL risk increased for those exposed indoors to >2 smokers during childhood (OR = 1.84, 95%CI = 1.11–3.04). For cases, current smoking and the highest categories of smoking duration and lifetime cigarette exposure were associated with elevated all-cause mortality. The hazard ratio for current smoking and FL-specific mortality was 2.97 (95%CI = 0.91–9.72). We found no association between recent alcohol consumption and FL risk, all-cause or FL-specific mortality. Our study showed consistent evidence of an association between smoking and increased FL risk and possibly also FL-specific mortality. Strengthening anti-smoking policies and interventions may reduce the population burden of FL.

Background: Approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) are >70 years old and have poor clinical outcomes attributable to treatment-related factors or to disease biology. Genotyping data in elderly DLBCL patients is limited because of lack of representation in clinical trials. R-mini-CHOP is better tolerated than R-CHOP in elderly DLBCL but with reduced efficacy. The addition of ibrutinib to R-CHOP has been shown to be effective in younger pts aged < 60 years but is associated with poor tolerability and outcomes in older patients. The ALLG Ibrutinib with R-mini-CHOP (IRiC) study, a prospective multicentre single-arm phase II study in elderly (≥ 75 years) DLBCL patients provided an opportunity to genotype this uncommon cohort. We therefore aimed to map the genetic landscape of mutations in elderly DLBCL and compare them to a non-trial younger cohort. Methods: Mutations in genes commonly associated with DLBCL were assessed in 55 IRIC study patients with a median age of 81 years (75-91 years) and a gender ratio of 1.0 (27 M/28 F). A cohort of 51 non-trial patients withde novoDLBCL treated with anthracycline-based regimens was also genotyped. The median age of the control group was 65 years (29-91 years) with a gender ratio of 1.2:1 (28 M/23 F). The cell of origin (COO) measured using gene expression profiling on 39/55 trial patients (non-GC=13, GC= 22, unclassified= 4), and Hans algorithm on 45/51 non-trial patients (non-GC=14, GC=31) was comparable (p=0.571). Outcome data was available at a median follow-up of 18 and 40 months for the trial and non-trial cohorts respectively. We extracted genomic DNA from and performed next generation sequencing on diagnostic formalin-fixed paraffin-embedded or fresh frozen tissue samples using a customized capture library (SureSelectXT Target Enrichment System, Aqilent Technologies) covering genes involved in lymphomagenesis. The purified libraries were sequenced on the Illumina NextSeq500 platform at AGRF (Australian Genome Research Facility, Australia). Mutations in the following genes were compared across the two cohorts: ARID1A, BCL2, BTG1, BTG2, CARD11, CCND3, DTX1, EP300, ETS1, EZH2, FOXO1, GNA13, HIST1H1C, IKBKB, IRF8, KDM2B, KLHL6, MYC, MYD88, NOTCH1, NOTCH2, PIK3CD, PIM1, PRDM1, PTEN, PTPN21, SGK1, SPEN, STAT3, TET2, TNFAIP3, TNFRSF11A, TNFRSF14, TP53 and TRAF5. Statistical analysis for nominal data was done using the chi-square test and for ordinal data using the Kruskal-Wallis test (p < 0.05= significant). Kaplan-Meier curves were calculated for patients with and without each mutation and the curves compared using a log-rank approach. Results: Patients were divided into 2 groups, IRiC trial cohort aged >75 years (n=55) + non-trial elderly patients >75 years (n=9) =elderly cohort(n=64) and non-trialnon-elderly cohortof patients < 75 years (n=42). As expected, elderly patients were more likely to have high-risk disease with higher IPI of ≥ 3 (n=42, n=17, p=0.009). There was no significant difference in gender or COO. The frequency of mutations in the elderly (n=64) was compared to the non-elderly cohort (n=42). NOTCH2 was the most common mutation irrespective of age (34 [53%]; 16 [38%], p=0.129). Notably, we found that mutations in MYC (8 [12.5%]; 0, p= 0.021), PTEN (17 [26.5%]; 4 [9%], p=0.045) and TET2 (28 [43.7%]); 7 [16.6%], p=0.004) were more frequent in the elderly. As expected, MYD88 and CD79B mutations were more frequently associated with non-GC subtype (p=0.001). No other associations with COO were identified. No clear prognostic individual genes or gene clusters could be identified in the trial or the elderly cohort. Ibrutinib-responsive (MYD88 [L265P n=7] and CD79B [n=11]) and ibrutinib-resistant mutations (CARD11 [n=6] or PIM1 [n=12]) did not show clear associations with response rate, overall survival or progression-free survival. Conclusions: Our study found that the mutational profile of elderly DLBCL patients aged ≥ 75 years is enriched for targetable mutations in MYC, PTEN and TET2 compared to those < 75 years. PTEN and TET2 are tumour suppressors and MYC is an oncogene with an important regulatory role in cell growth and proliferation. We hypothesize that hypo-methylating agents targeting TET2, BET inhibitors in MYC mutated tumours and PI3K inhibitors to target PTEN deficient lymphoma may help improve clinical outcomes in elderly DLBCL. No clear prognostic markers were identified in this small cohort. Disclosures Trotman: Celgene:Research Funding;BeiGene:Research Funding;Takeda:Research Funding;PCYC:Research Funding;F. Hoffmann-La Roche:Research Funding.Verner:Janssen Cilag Pty Ltd.:Research Funding.Gandhi:Celgene:Research Funding;Bristol-Myers Squibb:Research Funding;Mater Research:Current Employment;Janssen-Cilag:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Roche:Other: Travel, accommodation, expenses ;Genentech:Honoraria;Gilead Sciences:Honoraria;Amgen:Honoraria;Merck Sharp & Dohme:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.Gandhi:Integrated Sciences:Current Employment.Talaulikar:Takeda:Research Funding;Amgen:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction Midostaurin is the only approved FLT3 inhibitor for combination with intensive induction and consolidation chemotherapy in newly diagnosed patients with FLT3 mutant AML. The FLT3 inhibitor, sorafenib, was investigated in the randomized SORAML trial (Röllig, Lancet Onc 2015), in combination with intensive chemotherapy (IC) for newly diagnosed adults with AML Methods The Australasian Leukaemia and Lymphoma Group (ALLG) conducted a randomized phase 2 study [ACTRN12611001112954] in 99 adults aged 18-65 years with newly diagnosed FLT3-ITD positive (allelic ratio (AR) ≥0.05) AML to determine whether addition of SOR to IC would improve event-free survival (EFS). The study was powered to identify a 25% increase in 2-year EFS with SOR. Patients 18-55 yrs received induction with IDAC-3 (idarubicin [IDA] 12 mg/m2 D1-3 and ara-C 1.5 g/m2 BD D1,3,5,7); patients 56-65 received 7+3 (IDA 12 mg/m2 D1-3 and ara-C 100 mg/m2 D1-7 IVI). Patients were randomized 2:1 to SOR or PBO 400 mg BD on days 4-10 of induction and each consolidation cycle. Due to the pharmacokinetic interaction between SOR and azoles, antifungal prophylaxis during induction was with AmBisome 5 mg/kg IV twice weekly. For consolidation, patients 18-55 yrs received 2 cycles of IcE (IDA 9 mg/m2 D1-2, ara-C 100 mg/m2 D1-5 IVI and etoposide 75 mg/m2 D1-5), those 56-65 yrs received 2 cycles of IDAC-2 (IDA 12 mg/m2 D1-2 and ara-C 1g/m2 BD D1,3,5). Maintenance was with SOR/PBO 400 mg bd days 1-28 for 12 cycles. Allogeneic HCT (allo-HCT) was at investigator discretion. SOR/PBO was not continued post allo-HCT. The primary endpoint was EFS without censoring for allo-HCT with events defined as failure to achieve complete remission (CR) or CR with incomplete hematologic recovery (CRi), relapse or death. Pre-specified secondary endpoints included overall response rate (ORR) defined as CR and CRi, tolerability, EFS according to FLT3-ITD AR < or ≥ 0.7 and impact of randomization on allograft outcome. Results Between Jan 2013-May 2018, 18 centers randomized 99 patients to induction with either SOR (n=65) or PBO (n=33); one patient later found to be FLT3-ITD negative was excluded. Patient characteristics are shown in Table 1. Treatment arms were balanced apart from fewer patients in the SOR arm with NPM1 mutant AML. Deliverability of therapy was comparable, with commencement of consolidation in 78% and 79% and maintenance therapy in 32% and 27% in the SOR and PBO arms, respectively. The overall response rate (ORR) was high in both arms; 91% in the SOR (CR 80%, CRi 11%) and 94% in the PBO (CR 70%, CRi 24%) arm. In the SOR arm, 5% achieved partial remission, went off study and were deemed treatment failures. With a median overall follow-up of 25 mo, there was no significant difference in EFS (HR 0.87 95% CI 0.50-1.49; P=0.61)(Fig A) or OS (HR 0.70 95% CI 0.38-1.29; P=0.26)(Fig. B), nor in a sensitivity analysis with censoring at HCT. 2 yr EFS was 47.9% (SOR) vs 45.4% (PBO) and 2-year OS 66.8% (SOR) vs 56.4% (PBO). Hematopoietic cell transplant (HCT) in CR1 was performed in 62% and 58% in the SOR and PBO arms, respectively. For patients in CR1, 2 yr OS post-HCT was 78.5% (SOR) vs 54.2% (PBO)(Fig C). Suggestive of an on-target effect against FLT3-ITD, the impact of SOR on OS appeared greater for patients with higher FLT3-ITD AR ≥0.7 (Fig. D) (Table 2). Only one early death (within 30 days) was recorded in each treatment arm. The frequency of grade 3-4 adverse events (AEs) were similar between the two arms, apart from palmar-plantar rash, reported as drug-related in 15.4% and 6.1% pts in the SOR and PBO arms, respectively. Correlative studies will be reported in a companion abstract. Conclusions SOR did not improve EFS when combined with intensive chemotherapy in adults with newly diagnosed FLT3-ITD AML. Although not powered for significance, SOR showed a trend for improved OS among patients with higher FLT3-ITD AR or receiving HCT in CR1. Further exploration of more potent FLT3 inhibitors in the pre- and post-allograft setting are warranted for patients with newly diagnosed FLT3 mutant AML. Acknowledgements: The ALLG AMLM16 trial was funded through an Australian Government NHMRC grant and a research grant from the Leukaemia Foundation of Australia. Bayer supplied sorafenib and Gilead AmBisome. Disclosures Wei: Roche: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; Macrogenics: Honoraria. Enjeti:Novartis: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau; Bayer: Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. D'Rozario:Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS/ Celgene: Membership on an entity's Board of Directors or advisory committees. Marlton:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Verner:Janssen Cilag Pty Ltd.: Research Funding. Hahn:Roche: Honoraria; Astra Zeneca: Honoraria. Hiwase:Novartis Australia: Research Funding. Anstee:Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Levis:FujiFilm: Honoraria, Research Funding; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; Menarini: Honoraria; Astellas: Honoraria, Research Funding. Bajel:Abbvie: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria. Roberts:Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties; Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: Sorafenib for FLT3-ITD AML

Introduction R-mini-CHOP is an established standard of care in elderly patients with DLBCL, with a 2yr OS of 59% and PFS of 47% (Peyrade et al, Lancet Oncol 2011). The addition of ibrutinib to full dose R-CHOP in younger pts with DLBCL has efficacy, but significant toxicity limits the ability to complete therapy in pts ≥60 yrs (Younes et al, JCO 2019). We previously demonstrated the deliverability of ibrutinib with R-mini-CHOP in 80 pts ≥75yrs with DLBCL with a median average relative total dose of 97%; 77% of pts received 6 cycles of R-mini-CHOP despite SAEs in 62% (Verner et al, Haematol Oncol 2019). Here we present the primary efficacy endpoint and key secondary and exploratory endpoints. Methods This was a prospective, multicenter, single-arm, phase 2 study of patients aged ≥75yrs with newly diagnosed DLBCL. Pts received six 21-day cycles of ibrutinib 560mg/d and R-mini-CHOP (Rituximab 375mg/m 2, cyclophosphamide 400mg/m 2, doxorubicin 25mg/m 2, vincristine 1mg on day 1 & prednisone 40mg/m 2 or 100mg/d x 5) followed by an additional two 21-day cycles of rituximab + ibrutinib (or high dose methotrexate for CNS prophylaxis). The efficacy primary endpoint was 2yr OS. Sample size calculations were made using a one-sample two-sided approach to detect a 15% improvement on the fixed reference OS (59%) and PFS (47%) rates (Peyrade et al, Lancet Oncol 2011). Results Eighty pts were recruited from Nov 2015 to Dec 2018. One died prior to receiving treatment and is not included in the analysis. Median age was 82yrs (75-95); 51% female, 81% stage III/IV and 63% IPI 3-5: 47% had a CIRS-G score of ≥6 (range 0-17). On centralized immunohistochemistry (IHC), 57% (45/79) were non-Germinal Centre B cell-like (GCB) subtype; 43% (34/79) were GCB. At a data cut-off of 6June 21, median follow-up was 29.5 months (m) (0.2 to 66.3). Two-year OS was 68% (95% CI 55-77%), not differing significantly from the null hypothesis of 59% (p=0.10), (Figure 1A). Median OS was not reached (NR) (95% CI 34m to NR), and was longer in those with lower IPI (IPI 1-3: NR, IPI 4: 35m, IPI 5: 19m). Two-year PFS was 60% (95% CI 47-70%), significantly different from the reference 47% (p At least one adverse event (AE) occurred in 99% pts (78/79): 30% (24/79) grade 1-2, 64% (49/79) grade 3-4, and 6% (5/79) grade 5. Most common grade ≥3 AEs were lung infection (13%), other infections (11%), anemia (11%), febrile neutropenia (9%), thrombocytopenia (9%), and atrial fibrillation (8%). Serious AEs occurred in 67%: most commonly lung infection (11%), atrial fibrillation (9%), fever (9%), and other infection (9%). 12/14 pts with atrial fibrillation/flutter were new onset. Ibrutinib was temporarily ceased in 62% of patients, and permanently ceased in 25%, mostly due to adverse events. As previously reported, the overall response rate on an intention to treat basis was 57/80 (71%) (Verner et al, ASH 2019). Response rates did not differ by cell of origin (COO) (ORR: non-GCB 76%, GCB 68% p=0.44). When recorded, pt's EORTC-QLQ-C30 global health status significantly improved between screening [n=78; mean (SD) 58(25)], end of treatment [n=57; 63(23)] and 18mo post-treatment [n=29; 74(19)] p=0.007. Significant reductions in fatigue, nausea and vomiting, pain, insomnia, appetite loss, constipation and diarrhea were also observed in respondents. There was no impact of CIRS-G score on disease response rate or risk of death. Conclusion The addition of ibrutinib to R-mini-CHOP was deliverable and improved 2-yr PFS compared to R-mini-CHOP alone. However, while there was a trend towards improvement in 2-yr OS, a target 15% increase was not achieved in this small sample size. Despite considerable and not unexpected toxicity in this elderly cohort, the QOL and functional improvements in survivors are also promising. These data support further study of the addition of ibrutinib to R-mini-CHOP in elderly patients with DLBCL. Figure 1 Figure 1. Disclosures Verner: Janssen-Cilag Pty Ltd: Research Funding. Hawkes: Merck KgA: Research Funding; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Specialised Therapeutics: Consultancy; Antigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee: Roche: Honoraria; BeiGene: Membership on an entity's Board of Directors or advisory committees. Cheah: BMS: Consultancy, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Ascentage Pharma: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding. Purtill: Novartis: Honoraria; Gilead: Honoraria; BMS Celgene: Honoraria. Enjeti: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Honoraria; Sanofi: Honoraria; Astra Zeneca: Honoraria. Curnow: Bayer: Consultancy, Research Funding; Pfizer/BMS: Consultancy, Honoraria; Mylan: Consultancy; Norgine: Consultancy, Honoraria. Butcher: WriteSource: Current Employment, Other: Medical writing for Pharma companies. Not pertinent to this abstract for which author is study Statisticiam. Trotman: JANSSEN: Research Funding; TAKEDA: Research Funding; BMS: Research Funding; PCYC: Research Funding; roche: Research Funding; beigene: Research Funding. OffLabel Disclosure: Ibrutinib is not approved for use in DLBCL

The advent of pediatric inspired regimens has improved the outcome for younger adults with Acute Lymphoblastic Leukemia (ALL), however this comes at a considerable toxicity burden limiting its applicability in older adults. The advent of novel immunotherapies, such as Blinatumomab, an anti-CD19 targeting Bi-specific T-cell engager, has improved outcomes for adults with relapsed refractory and minimal residual disease (MRD) positive B-precursor (BCP) ALL. The Australasian Leukemia and Lymphoma Group (ALLG) undertook a phase 2 proof-of-concept study to explore the combination of Blinatumomab with reduced intensity chemotherapy in adults with newly diagnosed Ph- BCP ALL. Patients received an initial pre-phase of corticosteroids (Prednisolone 100mg/d, 5 days) followed by a low intensity chemotherapy debulking (Cyclophosphamide 150mg/m 2 BD D1-3, Vincristine 2mg IV D1, 11 and Dexamethasone 10mg/m 2 D1-4, D11-14). Following this patients received Blinatumomab at 9mcg/d days 1-7 and 28mcg/d days 8-28. A B cycle of Hyper-CVAD (Cytarabine 3g/m 2 BD for 4 doses and Methotrexate 1g/m 2 D1 with Methylprednisolone 50mg BD D1-3). Patients then received 3 alternating cycles of Blinatumomab (28mcg/d for 28 days) and B-cycles of Hyper-CVAD followed by 2-years of POMP maintenance in subjects not proceeding to allogeneic stem cell transplant (alloHSCT) which was at investigator discretion. MRD assessments by ASO-PCR were performed after the first B cycle, second B cycle and prior to maintenance therapy with an MRD response being a level of 10 -4 or less. This analysis is from a pre-specified interim analysis with a data cutoff of 29 th June 2021. 30 patients were enrolled with a median age of 51.7(range, 39.5 - 66.5 years) with 70% male subjects. ECOG performance score was 0 in 14 subjects, 1 in 12 and 2 in 4. High risk disease was identified in 5 subjects (1 t(4;11), 2 hypodiploid, 1 t(1;19) and 1 Ph-like). All patients attained a CR, with 28 at end of 1B and a further 2 at end of 2B. Of 26 patients evaluable for MRD, 70% had achieved an MRD response after cycle 1B and 83% at the end of cycle 2B. 15 patients have ceased study therapy; 6 patients died with progressive disease, 4 subjects exited to allogeneic stem cell transplant, 1 patient was withdrawn due to progressive disease, 1 had intolerable toxicity (peripheral neuropathy) and 1 at investigator discretion. There were no treatment related deaths. 15 remain on protocol in maintenance with the remainder having completed therapy. At data cut-off the median event free survival (EFS) was not reached (95% CI 8.3 months - NA) with an estimated 24 month EFS of 61.8% (95% CI 36.3 - 84.2%) (figure 1A), and similarly the median overall survival (OS) S was not reached (95% CI 21.0 months - NA) with an estimated 24 month OS of 68.6% (95% CI 41.5 - 85.1%)(figure 1B). This predicted EFS was greater than the pre-specified stopping rule of a 24-month EFS of 50%. 2 episodes of cytokine release syndrome (CRS) were recorded (1 grade 2, 1 grade 3) with the major toxicity being infective (53 episodes of sepsis, infection or febrile neutropenia) predominately related to chemotherapy cycles. 7 episodes of neurological toxicity were demonstrated (1 myelopathy and 4 peripheral neuropathy occurring during chemotherapy and 2 encephalopathy occurring during Blinatumomab administration). Overall, the combination of Blinatumomab with chemotherapy was tolerable and appeared efficacious with a high rate of remission and deep MRD responses observed. Responses appeared durable despite a low rate of alloHSCTin first remission. The major toxicity was infective and occurred in the context of chemotherapy cycles. Future developments from this protocol will emphasise further reduction in cytotoxic chemotherapy through incorporation of further novel agents to minimise this toxicity. Figure 1 Figure 1. Disclosures Fleming: Servier: Honoraria; Pfizer: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau. Reynolds: Abbvie: Research Funding; Novartis AG: Current equity holder in publicly-traded company; Alcon: Current equity holder in publicly-traded company. Bajel: Abbvie, Amgen, Novartis, Pfizer: Honoraria; Amgen: Speakers Bureau. Yeung: BMS: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria; Novartis: Honoraria, Research Funding. Verner: Janssen-Cilag Pty Ltd: Research Funding. Wei: Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Honoraria; Novartis, Abbvie, Celgene/BMS: Speakers Bureau; Servier: Consultancy; Abbvie, Amgen, AstraZeneca, Celgene/BMS, Novartis, Servier and F. Hoffmann-La Roche: Research Funding; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Former employee of Walter and Eliza Hall Institute: Patents & Royalties: Prof. Andrew Wei is a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax. Greenwood: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Blinatumomab - usage in front-line therapy for Acute Lymphoblastic Leukaemia

Background: BCL2, a key regulator of apoptosis, is aberrantly expressed in many hematologic malignancies, which can lead to pathologic cancer cell survival. BCL2 inhibitors have been shown to be safe and effective, resulting in their approval for the treatment of pts with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and acute myeloid leukemia. Treatment with the currently approved BCL2 inhibitor, venetoclax, can be limited by common gastrointestinal toxicities, neutropenia, and the emergence of specific BCL2 mutations around the BH3-binding groove causing resistance. BGB-11417 was developed as a potent and highly selective inhibitor of BCL2. It has shown antitumor activity superior to venetoclax in human acute lymphoblastic leukemia, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) xenograft models (Hu, AACR 3077). BGB-11417 also has a favorable pharmacokinetic profile with excellent bioavailability and selectivity for BCL2 at concentration The combination of a BCL2 inhibitor and a BTK inhibitor is tolerable with synergistic activity in CLL and MCL pts (Hillmen, J Clin Oncol 2019;37(30):2722-9; Jain, N Engl J Med 2019;30;380(22):2095-103; Siddiqi, ASH 2020 S158; Tam, N Engl J Med 2018; 378:1211-23). Zanubrutinib is a next-generation BTK inhibitor that has shown excellent activity and favorable toxicity in pts with CLL/SLL (Hillmen, EHA 2021 LB1900) and MCL (Tam, Blood Adv 2021;5(12):2577-85); with approval for treatment in MCL. Here we report preliminary results of the BGB-11417-101 trial (NCT04277637) in pts with non-Hodgkin lymphoma (NHL) or CLL/SLL treated with BGB-11417 monotherapy or in combination with zanubrutinib. Methods: BGB-11417-101 is a phase 1, open label, multicenter, dose-escalation and expansion study. Pts with NHL or CLL/SLL are treated with BGB-11417 as monotherapy or in combination with zanubrutinib. For dose escalation, pts with R/R B-cell malignancies are enrolled in 1 of 5 potential dose levels of BGB-11417 (40, 80, 160, 320, or 640 mg once daily). All pts utilize a ramp-up to intended target dose that varies by disease type. Pts in the combination therapy arm receive zanubrutinib 320 mg daily beginning 8-12 weeks before BGB-11417 is introduced. Adverse events (AEs) are reported per Common Terminology Criteria for AEs v5.0. Dose-limiting toxicity (DLT; assessed from ramp-up through day 21 at intended daily dose), evaluated by Bayesian logistic regression model, will be used to determine the maximum tolerated dose (MTD). Results: As of 24 May 2021 (data cutoff) 19 pts had been treated; 14 pts with monotherapy (NHL: n=11; CLL/SLL: n=3) and 5 pts with combination (all CLL; 3 pts were still on zanubrutinib pretreatment; 2 had started combination treatment). Median age was 72 y (range, 50-86); median follow-up was 1.9 mo (range, 0.7-12.4); all pts were R/R with a median of 2 prior regimens (range, 1-4). No DLTs were observed in pts with NHL receiving BGB-11417 monotherapy (n=11) up to the 160 mg dose level. AEs across all dose levels occurring in ≥2 pts (monotherapy) or ≥1 pt (combination) are listed in Table 1. A total of 5 pts discontinued treatment (all NHL) due to disease progression (n=4; 2 at 40 mg, 2 at 80 mg) or lack of efficacy (n=1 at 40 mg). No pt discontinued due to AEs. Laboratory tumor lysis syndrome was observed in 1 pt with CLL and high tumor burden (resolved with no sequelae). Initial efficacy after 3-month restaging in pts with CLL/SLL demonstrated 1 partial response (monotherapy arm) at the first dose level tested. All pts with CLL/SLL who have completed ramp-up (n=2, both monotherapy) normalized absolute lymphocyte count (ALC). Marked decreases in ALC were observed in pts with CLL at doses as low as 1 mg (Figure 1). Conclusion: Preliminary results suggest that BGB-11417 monotherapy is tolerable in pts with R/R NHL at the tested dose levels. Further assessment of safety and efficacy of BGB-11417 +/- zanubrutinib in CLL/SLL and NHL will be presented at the meeting, and evaluation in patients with treatment naïve CLL/SLL, R/R MCL, and R/R WM is planned. Figure 1 Figure 1. Disclosures Tam: AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Loxo: Consultancy; Novartis: Honoraria; Pharmacyclics: Honoraria. Verner: Janssen-Cilag Pty Ltd: Research Funding. Lasica: Celgene: Other: Travel, Accommodations, Expenses; Janssen: Other: Education. Arbelaez: Amgen: Other: Travel, Accommodations, Expenses. Browett: AbbVie: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Soumerai: BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy; GlaxoSmithKline: Research Funding; BostonGene: Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy, Research Funding. Hilger: BeiGene: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Fang: BeiGene (Shanghai) Co, Ltd.: Current Employment, Current equity holder in publicly-traded company. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Simpson: Janssen: Research Funding; GSK: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; MSD: Research Funding; Roche: Research Funding; Celgene: Research Funding; Amgen: Research Funding; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; BeiGene: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Opat: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GIlead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Monash Health: Current Employment; BeiGene: Research Funding; Sandoz: Research Funding. Cheah: Ascentage Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not been approved for NHL or CLL/SLL in the US

Background: Zanubrutinib (zanu) is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (Guo, J Med Chem 2019;62:7923-40). In a phase 1/2 study, zanu demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL (Tam, Blood 2019;134:851-9). Here, we present interim results for the phase 3 SEQUOIA (BGB-3111-304; NCT03336333) trial, which evaluated the efficacy and safety of zanu vs BR in TN pts with CLL/SLL. Methods: SEQUOIA is an open-label, global phase 3 study that randomized TN pts with CLL/SLL without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m 2 on day 1 and 2 and rituximab 375 mg/m 2 in cycle 1, 500 mg/m 2 in cycles 2-6 for 6 × 28-day cycles. Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Hallek, Blood 2008;111:5446-56) were eligible if they were either ≥65 y or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridization was required. Pts were stratified by age ( Results: From 31 Oct 2017-22 Jul 2019, 479 pts without del(17p) were randomized to zanu (n=241) and BR (n=238). Treatment groups were well balanced for demographic and disease characteristics (zanu vs BR): median age, 70.0 y vs 70.0 y; unmutated IGHV, 53.4% (125/234) vs 52.4% (121/231); and del(11q), 17.8% vs 19.3%. At median follow-up (26.2 mo), PFS by IRC was significantly prolonged with zanu vs BR (HR 0.42, 95% CI 0.28-0.63, 1-sided and 2-sided P The most common AEs are shown in the Table. AEs of interest occurring during the full reporting period (pooled terms, zanu vs BR) included atrial fibrillation (any grade [gr]: 3.3% vs 2.6%), bleeding (any gr/gr≥3: 45.0%/3.8% vs 11.0%/1.8%), hypertension (any gr: 14.2% vs 10.6%), infection (any gr/gr≥3: 62.1%/16.3% vs 55.9%/18.9%), and neutropenia (any gr/gr≥3: 15.8%/11.7% vs 56.8%/51.1%). Treatment discontinuation due to AEs occurred in 20 pts (8.3%) receiving zanu vs 31 pts (13.7%) receiving BR; 85.5% of pts receiving zanu remain on treatment. AEs leading to death occurred in 11 pts (4.6%) receiving zanu vs 12 pts (5.3%) receiving BR. No sudden deaths were reported. Conclusions: In this global registrational trial, zanu demonstrated statistically significant improvement in PFS compared to BR as assessed by IRC. Superiority was also observed in PFS by INV as well as ORR by both IRC and INV. Zanu was generally well tolerated, with low rates of atrial fibrillation consistent with those observed in the phase 3 ASPEN (Tam, Blood 2020;136:2038-2050) and ALPINE studies (Hillmen, EHA 2021 #LB1900). These data support the potential utility of zanu in the frontline management of pts with TN CLL/SLL. Figure 1 Figure 1. Disclosures Tam: AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Honoraria; Novartis: Honoraria; Loxo: Consultancy; Roche: Consultancy, Honoraria. Giannopoulos: Polish Myeloma Consortium, Next Generation Hematology Association: Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Honoraria; Pfizer: Honoraria; Teva: Honoraria; TG Therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria, Research Funding; Bei-Gene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi-Genzyme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Jurczak: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Bayer: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Celgene: Research Funding; Debbiopharm: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Šimkovič: Janssen, Gilead, Roche, AstraZeneca, and AbbVie: Other: consultancy fees, advisory board participation fees, travel grants, and honoraria; University Hospital Hradec Kralove: Current Employment; AbbVie: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Merck: Current equity holder in publicly-traded company; Eli Lilly: Current equity holder in publicly-traded company; J&J: Current equity holder in publicly-traded company; Gilead: Other: Travel, Accommodations, Expenses. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Österborg: BeiGene: Research Funding; Gilead: Research Funding. Laurenti: Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Gilead: Honoraria; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Honoraria. Walker: BeiGene: Consultancy; Acerta: Consultancy. Opat: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Sandoz: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Monash Health: Current Employment. Chan: AbbVie: Membership on an entity's Board of Directors or advisory committees; Eusa: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel, Accommodations, Expenses; Celgene: Other: Travel, Accommodations, Expenses; Roche: Speakers Bureau. Ciepluch: Copernicus Wojewodzkie Centrum Onkologii: Current Employment. Greil: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding. Trněný: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. Brander: Verastem: Consultancy; ArQule: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; MEI Pharma: Research Funding; Novartis: Research Funding; LOXO: Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding; DTRM: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Flinn: Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Verner: Janssen-Cilag Pty Ltd: Research Funding. Brown: Janssen: Consultancy; MEI Pharma: Consultancy; Rigel: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Novartis: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; TG Therapeutics: Research Funding; Abbvie: Consultancy; Acerta/Astra-Zeneca: Consultancy; Beigene: Consultancy; Catapult: Consultancy; Loxo/Lilly: Research Funding; Sun: Research Funding; Nextcea: Consultancy; Gilead: Research Funding; SecuraBio: Research Funding; Eli Lilly and Company: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Morphosys AG: Consultancy. Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Ghia: Sunesis: Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tian: BeiGene: Current Employment; AbbVie: Ended employment in the past 24 months. Marimpietri: BeiGene USA: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Paik: BeiGene USA, Inc.: Current Employment, Current equity holder in publicly-traded company. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Hillmen: Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria; BeiGene: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not been approved for TN CLL/SLL without del(17p) in the US

Background Multidisciplinary team (MDT) meetings aimed at facilitating peer review have become standard practice in oncology. However, there is scant literature on the optimal structure and conduct of such meetings. Aims To develop a process for formal peer review of patients with haematological malignancies and to audit any resulting changes made to the management recommendations of the treating physician. Methods A standard operating procedure (SOP) for MDT meetings was developed essentially to integrate clinical peer review with weekly pathology and radiology meetings. The centrepiece is the electronic submission of a patient-specific proforma (Microsoft InfoPath) prior to the meeting. It serves as the template for presentation, discussion and recording of recommendations and conclusions. The final verified document is stored in the electronic patient record, and a copy is sent to the general practitioner. The proposed management plans were compared to the consensus recommendations of the meeting for the first 4 years since inception. Results Both SOP and proforma underwent continual improvements. These provided the framework for the conduct of a robust weekly MDT meeting for peer review of the management of patients with haematological malignancies. On 20% of occasions, patient management plans were altered to optimise patient care as a direct consequence on peer review at the MDT. Conclusion Our streamlined process, in its ultimate format, has provided a mature and efficient forum for formal peer review in a genuine multidisciplinary environment. Both initial data and informal feedback support its ongoing activity as an integral component of delivering quality patient care.

Background: Patients (pts) with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor. In the ASPEN study of pts with Waldenström macroglobulinemia, zanubrutinib was associated with important safety advantages compared to ibrutinib, especially regarding cardiovascular toxicity (Blood; in press). The initial results from Arm C of the SEQUOIA (BGB-3111-304) trial of zanubrutinib in a large cohort of TN CLL/SLL pts with del(17p) were recently presented with a median follow-up of 10 months (Blood 2019;134:851). Presented here is an updated analysis for safety and efficacy in this cohort. Methods : The SEQUOIA trial (NCT03336333) is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm C) of TN pts with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Blood 2008;111:5446) were eligible if they were aged ≥65 y or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response was evaluated by investigator for CLL per modified iwCLL criteria (Blood 2008;112:5259; J Clin Oncol. 2012;30:2820) and for SLL per Lugano criteria (J Clin Oncol. 2014;32:3059). Results : As of 15 Apr 2020 (data cutoff), median follow-up was 18.2 mo (range, 5.0-26.3) for the 109 pts enrolled; 97 pts (89.0%) remained on treatment with zanubrutinib. The best overall response rate (ORR) was 94.5% (3.7% complete response [CR] or CR with incomplete bone marrow recovery, 87.2% partial response [PR], 3.7% PR with lymphocytosis, 4.6% stable disease, 0.9% progressive disease). Five pts (4.6%) met clinical CR criteria but did not undergo bone marrow biopsy. Median progression-free survival (PFS), duration of response (DoR), and overall survival (OS) were not reached. Estimated 18-mo PFS (Figure), 18-mo DoR, and 18-mo OS were 88.6% (95% CI, 79.0-94.0), 84.0% (95% CI, 67.5-92.6), and 95.1% (95% CI, 88.4-97.9), respectively. Investigator-reported transformation occurred in 5 pts (4.6%), of whom 4 had histologic confirmation. Median time to transformation was 13.6 mo (time to transformation for each pt: 3.9, 7.0, 13.6, 13.8, and 15.7 mo). In an exploratory analysis, 37.2% and 26.7% of pts with evaluable karyotypes had at least 3 or 5 distinct karyotypic abnormalities, respectively; no differences in ORR or PFS were observed between pts with or without complex karyotype. With extended follow-up, adverse events (AEs) reported in ≥10% of treated pts included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), diarrhea (16.5%), nausea (14.7%), constipation (13.8%), rash (13.8%), back pain (12.8%), cough (11.9%), arthralgia (11.0%), and fatigue (10.1%). Grade ≥3 AEs occurring in >2% of pts included neutropenia/neutrophil count decreased (12.9%) and pneumonia (3.7%). AEs of interest (pooled terms) included infections (64.2%), bleeding (47.7%; 5.5% grade ≥3 or serious), headache (8.3%), hypertension (8.3%), and myalgia (4.6%). Skin tumors were reported in 9.2%, and non-skin second malignancies were reported in 4.6% of pts. Three pts (2.8%) reported an AE of atrial fibrillation or flutter of which 2 events occurred in the setting of sepsis. Four pts (3.7%) discontinued zanubrutinib due to AEs (including pneumonia, sepsis secondary to Pseudomonas, melanoma, and acute kidney injury [in the context of disease progression]), of which 2 pts have died. Three additional pts died, 2 due to disease progression and 1 from sepsis after progression. No sudden or unknown deaths were reported. Conclusions : Extended follow-up of zanubrutinib monotherapy in TN CLL/SLL pts with del(17p) showed the durability of responses in this high-risk cohort, with an estimated 18-mo PFS of 88.6% and estimated 18-mo OS of 95.1%. Zanubrutinib was generally well tolerated, with low rates of discontinuation due to AEs. These data support the potential utility of zanubrutinib in the frontline management of pts with high-risk disease. Disclosures Brown: TG Therapeutics: Consultancy; Sunesis: Consultancy; MEI Pharma: Consultancy; Nextcea: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Rigel Pharmaceuticals: Consultancy; Verastem: Consultancy, Research Funding; Kite: Consultancy; Acerta: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Sun: Research Funding; Loxo: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Catapult: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Eli Lilly and Company: Consultancy; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy; Juno/Celgene: Consultancy. Robak:Bristol Meyers Squibb: Research Funding; Sandoz: Consultancy, Honoraria; Pfizer: Research Funding; Momenta: Consultancy; UCB: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Octapharma: Honoraria; BioGene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta: Research Funding; GSK: Research Funding; Medical University of Lodz: Current Employment; Morphosys: Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; UTX-TGR: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding. Ghia:Novartis: Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Adaptive, Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; AstraZeneca Pharmaceuticals LP: 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, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding. Walker:Alfred health: Current Employment; Peninsula Health: Current Employment; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Janowski:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy. Chan:Amgen: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company). Shadman:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sound Biologics: 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, Research Funding; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: 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; Sunesis: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Acerta Pharma: Ended employment in the past 24 months; Gilead: Research Funding; MophoSys: 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; TG therapeutics: Research Funding. Laurenti:Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Opat:F. Hoffmann-La Roche Ltd: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: 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; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding. Ciepluch:Copernicus Wojewodzkie centrum Onkologii: Current Employment. Verner:Cilag Pty Ltd: Research Funding; Concord Repatriation General Hospital: Current Employment; Janssen: Research Funding. Šimkovič:University Hospital Hradec Kralove: Current Employment; Acerta Pharma: Consultancy; Gilead Sciences: Consultancy, Other: Travel, Accommodations, Expenses; Janssen-Cilag: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Österborg:Sanofi: Consultancy; Kancera: Current equity holder in publicly-traded company, Research Funding; BeiGene: Research Funding; Karolinska Univeristy Hospital, Stockholm, Sweden: Current Employment. Trněný:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy. Tedeschi:BeiGene: 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; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Consultancy; Department of Hematology Niguarda Hospital Milano: Current Employment. Blombery:Invivoscribe: Honoraria; Janssen: Honoraria; Amgen: Consultancy; Novartis: Consultancy. Paik:BeiGene: Current Employment, Current equity holder in publicly-traded company. Yin:BeiGene: Current Employment, Current equity holder in publicly-traded company; Arcus Biosciences: Current equity holder in publicly-traded company; Cornell University: Patents & Royalties: A genetically modified mouse model, licensed to pharmaceutical companies. Feng:BeiGene: Current Employment, Current equity holder in publicly-traded company. Ramakrishnan:BeiGene: Current Employment, Current equity holder in publicly-traded company. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Hillmen:F. Hoffmann-La Roche: Honoraria, Research Funding; Astra Zeneca: Honoraria; Gilead: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. Tam:BeiGene: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for TN CLL/SLL with del(17p) in the US

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 – 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 – 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 – 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 – 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

8051 Background: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment-naïve (TN) and relapsed/refractory (R/R) patients with WM. Methods: Patients had TN or R/R WM and required treatment as per International Workshop on WM (IWWM) criteria. Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 50) or 320 mg once daily (n = 23) until disease progression or unacceptable toxicity. Efficacy endpoints included the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) in accordance with IWWM-6 criteria. Efficacy analyses were conducted on the 73 patients evaluable (24 TN, 49 R/R). Results: Between September 2014 and August 2018, 77 patients with WM (24 TN and 53 R/R) began treatment with zanubrutinib (55% aged > 65 years; 21% aged > 75 years). At a median follow up of 32.7 months, 73% remain on treatment. Reasons for treatment discontinuation included adverse events (AE) in 13% (only one related), disease progression (10.4%), and other (3.9%). Results are presented for TN and R/R combined. The overall response rate was 96% and VGPR/CR rate was 45%. The rates of VGPR/CR increased over time; 22% at 6 mos, 33% at 12 months and 45% at 24 months. Three-year progression-free survival (PFS) was 81%, and overall survival (OS) was 85%. The most commonly reported AEs were upper respiratory tract infection (52%), contusion (33%, all grade 1) and cough (22%). AEs of interest include neutropenia (18.2%), major hemorrhage (4%), atrial fibrillation/flutter (5%), and grade 3 diarrhea (3%). Conclusions: Long-term follow up with continued zanubrutinib treatment demonstrated deep and durable responses in the majority of WM patients. The rates of VGPR/CR increased with prolonged therapy. Disease progression was uncommon. The safety profile of long-term zanubrutinib therapy in these patients was tolerable. Clinical trial information: NCT02343120 . [Table: see text]

Background: Patients with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Several new options targeting B-cell receptor signaling have emerged as potential effective therapies in this high-risk group. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor, designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. It has been shown to be highly potent, selective, and bioavailable with potentially advantageous pharmacokinetic and pharmacodynamic properties. In an early phase study, zanubrutinib demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and has been associated with durable clinical responses in patients with CLL/SLL (Tam, Blood 2019). Here, we present safety and efficacy data in treatment-naive (TN) patients with del(17p) CLL/SLL who are enrolled in the non-randomized Arm C of the SEQUOIA (BGB-3111-304) trial. Methods : The SEQUOIA trial is an open-label, global, multicenter, phase 3 study that includes a non-randomized cohort (Arm C) of TN patients with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult patients with CLL/SLL who met iwCLL criteria for treatment (Hallek, Blood 2008) were eligible if they were either ≥ 65 y of age or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response assessment was evaluated by investigator for CLL per modified iwCLL criteria (Hallek, Blood 2008; Cheson, J Clin Oncol 2012) and for SLL per Lugano criteria (Cheson, J Clin Oncol 2014). Results : In total, 109 patients with centrally confirmed del(17p) were enrolled into Arm C (complete accrual). As of 19 April 2019 (data cutoff), all patients had received ≥1 dose of zanubrutinib and were included in the safety analysis. Median age was 70.0 y (range, 42-86) and median follow-up in the safety analysis set was 6.3 mo (Table 1). At data cutoff, 106 patients remained on study treatment. Adverse events (AEs) reported in ≥10% of treated patients included contusion (20.2%), rash (11.0%), upper respiratory tract infection (10.1%), and nausea (10.1%). Grade ≥3 AEs were reported in 33 patients (30.3%). Grade ≥3 AEs that occurred in >1 patient included neutropenia/decreased neutrophil count (n = 10), anemia, pneumonia, nephrolithiasis, and hypertension (each n = 2). One patient died due to grade 5 pneumonia that occurred 8 days after the last dose of zanubrutinib. AEs of interest (pooled terms) included infections (39.4%), bruising (24.8%), minor bleeding (18.3%), neutropenia (13.8%), arthralgia/myalgia (8.3%), diarrhea (8.3%), anemia (6.4%), hypertension (6.4%), thrombocytopenia (5.5%), fatigue (5.5%), headache (4.6%), petechiae (4.6%), second primary malignancy (2.8%), and major bleeding (2.8%). To date, no AEs of atrial fibrillation have been reported. At data cutoff, 90 patients were evaluable for efficacy with median follow-up of 7.0 mo; of these, 87 patients remained on study treatment. The overall response rate was 92.2% (Table 2). Two patients had disease progression due to Richter transformation and 1 patient died due to grade 5 pneumonia. No patient had progressed with CLL/SLL. Conclusions : In this study, we have completed enrollment of one of the largest prospective cohorts of TN patients with del(17p) CLL/SLL. Preliminary results suggested that zanubrutinib was active and generally well tolerated. Clinical trial information: NCT03336333. Disclosures Tam: Novartis: Honoraria; BeiGene: Honoraria; Roche: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Robak:Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Morphosys AG: Research Funding. Ghia:AbbVie: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Acerta/AstraZeneca: Consultancy, Honoraria; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria. Kahl:BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy. Walker:Alfred Health: Employment; Peninsula Health: Employment. Janowski:AstraZeneca: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Simpson:GSK: Research Funding; Sanofi: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; MSD: Research Funding; Celgene: Research Funding; Roche: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Research Funding; Amgen: Research Funding; Jannsen: Honoraria. Shadman:AbbVie: Consultancy, Research Funding; Sunesis: Research Funding; TG Therapeutic: Research Funding; Acerta Pharma: Research Funding; Atara Biotherapeutics: Consultancy; Genentech: Consultancy, Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy; Astra Zeneca: Consultancy; Gilead: Consultancy, Research Funding; Verastem: Consultancy; Pharmacyclics: Consultancy, Research Funding; Mustang Bio: Research Funding; Sound Biologics: Consultancy; BeiGene: Research Funding. Ganly:Canterbury District Health Board: Employment. Opat:Takeda: Consultancy, Research Funding; Novartis: Consultancy; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Epizyme: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ciepluch:Copernicus Wojewodzkie Centrum Onkologii Gdansk: Employment. Verner:Janssen-Cilag Pty Ltd: Research Funding. Simkovic:Roche: Honoraria; University Hospital Hradec Kralove: Employment; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria. Österborg:Abbvie: Research Funding; Kancera AB: Research Funding; BeiGene: Research Funding; Gilead: Research Funding; Janssen: Research Funding. Trněný:Gilead Sciences: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Tedeschi:Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria; SUNESIS: 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; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy. Paik:BeiGene: Employment, Equity Ownership. Marimpietri:BeiGene: Employment, Equity Ownership. Feng:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Apellis: Research Funding; Gilead: Research Funding; Roche: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Brown:Juno/Celgene: Consultancy; Verastem: Consultancy, Research Funding; Sunesis: Consultancy; Octapharma: Consultancy; Invectys: Other: Data safety monitoring board; Morphosys: Other: Data safety monitoring board; Teva: Honoraria; TG Therapeutics: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Janssen: Honoraria; Dynamo Therapeutics: Consultancy; AbbVie: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy; Catapult Therapeutics: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Pharmacyclics: Consultancy; Sun Pharmaceuticals: Research Funding. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US

Introduction The addition of Ibrutinib to R-CHOP in younger pts with DLBCL has efficacy, but significant toxicity limits the ability to complete therapy in pts ≥60 yrs (Younes et al, JCO 2019). We have previously demonstrated the deliverability of Ibrutinib with R-mini-CHOP in 80 pts ≥75yrs with DLBCL with a median Average Relative Total Dose of 97%; 77% of pts received 6 cycles of R-mini-CHOP despite SAEs in 62% (Verner et al, Haematol Oncol 2019). Here we present response rates, Cumulative Illness Rating Scale-Geriatrics (CIRS-G) score, left ventricular ejection fraction (LVEF) and quality of life (QoL) data. Methods Pts received six 21 day cycles of ibrutinib 560mg/d and R-mini-CHOP (Rituximab 375mg/m2, cyclophosphamide 400mg/m2, doxorubicin 25mg/m2, vincristine 1mg on day 1 &prednisone 100mg/d x 5) followed by an additional two 21 day cycles of rituximab + ibrutinib (or high dose methotrexate for CNS prophylaxis). Baseline comorbidities assessed by CIRS-G, end of treatment (EOT) response assessment per Lugano 2014 criteria and QoL (EORTC-QLQ-C30 and EQ-5D-5L visual analogue scores (VAS)) are presented for screening, throughout therapy and 1-month post treatment, with differences assessed using ANOVA. Missing values were not imputed. Results 80 pts were recruited from Nov 2015 to Dec 2018. Median age at registration was 81yrs (75-95); 51% female, 81% stage III/IV and 63% IPI 3-5. The majority of pts (88%; 70/80) had a CIRS-G score of ≥6 (range 4-21), a cut-off shown to be associated with a higher risk of early chemotherapy discontinuation in haematological malignancies (Poisson et al, EHA 2016). Median follow-up was 13.1 months (range 0.2 to 42.6). Treatment discontinuation occurred in 31% (25/80) pts. 23/80 (29%) have died; 14 due to progressive lymphoma, 5 due to infection, 1 intra-abdominal haemorrhage, 1 respiratory failure, 1 cardiac arrest, and 1 MPN/MDS. There was no association between baseline CIRS-G score, and completion of treatment, death or disease response. The overall response rate (ORR) on an intention to treat basis was 57/80 (71%). Eight cycles of treatment were completed by 55/80 (69%) pts, of whom 54 had an EOT PET. Of this population there was an ORR of 93% (50/54), with complete metabolic response (CMR) in 47/54 (87%); partial metabolic response in 4/54 (7%); and progressive metabolic disease in 3/54 (6%). A further 6 pts who discontinued treatment early achieved a CMR (between cycles 3-6) and 1 had stable metabolic disease. Progressive disease prior to cycle 8 occurred in 7/80 pts (9%). Eleven pts had no treatment response assessment, either due to death (n=5), withdrawal of consent (n=3), loss to follow up (n=2), or death prior to commencing chemotherapy. 2/80 (2%) pts had a recorded ≥10% decline in LVEF to QoL outcomes are presented in Figures 1 and 2. QOL, as assessed by two globally accepted tools, improved with treatment in the population completing EOT assessment. Patients' EORTC-QLQ-C30 global health status and emotional functioning improved substantially while maintaining physical and cognitive functioning. There was a significant reduction in nausea, vomiting, pain, insomnia, constipation, and diarrhoea and an improvement in appetite with treatment. Similarly EQ-5D-5L VAS demonstrated that patients maintained mobility and independence with a significant reduction in pain/discomfort and improvement in mood. Conclusions Albeit with considerable toxicity and early mortality, Ibrutinib-R mini-CHOP is a deliverable and effective treatment for most pts ≥75yrs with DLBCL. While longer follow-up is required to assess our primary efficacy endpoint of 2yr overall survival, this promising response and reassuring QoL data highlights the merits of ongoing study to identify deliverable and effective treatments for DLBCL in the very elderly. Disclosures Verner: Janssen-Cilag Pty Ltd: Research Funding. Hawkes:Astra Zeneca: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharpe & Dohme: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding, Speakers Bureau; Merck KgA: Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Speakers Bureau; Mundi pharma: Research Funding; Bristol-Myers Squibb: Research Funding, Speakers Bureau. Lee:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; MSD: Membership on an entity's Board of Directors or advisory committees. Cheah:F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Gilead: Honoraria; Janssen: Honoraria; Acerta: Honoraria; Loxo: Honoraria. Purtill:MSD: Honoraria; Novartis: Honoraria, Other: Travel for speaking and advisory boards; Gilead: Honoraria, Other: Travel for speaking and advisory boards; Janssen: Honoraria. Enjeti:Astellas: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; Bayer and Sanofi: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Curnow:NovoNordisk: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL: Honoraria; Mylan Pharmaceuticals: Consultancy; Freeline: Membership on an entity's Board of Directors or advisory committees; Boehringher Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria; Pfizer/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Butcher:ALLG: Honoraria; Abbvie: Honoraria; Astellas: Honoraria; BMS: Honoraria; Janssen-Cilag Pty Ltd: Honoraria; MSD: Honoraria; Novartis: Honoraria; Roche: Honoraria; Shire: Honoraria; Sandoz: Honoraria. Trotman:Pharmacyclics: Research Funding; Celgene: Research Funding; Janssen: Research Funding; BeiGene: Research Funding; Roche: Research Funding. OffLabel Disclosure: Ibrutinib is not currently approved for use in DLBCL

Background - Conventional chemotherapy for adults with Acute Lymphoblastic Leukaemia (ALL) is associated with considerable treatment-related toxicity. Blinatumomab is a CD19/CD3 targeting bi-specific T-cell engager that has demonstrated promising efficacy in relapsed/refractory ALL, and in combination with chemotherapy in newly diagnosed patients. Preliminary studies also suggest less toxicity and good efficacy (CR/CRh 66%) when delivered as induction to older adults (median age 75) with newly diagnosed B-ALL (Advani, ASH 2018). Of responders, Minimal Residual Disease (MRD) negativity in this trial was achieved in 92%. Given this, the Australasian Leukaemia & Lymphoma Group (ALLG) has explored the potential for upfront Blinatumomab as induction for younger adults with Ph- B-lineage Acute Lymphoblastic Leukaemia, alternating with CNS-directed chemotherapy cycles. Aim - To assess response to therapy of the first 10 patients enrolled on this study by molecular MRD analysis as a surrogate measure of short-term efficacy of this combination. Method - The ALLG ALL8 study (ACTRN12617000084381) is a phase II proof-of-concept front-line study for patients fit for treatment with a Hyper-CVAD-like regimen (between 40-65 years) with newly diagnosed Ph- B-lineage ALL. Those with CNS positive disease are excluded. Patients receive a steroid pre-phase (Prednisolone 100mg daily for 7 days) followed by a disease debulking phase of cyclophosphamide 150mg/m2 BD day 1-3, vincristine 2mg day 1 & 11 and dexamethasone 10mg/m2 day 1-4 and 11-14. Patients then receive alternating cycles of Blinatumomab (at 9mcg/d for the first 7 days of cycle 1 followed by 28mcg/d until day 28) with B-cycles of Hyper-CVAD (Methotrexate 1g/m2 day 1, Cytarabine 3g/m2 BD day 2,3, Methylprednisolone 50mg BD day 1-3) (figure 1). All patients receive intrathecal prophylaxis with methotrexate, cytarabine and hydrocortisone prior to blinatumomab treatment blocks and day 1 and 8 of each B-cycle until a total of 8 doses were administered. At the completion of therapy, high-risk patients (MLL translocations, hypodiploid, complex karyotype or MRD positive at TP3) are recommend to proceed to allogeneic stem cell transplant while others receive 24 months of POMP maintenance. Minimal residual disease analysis was performed at a centralised EuroMRD accredited laboratory utilising Taqman probes and patient specific PCR primers targeted at immunoglobulin heavy chain or T-cell receptor (Ig/TCR) gene rearrangements. MRD positivity was defined as a detectable level of ≥ 1 x 10-4. Results - The following results are based upon the first 10 patients enrolled on ALL8. Median age of 54.7 years (range 43 to 66 years) and 70% were male. Median ECOG PS was 0 (range 0 - 2). 6 patients had an abnormal karyotype, 2 high-risk (one with hypodiploid karyotype, one with t(1;19). Median white cell count at diagnosis was 3.36 x 109/L (range 1.95 - 12.05 x 109/L). All patients (10/10) attained CR/CRi following induction therapy with no treatment related deaths. At the end of the induction phase (MRD TP1) 4 out of 10 had attained MRD negativity, 2 had detectable unquantifiable MRD and 4 were MRD positive. By the end of the 1st consolidation cycle (MRD TP2) 1 additional patient had become MRD negative and 1 MRD positive patient had become MRD unquantifiable. 1 patient was not evaluable at TP2 being withdrawn prior to this, 2 do not have TP2 available at this time (1 being MRD negative at TP1, 1 with unquantifiable low-level MRD). One patient had MRD increase between TP1 and TP2, this subject had a hypodiploid karyotype. Thus, by completion of 1st consolidation an aggregate of 7 out of 10 patients were MRD negative or had unquantifiable low-level MRD, 3 remaining MRD positive (with 1 MRD progression). Updated results will be presented at the meeting. Conclusion - Front-line therapy with Blinatumomab in combination with chemotherapy is feasible in adults and results in high levels of MRD response by the end of the first consolidation block with the majority of MRD negative responses attained after the first treatment block. Despite early incorporation of Blinatumomab into this treatment protocol, MRD progression was seen in one patient with high-risk cytogenetic abnormalities. Disclosures Fleming: Astellas: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Reynolds:Novartis Australia: Honoraria; Novartis AG: Equity Ownership; AUSTRALASIAN LEUKAEMIA & LYMPHOMA GROUP (ALLG): Consultancy; Alfred Health: Employment, Other: Biostatistician for trials funded by the Australian government and Abbvie, Amgen, Celgene, GSK, Janssen-Cilag, Merck, Novartis, Takeda, but sponsored by Alfred Health.. Nguyen:Australasian Leukaemia & Lymphoma Group: Employment. Yeung:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria. Greenwood:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Verner:Janssen-Cilag Pty Ltd: Research Funding. Bajel:AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: travel funding. Wei:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: 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, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: 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; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria. OffLabel Disclosure: Blinatumomab is not currently approved for the front-line treatment of adults with Ph- B-ALL

Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea complications have been reported in Philadelphia-negative myeloproliferative neoplasms (MPNs), but their incidence and clinical consequences have not been defined in a large cohort of patients. We conducted a retrospective analysis of 188 consecutive patients with MPNs specifically addressing the incidence of these complications. Cyclical thrombocytosis was documented in 29 patients (15%), the majority of whom were receiving hydroxyurea. Acquired von Willebrand syndrome was identified in 17 of the 84 screened patients (20%), but was not associated with any major bleeding complications. Non-melanoma skin cancers were reported in 51 patients (27%). Hydroxyurea-related fever occurred in nine of 149 patients (6%) who received hydroxyurea. Seventy-three patients (39%) experienced a total of 98 major thrombotic events, with the majority of these occurring prior to or within 3 months of the diagnosis. Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea-related complications are not infrequent in MPNs and have important clinical consequences for management.

Multidisciplinary team (MDT) meetings aimed at facilitating peer review have become standard practice in oncology. However, there is scant literature on the optimal structure and conduct of such meetings.To develop a process for formal peer review of patients with haematological malignancies and to audit any resulting changes made to the management recommendations of the treating physician.A standard operating procedure (SOP) for MDT meetings was developed essentially to integrate clinical peer review with weekly pathology and radiology meetings. The centrepiece is the electronic submission of a patient-specific proforma (Microsoft InfoPath) prior to the meeting. It serves as the template for presentation, discussion and recording of recommendations and conclusions. The final verified document is stored in the electronic patient record, and a copy is sent to the general practitioner. The proposed management plans were compared to the consensus recommendations of the meeting for the first 4 years since inception.Both SOP and proforma underwent continual improvements. These provided the framework for the conduct of a robust weekly MDT meeting for peer review of the management of patients with haematological malignancies. On 20% of occasions, patient management plans were altered to optimise patient care as a direct consequence on peer review at the MDT.Our streamlined process, in its ultimate format, has provided a mature and efficient forum for formal peer review in a genuine multidisciplinary environment. Both initial data and informal feedback support its ongoing activity as an integral component of delivering quality patient care.

We present two cases of blastic plasmacytoid dendritic cell neoplasm (BPDCN). Patient 1, an 86-year-old male, presented with a 3-month history of an enlarging facial lesion associated with a gradua...

Introduction: The BTK inhibitor ibrutinib (IB) is highly active in WM, achieving major responses (CR+VGPR+PR) in approximately 70% of pts. However, VGPR is infrequent, with rates ≤15% in reported series (Treon NEJM 2015, Dimopoulos EHA 2016). BGB-3111 is a potent, highly-specific and irreversible BTK inhibitor, with greater selectivity than IB for BTK vs. other TEC- and HER-family kinases, and superior bioavailability. We previously reported that the recommended phase 2 dose of BGB-3111 is 320mg daily (in single or split dose) in pts with advanced B cell malignancies. This achieves plasma levels equivalent to 6-10 fold that of IB, and >90% continuous inhibition of BTK in lymph node biopsies. We specifically investigated the safety and efficacy of BGB-3111 in pts with WM in an expansion cohort of the initial Phase 1 trial. Reported here are updated results of this study, including data from WM specific expansion cohorts. Aims: To define the safety profile, and clinical activity of BGB-3111 in pts with WM. Methods: These results are from a pre-specified a component of a Phase 1 study (Part 1: dose escalation [DEsc] in pts with R/R B cell malignancies, Part 2: disease-specific dose expansion cohorts [EC] at the recommended Phase 2 dose that included patients with relapsed / refractory or previously untreated WM). Adverse events (AEs) were reported per CTCAE v4.03. Responses were determined according to the modified Sixth International Workshop on WM (IWWM) criteria. The data cut-off is 10 June 2016. Results: As of 10 June 2016, 31 pts with WM have been enrolled; 6 pts in DEsc (40mg [n=2], 80mg [n=2], 160mg QD [n=1], and 320mg QD [n=1]), and 25 in the WM EC (160mg BID [n=18], 320mg QD [n=7]). Three pts in DEsc were increased to 160mg QD after analysis of DEsc data, as allowed by protocol. Twenty-four pts are included in this analysis; 5 pts were excluded because of short (Gr 1 severity within the first 12 weeks of therapy. The most frequent AEs (>20%) of any attribution (all Gr 1/2) were upper respiratory infection (25%), diarrhea (25%), and nausea (21%). There were 2 SAEs assessed as possibly related to BGB-3111 (Gr 2 atrial fibrillation, Gr 3 cryptococcal meningitis); in both cases, BGB-3111 was temporarily held but safely resumed. In total, 2 pts developed AF (one Gr 1, one Gr 2). No serious hemorrhage (≥Gr 3 or CNS hemorrhage of any grade) was reported. After a median follow-up of 7.6 months (2-21 months), the response rate was 92% (22/24). The major response rate was 83% (20/24), with VGPR (>90% reduction in IgM and reduction in extramedullary disease) in 33% (8/24) and PR (50-90% reduction in IgM and reduction in extramedullary disease) in 50% (12/24) pts. Pts with WM refractory to their last therapy were equally responsive: major response 77% [10/13], VGPR 31% [4/13], PR 46% [6/13]. Median time to initial response and major response were 29 days and 34 days, respectively. IgM decreased from a median of 29.9g/l at baseline to 3.0g/l; hemoglobin increased from a median of 10.1 g/dl at baseline to 13.5g/l. Two of 3 pts who had a dose increase after reaching a stable IgM plateau had further falls in IgM levels after dose escalation. Kinetics of IgM and hemoglobin response are presented in Figure 1. Lymphadenopathy was present in 8 pts at baseline; serial CT demonstrated reduction or resolution in all 8 pts (27%-100% reduction in SPD). Only one patient discontinued BGB-3111, due to exacerbation of pre-existing bronchiectasis while in VGPR. There have been no cases of disease progression. Analysis of response by genomic characteristics (including MYD88 and CXCR4 mutational status) is ongoing. Conclusions: BGB-3111 is well-tolerated and highly active in WM. The depth and quality of responses, as reflected by the VGPR rate of 33%, warrant a randomized comparison against ibrutinib in pts with WM. Table 1. Table 1. Figure 1. Figure 1. Disclosures Tam: Roche: 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; janssen: Honoraria, Research Funding. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Simpson:Amgen Pharmaceuticals: Research Funding; Celgene, Roche, Janssen: Honoraria. Anderson:Walter and Eliza Hall Institute of Medical Research: Other: Walter and Eliza Hall Institute of Medical Research receives milestone payments for the development of venetoclax. Kirschbaum:Beigene: Employment. Wang:Beigene: Employment. Xue:Beigene: Employment. Yang:BeiGene: Employment. Hedrick:Beigene: Employment. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roberts:AbbVie: Research Funding; Servier: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax.