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PURPOSE The CLL14 study has established one-year fixed-duration treatment of venetoclax and obinutuzumab (Ven-Obi) for patients with previously untreated chronic lymphocytic leukemia. With all patients off treatment for at least three years, we report a detailed analysis of minimal residual disease (MRD) kinetics and long-term outcome of patients treated in the CLL14 study. PATIENTS AND METHODS Patients were randomly assigned to receive six cycles of obinutuzumab with 12 cycles of venetoclax or 12 cycles of chlorambucil (Clb-Obi). Progression-free survival (PFS) was the primary end point. Key secondary end points included rates of undetectable MRD and overall survival. To analyze MRD kinetics, a population-based growth model with nonlinear mixed effects approach was developed. RESULTS Of 432 patients, 216 were assigned to Ven-Obi and 216 to Clb-Obi. Three months after treatment completion, 40% of patients in the Ven-Obi arm (7% in the Clb-Obi arm) had undetectable MRD levels < 10−6 by next-generation sequencing in peripheral blood. Median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median 80 v 69 days). At a median follow-up of 52.4 months, a sustained significant PFS improvement was observed in the Ven-Obi arm compared with Clb-Obi (median not reached v 36.4 months; hazard ratio 0.33; 95% CI, 0.25 to 0.45; P < .0001). The estimated 4-year PFS rate was 74.0% in the Ven-Obi and 35.4% in the Clb-Obi arm. No difference in overall survival was observed (hazard ratio 0.85; 95% CI, 0.54 to 1.35; P = .49). No new safety signals occurred. CONCLUSION Appearance of MRD after Ven-Obi is significantly slower than that after Clb-Obi with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of Ven-Obi–treated patients remaining in remission.

Background: Glofit is a novel, CD20xCD3 T-cell-engaging bispecific antibody that provides monovalent binding to CD3 on T cells and bivalent binding to CD20 on B cells. As monotherapy, Glofit has shown promising response rates with manageable safety in R/R B-cell non-Hodgkin lymphoma (B-NHL) patients (pts; [Carlo-Stella et al. EHA 2021]). Because of their distinct and complementary mechanism of action, there is a rationale for combining Glofit with the anti-CD79b-targeted antibody-drug conjugate, Pola. NP39488 (NCT03533283) is a Phase Ib/II, open-label, multicenter, dose-escalation (DE) and expansion study evaluating Glofit + Pola or atezolizumab in R/R B-NHL pts (Hutchings et al. ASH 2019). Here, we report preliminary safety and efficacy data for Glofit + Pola in pts with R/R DLBCL during DE and expansion at the recommended Phase II dose (RP2D). Methods: To mitigate the risk of cytokine release syndrome (CRS), a single 1000mg dose of obinutuzumab pre-treatment was administered on Cycle (C) 1 Day (D) 1 alongside step-up dosing (SUD) of Glofit on C1D8 and C1D15. Glofit was subsequently administered at the target dose from C2D1, every 3 weeks up to C12. Pola was administered at 1.8mg/kg on C1D2 and then on D1 of each subsequent cycle up to C6. The primary objective was to establish the RP2D of Glofit in combination with Pola. Results: As of June 10, 2021 (clinical cut-off date [CCOD]), 44 pts were treated with ≥1 cycle; median follow-up was 3.2 months (95% confidence interval: 1.4-3.5). In the first DE cohort, 7 pts had received Glofit at 2.5mg (C1D8)/10mg (C1D15)/10mg (C2D1 onwards) plus Pola. In the second DE cohort, 4 pts received the Glofit target dose of 30mg on C1D15 and this was established as the RP2D. During the expansion phase at RP2D, an additional 34 pts were treated with ≥1 cycle. Of 44 pts, 29 (66%) had histology of R/R DLBCL, 8 (18%) had R/R high-grade B-cell lymphoma (HGBCL; 2 HGBCL not otherwise specified; 5 double-hit DLBCL; 1 triple-hit DLBCL) and 7 (16%) had R/R transformed follicular lymphoma. Pts (61% male) had a median age of 65.5 years (range: 29-82) and received a median of two prior lines (range: 1−5). Twenty-eight (64%) pts were refractory to their last therapy; 2 pts had not been treated with Glofit at the CCOD. The most frequent adverse event (AE) was CRS (55%; 23/42 pts): Grade (Gr) 1 (n=18); Gr 2 (n=7); no Gr ≥3 CRS events were observed (Lee et al. 2019 ASTCT criteria). Of the 7 pts with Gr 2 CRS, 5 were treated with tocilizumab and fluids for hypotension, and 4 pts were treated with low-flow oxygen due to hypoxia. None of the pts required vasopressors or intensive care unit admission. Gr >3 AEs occurred in 52% (n=23) of pts; most commonly, neutropenia (27%) and anemia (23%). For neurological AEs (NAEs), 13 events were reported in 13 patients (29.5%, 13/44 pts), all were limited to Gr 1−2. The most common NAEs were headache and (11%, 5/44 pts) and insomnia (4.5%, 2/44 pts). No immune effector cell-associated neurotoxicity syndrome-like AEs were reported. Peripheral neuropathy due to Pola was reported in 5/44 pts (11%); all events were Gr 1. Serious AEs occurred in 22 pts (52%); none were CNS or neurological events. One pt experienced fatal COVID-19 pneumonia (not related). Study treatment was discontinued in 2 pts due to AEs (Gr 4 thrombocytopenia, and Gr 3 worsening of pre-existing renal impairment; both events were related to Glofit and Pola). At CCOD 33/44 pts were evaluable for interim (after 2 cycles, 1 target dose of Glofit) or primary (after 8 cycles) response; 6/33 pts had experienced progressive disease and discontinued study treatment. Overall response (OR) rate for both dosing cohorts was 73% (24/33) and complete response (CR) rate, per investigator was 51.5% (17/33). Of 7 pts treated with 2.5/10/10mg SUD Glofit, OR and CR rates were both 86% (6/7); durable responses at ≥6 months post-end of treatment were observed. Of 26 pts treated with 2.5/10/30 mg SUD Glofit, OR rate was 73% (19/26) and CR rate was 46% (12/26); 11.5% (3/26) pts had stable disease after 2 cycles of therapy. Duration of response and time on study by dosing cohort is shown in Figure. Biomarker and pharmacokinetic data will be provided. Conclusions: Glofit in combination with Pola showed tolerable safety and encouraging preliminary efficacy in R/R DLBCL pts. CRS and NAEs were limited to Gr 1 or 2, no new safety signals were detected for this combination, and the safety profile was consistent with that of the individual drugs. Updated data will be presented. Figure 1 Figure 1. Disclosures Hutchings: Genmab: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding. Sureda: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Support for attending meetings and/or travel; GSK: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Consultancy; MSD: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: 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, Speakers Bureau. Terol: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Consultancy; BMS: Consultancy; Hospital Clinico Valencia: Current Employment; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Bosch Albareda: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Abbvie: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Kite: Honoraria; Sanofi: Honoraria; Lilly: Honoraria. Corradini: KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; Incyte: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations. Larsen: Novartis: Consultancy; Gilead: Consultancy; Odense University Hospital, Denmark: Current Employment; Celgene: Consultancy; BMS: Consultancy. Rueda Dominguez: Hospital Regional Universitario de Malaga: Current Employment; Roche: Consultancy; Takeda: Consultancy; Gilead: Consultancy; Merck Serono: Consultancy; BMS: Consultancy; MSD: Consultancy. Panchal: F. Hoffmann-La Roche Ltd: Current Employment. Bottos: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Carlile: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Wang: F. Hoffmann-La Roche Ltd: Current Employment; Peking University Third Hospital, Beijing, China: Ended employment in the past 24 months. Filézac De L'Étang: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Tandon: Roche Products Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Sellam: Roche: Current Employment, Current equity holder in publicly-traded company. Gritti: Takeda: Consultancy; Roche: Consultancy; Kite Gilead: Consultancy; IQvia: Consultancy; Italfarmaco: Consultancy; Clinigen: Consultancy. OffLabel Disclosure: Glofitamab is a full-length, humanized immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent. Polatuzumab vedotin (Polivy) is a CD79b-directed antibody-drug conjugate indicated in combination with bendamustine and a rituximab product for the treatment of adult pts with relapsed or refractory DLBCL, not otherwise specified, after at least two prior therapies.

Background There is no effective intravesical second-line therapy for non–muscle-invasive bladder cancer (NMIBC) when bacillus Calmette-Guerin (BCG) fails. Objective To compare disease-free survival time (DFS) between radiofrequency-induced thermo-chemotherapy effect (RITE) and institutional standard second-line therapy (control) in NMIBC patients with recurrence following induction/maintenance BCG. Design, settings, and participants Open-label, phase III randomised controlled trial accrued across 14 centres between May 2010 and July 2013 (HYMN [ClinicalTrials.gov: NCT01094964]). Intervention Patients were randomly assigned (1:1) to RITE (60min, 40mg mitomycin-C, 42±2°C) or control following stratification for carcinoma in situ (CIS) status (present/absent), therapy history (failure of previous induction/maintenance BCG), and treatment centre. Outcome measurements and statistical analysis Primary outcome measures were DFS and complete response (CR) at 3 mo for the CIS at randomisation subgroup. Analysis was based on intention-to-treat. Results and limitations A total of 104 patients were randomised (48 RITE: 56 control). Median follow-up for the 31 patients without a DFS event was 36 mo. There was no significant difference in DFS between treatment arms (hazard ratio [HR] 1.33, 95% confidence interval [CI] 0.84–2.10, p=0.23) or in 3-mo CR rate in CIS patients (n=71; RITE: 30% vs control: 47%, p=0.15). There was no significant difference in DFS between treatment arms in non-CIS patients (n=33; RITE: 53% vs control: 24% at 24 mo, HR 0.50, 95% CI 0.22–1.17, p=0.11). DFS was significantly lower in RITE than in control in CIS with/without papillary patients (n=71; HR 2.06, 95% CI 1.17–3.62, p=0.01; treatment-subgroup interaction p=0.007). Disease progression was observed in four patients in each treatment arm. Adverse events and health-related quality of life between treatment arms were comparable. Conclusions DFS was similar between RITE and control. RITE may be a second-line therapy for non-CIS recurrence following BCG failure; however, confirmatory trials are needed. RITE patients with CIS with/without papillary had lower DFS than control. HYMN highlights the importance of the control arm when evaluating novel therapies. Patient summary This study did not show a difference in bladder cancer outcomes between microwave-heated chemotherapy and standard of care treatment. Papillary bladder lesions may benefit from microwave-heated chemotherapy treatment; however, more research is needed. Both treatments are similarly well tolerated.

Background: Over a third of pts with 1L DLBCL do not respond to, or relapse after, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP; [Sarkozy and Sehn. Ann Lymphoma 2019]). Despite recent advances, pts with R/R NHL have limited curative options. Glofitamab (Glofit) is a novel, T-cell-engaging bispecific antibody with a 2:1 molecular configuration that allows bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells. Unlike other CD20xCD3 bispecific antibodies, this format uniquely enables combination with anti-CD20 antibodies, including rituximab. Glofit monotherapy induces high response rates in R/R B-cell NHL (Hutchings et al. J Clin Oncol 2021). We present results of the ongoing NP40126 study (NCT03467373), designed to assess the feasibility and safety of Glofit + R-CHOP in R/R NHL (dose-escalation phase) and 1L DLBCL (safety run-in phase). Methods: R/R NHL dose-escalation: Pts (Eastern Cooperative Oncology Group performance status [ECOG PS] 0-2) received increasing Glofit doses in separate cohorts (70µg, 1800µg, 10mg and 30mg) plus standard R-CHOP for 6-8 cycles (each 21-day). To mitigate CRS risk, R- or obinutuzumab (G)-CHOP was given in Cycle (C)1, with the aim of tumor debulking. Glofit was given from C2 onwards. For 70µg and 1800µg cohorts, fixed-dose Glofit was given on C2 Day (D)8 and onwards. For 10mg and 30mg cohorts, step-up dosing was used to further mitigate CRS risk (2.5mg C2D8, 10mg C2D15, target dose C3D8 and onwards). Optional Glofit maintenance was permitted (every 2 months for 1L DLBCL safety run-in: Pts (ECOG PS 0-3) received Glofit 30mg plus standard R-CHOP for 6-8 cycles (each 21-day). Pts received R-CHOP in C1; Glofit step-up dosing began in C2 (2.5mg C2D8, 10mg C2D15, 30mg C3D8 and onwards). Response rates were assessed by PET-CT (Lugano criteria; [Cheson et al. J Clin Oncol 2014]). CRS events were graded by ASTCT criteria [Lee et al. Biol Blood Marrow Transplant 2019]. Results: R/R NHL dose-escalation: At data cut-off (June 10, 2021), 31 pts (23 follicular lymphoma [FL]; 6 transformed FL; 1 marginal-zone lymphoma; 1 mantle-cell lymphoma) had received Glofit with R/G-CHOP. Median age was 62 years, median prior lines of therapy was 2 (range: 1-5). In efficacy-evaluable pts (n=31), after a median 9.0 months' (range: 0-29) follow-up, the overall response rate (ORR) was 90% (n=28) and complete response rate (CRR) was 77% (n=24). Median duration of response was not reached. The Figure shows change in tumor size. Grade (Gr) ≥3 adverse events (AEs) occurred in 28 (90%) pts, serious AEs in 21 (68%) pts and CRS in 17 (55%) pts (mostly low grade; majority after the first 2.5mg Glofit dose; Table). One (3%) pt had a Gr 5 AE (COVID-19 pneumonia not related to study treatment). AEs led to Glofit dose modification/interruption in 2 (6%) pts and Glofit withdrawal in 1 (3%) pt. Neurologic AEs (NAEs) occurred in 20 (65%) pts: Gr 1-2 (16 pts, 52%); Gr 3 (4 pts, 13%). Immune effector cell-associated neurotoxicity syndrome (ICANS)-like AEs were uncommon; a serious AE was reported in 1 pt only (Gr 3 epilepsy during the maintenance phase; resolved in 3 days). Neutropenia occurred in 24 (77%) pts. Median dose intensity was 100% for all R-CHOP components. 1L DLBCL safety run-in: At data cut-off, 13 pts were enrolled (safety population); of these, 4 pts received Glofit 30mg with R-CHOP and were efficacy-evaluable. Median age was 68 years, all pts had Ann Arbor Stage 3/4 disease. At interim assessment (C3), CRR was 100% (4/4). Of 13 pts, 1 (8%) had a CRS event (Gr 1 with fever only) after the first 2.5mg Glofit dose; no other CRS events observed. Gr ≥3 AEs occurred in 8 (62%) pts and Gr ≥3 AEs related to Glofit in 1 (8%) pt only. One (8%) pt had a serious AE and 1 (8%) pt had a Gr 5 AE (infusion-related reaction related to rituximab on C1D1). No AEs led to Glofit or R-CHOP dose interruptions. NAEs occurred in 3 (23%) pts (all Gr 1-2; none were ICANS-like). Neutropenia occurred in 6 (46%) pts. Median dose intensity was 100% for all R-CHOP components. Conclusions: Initial data show that Glofit + R-CHOP has tolerable safety in R/R NHL and 1L DLBCL. R-CHOP dose intensity was maintained in all pts. The very low CRS rate and no neurotoxicity in 1L DLBCL may render Glofit particularly suitable for the outpatient setting without the need for hospitalization. Updated data, including end-of-treatment responses from the 1L DLBCL safety run-in phase, will be presented. Figure 1 Figure 1. Disclosures Ghosh: Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Genentech: Research Funding. Townsend: Celgene (Bristol-Myers Squibb): Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Dickinson: Amgen: Honoraria; Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau. Topp: Celgene: Consultancy, Research Funding; Janssen: Consultancy; Universitatklinikum Wurzburg: Current Employment; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy, Research Funding; Gilead: Research Funding; Regeneron: Consultancy, Research Funding; Macrogeniecs: Research Funding; Amgen: Consultancy, Research Funding. Santoro: Sandoz: Speakers Bureau; Eli-Lilly: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Speakers Bureau; Roche: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Consultancy; Arqule: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Crump: Novartis: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding; Roche: Research Funding. Morschhauser: Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Mehta: Kite/Gilead; Roche-Genetech; Celgene/BMS;Oncotartis; Innate Pharmaceuticals; Seattle Genetics;Incyte; Takeda; Fortyseven Inc/Gilead; TG Therapeutics;Merck; Juno Pharmaceuticals/BMS: Research Funding; Seattle Genetics; Incyte; TG Therapeutics: Consultancy; Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Panchal: F. Hoffmann-La Roche Ltd: Current Employment. Wu: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Barrett: Roche Products Ltd: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Qayum: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Hutchings: Novartis: Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Glofitamab is a full-length, humanized immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent. Rituximab (Rituxan) is a CD20-directed cytolytic antibody indicated for the treatment of adult pts with: relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL as a single agent; previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy (chemo) and, in pts achieving a CR or PR to a rituximab product in combination with chemo, as single-agent maintenance therapy; non-progressing (including stable disease), low-grade, CD20 positive, B-cell NHL as a single agent after first-line CVP chemo; previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP or other anthracycline-based chemo regimens; previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide.

Background: FL is an indolent yet incurable disease characterized by recurrent relapses. Pts with R/R FL often have a poor prognosis and limited treatment options, particularly those who have progression of disease within 24 months of frontline treatment (POD24) or are refractory to multiple agent classes. Glofitamab is a T-cell-engaging, CD20xCD3 bispecific, full-length, 2:1 format antibody with bivalent binding to CD20 (B cells) and monovalent binding to CD3 (T cells). Glofitamab monotherapy with obinutuzumab pretreatment (Hutchings, et al. JCO 2021), or combined with obinutuzumab (Morschhauser et al, Blood 2019; NCT03075696), has shown efficacy and manageable safety in heavily pretreated R/R NHL. Here, we present updated results of glofitamab with three different step-up dosing (SUD) regimens as monotherapy (mono) or combined with obinutuzumab (combo) in R/R FL. Methods: Obinutuzumab (1000mg) was given 7 days prior to the first dose of glofitamab. For the 3 mono cohorts, intravenous glofitamab SUD was given on Days (D) 1 and 8 of Cycle (C) 1; then at target dose on C2, or as SUD on C1D1, C1D8, C2D1 and target dose on C3D1. For the combo cohort, glofitamab SUD was given on D1 and D8 of C1, then at target dose combined with obinutuzumab 1000mg from C2D1 and onwards (every 21 days for up to 12 cycles). Response rates were based on the Lugano criteria (Cheson et al. J Clin Oncol 2014). Results: As of May 18, 2021, 53 pts received glofitamab mono SUD (2.5/10/16mg, n=3; 2.5/10/30mg, n=21; 0.5/2.5/10/30mg, n=29) and 19 pts received glofitamab combo SUD (2.5/10/30mg). All pts had FL Grade (Gr) 1-3A (FLIPI 1 high risk score: mono, 28 [53%] pts; combo, 11 [58%] pts). Median age was 64 years (range 33-83) in mono cohorts and 61 years (range 41-78) in the combo cohort; median number of prior therapies was 3 (range 1-12) and 2 (range 1-5), respectively. Twenty-eight (53%) pts in the mono cohorts and 8 (42%) pts in the combo cohort were refractory to last therapy; 16 (30%) and 7 (37%), respectively, were refractory to prior CD20 and alkylating therapy (double refractory). A total of 19 (36%) pts in the mono cohorts and 10 (53%) pts in the combo cohort had experienced POD24. In the mono cohorts, overall response rate (ORR) was 81% (n=43) and complete metabolic response rate (CMR) was 70% (n=37), with 72% (n=21) CMR in the 0.5/2.5/10/30mg cohort and 67% CMR in both the 2.5/10/16mg (n=2) and 2.5/10/30mg (n=14) cohorts. In the combo cohort, ORR was 100% (n=19) and CMR was 73.7% (n=14). In the mono cohorts 87% (32/37) pts were in CMR, while in the combo cohort 71% (10/14) pts were in CMR. Median follow-up of CMR ranged from 0-14 months (mono) and 0-5 months (combo), and at this cut-off the follow-up is insufficient to assess CMR duration. High CMR rates were observed in high-risk pts (Table). The most common adverse event (AE) was cytokine release syndrome (CRS): 66% and 79% in the mono and combo cohorts, respectively. CRS rates by mono cohort were as follows: 2.5/10/16mg cohort, 100% (3/3); 2.5/10/30mg cohort, 76% (16/21); 0.5/2.5/10/30mg cohort, 55% (16/29). With mono, CRS events (Lee et al. ASTCT 2019) were mostly Gr 1 (47.2%) and 2 (17.0%); 1 pt had a Gr 3 event (2.5/10/16mg cohort). With combo, 52.6% had Gr 1 CRS and 26.3% had Gr 2 CRS. There were no Gr 3 CRS events in the combo cohort and no Gr 4 or 5 CRS with either regimen. Of pts with CRS, tocilizumab was used to treat CRS in 22.9% pts in mono cohorts and 33.3% pts in the combo cohort. All CRS events were manageable and had resolved at data cut-off. Neurologic AEs were seen in 26 pts (16 mono, 10 combo; 36%); all Gr 1 (n=17) or Gr 2 (n=9). No ICANS-like events related to glofitamab were reported. Other common AEs were infusion related reactions and pyrexia (events separate from CRS; both 28%) and neutropenia (26%) with mono, and neutropenia (58%), anemia (37%) and thrombocytopenia (32%) with combo. Conclusions: Glofitamab SUD administered as monotherapy or in combination with obinutuzumab achieved high response rates in pts with heavily pretreated R/R FL, including high-risk subgroups. Response rates were comparable to those reported for CAR-T in R/R FL. The safety profile of glofitamab was manageable; CRS events were mostly low grade and occurred mainly in C1 and C2. Considering the short duration of follow-up, additional follow-up is required to further assess the safety and efficacy of glofitamab in this heterogeneously treated population. Further analyses will be presented. Figure 1 Figure 1. Disclosures Morschhauser: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Servier: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Carlo-Stella: AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, 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; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Dickinson: Celgene: Research Funding; Takeda: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Phillips: ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Houot: Bristol-Myers Squibb: Honoraria; CHU Rennes: Current Employment; Roche: Honoraria; Kite: Honoraria; Gilead: Honoraria; MSD: Honoraria; Celgene: Honoraria; Jsnssen: Honoraria; Novartis: Honoraria. Haioun: Celgene: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Miltenyi: Honoraria, Research Funding; Servier: Honoraria, Research Funding. Corradini: AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; Incyte: Consultancy; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy. Hutchings: Novartis: Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding. Sureda: GSK: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Amgen: 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, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Wrobel: Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau. Lundberg: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Mulvihill: F. Hoffmann-La Roche Ltd: Current Employment, Ended employment in the past 24 months. Perez-Callejo: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Relf: Harpoon Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; F-Star Therapeutics: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Roche Pharmaceutical Ltd: Current Employment, Current equity holder in publicly-traded company. Panchal: F. Hoffmann-La Roche Ltd: Current Employment. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. OffLabel Disclosure: Glofitamab is a full-length, humanized, immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent. Obinutuzumab (Gazyva) is a CD20-directed cytolytic antibody indicated: in combination with chlorambucil, for the treatment of pts with previously untreated CLL; in combination with bendamustine followed by obinutuzumab monotherapy, for the treatment of pts with FL who relapsed after, or are refractory to, a rituximab-containing regimen; in combination with chemo followed by obinutuzumab monotherapy in pts achieving at least a PR, for the treatment of adult pts with previously untreated stage II bulky, III or IV FL

Essential Thrombocythemia (ET) patients at high-risk of thrombosis require cytoreductive treatment, typically with hydroxycarbamide. Many patients are resistant or intolerant to hydroxycarbamide (HC-RES/INT) and are at increased risk of disease progression. MAJIC-ET is a randomized phase 2 study comparing ruxolitinib (RUX) to best available therapy (BAT) in HC-RES/INT ET, which showed no difference between the two arms in rates of hematological response or disease progression. The impact of additional non-MPN driver mutations (NDM) on the risk of disease complications in HC-RES/INT ET patients is unknown. Since the presence of NDM may influence trial outcomes, we expand the primary MAJIC-ET analysis to serially evaluate NDM in MAJIC-ET patients using a targeted myeloid 32-gene panel. NDM at baseline were detected in 30% of patients, most frequently affecting TET2 (11%) followed by TP53 (6.4%) and SF3B1 (6.4%). The presence of a NDM was associated with inferior 4-year transformation-free survival (TFS; 65.4% [95% CI 53.3 - 75%] vs. 82.8% [95% CI 73.2 - 89.1%], p=0.017). Specifically, TP53 (p=0.01) and splicing factor (SF, SF3B1, ZRSR2, SRSF2; p

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are unfit for or relapsed postautologous stem-cell transplantation have poor outcomes. Historically, mTORC1 inhibitors have produced responses in approximately 30% of patients in this setting. mTORC1 inhibitor efficacy may be limited by resistance mechanisms including AKT activation by mTORC2. To date, dual mTORC1/2 inhibitors targeting both the TORC1 and TORC2 complexes have not been investigated in DLBCL. This phase II trial investigated the oral dual mTORC1/2 inhibitor vistusertib in an intermittent dosing schedule of 125 mg b.d. for 2 days per week. Thirty patients received vistusertib and six received vistusertib-rituximab for up to six cycles (28-day cycles). Two partial responses were achieved on monotherapy. Durations of response were 57 and 62 days, respectively, for these patients. 19% had stable disease within six cycles. In the monotherapy arm, the median progression-free survival was1.69 (95% confidence interval [CI] 1.61-2.14) months and median overall survival was 6.58 (95% CI 3.81-not reached) months, respectively. The median duration of response or stable disease across the trial duration was 153 days (95% CI 112-not reached). Tumour responses according to positron emission tomography/computed tomography versus computed tomography were concordant. There were no differences noted in tumour volume response according to cell of origin by either gene expression profiling or immunohistochemistry. Vistusertib ± rituximab was well tolerated; across 36 patients 86% of adverse events were grade (G) 1-2. Common vistusertib-related adverse events were similar to those described with mTORC1 inhibitors: nausea (47% G1-2), diarrhoea (27% G1-2, 6% G3), fatigue (30% G1-2, 3% G3), mucositis (25% G1-2, 6% G3), vomiting (17% G1-2), and dyspepsia (14% G1-2). Dual mTORC1/2 inhibitors do not clearly confer an advantage over mTORC1 inhibitors in relapsed or refractory DLBCL. Potential resistance mechanisms are discussed within.

CD20-TCB (RG6026) is a novel T-cell-engaging bispecific (TCB) antibody with a '2:1' molecular format that comprises two fragment antigen binding regions that bind CD20 (on the surface of B cells) and one that binds CD3 (on the surface of T cells). CD20-TCB offers the potential for increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing versus other bispecific formats. CD20-TCB has demonstrated highly promising single-agent activity in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) patients (pts) (Dickinson et al. ICML 2019). Preclinical data demonstrate CD20-TCB-induced programmed cell death protein 1 (PD-1) and programmed cell death-ligand-1 (PD-L1) upregulation on T cells and tumor cells. We hypothesized that the combination of T-cell engagement by CD20-TCB and PD-L1 inhibition by atezolizumab could lead to additive anti-tumor activity in B-NHL. We report preliminary data from NP39488 (NCT03533283), an ongoing Phase Ib study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy (objective response rate [ORR] and complete response [CR] rate per modified Lugano 2014 criteria) of CD20-TCB in combination with atezolizumab in R/R B-NHL pts. A single dose of 1000mg obinutuzumab (G) is administered on Day −7 of Cycle 1 as pretreatment (Gpt) to mitigate for potential cytokine release syndrome (CRS). CD20-TCB is initiated on Day 1 of Cycle 1 and given in a q3w schedule. From Cycle 2 onwards, atezolizumab (1200mg) is added and given on the same day as CD20-TCB. CD20-TCB dose-escalation is ongoing and is guided by the modified continual reassessment method-escalation with overdose control (mCRM-EWOC). As of June 25, 2019, 38 pts with aggressive B-NHL (n=33; diffuse large B-cell lymphoma [DLBCL], transformed [tr] follicular lymphoma [FL], primary mediastinal large B-cell lymphoma, mantle cell lymphoma, tr lymphoplasmacytic lymphoma, tr Waldenstrom`s macroglobulinemia) or indolent B-NHL (n=5; FL) had received CD20-TCB doses from 0.07mg to currently 6mg. Pts (52.6% male) had a median age of 67 years (range: 38-82) and a median of three prior treatment lines (range: 1−10); 84% had refractory B-NHL. Two dose-limiting toxicities (Grade [Gr] 3 tumor flare at 6mg during Cycle 1 and Gr 3 myopathy at 1.8mg during Cycle 2) were transient and resolved completely. The most frequent adverse event (AE) was CRS (42%; 16/38 pts), with 24% Gr 1 (n=9), 18% Gr 2 (n=7), and no Gr ≥3 (according to Lee criteria, Lee et al. Blood 2014;124:188-95). The most common AEs (>20%) were pyrexia (37%), anemia (29%), fatigue (24%), neutropenia (21%), diarrhea (21%), and decreased appetite (21%). The most common Gr ≥3 AEs (>10%) were neutropenia (18%) and anemia (13%), with a single Gr 5 unrelated pneumonia. Three pts experienced a transient Gr ≥3 neurotoxicity (Gr 4 polyneuropathy, Gr 3 trigeminal nerve herpes zoster infection, and Gr 3 post-infection encephalopathy), all of which resolved. Thirty-six pts reached their first response assessment or withdrew early and were eligible for efficacy analysis. Across all doses, ORR and CR rates by investigator assessment were 36% (13/36 pts) and 17% (6/36), respectively (indolent NHL: 4/5 and 3/5 pts; aggressive NHL: 9/31 and 3/31 pts). All CRs are ongoing at the time of abstract submission. CD20-TCB exposure and receptor occupancy (RO%) increased dose-dependently across the dose-range evaluated, and are expected to be further optimized (Djebli et al. ASH 2019). At the higher CD20-TCB doses investigated, a trend towards increased clinical activity was observed (ORR of 60% [9/15 pts] in the 4mg and 6mg cohorts combined). The combination of CD20-TCB and atezolizumab has manageable safety in R/R B-NHL pts. No new safety signals or signs of increased immune-related AEs were detected, and the overall safety profile was consistent with that reported with single-agent CD20-TCB (Dickinson et al. ICML 2019). Dose escalation is ongoing and aims to optimize the dose and schedule of CD20-TCB when combined with atezolizumab using the established exposure-response model for CD20-TCB (Djebli et al. ASH 2019). Updated safety, efficacy, and biomarker data will be presented. Disclosures Hutchings: Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Takeda: 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; Novartis: Research Funding; Janssen: Research Funding; Incyte: Research Funding. Gritti:Roche: Other: Not stated; Abbvie: Other: Not stated; Becton Dickinson: Other: Not stated; Autolus Ltd: Honoraria. Sureda:Sanofi: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; BMS: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Terol:Roche: Consultancy; Abbvie: Consultancy; Astra Zeneca: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Research Funding. Dyer:Roche: Research Funding. Iacoboni:Novartis: Consultancy, Honoraria; Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Celgene: Honoraria. Townsend:Roche: Consultancy, Honoraria. Bacac:Roche: Employment, Equity Ownership, Patents & Royalties: Patents, including the one on CD20-TCB. Bröske:Roche: Employment, Equity Ownership. Dimier:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ferlini:Roche: Employment, Equity Ownership. Keelara:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Lahr:Roche: Employment, Honoraria. Lechner:Roche: Employment, Other: Roche shareholder. Moore:Roche: Employment, Equity Ownership. Morcos:Roche: Employment, Equity Ownership. Panchal:Roche: Employment. Weisser:Pharma Research and Early Development Roche Innovation Center Munich: Employment, Equity Ownership, Patents & Royalties. OffLabel Disclosure: CD20-TCB (also known as RG6026, RO7082859) is a full-length, fully humanized, immunoglobulin G1 (IgG1), T-cell-engaging bispecific antibody with two fragment antigen binding (Fab) regions that bind to CD20 (on the surface of B cells) and one that binds to CD3 (on the surface of T cells) (2:1 format). The 2:1 molecular format of CD20-TCB, which incorporates bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells, redirects endogenous non-specific T cells to engage and eliminate malignant B cells. CD20-TCB is an investigational agent.

MAJIC-ET is a phase 2 study comparing ruxolitinib (RUX) to best available therapy (BAT) in hydroxycarbamide resistant/intolerant (HC-RES/INT) essential thrombocythaemia (ET). The presence of additional non-driver mutations at baseline, in particular TP53 and SF3B1, were predictive for increased risk of disease transformation in this cohort (EHA-4276). Now, we expand the mutation analysis up to 5 years to evaluate clonal evolution after prolonged treatment and correlate with clinical outcome. Driver mutation (JAK2/CALR/MPL) allele burdens were quantified using targeted next-generation sequencing and non-driver mutation analysis was performed using an ISO accredited Illumina TruSeq Custom Amplicon Panel, including 31 gene mutation hotspots & exons (~36,000 bp, 287 amplicons). Data was censored in January 2017 with 47.3% (n=52) randomised to BAT & 52.7% (n=58) to RUX. Overall, 49.1% were JAK2-mutated, 30% CALR-mutated, 4.5% MPL-mutated and 16.4% triple-negative (TN). At 12 months (m), molecular responses (MR) occurred rarely with complete MR (CMR) in 2 patients (pts) and partial MR (PMR) in 3 pts. MR were exclusively seen in RUX-treated pts. 54% (50/92) of those with driver mutations had a >12m allele burden analysis. Median sample time was 48m after trial entry (24 - 60m). There was no significant change in allele burden in the overall cohort. A new JAK2 V617F mutation (allele burden of 6%) was detected at 36m in a "TN" pt at baseline. Of the 5 pts achieving a molecular response at 12m, 2 of these subsequently lost their molecular response; a JAK2-mutated pt achieving CMR at 12m but at 52m had an allele burden of 4% (now PMR) and a CALR-mutated pt with PMR (allele burden 65 to 9%) at 12m, switched from RUX due to toxicity and subsequently lost their MR at 60m (allele burden of 44%), associated with clonal evolution (gain of a new ASXL1 mutation). New MRs occurred in only 2 pts; PMR in a MPL-mutated pt on pegylated-interferon and in a CALR-mutated pt on RUX. 4 pts with a baseline allele burden of Analysis of non-driver mutations was performed on latest TP samples in 51 pts (46%) at a median of 40m after trial entry (6 - 60m). Additional non-driver mutations were present in 30% (33/110) of the cohort at baseline (EHA-4276). In 94% of pts with non-driver mutations at baseline, these were still detected at the latest TP (median 38m, 12 - 52m). There was a We report for the first time a comprehensive longitudinal mutational analysis of HC-RES/INT ET patients within the context of a clinical trial. In this cohort, we found that MR was rare, both early and late in the course of treatment. Initial MR was often not sustained and may signify clonal evolution. As the presence of SF3B1 and TP53 mutations at trial entry predicted for disease progression, we anticipate that the new SF3B1 and TP53 mutations identified at later TP will also increase risk of subsequent transformation during longer follow-up. These data highlight the clinical utility of longitudinal molecular analysis of patients with HC-RES/INT ET. Disclosures Harrison: Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau. Mead:ARIAD: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Cell Therapeutics: Consultancy; Celgene: Research Funding; Elstar: Research Funding; Evotek: Research Funding.

MAJIC is a phase II trial of Ruxolitinib (RUX) vs Best Available Therapy (BAT) in essential thrombocythemia (ET) patients with resistance/intolerance to Hydroxycarbamide (HC) per European LeukemiaNet (ELN) criteria. Primary outcome was rate of complete hematological response (CHR) within 1 year (ELN criteria); secondary outcomes included partial HR, safety, thrombosis, hemorrhage, progression free survival (including transformation), molecular response (MR), symptom & quality of life (QOL) assessment. We present new data concerning molecular, symptom & clinical responses. Patients were stratified by JAK2V617F status, patient-reported symptoms & QOL determined using EQ5D, MDASI & MPN Symptom Assessment Form (MPN10), & compared using linear mixed models of post-baseline scores through month 12 adjusting for baseline; response was defined as ≥50% reduction in MPN10 total symptom score (TSS). JAK2/CALR/MPL allele burdens were assessed at baseline & 4 monthly. 110 patients were eligible for the modified ITT analysis, 58 (52%) & 52 (48%) in RUX & BAT arms respectively, comprising 44 males, 66 females, mean age 64.2ys, & resistant (24.5%), intolerant (51.8%) or both (22.7%) to HC. CHR was achieved in 27 (46.6%) of RUX patients vs 23 (44.2%) BAT patients (χ2 test p= 0.81). PHR occurred in 26 (44.8%) & 27 (51.9%) of RUX & BAT treated respectively. Grade 3 or 4 anemia occurred in 19% & 0% for RUX arm vs 0% (both grades) for BAT arm, grade 3 or 4 thrombocytopenia in 5.2% & 1.7% of RUX vs 0% (both grades) of BAT patients respectively. Grade 3 or 4 infections occurred in 10.3% of RUX patients vs 3.6% BAT arm. 9 RUX treated patients had 10 thrombotic events & 1 RUX patient a hemorrhage; vs 5 thrombotic & 5 hemorrhagic events in BAT patients (adjusted following central review). Transformations to post-ET MF occurred in 8 RUX vs 3 BAT treated patients, 1 RUX patient developed AML. 2 non-treatment related deaths occurred in each arm. Mean MPN-10 TSS & individual symptoms of early satiety & itching during the first 12 months were all significantly lower for RUX vs BAT (all p Allele burden during study & MRs (per ELN-IWG criteria Barosi Blood 2013) are shown in Table 1. Assays for JAK2 V617F were performed independently in 3 centres using qPCR (Guy's), TSCA NGS (Oxford) & amplicon-based NGS (Salisbury) & revealed Mean (range): JAK2 (Guy's): 33.2 (0.1-94.6), N=52; JAK2 (Oxford): 38.0 (0.5-92.2), N=52; JAK2 (Sal): 38.3 (0-90.0), N=50 (limited to JAK2 positive only). With Interclass Correlation Coefficient as follows ICC (Guy's v Oxford): 0.92 (95% CI 0.86-0.95) ICC (Guy's v Sal): 0.92 (95% CI 0.86-0.95) ICC (Oxford v Sal): 0.997 (95% CI 0.994-0.998). Notably MRs (n=5) only occurred with RUX treatment. There was no pattern of MR or progression with C/PHR or transformation, but 1 patient who transformed to PET MF had a complete MR. In a separate analysis baseline symptoms & QOL were not associated with JAK2, CALR, nor MPL status. Within RUX, baseline symptoms & QOL did not predict MR; however, fatigue, early satiety & abdominal discomfort (all p Three non pre-specified multivariate analyses were performed to assess baseline factors influencing CHR (modelled for: treatment received, HC resistance or intolerance, white cell count, platelets, Hb & JAK2/CALR status); occurrence of ≥ grade 3 anemia or thrombocytopenia (modelled for: Hb (≥ 100g/dl) JAK2/CALR status); & transformation to PET-MF (modelled for: treatment, Hb ≤100g/dl). Only baseline Hb ≤100g/dl was significant for grade 3+ anemia (OR [95% CI]=0.17 [0.04, 0.72]), & PET-MF only occurred in patients with baseline WBC This updated analysis shows that HC resistant/intolerant ET is clinically & molecularly diverse. We confirm that these patients are at high risk of thrombosis & transformation as suggested in prior retrospective studies. Molecular responses were limited to RUX & for the first time we demonstrate such responses may correlate with symptom improvement but not always with progression events. Disclosures Harrison: Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Aliman:Novartis: Other: Institutional funding and grant for international conference. . Chen:Novartis: Other: Advisory Board. Coppell:Novartis: Other: Travel, accommodation and conference attendance. Knapper:ONO pharmaceuticals: Research Funding; Novartis: Honoraria, Other: Travel and expenses for international conferences. Ali:Novartis: Honoraria, Other: Conference sponsorship, advisory board meetings. Hamblin:Novartis: Other: Advisory Board. Dueck:Bayer: Honoraria. Cross:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Mesa:Celgene: Research Funding; Promedior: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. McMullin:Novartis: Honoraria, Speakers Bureau.