Search

Background Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017–1.109 and OR = 2.438, 95%CI 1.023–5.813, respectively). Conclusions Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.

Introduction: Patients (pts) with CLL may be at particular risk of severe COVID-19 given advanced age and immune dysregulation. Two large series with limited follow-up have reported outcomes for pts with CLL and COVID-19 (Scarfò, et al. Leukemia 2020; Mato, et al. Blood 2020). To provide maximal clarity on outcomes for pts with CLL and COVID-19, we partnered in a worldwide effort to describe the clinical experience and validate predictors of survival, including potential treatment effects. Methods: This international collaboration represents a partnership between investigators at 141 centers. Data are presented in two cohorts. Cohort 1 (Co1) includes pts captured through efforts by European Research Initiative on CLL (ERIC), Italian CAMPUS CLL Program, and Grupo Español de Leucemia Linfática Crónica. The validation cohort, Cohort 2 (Co2), includes pts from US (66%), UK (23%), EU (7%), and other countries (4%). There is no overlap in cases between cohorts. CLL pts were included if COVID-19 was diagnosed by PCR detection of SARS-CoV-2 and they required inpatient hospitalization. Data were collected retrospectively 2/2020 - 5/2020 using standardized case report forms. Baseline characteristics, preexisting comorbidities (including cumulative illness rating scale (CIRS) score ≥6 vs. The primary endpoint of this study was to estimate the case fatality rate (CFR), defined as the proportion of pts who died among all pts hospitalized with COVID-19. Chi-squared test was used to compare frequencies; univariable and multivariable analyses utilized Cox regression. Predictors of inferior OS in both Co1 and Co2 were included in multivariable analyses. Kaplan-Meier method was used to estimate overall survival (OS) from time of COVID-19 diagnosis (dx). Results: 411 hospitalized, COVID-19 positive CLL pts were analyzed (Co1 n=281, Co2 n=130). Table 1 describes baseline characteristics. At COVID-19 dx, median age was 72 in Co1 (range 37-94) and 68 in Co2 (range 41-98); 31% (Co1) and 45% (Co2) had CIRS ≥6. In Co1, 48% were treatment-naïve and 26% were receiving CLL-directed therapy at COVID-19 dx (66% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.6% chemo/chemoimmunotherapy (CIT), 1.4% PI3Ki, 4% other). In Co2, 36% were never treated and 49% were receiving CLL-directed therapy (65% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.4% multi-novel agent combinations, 1.6% CIT, 1.6% PI3Ki, 1.6% anti-CD20 monotherapy, 1.6% other). Most pts receiving CLL-directed therapy had it held at COVID-19 diagnosis (93% in Co1 and 81% in Co2). Frequency of most COVID-19 symptoms/laboratory abnormalities were similar in the two cohorts including fever (88% in both), lymphocytosis (ALC ≥30 x 109/L; 27% vs. 21%), and lymphocytopenia (ALC < 1.0 x 109/L; 18% vs. 28%), while others varied between Co1 and Co2 (p Median follow-up was 24 days (range 2-86) in Co1 and 17 days (1-43) in Co2. CFRs were similar in Co1 and Co2, 30% and 34% (p=0.45). 54% and 43% were discharged while 16% and 23% remained admitted at last follow-up in Co1 and Co2, respectively. The proportion of pts requiring supplemental oxygen was similar (89% vs. 92%) while rate of ICU admission was higher in Co2 (20% vs. 48%, p Conclusions : In the largest cancer dx-specific cohort reported, pts with CLL hospitalized for COVID-19 had a CFR of 30-34%. Advanced patient age at COVID-19 diagnosis was an independent predictor of OS in two large cohorts. This CFR will serve as a benchmark for mortality for future outcomes studies, including therapeutic interventions for COVID-19 in this population. The effect of CLL treatment on OS was inconsistent across cohorts; COVID-19 may be severe regardless of treatment status. While there were no significant differences in distribution of current lines of therapy between cohorts, prior chemo exposure was more common in Co1 vs. Co2, which may account for difference in OS. Extended follow-up will be presented. Disclosures Roeker: American Society of Hematology: Research Funding; Abbott Laboratories: Other: spouse with minority ownership interest ; AbbVie: Other: spouse with minority ownership interest . Scarfo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Eyre:AbbVie: Consultancy, Honoraria, Other: travel support; Gilead: Consultancy, Honoraria, Other: travel support; Janssen: Consultancy, Honoraria, Other: travel support; KITE, AZ, Loxo Oncology at Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Muntañola Prat:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards. Villacampa:AstraZeneca: Other: advisory role; Merck Sharp & Dohme: Honoraria. Leslie:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: 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; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria. Furman:Incyte: Consultancy; Genentech: Consultancy; Sunesis: Consultancy; Pharmacyclics: Consultancy; Loxo Oncology: Consultancy; Oncotarget: Consultancy; Janssen: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Verastem: Consultancy. Pagel:BeiGene, Astrazeneca, Loxo Oncology, Gilead: Consultancy. Hernandez-Rivas:Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees. Patel:Genentech: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Motta:Roche: Honoraria; Janssen: Honoraria. Lamanna:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Verastem: Research Funding; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vitale:Janssen: Honoraria. Kamdar:Roche: Research Funding. Österborg:BeiGene: Research Funding; Kancera: Current equity holder in publicly-traded company, Research Funding; Sanofi: Consultancy; Karolinska Univeristy Hospital, Stockholm, Sweden: Current Employment. Hanson:Janssen-Cilag: Research Funding; Gilead: Research Funding; AbbVie: Honoraria. Eichhorst:ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding. Reda:Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Varettoni:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses; AbbVie: Other: Travel/accommodations/expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Marchetti:Gilead: Consultancy; Novartis: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Other: Sponsored meetings; Takeda: Other: Sponsored meetings; Pfeizer: Other: Sponsored meetings. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Zabalza:Janssen: Honoraria, Other: travel grants; Roche: Other: travel grants; Novartis: Other: travel grants. Janssens:Amgen: Consultancy, Other: travel grants; speaker fees; Abbvie: Consultancy, Other: travel grants; speaker fees; Celgene: Consultancy, Other: travel grants; speaker fees; Janssen: Consultancy, Other: travel grants; speaker fees; Gilead: Consultancy, Other: travel grants; speaker fees; Novartis: Consultancy, Other: travel grants; speaker fees; Sanofi-Genzyme: Consultancy, Other: travel grants; speaker fees; Roche: Consultancy, Other: travel grants; speaker fees. Niemann:AstraZeneca: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sunesis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Danish Cancer Society: Honoraria, Research Funding; Novo Nordisk Foundation: Honoraria, Research Funding. Perini:Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Abbvie: Speakers Bureau. Patten:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria. Marasca: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; Shire: Honoraria. Iyengar:Janssen: Honoraria; Gilead: Honoraria. Ferrari:Abbvie: Honoraria. El-Sharkawi:Roche: Other: Conference fees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Itchaki:Abbvie Inc: Consultancy, Research Funding. Ma:Novartis: Research Funding; Juno: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding. Van Der Spek:AMGEN: Other: Teaching activities. Seymour:Seattle Genetics: Research Funding; Merck: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding. Rigolin:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mauro:Roche: Other; Octopharma: Other; Takeda-Shire: Other; Gilead: Other; Janssen: Other; Abbvie: Other. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Levin:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation. Špaček:Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Walewska:AbbVie: Other: sponsored for educational meetings, Speakers Bureau; Janssen: Other: sponsored for educational meetings, Speakers Bureau; Gilead: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Wiestner:Pharmacyclics LLC, an AbbVie Company; Acerta, Merck, Nurix, Verastem, and Genmab: Research Funding; National Institutes of Health: Patents & Royalties: and other intellectual property. Broom:Gilead: Other: Travel support, Speakers Bureau. Kater:Abbvie: Research Funding; Roche: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Genentech: Research Funding. Ujjani:AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Verastem Oncology: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Atara: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy. Vandenberghe:Celgene: Other: sponsorship to attend Lugano lymphoma meeting in 2019; Gilead: Other: travel grants, Research Funding; Abbvie: Other: travel grants, Research Funding; Janssen: Other: travel grants; Roche: Other: travel grants, Research Funding. Chong:Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; KITE Pharma: Membership on an entity's Board of Directors or advisory committees. Pu:Takeda Pharmaceuticals: Consultancy. Brown:Janssen, Teva: Speakers Bureau; Gilead, Loxo, Sun, Verastem: Research Funding; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Farina:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sanchez:Abbvie: Other: travel grants; Amgem: Other: travel grants; Janssen: Other: travel grants; Celgene: Other: travel grants; Roche: Other: travel grants. Shadman:Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding. Foglietta:Janssen: Honoraria; Gilead: Honoraria. Jaksic:Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Sportoletti:AbbVie: Honoraria; Janssen: Honoraria. Barr:Morphosys: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy, Research Funding; Verastem: Consultancy; Seattle Genetics: Consultancy; TG therapeutics: Consultancy, Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy; Janssen: Consultancy. Ruchlemer:Abbvie Inc: Consultancy, Research Funding. Kersting:Celgene: Other: travel grant; Janssen: Research Funding; Abbvie: Research Funding. Huntington:Pharmacyclics: Honoraria; AbbVie: Consultancy; Novartis: Consultancy; Genentech: Consultancy; DTRM: Research Funding; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; Astrazeneca: Honoraria; TG Therapeutics: Research Funding. Herishanu:Roche: Honoraria; Sanofi: Honoraria; Medison: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria. Jacobs:TG Therapeutics, Inc.: Research Funding; Astra Zeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics: Research Funding, Speakers Bureau; Seattle Genetics: Consultancy; Verastem: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Sanofi Genzyme: Speakers Bureau. Portell:BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Xencor: Research Funding; Bayer: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; AbbVie: Research Funding. Rambaldi:Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Amgen: 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). Research grant from Amgen Inc.; Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.. Brander:Verastem: Consultancy, Honoraria, Other, Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ArQule: Consultancy, Other, Research Funding; Ascentage: Other, Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding; DTRM: Other, Research Funding; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; MEI Pharma: Other, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Pfizer: Consultancy, Other; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding. Rossi:Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Coscia:Karyopharm Therapeutics: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Coombs:Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; MEI Pharma: Honoraria; LOXO Oncology: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cuneo:Astra Zeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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. Bosch:Jansen: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Roche: Honoraria. Stamatopoulos:AstraZeneca: Honoraria; Janssen, Gilead, Abbvie: Honoraria, Research Funding. Ghia:Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; 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; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria. Mato:Adaptive: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; LOXO: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding.

Advancing age and chronic health conditions, significant risk factors for severe COVID-19, are associated with a pro-inflammatory state, termed inflamm-aging. CXCR6+T cells are known to traffic to the lung and have been reported to increase with age. The ligand of CXCR6, CXCL16, is constitutively expressed in the lung and upregulated during inflammatory responses and the CXCR6/CXCL16 axis is associated with severe lung disease and pneumonia. Genome-wide association studies have also recently identified 3p21.31, encompassing theCXCR6gene, as a susceptibility locus for severe COVID-19. We assessed numbers T cells expressing the chemokine receptor CXCR6 and plasma levels of CXCL16, in control and COVID-19 patients. Results demonstrated that circulating CD8+CXCR6+T cells were significantly elevated with advancing age, yet virtually absent in patients with severe COVID-19. Peripheral levels of CXCL16 were significantly upregulated in severe COVID-19 patients compared to either mild COVID-19 patients or SARS-CoV-2 negative controls. This study supports a significant role of the CXCR6/CXCL16 axis in the immunopathogenesis of severe COVID-19.

Background Crovalimab is a novel anti-complement C5 antibody currently being studied as a treatment for paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disease associated with hemolytic anemia and thrombosis. Treatment with approved C5 inhibitors eculizumab or ravulizumab is effective, but can be limited by breakthrough hemolysis due to unsustained C5 inhibition, inadequate efficacy in patients with C5 mutational variants, and the requirement of regular intravenous infusions. Crovalimab is unique in that its properties allow for subcutaneous injections once every 4 weeks (Q4W) that can be self-administered. Additionally, crovalimab binds to C5 mutational variants. Promising results were obtained in the Phase I/II COMPOSER trial (NCT03157635; Röth et al, Blood. 2020) conducted in patients with PNH, with or without prior anti-C5 treatment. The efficacy and safety of crovalimab vs eculizumab will be evaluated in two Phase III, randomized, open-label trials in patients with PNH, with or without current complement C5 inhibition. Study Design and Methods COMMODORE 1 (NCT04432584) will enroll patients who are currently receiving complement C5 inhibitor therapy. This trial is divided into two parts (Figure). Patients aged ≥ 18 years will be randomized 1:1 to receive either crovalimab (Arm A) or eculizumab (Arm B) and will contribute to the primary efficacy analysis. Patients aged < 18 years can be enrolled in an exploratory descriptive arm (Arm C). Arm A and C patients will receive crovalimab loading and subsequent subcutaneous Q4W maintenance dosing from Week 5. Arm B patients will receive eculizumab intravenous maintenance dosing from Day 1, Q2W for a total of 24 weeks. Patients in Arm A and Arm C can continue to receive crovalimab, and patients in Arm B can switch to crovalimab after 24 weeks of treatment, as determined by the treating physician. The primary efficacy objective is to determine the non-inferiority of crovalimab vs eculizumab based on percentage change in lactate dehydrogenase levels from baseline, averaged over weeks 21, 23, and 25. Secondary efficacy objectives are to determine the proportion of patients who experience breakthrough hemolysis, achieve transfusion avoidance or hemoglobin stabilization, as well as determine mean change in fatigue according to the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire from baseline to Week 25. Safety and tolerability of crovalimab vs eculizumab will also be evaluated along with pharmacokinetic, immunogenicity, biomarker, and health status utility objectives. COMMODORE 2 (NCT04434092) will enroll patients not currently treated with C5 complement inhibitors. This trial is also divided into two parts (Figure). Patients aged ≥ 18 years will be randomized 2:1 to receive either crovalimab (Arm A) or eculizumab (Arm B) and will contribute to the primary efficacy analysis. Patients aged < 18 years will be enrolled in an exploratory descriptive arm (Arm C). Arm A and C patients will receive crovalimab loading and subsequent subcutaneous Q4W maintenance dosing from Week 5. Arm B patients will receive induction doses of eculizumab intravenously QW for 4 weeks followed by maintenance dosing Q2W up to 24 weeks. Patients in Arm A and Arm C can continue to receive crovalimab, and patients in Arm B can switch to crovalimab, after 24 weeks of treatment, as determined by the treating physician. The primary efficacy objective is to determine the non-inferiority of crovalimab vs eculizumab, based on the proportion of patients who 1) achieve transfusion avoidance from baseline to Week 25 and 2) with hemolysis control from Week 5-25 (co-primary efficacy endpoints). Safety and tolerability of crovalimab vs eculizumab will also be evaluated along with pharmacokinetic, immunogenicity, biomarker, and health status utility objectives. Figure 1 Figure 1. Disclosures Kulasekararaj: F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Akari: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Achilleon: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support. Risitano: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA Pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees; Jazz: Other: Lecture fees, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Lecture fees, Speakers Bureau; Apellis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Speakers Bureau. Roeth: Novartis: Consultancy, Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Consultancy, Honoraria; Kira: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria. He: LongBio Pharma: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd.: Consultancy. Pu: University of Arizona: Current Employment; Pennsylvania State University: Patents & Royalties; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Wright: Genentech, Inc.: Current Employment. Appius: F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment. Sreckovic: F. Hoffmann-La Roche Ltd.: Current Employment. Stanzel: F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Munir: F. Hoffmann-La Roche: Consultancy; Alexion: Honoraria. Nishimura: Apellis: Consultancy; Novartis: Consultancy; Chugai: Consultancy; Sanofi: Consultancy; Alexion: Consultancy; Roche: Consultancy; Biocryst: Consultancy.

There is a Blood Commentary on this article in this issue., Key Points Both watch-and-wait and treated CLL patients have high mortality rates when admitted for COVID-19. Receiving a BTKi for CLL at COVID-19 diagnosis severe enough to require hospitalization did not influence case fatality rate in this study., Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive (“watch and wait”), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi’s; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi’s at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi’s in COVID-19 are needed to provide definitive evidence of benefit., Visual Abstract

Introduction: Ibrutinib (Ibr) is the first approved irreversible BTK inhibitor. Cardiovascular (CV) adverse events, include hypertension (HT) and atrial fibrillation (AF). Ventricular tachyarrhythmias and sudden death have been reported possibly due to off target kinase inhibition. Several randomised Phase III trials have reported low numbers of cardiac deaths, sudden/unexplained deaths, and/or ventricular arrhythmias with Ibr including 9 deaths in RESONATE-2 Trial, 11 unexplained or unwitnessed deaths in Alliance Trial A041202 (med age 71; Ibr (n=7 [4%]), Ibr+ritux (IR; 4 [2%]), one death in the IR arm of ECOG1912 Trial (mean age 56.7) and 3 unexplained plus 5 cardiac deaths with BR + Ibr in the HELIOS trial (med age 64). Methods: FLAIR, a phase III, multicentre, randomised, controlled, open, trial recruiting 771 pts with untreated CLL requiring therapy. Pts were ≤75 years, considered fit for FCR and were randomized to IR or FCR. Pts with inadequately controlled symptomatic cardiac failure or unstable angina were excluded. We conducted ad hoc evaluations of the potential association of sudden or cardiac deaths with prior medical history or therapies for cardiac disorders (AF, Ischaemic heart disease, MI or angina) and HT via univariate analyses. We used Fisher's Exact test and estimated relative risk (RR) and associated confidence intervals under a normal approximation. Results: In FLAIR, 384 and 378 pts were treated with IR and FCR, respectively, median 52.7 months FU and treatment durations of 47.2 and 4.7 months. Median age 62. 84/384 (22%) IR pts had pre-existing HT and 17/384 (4%) a prior history of a cardiac disorder. 74/378 (20%) FCR pts had HT and 18/378 (5%) a cardiac disorder. To date 10 pts had a sudden or cardiac death: 2 (0.5%) FCR and 8 (2%) IR - median 33 mo (range: 13-48) from initiating IR to death. 9/10 pts were male aged 54 to 73 years at randomisation. 7/ 8 IR pts experiencing a sudden or cardiac death, had a prior history of HT and/or cardiac disorder (RR 23.6 vs pts with no HT/CV history, 95%CI [2.9-195]; Fisher's Exact P=0.0003; Table 1). Hypertensive cardiomyopathy and/or coronary artery disease was found at post mortem of all 3 IR pts having a PM. The risk of sudden or cardiac death with IR was 0.3% (1/291) in pts without pre-existing risk. The number of pts taking anti-hypertensives at trial entry (some taking more than one class) was: ACE inhibitors (ACEi) 47 IR, 37 FCR; Angiotensin II receptor blockers (ARB's) 15 IR, 17 FCR; Ca channel blockers 30 IR, 34 FCR; B-blockers 24 IR, 20 FCR; Diuretics 13 IR, 16 FCR; and alpha blockers 7 IR, 5 FCR. Overall, 291/384 (76%) IR and 296/378 (78%) FCR were taking no HT or cardiac medications at trial entry. The use of ACEi at study entry was associated with an increased risk of sudden or cardiac death with IR: 7/47 (15%) pts on ACEi at trial entry had a sudden or cardiac death compared to 1/336 (0.3%) not taking ACEi (RR 50.2, 95%CI [6.3-399]; P < 0.0001; Table 1). 2/7 pts had discontinued ACEi and switched to ARB's due to cough sometime prior to death. In contrast 0/37 FCR pts with a history of HTN/CV taking ACEi experienced a sudden or cardiac death. In the IR arm, none of the 46 pts receiving cardiac medication but not ACEi had a sudden or cardiac death suggesting that the risk was not simply a prior history of HT or cardiac disorder. 3/11 (27%) IR pts taking an ACEi plus a beta blocker at study entry had a sudden or cardiac death vs 4/32 (12.5%) pts on ACEi without a beta blocker. Factors potentially confounding the interpretation: 1) analyses did not take into account severity of underlying HT/CV risk, as it is possible that pts on ACEi had more severe underlying CV disease than others; and 2) analyses did not adjust for changes in HT/CV medications during the course of the study. However, the lack of any such signal in pts with a prior cardiovascular/HT history on therapies other than ACEi suggests a potential association with the medication itself. Conclusion: Sudden or cardiac deaths seen on IR in FLAIR were observed predominantly among male pts with a prior history of HT or cardiac disease. The prior use of ACEi was correlated with the risk of sudden or cardiac death in IR pts. In contrast, pts treated with IR who were not on ACEi (regardless of medical history) had a very low rate of cardiac or sudden death. Whilst these findings need confirming in other Ibr trials we believe that caution should be taken when concurrently administering ibrutinib and ACE inhibitors in pts with a medical history of HT or CV disease. Figure 1 Figure 1. Disclosures Munir: F. Hoffmann-La Roche: Consultancy; Alexion: Honoraria. Bloor: Novartis: Honoraria; Kite, a Gilead Company: Honoraria. Broom: AbbVie: Honoraria; AstraZeneca: Honoraria; Janssen-Cilag Ltd: Honoraria; Takeda UK Ltd: Honoraria; Celgene Ltd: Honoraria; Gilead: Honoraria. Furtado: Abbvie: Other: Conference support. Morley: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference support; AbbVie; Takeda: Other: Conference support; Janssen: Honoraria; Kite: Honoraria. Cwynarski: Atara: Consultancy; BMS/Celgene: Other; Celgene: Consultancy; Gilead: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Other; Kite, a Gilead Company: Consultancy, Speakers Bureau; Roche: Consultancy, Other, Speakers Bureau; Takeda: Consultancy, Other, Speakers Bureau. Gatto: Roche: Consultancy. Paneesha: AbbVie: Honoraria; Bristol Myers Squibb: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria. Fox: F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees. Howard: Roche: Current Employment. Cairns: Takeda: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Patten: NOVARTIS: Honoraria; ASTRA ZENECA: Honoraria; ABBVIE: Honoraria; JANSSEN: Honoraria; GILEAD SCIENCES: Honoraria, Research Funding; ROCHE: Research Funding. Hillmen: BeiGene: Honoraria; SOBI: Honoraria; AstraZeneca: Honoraria; Gilead: Research Funding; Roche: Research Funding; Pharmacyclics: Honoraria, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding.

Introduction: The most effective chemoimmunotherapy (CIT) in previously untreated CLL is the combination of fludarabine, cyclophosphamide and rituximab (FCR). Ibrutinib (I), the first irreversible inhibitor of Bruton's tyrosine kinase approved for CLL, has improved outcomes in numerous clinical trials compared to different CIT. Methods: FLAIR (ISRCTN01844152) is an ongoing, phase III, multicentre, randomised, controlled, open, parallel group trial for previously untreated CLL requiring therapy according to the IWCLL 2008 guidelines. Patients over 75 years or with >20% 17p-deleted cells were excluded. Participants were randomised on a 1:1 basis to receive 6 cycles of FCR (oral fludarabine 24mg/m 2/day for 5 days, oral cyclophosphamide 150mg/m 2/day for 5 days with IV rituximab [375 mg/m 2 on day 1/2 of cycle 1; 500 mg/m 2 on day 1 of cycles 2-6]) every 28-days or IR (Ibrutinib [420mg/day] plus rituximab [6 doses as for FCR]) given for up to 6 years with stratification by disease stage, age, gender and centre. The primary endpoint was to assess whether IR was superior to FCR in terms of investigator-assessed PFS. Secondary endpoints included overall survival,; attainment of undetectable MRD; response to therapy; safety and toxicity; health-related quality of life and cost-effectiveness. A formal interim analysis was planned when 191 events were observed in both arms or 109 events in the FCR arm alone with a p-value of 0.005 leading to reporting of the trial. Here we report the results of this planned interim analysis. Results: A total of 771 patients were randomised (385 to FCR and 386 to IR) from 113 UK Centres between 9/19/2014 and 7/19/2018. The data was locked on 5/24/2021. 73.3% were male, median age was 62 years (33.6% >65yo) and 45.1% were Binet Stage C. IGHV data was available for 728 (94.4%) patients with 53.2% IGHV unmutated (≥98% homology to germline), 40.5% IGHV mutated and 6.3% Subset 2. Hierarchical FISH testing revealed 0.4% 17p del, 15.4% 11q del, 12.3% trisomy 12, 29.7% normal and 35% 13q del; with 7.1% failed. The arms were well-balanced for disease variables with no significance differences. Median follow-up was 52.7 months. IR had a superior PFS compared to FCR (Median PFS not reached for IR versus 67 months for FCR; HR: 0.44; p Conclusion: Ibrutinib plus rituximab resulted in a superior PFS compared to FCR. There was no difference in overall survival, most likely due to effective second-line targeted therapy in patients progressing after FCR. Figure 1 Figure 1. Disclosures Hillmen: Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; SOBI: Honoraria; BeiGene: Honoraria; AstraZeneca: Honoraria. Bloor: Novartis: Honoraria; Kite, a Gilead Company: Honoraria. Broom: AbbVie: Honoraria; AstraZeneca: Honoraria; Janssen-Cilag Ltd: Honoraria; Takeda UK Ltd: Honoraria; Celgene Ltd: Honoraria; Gilead: Honoraria. Furtado: Abbvie: Other: Conference support. Morley: Kite: Honoraria; Janssen: Honoraria; AbbVie; Takeda: Other: Conference support; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference support. Cwynarski: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssenen: Other. Paneesha: Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria. Howard: Roche: Current Employment. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Patten: NOVARTIS: Honoraria; ROCHE: Research Funding; JANSSEN: Honoraria; ASTRA ZENECA: Honoraria; ABBVIE: Honoraria; GILEAD SCIENCES: Honoraria, Research Funding. Munir: F. Hoffmann-La Roche: Consultancy; Alexion: Honoraria.

Eculizumab, the monoclonal antibody targeting C5, is the only licensed treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH) in the UK. Inherent to the mechanism of action, C5 inhibitors increase patient susceptibility to encapsulated microorganisms, particularly Neisseria meningitidis. The PNH National service (UK), has 18 years of experience treating patients with PNH using complement inhibition. The risk of N. meningitidis is mitigated by vaccination, ciprofloxacin (500 mg bd) on days 1-13 since we moved to vaccination on day one of complement inhibitor therapy, followed by daily prophylaxis with penicillin (or erythromycin). Since a case of sepsis with penicillin-resistant meningococci was observed, patients also have a rescue course ciprofloxacin. Patient education, safety cards, prompt action in case of fever and a 24 hour on-call service for patients are equally important. Until 2010 patients were revaccinated with MenACWY every 3 years. Bexsero (MenB vaccine) vaccination (2 vaccines within first 6 months) with boosters every 5 years was added in 2015. In collaboration with the Public Health England Meningococcal Reference Unit in 2010 a program was developed to monitor antibody titers after vaccination and to revaccinate against MenACWY if titers declined to below protective levels. It is technically not possible to assay for meningoccal serogroup B antibody titers when on Eculizumab therapy. We present the outcome of this project. Methods: Antibody titers to serogroups ACWY were assayed following vaccination and then once per annum. Patients with unprotective antibody titers were revaccinated. We evaluate our practice and review the 9 meningococcal infections in 8 patients. We present disease characteristics, serogroup and outcome, vaccination history and antibody status. Results: Between May 2002 and July 2020, 324 patients commenced complement inhibitor treatment for PNH. 801 vaccinations with MenACWY were administered; median 2 vaccinations per patient (range 1 - 10). A total of 1,671 antibody titer assessments were conducted in 294 patients, median of 4 tests per patient (range 1 - 15). Every test assessed antibodies against all four serogroups. Titers were not assessed in 9% of patients (30), due to vaccination prior to change in practice or recent commencement on treatment. A protective antibody response to all serogroups after first vaccination was observed in 170 / 294 patients (57.8%) and a partial response (antibodies to 3 serotypes) in 51 /294 (17.3%). Revaccination of 51 partial responders resulted in an additional 21 patients with a full response. Revaccination of 73 non-responders (antibodies to 0-2 serotypes) resulted in 32 more partial or full responses. 287 of 324 patients received MenB vaccinations; median 2 vaccinations per patient (range 1 - 4). Eight of 324 (2%) patients with median age 22.5 years developed meningococcal sepsis (see table); patient 5 had 2 episodes. 3 of 5 cases with serogroup B infection were before serogroup B vaccination was introduced. The other 4 episodes in 3 patients were due to Y, C, W meningococci, in one the serogroup is unknown. All except patient 1 were compliant with antibiotic prophylaxis. Patient 7 died from meningococcemia, a delay in seeking medical attention may have contributed, however this was also a penicillin resistant strain. Discussion: We report the largest experience of managing meningococcal risk in patients on complement inhibitor therapy for PNH. Despite our proactive management we had 9 cases of meningococcal sepsis, with one fatal infection. Our most recently introduced practice of prompt treatment with ciprofloxacin if pyrexic on antibiotic prophylaxis will prevent cases like patient 7 with a penicillin resistant strain. Three patients had a meningococci sepsis with serogroups C, W and Y; whilst 1 patient had no check of titers due to recent commencement on treatment, the titres of the other 2 had suggested protective immunity. We demonstrated that a full antibody response can be obtained on a second vaccination in most patients if the first one failed. If no response is achieved upfront or revaccination then further MenACWY vaccination is not likely to be successful. Current practice significantly mitigates the risk of meningococcal disease, however it is essential patients remain vigilant for fever, seeking immediate medical attention stating their diagnosis of PNH on complement inhibitor therapy. Disclosures Arnold: Alexion Pharmaceuticals: Honoraria. Borrow:Pfizer: Research Funding; GlaxoSmithKline: Research Funding; Alexion pharmacueticals: Research Funding; Sanofi: Research Funding. Riley:Alexion: Honoraria. Munir:Alexion: Honoraria; F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Kelly:Alexion: Honoraria. Pike:Apellis: Research Funding. Hillmen:Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hemolytic and thrombotic condition. Patients can experience severe anemia due to intravascular hemolysis, thrombotic events, renal impairment and pulmonary hypertension. Symptomatic patients are treated with complement inhibitors either in clinical trials or with eculizumab the only licensed treatment in the UK. Due to the mechanism of action of eculizumab, it increases susceptibility to Neisseria infection, including Neisseria meningitidis. To reduce this risk of infection, worldwide practice is for patients to be vaccinated at least 2 weeks prior to receiving eculizumab (serogroups A, C, Y, W 135 and B). It was noted within the PNH National Service at Leeds (UK) that a small number of patients deteriorated with enhanced intravascular hemolysis and thrombosis during the period between vaccination and eculizumab, leading to a review of practice. We report five of 121 patients with events in the intervening 2 weeks between vaccination and commencement of eculizumab from 2002-2012:A 44 year female presented with hemolysis and hemoglobinuria, with a granulocyte PNH clone of 99.4%. She was transfusion dependent and on anticoagulation. She consented to the PNH pilot eculizumab study, undergoing meningococcal vaccination as per protocol. Twenty two days later, she suffered an ischemic stroke with left hemiplegia and permanent weakness, resulting in exclusion from the study. Two years later she received eculizumab in the TRIUMPH study.A 37 year male presented with hemoglobinuria and fatigue with a granulocyte PNH clone of 99.58%. He had significant hemolysis, managed initially with warfarin and blood transfusions. He consented to start eculizumab and received meningococcal vaccination. 4 days later he presented with a symptomatic right hepatic vein thrombosis, promptly commenced eculizumab.A 29 year male, with abdominal pain and hemoglobinuria for 3 years developed a stroke and portal vein thrombosis leading to a diagnosis of PNH, with a granulocyte PNH clone of 84.99%. He commenced anticoagulation. Four months after the stroke he received meningococcal vaccination in preparation for scheduled commencement with eculizumab. He experienced a left central retinal vein thrombosis 15 days after its administration prior to starting eculizumab.A 47 year old male, was diagnosed with haemolytic PNH but only had mild symptoms and anaemia. Twenty four years later, he developed increasing hemolysis and symptoms; granulocyte PNH clone of 96.45%. Eculizumab was planned and he received meningococcal vaccination, but presented ten days later with acute renal failure secondary to massive intravascular haemolysis, necessitating emergency eculizumab therapy.A 35 year female, with a granulocyte PNH clone of 99.87%. Although she had active intravascular hemolysis, eculizumab was declined, and anticoagulation commenced. Four years later she consented to start eculizumab, receiving meningococcal vaccination. She was admitted 24 hours later with a stroke and commenced eculizumab the same day, but has persistent neurological impairment to date. See Table 1 Discussion: The close time proximity of these serious events to the patients' vaccinations raised concern that the complement system was being activated by administration of the vaccine, precipitating complications of PNH. It is also concerning that 4 of the 5 patients experienced thrombotic events despite therapeutic anticoagulation, confirming that anticoagulation only partially mitigates the risk of thrombosis in patients with PNH. The decision was taken to administer the vaccination immediately after the first dose of eculizumab, with therapeutic doses of antibiotic (ciprofloxacin 500mg bd) for the first 14 days post vaccination, followed by long term meningococcal prophylaxis (penicillin V or erythromycin 500mg bd) whilst receiving a complement inhibitor. Since this change in practice in 2012 we have commenced eculizumab therapy in 211 patients with no similar complications as described. Thus the change in practice appears to reduce the occurrence of these severe complications associated with vaccinations prior to initiating anti-complement therapy. Whilst it is possible these events could have been caused by the underlying condition of PNH, we would advise colleagues to also adopt a change in practice to reduce potentially significant complications. Disclosures Arnold: Alexion Pharmaceuticals: Honoraria. Kelly:Alexion: Honoraria. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Pike:Apellis: Research Funding. Riley:Alexion: Honoraria. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees. Hillmen:Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding.

Introduction: Acalabrutinib is a highly selective, irreversible, next-generation, Bruton tyrosine kinase inhibitor (BTKi) approved for the treatment of patients with chronic lymphocytic leukemia (CLL). Acalabrutinib and ibrutinib are the only BTKis approved for the treatment of CLL, although acalabrutinib's minimal off-target effects may offer additional efficacy and safety benefits. ELEVATE-TN, a 3-arm, open-label, randomized, controlled trial (N=535 patients), found that acalabrutinib (as monotherapy or in combination with obinutuzumab) had superior efficacy and safety compared with chlorambucil plus obinutuzumab (C+O) for the frontline treatment of patients with CLL who were considered ineligible for fludarabine-based treatment because of age and comorbidity status. Countries such as the United Kingdom (UK) do not currently reimburse BTKi costs when used for the frontline treatment of CLL, except for patients with 17p deletions/TP53 mutations. Payers in these markets require evidence of cost-effectiveness, relative to the standard-of-care chemoimmunotherapy, for BTKi costs to be reimbursed in a broader frontline population. Therefore, the objective of this study is to evaluate the cost-effectiveness-from a UK National Health Service perspective-of acalabrutinib monotherapy compared to C+O in the frontline treatment of patients with CLL who are considered ineligible for fludarabine-based treatment. Methods: A semi-Markov model was developed, comprised of 3 health-state selections: progression-free survival (PFS), progressed disease, and death. ELEVATE-TN patient-level data were used to fit parametric survival functions to time-to-progression, preprogression-death, and postprogression-survival curves over a lifetime horizon of 30 years. Age- and gender-matched general population mortality rates were applied to ensure that the mortality rate in the modeled population never fell below that of the general population. Health-state utility data using EQ-5D scores were derived from published literature. Cost inputs included drug costs (list prices only), administration costs, subsequent-treatment costs, and adverse-event costs, and were sourced from relevant literature, including the British National Formulary, national reference costs, and UK CLL health technology assessment submissions. Subsequent treatment with ibrutinib was assumed in patients who experienced disease progression after C+O treatment, while patients who received acalabrutinib and had disease progression received rituximab in combination with venetoclax or bendamustine. Clinical validation was sought on model assumptions. A 3.5% discount rate was applied to both costs and outcomes, and an incremental cost-effectiveness ratio (ICER) of ≤ £30 000 per quality-adjusted life-year (QALY) was considered cost-effective. Results: Over a 30-year lifetime horizon, treatment with acalabrutinib monotherapy resulted in a gain of 1.14 QALYs versus C+O, while incurring incremental costs of £34 974, resulting in an ICER of £30 701 per QALY (Table). While acalabrutinib treatment resulted in higher treatment costs than C+O because of the longer duration of treatment from improved PFS, these costs were partially offset by lower subsequent treatment costs and fewer adverse events compared with C+O. The key model drivers included the proportion of patients who received subsequent treatment with ibrutinib or venetoclax and the BTKi list price. Conclusions: Our analysis found that in a UK setting, acalabrutinib monotherapy was marginally cost-effective when compared with chemoimmunotherapy. This assessment of acalabrutinib provides useful information to payers for decision making among the frontline treatment options for the patient with CLL who is not eligible for fludarabine-based treatment. Disclosures Munir: F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Gaitonde:AstraZeneca: Current Employment, Other: stocks and share. Waweru:AstraZeneca: Current Employment, Other: stocks and share.

Background Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired disorder characterised by intravascular hemolysis and thrombosis. Patients with symptomatic PNH are commenced on the complement inhibitor eculizumab (600mg weekly for 5 weeks then 900mg 2 weekly). This monoclonal antibody targets C5 in the complement cascade, halting terminal complement activation thus inhibiting intravascular hemolysis. In some patients intravascular hemolysis is not adequately controlled on the standard regimen. Patient symptoms, transfusion requirements and raised Lactate dehydrogenase (LDH) levels are indicators for suboptimal control of PNH and review of eculizumab dosing. The 50% hemolytic complement (CH50) test is a functional assay assessing capability of serum complement components of the classical pathway to lyse sheep red blood cells pre-coated with rabbit anti-sheep red blood cell antibody. Patients with complement inhibited PNH should demonstrate absent lysis. As the test is expensive and difficult to organise, we tested if incomplete complete blockade as determined by CH50 activity would be better to confirm under-dosing than LDH value. Methods The Leeds (UK) PNH National Service reviewed patients who underwent CH50 assay between January 2015 and March 2020. All patients were on eculizumab with clinical concerns regarding suboptimal control of PNH. Patients receive eculizumab infusions intravenously every 14 days and routine follow up from the PNH Service. Serum samples were obtained 24 hours prior to infusions for CH50 assay; LDH values were routinely collected. Complete complement blockade was defined by 1.5x upper limit of normal (ULN). Confidence intervals were set at 95% and significance set at p Results In the study period, 327 tests (median 2, range 1 - 8) were carried out in 146 patients (median age 54 years, range 16 - 89; 74 female). 81% (265) were successful; 19% (62) were unsuccessful due to processing errors. Of the successful tests, 74% (197 in 127 patients) indicated complete complement blockade and 26% (68 in 38 patients) indicated incomplete blockade. Of the patients with incomplete blockade, 68% (26) demonstrated complete blockade on repeat testing and 32% (12) had their eculizumab dose increased. Clinical symptoms of under-dosing in the 12 patients requiring a dose increase included increased transfusion requirements and/or breakthrough hemolysis (7), pregnancy (2; both returned to 900mg post pregnancy) and significant lethargy (3). Of the patients requiring a dose increase, 3 were on 1200mg before 2015; their dose was increased to 1500mg. Repeat testing was carried out in 10/12 patients after dose increase; 8 indicated complete blockade; 2 patients were incompletely blocked at 1200mg and received a further dose increase to 1500mg. Further testing indicated complete blockade in 1 patient; 1 required a 3rd dose increase to 1800mg due to incomplete blockade and ongoing transfusion requirement. Corresponding LDH values were analysed; median LDH for the complete blockade group was 1.16xULN (range 0.54 - 2.16) and 1.28xULN (range 0.76 - 2.38) for the incomplete blockade group. LDH values were not significantly higher in the incomplete blockade group compared to the complete blockade group, p=0.08. There was no significant difference in LDH values pre- and post-dose increase, p=0.38 (Figure 1); median pre-dose increase LDH 1.14xULN; median post-dose increase LDH 1.13xULN. Correlation coefficient shows that CH50 activity was positively correlated with LDH value, r(123)=0.18, p=0.04. Conclusion We report the effective utilisation of CH50 analysis where there is clinical concern of suboptimal control of PNH. All patients demonstrating hemolytic activity on CH50 assays indicated subsequent complement blockade following increase of eculizumab dose. Increasing eculizumab is costly requiring robust evidence of suboptimal complement inhibition; a positive correlation between CH50 activity and LDH values was shown however this is not sufficient to guide clinical decisions. LDH values of the incomplete blockade group were not significantly higher than those with complete blockade, suggesting the use of LDH values as an assessment of complement inhibition in patients with ongoing symptoms or transfusion requirements is not sufficient to guide eculizumab dose increases. Disclosures Munir: Alexion: Honoraria; F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Pike:Apellis: Research Funding. Arnold:Alexion Pharmaceuticals: Honoraria. Hillmen:AstraZeneca: Consultancy, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees.

Background Crovalimab is a novel anti-human complement component 5 (C5) antibody currently under investigation as a therapy for paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disorder characterized by hemolytic anemia and thrombosis. In the Phase I/II COMPOSER trial (NCT03157635; Röth et al. Blood. 2020), crovalimab showed promise as a therapy for PNH in patients with or without prior treatment with C5 inhibitors. Eculizumab and ravulizumab are C5 inhibitors currently approved for the treatment of patients with PNH, yet treatment limitations remain. Some patients experience breakthrough hemolysis due to unsustained C5 inhibition, there may be a lack of efficacy in patients with C5 mutational variants, and the requirement for regular intravenous (IV) infusions contributes to the treatment burden. Crovalimab is engineered to have a significantly extended half-life, enabling subcutaneous (SC) administration once every 4 weeks (Q4W), which could significantly reduce the treatment burden on patients with PNH. Study Design and Methods The Phase III, randomized, open-label, active-controlled, multicenter COMMODORE 1 study (NCT04432584) is evaluating the efficacy and safety of crovalimab compared with eculizumab in adult and adolescent patients with PNH currently treated with complement inhibitors. The study design is divided into 2 parts: randomized arms (Arms A and B) for primary and secondary efficacy analyses and a descriptive arm (Arm C) for exploratory analysis in patients of clinical relevance and importance (Figure). Adult patients with PNH (aged ≥ 18 years) are randomized 1:1 to receive either crovalimab (Arm A) or eculizumab (Arm B). The crovalimab regimen includes a loading series of an IV dose on Day 1 followed by weekly SC doses for 4 weeks starting on Day 2. This is followed by SC Q4W maintenance dosing starting at Week 5. Arm B patients receive IV maintenance dosing starting on Day 1 and then once every 2 weeks (Q2W) for 24 weeks. The descriptive analysis arm (Arm C) patients will receive crovalimab (same dosing regimen as Arm A patients). It will include: 1. Adolescent patients (aged 12-17 years) currently treated with eculizumab 2. Patients (aged ≥ 12 years) currently treated with ravulizumab 3. Patients (aged ≥ 12 years) currently treated with eculizumab at a dose > 900 mg and/or more frequent than Q2W 4. Patients (aged ≥ 12 years) with a known C5 polymorphism whose hemolysis was poorly controlled After 24 weeks of treatment, patients from each treatment arm can continue crovalimab or switch from eculizumab to crovalimab if their physician determines this is in their best interest. The primary efficacy objective for the randomized arms is to determine the noninferiority of crovalimab compared with eculizumab based on mean percent change in lactate dehydrogenase (LDH) levels from baseline to after 24 weeks of treatment. Secondary efficacy objectives are to determine the noninferiority of crovalimab compared with eculizumab based on (1) proportion of patients who achieve transfusion avoidance, (2) proportion of patients who experience breakthrough hemolysis, (3) proportion of patients who achieve stabilization of hemoglobin, and (4) mean change in fatigue as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. The safety objective is to evaluate the safety and tolerability of crovalimab compared with eculizumab based on the incidence and severity of adverse events, including infections (meningococcal meningitis and other infections), injection-site reactions, infusion-related reactions, hypersensitivity, adverse events leading to study drug discontinuation, and type 3 hypersensitivity reactions in patients who switch to crovalimab from eculizumab or ravulizumab. Pharmacokinetic, immunogenicity, biomarker, and health status utility objectives will also be assessed. Disclosures Risitano: Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees. Röth:Biocryst: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Apellis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pu:F. Hoffmann-La Roche Ltd: Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Pennsylvania State University: Patents & Royalties; SUNY Upstate Medical University: Current Employment. Nishimura:Chugai: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Wright:Genentech, Inc: Current Employment; F. Hoffmann-La Roche Ltd: Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Appius:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sreckovic:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Vignal:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria.

Background Genomic abnormalities such as del(17p)/TP53 mutation, del(11q), and unmutated IGHV are risk factors that predict inferior outcomes with chemoimmunotherapy (CIT) in patients (pts) with CLL/SLL (Byrd J Clin Oncol 2006). Mutations in BIRC3, NOTCH1, SF3B1, and XPO1 have also been associated with poor outcomes with CIT in pts with CLL (Foa Haematologica 2013; Jain Am J Hematol 2016). Ibrutinib (ibr) is the only once-daily Bruton's tyrosine kinase inhibitor with significant progression-free survival (PFS) and overall survival (OS) benefit shown in multiple randomized phase 3 studies versus established therapies in pts with previously untreated or relapsed/refractory CLL/SLL. Superior outcomes were demonstrated with ibr-based therapy versus comparators in the overall population, and in pts with high-risk disease features, such as TP53 aberrations, del(11q), and/or unmutated IGHV in the RESONATE-2 study of first-line single-agent ibr (Burger Leukemia 2020) and in the iLLUMINATE study of first-line ibr-obinutuzumab (Moreno Lancet Oncol 2019). In pts with relapsed/refractory CLL/SLL who were treated with ibr, mutations in BIRC3, NOTCH1, SF3B1, or XPO1 had no significant impact on the PFS benefit conferred by ibr (Byrd Blood 2019). To better understand outcomes in pts with previously untreated CLL with various high-risk genomic features, including integrated FISH cytogenetics and single gene mutations, we performed a pooled analysis of two phase 3 studies of ibr-based therapy in the first-line treatment of CLL/SLL (RESONATE-2 and iLLUMINATE). Methods In RESONATE-2 (NCT01722487), pts aged ≥65 years without del(17p) were randomized to single-agent ibr or chlorambucil (clb). In iLLUMINATE (NCT02264574), pts aged ≥65 years, or Results The pooled analysis included 498 pts treated with first-line ibr-based or clb-based therapy (n=249 each) with median follow-up of 49.1 mos (range, 0.1-78.7). Ibr-based therapy significantly improved ORR and PFS vs comparator (clb-based) therapy. At 42 mo, PFS rates were significantly higher across high-risk genomic subgroups in ibr-treated pts (63-82%) compared with clb-treated pts (6-34%), and consistent PFS benefit with ibr was observed across all high-risk genomic subgroups (Figure). When comparing ibr-treated pts with specified high-risk genomic features vs those without, PFS and ORR were comparable in the different subgroups, including pts with unmutated vs mutated IGHV (PFS HR, 1.79, 95% CI 0.99-3.24) or mutated vs not mutated NOTCH1 (PFS HR, 1.05, 95% CI 0.65-1.69) (Table). Improved outcome was also noted for pts with del(17p)/TP53 mutated/BIRC3 mutated, the highest risk category per Rossi 2013 (HR 1.05, 95% CI 0.54-2.04). At a median duration of ibr treatment of 35.7-43.8 mo across these high-risk subgroups, there were no meaningful differences in the rates of treatment-emergent adverse events (AEs) of any grade or grade ≥3 AEs compared to those of the overall population. Conclusions This integrated analysis of pts undergoing first-line ibr-based treatment, with up to 79 mo follow up, demonstrated similar PFS and ORR for ibr-treated pts with or without high-risk genomic features, and confirmed significant PFS and ORR benefits with ibr-based therapy versus clb (± obinutuzumab). This analysis across two phase 3 studies demonstrated the efficacy of first-line ibr-based treatment irrespective of cytogenetic and mutational risk features, including those with unmutated IGHV, NOTCH1 mutation, and those with the highest risk classification of del(17p)/TP53 mutation/BIRC3 mutation. Disclosures Burger: Gilead, Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company: Other: Travel/accomodations/expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; BeiGene, Gilead, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company: Research Funding. Robak:BioGene: Honoraria, Research Funding; UCB: Honoraria, Research Funding; UTX-TGR: Research Funding; Bristol Meyers Squibb: Research Funding; Momenta: Consultancy; Medical University of Lodz: Current Employment; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; Sandoz: Consultancy, Honoraria; Octapharma: Honoraria; Pfizer: Research Funding; GSK: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta: Research Funding; Morphosys: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Demirkan:AbbVie, Amgen, AstraZeneca, and Roche: Consultancy; AbbVie, AstraZeneca, Janssen, and Pharmacyclics LLC, an AbbVie Company: Research Funding; AbbVie, Amgen, and Janssen: Speakers Bureau; AbbVie, Amgen, Janssen, and Pfizer: Other: Travel/accommodations/expenses. Bairey:AbbVie: Consultancy; Janssen: Consultancy, Research Funding. Moreno:Janssen: Speakers Bureau; AbbVie and Janssen: Research Funding; Janssen, AbbVie, Sunesis, and AstraZeneca: Consultancy. Simpson:BeiGene: Current Employment, Current equity holder in publicly-traded company; AbbVie and Janssen: Honoraria, Other: Travel/accommodations/expenses; AbbVie, Acerta, Amgen, BeiGene, Celgene, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Roche, Sanofi, and Pharmacyclics LLC, an AbbVie Company: Research Funding. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Dai:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie, Bristol-Myers Squibb, Exelixis, Gilead, GlaxoSmithKline, and Revance: Current equity holder in publicly-traded company. Cheung:Pharmacyclics LLC, an AbbVie Company: Current Employment, Patents & Royalties: and other intellectual property; AbbVie and Eli Lilly: Current equity holder in publicly-traded company. Kwei:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie and Gilead: Current equity holder in publicly-traded company. Lal:Pharmacyclics LLC, an AbbVie Company: Current Employment; The Permanente Medical Group (spouse): Current Employment; AbbVie, Clovis, Gilead Sciences, Infinity, Reviva Pharmaceuticals, and The Permanente Medical Group: Current equity holder in publicly-traded company. Hsu:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Kipps:AbbVie, Genentech-Roche, Oncternal, and Pharmacyclics LLC, an AbbVie Company: Research Funding; AbbVie, Celgene, Genentech-Roche, Gilead, and Pharmacyclics LLC, an AbbVie Company: Consultancy. Tedeschi: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; Department of Hematology Niguarda Hospital Milano: Current Employment; Sunesis: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Spontaneous regression is a recognized phenomenon in chronic lymphocytic leukemia (CLL) but its biological basis remains unknown. We undertook a detailed investigation of the biological and clinical features of 20 spontaneous CLL regression cases incorporating phenotypic, functional, transcriptomic, and genomic studies at sequential time points. All spontaneously regressed tumors were IGHV-mutated with no restricted IGHV usage or B-cell receptor (BCR) stereotypy. They exhibited shortened telomeres similar to nonregressing CLL, indicating prior proliferation. They also displayed low Ki-67, CD49d, cell-surface immunoglobulin M (IgM) expression and IgM-signaling response but high CXCR4 expression, indicating low proliferative activity associated with poor migration to proliferation centers, with these features becoming increasingly marked during regression. Spontaneously regressed CLL displayed a transcriptome profile characterized by downregulation of metabolic processes as well as MYC and its downstream targets compared with nonregressing CLL. Moreover, spontaneous regression was associated with reversal of T-cell exhaustion features including reduced programmed cell death 1 expression and increased T-cell proliferation. Interestingly, archetypal CLL genomic aberrations including HIST1H1B and TP53 mutations and del(13q14) were found in some spontaneously regressing tumors, but genetic composition remained stable during regression. Conversely, a single case of CLL relapse following spontaneous regression was associated with increased BCR signaling, CLL proliferation, and clonal evolution. These observations indicate that spontaneously regressing CLL appear to undergo a period of proliferation before entering a more quiescent state, and that a complex interaction between genomic alterations and the microenvironment determines disease course. Together, the findings provide novel insight into the biological processes underpinning spontaneous CLL regression, with implications for CLL treatment.

Background: Acalabrutinib is a highly selective, covalent irreversible Bruton tyrosine kinase inhibitor with minimal activity against other kinases. Acalabrutinib has demonstrated durable responses as a single agent or combined with O in treatment-naïve (TN) CLL. Here, interim results are presented for the multicenter, open-label Phase 3 ELEVATE-TN study (NCT02475681), which evaluated the efficacy and safety of acalabrutinib + O vs acalabrutinib alone vs O + Clb in pts with TN CLL. Methods: Eligible pts had TN CLL requiring treatment per iwCLL criteria and were aged ≥65 y or 6, creatinine clearance Results: From 9/14/2015-2/8/2017, 535 pts were randomized to the acalabrutinib + O (n=179), acalabrutinib (n= 179), or O + Clb (n=177) arms. The median age was 70 y (range, 41-91); 69% had high- and 12% had very high-risk CLL IPI scores. At a median follow-up of 28 mo, acalabrutinib + O significantly prolonged PFS vs O + Clb (median not reached [NR] vs 22.6 mo; HR 0.10, 95% CI 0.06-0.18, P IRC-assessed ORR was higher with acalabrutinib + O (94%; 95% CI, 89.3%-96.5%) vs O + Clb (79%; 95% CI, 71.9%-83.9%; P The median treatment duration was 27.7 mo for acalabrutinib + O (range, 2.3-40.3) and acalabrutinib (range, 0.3-40.2) and 5.6 mo (range, 0.9-7.4) for O + Clb. Common adverse events (AEs) are shown in the Table. AEs were similar between the acalabrutinib-containing arms. Infusion reactions were less frequent with acalabrutinib + O (13%) than with O + Clb (40%). AEs led to treatment discontinuation in 20 pts (11%) on acalabrutinib + O, 16 pts (9%) on acalabrutinib, and 25 pts (14%) on O + Clb. With >2 y of follow-up, 79.3% of pts in both the acalabrutinib-containing arms remain on single-agent acalabrutinib. AEs of interest (acalabrutinib + O or acalabrutinib vs O + Clb) were atrial fibrillation (any grade: 3% or 4% vs 1%), bleeding (any grade/Grade ≥3: 43%/2% or 39%/2% vs 12%/0%), and hypertension (Grade ≥3: 3% or 2% vs 3%). Conclusions: Acalabrutinib + O and acalabrutinib monotherapy significantly improved PFS vs O + Clb, with tolerable safety in pts with TN CLL. Despite cross over for disease progression in the O + Clb arm, a trend toward improved OS was observed in both acalabrutinib arms, though longer follow-up is needed. Disclosures Sharman: AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding. Banerji:CIHR: Research Funding; LLSC: Research Funding; Research Manitoba: Research Funding; CCMF: Research Funding; CancerCare Manitoba/University of Manitoba: Employment; CAPhO: Honoraria; BIOGEN: Other: Licensing fee; Dana-Farber Cancer Institute: Other: Licencing fee; Gilead: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Licensing fee, Research Funding; Abbvie: Consultancy, Honoraria. Herishanu:Janssen: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Munir:Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; AbbVie: Honoraria. Walewska:Gilead: 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, Other: Travel grant, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Speakers Bureau; Takeda: Other: Travel grant; Novartis: Other: travel grant. Follows:Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Karlsson:Skane University Hospital: Employment. Ghia:AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Juno/Celgene: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Corbett:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Tauranga Hospital: Employment; Pathlab Waikato: Equity Ownership. Walker:Peninsula Health (public hospital): Employment; Alfred health (public hospital): Employment; Roche: Other: Travel grant. Jurczak:Incyte: Research Funding; Takeda: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Roche: Research Funding; Gilead: Research Funding; Celgene: Research Funding; MorphoSys: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Research Funding. Salles:Epizyme: Consultancy, Honoraria; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events. Janssens:Novartis: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; idem consultancy: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Cymbalista:AstraZeneca: Honoraria; Janssen: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Gilead: Honoraria; Abbvie: Honoraria. Wierda:Juno Therapeutics: Research Funding; Janssen: Research Funding; Cyclcel: Research Funding; KITE pharma: Research Funding; Loxo Oncology Inc.: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; Miragen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Gilead Sciences: Research Funding; GSK/Novartis: Research Funding. Coutre:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; BeiGene: Other: Travel, Accommodations, Expenses & Data Safety Monitoring Committee; Genentech: Consultancy. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Skarbnik:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau. Kamdar:AstraZeneca: Consultancy; University of Colorado: Employment; Celgene: Consultancy; Seattle Genetics: Speakers Bureau; Pharmacyclics: Consultancy. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Izumi:AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib patents. Munugalavadla:Acerta Pharma: Employment; Gilead Sciences: Equity Ownership; AstraZeneca: Equity Ownership. Patel:Acerta Pharma: Employment, Equity Ownership; AstraZeneca: Equity Ownership. Wang:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Wong:Acerta Pharma: Employment. Byrd:Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Acerta: Research Funding; Acerta: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; BeiGene: Research Funding; BeiGene: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau.

Background Crovalimab is a novel anti-human complement component 5 (C5) antibody currently under investigation as a therapy for paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disorder characterized by hemolytic anemia and thrombosis. In the Phase I/II COMPOSER trial (NCT03157635; Roth et al. Blood. 2020), crovalimab showed promise as a therapy for PNH in patients with or without prior treatment with C5 inhibitors. Eculizumab and ravulizumab are C5 inhibitors currently approved for the treatment of patients with PNH, yet treatment limitations remain. Some patients experience breakthrough hemolysis due to unsustained C5 inhibition, there may be a lack of efficacy in patients with C5 mutational variants, and the requirement for regular intravenous (IV) infusions contributes to the treatment burden. Crovalimab is engineered to have a significantly extended half-life, enabling subcutaneous (SC) administration once every 4 weeks (Q4W), which could significantly reduce the treatment burden on patients with PNH. Study Design and Methods The Phase III, randomized, open-label, active-controlled, multicenter COMMODORE 1 study (NCT04432584) is evaluating the efficacy and safety of crovalimab compared with eculizumab in adult and adolescent patients with PNH currently treated with complement inhibitors. The study design is divided into 2 parts: randomized arms (Arms A and B) for primary and secondary efficacy analyses and a descriptive arm (Arm C) for exploratory analysis in patients of clinical relevance and importance (Figure). Adult patients with PNH (aged ≥ 18 years) are randomized 1:1 to receive either crovalimab (Arm A) or eculizumab (Arm B). The crovalimab regimen includes a loading series of an IV dose on Day 1 followed by weekly SC doses for 4 weeks starting on Day 2. This is followed by SC Q4W maintenance dosing starting at Week 5. Arm B patients receive IV maintenance dosing starting on Day 1 and then once every 2 weeks (Q2W) for 24 weeks. The descriptive analysis arm (Arm C) patients will receive crovalimab (same dosing regimen as Arm A patients). It will include: 1. Adolescent patients (aged 12-17 years) currently treated with eculizumab 2. Patients (aged ≥ 12 years) currently treated with ravulizumab 3. Patients (aged ≥ 12 years) currently treated with eculizumab at a dose > 900 mg and/or more frequent than Q2W 4. Patients (aged ≥ 12 years) with a known C5 polymorphism whose hemolysis was poorly controlled After 24 weeks of treatment, patients from each treatment arm can continue crovalimab or switch from eculizumab to crovalimab if their physician determines this is in their best interest. The primary efficacy objective for the randomized arms is to determine the noninferiority of crovalimab compared with eculizumab based on mean percent change in lactate dehydrogenase (LDH) levels from baseline to after 24 weeks of treatment. Secondary efficacy objectives are to determine the noninferiority of crovalimab compared with eculizumab based on (1) proportion of patients who achieve transfusion avoidance, (2) proportion of patients who experience breakthrough hemolysis, (3) proportion of patients who achieve stabilization of hemoglobin, and (4) mean change in fatigue as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. The safety objective is to evaluate the safety and tolerability of crovalimab compared with eculizumab based on the incidence and severity of adverse events, including infections (meningococcal meningitis and other infections), injection-site reactions, infusion-related reactions, hypersensitivity, adverse events leading to study drug discontinuation, and type 3 hypersensitivity reactions in patients who switch to crovalimab from eculizumab or ravulizumab. Pharmacokinetic, immunogenicity, biomarker, and health status utility objectives will also be assessed. Download : Download high-res image (223KB) Download : Download full-size image Disclosures Risitano: Amyndas: Consultancy; Samsung: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity’s Board of Directors or advisory committees; Jazz: Speakers Bureau; RA pharma: Research Funding; Biocryst: Membership on an entity’s Board of Directors or advisory committees; Apellis: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; Achillion: Membership on an entity’s Board of Directors or advisory committees. Roth: Biocryst: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Apellis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding. Kulasekararaj: Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Pu: F. Hoffmann-La Roche Ltd: Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Pennsylvania State University: Patents & Royalties; SUNY Upstate Medical University: Current Employment. Nishimura: Chugai: Membership on an entity’s Board of Directors or advisory committees; Alexion: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity’s Board of Directors or advisory committees, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Wright: Genentech, Inc: Current Employment; F. Hoffmann-La Roche Ltd: Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Appius: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sreckovic: F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Vignal: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Munir: F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria.

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

Introduction: Hematopoiesis is severely reduced in severe aplastic anemia (SAA) probably due to immunological destruction of hematopoietic stem and progenitor cells. Bone marrow transplantation is preferred as first-line therapy in patients younger than 40 years with a matched related sibling donor. For those who are not candidate for transplant, immunosuppressive therapy with horse antithymocyte globulin (hATG) plus cyclosporine (CsA) remains the standard of care. However, hATG was discontinued in most Asian, South American, and European countries with only rabbit ATG (rATG) available. rATG is a more potent immunosuppressant which has associated with a worst hematological response and survival at 6 months in prospective studies. Using rATG in first-line therapy appears to add little to what has been observed with CSA alone. Alemtuzumab (ALZ), a humanized anti-CD52 monoclonal antibody is also active in AA due to its lymphocytotoxic properties. The use of ALZ in monotherapy has shown an overall response rate (ORR) comparable to that of r-ATG (37% and 33%, respectively) when applied as salvage (following hATG failure) in a randomized study. Other experiences which combined ALZ and CsA led to a 58% ORR in SAA patients after a cumulative dose of 103 mg of subcutaneous (SC) ALZ. Here we describe a multicenter retrospective analysis of SC ALZ in association with CsA for patients with AA. Methods: We retrospectively analyzed all patients who received outpatient SC ALZ for the treatment of aplastic anemia in 2 centers: Universidade Federal de Sao Paulo (Sao Paulo-BRAZIL) and Leeds Teaching Hospitals, UK from March 2009 until March 2019. In Sao Paulo, alemtuzumab total dose was 103 mg in an escalating dose of 3-10-30-30-30 mg, except for three elderly patients who received a total dose of 73. In Leeds-UK, total dose varied from 120 mg to 150 mg. The primary outcome was overall response rate (ORR) at six months. Median follow up was 31 months (range 4-110 months). Results: We identified 35 treatments with SC ALZ in 32 AA patients of which 78% had SAA or very severe aplastic anemia. Calcineurin inhibitors were used in association with ALZ in 80% of cases (cyclosporine in 26 cases, tacrolimus in 2 cases). Median age was 44 years (range: 18-79), and nineteen patients (59%) were male. Seventeen patients (53%) were treatment-naïve, and six patients (19%) had one prior line of therapy. Nine patients (28%) were relapsed/refractory, and received ALZ after at least two lines of prior therapy. Seventeen patients (53%) presented a PNH clone at diagnosis. Median time between diagnosis and ALZ treatment was 6 months (range 1-293). No treatment-related serious adverse events were observed. Infectious complications were infrequent: there was only one case of successfully treated CMV reactivation and one case of fatal EBV-related infection. ORR at 6 months was 57% (complete response: 11%, partial response: 46%), with corresponding cumulative incidence of response of 47% at 6 months and 62% at 1 year (figure 1). ORR was 69% in treatment-naïve patients younger than 60 years. Overall survival was 72% at 2 years. Adverse events were of low grade and infectious events were infrequent. Conclusion: Subcutaneous alemtuzumab appears to be a feasible, effective and safe alternative to hATG in patients with AA requiring immunosuppressive treatment, especially in centers with limited access to hATG. Disclosures Hill: Apellis: Honoraria; Roche: Honoraria; Akari: Honoraria; Alexion: Honoraria; Bioverativ: Honoraria; Novartis: Honoraria; Regeneron: Honoraria; Ra Pharma: Honoraria. Munir:AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees. Hillmen:Roche: Research Funding; Acerta: 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 Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Apellis: Research Funding; Gilead: Research Funding. Risitano:Achillion: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Biocryst: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Ra Pharma: Research Funding; Alnylam: Research Funding; Achillion: Research Funding; Alexion: Honoraria, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Ra Pharma: Research Funding; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Research Funding, Speakers Bureau. Scheinberg:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer,: Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau.

Introduction: Patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) who failed treatment with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib have a poor outcome and are difficult to treat. This ongoing, two-cohort, Phase II trial evaluates the safety and preliminary efficacy of tafasitamab (MOR208), an Fc-enhanced anti-CD19 monoclonal antibody in combination with idelalisib (IDE) (Cohort A) or venetoclax (VEN) (Cohort B) in R/R CLL pts previously treated with a BTKi. Preliminary results were published at EHA 2018 for Cohort A and at ASH 2018 for Cohort B. Here, we report the results of the primary analysis for both cohorts. Methods and Patients: Pts who either progressed or were intolerant to BTKi were enrolled at 12 sites in six countries in Europe and the US from Nov 2016 to Apr 2018. The primary endpoint is the incidence and severity of adverse events (AEs); secondary endpoints include overall response rate (ORR) as per investigator assessment according to International Workshop on CLL (IWCLL) 2008 guidelines. Complete response (CR) was confirmed by computed tomography assessment and by bone marrow (BM) biopsy. The exploratory endpoint minimal residual disease (MRD) was assessed centrally by quantitative allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in peripheral blood (PB) and BM. Each treatment cycle (C) lasts 28 days (D). Dose and administration: tafasitamab intravenous infusion, 12 mg/kg weekly in C1-C3, every other week in C4-C6 and monthly from C7D1; IDE orally, 150 mg twice daily; VEN orally, weekly ramp up starting on C1D8 at 20 mg to full daily dose of 400 mg. Patients: mean time since first CLL diagnosis was 135 months (mos) for pts in Cohort A and 105 mos in Cohort B. Median number of prior therapy lines was five (2-9) and three (1-5), respectively. All pts had received ibrutinib; one pt had subsequent acalabrutinib treatment as last prior therapy line. Mutations of BTK and PLCγ2 were assessed in nine pts in Cohort A and 13 pts in Cohort B. BTK/PLCγ2 mutations were centrally detected in 4/3 pts in Cohort A and in 2/3 pts in Cohort B, respectively. Complex karyotype was observed in six (54.5%) pts in Cohort A and 12 (92.3%) pts in Cohort B. Results with a data cut-off date of 9 Nov 2018 are presented. Results: Cohort A: Median time on study was 9.9 mos (95% confidence interval [CI]: 5.7-not reached). Eleven pts were enrolled and received tafasitamab and IDE. Two pts discontinued treatment due to AEs (aspartate-aminotransferase increased; acute pancreatitis), two due to progressive disease (PD) and one pt by physician's decision. One pt died due to PD and one pt due to cardiac failure. At the cut-off date, treatment was ongoing in four pts. Table 1 summarizes treatment-emergent adverse events (TEAEs) with neutropenia Grade ≥3 being most common (5 [46%]). Fourteen treatment-emergent serious AEs (SAEs) were reported in eight (72.7%) pts. ORR was 90.9% (CR=9.1%, partial response [PR]=81.8%), disease control was achieved in all 11 pts. One of eight pts (12.5%) assessed for MRD status reached MRD-negativity in PB at C14. Cohort B: Median time on study was 12 mos (95% CI: 2.8-not reached). Eleven of 13 enrolled pts received tafasitamab and VEN while two pts received tafasitamab only. Three pts discontinued treatment due to AEs (infusion-related reactions [two pts], diarrhea [one pt], one due to PD and one withdrew consent. At the cut-off date, treatment was ongoing in eight patients. Table 2 summarizes TEAEs, neutropenia Grade ≥3 was most commonly observed (six [46%] pts). Fourteen SAEs were reported in nine (69.2%) pts. The ORR in all 13 pts was 76.9% (CR=23.1%, PR=53.8%, not evaluable=23.1%). Six of seven pts assessed for MRD in PB (46.2% of 13 [100%] pts) reached negative status in PB by C7 at the latest. One of three pts assessed for MRD in BM (7.7% of 13 [100%] pts) reached MRD negative status in BM at C15. Conclusions: This trial demonstrates that in heavily pretreated pts with R/R CLL who failed prior BTKi, tafasitamab in combination with IDE or VEN is a potential therapeutic option. The safety profiles of the combinations are influenced by the combination partner, but both combinations are manageable. The response rates and MRD-negativity rates indicate that combinations of targeted agents with anti-CD19 tafasitamab have valuable antitumor activity and warrant further investigation of tafasitamab-based combinations in CLL. Disclosures Staber: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jurczak:Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Celgene Corporation: Research Funding; Incyte: Research Funding; Servier: Research Funding; Roche: Research Funding; Novo Nordisk: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Gilead: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Brugger:AstraZeneca: Equity Ownership; MorphoSys: Employment. Chanan-Khan:Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; Xencor: Research Funding; AbbVie: Research Funding. Greil:Mundipharma: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Sandoz: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Janssen-Cilag: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Dirnberger-Hertweck:MorphoSys: Employment. Kelemen:MorphoSys: Employment. Middeke:Janssen: Consultancy, Speakers Bureau; MSD: Consultancy; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Roche: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau. Montillo:Roche: Consultancy, Honoraria, Research Funding; Acerta: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Versatem: Membership on an entity's Board of Directors or advisory committees. Munir:Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: TBC; AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy. Parikh:Pharmacyclics: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; MorphoSys: Research Funding; Acerta Pharma: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Research Funding. Stilgenbauer:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Weirather:MorphoSys: Employment. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Wendtner:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffman-La Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background : Ibrutinib is the only once-daily Bruton's tyrosine kinase inhibitor with significant progression-free survival (PFS) benefit demonstrated in 5 randomized phase 3 studies in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) compared with standard-of-care chemotherapy and/or immunotherapy (RESONATE, RESONATE-2, iLLUMINATE, Alliance 041202, and ECOG 1912), and significant overall survival (OS) benefit in 3 of these studies. To understand how treatment with single-agent ibrutinib in earlier lines impacts patient outcomes, we evaluated long-term follow-up data from RESONATE and RESONATE-2 to compare efficacy and safety by number of prior lines of therapy. Methods : This integrated analysis included patients treated with single-agent ibrutinib in the first-line (RESONATE-2, NCT01722487) and relapsed/refractory (R/R; RESONATE, NCT01578707) settings. R/R patients were grouped by number of prior lines of therapy (1-2 vs ≥3). Patients with del(17p) were excluded from this analysis given their exclusion from RESONATE-2. Patients with high-risk prognostic features were defined as having TP53 mutation, del(11q), and/or unmutated IGHV. Outcomes included investigator-assessed PFS and objective response rate (ORR), OS, and safety. Results : This analysis of 271 patients included 136 patients in the first-line and 135 patients in the R/R groups (1-2 prior: n=68; ≥3 prior: n=67). Patients in the first-line group were older (median age [range], 73 years [65-89]) than those with 1-2 prior lines (65 years [30-86]) and ≥3 prior lines (67 years [44-83]). The proportion of patients with high-risk prognostic features was lower in the first-line group (first-line: 54%; 1-2 prior: 81%; ≥3 prior: 76%). Median follow-up was 59.8 months for first-line, 66.2 months for 1-2 prior, and 65.1 for ≥3 prior. Median PFS was not reached (NR) for first-line or 1-2 prior lines and was 40.1 months for ≥3 prior lines (Figure 1A). A greater proportion of patients treated with ibrutinib in earlier lines remained progression-free or alive at 60 months (first-line: 70%; 1-2 prior: 60%; ≥3 prior: 33%). First-line treatment resulted in a 34% reduction in risk of disease progression or death compared to 1-2 prior lines (HR: 0.66 [95% CI, 0.40-1.09]). PFS was significantly prolonged for first-line vs ≥3 prior lines (HR: 0.32 [95% CI, 0.21-0.49]) and 1-2 prior vs ≥3 prior lines (HR: 0.48 [95% CI, 0.30-0.77]). For patients with high-risk prognostic features, median PFS was NR for first-line or 1-2 prior lines and was 42.5 months for ≥3 prior lines (Figure 1B); treatment in earlier lines resulted in better PFS for these patients (first-line vs 1-2 prior, HR: 0.64 [95% CI, 0.35-1.18]; first-line vs ≥3 prior, HR: 0.33 [95% CI, 0.19-0.57]; 1-2 prior vs ≥3 prior HR: 0.51 [95% CI, 0.30-0.87]). Median OS for the overall population was NR (range, 0.10+-66.04+) for first-line, NR (5.98-71.56+) for 1-2 prior, and 67.4 months (1.15-69.78+) for ≥3 prior lines. The ORR was 91%, 94%, and 82% for first-line, 1-2 prior, and ≥3 prior lines, respectively. The CR rate (CR+CR with incomplete marrow recovery) was highest for the first-line group (first-line: 30%; 1-2 prior: 12%; ≥3 prior: 10%). At the time of analysis, 58% of patients remain on ibrutinib treatment in the first-line group. Prior to study closure, 38% of patients with 1-2 prior and 18% of patients with ≥3 prior lines remained on ibrutinib treatment. In the overall population, 8 patients (6%) in the first-line group discontinued due to progressive disease while it was the most common reason for discontinuation for patients with 1-2 (n=15, 22%) and ≥3 prior lines (n=25, 37%). Across all three groups, 52 patients (19%) discontinued due to adverse events (AEs) (first-line: n=29, 21%; 1-2 prior: n=13, 19%; ≥3 prior: n=10, 15%). AEs leading to dose reduction occurred in 20% of first-line, 13% of 1-2 prior, and 22% of ≥3 prior lines. Conclusions : Overall, this integrated analysis of data with up to 6 years of long-term follow-up demonstrates that using single-agent ibrutinib in earlier lines of treatment results in better PFS, OS, and ORR with sustained efficacy for patients with CLL, including patients with high-risk prognostic features. During this extended follow-up, only 6% of patients treated in the first-line setting discontinued due to progressive disease. Ibrutinib was well tolerated with only 19% of patients across all lines of therapy discontinuing due to AEs. Disclosures Barr: Gilead: Consultancy; Verastem: Consultancy; Seattle Genetics: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding. Tedeschi:Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, 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; BeiGene: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Munir:AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees. Hillmen:Acerta: Membership on an entity's Board of Directors or advisory committees; Apellis: Research Funding; Gilead: Research Funding; Roche: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; BeiGene: Research Funding. Ghia:ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Juno/Celgene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy. Mulligan:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Participant, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Participant, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Clinical Trial participant, Research Funding, Speakers Bureau; Commonwealth Serum Laboratories (CSL): Other: Clinical Trial participant; Sanofi-Aventis: Other: Clinical Trial participant; Acerta: Other: Clinical Trial participant. Dai:AbbVie: Equity Ownership; Celgene: Equity Ownership; Exelixis: Equity Ownership; Gilead: Equity Ownership; GSK: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Amaya-Chanaga:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Dean:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. o'Brien:Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Astellas: Consultancy; Celgene: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Kite: Research Funding; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy.

BACKGROUND Antigen-mediated proliferation and Bcl-2 mediated survival are key to chronic lymphocytic leukemia (CLL) pathogenesis. Ibrutinib is an oral BTK inhibitor affecting antigen-induced proliferation and cell adhesion/migration whilst venetoclax is a potent, highly selective, orally bioavailable Bcl-2 inhibitor affecting CLL cell survival. The treatment of CLL has been revolutionized by these targeted therapies. Both significantly improve survival in CLL but rarely lead to eradication of detectable minimal residual disease (MRD) when given as single agents. The Bloodwise TAP CLARITY trial combined ibrutinib with venetoclax in order to eradicate detectable CLL with the intention of stopping therapy. METHODS AND PATIENTS CLARITY is a Phase II trial combining ibrutinib with venetoclax in 50 patients with relapsed or refractory CLL. After 8 weeks of ibrutinib monotherapy (420mg/day), venetoclax was added first at a dose of 10mg/day with weekly escalations to 20mg, 50mg, 100mg, 200mg to a final dose of 400mg/day. No tumour lysis syndrome (TLS) was seen for the first 3 patients starting at 10mg/day of venetoclax so all subsequent patients began at 20mg/day. The primary end-point of CLARITY was the eradication of MRD ( RESULTS There were no cases of clinical tumor lysis syndrome (TLS) and only a single case of biochemical TLS (grade 3) which resolved with treatment. Other side-effects were mild and/or manageable, most commonly neutropenia (3/32 grade 2, 29/32 grade 3/4) or gastro-intestinal events (268/278 grade 1/2, 10/278 grade 3/4). Two Suspected Unexpected Serious Adverse Reactions (SUSARs) were reported (abdominal pain and pemphigus), 31 Serious Adverse Events (SAEs), and 918 Adverse Events (AEs) (of which 75 were grade 3 or 4) were reported. Notably there were nine grade 3 or 4 infections and 29 events of grade 3 or 4 neutropenia. Thus far all SAEs have resolved with appropriate management, and all patients remained on trial following resolution. After 6 months of combined ibrutinib plus venetoclax, undetectable MRD was achieved in 19/49 (39%) patients in peripheral blood (PB) and 12/49 (24%) in bone marrow (BM). After 12 months of combined therapy all patients had responded by IWCLL criteria and 23/40 (58%) had achieved a complete remission (CR or CRi). In addition after 12 months of combined therapy 27/31 (87%) have no morphological evidence of CLL in the BM biopsy, 32/34 (94%) had less than 1% CLL cells in the BM aspirate, undetectable MRD (MRD4) was achieved in 23/40 (58%) patients in PB and 17/41 (41%) in BM. There was a continuous improvement in the depth of MRD reduction with 41% of patients achieving less than MRD4 and 29% having undetectable disease by flow cytometry ( CONCLUSIONS The combination of ibrutinib and venetoclax was well tolerated in patients with relapsed or refractory CLL. Every patient responded and there was a high rate of MRD eradication, in some cases leading to the cessation of therapy. Figure Figure. Disclosures Hillmen: Pharmacyclics: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Rawstron:Pharmacyclics: Consultancy, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beckman Coulter: Research Funding; BD Biosciences: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brock:GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Lilly: Honoraria; Roche: Other: Reimbursement of expenses; Merck Sharp Dohme: Other: Reimbursement of conference fees. Fegan:Abbvie: Honoraria; Roche: Honoraria; Napp: Honoraria; Gilead Sciences, Inc.: Honoraria; Janssen: Honoraria. McCaig:AbbVie: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau. Schuh:Giles, Roche, Janssen, AbbVie: Honoraria. Pettitt:AstraZeneca: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Roche: Research Funding; GSK/Novartis: Research Funding; Napp: Research Funding; Chugai: Research Funding. Gribben:NIH: Research Funding; Novartis: Honoraria; Cancer Research UK: Research Funding; Medical Research Council: Research Funding; TG Therapeutics: Honoraria; Abbvie: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Acerta Pharma: Honoraria, Research Funding; Kite: Honoraria; Unum: Equity Ownership; Wellcome Trust: Research Funding; Pharmacyclics: Honoraria; Roche: Honoraria. Patten:L Hoffman La Roche: Honoraria, Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding; AbbVie Inc: Honoraria, Other: travel; Janssen: Honoraria, Other: travel. Devereux:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Personal fees; Novartis: Membership on an entity's Board of Directors or advisory committees. Bloor:AbbVie: Research Funding; Janssen: Research Funding. Fox:Roche: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Sunesis: Consultancy; Gilead: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: travel support, Speakers Bureau; Abbvie: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: travel support, Speakers Bureau. Forconi:Janssen-Cilag: Consultancy; Abbvie: Consultancy. Munir:Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Novartis: Honoraria; Alexion: Honoraria; MorphoSys: Membership on an entity's Board of Directors or advisory committees.

Background: Ibrutinib inhibits CLL cell proliferation and results in prolonged remission, but MRD responses are rare. Obinutuzumab is a second generation anti-CD20 monoclonal antibody that is effective in CLL and can result in MRD responses. In the IcICLLe study (ISRCTN12695354), 40 participants with CLL requiring treatment (20 treatment-naïve, 20 with relapsed/refractory [R/R] disease) received ibrutinib until complete remission with Aim: to determine the MRD response rates for patients with R/R CLL treated with ibrutinib and obinutuzumab in ibrutinib-naïve trial participants compared to those treated with >1 year prior ibrutinib. Patients: The IcICLLe Extension Study recruited 40 participants with relapsed/refractory CLL requiring treatment. They received continuous ibrutinib (420mg OD) with 6 cycles of obinutuzumab given over 6 months (M). Ten participants had >1 year of prior ibrutinib monotherapy in IcICLLe and 30 were ibrutinib-naïve with obinutuzumab started 24 hours after first ibrutinib dose. Patient characteristics and Adverse Events (AEs, collected from registration until 30 days after treatment cessation and reported at 1, 3, and 6M, and 6-monthly thereafter using the Common Terminology Criteria for Adverse Events v4.0) are shown in Table 1. MRD assessment was performed according to ERIC guidelines with a maximum detection limit of 0.001%/10-5. Results: In the 20 R/R patients treated with ibrutinib monotherapy there were no IWCLL CR/CRi responses and no patients achieved 1 year prior to combination with obinutuzumab (see Table 1). Patients receiving obinutuzumab after >1 year prior ibrutinib monotherapy achieved a higher response rate compared to ibrutinib-naive patients (IWCLL CR/CRi 50% vs. 30%), with a higher proportion of patients achieving PB MRD levels continued to improve in ibrutinib-naïve patients after cessation of obinutuzumab with 30% (9/30 with 4/30 inevaluable) achieving PB MRD 1 year prior to starting obinutuzumab. The difference in extent of disease depletion observed with obinutuzumab may be related to the pre-obinutuzumab disease bulk because the majority of patients (7/10) with >1 year prior ibrutinib treatment had already resolved any lymphadenopathy prior to receiving obinutuzumab. Conclusions: The results suggest that the addition of obinutuzumab to ibrutinib may result in a substantial improvement in the depletion of CLL cells from the PB and BM for ibrutinib-naïve patients. However, a greater impact in MRD response rate and depth of depletion was seen when obinutuzumab was introduced after >1 year of ibrutinib treatment and tumour bulk was low. For patients with persistent disease during/ following pathway inhibition treatments, the addition of anti-CD20 antibody therapy may be effective at improving MRD response rates. Disclosures Rawstron: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BD Bio-sciences: Research Funding; Beckman Coulter: Research Funding; Celgene: 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; Pharmacyclics: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munir:MorphoSys: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Brock:GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Merck Sharp Dohme: Other: Reimbursement of conference fees; Roche: Other: Reimbursement of expenses; Lilly: Honoraria. Pettitt:AstraZeneca: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Roche: Research Funding; GSK/Novartis: Research Funding; Gilead: Research Funding; Napp: Research Funding. Fox:Celgene: Consultancy, Other: Travel support, Speakers Bureau; Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Sunesis: Consultancy. Devereux:Janssen: Other: Personal fees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Fegan:Janssen: Honoraria; Gilead Sciences, Inc.: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Napp: Honoraria. Bloor:Janssen: Research Funding; AbbVie: Research Funding. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Combination immunochemotherapy such as fludarabine, cyclophosphamide and rituximab is the standard first line therapy in fit patients, but there is limited evidence regarding the optimal treatment of patients after relapse. Ofatumumab as monotherapy has been proven to be effective in the treatment of relapsed, refractory CLL, and as it is not myelotoxic, it is an ideal drug to combine with chemotherapy. However, the optimal dose of ofatumumab in this setting is not known. The Chemotherapy plus Ofatumumab at Standard or Mega dose in relapsed CLL (COSMIC) trial will assess the efficacy and safety of standard and high (mega) doses of ofatumumab combined with bendamustine or a combination of fludarabine and cyclophosphamide to determine which, if either, schedule should progress to a phase III trial. Methods/design COSMIC is a phase II, multi-centre, randomised, open, parallel group trial for patients with relapsed CLL who are not refractory to fludarabine-based chemotherapy. Participants will be randomised to receive either standard dose or mega dose ofatumumab. Both doses will be given in combination with either bendamustine or fludarabine and cyclophosphamide chemotherapy backbone. The primary objective is to assess the proportion of participants achieving a complete remission following therapy with the two treatment arms (mega versus standard), as assessed at 3 months post treatment. The treatment groups will be assessed independently to determine whether the level of response is acceptable in relation to pre-specified criteria. If both treatment groups show an acceptable level of response, selection criteria will be used to determine which to take forward to a confirmatory phase III trial. A key secondary objective is to assess the dynamics of minimal residual disease (MRD) levels in relapsed disease. Eighty-two participants are planned to be recruited from 18 research centres in the UK. Discussion Currently there is limited evidence regarding the optimal treatment of patients with relapsed or refractory CLL, and so suitable therapies are urgently needed. The COSMIC trial will identify whether ofatumumab given in combination with chemotherapy is safe and effective in this population, and will identify the optimal doses for further investigation. Trial registration ISRCTN51382468. Registered on 21 September 2011. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1581-0) contains supplementary material, which is available to authorized users.

TPS7567 Background: Patients (pts) with R/R CLL who discontinue treatment with the BTKi ibrutinib due to progression have a particularly dismal prognosis. A phase I study showed that the Fc-enhanced, humanized, CD19 antibody MOR208 was well tolerated with encouraging single-agent activity in pts with R/R CLL/SLL. In preclinical models, MOR208 showed synergy with idelalisib (an inhibitor of PI3K delta) and venetoclax (an inhibitor of BCL-2), both approved for the treatment of CLL. Methods: This two-cohort, phase II study will investigate MOR208 combined with idelalisib (cohort A) or venetoclax (cohort B) in pts with R/R CLL or R/R SLL and includes a safety run-in phase for each cohort, to be evaluated by an Independent Data Monitoring Committee. Key inclusion criteria: aged ≥18 years, R/R CLL/SLL while receiving a BTKi therapy or intolerance of such therapy, BTKi administered as a single-agent or in combination for at least 1 month as the most recent prior anticancer therapy, ECOG performance status of 0–2, and adequate organ function. Key exclusion criteria: transformed CLL/SLL or Richter’s syndrome, BTKi treatment within 5 days prior to study drug dosing, prior treatment with a CD19-targeted therapy, a PI3K inhibitor (cohort A) or a BCL-2 inhibitor (cohort B). Pts will be treated for a maximum of 24 (28-day) cycles or until disease progression. Treatment will be MOR208 12 mg/kg IV (weekly for the first 3 months, every second week for the next 3 months, and monthly thereafter) in combination with oral idelalisib 150 mg twice-daily or venetoclax administered on a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg. Primary endpoint: overall response rate based on independent review; secondary and exploratory endpoints include: progression-free and overall survival, duration of response, safety, pharmacokinetics, MOR208 immunogenicity, quality of life and minimal residual disease negativity. 120 pts per cohort are planned. Clinical trial information: 2015-002915-14.

Background:Uncontrolled complement activation plays a pivotal role in a variety of disorders such as paroxysmal nocturnal hemoglobinuria (PNH). Challenges to be addressed with eculizumab therapy include inter-individual variation in clearance of eculizumab, economic burden, and improvements in the current biweekly intravenous infusion maintenance schedule. ALN-CC5 is a subcutaneous (SC) investigational RNA interference (RNAi) therapeutic targeting hepatic complement C5 (C5) synthesis. Previously presented data from our ongoing Phase 1/2 study showed that ALN-CC5 was generally well tolerated and exhibited a clamped C5 knockdown and complement activity inhibition in healthy volunteers (Hill et al. Haematologica 2016; 101, Suppl 1). The aim of this abstract is to report updated tolerability and clinical activity of ALN-CC5 in patients with PNH. Methods: A phase 1/2 single-ascending dose (Part A) and multiple-ascending dose study (Part B) of ALN-CC5 was conducted in healthy adult volunteers and in patients with PNH (Part C). In Part C, patients with PNH received weekly doses of 200 mg or 400 mg of ALN-CC5 for 2 to 16 weeks; ALN-CC5 is administered subcutaneously at a concentration of 200 mg/mL. The primary endpoints are safety and tolerability and secondary endpoints include: pharmacokinetics (PK), reduction of circulating C5 and complement activity, as measured by CAP/CCP Wieslab ELISA assays and sheep erythrocyte hemolysis assay, as well as reduction in LDH. Results: Part C included 6 patients with PNH (treatment naïve n=3; patients receiving eculizumab n=3), including 1 patient who was experiencing breakthrough hemolysis despite receiving 1200mg eculizumab q2wk. ALN-CC5 was generally well tolerated in patients with PNH after multiple doses with the majority of adverse events (AEs) being mild or moderate in severity. There were no serious AEs or discontinuations due to AEs. One patient, who was also taking eculizumab, cyclosporine and anabolic steroids as concomitant medications, experienced a transient asymptomatic grade 3 elevation of liver transaminases that was deemed possibly related to study drug. In eculizumab naïve patients (n=3), ALN-CC5 monotherapy achieved a mean maximum C5 knockdown of 98.2% ± 0.3%, residual C5 levels of 0.9 mcg/mL and a mean maximum CCP inhibition of 94.2 ± 1.7%. During treatment with ALN-CC5, maximum reduction in LDH was 37% and 50% in 2 patients who received 17 doses of ALN-CC5 but remained above the goal of less than 1.5 times the ULN. In the remaining eculizumab naïve patient, LDH lowering was not observed following 8 doses of ALN-CC5. After completion of ALN-CC5 dosing and in the setting of ongoing >95% ALN-CC5-mediated KD of serum C5, treatment naïve patients received a single 600 mg dose of eculizumab (labeled induction dose is 600 mg weekly x 4) for the treatment of residual hemolysis followed by close clinical monitoring. An exploratory analysis was conducted to understand the potential for ALN-CC5 to reduce eculizumab dose and frequency. All 3 patients achieved sustained lowering of LDH Conclusion: ALN-CC5 was shown to be generally well tolerated in patients with PNH. The PD effects of ALN-CC5 were found to be durable, with clamped C5 knockdown and complement activity inhibition. Collectively, the data suggest that clamped inhibition of hepatic C5 synthesis may provide the foundation to potentially reduce the dose and frequency of eculizumab administration for patients with PNH, and to improve disease control in patients with inadequate response to eculizumab. Disclosures Hill: Alnylam Pharmaceuticals: Consultancy, Honoraria. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference support. Munir:Alexion pharmaceuticals: Honoraria. Borodovsky:Alnylam Pharmaceuticals: Employment, Equity Ownership. Kawahata:Alnylam Pharmaceuticals: Employment, Equity Ownership. Mclean:Alnylam Pharmaceuticals: Employment, Equity Ownership. Shi:Alnylam Pharmaceuticals: Employment, Equity Ownership. Partisano:Alnylam: Employment, Equity Ownership. Kim:Alnylam Pharmaceuticals: Employment, Equity Ownership. Najafian:Alnylam Pharmaceuticals: Employment, Equity Ownership.

Introduction Aplastic anaemia (AA) affects 1-2 per million of the UK population. At least 50% of patients have a Paroxysmal Nocturnal Hemoglobinuria (PNH) clone, which may either require monitoring or concomitant management with the aplasia if clinical indications for eculizumab are fulfilled. There is a paucity of data available to guide concurrent treatment for AA and PNH. Method The UK PNH National Service (Leeds and London) database was reviewed retrospectively. Patients commencing eculizumab within a year of AA treatment, or those treated for aplasia who were already established on eculizumab were selected. Response to AA therapy was assessed according to aplastic anaemia guidelines. Results Twenty six patients were identified who were treated with eculizumab and immunosuppressive therapy (IST) concurrently. Median age 39.5 years (range 7-75). Median granulocyte clone immediately prior to eculizumab was 82%. Ten patients had severe AA, 15 non severe and one had hypoplastic MDS. Treatment varied as per national guidelines dependant on patient's age, patient choice, prior treatment and co-morbidities. Eight patients received ATG and ciclosporin (median follow-up 21 months post ATG treatment), 14 patients received ciclosporin monotherapy (median follow-up from commencement of ciclosporin 29 months). One patient received androgens as a single agent achieving a partial response (PR),3 patients underwent haematopoietic stem cell transplant (HSCT) as initial treatment at the time of eculizumab and IST overlap (5 other patients received HSCT as discussed below). Six of the 8 (75%) patients receiving ATG+Ciclosporin responded, one patient achieved complete remission (CR) and five PR, one of whom subsequently achieved a CR with androgen therapy. Two patients did not respond and both achieved a CR after HSCT. In five patients who had data available six months post ATG there was no change in the median granulocyte or monocyte PNH clone size. Of 14 patients treated with single agent ciclosporin, 1 patient achieved CR; 7 PR, 2 of whom achieved a subsequent CR with further therapy ( androgens N=1, HSCT N=1); 6 had no response, 3 of whom received subsequent treatment, two HSCT (one achieved a CR and one died), and one eltrombopag (response awaited; follow-up 12 weeks) . Three patients underwent HSCT during the defined entry criteria above. 2 had frontline HSCT, and 1 had a transplant due to late relapse following ATG and ciclosporin 6 years prior. Five other patients underwent HSCT as discussed above for second or third line treatment (ATG and ciclosporin N=2, ciclosporin single agent N=3). All transplant patients achieved a CR except 1 who died during the procedure. All 7 patients who survived transplant stopped eculizumab due to resolution of PNH. Six of 26 (9.8%) patients died,1 who achieved a CR with HSCT and died 2 years later of GVHD , two patients who had achieved a partial response to treatment one of whom died of infection, two had not responded to treatment, and one HSCT recipient died during the procedure. Fourteen age matched controls not on eculizumab received similar therapies, 9 of whom received ATG and ciclosporin, median follow-up from ATG commencement 37 months. Four of the 9 had a CR, 1 had a CR then a relapse with no response to the re-introduction of ciclosporin, 3 had a partial response one of whom achieved a CR with androgens and 1 patient had no response achieving a CR with HSCT. 5 matched controls were treated with ciclosporin single agent, median follow-up from ciclosporin commencement 115 months. Two patients had a CR, 1 had a PR then relapsed, 2 had no response. Conclusion This is the largest reported cohort of patients receiving concurrent treatment for both AA and PNH. The presence of symptomatic PNH requiring complement inhibition should not influence AA treatment decisions. The response rates for IST in patients on eculizumab compared with age matched controls were similar, with similar numbers of patients achieving CR or PR with immunosuppressive therapy, suggesting no detriment to response to IST with concurrent eculizumab therapy. Therefore, patients with concurrent AA and PNH should be treated as per AA guidelines and PNH can be managed concurrently if required. This strategy will increasingly be required in the future, especially with improved life expectancy for PNH patients receiving complement inhibition therapy. Eculizumab therapy does not appear to affect response to IST for AA patients Disclosures Griffin: Alexion Pharmaceuticals: Honoraria, Other: Conference support. Kulasekararaj:Alexion pharmaceuticals: Honoraria, Other: conference support. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Munir:Alexion pharmaceuticals: Honoraria. Richards:Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding. Arnold:Alexion Pharmaceuticals: Honoraria. Riley:Alexion pharmaceuticals: Other: Travel for conference. Marsh:Alexion pharmaceuticals: Honoraria. Hill:Alnylam Pharmaceuticals: Consultancy, Honoraria.

Background: The detection of minimal residual disease (MRD) in CLL using a 0.01% cut-off is an independent predictor of progression-free (PFS) and overall survival (OS) after chemo-immunotherapy. There are several new treatments available and using MRD as a trial endpoint could greatly speed up the identification of the best treatment approaches. MRD assessments can be made in the peripheral blood (PB) or bone marrow (BM) but there is substantial variation in the extent to which different treatments deplete disease in the PB, BM, and nodal compartments. Aims: To compare MRD levels in the PB & BM during/after different treatment approaches to determine differential compartment effects and evaluate the impact on predicting PFS/OS. Methods: The level of residual disease was determined using multi-parameter flow cytometry according to ERIC consensus protocols with a limit of quantification of 10-4 / 0.01% or better; "+" and "-" denotes ≥0.01% and Results: The MRD level in PB & BM samples taken at the same time, either during or within 6 months of treatment, was available in 556 cases of which 85 (15%) showed discordant results at the 0.01% threshold. The frequency of discrepant PB & BM MRD levels varied across treatment and patient groups (table 1). In 322 evaluable cases from the ADMIRE/ARCTIC trials at 3 months after the end FCR-based therapy, 66/322 were BM+PB-, representing 54% of the total MRD+ cases. Discrepant results with >1 log difference between PB & BM MRD levels were most common in refractory patients treated with alemtuzumab. There were no discrepant results in patients undergoing idelalisib or ibrutinib monotherapy although all patients have ≥0.01% MRD to date. A small compartment effect was apparent in patients treated with a combination of ibrutinib and obinutuzumab but the relative difference in PB vs. BM disease level appears to be approximately half that of rituximab in combination with chemotherapy. To determine whether the discrepant results affect the ability of MRD status to predict outcome, we compared the PFS according to BM & PB MRD status. In the CLL202 (fludarabine + alemtuzumab) trial the PFS for BM+PB- cases was similar to BM+PB+ cases (median PFS was 1.6 and 6.5 months respectively) and both were substantially shorter than for BM-PB- cases (median PFS 44.7 months, Log-rank P66 months vs. 54 months vs. 33 months for BM-PB- vs. BM+PB- vs. BM+PB+ respectively, Log-rank P1% MRD in the PB also had >1% disease in the BM. Summary/Conclusion: The compartment effect varies greatly according to patient group and treatment. Rituximab typically results in 0.7log lower disease in the PB compared to BM. Patients on BCR-pathway inhibitors have similar levels of disease in PB & BM even in combination with obinutuzumab. This suggests either that BCR-pathway inhibitors counteract the compartment effects of anti-CD20 antibody treatment, or that obinutuzumab is more effective in depleting bone marrow disease than rituximab. Peripheral blood MRD status may be appropriate for predicting outcome in some settings but underestimates MRD level in a substantial proportion of patients. Bone marrow remains the most sensitive and reliable source for MRD detection but is not required if there is >1% MRD in the blood. Evaluating the compartment effect of specific treatment combinations will help to identify approaches to achieve maximal MRD response using peripheral blood monitoring. Table 1 Compartment effect - difference in MRD detection in PB vs. BM samples across different trials. * median log difference only calculated in cases with >0.01% MRD in both PB & BM so may underestimate compartment effect. Table 1. Compartment effect - difference in MRD detection in PB vs. BM samples across different trials. / * median log difference only calculated in cases with >0.01% MRD in both PB & BM so may underestimate compartment effect. Disclosures Rawstron: AbbVie: Honoraria; Roche: Honoraria; Celegene: Honoraria; Janssen: Research Funding; BD Biosciences: Other: Remuneration; Gilead: Consultancy, Honoraria, Research Funding; Genzyme: Honoraria; GlaxoSmithKline: Honoraria. Munir:Alexion pharmaceuticals: Honoraria. Brock:AstraZeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding.

Background: A major aim of treatment in CLL is to eradicate detectable minimal residual disease (MRD). Ibrutinib is a major step forward in the treatment of CLL but results in an immediate lymphocytosis that persists in most patients for at least several months. Obinutuzumab is a second generation anti-CD20 monoclonal antibody which appears to be highly effective in CLL resulting in a rapid eradication of peripheral blood lymphocytosis and the eradication of MRD in a proportion of patients. The IcICLLe Extension Study expands on the IcICLLe trial (ISRCTN 12695354) to examine the efficacy and safety of the combination treatment of obinutuzumab and ibrutinib. Patients: The IcICLLetrial recruited 40 participants with CLL requiring treatment (20 treatment-naïve, 20 relapsed/refractory disease) receive continuous ibrutinib therapy until achievement of 20 will have had no prior Ibrutinib treatment (ibrutinib naive), and ≤20 will have received at least 12 months of Ibrutinib monotherapy as part of the IcICLLe trial before enrolling in the Extension Study . Adverse Events (AEs) are collected from registration until 30 days after treatment cessation and reported at 1, 3 and 6 months, and 6-monthly thereafter using the Common Terminology Criteria for Adverse Events v4.0. Results: 17 participants (12 ibrutinib naïve and 5 IcICLLe monotherapy patients) are evaluable for response assessment after one month of combination treatment. In the 12 Ibrutinib-naïve cases, the peripheral CLL counts remained at or below baseline levels in most (9/12) cases from week 1 onwards. After one month of combination therapy the peripheral B-cell count was a median 35% of baseline levels (range Bone marrow assessment was not mandated for the 5 patients previously on ≥12 months (range 14-20 months) continuous ibrutinib monotherapy because they had already undergone 4 biopsies in the prior year, however all five patients showed a reduction in peripheral CLL counts (median 1.3 log reduction, range 0.3 to 2.4 log) which was significantly greater than the reduction seen in the prior 6 months of ibrutinib monotherapy (median 0.5 log reduction, range -1.0 to 0.8, paired t-test P=0.043) Of the 17 participants recruited to the IcICLLe Extension Study there have been no reports of Tumour Lysis Syndrome within the first month of combination treatment. There was a single report of a grade 2 Infusion Related Reaction (IRR) for one participant following the first infusion (100mg) of obinutuzumab. No further IRRs have been reported. Conclusions: The data indicate that the addition of obinutuzumab to ibrutinib results in a substantial improvement in the depletion of CLL cells from the peripheral blood and bone marrow after only one month of combination therapy. Date of Data Freeze: 19-Jul-2016 Disclosures Rawstron: Gilead: Consultancy, Honoraria, Research Funding; BD Biosciences: Other: Remuneration; Celegene: Honoraria; Roche: Honoraria; Janssen: Research Funding; GlaxoSmithKline: Honoraria; AbbVie: Honoraria; Genzyme: Honoraria. Munir:Alexion pharmaceuticals: Honoraria. Brock:AstraZeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership. Bloor:Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. Pettitt:Roche: Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Infinity: Research Funding. Fox:Roche: Consultancy; Janssen: Honoraria, Other: Travel support. Fegan:Gilead Sciences: Honoraria; Roche: Honoraria; AbbVie: Honoraria. Devereux:Roche: Consultancy, Other: Travel, Accommodations, Expenses ; GSK: Consultancy; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding.

Background: Patients (pts) with CLL harboring 17p deletion [del(17p)] are considered to have very poor prognosis. Venetoclax (VEN) is an orally bioavailable, selective BCL-2 inhibitor that induces apoptosis in CLL cells independent of p53. A phase 1 study of VEN showed high response rates in pts with relapsed/refractory (R/R) CLL, including del(17p) CLL (overall response rate, ORR = 77%). This pivotal phase 2, single-arm, multicenter study evaluated VEN monotherapy in pts with R/R del(17p) CLL. Methods: Pts with R/R del(17p) CLL, assessed in peripheral blood (PB) by a central laboratory ( >7% cells by Vysis FISH probe), commenced VEN once daily with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over a period of 5 weeks with tumor lysis syndrome (TLS) prophylaxis. Pts were treated with daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary objective was to determine the ORR. Responses were determined by both an independent review committee (IRC) and investigators using iwCLL 2008 criteria. Efficacy analyses were pre-specified to occur once pts completed 36 weeks of VEN, had disease progression, or permanently discontinued. Secondary objectives included CR and PR rates, time to first response, duration of response (DoR), progression-free survival (PFS), overall survival (OS), the proportion of pts proceeding to allogeneic stem cell transplant (allo-SCT), and safety. The level of minimal residual disease (MRD) in PB and/or bone marrow (BM) was assessed in a subset of pts by multi-color flow cytometry using iwCLL-recommended sensitivity criteria of Results: A total of 107 pts were enrolled in the main cohort (June 2013–June 2014). Median (range) age was 67 (37–85) years; 65% were male. Median number of prior regimens was 2 (1–10); 78 pts (72.9%) had received prior fludarabine (F), 34 (37.4%) were F-refractory, 54 (50.5%) received prior bendamustine (B), and 27 (50%) were B-refractory. 45 pts (42.1%) were high-risk for TLS based on lymph nodes ≥10 cm (or nodes ≥5 cm with ALC ≥25x109/L). All pts but one had del(17p); 60 of 83 pts with available data (72.3%) had mutated TP53 (investigator reported). As of the data cut-off (April 30, 2015), the median time on study was 12.1 (0.03–21.5) months. The primary endpoint of IRC-assessed ORR was 79.4% (95% CI: 70.5%–86.6%). Deep responses included 7.5% CR/CRi and 2.8% nPR, by IRC (Table). Among pts who achieved PR (69.2%, excluding nPR) or non-responders (20.6%) by IRC, 17 pts (15.9%) had no morphological evidence of CLL in the BM. Investigator-assessed ORR is also reported in the Table. 45 pts had an MRD assessment. Notably 18 pts (17% of whole cohort, 21% of responders) had no detectable MRD in the PB; 10 of these were also tested in BM, 6 were MRD-negative. Median time-to-first response was 0.8 months (0.1–8.1); median time to CR/CRi was 8.2 months (3.0–16.3) by IRC. Overall median DoR, PFS, and OS were not reached. The actuarial 12-month PFS and OS rates were 72.0% and 86.7%, respectively (actuarial 12-month DoR rates in Table). 37 pts discontinued treatment: 22 due to PD (9 Richter's transformation), 9 due to AE, 2 withdrew consent, and 1 with non-compliance; 3 pts proceeded to allo-SCT (2 PR, 1 CR by IRC at time of transplant). 11 deaths occurred (≤30 days from last dose of VEN): 7 due to PD, 4 due to AE (stroke, liver derangement, septic shock, and cardio-respiratory insufficiency). 7 additional deaths occurred beyond 30 days from VEN discontinuation (39-328 days) due to PD. Treatment-emergent AEs (all grades) in ≥20% pts were neutropenia (43%), diarrhea (29%), nausea (29%), anemia (27%), and fatigue (22%). Grade 3/4 AEs in ≥10% pts were neutropenia (40%; 25 pts had grade 4), anemia (18%), and thrombocytopenia (15%). 22.4% of pts had neutropenia (any grade) at study entry. Infection ≥ grade 3 occurred in 20% of pts; most common was pneumonia (5%). Laboratory TLS was reported in 5 pts; none had clinical consequences, and all were manageable with electrolyte management and 1-day dose interruption (2 pts). Conclusions: VEN monotherapy achieved a high ORR and sustained remissions with acceptable toxicity in this ultra-high risk pt population with R/R del(17p) CLL. Undetectable MRD was observed in >20% of responders. More than 10% of all pts achieved independently assessed deep responses (CR, CRi, or nPR). Such depths of response have not been previously reported for this population. Disclosures: Stilgenbauer: AbbVie, Amgen, Boehringer-Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffman La Roche: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Research Funding. Off Label Use: Venetoclax is an investigational drug and has no label at this time. Eichhorst:AbbVie, Roche: Membership on an entity’s Board of Directors or advisory committees , Research Funding , Speakers Bureau. Schetelig:GSK, Sanofi, Janssen, Neovii: Membership on an entity’s Board of Directors or advisory committees , Research Funding. Coutre:AbbVie: Research Funding ; Gilead: Research Funding ; Pharmacyclics LLC, an AbbVie Company: Consultancy , 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 ; Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Celgene Business Advisory Board: Membership on an entity’s Board of Directors or advisory committees ; Novartis: Research Funding. Seymour:Gilead: Honoraria , Membership on an entity’s Board of Directors or advisory committees ; Genentech, Inc.: Membership on an entity’s Board of Directors or advisory committees ; Celgene: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Other: Travel support , Speakers Bureau ; Incyte: Honoraria , Membership on an entity’s Board of Directors or advisory committees ; AbbVie: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Other: Travel support , Research Funding , Speakers Bureau ; Janssen: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Phebra: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees ; Takeda: Honoraria , Membership on an entity’s Board of Directors or advisory committees ; Roche: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Other: Travel support , Research Funding ; Infinity: Honoraria , Membership on an entity’s Board of Directors or advisory committees. Puvvada:Genentech, AbbVie, Spectrum, Janssen and Takeda, Pharmacyclics, Genentech/Roche: Consultancy , Membership on an entity’s Board of Directors or advisory committees , Other: Travel funding for Investigators meeting , Research Funding. Wendtner:Mundipharma: Consultancy , Other: travel grants , Research Funding ; Celege: Consultancy , Other: Travel grants , Research Funding ; Gilead: Consultancy , Other: travel grants , Research Funding ; Glaxo-SmithKline: Consultancy , Other: travel grants , Research Funding ; Janssen-Cilag: Consultancy , Other: travel grants , Research Funding ; Pharmacyclics: Consultancy , Other: travel grants , Research Funding ; Hoffmann-LaRoche: Consultancy , Other: travel grants , Research Funding ; Genentech: Consultancy , Other: travel grants , Research Funding ; AbbVie: Consultancy , Other: travel grants , Research Funding. Roberts:AbbVie and Genentech: Research Funding ; Walter and Eliza Hall Institute of Medical Research: Employment. Jurczak:CELLTRION, Inc,: Research Funding ; Celgene, Eisai, Gilead, Janssen, Mundipharma, Pharmacyclics, Pfizer, Roche, Sandoz –Novartis, Spectrum, Takeda, AbbVie, Morphosys, Janssen, Mundipharma, Sandoz –Novartis, Spectrum, Takeda, Teva, Morphosys: Membership on an entity’s Board of Directors or advisory committees , Research Funding. Mulligan:Sanofi Aventis: Research Funding ; Celgene: Consultancy , Honoraria ; Roche: Consultancy , Honoraria , Research Funding , Speakers Bureau ; Janssen: Consultancy , Honoraria , Speakers Bureau ; AbbVie: Membership on an entity’s Board of Directors or advisory committees. Boettcher:AbbVie: Honoraria , Research Funding ; Celgene: Research Funding ; Roche: Honoraria , Other: travel grants , Research Funding. Mobasher:Genentech, Inc.: Employment ; Roche: Equity Ownership. Zhu:AbbVie: Employment , Equity Ownership. Chyla:AbbVie: Employment , Equity Ownership. Verdugo:AbbVie: Employment , Equity Ownership. Enschede:AbbVie: Employment , Equity Ownership. Cerri:AbbVie: Employment , Equity Ownership. Humerickhouse:AbbVie: Employment , Equity Ownership. Gordon:AbbVie: Employment , Equity Ownership. Hallek:GSK, Genentech: Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Celgene: Honoraria , Other: Speakers Bureau and/or Advisory Boards , Research Funding ; Janssen: Honoraria , Other: Speakers Bureau and/or Advisory Boards , Research Funding ; Mundipharma: Honoraria , Other: Speakers Bureau and/or Advisory Boards , Research Funding ; Boehringher Ingelheim: Honoraria , Other: Speakers Bureau and/or Advisory Boards ; Pharmacyclics: Honoraria , Other: Speakers Bureau and/or Advisory Boards , Research Funding ; Roche: Honoraria , Other: Speakers Bureau and/or Advisory Boards , Research Funding ; Gilead: Honoraria , Other: Speakers Bureau and/or Advisory Boards , Research Funding ; AbbVie: Honoraria , Other: Speakers Bureau and/or Advisory Boards , Research Funding. Wierda:AbbVie, Genentech: Consultancy , Research Funding.

BACKGROUND: Minimal residual disease (MRD) in CLL is an independent predictor of progression-free and overall survival after chemo-immunotherapy. Data from the DCLLSG trials indicate that a high, intermediate and low risk of disease progression is seen in patients with >1%, 0.01-1%, or AIM: To apply the ERIC consensus 1-tube multiparameter MRD strategy prospectively in two UK clinical trials of FCR-based treatment (ADMIRE and ARCTIC) to determine the survival benefit per log depletion. METHODS: The level of residual disease was determined using multi-parameter flow cytometry according to the ERIC consensus protocol with a limit of quantification of 10-4 / 0.01% or better on 415 patients at 3 months after end of treatment. RESULTS: The level of MRD at end of treatment was a powerful predictor of PFS and OS independent of age, stage, IWCLL response, FISH and IGHV mutation status. Per log reduction in CLL level, the hazard of disease progression decreased by 33% (95%CI 27-38%) and the hazard of dying decreased by 22% (95%CI 13-29%). Although there were statistically significant improvements per log reduction, the DCLLSG 2-log model showed more meaningful differences in outcome over the period of follow-up. The median PFS for patients with >1% vs. 0.01-1% vs 1% MRD predicts equivalent or worse outcome than a clinical PR. PB MRD analysis at 18 months after randomisation (~1 year after treatment) was also strongly predictive of outcome: 98% of patients with CONCLUSIONS: Prospective enumeration of MRD using the ERIC consensus 1-tube multiparameter protocol confirms that MRD at end of treatment is a powerful independent predictor of progression-free and overall survival. Post-treatment follow-up using peripheral blood MRD could be more informative than clinic assessments because patients with 1% MRD at end of treatment in the peripheral blood have a similar outcome to those with a clinical PR and a bone marrow assessment is not informative in these cases. The level of MRD is highly informative with sequential improvements in outcome per log depletion. The DCLLSG 2-log categorisation (>1%, 0.01-1%, or 6yrs. Figure 1. the level of MRD in the bone marrow at 3 months after treatment is highly predictive of outcome with >1% MRD equating to 5yrs median PFS Figure 1. the level of MRD in the bone marrow at 3 months after treatment is highly predictive of outcome with >1% MRD equating to 5yrs median PFS Figure 2. sequential PB MRD analysis identifies patients with negligible risk of requiring treatment within the following 12 months. Figure 2. sequential PB MRD analysis identifies patients with negligible risk of requiring treatment within the following 12 months. Disclosures Rawstron: BD Biosciences: Patents & Royalties; Roche: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Gilead: Honoraria, Research Funding; Pharmacyclics: Research Funding. Gregory:Celgene: Honoraria; Janssen: Honoraria. Hillmen:Roche: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Research Funding.

Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired bone marrow disorder characterised by intravascular hemolysis and hemoglobinuria, potentially life-threatening thrombosis and an association with aplastic anemia. Most of the clinical features and complications of PNH are due to the unopposed activity of complement due to the absence of CD59 and CD55, two key regulators of complement. Eculizumab prevents the cleavage of C5 complement thereby preventing terminal complement activity and protecting PNH cells from lysis. The inhibition of C5 preserves the early part of complement pathway and leads to the build up of C3 on the PNH red cells, perhaps in part due to their lack of CD55. The majority of PNH patients receiving eculizumab have evidence of extravascular haemolysis that can be clinically significant, including with anemia, hyperbilirubinemia and in some a continued requirement for transfusions. This extravascular hemolysis in thought to be due to the C3 loading of PNH red cells. Methods We report the C3-loading of the PNH red cells from 119 patients treated with eculizumab and correlate this with hemoglobin, LDH, bilirubin, reticulocytes and transfusions. We have studied genetic polymorphisms that affect both C3 and FCγR. We have genotyped 46 eculizumab patients for a functional mutation in the C3 gene (rs2230199). The two alleles of this gene can be distinguished by the presence or absence of a HindIII restriction site that distinguishes the electophoretically slow (arg80) from the electrophoretically fast (gly80) allotype. The fast (C3F) allotype allele of this snp is associated with a range of disorders including age-related macular degeneration, IgA nephropathy, systemic vasculitis and partial lipodystrophy. APL-1 is a small cyclic peptide that binds to and inhibits the activation of complement C3. APL-2 is a large conjugate of APL-1 with enhanced bioactivity and a long systemic half-life. APL-1 and APL-2 molecules as well as other complement inhibitors were studied for lysis of red cells and C3 loading in vitro in a modified Ham test in which flow cytometry was used to identify non-lysed cells. Results Out of the 119 Eculizumab treated patients, 55 (46.2%) required at least one transfusion on treatment. 110 patients had C3 detectable by flow cytometry on their PNH red cells (mean of 19.8%; range: We studied one functional polymorphism in the Fcγ receptor but this showed no correlation with haemolytic parameters. Conversely, for the C3 polymorphism eculizumab-treated patients homozygous for the slow (C3S) allele had a significantly higher degree of C3 loading on PNH red blood cells with C3S/C3S having a mean of 33.7% C3 loaded PNH red cells (n=26), C3S/C3F 19.0% (n=19) and C3F/C3F 12.8% (n=3)(all P In vitro experiments show that inhibitors of C5, such as eculizumab, protect the PNH red cells from lysis but lead to a very rapid deposition of C3 on the PNH red cells. However both APL1 and APL2 demonstrated similar protection of PNH red cell lysis with virtually no C3 loading on PNH red cells. Conclusion A significant proportion of patients on eculizumab experience extravascular haemolysis with the majority of patients developing C3 loading. We show for the first time that a functional polymorphism in the C3 gene is associated parameters of hemolysis. The S(low) allele alters the function of C3 protein and appears to be associated with extravascular haemolysis in patients with PNH. The C3 inhibitors, APL-1 and APL-2, protect PNH red cells and prevent C3 loading in vitro and if safe to be given chronically would be expected to reduce extravascular hemolysis significantly. Disclosures: Hill: Alexion Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kelly:Alexion: Honoraria. Richards:Alexion Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Hillmen:Alexion: Honoraria, Membership on an entity’s Board of Directors or advisory committees.