Advisory Role Research Articles

Strategic Planning and Family Business Sustainability: The Moderating Role of Advisory Role

Strategic Planning and Family Business Sustainability: The Moderating Role of Advisory Role

Structural embeddedness, entrepreneurial behavior, and firm performance in the industry network of small tourism enterprises: The moderating role of relational embeddedness and leadership self-efficacy

The survival and economic sustainability of small tourism enterprises (STEs) represent pressing industry issues that require attention. Drawing on network embedding theory, this paper proposes a conceptual framework that links the structural embeddedness of STEs' industry networks to entrepreneurial behavior and firm performance, while exploring the moderating roles of relational embeddedness and leadership self-efficacy. Empirical analysis using a sample of 420 STEs in China revealed several key findings: (1) STEs with a dominant position in the industry network tend to exhibit higher firm performance, and do so through timely and effective entrepreneurial behavior; (2) maintaining a dominant position in the industry network structure requires not only deep cooperation between business owners and other industry participants, but also the advisory role of family, relatives, and friends, who are close and responsible partners providing practical advice to small business owners that influence their entrepreneurial behavior; (3) however, the aforementioned benefits are conditional on entrepreneurs possessing a strong sense of leadership self-efficacy. Theoretical and practical implications are further discussed in this regard.

Out of the ivory tower: an explanation of the policy advisory roles of political scientists in Europe

Out of the ivory tower: an explanation of the policy advisory roles of political scientists in Europe

How Do Women on Board Reduce a Firm’s Risks to Ensure Sustainable Performance during a Crisis?

The research applies the Upper Echelons Theory and the Lehman Sisters Hypothesis to explain how women board members use investment, financial, and liquidity techniques to reduce risk and increase a firm’s value. An original dataset of listed US companies is analyzed to show how women strategists contribute to value creation and mitigate stock volatility and bankruptcy. A simultaneous equations approach captures the interplay between a company’s use of debt and financial derivatives. According to this research, organizations that employ derivative instruments benefit more from having women in advisory roles because women encourage proactive risk management and develop effective risk control measures. The research implies that businesses should actively promote gender equality on their boards rather than merely recognizing the need for diversity.

A Contextual-Ethnographic Study of Nzema Proverbs Related to Some ‘Medical Conditions’

Proverbs are terse but ‘condensed’ expressions which contain moral lessons. In every culture, proverbs form part of the nuggets of popular wisdom, expressed in the form of wise sayings (Maledo 2015). Among the Nzema of Ghana, proverbs permeate almost all communicative encounters. They are ‘injected’ into discourses to motivate people to behave well, and to repudiate vices in the society. This paper discusses the didactics and communicative values of Nzema proverbs related to health conditions (and impairments) such as blindness, deafness, leprosy, hunchback, goitre, hernia, rickets and migraine. Using primary data recorded during arbitration proceedings among the Nzema, the paper examines the advisory role of the proverbs. The findings demonstrate that many virtues are concealed in Nzema proverbs that incorporate certain medical conditions, which paradoxically are not about the mere experiences of such conditions; rather, the deeper meanings highlight the essence of hospitality, contentment, patience, hard-work, and genuine love among others. The paper has also shown that the Nzema employ such proverbs in appropriate discourse contexts to rebuke deviants, and to redirect the paths of members of the society. It is argued that the advisory messages entrenched in this category of proverbs largely promote ethical standards and help maintain social equilibrium and solidarity. The paper engages Hymes’ Ethnography of Communication model in the data analysis.

Spirometry services in England post-pandemic and the potential role of AI support software: a qualitative study of challenges and opportunities.

Spirometry services to diagnose and monitor lung disease in primary care were identified as a priority in the NHS Long Term Plan, and are restarting post-COVID-19 pandemic in England; however, evidence regarding best practice is limited. To explore perspectives on spirometry provision in primary care, and the potential for artificial intelligence (AI) decision support software to aid quality and interpretation. Semi-structured interviews with stakeholders in spirometry services across England. Participants were recruited by snowball sampling. Interviews explored the pre- pandemic delivery of spirometry, restarting of services, and perceptions of the role of AI. Transcripts were analysed thematically. In total, 28 participants (mean years' clinical experience = 21.6 [standard deviation 9.4, range 3-40]) were interviewed between April and June 2022. Participants included clinicians (n = 25) and commissioners (n = 3); eight held regional and/or national respiratory network advisory roles. Four themes were identified: 1) historical challenges in provision of spirometry services; 2) inequity in post- pandemic spirometry provision and challenges to restarting spirometry in primary care; 3) future delivery closer to patients' homes by appropriately trained staff; and 4) the potential for AI to have supportive roles in spirometry. Stakeholders highlighted historic challenges and the damaging effects of the pandemic contributing to inequity in provision of spirometry, which must be addressed. Overall, stakeholders were positive about the potential of AI to support clinicians in quality assessment and interpretation of spirometry. However, it was evident that validation of the software must be sufficiently robust for clinicians and healthcare commissioners to have trust in the process.

Zero-Shot Assistance in Sequential Decision Problems

We consider the problem of creating assistants that can help agents solve new sequential decision problems, assuming the agent is not able to specify the reward function explicitly to the assistant. Instead of acting in place of the agent as in current automation-based approaches, we give the assistant an advisory role and keep the agent in the loop as the main decision maker. The difficulty is that we must account for potential biases of the agent which may cause it to seemingly irrationally reject advice. To do this we introduce a novel formalization of assistance that models these biases, allowing the assistant to infer and adapt to them. We then introduce a new method for planning the assistant's actions which can scale to large decision making problems. We show experimentally that our approach adapts to these agent biases, and results in higher cumulative reward for the agent than automation-based alternatives. Lastly, we show that an approach combining advice and automation outperforms advice alone at the cost of losing some safety guarantees.

IMMUNE CONTEXTURE ANALYSIS IN POLARIX SUGGESTS RESPONSE TO POLA‐R‐CHP TREATMENT REDUCES TUMOR MICROENVIRONMENT DEPENDENCY

IMMUNE CONTEXTURE ANALYSIS IN POLARIX SUGGESTS RESPONSE TO POLA‐R‐CHP TREATMENT REDUCES TUMOR MICROENVIRONMENT DEPENDENCY

Long‐term efficacy and safety of zanubrutinib (ZANU) in relapsed/refractory marginal zone lymphoma (R/R MZL): final analysis of the MAGNOLIA (BGB‐3111‐214) trial

Long‐term efficacy and safety of zanubrutinib (ZANU) in relapsed/refractory marginal zone lymphoma (R/R MZL): final analysis of the MAGNOLIA (BGB‐3111‐214) trial

MOSUNETUZUMAB DEMONSTRATES DURABLE RESPONSES IN PATIENTS WITH RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA AND ≥2 PRIOR THERAPIES: UPDATED ANALYSIS OF A PIVOTAL PHASE II STUDY

MOSUNETUZUMAB DEMONSTRATES DURABLE RESPONSES IN PATIENTS WITH RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA AND ≥2 PRIOR THERAPIES: UPDATED ANALYSIS OF A PIVOTAL PHASE II STUDY

CIRCULATING TUMOR DNA (CTDNA) STATUS AND CLINICAL OUTCOMES IN PATIENTS (PTS) WITH PREVIOUSLY UNTREATED DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL) IN THE POLARIX STUDY

CIRCULATING TUMOR DNA (CTDNA) STATUS AND CLINICAL OUTCOMES IN PATIENTS (PTS) WITH PREVIOUSLY UNTREATED DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL) IN THE POLARIX STUDY

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Bruton tyrosine kinase inhibitors (BTKi) block B-cell receptor pathway signaling, leading to growth inhibition and cell death in malignant B-cells. First-generation BTKi, ibrutinib (ibr) revolutionized treatment; however, inhibition of off-target kinases such as EGFR, HER2, TEC, and CSK may be associated with toxicities, including diarrhea, rash, bleeding, and atrial fibrillation (Afib), that limit its use. Zanubrutinib (zanu), a potent and selective next-generation BTKi, maximizes BTK occupancy and minimizes off-target effects. Here, we characterized the overall safety/tolerability of zanu and compared it with ibr in patients (pts) with B-cell malignancies using the zanu clinical safety database. Methods: Safety data were pooled from 10 clinical trials of zanu monotherapy; 2 of the included studies (ASPEN; ALPINE) compared zanu head to head with ibr. Pts with CLL/SLL, MCL, MZL, WM, FL and other B-cell malignancies were included. Treatment-emergent adverse events (TEAEs) were summarized using MedDRA preferred terms; adverse events of special interest (AESI) were defined using pooled terms. Rates of TEAEs, exposure-adjusted incidence rates (EAIRs), and prevalence over time of AESI were assessed. Results: Pooled analyses included 1550 pts treated with zanu. Median zanu exposure was 28.6 months with 31.2% of pts having treatment exposure of ≥36 mo. Most common nonhematologic AEs were upper respiratory tract infection (29.0%), diarrhea (19.9%), contusion (19.4%), cough (17.2%), and rash (16.2%); grade ≥3 nonhematologic AEs occurring in ≥5% of pts included pneumonia (7.9%) and hypertension (7.4%). The most common serious AE was pneumonia (7.5%). Zanu discontinuation due to AE occurred in 12.3% of pts; AEs leading to dose reduction occurred in 9.6%. Disease progression was the most common cause of death (7.2%); deaths attributed to AEs occurred in 5.6% of pts, and most (3.2%) were due to infections including COVID-19-related AEs. The most common AESI in the pooled zanu population and in ibr-treated pts from ASPEN and ALPINE (N = 422) were infections and hemorrhage (Table). With the exception of neutropenia, EAIRs were numerically lower for zanu versus ibr, most notably hypertension (0.57 vs. 1.15 person/100 person-months), anemia (0.54 vs. 0.84 person/100 person-months), and atrial fibrillation or flutter (0.15 vs. 0.70 person/100 person-months). Prevalence of zanu AESI tended to remain constant or decrease with longer follow-up. Conclusions: As BTKi therapy requires continuous treatment, long-term tolerability and low treatment discontinuation rates are needed for successful outcomes. zanu was well tolerated, with generally mild-to-moderate AEs that tended not to lead to treatment discontinuation. Prevalence of AESI generally trended down over time without emergence of new safety signals, supporting zanu as a good option for long-term treatment. Encore Abstract - previously submitted to EHA 2023 The research was funded by: BeiGene Keywords: Aggressive B-cell non-Hodgkin lymphoma, Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract. J. R. Brown Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Octapharma, Oncternal, MingSight, TG Therapeutics Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, SecuraBio, Sun, TG Therapeutics B. Eichorst Consultant or advisory role: Janssen, AbbVie, Gilead, AstraZeneca, BeiGene, MSD, Lilly Honoraria: Roche, AbbVie, BeiGene, AstraZeneca, MSD Research funding: Janssen, Gilead, Roche, AbbVie, BeiGene, AstraZeneca Educational grants: BeiGene P. Ghia Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo Oncology, MSD, Roche Honoraria: AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo Oncology, MSD, Roche Research funding: AbbVie, AstraZeneca, BMS, Janssen W. Jurczak Consultant or advisory role: Abbvie, Astra Zeneca, BeiGene, Lilly, Roche, Takeda Research funding: Abbvie, Astra Zeneca, BeiGene, Janssen, Lilly, Roche, Takeda B. S. Kahl Consultant or advisory role: BeiGene, Pharmacyclics, AstraZeneca, Abbvie, Janssen Other remuneration: BeiGene N. Lamanna Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Janssen, Pharmacyclics Research funding: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Octapharma, Oncternal, MingSight, TG Therapeutics T. Robak Honoraria: AstraZeneca, BeiGene, Janssen, Abbvie, Octapharma, Regeneron, GSK Research funding: BeiGene,OctaPharma, AstraZeneca, Janssen, Regeneron, GSK, Educational grants: AstraZeneca M. Shadman Consultant or advisory role: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys/Incyte, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio, Regeneron, Merck, Fate therapeutics, MEI pharma and Atara Biotherapeutic Research funding: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, AbbVie, TG Therapeutics, Beigene, AstraZeneca, Sunesis,Atara Biotherapeutics, Genmab, Morphosys/Incyte C. S. Tam Honoraria: BeiGene, AbbVie, Janssen Research funding: Janssen, AbbVie Other remuneration: BeiGene L. Qiu Consultant or advisory role: Janssen, Astra Zeneca, Takeda, Roche, Abbvie, Beigene A. Cohen Employment or leadership position: BeiGene Stock ownership: BeiGene M. Zhang Employment or leadership position: BeiGene T. Salmi Employment or leadership position: BeiGene International GmbH Stock ownership: BeiGene Ltd. J. Paik Employment or leadership position: BeiGene L. Wang Employment or leadership position: BeiGene Stock ownership: BeiGene J. Zhang Employment or leadership position: BeiGene Stock ownership: BeiGene H. Ma Employment or leadership position: BeiGene Stock ownership: BeiGene A. Tedeschi Consultant or advisory role: BeiGene, AstraZeneca, AbbVie, Janssen Honoraria: BeiGene, AstraZeneca, AbbVie, Janssen

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas with a poor prognosis for relapsed/refractory disease. The WHO classification of NK and T-cell lymphomas includes 39 entries; the 3 most common subtypes in the US are PTCL-NOS (not otherwise specified), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large-cell lymphoma (ALCL). Except for brentuximab vedotin in CD30-positive disease, agents were generally approved based on overall response rates (ORR) of less than 30%. The PRIMO Trial (NCT03372057; sponsored by Secura Bio, Inc.) evaluated duvelisib (DUV), an oral dual inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ and PI3K-γ isoforms in PTCL. Anti-tumor activity of single agents may not be uniform across different PTCL subtypes. Here we present data on 3 specific subtypes of some of the patients (pts) included in the PRIMO trial (fully enrolled as of January 2022). Methods: Eligibility criteria included adults with pathologically confirmed PTCL after ≥2 cycles of at least 1 prior standard regimen. A criterion for CD4 lymphocyte count ≥50/mm3 was added for the Expansion Phase (EP). Based on dose optimization results, the EP dose was DUV 75 mg BID for 2 cycles, to maximize disease control, followed by 25 mg BID, to mitigate late toxicities, until progressive disease/unacceptable toxicity. Pneumocystis jirovecii prophylaxis was required; herpes simplex and varicella zoster virus prophylaxis were indicated as needed. The primary endpoint was ORR by IRC assessment (Lugano 2014 criteria); efficacy is or will be assessed in all pts who received ≥1 dose of DUV. Secondary objectives included additional outcome measures, safety, and pharmacokinetics. Exploratory endpoints included pharmacodynamics and biomarkers. Results: The PRIMO study included 101 pts from the EP (data cutoff October 1, 2021), with a median follow-up of 8.7 months (mo) from time of first response. In the overall PRIMO study (N = 101), pts had a median age of 67.0 (21–92) years, a median of 3 (1–9) prior lines of therapy, an ORR (by IRC) of 49%, a CR rate of 34%, and a median PFS of 3.6 mo. Pts with the 3 most common histology subtypes from the PRIMO study are included in the current analysis (n = 97); these are PTCL-NOS (n = 52), AITL (n = 30), and ALCL (n = 15). Median PFS stratified by baseline histology was 3.5 mo (PTCL-NOS), 9.1 mo (AITL), and 1.5 mo (ALCL). Table 1 shows additional outcomes by histology. Adverse events seen were consistent with those observed previously in the PRIMO trial with no additional unexpected treatment-related toxicities. Conclusions: The ORR (by IRC) of DUV was higher in pts with PTCL-NOS (48%) and AITL (67%), compared with ALCL (13%). This corresponded to a longer median PFS of 3.5 mo in PTCL-NOS and 9.1 mo in AITL compared with 1.5 mo in ALCL. Although not powered for subset analyses, this analysis suggests activity of DUV may not be uniform across different types of lymphomas. Encore Abstract - previously submitted to EHA 2023 The research was funded by: Secura Bio, Inc. Keywords: molecular targeted therapies, ongoing trials Conflicts of interests pertinent to the abstract. N. Mehta-Shah Consultant or advisory role: AstraZeneca, Celgene/BMS, C4 Therapeutics, Celgene, Corvus, Daiichi Sankyo, Genentech/Roche, Innate Pharmaceuticals, Karyopharm, Kyowa Kirin, ONO Pharmaceuticals, Secura Bio, Verastem ​ E. D. Jacobsen Consultant or advisory role: Ascerta, Astra-Zeneca, Merck; Pharmacyclics, F. Hoffman-LaRoche, Novartis, Takeda P. L. Zinzani Consultant or advisory role: Celltrion, Gilead, Janssen-cilag, BMS, Servier, Sandoz, MSD, TG therapeutics, Takeda, Roche, Eusapharma, Kyowa Kirin, Novartis, ADC Therapeutics, Incyte, Beigene, Secura Bio​ J. Zain Consultant or advisory role: Kyowa Kirin, Mundi, Seattle Genetics​ G. Gritti Consultant or advisory role: Beigene, Clinigen, Genmab, Ideogen, Incyte, IQVIA, Italfarmaco, Kite-Gilead, Roche, Sandoz, Takeda K. Izutsu Consultant or advisory role: Celgene/BMS, MSD, AstraZeneca, AbbVie, Eisai, Incyte, Solasia, Novartis, Bayer, Pfizer, Janssen, Yakult, Kyowa Kirin, ONO Pharmaceuticals, Daiichi Sankyo, Chugai, Takeda, Beigene, Genmab, Otsuka, Loxo Oncology, FUJIFILM Toyamachemical, Symbio​ S. Waters Employment or leadership position: Secura Bio, Inc. J. E. Brammer Consultant or advisory role: BMS, Verastem Consultancy: Kymera, Seattle Genetics B. Pro Consultant or advisory role: Takeda, Seattle Genetics, Celgene, Verastem, Astex pharmaceuticals S. M. Horwitz Consultant or advisory role: ADC Therapeutics, Affimed, Celgene, Crispr Therapeutics, Daiichi Sankyo, Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Verastem/SecuraBio, Acrotech Biopharma, C4 Therapeutics, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, SecuraBio, Shoreline Biosciences, Inc., Takeda, Trillium Therapeutics, Tubulis, Cimieo Therapeutics

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Off-the-shelf allogeneic T-cell therapies face the major challenges of graft-versus-host disease (GVHD) and graft rejection mediated by host and recipient alloreactive T cells, respectively. To address GVHD, we are using Epstein-Barr Virus-specific T cells (EBVST), which are virus specific rather than allo-specific and have not produced GVHD in over 300 allogeneic recipients. To prevent graft rejection, we modified the EBVST with a chimeric antigen receptor (CAR) targeting CD30, an antigen that is upregulated on allo-activated T-cells, which will consequently become targets for CD30.CAR EBVST. Hence, CD30.CAR EBVST can kill both CD30+ lymphoma cells and alloreactive T cells through their CAR, and may be boosted in vivo in EBV+ recipients via their native TCR. We are evaluating this approach in a phase 1 trial (NCT04288726) in patients with CD30+ lymphoma. We generated a bank of 7 CD30.CAR EBVST products by stimulating PBMC from healthy donors with overlapping EBV peptide mixtures followed by retroviral transduction with a 2nd generation, CD28-containing CD30.CAR. We have treated 16 patients (median age 36, range 22–53) with relapsed or refractory HL. Patients had undergone a median of 5 (range 3–7) prior lines of treatment. Escalating doses of 4 × 107 − 8 × 108 (DL1–4) CD30.CAR EBVST were infused after lymphodepletion. The frequency of CD30.CAR EBVST was measured by real time qPCR for the transgene in blood. Changes in the frequency of T-cells responding to EBV or tumor-associated antigens (epitope spreading) were measured by IFNɣ ELISpots. Clinical responses were assessed per Lugano criteria by PET/CT scans performed 4–8 wks post infusion. CD30.CAR EBVST were well tolerated, with no GVHD and only two patients having reversible grade 4 cytopenia. Five patients at DL3–4 had grade 1 cytokine release syndrome (CRS), but all resolved without treatment. Of the 16 patients treated, 6 had partial responses (PR) and 6/13 patients at DL2–4 had complete responses (CR), giving an overall objective response rate (ORR) of 75%. Despite these remarkable responses, qPCR for the CD30.CAR transgene showed near background levels by wk 1 post infusion. Although this could mean that CAR-T are quickly eliminated by alloreactive T-cells, additional infusions from the same donor product into the same patient can be associated with response (Figure 1); an alloreactive response would be anticipated to be amplified after each infusion and preclude additional responses. We are therefore analyzing tumor biopsy samples to determine the presence of CD30.CAR EBVST at tumor sites and characterize their phenotype for functionality. The research was funded by: Leukemia and Lymphoma Society SCOR (Heslop) and Tessa Therapeutics (Rooney/Ramos) through a grant to Baylor College of Medicine. Keywords: cellular therapies, Hodgkin lymphoma Conflicts of interests pertinent to the abstract C. A. Ramos Consultant or advisory role: Novartis, Genentech, CRISPR Therapeutics Research funding: Tessa Therapeutics, Athenex Therapeutics Other remuneration: Royalties: Tessa Therapeutics D. H. Quach Research funding: Tessa Therapeutics P. D. Lulla Research funding: Marker Therapeutics, Allovir R. H. Rouce Consultant or advisory role: Pfizer, Novartis Honoraria: Novartis, Medline Plus Research funding: Tessa Therapeutics B. J. Grilley Consultant or advisory role: Allovir, Marker Therapeutics, Tessa Therapeutics, Lokon Pharma, March Bio and Proxima Clinical Research Stock ownership: Allovir, QBRegulatory LLC N. Lapteva Consultant or advisory role: Tessa Therapeutics Research funding: Tessa Therapeutics M. K. Brenner Employment or leadership position: Founder Member Marker Therapeutics Consultant or advisory role: Tessa Therapeutics, Marker Therapeutics, Allogene, Walking Fish, Athenex, Turnstone Biologics, Posedia, Tscan, Bluebird Bio, Adaptimmune Therapeutics, Adintus, Onkimure, Triumvira Immunologics, Bellicum Pharmaceuticals, Memgen LLC, Brooklyn Immunotherapeutics, Coya, Astrazeneca Pharmaceuticals Stock ownership: Allovir, Marker Therapeutics, Tessa Therapeutics, Turnstone, Bluebird Bio, Allogene, Walking Fish, AlloVir, Tessa, Tscan Other remuneration: Royalties: Takeda, Bellicum, Marker Therapeutics H. E. Heslop Consultant or advisory role: Gilead Biosciences, Novartis, Tessa Therapeutics, Marker Therapeutics, Kiadis, PACT Pharma, Mesoblast, Ankyra Therapeutics Stock ownership: Allovir, Marker Therapeutics, Fresh Wind Biotechnologies, CoRegen Inc. Research funding: Tessa Therapeutics, Athenex Therapeutics C. M. Rooney Consultant or advisory role: Tessa Therapeutics, Marker Therapeutics, Cell Genix Stock ownership: Allovir, Marker Therapeutics Research funding: Tessa Therapeutics Other remuneration: Royalties: Takeda, Marker, Allovir, Bellicum

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: BTK-inhibitors have revolutionized treatment of CLL. However, although patients (pts) above 80 years of age represent roughly 20% of the general CLL-population they remain underrepresented in clinical trials. Comorbidities, frailty, and organ dysfunction have a high prevalence in older pts and significant impact on efficacy and tolerability of treatments as well as survival. The CLL-Frail trial aims to evaluate the efficacy and safety of acalabrutinib monotherapy in pts ≥80 years of age and/or a FRAIL scale score of ≥3. The FRAIL scale score is a 5-item questionnaire for pts correlating with Fried‘s frailty phenotype. Methods: Pts in need of treatment with previously treated and untreated CLL and ≥80 years of age and/or a FRAIL scale score ≥3 were eligible. A maximum of one previous therapy was allowed. At least 50% of pts needed to fulfil frailty criteria. Pts received acalabrutinib 100 mg BID until progression or intolerance. The primary endpoint was overall response rate at initial response assessment (cycle 7, day 1 = ∼6 months after initiation of therapy). A pre-planned interim safety analysis was conducted once 30 pts reached cycle 7, day 1. Results: 30 pts were enrolled in the first 12 months of recruitment. Median age was 82 years, 50% had a FRAIL scale score of ≥3. Median CIRS score was 10, with 73% of pts having a score >6. Median ECOG-Score was 1. Most pts had a Binet stage A (77%). Unmutated IGHV and TP53mut/del was present in 63% and 10%, respectively. 19 pts (63%) were treatment naïve. In the previously treated cohort, prior lines of treatment included chemoimmunotherapy in 73% and ibrutinib + obinutuzumab + venetoclax, bendamustine + ibrutinib + ofatumumab and obinutuzumab + venetoclax in 9% of pts each. At the data cut in November 2022 the median observation time was 8 months, 21 pts remained on therapy. Reasons for discontinuation were adverse events in five (56%) and death and withdrawn consent in two (22%) pts each, respectively. All pts experienced at least one AE, totalling in 200 AEs of which 35 (18%) were CTC grade >3 (patient level analysis is shown in Table 1). 15 severe adverse events were reported, of which eight (53%) were assessed as treatment-related by the investigator. There were no cases of severe (Grade ≥3) bleeding, two pts (6%) experienced atrial fibrillation with CTC grade two and three, respectively. Two cardiac SAEs termed cardiac failure were reported in pts who both had prior existing hypertension and atrial fibrillation. Four pts (13%) died, of which one death was deemed treatment related. Causes of death were infection in three cases (one bacterial and two COVID-19 pneumonia) and concomitant disease in one case. Conclusions: The first interim analysis of this international phase II study evaluating treatment with acalabrutinib in very old and/or frail pts with CLL did not show unexpected safety signals in comparison to prior published data. Encore Abstract - previously submitted to EHA 2023 The research was funded by: AstraZeneca Keywords: Cancer Health Disparities, Chronic Lymphocytic Leukemia (CLL), Ongoing Trials Conflicts of interests pertinent to the abstract. F. Simon Research funding: AstraZeneca T. Nösslinger Honoraria: Astra Zeneca, Abbvie, Beigene, Janssen, Roche, Gilead J. Bohn Other remuneration: Astra Zeneca, Abbvie, Janssen J. von Tresckow Consultant or advisory role: AbbVie, Amgen, AstraZeneca, Beigene, Janssen, Lilly, Roche Honoraria: AbbVie, AstraZeneca, Beigene, Janssen, Lilly. Roche Educational grants: AbbVie, AstraZeneca, Beigene, Janssen, Lilly, Roche C. Schneider Honoraria: AbbVie, AstraZeneca S. Stilgenbauer Consultant or advisory role: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis Honoraria: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis Research funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis K. Kreuzer Consultant or advisory role: Roche, Janssen, Abbvie, Mundipharma Honoraria: Roche, Janssen, Abbvie, Mundipharma Research funding: Roche, Janssen, Abbvie, Mundipharma A. Fink Honoraria: AstraZeneca Research funding: AstraZeneca, Celgene Educational grants: AbbVie K. Fischer Consultant or advisory role: AstraZeneca Honoraria: AbbVie, Roche, Lilly Educational grants: Roche V. Goede Consultant or advisory role: Astra Zeneca, AbbVie, Janssen, Gilead, Merck, Berlin Chemie Honoraria: Astra Zeneca, AbbVie, Janssen, Gilead, Heel M. Hallek Consultant or advisory role: Roche, Janssen, Gilead, Bristol Myers Squibb, Abbvie Honoraria: Roche, Janssen, Gilead, Bristol Myers Squibb Research funding: Roche, Janssen, Gilead, Bristol Myers Squibb, Abbvie B. Eichhorst Consultant or advisory role: Abbvie, Beigene, AstraZeneca, Novartis, Celgene, ArQule, Oxford Biomedica (UK), MSD, Fa. Hoffmann-La Roche Ltd., Gilead, Janssen Honoraria: Abbvie, Beigene, AstraZeneca, Novartis, Celgene, ArQule, Oxford Biomedica (UK), MSD, Fa. Hoffmann-La Roche Ltd., Gilead, Janssen, Adapative Biotechnologies, Hexal Research funding: Abbvie, Beigene, AstraZeneca, Fa. Hoffmann-La Roche Ltd., Gilead, Janssen Educational grants: Abbvie, Beigene, AstraZeneca, Novartis, Celgene, Fa. Hoffmann-La Roche Ltd., Gilead, Janssen

Indolent lymphoma: Bendamustine, rituximab and acalabrutinib in Waldenstroms Macroglobulinemia (BRAWM)

Background: Waldenström’s macroglobulinaemia (WM) is an uncommon lymphoproliferative disorder. Many options are available, however, an optimal first-line therapy for WM has not be defined. We postulated that combining bendamustine and rituximab (BR) with a next generation BTK inhibitor would result in deeper responses as measured by complete response (CR) and very good partial response (VGPR) rates, and provide a longer duration of response. Objectives: The primary objective of this trial is to document the CR and VGPR rates Methods: The BRAWM clinical trial combines BR with acalabrutinib in a fixed duration treatment course including six cycles of BR and 12 months of acalabrutinib. This trial is taking place at 8 clinical sites across Canada and 33 patients have been enrolled, with a recruitment goal of 59. Results: A pre-defined interim analysis of the first 30 enrolled patients showed; median age of patients was 66; 25 were male; two patients were low risk, 14, intermediate and 15 high risk. Seventeen patients completed combination therapy, 9 completed monotherapy and 2 were followed-up at 18 months (6 months post therapy). Clinical results to date: Two patients discontinued treatment early; 1 at cycle 7 (with a VGPR) but experienced an adverse event requiring treatment; 1 at cycle 3 with possible disease progression. There were 186 treatment related adverse events (TRAEs) among 25 of 30 participants; 5 participants did not experience a TRAE; 163 of these occurred during combination therapy; 23 during monotherapy in 7 of 17 participants, where 10 participants did not experience a TRAE. During combination therapy, 16 of the 163 TRAE’s were grade 3; neutropenia (n = 8), including 2 that were febrile neutropenia, n = 1 for each: atrial fibrillation, transaminitis, cellulitis, fatigue and pulmonary emphysema. An additional five were also considered serious and included febrile neutropenia (n = 2), and n = 1 for each fever, allergic reaction and bowel obstruction. During monotherapy, there were no serious TRAEs. There were 2 grade 3 events during monotherapy in two different patients; decreased neutrophil count, and syncope. There were 21 dose interruptions in 11 participants, all but one of whom returned to regular dosage. Of assessed patients, 20/20 have MyD88 mutations, 4/20 have a CXCR4 mutation, and none had a TP53 mutation. Minimal residual disease (MRD) analysis using next generation sequencing of the IgV regions will be reported. Conclusions: Bendamustine, rituximab and acalabrutinib front-line therapy for WM is safe and well tolerated and initial clinical results show that this treatment induces a high percentage of VGPRs. The research was funded by: AstraZeneca Keywords: Combination Therapies, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. N. L. Berinstein Consultant or advisory role: AstraZeneca Research funding: AstraZeneca, Merck, IMV N. Forward Honoraria: AstraZeneca, AbbVie, BeiGene, Celgene/BMS, IMV, Kite, Janssen, Pfizer, Roche, Servier Research funding: Astellas, AstraZeneca, IMV, Merk, MorphoSys, Seattle Genetics, Roche Other remuneration: Speaker Fees: Pfizer, BeiGene, AstraZeneca M. Shafey Consultant or advisory role: Jansen, Roche Canada, Kite/Gilead, Novartis, BeiGene, Incyte, Abbvie, BMS, AstraZeneca A. Nikonova Consultant or advisory role: Forus, Janssen, Astra Zeneca, Apotex, Incyte Educational grants: Janssen D. MacDonald Honoraria: Abbvie, Astra Zeneca, Beigene, BMS, Incyte, Kite Gilead, Roche, and Seattle Genetics D. Villa Consultant or advisory role: AZ, BeiGene, Janssen, Roche, Kite/Gilead, Merck, BMS/Celgene, ONO Pharmaceuticals. Honoraria: AZ, BeiGene, Janssen, Roche, Kite/Gilead, Merck, BMS/Celgene, ONO Pharmaceuticals. Research funding: Roche, AstraZeneca I. Sandhu Honoraria: Celgene/BMS, Kite/Gilead, Janssen, Sanofi, FORUS, Pfizer M. Aljama Consultant or advisory role: Jansen, Sanofi, Pfizer, Beigene J. Larouche Consultant or advisory role: Incyte, Gilead Research funding: Incyte, Astra-Zeneca, Genmab

Outcomes with bendamustine lymphodepletion and brexucabtagene autoleucel for mantle cell lymphoma

Introduction: Brexucabtagene autoleucel (brexu-cel) is approved for relapsed/refractory mantle cell lymphoma (MCL). Cyclophosphamide/fludarabine for lymphodepletion (LD) is standard LD prior to brexu-cel. Due to a recent fludarabine shortage, we have utilized alternatives to fludarabine-based LD prior to brexu-cel, primarily bendamustine. We have previously reported our institutional experience with bendamustine LD prior to another anti-CD19 CAR T cell product. Methods: We retrospectively examined all patients with MCL who were treated with bendamustine LD followed by brexu-cel at our center from 2020 to 2022. Progression-free survival (PFS) was analyzed by Kaplan-Meier survival analysis. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus criteria. Results: Of 26 patients who received brexu-cel, 16 patients received bendamustine followed by brexu-cel. Median age was 65 years (range: 54–76). Median number of prior therapies was 3 (range: 3–8). All patients (100%) had received a BTK inhibitor prior to brexu-cel; 9/16 (56%) were BTKi refractory. 14/16 (88%) had received bridging therapy. 14/16 (88%) patients developed CRS; 11/14 (79%) had grade 1–2 CRS and 3 (19%) had grade 3 or greater CRS. 5 (31%) patients had ICANS; 2 (12.5%) had grade 1–2 ICANS, and 3 (19%) had grade 3 or greater ICANS. 10 (63%) patients received tocilizumab, 8 (50%) received dexamethasone, and 3 (19%) received anakinra for management of CRS and/or ICANS. Best objective response rate (ORR) was 81% with 11 (69%) patients achieving CR. Median follow-up was 13.4 months. Six month progression-free survival was 86% (95% CI: 54%–96%) and 12-month progression-free survival was 63% (95% CI: 32–82). Of 6 patients who had disease progression, two have died; median time to progression was 8.8 months. Encore Abstract - previously submitted to ASCO 2023 Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Immunotherapy Conflicts of interests pertinent to the abstract. E. A Chong Consultant or advisory role: Novartis, BMS, Beigene, Kite Research funding: Genentech J. N Gerson Research funding: LOXO D. J Landsburg Consultant or advisory role: Karyopharm, Morphosys, ADC Therapeutics, Calithera, Epizyme Research funding: Curis, Triphase S. K Barta Honoraria: Acrotech, Affimed, Daiichi Sankyo, Janssen, Kyowa Kirin J. Svoboda Consultant or advisory role: SEAGEN, Pharmacyclics, Incyte, Genmab, BMS, Atara, Astra Zeneca, Adaptive, ADCT Research funding: TG, SEAGEN, Pharmacyclics, Merck, Incyte, BMS, Astra Zeneca, Adaptive M. Ruella Other remuneration: Patent related to CAR T cells managed by the University of Pennsylvania D. L Porter Consultant or advisory role: Novartis, Kite/Gilead, Incyte, Gerson Lehrman Group, Janssen (Johnson and Johnson), Jazz, DeCART. BMS, Bluebird Bio, Angiocrine, Mirror Biologics, Capstan Therapeutics Stock ownership: Genentech, Roche (Spouse former employment) Research funding: Novartis Other remuneration: Patents, Royalties, Other Intellectual Property: Novartis, Tmunity N. V Frey Consultant or advisory role: Kite Pharmaceuticals, Sana Biotechnology, Mneumo therapeutics, Pfizer

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: TRANSFORM (NCT03575351) is a multinational, phase 3 study that compared efficacy and safety of liso-cel versus SOC, including overall survival (OS) as a key secondary endpoint, as a 2L treatment for patients (pt) with relapsed/refractory (R/R) large B-cell lymphoma who were eligible for transplant. The study design permitted pts treated with 2L SOC to receive liso-cel as third line (3L) treatment if protocol-defined conditions were met and requested by investigators. The intention-to-treat (ITT) analysis of OS for liso-cel versus SOC in TRANSFORM addressed a specific research question that did not account for treatment switching. Additionally, as real-world use of chimeric antigen receptor (CAR) T cell therapies in 3L may be less common compared with TRANSFORM, the ITT analysis may provide a conservative estimate of the treatment effect for liso-cel versus SOC on OS. Here, we conducted a complementary analysis of OS to adjust for crossover and estimate the relative effect of liso-cel versus SOC in the absence of 3L CAR T cell therapy. Methods: An external control arm based on external data from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) phase 3 study (NCT00137995) was created using the inverse probability of treatment weighting (IPTW) method. CORAL provided relatively mature survival data and reflects OS in the absence of CAR T cell therapies, which were not available at the time CORAL was conducted. After aligning inclusion/exclusion criteria of the 2 studies, 258 pts from CORAL were retained. To control for confounding, the 2L SOC cohort from CORAL was weighted to match the baseline distributions of prognostic factors and treatment effect modifiers of the liso-cel population in TRANSFORM. Relative efficacy was estimated by fitting a weighted Cox regression model to survival data for the external SOC arm from CORAL and the liso-cel arm from TRANSFORM. Results: After population adjustment via IPTW, the effective sample size (ESS) for SOC (CORAL) was 43.6% of the unadjusted sample size. The IPTW approach generally reduced imbalances in baseline characteristics between the 2 populations. The adjusted hazard ratio (HR; 95% CI) for liso-cel versus SOC was 0.50 (0.32–0.78), indicating that liso-cel was associated with a survival benefit in comparison with SOC in the absence of treatment switching (Table). Conclusions: These analyses demonstrated that liso-cel is associated with prolonged OS in comparison with SOC under a scenario of no 3L CAR T cell therapy, and the consideration of external data is a suitable alternative to existing statistical methods to adjust for treatment switching. The research was funded by: This study was funded by Bristol Myers Squibb. All authors contributed to and approved the abstract; writing and editorial assistance were provided by Emily Burke, PhD, of The Lockwood Group (Stamford, CT, USA), funded by Bristol Myers Squibb. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. F. Morschhauser Consultant or advisory role: Roche, Gilead, Abbvie Other remuneration: Membership on an entity's Board of Directors or advisory committees: Roche, Gilead, Novartis, BMS, Abbvie, Genmab, Miltenyi, Allogene therapeutics, AstraZeneca, Janssen H. Ghesquieres Consultant or advisory role: Gilead Sciences, Roche Honoraria: Gilead Sciences, Roche, Takeda Educational grants: Abbvie M. Kamdar Consultant or advisory role: AstraZeneca, Adaptive Biotechnologies, Abbvie, BeiGene, ADC Therapeutics, Syncopation Life Sciences, Bristol-Myers Squibb, Genetech/Roche Research funding: Novartis Other remuneration: Speakers' Bureau: Seattle Genetics F. F. Liu Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb C. Chandler Employment or leadership position: Conor Chandler is employed by Evidera, an independent research company that provides consulting services to life science companies; in his salaried position, he works with a variety of companies and is precluded from receiving payments or honoraria directly from these organizations for services rendered. Evidera received payment from Bristol Myers Squibb for the conduct of this study. A. Crotta Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb S. L. Klijn Employment or leadership position: Bristol Myers Squibb Consultant or advisory role: Bayer, Bristol Myers Squibb, Kite, Janssen - Payments made to OPEN Health Stock ownership: Bristol Myers Squibb A. Elsada Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb A. Previtali Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb I. Proskorovsky Employment or leadership position: Full-time employee of Evidera, which received funding from Bristol Myers Squibb to conduct this research. N. Schmitz Honoraria: Allogene Educational grants: Allogene, Miltenyi Other remuneration: Grants from Janssen, AstraZeneca, Abbvie J. S. Abramson Consultant or advisory role: Celgene, Novartis, Abbvie, Kite, Genetech, EMD Serono, MorphoSys, Alimera Sciences, Karyopharm Therapeutics, Bristol-Myers Squibb, C4 Therapeutics, BeiGene, AstraZeneca, Incyte, Bluebird Bio, Kymera, Epizyme, Genmab, MustangBio, Ono Pharmaceutical, Century Therapeutics, Lilly, Caribou Biosciences, Janssen, Takeda Honoraria: Regeneron, AstraZeneca, Janssen, Bristol-Myers Squibb Research funding: Seattle Genetics, AI Therapeutics, Bristol-Myers Squibb/Celgene

IMPACT OF RESPONSE TO SYSTEMIC BRIDGING THERAPY ON CLINICAL OUTCOMES AND CYTOKINE PROFILE IN PATIENTS RECEIVING CAR T‐CELL THERAPY FOR AGGRESSIVE B‐CELL LYMPHOMA

Background: It is unclear whether a deeper response to bridging therapy (BT) before chimeric antigen receptor (CAR) T cell therapy improves CAR-T treatment outcome in large B cell lymphoma (LBCL). We studied the impact of response to systemic BT on clinical outcomes and cytokine profiles of LBCL patients (pts) treated with CD19-directed CAR-T. Methods: We included LBCL pts treated with systemic BT before receiving commercial CD19-CAR-T at two academic centers, and excluded those who received monotherapy with glucocorticosteroids or isolated radiation therapy. BT was classified as Polatuzumab- (pola) based, intensive chemotherapy, lenalidomide/ Bruton tyrosine kinases inhibitors (len/BTKi), or other. PET/CT scans obtained before and after BT, and after CAR-T were evaluated using Lugano 2014 response criteria. Association between BT and response rates (RR) were examined using Fisher’s exact test, and the associations with cytokine levels were examined using Kruskal Wallis tests. Kaplan Meier analysis was used to estimate overall (OS) and progression free survival (PFS) from time of CAR T infusion. Cox proportional hazards models were used for univariable and multivariable analyses. Results: We identified 148 pts whose median age was 65 (range 23–85), and 96 (65%) were male. BTs included: 62 (42%) pola-based, 48 (32%) intensive chemotherapy, 25 (17%) len/BTKi, and 13 (9%) other BT. Among all pts, 77 (52%) received Axicel, 42 (28%) received Tisacel and 29 (20%) received Lisocel. Median time from apheresis to CAR-T was 35 days. Among evaluable pts RR to BT were: 10 (7%) complete responses (CR), 39 (29%) partial responses (PR), 87 (64%) either stable disease (SD) or progressive disease (PD). RR did not differ among different BT regimens (p = 0.27). At day 100 post-CAR-T, RR were: 74 (50%) CR, 27 PR (18%) and 44 (30%) SD/PD. With a median follow up of 18.9 months, PFS was 5.03 months (95% CI: 3.25, 9.53) and median (OS) was 16.1 months (95% CI 12.2–31.3) (Figure 1A). In multivariable analysis, poor response to BT (SD/PD) and elevated LDH prior to CAR-T infusion were associated with worse PFS, but not with OS. LDH (Figure 1B), ferritin, IL-6, IL-10 and C-reactive protein measured prior to lymphodepletion (LD) and at day 0 of CAR-T infusion were significantly higher in pts with SD/PD compared to pts achieving a CR/PR to BT. Ferritin levels prior to LD were higher in pts who received intensive chemotherapy compared to other BT. Keywords: aggressive B-cell non-Hodgkin lymphoma, cellular therapies Conflicts of interests pertinent to the abstract G. L. Shah Research funding: Janssen, Amgen, Beyond Spring, and BMS. DSMB for ArcellX M. Scordo Consultant or advisory role: McKinsey & Company, Angiocrine Bioscience, Inc., and Omeros Corporation; served on ad hoc advisory boards for Kite—A Gilead Company Honoraria: Received honoraria from i3Health and Medscape for CME-related activity Research funding: received research funding from Angiocrine Bioscience, Inc., and Omeros Corporation R. J. Lin Consultant or advisory role: Kite G. Salles Consultant or advisory role: Abbvie, Atbtherapeutics, Bayer, Beigene, BMS/Celgene, Debiopharm, Epizyme, Genentech/Roche, Genmab, Incyte, Ipsen, Janssen, Kite/Gilead, Loxo/Lilly, Molecular Partners, Morphosys, Nordic Nanovector, Novartis, Regeneron, Takeda H Stock ownership: Owkin M. Perales Consultant or advisory role: Adicet, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Syncopation, VectivBio AG, and Vor Biopharma. He serves on DSMBs for Cidara Therapeutics, Medigene, and Sellas Life Sciences, and the scientific advisory board of NexImmune. Research funding: He has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis. Other remuneration: He has ownership interests in NexImmune, Omeros and OrcaBio. M. L. Palomba Consultant or advisory role: Synthekine, Cellectar, Beigene, Kite, BMS

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: While nearly all younger patients (pts) with Hodgkin's lymphoma (HL) are cured with conventional chemotherapy, outcomes are significantly worse in those over age 60. Intriguingly, among older HL pts, those with EBV+ disease have even poorer outcomes (Keegan et al., JCO 2005), yet the biological basis for this phenomenon is not understood. The paucity of malignant cells in HL tumors has hampered genomic studies. Circulating tumor DNA (ctDNA) profiling can overcome these limitations, allowing noninvasive genotyping and risk stratification in HL (Spina et al., Blood 2018; Alig et al., ASH 2022). Here, we use a fully non-invasive approach for genomic profiling of elderly HL pts, focusing on the impact of ctDNA and EBV status on clinical outcomes. Methods: We profiled 57 pts (64%) from NCT02414568, a prospective, multicenter phase II LYSA-PVAB study of newly diagnosed classical HL >60 years (Ghesquières et al., ASH2019). All pts received 6 cycles of PVAB (prednisone, vinblastine, doxorubicin, and bendamustine). Plasma cfDNA was genotyped using Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq); MRD was monitored using Phased variant Enrichment and Detection Sequencing (PhasED-Seq). Pts were classified into high and low pretreatment ctDNA levels using a threshold of 2.5 log hGE/mL (Alig et al., ASH2022). We defined EBV status either by LMP1 staining of FFPE tumor tissue or by VirCAPP-Seq targeting 180 viral species, where a predefined threshold of 32 genomes/ml was previously validated as 94% accurate (Garofalo et al., ASH 2022). Results: Pretreatment ctDNA was detected in 94% of pts with a median concentration of 2.2% (MAF), which was significantly correlated with disease burden measured by TMTV (p = 0.034). Pts with high pre-treatment ctDNA levels (39%) had significantly worse PFS (HR = 2.3, p = 0.039). EBV+ pts also had inferior PFS (HR = 2.2, p = 0.04) and OS (HR = 3.1, p = 0.028) (Figures A-B). In multivariate analysis, both indices remained independently associated with worse outcomes (HR = 2.5, p = 0.01 for pre-treatment ctDNA and HR = 2.7, p = 0.01 for EBV status). Interestingly, pre-treatment ctDNA levels did not differ between EBV+ and EBV- tumors (p = 0.92), while specific genetic aberrations were significantly associated with respective EBV status (Figure C). Among evaluable pts for MRD monitoring, detection of ctDNA after four cycles of chemotherapy was highly associated with risk of death (Figure D). The research was funded by: NIH/NCI R01 R01CA257655 Keywords: Diagnostic and Prognostic Biomarkers, Genomics, Epigenomics, and Other -Omics, Hodgkin lymphoma Conflicts of interests pertinent to the abstract. C. Rossi Consultant or advisory role: Genmab, Janssen, Incyte Educational grants: Kyte, Abbvie S. K. Alig Consultant or advisory role: Takeda Pharmaceuticals D. M. Kurtz Consultant or advisory role: Adaptive Biotechnologies, Roche, Foresight O. Casasnovas Consultant or advisory role: Roche, Takeda Educational grants: Roche, Takeda, BMS, Janssen A. A. Alizadeh Consultant or advisory role: Adaptive Biotechnologies, Foresight Diagnostics, Roche, BMS, Gilead, Genentech, Karyopharm