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This study used a real-world population as a synthetic comparator for the single-arm TRANSCEND NHL 001 study (TRANSCEND; NCT02631044) to evaluate the efficacy of lisocabtagene maraleucel (liso-cel) compared with conventional (noncellular) therapies in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Inclusion and exclusion criteria for the real-world study closely matched the enrollment criteria in TRANSCEND. The analytic comparator cohort was created by matching and balancing observed baseline characteristics of real-world patients with those in TRANSCEND using propensity score methodology. Efficacy outcomes comparing liso-cel– (n = 257) and conventional therapy–treated (n = 257) patients, respectively, significantly favored liso-cel: overall response rate (74% vs 39%; p < 0.0001), complete response rate (50% vs 24%; p < 0.0001), median overall survival (23.5 vs 6.8 months; p < 0.0001), and median progression-free survival (3.5 vs 2.2 months; p < 0.0001). These results demonstrated a statistically significant and clinically meaningful benefit of liso-cel in patients with third- or later-line R/R LBCL relative to conventional therapies. Clinical trial registration: ClinicalTrials.gov identifier: NCT02631044.

Despite being predominantly a childhood disease, the incidence of acute lymphoblastic leukemia (ALL) has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterization to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1-positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and

Chromosomal abnormalities are established prognostic markers in adult ALL. We assessed the prognostic impact of established chromosomal abnormalities and key copy number alterations (CNA) among 652 patients with B-cell precursor ALL treated on a modern MRD driven protocol. Patients with KMT2A-AFF1, complex karyotype (CK) and low hypodiploidy/near-triploidy (HoTr) had high relapse rates 50%, 60% & 53% and correspondingly poor survival. Patients with BCR-ABL1 had an outcome similar to other patients. JAK-STAT abnormalities (CRLF2, JAK2) occurred in 6% patients and were associated with a high relapse rate (56%). Patients with ABL-class fusions were rare (1%). A small group of patients with ZNF384 fusions (n = 12) had very good survival. CNA affecting IKZF1, CDKN2A/B, PAX5, BTG1, ETV6, EBF1, RB1 and PAR1 were assessed in 436 patients. None of the individual deletions or profiles were associated with survival, either in the cohort overall or within key subgroups. Collectively these data indicate that primary genetic abnormalities are stronger prognostic markers than secondary deletions. We propose a revised UKALL genetic risk classification based on key established chromosomal abnormalities: (1) very high risk: CK, HoTr or JAK-STAT abnormalities; (2) high risk: KMT2A fusions; (3) Tyrosine kinase activating: BCR-ABL1 and ABL-class fusions; (4) standard risk: all other patients.

Background: Tafasitamab, an anti-CD19 immunotherapy that enhances antibody-dependent cellular cytotoxicity and phagocytosis, received accelerated approval in the USA and conditional authorization in Europe in combination with lenalidomide (LEN) for patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) based on the results of the open-label, multicenter, single-arm, Phase II L-MIND study (NCT02399085; Salles G, et al. Lancet Oncol 2020, Duell J, et al. Haematologica 2021). Here, we report the final, 5-year follow-up of L-MIND. Data cut-off was Nov 14, 2022. Methods: Pts were aged ≥18 years with ASCT-ineligible R/R DLBCL, 1-3 prior systemic therapies (including a CD20-targeting regimen), and ECOG PS 0-2. Tafasitamab (12 mg/kg) was given for up to 12 cycles in combination with LEN (25 mg), then as monotherapy until disease progression (PD) or unacceptable toxicity. The primary endpoint was best objective response rate (ORR; complete response [CR] or partial response [PR], by independent radiology committee). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and incidence and severity of adverse events (AEs). Exploratory analyses evaluated efficacy endpoints by prior lines of therapy (pLoT). Results: Of 81 pts enrolled, 80 were treated (full analysis set [FAS]). The ORR (FAS) of 57.5% [95% CI: 45.9-68.5], with CR of 41.2% [30.4-51.6] (n=33) and PR of 16.2% [8.9-26.2] (n=13), was generally consistent with the primary and 3-year analyses. Median DoR was not reached (NR) with median follow up (mFU) of 44.0 months [29.9-57.0]. Median PFS was 11.6 months [5.7-45.7] (mFU 45.6 [22.9-57.6]) and median OS was 33.5 months [18.3-NR] (mFU 65.6 [59.9-70.3]). At data cut-off, OS was >60 months in 21 pts (18 with best response of CR, 1 PR, 1 stable disease and 1 PD), including 14 with 1 pLoT and 7 with ≥2 pLoT. Pts with 1 pLoT (n=40) in the FAS had higher ORR (67.5%; 52.5% CR [n=21] and 15% PR [n=6]) compared to pts with ≥2 pLoT (n=40; 47.5%; 30% CR [n=12] and 17.5% PR [n=7]). However, median DoR was not reached for both subgroups, indicating similar long-term efficacy for responders. AEs were consistent with previous reports and manageable; incidence declined after transition from combination to tafasitamab monotherapy and again with monotherapy >2 years. Conclusion: The final, 5-year analysis of L-MIND showed prolonged durable responses with tafasitamab + LEN combination therapy, followed by long-term tafasitamab monotherapy, in pts with R/R DLBCL ineligible for ASCT, with median DoR not reached after 44 months mFU. No new safety signals were identified, confirming the tolerability profile observed with earlier data cuts. These long-term data suggest that this immunotherapy may have curative potential that is being explored in further studies. Citation Format: Johannes Duell, Pau Abrisqueta, Marc Andre, Marinela Augustin, Gianluca Gaidano, Eva González Barca, Wojciech Jurczak, Nagesh Kalakonda, Anna Marina Liberati, Kami J. Maddocks, Tobias Menne, Zsolt Nagy, Olivier Tournilhac, Abhishek Bakuli, Aasim Amin, Konstantin Gurbanov, Gilles Salles. Five-year efficacy and safety of tafasitamab in patients with relapsed or refractory DLBCL: Final results from the phase II L-MIND study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT022.

Patients with hematological malignancies are at increased risk of severe COVID-19 outcomes due to compromised immune responses, but the insights of these studies have been compromised due to intrinsic limitations in study design. Here we present the PROSECO prospective observational study (NCT04858568) on 457 patients with lymphoma that received two or three COVID-19 vaccine doses. We show undetectable humoral responses following two vaccine doses in 52% of patients undergoing active anticancer treatment. Moreover, 60% of patients on anti-CD20 therapy had undetectable antibodies following full vaccination within 12 months of receiving their anticancer therapy. However, 70% of individuals with indolent B-cell lymphoma displayed improved antibody responses following booster vaccination. Notably, 63% of all patients displayed antigen-specific T-cell responses, which increased after a third dose irrespective of their cancer treatment status. Our results emphasize the urgency of careful monitoring of COVID-19-specific immune responses to guide vaccination schemes in these vulnerable populations.

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA)., Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.

Introduction: Chimeric Antigen Receptor T-cell therapy (CAR-T) is a potentially life-saving treatment for refractory haematological malignancies. Many UK CAR-T services are in their infancy. Patient perspectives on service delivery, treatment toxicity and impact on health related quality of life (HRQoL) are lacking. This qualitative evaluation aimed to explore the patient and carer experience of CAR-T and identify areas for service improvement. Methods: Patients who received CAR-T between April 2019 and March 2021 at the Freeman Hospital, Newcastle-upon-Tyne, who attended primary or follow-up appointments between December 2020 and March 2021 were asked if they wanted to take part in the evaluation. 16 semi-structured qualitative interviews were carried out with 10 patients and 4 carers at specific time points in the patient journey: hospital admission prior to CAR T-cell infusion, day 28 postinfusion and routine follow-up appointments after treatment (8, 9, 12 and 18 months). Five patients completed 2 interviews (pre-infusion and day 28). Results: The mean age of the patients was 54 and 60% were female. Nine patients had diffuse large B-cell lymphoma and one had primary mediastinal B-cell lymphoma. Inductive thematic analysis identified three main themes. The importance of the CAR-T nurse specialist as a point of contact was consistently identified by patients and carers as vital to navigating the treatment process. The continuity of care and approachability associated with this role were linked to patient satisfaction and perceived level of support received. Reported treatment toxicity centred on fatigue, poor appetite/weight loss and problems with memory and cognition. Patients and carers were well prepared for side effects in the acute treatment phase but some felt less prepared for prolonged impact on physical function and cognition after discharge. CAR-T therapy was viewed as a 'lifeline,' but the uncertainty of treatment outcome caused significant anxiety, disruption to employment and family life, and made it difficult to make future plans. Many responses were framed by the COVID-19 pandemic which increased feelings of isolation and vulnerability and had a significant, negative impact on HRQoL. Conclusions: To our knowledge this is the first qualitative work exploring the views of CAR-T patients and carers at multiple points in the patient journey, including perspectives on long-term treatment impact. Considerations for service creation and development nationally and internationally include: the importance of a dedicated nurse specialist, preparing patients for and supporting them with prolonged treatment side effects, and the psychological challenges associated with prognostic uncertainty. Expanding indications of CAR-T therapy mean there is an urgent need for multi-centre studies incorporating patient-reported outcome data to inform patient centred care and service delivery.

Introduction The phase 3 ECHELON-2 study (NCT01777152) demonstrated that frontline treatment with brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for patients (pts) with systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL) (Horowitz S, et al. Lancet 2019). With a median follow-up of 36.2 months for progression-free survival (PFS), the hazard ratio (HR) (0.71 [95% confidence interval {CI}: 0.54, 0.93], P=0.01) favored A+CHP over CHOP. The median PFS was 48.2 months (95% CI: 35.2, not evaluable) versus 20.8 months (95% CI: 12.7, 47.6) for A+CHP and CHOP, respectively. With a median follow-up of 42.1 months for overall survival (OS), the HR (0.66 [95% CI: 0.46, 0.95], P=0.02) also favored A+CHP over CHOP. Median OS was not reached for either arm. With these results, A+CHP was the first treatment regimen to show an OS benefit over CHOP in this pt population. Herein, we report results with a median follow-up of 44.3 months for PFS and 55.5 months for OS. Methods ECHELON-2 is a phase 3, randomized, double-blind, double-dummy, placebo-controlled, active-comparator, multicenter study. Eligible adult pts with previously untreated CD30-positive PTCL (targeting 75% ± 5% with sALCL) were randomized to A+CHP or CHOP for six or eight cycles. Randomization was stratified by histological subtype and international prognostic index score. The primary endpoint of PFS was assessed per blinded independent central review in the primary analysis and per investigator in this updated analysis. Key secondary endpoints were OS, PFS in sALCL, complete remission (CR) rate, and objective response rate (ORR). Subsequent therapies, including BV or BV-containing regimens, were permitted. Results A total of 452 pts were enrolled and randomized 1:1 with 226 pts in each arm. The study included pts with advanced disease (Stage III [27%] and Stage IV [53%]; IPI ≥2 [78%]); given target enrollment, most pts (316 [70%]) had sALCL (218 [48%] anaplastic lymphoma kinase [ALK]-negative and 98 pts [22%] ALK-positive). With additional follow-up, the HRs for PFS per investigator (0.70 [95% CI: 0.53, 0.91], P=0.0075) (Figure 1) and OS (0.74 [95% CI: 0.54, 1.02], P=0.0688) continue to favor A+CHP over CHOP. The median PFS was 63.5 months (95% CI: 42.0, not evaluable) versus 23.8 months (95% CI: 13.6, 55.9) for A+CHP and CHOP, respectively. The estimated 5-year PFS was 50.9% (95% CI: 42.1, 59.1) for the A+CHP arm versus 42.7% (95% CI: 35.3, 49.8) for the CHOP arm. Median OS was not reached for either arm. The estimated 5-year OS was 68.7% (95% CI: 61.3, 75.0) for the A+CHP arm versus 60.3% (95% CI: 52.8, 67.0) for the CHOP arm. The PFS analyses for key prespecified subgroups were generally consistent with the overall study results (Figure 2). In the subset of pts with sALCL, the HR for PFS (0.55 [95% CI: 0.39, 0.78]) also favors A+CHP over CHOP, with an estimated 5-year PFS of 59.8% (95% CI: 48.0, 69.7) for the A+CHP arm versus 48.1% (95% CI: 39.1, 56.6) for the CHOP arm. A total of 23 pts (10%) in the A+CHP arm (16 pts with sALCL, 4 pts with PTCL not otherwise specified, and 3 pts with angioimmunoblastic T-cell lymphoma) and 51 pts (23%) in the CHOP arm received subsequent systemic therapy with BV. In the A+CHP arm, the median time to retreatment was 12.3 months (range, 3, 51); 15 pts (ORR: 65%) had CR (9 pts) or partial remission (6 pts) after retreatment with BV monotherapy (21 pts) or BV-containing regimen (2 pts). With additional follow-up in pts with treatment-emergent peripheral neuropathy (PN) (117 pts A+CHP and 124 pts CHOP), 68% of pts in the A+CHP arm had either resolution or improvement of these events compared with 77% of pts in the CHOP arm. Of the pts with ongoing PN events at last follow-up, 73% in A+CHP arm and 74% in the CHOP arm had grade 1 events, 25% and 23% of pts, respectively, had grade 2 events, and 2% of pts in each arm had grade 3 events. Conclusions At 5 years, frontline treatment with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, including ongoing remission in ~60% of pts with sALCL, with a manageable safety profile, including continued resolution or improvement of PN. Additional 5-year results, including data from prespecified subgroups, will be presented. Disclosures Horwitz: C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Affirmed: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; ASTEX: Consultancy; Vividion Therapeutics: Consultancy; Beigene: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding. Pro:Verastem Oncology: Research Funding. Illidge:Takeda: Current Employment, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Iyer:Legend Biotech: Consultancy; Rhizen: Research Funding; Spectrum: Research Funding; CRISPR: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Target Oncology: Honoraria; Afffimed: Research Funding; Daiichi Sankyo: Consultancy; Merck: Research Funding; Seattle Genetics, Inc.: Research Funding. Advani:Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy; Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding. Bartlett:BTG: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy; Forty Seven: Research Funding; Autolus: Research Funding; Acerta: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed Therapeutics: Research Funding; BMS/Celgene: Research Funding; Roche/Genentech: Consultancy, Research Funding. Christensen:Odense University Hospital: Current Employment; Seattle Genetics, Inc.: Research Funding. Morschhauser:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Domingo-Domenech:Takeda: Consultancy, Other: Travel, accomodations and expenses , Research Funding; Bristol-Myers Squibb: Other: Travel, Research Funding; Roche: Other: Travel, accomodations and expenses ; Janssen: Other: Travel, accomodations and expenses ; Seattle Genetics, Inc.: Research Funding. Rossi:Takeda: Honoraria, 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; Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Kim:Donga: Research Funding; Joihnson & Johnson: Research Funding; Kyowa Kirin: Research Funding; Mundipharma: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Takeda: Research Funding; Celltrion: Research Funding. Feldman:Celgene: Honoraria, Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Rhizen: Research Funding; Janssen: Speakers Bureau; Pharmacyclics: Honoraria, Other, Speakers Bureau; AstraZeneca: Consultancy; Bayer: Consultancy, Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Other: Travel expenses; Pfizer: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Trillium: Research Funding; Portola: Research Funding; Corvus: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Viracta: Research Funding. Menne:Daiichi Sankyo: Honoraria; Kyowa Kirin: Other: Travel expenses; Pfizer: Honoraria, Other; Roche: Honoraria; Bayer: Other: Travel expenses; Kite/Gilead: Honoraria, Other: Travel expenses; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel expenses; Takeda: Honoraria; Atara: Honoraria; AstraZeneca: Research Funding; Amgen: Honoraria, Other: Travel expenses; Janssen: Honoraria, Research Funding. Belada:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Janssen: 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, Other: Travel expenses, Research Funding; Celgene: Research Funding. Illés:Celgene, Janssen, Novartis,Roche, Takeda: Consultancy; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria; Takeda, Seattle Genetics: Research Funding. Tobinai:Daiichi Sankyo: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria; Ono Pharma: Consultancy, Honoraria; Solasia: Honoraria; SymBio: Consultancy; Takeda: Consultancy, Honoraria; HUYA Bioscience: Consultancy, Honoraria; Eisai: Honoraria; Yakult: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Chugai Pharma: Consultancy, Honoraria. Tsukasaki:Ono Pharma: Consultancy; Mundy Pharma: Honoraria; HUYA: Consultancy, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Eizai: Research Funding; Seattle Genetics: Research Funding. Yeh:AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Shustov:Seattle Genetics: Research Funding. Hüttmann:Lead Discovery Center GmbH: Consultancy; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Other: Travel expenses; Seattle Genetics: Research Funding; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment. Savage:Verastem: Honoraria; Takeda: Honoraria; Servier: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria. Zinzani:Roche: Consultancy, Honoraria, 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; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Miao:Takeda: Current equity holder in publicly-traded company. Bunn:Seattle Genetics: Research Funding; Takeda: Current Employment. Fenton:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Puhlmann:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Truemper:Janssen: Consultancy; Mundipharma: Research Funding; Nordic Nanovector: Consultancy; Roche: Research Funding; Seattle Genetics: Research Funding; Takeda Europe: Consultancy, Research Funding.

IntroductionEvent free survival rates at 15 years for paediatric patients with relapsed/refractory acute lymphoblastic leukaemia (ALL) are 30-50%, with 5-year survival for adult patients only 20%. A large proportion of patients with newly diagnosed and relapsed ALL harbour somatic mutations that activate the RAS-signalling cascade. Steroids are a backbone of all induction blocks of ALL therapy, with preclinical data suggesting the combination of dexamethasone with the MEK1/2 inhibitor, selumetinib (ARRY-142886), results in a potent synergistic anti-cancer effect.Methods and analysisThe SeluDex trial is an international, parallel-group, dose-finding with expansion, phase I/II trial to assess the selumetinib/dexamethasone combination in adult and paediatric patients with relapsed/refractory, RAS pathway mutant ALL. The Cancer Research UK Clinical Trials Unit at University of Birmingham is the UK Coordinating Centre, with national hubs in Copenhagen, Denmark; Monza, Italy; Münster, Germany; Paris, France; and Utrecht, Netherlands. Paediatric centres are all part of the Innovative Therapies for Children with Cancer consortium. Patients with morphologically proven relapsed/refractory or progressive B-cell precursor or T-ALL, with demonstrated RAS pathway activating mutations are eligible. Adult patients are ≥18 years old, ECOG ≤2 and paediatric Ethics and disseminationMedical ethical committees of all the participating countries will approve the study protocol. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications.Trial registration numberThe trial was registered on EudraCT 2016-003904-29 on 21st September 2016, ISRCTN 92323261, ClinicalTrials.GovNCT03705507, and ITCC-063 study.Strengths and limitations of this studyNovel combination of the MEK1/2 inhibitor, selumetinib, with dexamethasoneSeamless phase I/II Bayesian trial design with a Continual Reassessment Method for dose escalation in phase IParallel cohort trial design of adult and paediatric patients within one protocolAvailability of CAR T-cell therapy since this trial started recruitment has competed for the same patient populationOffers a bridging treatment option for patients awaiting CAR T-cell therapy outside clinical studies or at relapse after CAR-T treatment

Background: In the treatment of advanced Hodgkin lymphoma, it is increasingly common UK practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3) to reduce haematopoietic stem cell and gonadal toxicity. However, published data of the "escalated BEACOPDac (eBPDac)" regimen are very limited. Methods: This is a retrospective study of 225 patients from 20 centres in the UK, Ireland and France who were treated with eBPDac first line for advanced stage Hodgkin Lymphoma. Toxicity outcomes were compared with 58 matched patients treated with eBPP at 4 UK centres and survival outcomes were compared with 2073 eBPP patients in the HD18 trial 1 and with 1088 patients aged 18-59y in the RATHL trial 2,3. Most eBPDac patients were treated as per HD18 protocol. The 34 patients treated in Paris followed the AHL2011 protocol with two courses of eBPDac given upfront and if iPET2 negative were deescalated to 4 cycles of ABVD. Toxicity outcomes: Toxicity was compared between eBPDac patients (n=225; median follow-up 22.1 months) and matched real-world UK eBPP patients (n=58; median follow-up 52.7 months) over the first 4 cycles. eBPP and eBPDac patients were well matched with no significant differences in age (median 23 y vs 26 y), sex, stage (stage 3/4 82% vs 83%) and international prognostic score (IPS 3+ 74% vs 65%). 55% of eBPDac patients received only 4 cycles (vs 12% of eBPP patients; p Disease outcomes: The eBPDac patients (n=225) were younger than the HD18 patients (median age 26 y vs 35 y, p Figure 1 shows Kaplan-Meier plots for progression-free survival (PFS) and overall survival (OS). The PFS at 22 months (median follow-up) of eBPDac patients was 94.9% (91.7-98.3%) which is similar to HD18 3 year PFS of 92.3% (91.1-93.5%) and appears superior to RATHL 5 year PFS 81.4% (78.9-83.7%). The difference in PFS between eBPDac and RATHL is most marked in IPS3+ patients. The OS rates with all 3 regimens are excellent, with 22 month eBPDac OS estimate of 98.9% (97.4-100%). Summary/Conclusion: Accepting the limitations of a retrospective study, we suggest that substituting dacarbazine for procarbazine is unlikely to compromise the efficacy of eBPP and may have some toxicity benefits. Despite the clear preference of clinicians to offer this regimen to high-risk advanced stage patients, with nearly 2 years median follow-up we have observed similar PFS and OS compared to HD18 but superior survival estimates compared with 18-59y RATHL patients, suggesting that eBPDac is highly efficacious for the treatment of Hodgkin lymphoma. References: 1Borchmann P et al. Lancet 2017; 390:2790-2802 2Johnson P et al. NEJM. 2016; 374:2419-2429 3Russell J et al. Ann Hematol 2021; 100:1049-1058 Figure 1 Figure 1. Disclosures Brice: MSD: Research Funding; Amgen: Other: Travel/accommodations/expenses; Roche: Other: Travel/accommodations/expenses; Takeda: Research Funding. Menne: Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Astra Zeneca: Research Funding; Jazz: Other: Travel grants; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Bayer: Other: Travel grants; Kyowa Kirin: Other: Travel grants; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Atara: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Honoraria for Lectures; Roche: Other: Honoraria for Lectures. Osborne: Roche: Other; Takeda: Other; Pfizer: Other; Servier: Other; Gilead: Other; Novartis: Other; MSD: Other. Ardeshna: Gilead, Beigene, Celegene, Novartis and Roche: Membership on an entity's Board of Directors or advisory committees; Gilead, Beigene, Celegene, Novartis and Roche: Honoraria; Norvartis, BMS, Autolus, ADCT, Pharmocyclics and Jansen: Research Funding. Collins: Pfizer: Honoraria; Amgen: Research Funding; AstraZeneca: Honoraria, Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Celgene: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celleron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. Cwynarski: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssenen: Other. Davies: Janssen: Honoraria, Research Funding; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma/AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; BioInvent: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding. Furtado: Abbvie: Other: Conference support. Gallop-Evans: Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Iyengar: Gilead: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: conference support; Janssen: Other: conference support, Speakers Bureau. Linton: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptitude Health: Honoraria; Hartley Taylor: Honoraria; University of Manchester: Current Employment; Celgene: Research Funding; BeiGene: Research Funding; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinez-Calle: Abbvie: Other. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Other: Travel Support; KITE: 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, Other: Travel Support; Janssen: Honoraria, Other: Travel Support; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nagumantry: Takeda, Alexion, Abbvie: Other. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Uttenthal: Jazz: Other; Takeda: Other; Roche: Other. McMillan: Pfizer: Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Abvie: Membership on an entity's Board of Directors or advisory committees. Follows: Janssen, Abvie, Roche, AZ: Other.

Background Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) CD19 CAR-T therapies are licensed in the UK for relapsed/refractory large B-cell lymphoma (LBCL). Corticosteroids for CAR-T toxicity were administered to 28% and 10% of patients in ZUMA-1 and JULIET respectively, but real-world steroid use is reported to be much higher (Nastoupil et al, JCO 2020), with concerns that this may adversely impact on OS and PFS following CAR-T. Analysis of real-world datasets may facilitate the identification of modifiable risk factors for toxicity. Here, we report the UK experience of CAR-T toxicity and its management in 341 LBCL patients with a focus on predictors for corticosteroid use and the impact of steroids on OS/PFS post CAR-T therapy. Methods Data were collected in 10 UK centres from January 2019 to April 2021. CRS/ICANS were graded prospectively (ASTCT). Low (LG) and high-grade (HG) CRS/ICANS were classified as grade 1-2 and 3-5 respectively. Hyper-acute CRS was defined as onset within 24 hours of cells. Steroid cumulative dosing for CAR-T toxicity was calculated as dexamethasone equivalent up to day 30. Product selection was at the discretion of the treating physician. Toxicity management in the UK follows EBMT and ASCT guidance. Results A total of 341 patients received axi-cel (n=261) and tisa-cel (n=80) with a median follow-up of 14.8 (3.4-30) and 13.9 (range 7.5-27) months. Median age was 59 (range 18-80), 61% were male (M=207, F=134) and 79% received bridging therapy (BT). HG CRS, hyperacute CRS and HG ICANS with axi-cel (8.8%; 38%; 21% respectively) and with tisa-cel (7.5%; 26%; 5% respectively) were observed, with incidence of HG ICANS post axi-cel lower than published reports. Risk factors for HG CRS were age0 at infusion (0.001); and hyper-acute CRS was associated with stable (SD) or progressive disease (PD) after BT (p=0.036). On multivariate analysis (MVA), ECOG >0 (OR 3.4, 95% CI 1.3-9.1, p=0.015) and SD/PD post BT (OR 1.8, 95% CI 1.03-3.3, p=0.039) were predictive of HG CRS and hyper-acute CRS respectively. Risk factors for HG ICANS were age0 (p=0.009), SD/PD post BT (p=0.011), extranodal disease (p=0.02) and LDH>normal on Day 0 (p=0.02). By MVA, LDH>normal on Day 0 (OR 3.8, 95% CI 1.4-10.5, p=0.009) was predictive of HG ICANS. Steroids were used in 44% (n=115) of axi-cel treated patients, administered at day 6 (median; range 1-22), at a median dose of 165mg (range 10-2182) over a median of 8 days (range 1-86). Anakinra was given as an adjunctive agent for high-grade ICANS (n=26, 10%), CRS (n=10, 4%) or HLH (n=3, 1%) at a median of day 8 (range 5-43) for a median of 6 days (range 1-16). 18% of tisa-cel patients (n=14) received steroids, administered at day 4 (median; 2-26) at a median dose of 95mg (range 10-220) over a median of 4 days (range 1-8). Tocilizumab was used in 74% and 48% of axi-cel and tisa-cel patients respectively. Clinical factors associated with steroid use included ECOG>0 (OR 1.8, 95% CI 1.2-5.6, p=0.002), and the emergence of SD/PD post BT (OR 1.7, 95% CI 1.02-2.8, p=0.04). SD/PD post BT also predicted for higher total steroid dose (>median; OR 1.7, 95% CI 1.1-2.9, p=0.03), and prolonged (>1 week) administration (OR 1.8, 95% CI 1.1-2.9, p=0.03) (Table 1). The impact of clinical parameters including toxicity and steroids on PFS and OS post-CAR-T were assessed. Adjusted for age, sex, ECOG and LDH>normal pre-LD, HG ICANS (but not HG CRS) was associated with worse OS (HR 2.4, 95% CI 1.3-4.4, p=0.004). 100 day NRM was 3.5% for the whole cohort. Median OS was not reached. In contrast to other published series, early steroid use (HR 1.0, 95% CI 0.6-1.6, p=0.99), higher total doses (HR 1.2, 95% CI 0.7-1.9 p=0.6) and prolonged (>1 week) steroid exposure (HR 1.3, 95% CI 0.8-2.2, p=0.25) were not associated with worse OS. Early steroid use (HR 0.7, 95% CI 0.3-1.6, p=0.4), higher doses (HR 0.5, 95% CI 0.2-1.2, p=0.13) and prolonged exposure (HR 0.9, 95% CI 0.4-2.0, p=0.8) also had no significant impact on PFS. Conclusion Patients who are refractory to BT or with other markers of high disease burden at infusion are more likely to require steroids for CAR-T toxicity, with axi-cel associated with more HG ICANS and cumulative steroid exposure than tisa-cel. Despite this, steroid use for CAR-T toxicity did not negatively impact on PFS or OS. Rates of HG ICANS with axi-cel were comparatively lower in this UK dataset. Figure 1 Figure 1. Disclosures Sanderson: Kite, a Gilead Company: Honoraria; Novartis: Honoraria. Kuhnl: Kite: Honoraria; Novartis: Research Funding. Menne: Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Astra Zeneca: Research Funding; Jazz: Other: Travel grants; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Bayer: Other: Travel grants; Kyowa Kirin: Other: Travel grants; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Atara: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Honoraria for Lectures; Roche: Other: Honoraria for Lectures. Chaganti: Celgene-BMS: Consultancy, Honoraria, Other: Travel support; Takeda: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Atara Bio: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding; Incyte: Honoraria, Speakers Bureau. Nicholson: Novartis: Consultancy, Other: Conference fees; Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; BMS/Celgene: Consultancy; Pfizer: Consultancy. Latif: Takeda UK: Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis,: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Speakers Bureau. Jones: Janssen: Consultancy; Kite/Gilead: Honoraria; Novartis: Honoraria. Sharplin: Kite Gilead: Honoraria; Novartis: Other: Travel Support. Jalowiec: Kite Pharma Gilead Sciences': Honoraria, Speakers Bureau. Roddie: Novartis: Consultancy; Celgene: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. OffLabel Disclosure: Anakinra for CAR-T toxicity management

Purpose/Objective(s) Radiotherapy (RT) has potential synergistic effects with CD19 CAR-T but is not yet widely used as bridging therapy for lymphoma. Comprehensive outcome data of RT bridged patients are limited, and selection criteria for RT bridging and optimal dose / fractionation are unknown. We hypothesized that RT is a safe, well tolerated and effective bridging to CAR-T even in patients with advanced stage and high-risk features. We analyzed details of RT bridging in a prospective national CAR-T cohort, examining patient, disease and treatment factors which may affect outcome of RT bridging. Materials/Methods We analyzed consecutive patients with r/r high-grade lymphoma who had leukapheresis for axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) between Dec 2018 - Nov 2020 in 10 UK centers and received RT bridging. Results Of 371 leukapheresed patients, 76 (21%) received RT bridging (61 RT alone, 15 combined modality treatment (CMT)). Median age was 58 years. 65% had de novo diffuse large B-cell lymphoma, 7% primary mediastinal B-cell, and 28% transformed lymphoma. 64 were infused (50 axi-cel, 14 tisa-cel), with a median turnaround time of 44 days from apheresis to infusion. 12/75 (16%) patients did not proceed to CAR-T infusion (6 progressive disease (PD), 4 deaths (not related to RT), 1 manufacturing failure, 1 CR after bridging). The dropout rates were 11%, 33% & 22% for RT, CMT and chemotherapy-bridged patients respectively (P = 0.086). Disease characteristics were similar in RT & CMT groups; the majority had advanced stage (71% and 86%), 34% & 43% bulky disease, 59% & 73% extranodal involvement, 55% & 57% were primary refractory to R-CHOP, 75% & 67% had SD/PD as best response to last treatment, 18% & 13% had prior autologous transplant, and 31% & 33% had double/triple hit or -expression. In-field response in 53 cases bridged with RT alone (doses 20 – 40Gy) was 85% (11/14) for early stage (3 CR) and 63% (22/35) for advanced stage. Details of the radiation techniques and RT-related toxicities will be provided at the meeting. The ongoing overall response rate at 3 months post infusion was 63% (50% CR). With a median follow-up of 11.5 months, the median time to progression has not been reached. The 6- & 12-months event-free survival was 60% (95% CI: 47-71) and 58% (95% CI: 45 -69), respectively, with no significant difference between RT and CMT. The median overall survival (OS) was 17.8 months (95% CI: 8.9-NR), with 6- & 12-months OS rates of 77% (95% CI: 64 – 86) and 65% (95% CI: 50-76). Post CAR-T toxicity was favorable, with 7/64 (11%) experiencing G3/4 cytokine release syndrome, 8/64 (13%) G3/4 neurotoxicity. Treatment-related mortality was 4.6%. Conclusion RT is a safe and effective bridging therapy prior to CD19 CART in lymphoma. In this large prospective real world national cohort with high proportion of advanced stage and high-risk features, RT bridging was given successfully with low dropout rate and excellent survival outcomes.

Objective Brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) significantly prolonged progression-free survival (PFS) and overall survival (OS) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with systemic anaplastic large-cell lymphoma (sALCL) or other CD30-positive peripheral T-cell lymphomas (PTCL) in ECHELON-2 (Horwitz S et al., Lancet 2019). We report updated results; median follow-up was 47.6 months for PFS and 66.8 months for OS. Design This phase 3, double-blind study (NCT01777152) randomized patients aged ≥18 years with previously untreated CD30-positive PTCL (targeting 75% ± 5% with sALCL) to A+CHP or CHOP for 6 or 8 cycles. Primary endpoint of PFS was assessed per investigator in this updated analysis. Key secondary endpoints included OS and PFS in sALCL. BV or BV-containing regimens were permitted as subsequent/retreatment therapies. Results 452 patients were enrolled (226 patients in each arm); 316 (70%) patients had sALCL. Patients with advanced disease were included (stage III [27%] and stage IV [53%]; International Prognostic Index ≥2 [78%]). Data continues to favor A+CHP: HRs were 0.70 (95% CI: 0.53–0.91, P=0.0077) for PFS per investigator and 0.72 (95% CI: 0.53–0.99, P=0.0424) for OS. 5-year PFS was 51.4% (95% CI: 42.8–59.4) with A+CHP versus 43.0% (95% CI: 35.8–50.0) with CHOP; median PFS was 62.3 months (95% CI: 42.0–not evaluable) with A+CHP and 23.8 months (95% CI: 13.6–60.8) with CHOP. 5-year OS was 70.1% (95% CI: 63.3–75.9) and 61.0% (95% CI: 54.0–67.3) with A+CHP and CHOP, respectively. Median OS was not reached in either arm. PFS favored A+CHP (HR: 0.55 [95% CI: 0.39–0.79]) in sALCL. 29 (13%) and 54 (24%) patients with A+CHP and CHOP received subsequent BV, respectively. Treatment-emergent peripheral neuropathy (PN), resolved/improved in 72% (n=84/117) and 78% (n=97/124) of patients with PN on A+CHP and CHOP, respectively; 98% and 97% of ongoing PN events were grade 1/2 with A+CHP and CHOP, respectively. Conclusions At this important 5-year milestone, A+CHP still provides clinically meaningful improvement in both PFS and OS versus CHOP, with a manageable safety profile, including continued resolution/improvement of PN. Funded by NIH/NCI Support Grant P30 CA008748.

BACKGROUND Bendamustine and Rituximab (BR) therapy is recommended in international consensus guidelines for treatment of Waldenström Macroglobulinaemia (WM) in both frontline and relapsed settings. The optimal dose and schedule of Bendamustine is not well established. Dose options include 90mg/m2 or 70mg/m2 on days 1&2 of each of 6 cycles (total Bendamustine dose of 1080mg/m2 and 840mg/m2, respectively) +/- reduction from 6 to 4 cycles. AIMS Determine response rates (IWWM criteria), PFS and toxicity following BR in frontline and relapsed settings Determine the impact of depth of response and Bendamustine dose on PFS METHODS A multicentre, retrospective cohort analysis was undertaken of consecutive WM patients treated with BR in the frontline or relapsed settings. Data were collected from 17 sites across 4 countries, including UK centres participating in the Rory Morrison Registry. RESULTS Data from Sep 2010 to May 2020 were collected for 250 patients. Frontline (n=139, 55.6%) and relapsed (n=111, 44.4%) cohorts were matched in terms of sex, age at commencement of BR, ECOG score, and baseline parameters including: haemoglobin, platelet count, bone marrow infiltration, and presence of adenopathy, splenomegaly and extranodal disease. At a median follow up of 37 months, disease progression had occurred in 25 frontline patients (18.0%) and 48 relapsed patients (43.2%; p Major responses (≥PR) differed significantly between frontline and relapsed cohorts (91.4% vs 73.9%, respectively; p Best response significantly impacted on PFS and OS. Two-year predicted PFS rates for those achieving CR/VGPR vs PR were 96% vs 82%, respectively (p=0.002, Fig. 1A). Median OS was 83 months after achieving CR/VGPR, 65 months after achieving PR/MR and 28 months after achieving SD/PD (p Relapsed patients had received 1 (n=53, 47.7%), 2 (n=28, 25.2%) or ≥3 (n=30, 27.0%) prior therapies. PFS was significantly longer in the frontline cohort compared with recipients of ≥2 prior lines of treatment, but not between cohorts treated frontline vs after 1 prior therapy line (Fig. 1B). Rates of toxicity-related treatment truncation were significantly lower in the frontline setting (17.3% vs 35.1%; p Frontline patients received higher total Bendamustine doses than relapsed patients (median total dose 1080mg/m2 vs 720mg/m2; p Age did not significantly affect tolerated dose in the frontline cohort, with similar median total Bendamustine doses in the CONCLUSION Outcomes for WM patients following BR are excellent. Frontline patients tolerate higher doses of Bendamustine, and achieve deeper responses and longer PFS than relapsed patients. In both settings, attaining CR/VGPR results in superior PFS and OS. Our data clearly delineate the Bendamustine doses required to achieve optimum PFS. At frontline, 6 cycles of 90mg/m2 on days 1&2 is superior to lower doses with respect to response and PFS. In the relapsed cohort, maximum response and PFS benefit are seen with 4 cycles of 90mg/m2 on days 1&2; a starting dose of 70mg/m2 on days 1&2 is also sufficient provided 5-6 cycles are administered. Disclosures Menne: Kyowa Kirin: Other: Travel expenses; AstraZeneca: Research Funding; Pfizer: Honoraria, Other; Atara: Honoraria; Novartis: Honoraria, Research Funding; Kite/Gilead: Honoraria, Other: Travel expenses; Celgene: Honoraria, Other: Travel expenses; Daiichi Sankyo: Honoraria; Amgen: Honoraria, Other: Travel expenses; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Bayer: Other: Travel expenses; Roche: Honoraria. Talaulikar:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding. Pratt:Binding Site Ltd: Other: Personal fees; Amgen: Other: Personal fees; Janssen: Other: Personal fees; Celgene: Other: Personal fees; Takeda: Other: Personal fees; Gilead: Other: Personal fees; Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Manos:Bristol-Myers Squibb: Other: Conference sponsorship. Gavriatopoulou:Genesis Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Minnema:Kite, a Gilead Company: Speakers Bureau; Celgene: Other: travel support, Research Funding; Servier: Consultancy; Amgen: Consultancy. El-Sharkawi:Roche: Other: Conference fees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kersten:Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support; Novartis: Consultancy, Honoraria, Other: travel support; Miltenyi: Consultancy, Honoraria, Other: travel support; Roche: Research Funding; Takeda: Research Funding; Celgene: Research Funding. McCarthy:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Bishton:Janssen: Consultancy; Takeda: Other: Travel/accommodations/expenses, Research Funding; Roche: Other: Travel/accommodations/expenses, Research Funding; Gilead: Other: Travel/accomodations/expenses, Research Funding; AbbVie: Research Funding. Follows:Roche: Consultancy, Other: Paid lecturing; Karyopharm: Consultancy, Other: Paid lecturing; Janssen: Consultancy, Other: Paid lecturing; Abbvie: Consultancy, Other: Paid lecturing; Bristol Myers Squibb: Consultancy, Other: Paid lecturing; Astrazeneca: Consultancy, Other: Paid lecturing. Wechalekar:Janssen, Takeda, Caelum, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. D'Sa:BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sanofi: Honoraria.

Context: Tafasitamab, a humanized anti-CD19 antibody, has demonstrated encouraging activity with durable responses with lenalidomide (LEN) in autologous stem cell transplant (ASCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the Phase II L-MIND study ( NCT02399085 ). In the primary analysis (cut-off November 30, 2018), the objective response rate (ORR) was 60.0%, median duration of response (DOR) was 21.7 months and median follow-up was 17.3 months. Objective: To report the long-term clinical efficacy and safety of tafasitamab + LEN in the L-MIND study after one additional year of follow-up (cut-off November 30, 2019). Design & Setting: An open-label, single-arm, Phase II study. Patients: Aged ≥18 years with R/R DLBCL (1–3 prior systemic therapies, including ≥1 CD20-targeting regimen), an ECOG performance status 0–2, and ASCT ineligible. Interventions: Tafasitamab (12 mg/kg intravenously, 28-day cycles) was administered once weekly during Cycles 1–3 with a loading dose on Cycle 1 Day 4, then every 2 weeks during Cycles 4–12. LEN (25 mg orally) was self-administered on Days 1–21 of Cycles 1–12. After Cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. Main Outcome Measure(s): The primary endpoint was ORR (independent review committee). Secondary endpoints included DOR, progression-free survival (PFS), overall survival (OS), and safety. Results: In this long-term analysis, 80 of 81 enrolled patients received tafasitamab + LEN and were included in the efficacy analysis. ORR was 58.8% (n=47/80); 41.3% (n=33/80) with complete response; and 17.5% (n=14/80) with partial response. Median DOR was 34.6 months (95% confidence interval [CI]: 26.1–not reached [NR]). Median OS was 31.6 months (95% CI: 18.3–NR) with a median follow-up of 31.8 months. Median PFS was 16.2 months (95% CI: 6.3–NR) with a median follow-up of 22.6 months. No unexpected toxicities were reported. Conclusions: After a minimum of two years' follow-up, outcomes are consistent with the primary analysis and confirm the durability of response and meaningful OS of tafasitamab + LEN followed by tafasitamab in ASCT-ineligible patients with R/R DLBCL. Along with an acceptable safety profile, these data support a clinically relevant benefit with this immunological combination.

7513 Background: L-MIND (NCT02399085) is an ongoing, open-label, Phase II study of tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, plus LEN in ASCT-ineligible patients (pts) with R/R DLBCL. Primary analyses and 2-year efficacy results were previously presented; we report an updated efficacy analysis with ≥35 months follow up (cut-off: October 30, 2020). Methods: Pts were aged ≥18 years with ASCT-ineligible R/R DLBCL, had 1–3 prior systemic therapies (Tx), including ≥1 CD20-targeting regimen, with an ECOG status of 0–2. Pts received 28-day cycles (C) of tafasitamab (12 mg/kg IV), once weekly during C1–3, with a loading dose on Day 4 of C1, then every 2 weeks (Q2W) during C4–12. LEN (25 mg PO) was administered on Days 1–21 of C1–12. After C12, progression-free pts received tafasitamab Q2W until disease progression. The primary endpoint was objective response rate (ORR), assessed by IRC. Secondary endpoints included duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Results: Eighty of 81 enrolled pts received tafasitamab + LEN and were included in the full analysis set (1 prior Tx, n=40; 2+ prior Tx, n=40). At data cut-off, the overall ORR was 57.5% (n=46/80), including complete response (CR) in 40% of pts (n=32/80) and partial response (PR) in 17.5% of pts (n=14/80) (Table). Kaplan-Meier estimates: median DoR=43.9 months (95% CI: 26.1–not reached [NR]), and NR in pts who achieved a CR (95% CI: 43.9–NR); median PFS=11.6 months (95% CI: 6.3–45.7), with median follow-up 33.9 months; median OS=33.5 months (95% CI: 18.3–NR), with median follow-up 42.7 months. There were no unexpected toxicities or new safety signals. Conclusions: Combination Tx with tafasitamab + LEN followed by tafasitamab monotherapy provided durable responses in pts with R/R DLBCL not eligible for ASCT, with a manageable safety profile. These long-term data indicate the potential of tafasitamab + LEN followed by extended tafasitamab monotherapy in achieving prolonged remission and survival benefit in this patient population, especially at first relapse. Clinical trial information: NCT02399085. [Table: see text]

Introduction Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT) have a poor prognosis. Tafasitamab (MOR208) is an Fc-enhanced, humanized, monoclonal antibody that targets CD19, which is broadly expressed across B-cell malignancies, including DLBCL. Lenalidomide (LEN) is an immunomodulatory drug with antiproliferative and antiangiogenic effects. Combined tafasitamab + LEN has shown enhanced activity in in vitro and in vivo lymphoma models. L-MIND (NCT02399085) is an ongoing, open-label, single-arm, Phase II study of tafasitamab + LEN in patients with R/R DLBCL who are ineligible for ASCT. Here, we present results from prespecified patient subgroup analyses from L-MIND. Methods Patients aged ≥18 years with R/R DLBCL (1-3 prior systemic therapies, including ≥1 CD20-targeting regimen) with an Eastern Cooperative Oncology Group performance status 0-2, and who were ineligible for ASCT were enrolled. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during Cycles 1-3 with a loading dose on Cycle 1 Day 4, then every 2 weeks during Cycles 4-12. LEN (25 mg orally) was administered on Days 1-21 of Cycles 1-12. After Cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint is objective response rate (ORR; partial response [PR] + complete response [CR]), assessed centrally by an independent review committee (IRC) per International Working Group criteria 2007, incorporating PET-based imaging. Secondary endpoints include ORR (investigator-assessed), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety and biomarker analyses. Results Of 81 patients enrolled, 80 patients received tafasitamab + LEN and were included in the full analysis set (FAS) for efficacy (data cut-off 30 Nov 2018). Median follow-up was 17.3 months. In the FAS, ORR was 60.0% (95% confidence interval [CI]: 48.4-70.8) (Figure 1A). The CR rate was 42.5% (n=34/80), of which 88.2% (n=30/34) were PET-confirmed. Median time to response (PR or CR) was 2.0 months and median time to CR was 7.1 months. Median DOR was 21.7 months (95% CI: 21.7-not reached [NR]); median PFS was 12.1 months (95% CI: 5.7-NR); and median OS was NR (95% CI: 18.3-NR) with a median follow-up of 19.6 months. The 12-month DOR and OS rates were 71.6% (95% CI: 55.1-82.9) (Figure 1B) and 73.7% (95% CI: 62.2-82.2) (Figure 1C), respectively. In the subgroup analysis, patients with CR as best objective response (BOR) had better outcomes than those with PR: median DOR, NR (95% CI: 21.7-NR) vs 4.4 months (95% CI: 2.0-9.1); 12-month DOR rate, 93.2% (95% CI: 75.4-98.3) vs 14.4% (95% CI: 1.1-43.7); and 12-month OS rate, 97.1% vs 76.9%. Patients with one prior line of therapy had a trend for better outcomes than those with ≥2 prior lines: ORR, 70.0% vs 50.0%; and 12-month OS rate, 86.9% vs 60.1%. However, the 12-month DOR rate was similar regardless of the number of prior lines (one prior line: 70.5% [95% CI: 47.2-85.0] vs ≥2 prior lines: 72.7% [95% CI: 46.3-87.6]). For patients who were refractory to primary therapy or their last line of therapy, similar ORRs were observed to non-refractory patients (60.0% vs 60.0%); 12-month DOR was similar regardless of refractory status to last therapy; and 12-month OS rates were higher in non-refractory patients (Figure 1C). As expected, patients with a low/low-intermediate International Prognostic Index (IPI) score had better outcomes than those with an intermediate-high/high score: ORR, 70.0% vs 50.0%; 12-month DOR rate, 86.5% vs 50.4%; and 12-month OS rate, 87.0% vs 59.9%. Based on Hans algorithm, encouraging outcomes were reported in patients with germinal center B-cell (GCB) DLBCL (n=37), and outcomes were even better in those with non-GCB DLBCL (n=21): ORR, 48.6% vs 71.4%; median DOR, NR vs 21.7 months; 12-month DOR rate, 53.5% vs 83.1%; and 12-month OS rate, 65.4% vs 84.2%. Conclusions Tafasitamab + LEN combination followed by tafasitamab monotherapy shows encouraging activity with durable responses in ASCT-ineligible patients with R/R DLBCL. L-MIND includes a substantial number of poor prognosis patient subgroups. While the influence of these risk factors is evident, the clinical activity of tafasitamab + LEN in these difficult-to-treat patients is promising, particularly in those who were refractory to prior therapies. Disclosures Duell: Regeneron Pharmaceuticals, Inc.: Research Funding. Maddocks:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Merck: Research Funding; BMS: Research Funding. González-Barca:Janssen: Consultancy, Honoraria; Kiowa: Consultancy; Celtrion: Consultancy; Celgene: Consultancy; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Honoraria. Jurczak:TG Therapeutics: Research Funding; Roche: Research Funding; Takeda: Research Funding; Servier: Research Funding; Celtrion: Research Funding; Novo Nordisk: Research Funding; Incyte: Research Funding; Bayer: Research Funding; Loxo: 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, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding. Liberati:Incyte: Consultancy; Janssen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol & Mayer: Honoraria. de Vos:Bayer: Consultancy; Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Nagy: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; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abrisqueta:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. André:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding; Chugai: Research Funding; Celgene: Other: Travel grants, Research Funding. Dreyling:Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Other: Scientific advisory board, Research Funding; Novartis: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau; Sandoz: Other: Scientific advisory board; Acerta: Other: Scientific advisory board; Bayer: Other: Scientific advisory board, Speakers Bureau. Menne:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau. Dirnberger-Hertweck:MorphoSys: Employment. Weirather:MorphoSys: Employment. Ambarkhane:MorphoSys: Employment. Salles:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, 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; Epizyme: Consultancy, Honoraria; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: 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; BMS: Honoraria.

Introduction: Attempts to improve on the 20% complete remission (CR) rate and 10.4 month median overall survival (OS) in the frontline treatment (1L) of older unfit patients (pts) with acute myeloid leukemia (AML) using azacitidine (AZA) combination therapy have been met with cytopenic complications that may result in cycle (Cyc) 2 dose delays as frequently as 33% of the time. Glasdegib in combination with low-dose cytarabine (LDAC) showed superior overall survival vs LDAC alone in the BRIGHT AML 1003 trial that included pts with newly diagnosed AML who were ineligible for intensive chemotherapy (IC). The combination did not appear to increase cytopenias, bleeding, or infection. We analyzed the safety profile of glasdegib in combination with AZA or LDAC in 1L AML, focusing on cytopenias, infections, and dose delays. Methods: BRIGHT MDS & AML 1012 (NCT02367456) is an ongoing single-arm study in which untreated pts with myelodysplastic syndromes (MDS) or AML who were ineligible for IC received glasdegib (100 mg once daily [QD]) + AZA (75 mg/m2/day) on Days 1-7 every 28 days until disease progression, unacceptable toxicity, death, or pt refusal. Efficacy outcomes are reported as of Jun 17, 2019; all others as of Apr 19, 2019. BRIGHT AML 1003 (NCT01546038) is a completed study in which untreated pts with MDS or AML who were ineligible for IC were randomized to receive glasdegib (100 mg QD) + LDAC (20 mg twice daily on Days 1-10 every 28 days) or LDAC alone. Outcomes reported as of Oct 11, 2018. To minimize bias due to imbalances in survival between the 1003 study arms, safety outcomes within the first 90 days for the AML cohorts of each study are presented here. Results: Thirty pts with AML received treatment with glasdegib + AZA (Table 1). Median treatment duration was 5 Cyc (range, 1-11); median follow-up time was 7.8 months (95% CI, 5.9-9.6). CR was achieved by 6 pts (20.0%) receiving glasdegib + AZA. Two additional pts achieved CR with incomplete hematologic recovery (CRi) and discontinued treatment to prepare for transplant. Six-month survival probability was 70.0% (95% CI, 50.3-83.1), with 19 pts still in survival follow-up. Pts (N=116) were assigned to treatment with glasdegib + LDAC (n=78) or LDAC alone (n=38 [Table 1]); median treatment duration (range) was 3 Cyc (1-44) for glasdegib + LDAC and 2 Cyc (1-9) for LDAC alone; median follow-up time (95% CI) was 43.4 (39.7-49.1) and 42.0 (CI not evaluable) months, respectively. As previously reported, glasdegib + LDAC significantly improved OS vs LDAC alone (hazard ratio, 0.495 [95% CI, 0.325-0.752]; P=0.0004). The incidence of select treatment-emergent adverse events (TEAEs) and serious TEAEs associated with cytopenias, bleeding, and infection did not appear worse with glasdegib + AZA or glasdegib + LDAC than with LDAC alone, with some AEs even occurring less frequently (Table 1). Dose delays due to AEs were required in Cyc 2 by 8.7% (n=2/23, glasdegib + AZA), 6.7% (n=4/60, glasdegib + LDAC), and 4.2% (n=1/24, LDAC alone) of pts. Recovery of absolute neutrophil count, hemoglobin, and platelets at 2 cell-count thresholds was seen as early as Cyc 1 in approximately half of the evaluable pts (Table 2). Gastrointestinal toxicities, including nausea and vomiting, were frequent in pts receiving glasdegib + AZA (60.0 and 40.0%, respectively) and glasdegib + LDAC (29.3 and 20.0%, respectively). Glasdegib treatment was associated with AEs thought to be linked to inhibition of the Hedgehog pathway in normal tissue (muscle spasms, dysgeusia, alopecia [Table 1]). Conclusions: The addition of glasdegib to AZA does not appear to increase hematologic toxicities or cytopenic complications substantially, in contrast to the increased toxicity typically observed with combinational therapy. In the context of different baseline characteristics of the populations studied with AZA alone in 1L AML (Dombret, et al. Blood 2016), glasdegib + AZA did not substantially increase AEs related to cytopenias like infections, especially given the low rates of Cyc 2 delays due to AEs. These results are consistent with the lack of substantially increased toxicities with glasdegib + LDAC vs LDAC alone. In light of the survival benefit observed with glasdegib + LDAC vs LDAC alone, the addition of glasdegib to AZA may improve clinical outcomes without substantially increasing toxicities. A randomized phase 3 trial looking at the addition of glasdegib to AZA (vs AZA alone) in 1L AML (NCT03416179) is ongoing. Disclosures Zeidan: Astellas: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding. Schuster:Incyte: Research Funding; Karyopharm Therapeutics: Research Funding; Morphosys: Research Funding; Nordic Nanovector: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau; Rafael: Research Funding; F2G Ltd.: Research Funding; AbbVie: Speakers Bureau; Amgen: Speakers Bureau; Astellas: Speakers Bureau; Celgene: Speakers Bureau; Genentech: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Speakers Bureau; Verastem: Speakers Bureau; Actinium: Research Funding. Krauter:Pfizer: Honoraria. Maertens:Pfizer: Other: Grant and personal fees; Astellas Pharma: Other: Personal fees and non-financial support; Gilead Sciences: Other: Grants, personal fees and non-financial support; Merck: Other: Personal fees and non-financial support; F2G: Other: Personal fees and non-financial support; Cidara: Other: Personal fees and non-financial support; Amplyx: Other: Personal fees and non-financial support. Gyan:Pfizer: Honoraria. Menne:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau. Vyas:Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding; Celgene: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau. Ma:Pfizer: Employment, Equity Ownership. O'Connell:Pfizer: Employment, Equity Ownership. Zeremski:Pfizer: Employment, Equity Ownership. Kudla:Pfizer: Employment, Equity Ownership. Chan:Pfizer Inc: Employment, Equity Ownership. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Glasdegib is approved in the US in combination with low-dose cytarabine for treatment of newly diagnosed AML in patients not suitable for intensive chemotherapy due to comorbidities or age (75 years or older). Here we report data from a phase 1b trial where glasdegib was combined with azacitidine in patients with AML similarly ineligible for intensive chemotherapy.

Introduction: Standard treatment for Hodgkin lymphoma (HL) is poorly tolerated in older patients and results are disappointing. Brentuximab vedotin (BV) is a CD30 targeted antibody‐drug conjugate licenced for the treatment of relapsed or refractory HL on the basis of excellent safety and efficacy demonstrated in the pivotal phase 2 clinical trial. BREVITY trial was designed to evaluate the efficacy and tolerability of BV monotherapy in previously untreated patients (pts) with HL unfit for standard treatment due to age, frailty or co‐morbidity. Methods: This response adaptive phase II, Simon 2‐stage, single arm study required 30 evaluable pts. Primary outcome was complete metabolic response (CMR, Deauville Score 1‐3) by centrally reviewed PET‐CT after 4 cycles of BV. Secondary outcomes included PFS, OS, toxicity and comorbidity assessment (CIRS‐G). Inclusion criteria were previously untreated HL stage 2 (with B symptoms and/or mediastinal bulk) to stage 4 with cardio‐respiratory compromise (at any age), or ECOG PS ≤3 and considered unfit for standard chemotherapy (in pts ≥60 yrs). BV dose was 1.8 mg/kg every 3 weeks, reduced to 1.2 mg/kg for toxicity. Pts responding after 4 doses of BV continued to a maximum of 16 cycles if CT/PET‐CT every 4 cycles confirmed ongoing response. Pts also underwent exploratory blinded PET‐CT after cycle 2. Results: 38 pts were recruited from Feb 2014‐Oct 2015 at 12 UK centres; demographics are shown in Table 1. 35 treated pts were evaluable for toxicity, 31 were evaluable for response. A median of 4 cycles was given (range 1‐16). Dose was reduced in 28 cycles across 14 pts due to toxicity and 11 pts stopped treatment due to adverse events (AEs). 716 AEs were reported, 626 (88%) were grade 1/2. 27 (77%) pts had at least one AE ≥ grade 3, most commonly infection, myelosuppression or neuropathy. CMR at PET4 was 26% (95% CI 14, 43) and overall objective response was 84% (95%CI: 67, 93). There was a significant correlation of interim PET2 with PET4 (Rho = 0.67, p < 0.001) with a CMR rate at PET 2 of 32% (95% CI 17, 52). To date 28 of 31 evaluable pts have progressed and median PFS is 7.4 months (95% CI 5.3, 10.2). Conclusions: In this study BV monotherapy produced a high overall response rate although the CMR rate after 4 cycles did not meet the pre‐specified 40% level, and PFS was short. Toxicity was greater than in the pivotal study in a younger/fitter population and led to treatment termination in some pts. A follow‐on study aims to improve CMR and PFS by using a lower dose of BV in combination with other agents. Table 1Patient Characteristicn=38 Median (Range)Age 76 (59, 90) CIRS‐G ScoreNo. categories endorsed Severity Total score 3 (0, 7) 1.5 (0, 3) 6 (0, 11) n (%) GenderMale Female 22 (57.9) 16 (42.1) StageStage 2 Stage 3 Stage 4 7 (18.4) 13 (34.2) 18 (47.4) B symptoms 27 (71.1) Bulky Disease 5 (13.2) Extranodal disease 22 (57.9) ECOG Performance Status0 1 2 3 4 3 (7.9) 16 (42.1) 11 (28.9) 7 (18.4) 1 (2.6)