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PURPOSE Epcoritamab is a subcutaneously administered CD3xCD20 T-cell–engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20+ B cells. Single-agent epcoritamab previously demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes. PATIENTS AND METHODS In the dose-expansion cohort of a phase I/II study (ClinicalTrials.gov identifier: NCT03625037 ), adults with relapsed or refractory CD20+ large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee. RESULTS As of January 31, 2022, 157 patients were treated (median age, 64 years [range, 20‐83]; median of three [range, 2-11] prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell–associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event. CONCLUSION Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.

Diffuse large B-cell lymphoma and follicular lymphoma are the most commonly encountered non-Hodgkin lymphomas in clinical practice. Both are biologically heterogeneous, with management strategies that are becoming increasingly complex. Diffuse large B-cell lymphoma typically exhibits aggressive behavior but can be cured in the majority of cases with immunochemotherapy. While R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard of care for decades, the recent combination of polatuzumab-vedotin-R-CHP (rituximab plus cyclophosphamide, doxorubicin, and prednisone) has demonstrated improved progression-free survival for patients with intermediate- and intermediate-high–risk disease. Numerous novel therapies, including targeted agents and immunotherapy-based approaches, have recently been approved for relapsed/refractory disease and have led to improved outcomes. Follicular lymphoma is an indolent lymphoma that remains incurable with standard approaches. Overall survival in most patients is excellent, although a proportion of patients will have early relapsing disease and poorer outcomes. The availability of novel agents in the relapsed/refractory setting has shifted the treatment algorithm, which requires thoughtful consideration of sequencing. This article will review recent developments in the treatment of diffuse large B-cell lymphoma and relapsed/refractory follicular lymphoma.

Fig. S1: BTK mutations detected in cDNA in five FL BTK mutant cases. Fig. S2:BTK mutations destabilize the mutant BTK proteins. Fig. S3:BTK mutations do not influence PLCγ2-1217 phosphorylation in reconstituted lymphoma cell lines. Fig. S4:BTK mutations do not influence PLCγ2-759 phosphorylation in reconstituted lymphoma cell lines Fig. S5:Preserved PLCγ2-1217 phosphorylation in OCI-LY7 BTK-/- BLK-/- cells. Fig. S6:PLCγ2-1217 or PLCγ2-759 phosphorylation in OCI-LY7 BTK-/- BLK-/- or SUDHL4 BTK-/- BLK-/- cells treated with kinase inhibitors. Fig. S7:BTK mutations enhance anti-IgM induced AKT308 phosphorylation Fig. S8: Acute inhibition of BTK by ibrutinib or acalabrutinib does not augment anti-Ig induced AKT phosphorylation Fig. S9: The proteolysis targeting chimera (PROTAC)-mediated degradation of BTK protein results in augmentation of sIG-crosslinking induced AKT phosphorylation. Fig. S10:Primary human FL B cells have augmented AKT phosphorylation following surface IgM crosslinking: Fig. S11: The augmented phosphorylation of AKT by BTK mutants following anti-Ig treatment is abolished by pre-treatment with a PI3KÎ' inhibitor (CAL101) Fig. S12: Effects of BTK mutations on ibrutinib sensitivities in HBL1 and TMD8 cell lines

Supplementary Figure and Table legends

Results from IP-mass spec of HA-BTK WT and two HA-BTK mutants and a control (BTK-/- reconstituted with empty vector FG9) and embedded VENN diagram

Purpose:On the basis of the recent discovery of mutations in Bruton tyrosine kinase (BTK) in follicular lymphoma, we studied their functional properties.Experimental Design:We identified novel somatic BTK mutations in 7% of a combined total of 139 follicular lymphoma and 11 transformed follicular lymphoma cases, none of which had received prior treatment with B-cell receptor (BCR) targeted drugs. We reconstituted wild-type (WT) and mutant BTK into various engineered lymphoma cell lines. We measured BCR-induced signal transduction events in engineered cell lines and primary human follicular lymphoma B cells.Results:We uncovered that all BTK mutants destabilized the BTK protein and some created BTK kinase-dead mutants. The phospholipase C gamma 2 (PLCγ2) is a substrate of BTK but the BTK mutants did not alter PLCγ2 phosphorylation. Instead, we discovered that BTK mutants induced an exaggerated AKT phosphorylation phenotype in anti-Ig-treated recombinant lymphoma cell lines. The short hairpin RNA–mediated knockdown of BTK expression in primary human nonmalignant lymph node–derived B cells resulted in strong anti-Ig-induced AKT activation, as did the degradation of BTK protein in cell lines using ibrutinib-based proteolysis targeting chimera. Finally, through analyses of primary human follicular lymphoma B cells carrying WT or mutant BTK, we detected elevated AKT phosphorylation following surface Ig crosslinking in all follicular lymphoma B cells, including all BTK-mutant follicular lymphoma. The augmented AKT phosphorylation following BCR crosslinking could be abrogated by pretreatment with a PI3Kδ inhibitor.Conclusions:Altogether, our data uncover novel unexpected properties of follicular lymphoma–associated BTK mutations with direct implications for targeted therapy development in follicular lymphoma.See related commentary by Afaghani and Taylor, p. 2123

Background Since Food and Drug Administration approval of brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (A + CHP) as initial therapy for previously untreated CD30-expressing peripheral T-cell lymphoma (PTCL), there has been limited research on real-world patient characteristics, treatment patterns, and clinical outcomes. Methods We retrospectively analyzed claims of patients with PTCL treated with frontline A + CHP or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) using the Symphony Health Solutions database. Adults with International Classification of Diseases-9/10 PTCL diagnosis codes who initiated A + CHP or CHOP between November 2018 and July 2021 were included. A 1:1 propensity score matching analysis was performed that adjusted for potential confounders between groups. Results A total of 1344 patients were included (A + CHP, n = 749; CHOP, n = 595). Before matching, 61% were men; median age at index was 62 (A + CHP) and 69 (CHOP) years. The most common A + CHP-treated PTCL subtypes were systemic anaplastic large cell lymphoma (sALCL; 51%), PTCL-not otherwise specified (NOS; 30%), and angioimmunoblastic T-cell lymphoma (AITL; 12%); the most common CHOP-treated subtypes were PTCL-NOS (51%) and AITL (19%). After matching, similar proportions of patients treated with A + CHP and CHOP received granulocyte colony-stimulating factor (89% vs. 86%, P = .3). Fewer patients treated with A + CHP received subsequent therapy than CHOP overall (20% vs. 30%, P Conclusions Characteristics and management of this real-world PTCL population who were older and had a higher comorbidity burden than that in the ECHELON-2 trial demonstrate the importance of retrospective studies when assessing the impact of new regimens on clinical practice.

International audience; Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator that controls the normal biology of germinal B cells. Overexpression or mutation of EZH2 is associated with malignant transformation in a number of B-cell malignancies; thus, EZH2 inhibitors are an attractive therapeutic option for these targets. Several EZH2 inhibitors have entered clinical trials, but there remains an important question as to how EZH2 inhibitor mechanism of action differs in patients with mutant and wild-type EZH2. This review discusses the EZH2-driven mechanisms that lead to the development of B-cell lymphomas and act as therapeutic targets. Another key area of investigation is whether EZH2 inhibitors will work synergistically with existing immunomodulatory drugs and chemotherapy regimens. In summary, EZH2 inhibitors show potential as treatment for a range of B-cell lymphomas, and numerous clinical evaluations are currently underway.

Novel treatment strategies have shifted the treatment landscape for patients with diffuse large B-cell lymphoma, particularly for those with relapsed/refractory disease. However, uncertainty remains regarding the therapeutic value of these novel agents compared to existing salvage chemotherapy regimens. In addition, the high cost associated with these agents puts both patients and health systems at risk of financial toxicity, further complicating their use. The development of clinical pathways incorporating oncology stewardship principles are necessary in order to maximize value-based care. This comprehensive review assesses the efficacy and safety data available for novel treatment options in relapsed/refractory diffuse large B-cell lymphoma and applies stewardship principles to evaluate their optimal place in therapy, with the aim of optimizing safe, effective, and financially responsible patient care.

PURPOSE Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. METHODS We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. RESULTS In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. CONCLUSION The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.

Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P

Follicular lymphoma (FL) is the 2nd most common lymphoma in the USA/Western Europe. While incurable, the majority of patients are able to survive at least a decade with this disease. Response duration though varies, and subset of patients will relapse within 24 months of initial therapy (POD24). These patients have shortened survival compared to those who achieve more durable responses. Treatment interventions for patients are varied and include observation, radiation, or systemic therapies. Treatment outcomes have improved considerably over the last several decades with the introduction of new agents such as the CD 20 antibody rituximab and more recently with the advent of more targeted therapy. Most of the newer agents work differently from cytotoxic chemotherapy and either inhibit tumor-specific mutations, survival pathways, or harness the immune systems. While outcomes with traditional cytotoxic agents have been historically poor in certain subtypes such as POD24 and rituximab refractory disease, the reported outcomes with the newer agents have been encouraging as evident by several new drug approvals in FL. The biggest impact has been in the relapsed/refractory setting where we have approval of the immunomodulatory agent lenalidomide given in combination with rituximab. Based on the AUGMENT study, this agent has been approved for patients with R/R FL after one previous line of therapy. The EZH2 inhibitor, tazemetostat, was approved recently for patients with a known EZH2 mutation after one prior line of therapy or for FL patients who are deemed intolerant to other agents given the impressive safety profile in all patients. Finally, there is a plethora of agents that are designed to harness the immune system to combat this lymphoma. The data for these agents is still very early but nonetheless very impressive. In summary, FL is an incurable lymphoma without any standard of care options but has numerous treatments that have demonstrated some degree of efficacy. Recently we have made enormous strides in the understanding of some of the biological drivers of this disease which has allowed for refinement of treatment options. Moving forward, I would anticipate that we will continue to explore the use of agents that target specific mutations or utilize the immune system to hopefully one day achieve a cure.

Purpose: On the basis of the recent discovery of mutations in Bruton tyrosine kinase (BTK) in follicular lymphoma, we studied their functional properties. Experimental Design: We identified novel somatic BTK mutations in 7% of a combined total of 139 follicular lymphoma and 11 transformed follicular lymphoma cases, none of which had received prior treatment with B-cell receptor (BCR) targeted drugs. We reconstituted wild-type (WT) and mutant BTK into various engineered lymphoma cell lines. We measured BCR-induced signal transduction events in engineered cell lines and primary human follicular lymphoma B cells. Results: We uncovered that all BTK mutants destabilized the BTK protein and some created BTK kinase-dead mutants. The phospholipase C gamma 2 (PLCγ2) is a substrate of BTK but the BTK mutants did not alter PLCγ2 phosphorylation. Instead, we discovered that BTK mutants induced an exaggerated AKT phosphorylation phenotype in anti-Ig-treated recombinant lymphoma cell lines. The short hairpin RNA–mediated knockdown of BTK expression in primary human nonmalignant lymph node–derived B cells resulted in strong anti-Ig-induced AKT activation, as did the degradation of BTK protein in cell lines using ibrutinib-based proteolysis targeting chimera. Finally, through analyses of primary human follicular lymphoma B cells carrying WT or mutant BTK, we detected elevated AKT phosphorylation following surface Ig crosslinking in all follicular lymphoma B cells, including all BTK-mutant follicular lymphoma. The augmented AKT phosphorylation following BCR crosslinking could be abrogated by pretreatment with a PI3Kδ inhibitor. Conclusions: Altogether, our data uncover novel unexpected properties of follicular lymphoma–associated BTK mutations with direct implications for targeted therapy development in follicular lymphoma. See related commentary by Afaghani and Taylor, p. 2123

Background. BL is a rare, high-grade B-cell lymphoma that is often studied in trials with small sample sizes. Historical definitions of "low-risk BL" vary between studies, use arbitrary cutoffs for lactate dehydrogenase (LDH), and identify a small favorable group, leaving >80-90% of patients (pts) in an undifferentiated "high-risk" category. A validated prognostic index will help compare study cohorts and better define good-prognosis pts for whom reduced treatment would be appropriate vs a poor-prognosis group in need of new approaches. Herein, we constructed and validated a simplified prognostic model for BL applicable to diverse clinical settings across the world. Methods. We derived the BL-IPI from a large real-world evidence cohort of US adults treated for BL in 2009-2018 (Evens A, Blood 2020). Progression-free survival (PFS) from diagnosis until BL recurrence, progression, death, or censoring was the primary outcome. We first determined the best prognostic cutoffs for age, LDH (normalized to local upper limit normal, ULN), hemoglobin (Hgb), and albumin. Independent risk factors were ascertained by forward stepwise selection into Cox regression from candidate variables: age, sex, HIV+ status, ECOG performance status (PS) ≥2, advanced stage (3/4), involvement of >1 extranodal site, bone marrow, central nervous system (CNS), values of LDH, Hgb, and albumin. Derivation models used multiple imputation to mitigate bias from missing data and reported hazard ratios (HR) with 95% confidence interval (CI). BL-IPI groups, defined by inspection of survival curves, were compared using log-rank test for trend. We validated performance of the BL-IPI in an external retrospective dataset of BL pts treated contemporaneously in centers from the United Kingdom, Scandinavia, Canada, and Australia. Results. Characteristics of pts in the derivation (N= 633) and validation (N=457) cohorts are shown in the Table. Age ≥40 years (yr), LDH >3xULN, Hgb 3xULN, low Hgb, and low albumin were associated with inferior PFS in univariate tests. In the multivariable model age ≥40 yr, LDH >3xULN, PS ≥2, and CNS involvement were selected as 4 independent prognostic factors; adding stage did not enhance the model. The model was simplified to 3 groups with 0 (low risk; 18% of pts), 1 (intermediate risk; 36% of pts; HR=3.14; 95%CI, 1.61-6.14), or 2-4 factors (high risk; 46% of pts; HR=6.52; 95%CI, 3.48-12.20; Fig A) with 3 yr PFS of 92%, 72%, and 53%, respectively (P Among pts with stage III/IV (historically classified as "high-risk" and constituting 78% of all pts in the cohort), the BL-IPI further discriminated subgroups with 3 yr PFS of 87%, 71%, and 52%, respectively (P In the international validation cohort, fewer pts had CNS involvement; most received CODOX-M/IVAC+R; and PFS/OS estimates at 3 yr were higher. BL-IPI categories were of similar size (low-risk 15%, intermediate-risk 35%, high-risk 50%), and provided similar risk discrimination (Harrell's C=.65 in both datasets). PFS at 3 yr was 96%, 82%, and 63%, respectively (P Conclusions. BL-IPI is a novel prognostic index specific to BL, which was validated to allow for simplified stratification and comparison of risk distribution in geographically diverse cohorts. The index identified a low-risk group with PFS >90-95%, which could be targeted with future strategies for treatment de-escalation. Conversely, only about 55-60% of pts in the high-risk group achieved cure with currently available immunochemotherapy. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Jakobsen:Takeda: Honoraria. Collins:ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Pfizer: Honoraria; Celgene: Research Funding. Cwynarski:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau. Bachanova:Incyte: Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Danilov:Abbvie: Consultancy; BeiGene: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Gilead Sciences: Research Funding; Takeda Oncology: Research Funding; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Research Funding; Karyopharm: Consultancy; Aptose Biosciences: Research Funding; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy. Diefenbach:Trillium: Research Funding; Millenium/Takeda: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Denovo: Research Funding. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Farooq:Kite, a Gilead Company: Honoraria. Feldman:Pfizer: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Cell Medica: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding; Kyowa Kirin: Consultancy, Research Funding. Gerrie:AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Sandoz: Consultancy. Jagadeesh:Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Kamdar:BMS: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Speakers Bureau. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; Karyopharm: Honoraria; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Khan:Seattle Genetics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria; Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Lossos:Verastem: Consultancy, Honoraria; Stanford University: Patents & Royalties; Seattle Genetics: Consultancy, Other; Janssen Biotech: Honoraria; NCI: Research Funding; Janssen Scientific: Consultancy, Other. Lunning:ADC Therapeutics: Consultancy; Legend: Consultancy; Acrotech: Consultancy; AstraZeneca: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; TG Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Curis: Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding. Martin:I-MAB: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Sandoz: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy. Martinex-Calle:Abbvie: Other: Travel grant. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Palmisiano:Genentech: Research Funding; AbbVie: Research Funding. Phillips:Beigene: Honoraria; Roche: Research Funding. Phillips:Seattle Genetics: Consultancy; Incyte: Consultancy, Other: travel expenses; AstraZeneca: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy, Research Funding; Cardinal Health: Consultancy. Portell:Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; Bayer: Consultancy; Amgen: Consultancy; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; BeiGene: Consultancy, Research Funding. Reddy:Celgene: Consultancy; BMS: Consultancy, Research Funding; Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy. Yazdy:Abbvie: Consultancy; Genentech: Research Funding; Octapharma: Consultancy; Bayer: Honoraria. Smith:Bristol Meyers Squibb: Research Funding; Ayala: Research Funding; Seattle Genetics: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Beigene: Consultancy; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Karyopharm: Consultancy. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Evens:Research To Practice: Honoraria, Speakers Bureau; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.

Summary Background Activating mutations of EZH2, an epigenetic regulator, are present in approximately 20% of patients with follicular lymphoma. We investigated the activity and safety of tazemetostat, a first-in-class, oral EZH2 inhibitor, in patients with follicular lymphoma. Methods This study was an open-label, single-arm, phase 2 trial done at 38 clinics or hospitals in France, the UK, Australia, Canada, Poland, Italy, Ukraine, Germany, and the USA. Eligible patients were adults (≥18 years) with histologically confirmed follicular lymphoma (grade 1, 2, 3a, or 3b) that had relapsed or was refractory to two or more systemic therapies, had an Eastern Cooperative Oncology Group performance status of 0–2, and had sufficient tumour tissue for central testing of EZH2 mutation status. Patients were categorised by EZH2 status: mutant (EZH2mut) or wild-type (EZH2WT). Patients received 800 mg of tazemetostat orally twice per day in continuous 28-day cycles. The primary endpoint was objective response rate based on the 2007 International Working Group criteria for non-Hodgkin lymphoma, assessed by an independent radiology committee. Activity and safety analyses were done in patients who received one dose or more of tazemetostat. This study is registered with ClinicalTrials.gov , NCT01897571 , and follow-up is ongoing. Findings Between July 9, 2015, and May 24, 2019, 99 patients (45 in the EZH2mut cohort and 54 in the EZH2WT cohort) were enrolled in the study. At data cutoff for the analysis (Aug 9, 2019), the median follow-up was 22·0 months (IQR 12·0–26·7) for the EZH2mut cohort and 35·9 months (24·9–40·5) for the EZH2WT cohort. The objective response rate was 69% (95% CI 53–82; 31 of 45 patients) in the EZH2mut cohort and 35% (23–49; 19 of 54 patients) in the EZH2WT cohort. Median duration of response was 10·9 months (95% CI 7·2–not estimable [NE]) in the EZH2mut cohort and 13·0 months (5·6–NE) in the EZH2WT cohort; median progression-free survival was 13·8 months (10·7–22·0) and 11·1 months (3·7–14·6). Among all 99 patients, treatment-related grade 3 or worse adverse events included thrombocytopenia (three [3%]), neutropenia (three [3%]), and anaemia (two [2%]). Serious treatment-related adverse events were reported in four (4%) of 99 patients. There were no treatment-related deaths. Interpretation Tazemetostat monotherapy showed clinically meaningful, durable responses and was generally well tolerated in heavily pretreated patients with relapsed or refractory follicular lymphoma. Tazemetostat is a novel treatment for patients with follicular lymphoma. Funding Epizyme.

Background Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis despite the availability of multiple treatment options. Preliminary evidence suggests that DLBCL may be responsive to programmed death ligand 1 (PD-L1)/programmed death 1 inhibitors. Objective The JAVELIN DLBCL study was conducted to assess whether a combination of agents could augment and sustain the antitumor immunity of avelumab, an anti-PD-L1 antibody, in R/R DLBCL. Methods This was a multicenter, randomized, open-label, parallel-arm study with a phase Ib and a phase III component. Reported here are the results from the phase Ib study, wherein 29 adult patients with DLBCL were randomized 1:1:1 to receive avelumab in combination with utomilumab (an immunoglobulin G2 4-1BB agonist) and rituximab (arm A), avelumab in combination with utomilumab and azacitidine (arm B), or avelumab in combination with bendamustine and rituximab (arm C). The primary endpoints were dose-limiting toxicities and objective response as assessed by the investigator per Lugano Response Classification criteria. Results Of the seven patients in arm A, one (14.3%) experienced two grade 3 dose-limiting toxicities (herpes zoster and ophthalmic herpes zoster); no dose-limiting toxicities were reported in arms B or C. No new safety concerns emerged for avelumab. One partial response was reported in arm A, three complete responses in arm C, and no responses in arm B. Given the insufficient antitumor activity in arms A and B and the infeasibility of expanding arm C, the study was discontinued before initiation of the phase III component. Conclusions The low level of clinical activity suggests that PD-L1 inhibitor activity may be limited in R/R DLBCL. ClinicalTrials.gov Identifier NCT02951156. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00849-8.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a high initial response rate followed almost invariably by relapse. Here we report the pooled data from 2 studies, BGB-3111-AU-003 and BGB-3111-206, to explore the efficacy of zanubrutinib monotherapy in relapsed/refractory (R/R) MCL. A total of 112 patients were included. Median follow-up durations were 24.7 and 24.9 months for BGB-3111-AU-003 and BGB-3111-206, respectively. Overall response rate (ORR) and complete response (CR) rate were 84.8% and 62.5%, and median duration of response, progression-free survival (PFS) and overall survival (OS) were 24.9, 25.8 and 38.2 months, respectively. After weighting, the PFS (median: NE vs. 21.1 months, P = 0.235) and OS (median: NE vs. 38.2 months, P = 0.057) were similar but numerically better in the second-line than later-line group. Zanubrutinib was well-tolerated with treatment discontinuation and dose reduction for adverse events in 12.5% and 2.7% of patients, respectively. Hypertension, major hemorrhage and atrial fibrillation/flutter rates were 11.6%, 5.4% and 1.8%, respectively. Zanubrutinib is efficacious in R/R MCL, with a favorable safety profile. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-021-01174-3.

Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton’s tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit–risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities in contemporary treatment algorithms for mantle cell lymphoma (MCL). Chimeric antigen receptor (CAR) T cell therapy recently received approval for MCL; however, its exact place and sequence in relation to HCT remain unclear. The American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and the European Society for Blood and Marrow Transplantation jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-HCT, allo-HCT, and CAR T cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated, with a few key statements as follows: in the first line setting, auto-HCT consolidation represents standard of care in eligible patients, whereas there is no clear role of allo-HCT or CAR T cell therapy outside of clinical trials. In the R/R setting, the preferential option is CAR T cell therapy, especially in patients with MCL failing or intolerant to at least one Bruton’s tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T cell therapy fails or is infeasible. Several recommendations were based on expert opinion, where the panel developed consensus statements for important real-world clinical scenarios to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.

International audience; Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.

Background: Tazemetostat, a first-in-class, oral, enhancer of zeste homolog 2 (EZH2) inhibitor was recently approved by the US Food and Drug Administration in patients with relapsed/refractory (R/R) follicular lymphoma (FL) after demonstrating single-agent, antitumor activity in patients with wild-type (WT) or mutant (MT) EZH2. Progression of disease within 24 months (POD24), exposure to multiple lines of prior therapy, and refractoriness to rituximab therapy have been shown to adversely affect the prognosis of patients receiving second- or third-line regimens for R/R FL, including chemoimmunotherapy. We performed a post hoc exploratory analysis to better understand how these factors impact the outcomes in patients receiving tazemetostat. Methods: This open-label, multicenter study (NCT01897571) evaluated tazemetostat 800 mg administered orally twice daily in patients with MT or WT EZH2 R/R FL. The primary endpoint was objective response rate (ORR; complete response + partial response) as assessed by an independent review committee (IRC); secondary efficacy endpoints included duration of response (DOR) by IRC, progression-free survival (PFS) by IRC, and overall survival (OS) by investigator assessment. Predictive modeling using baseline demographic and disease characteristic variables combined from patients with MT or WT EZH2 R/R FL was performed to identify variables predictive of response (ORR, DOR, PFS, and OS). Models were fitted for variables that were categorical and had no missing observations; they also were fitted with/without Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria and with the number of prior lines of therapy (1, 2, or >2, and 1 or 2 vs >2). Due to incomplete data collection, GELF criteria were analyzed with missing observations (n=28) set to "no." Stepwise logistic and Cox regression was used to determine possible predictors; inclusion at a specified step was based on P≤0.40. Final model inclusion was based on P≤0.20. A final model was run using the possible predictors identified from the previous stepwise regressions. Contingency tables and Kaplan-Meier plots were used to examine significant variables (P≤0.05). Results: In the phase 2 study, the efficacy outcomes by IRC in combined WT and MT EZH2 populations (N=99) were: ORR, 51% (n=50); median DOR, 11 months (95% CI: 7, 19); and median PFS, 12 months (95% CI: 8, 15). Median OS was not reached (95% CI: 38.2, not estimable). Predictive modeling using 17 baseline variables identified possible predictors of efficacy outcome. For ORR, the number (1 or 2 vs >2) of prior lines of therapy was identified as possibly predictive (Table). Patients with 1 line of prior therapy had an ORR of 66% (n=27) vs 40% (n=23) in patients with 2 prior lines of therapy. Disease refractory to rituximab and number (1, 2, or >2) of prior lines of therapy (Table) were identified as possible predictors for DOR. Disease refractory to rituximab, GELF criteria, disease refractory to any treatment, and sex (Table) were possibly predictive for PFS. However, the percentage of subjects that met GELF criteria may be underestimated due to retrospective collection of qualifying data points; therefore, the translation of GELF criteria as a predictive factor for PFS should be interpreted with caution. Other baseline demographic and disease characteristics, including patient age (≤65 y, >65 y), double refractory disease, ECOG performance status, myelosuppression, POD24, disease refractory to last therapy, prior stem cell transplant, and time since last therapy, were not found to be predictive of response, as measured by ORR, DOR, PFS, and OS. Conclusions: In this post hoc exploratory analysis of patients with R/R FL (WT and MT EZH2 cohorts combined), variables associated with heavily pretreated patients (ie, refractory to rituximab, treatment-refractory disease, and number of prior treatments) were identified as possible predictors of response. However, in these analyses other high-risk disease characteristics, such as POD24, were not predictive, although the results may be confounded by the small number of patients in some of the groups. In addition to reinforcing the efficacy of tazemetostat in heavily pretreated patients, these data also suggest that ORR is greater in patient populations who receive treatment as an earlier line of therapy. Prospective confirmatory studies are warranted to confirm these post hoc observations. Disclosures Salles: Kite: Consultancy, Honoraria, Other; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Bristol Myers Squibb: Consultancy, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Genmab: Consultancy; Epizyme: Consultancy; Debiopharm: Consultancy; MorphoSys: Consultancy, Honoraria, Other; Karyopharm: Consultancy; Novartis: Consultancy, Honoraria, Other. Tilly:BMS: Honoraria. McKay:Greater Glasgow and Clyde Health Board: Current Employment; Roche, Gilead, Takeda, Janssen: Other: For lectures etc; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Phillips:Beigene: Consultancy; Karyopharm: Consultancy; AstraZeneca: Consultancy; Incyte: Consultancy, Other: travel expenses; Seattle Genetics: Consultancy; BMS: Consultancy; Bayer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy; Cardinal Health: Consultancy. Assouline:Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Batlevi:Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding; Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Ribrag:BAY1000394 studies on MCL: Patents & Royalties; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; argenX: Current equity holder in publicly-traded company, Research Funding; Institut Gustave Roussy: Current Employment; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; arGEN-X-BVBA: Research Funding; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria; Servier: Consultancy, Honoraria; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AZD: Honoraria, Other; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Damaj:Roche, Takeda, Accord: Honoraria; Roche, Takeda, Iqone, Accord: Consultancy; Abbevie, Pfizer, Takeda, Roche: Other: Travel. Dickinson:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jurczak:BeiGene: Consultancy, Research Funding; Celgene: Research Funding; Epizyme: Consultancy; Gilead Sciences: Research Funding; MorphoSys: Research Funding; Nordic Nanovector: Research Funding; Servier: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Sandoz-Novartis: Consultancy; European Medicines Agency,: Consultancy; AstraZeneca: Consultancy; Takeda: Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Afimed: Research Funding; Janssen China R&D: Consultancy, Research Funding; MEI Pharma: Research Funding; Acerta: Consultancy, Research Funding; Bayer: Research Funding; TG Therapeutics, Inc.: Research Funding. Kaźmierczak:Department of Hematology and Bone Marrow Transplantation Poznan University of Medical Sciences: Current Employment. Opat:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Epizyme: Research Funding; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Research Funding. Radford:GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse. Schmitt:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen: Honoraria. Whalen:TESARO (ended employment Nov 2018): Ended employment in the past 24 months; Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Hamlett:Epizyme, Inc.: Current Employment, Research Funding; Sanofi: Ended employment in the past 24 months. Kamp:Karyopharm: Consultancy; Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Adib:Epizyme, Inc.: Consultancy; Alacrita: Current Employment. Morschhauser:Janssen: Honoraria; Genentech, Inc.: Consultancy; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees.

Introduction: Polatuzumab vedotin (Pola) combined with rituximab (R) demonstrated activity and tolerability in a Phase (Ph) II trial of patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (Morschhauser et al. Lancet 2019). The pro-survival MCL-1 protein has been identified as a mechanism of resistance to venetoclax (Ven), a potent inhibitor of BCL-2, in non-Hodgkin lymphoma cell lines. Preclinical studies have demonstrated that concurrent treatment with Pola promotes MCL-1 degradation and enhances anti-tumor efficacy in vivo, thus providing a strong rationale for the combination with Ven (Amin et al. AACR 2020). We sought to determine whether the combination of Pola-Ven-R might further enhance anti-tumor response. Here, we present the primary efficacy and safety analysis from a Ph Ib/II study of Pola-Ven-R in pts with R/R DLBCL (GO29833; NCT02611323). Methods: GO29833 is an open-label, multicenter study of pts with R/R DLBCL who had received ≥1 prior anti-CD20 chemo-immunotherapy regimen. The recommended Ph II dose (RP2D) combination for Pola-Ven-R was initially defined in a 3+3 dose escalation phase and was then expanded into Ph II. Pts in the expansion cohort received induction therapy with six 21-day cycles of: intravenous (IV) Pola 1.8mg/kg (Cycle [C] 1-6: Day [D]1), Ven 800mg by mouth daily and R 375mg/m2 IV (C1-6: D1). Responders received consolidation therapy for 8 months (Ven 800mg daily and R 375mg/m2 on D1 every 2 months). The primary safety objectives were to determine the RP2D for Pola and Ven when given in combination with R and to evaluate the safety and tolerability of the Pola-Ven-R combination. The primary efficacy endpoint was complete response (CR) at end of induction (EOI), as determined by the Independent Review Committee (IRC) based on positron emission tomography-computed tomography (PET-CT) scans using modified Lugano 2014 response criteria. Secondary objectives included CR-rate at EOI and best overall response (BOR) determined by the investigator (INV). Exploratory objectives included INV-assessed progression-free survival (PFS) and overall survival (OS). Results: At the primary analysis (January 30, 2020), 57 pts from the Ph Ib/II populations were enrolled and received at least one study drug; the median duration of follow-up was 7.0 (range 0.2-30.4) months. Baseline characteristics of the safety-evaluable pts are shown in Table 1: median age, 65 years; male, 49%; Ann Arbor Stage III-IV, 84%; International Prognostic Index (IPI) ≥3, 54%; median prior lines of therapy, 3; refractory to last line, 83%; primary refractory, 65%. Dose limiting toxicity was not observed in Ph I and the maximum dose level was chosen as RP2D. All except two pts experienced at least one adverse event (AE), 21 (37%) had a serious AE, and 45 (79%) had a Grade 3-4 AE. The most common Grade 3-4 AEs were neutropenia (30 pts, 53%), infections (9 pts, 16%), and anemia (6 pts, 11%). AEs leading to dose reduction or interruption of any drug occurred in 10 (18%) and 35 (61%) pts, respectively; the majority of dose modifications were changes to Ven dosing. Seven (12%) pts had an AE that led to the discontinuation of any study drug (Pola [n=5]; Ven [n=7]; R [n=6]). One grade 5 AE was reported (pneumonia); however, it was not considered related to study treatment as the pt had received new anti-lymphoma therapy following disease progression. In the primary efficacy-evaluable population (n=48), the IRC-assessed modified Lugano CR rate at EOI was 29% (Table 2). The INV-assessed CR rate at EOI and BOR were 31% and 65%, respectively, with a median duration of response of 5.8 months (95% confidence interval [CI]: 3.4-6.7). The median PFS and OS were 4.4 months (95% CI: 3.0-7.1) and 11.0 months (95% CI: 6.7-not evaluable), respectively. Conclusions: Our study of the novel triplet combination, Pola-Ven-R, demonstrates a safety profile consistent with the known profiles of the individual drugs. This first report of the full efficacy population showed promising activity in a heavily pre-treated and refractory population of pts with R/R DLBCL. Further evaluation of Pola-Ven-R and the impact of consolidation therapy is warranted to address the significant unmet medical need in this patient population. Disclosures Gritti: Autolus: Consultancy; Takeda: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Amgen: Honoraria; Kite: Consultancy; Italfarmaco: Consultancy; Jannsen: Other: Travel Support; IQVIA: Consultancy. Marlton:Astellas: 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; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Phillips:Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy; Cardinal Health: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy; Incyte: Consultancy, Other: travel expenses; AstraZeneca: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy. Arthur:Royal North Shore Hospital: Current Employment. Bannerji:Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Sanofi-Pasteur: Other: Spouse is employee; F. Hoffmann-La Roche Ltd/Genentech, Inc and Pharmacyclics LLC, an AbbVie Company: Research Funding. Corradini:Incyte: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; KiowaKirin: Consultancy, Honoraria; Servier: Consultancy, Honoraria; BMS: Other; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Takeda: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Johnston:MSD: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Seymour:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, 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, Research Funding, Speakers Bureau; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy; Mei Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Nurix: Honoraria. Hirata:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Musick:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Roche/Genentech, Inc.: Current Employment. Saha:Genentech, Inc.: Consultancy; Genentech, Inc.: Current Employment. Croft:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Flowers:OptumRx: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Bayer: Consultancy; Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy; Acerta: Research Funding; Spectrum: Consultancy; Millennium/Takeda: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; AbbVie: Consultancy, Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Celgene: Consultancy, Research Funding; Kite: Research Funding. OffLabel Disclosure: Polatuzumab vedotin (Polivy) is approved in combination with bendamustine and rituximab or use in third-line or later treatment of relapsed/refractory (R/R) DLBCL in the USA and in second-line or later treatment in the EU. Venetoclax (Venclexta) is approved for the treatment of adult patients with CLL or SLL, and in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed AML in adults >75 years, or who have comorbidities that preclude use of intensive induction chemotherapy. Rituximab (Rituxan) is approved for use in relapsed/refractory low-grade NHL and in previously untreated DLBCL with CHOP, but is not approved for use in R/R DLBCL.

Context: Treatment options that are more tolerable, readily available, and capable of inducing deep and durable responses are needed in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Epcoritamab is a novel, subcutaneous (SC) CD3xCD20 bispecific antibody with preliminary potent antitumor activity. Objective: Report primary results from the LBCL expansion cohort in the phase 2 study of SC epcoritamab in patients with R/R B-cell NHL (EPCORE NHL-1; NCT03625037). Patients: Adults with R/R CD20+ LBCL were included. Patients had DLBCL (including double/triple-hit and transformed), high-grade B-cell lymphoma (HGBCL), primary mediastinal LBCL (PMBCL), or follicular lymphoma (FL) grade (G) 3B. As of January 31, 2022, 157 patients were treated. Interventions: Patients received epcoritamab (priming and intermediate doses followed by 48 mg) as 1-mL SC injections (QW, cycle [C] 1–3; Q2W, C4–9; Q4W, C≥10) until disease progression or unacceptable toxicity. Results: The 157 patients had a median of 3 (range, 2–11) prior lines of therapy (LOT), 61 (38.9%) received prior CAR T, 61% had primary refractory disease, and 83% were refractory to the last LOT. With a median follow-up of 10.7 mo, the overall response rate (ORR) by IRC (Lugano/PET-CT) was 63% with 39% complete response (CR). ORR/CR rates were 69%/42% for CAR T–naive patients and 54%/34% for CAR T–exposed patients. Median duration of response was 12 mo overall and not reached among complete responders. ORR was similar across prespecified subgroups of age, prior LOT, and de novo or transformed disease. The most common treatment-emergent AEs were CRS (49.7%; 31.8% G1, 15.3% G2, 2.5% G3), pyrexia (23.6%), fatigue (22.9%), neutropenia (21.7%), and diarrhea (20.4%). Ten patients (6.4%) experienced ICANS; all but one event was G1–2, and the G5 ICANS was the only treatment-related death. Conclusions: Epcoritamab is a convenient, SC, off-the-shelf therapy that demonstrated clinically meaningful, compelling efficacy including deep and durable responses in a challenging-to-treat, highly refractory LBCL population. Efficacy was observed in both CAR T–exposed and CAR T–naive patients. The safety profile was manageable and consistent with previous findings. Funding: This study was funded by Genmab A/S and AbbVie.