Maurer, Matthew J.

Abstract Introduction Transthyretin amyloid cardiomyopathy (ATTR-CM) is a chronic condition associated with progressive heart failure, resulting from extracellular deposition of misfolded transthyretin (TTR) protein as amyloid fibrils in the myocardium. Currently, there are few disease-modifying treatments. NNC6019–0001 is a humanized monoclonal antibody designed to deplete amyloid via antibody-mediated phagocytosis by targeting a unique epitope that is exposed only on misfolded monomeric and aggregated forms of TTR. In a phase 1, open-label, 3-month dose escalation trial, NNC6019–0001 was well tolerated at all doses tested (up to and including 30 mg/kg).1 The maximum tolerated dose was not reached. Exploratory cardiac endpoints were stable or indicated a possible benefit. Purpose To evaluate the effect of NNC6019–0001 30 mg/kg and 100 mg/kg on cardiac functional endpoints and predictive biomarkers in patients with ATTR-CM, and to assess pharmacokinetics, safety and tolerability, to establish the optimal dose for a phase 3 trial. Methods This is a randomized, double-blind, placebo-controlled trial recruiting 99 patients with hereditary or wild-type ATTR-CM (Figure). Inclusion criteria are New York Heart Association (NYHA) class II or III heart failure, left ventricle wall thickening (LVWT) ≥12 mm, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels ≥650 pg/mL in sinus rhythm and >1000 pg/mL in atrial fibrillation, and a 6-minute walk test (6MWT) distance of 150–450 m. Patients will be randomly assigned to receive intravenous NNC6019–0001 30 mg/kg or 100 mg/kg or placebo, each in addition to standard of care, every 4 weeks for 52 weeks, followed by a 12-week follow-up. In a sentinel dosing phase, three patients per arm will receive the study drug or placebo, in combination with 24-hour inpatient cardiac monitoring and 7 days of continuous cardiac (tele-) monitoring. The primary endpoints are change from baseline to week 52 in 6MWT and in NT-proBNP levels. Secondary endpoints include cardiac measures: extracellular volume on cardiac magnetic resonance imaging, global longitudinal strain, troponin T levels, hospitalization due to cardiovascular events, and urgent visits due to heart failure. Quality of life will be assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ). All-cause mortality, pharmacokinetics and treatment-emergent adverse events will also be assessed. Results The trial will start mid-2022 with global recruitment. Conclusion Disease-modifying treatments are needed for patients with ATTR-CM, where treatment is often limited to managing symptoms and best supportive care; the first disease-modifying therapies recently became available. This phase 2 trial will be used to determine the appropriate dose for the phase 3 trial of NNC6019–0001, a novel antibody therapy designed to deplete amyloid in patients with ATTR-CM. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This trial was funded by Novo Nordisk A/S. Medical writing support was provided by Johanna Scheinost PhD, PharmaGenesis Oxford Central, Oxford, UK, with funding from Novo Nordisk A/S.

Abstract An enhanced understanding of the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) has opened the door to clinical trials evaluating novel agents with subtype-specific activity. It is an emerging question whether core needle biopsies (CNB) can adequately meet the increasing tissue requirements of these clinical trials. This can potentially lead to selective enrollment of patients who can undergo excisional biopsy (EB). It is also important to know whether patients who can undergo extensive diagnostic work up differ in their disease characteristics and outcomes from those who cannot. In this observational study, we describe the characteristics, outcomes, and adequacy of diagnostic tissue in patients with newly diagnosed DLBCL and primary mediastinal large B-cell lymphoma who underwent EB vs CNB. Of the 1061 patients, 532 (49.8%) underwent EB and 529 (50.1%) underwent CNB. A significantly higher proportion of patients with CNB had advanced stage disease, an international prognostic index of ≥3, and inadequate tissue for molecular analyses. Patients with CNB had significantly worse 5-year event-free survival (67.6% vs 56.9%; hazard ratio [HR], 0.76; confidence interval [CI]95, 0.6-0.9, P < .001) and 5-year overall survival (76.4% vs 69.2%; HR, 0.8; CI95, 0.6-0.9, P < .001). Thus, patients who underwent CNB have poor-risk features and inferior outcomes on frontline chemoimmunotherapy, are more likely to have inadequate tissue for molecular analyses, and might not meet the tissue requirements of biomarker-driven clinical trials. Thus, the increasing tissue requirements of biomarker-driven clinical trials may result in the exclusion of patients with high-risk DLBCL who need novel agents.

Abstract Low-grade B-cell lymphomas other than follicular and small lymphocytic lymphoma (LGBCL) account for 10% of all B-cell non-Hodgkin lymphomas. Despite improvements in survival outcomes for these patients, little is known about cause of death (COD) in the rituximab era. For a better understanding, we studied 822 newly diagnosed patients with marginal zone, lymphoplasmacytic, and unclassifiable low-grade B-cell lymphoma prospectively enrolled in the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2015. COD was assigned based on medical record review using a standard protocol. At a median follow-up of 107 months, 219 (27%) patients had died. The incidence of lymphoma-related deaths when pooling across subtypes was lower than non–lymphoma-related deaths (10-year incidence, 8.0%; 95% confidence interval [CI]: 6.2-10.4 vs 13.6%; 95% CI: 11.2-16.6). The incidence of lymphoma-related deaths varied by subtype, ranging from 3.7% at 10 years in extranodal marginal zone lymphoma to 19.3% in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Patients with early progression or retreatment events, defined using event-free survival at 24 months from diagnosis, had significantly higher likelihood of lymphoma-related death compared with patients without early events (10-year estimate: 19.1% vs 5.1%, respectively; P < .001), whereas the rates for non–lymphoma-related death were comparable in patients with or without early events (10-year estimates: 11.0% vs 15.3%, respectively). In conclusion, the most common COD in LGBCLs in the first decade after diagnosis was for causes other than lymphoma. Progression or retreatment within the first 2 years of diagnosis was a strong predictor for risk of lymphoma-related death.

Abstract Cancer clinical trial eligibility criteria may create patient populations studied in trials that do not reflect the patient populations treated in the real-world setting. Follicular lymphoma (FL) is an indolent lymphoma with heterogeneous presentations across a broad range of individuals, resulting in many acceptable management strategies. We evaluated how first-line clinical trial eligibility criteria impacted the demographic makeup and outcomes of patients with FL for whom systemic therapy might be considered. We compared the characteristics of 196 patients with FL from a single institution to eligibility criteria from 10 first-line FL trials on clinicaltrials.gov. Next, we tabulated eligibility criteria from 24 first-line FL protocols and evaluated their impact on 1198 patients with FL with stages II to IV disease from the prospective Molecular Epidemiology Resource (MER) and Lymphoma Epidemiology of Outcomes (LEO) cohort studies. We found that 39.8% and 52.7% of patients with FL might be excluded from clinical trials based on eligibility criteria derived from clinicaltrials.gov and protocol documents, respectively. Patients excluded because of renal function, prior malignancy, and self-reported serious health conditions tended to be older. Expanding stage requirement from III-IV to II-IV, and platelet requirement from ≥150 000 to ≥75 000 increased population size by 21% and 8%, respectively, in MER and by 16% and 13%, respectively, in LEO, without impacting patient demographics or outcomes. These data suggest that management of older individuals with FL may not be fully informed by recent clinical trials. Moreover, liberalizing stage and platelet criteria might expand the eligible population and allow for quicker trial accrual without impacting outcomes.

Abstract Background: DLBCL is the most common non-Hodgkin lymphoma subtype in western countries and is clinically heterogeneous. Gene expression profiling has identified two major biologically distinctive DLBCL subtypes defined by their cell-of-origin (COO): germinal center B-cell (GCB) - characterized by BCL2 rearrangement and C-REL amplification, and activated B-cell (ABC) - characterized by constitutive activation of the NF-kB pathway. We evaluated putative DLBCL risk factors for etiologic heterogeneity as defined by COO. Methods: We used a clinic-based study of newly diagnosed NHL cases and frequency matched controls, enrolled from 2002-2014, with a total of 687 DLBCL cases and 2253 controls for this analysis. Using formalin-fixed, paraffin-embedded tumor tissue, we determined COO by either digital expression profiling (NanoString; classified as GCB, ABC, undetermined) or clinically using the Hans algorithm (immunohistochemical markers; classified as GCB, non-GCB, undetermined). Integrating these two sources of COO data, there were 271 GCB, 170 non-GCB, and 246 undetermined/missing (mainly due to lack of tissue) cases. Risk factor data were collected from self-administered questionnaires and included family history of hematologic malignancy; history of atopy, allergy, asthma, eczema, or autoimmune disease; blood transfusion; vaccination history; regular low-dose aspirin use; body mass index (BMI) 2 years prior diagnosis/enrollment; smoking history; alcohol consumption (never/current/former); leisure-time physical activity; and recreational sun exposure. Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for COO subtypes, adjusted for age, sex and residence. Results: The median age of cases was 64 years with 55% male; the median age of controls was 64 years and 53% male. The association with BMI (30+ vs. 18.5-24.9 kg/m2) was stronger for non-GCB (OR=2.21; 1.40-3.49) than for GCB (OR=1.70; 1.21-2.40) DLBCL (P-heterogeneity 0.02), while a family history of hematologic malignancy was associated with non-GCB (OR=2.27; 1.47-3.50) but not GCB (OR=1.30; 0.86-1.96) DLBCL, although the P-heterogeneity was not significant (P=0.13). For GCB, there was an inverse association with former (vs. never) alcohol use for GCB (OR=0.57; 0.39-0.83) but not for non-GCB (OR=0.98; 0.61-1.57) DLBCL (P-heterogeneity 0.007), and an inverse association with regular use of low-dose aspirin for GCB (OR=0.64; 0.47-0.87) but not for non-GCB (OR=0.88; 0.61-1.25) DLBCL (P-heterogeneity 0.05). No other risk factors evaluated showed important heterogeneity by COO. Conclusions: These initial results suggest most DLBCL risk factors do not show etiologic heterogeneity by DLBCL COO, although associations with BMI and family history with non-GCB DLBCL and alcohol and low-dose aspirin use with GCB DLBCL warrant follow-up. Citation Format: Geffen Kleinstern, Dennis P. Robinson, Lisa M. Rimsza, Melissa C. Larson, Rebecca L. King, Grzegorz S. Nowakowski, Carrie A. Thompson, Stephen M. Ansell, Matthew J. Maurer, Andrew L. Feldman, Susan L. Slager, Anne J. Novak, Thomas M. Habermann, James R. Cerhan. Evaluation of etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 741.

e19583 Background: Brexucabtagene autoleucel (BA) is an FDA approved therapy for relapsed/refractory (R/R) mantle cell lymphoma (MCL), based on results from ZUMA-2 study. We report the safety and efficacy of BA in standard of care practice among centers in the US Lymphoma CAR-T Consortium. Methods: 16 centers participated in this retrospective study. Patients (pts) who underwent leukapheresis by 12/31/2021 with an intent to manufacture BA were included. Baseline clinical characteristics, bridging therapy, adverse events after BA infusion, and post-infusion outcome data were collected. Eligibility for ZUMA-2 was retrospectively determined. Survival outcomes were analyzed using the Kaplan-Meier method. Results: At the data cut-off date, 189 pts underwent leukapheresis, among whom 167 (88%) completed BA infusion, 22 (12%) did not receive infusion. The median age was 67 years. 16% had high risk simplified MIPI, 57% had Ki-67≥50%, 41% had aggressive histology, 49% had TP53 alteration, 51% with POD24 and 10% had CNS involvement. The median number of prior lines of therapy was 3 (range 1-10). 86% had prior BTKi treatment (89% refractory). 130 (78%) pts would not have met ZUMA-2 eligibility criteria. 113 (68%) pts received bridging therapy, which included BTKi, venetoclax, chemotherapy. Median time from leukapheresis to lymphodepletion chemotherapy: 28 days (range 17-140). Cytokine release syndrome (CRS) rate was 90% (8% grade ≥3; 1 grade 5), and immune effector cell-associated neurotoxicity syndrome (ICANS) rate was 61% (32% grade ≥3). Grade 5 ICANS (n = 0). Medications used to manage CRS and ICANS were 125 (76%) for tocilizumab, 112 (68%) for corticosteroid, and 27 (16%) for anakinra. 32 (20%) pts required ICU admission, 18 pts required vasopressors, and 5 pts required mechanical ventilation. Day 30 response was evaluable in 155 pts (89% ORR, 70% CR). The best ORR was 89%, with 80% CR, 9% PR. The ORR/CR rates were 88%/79% for aggressive histology, 89%/77% for high Ki-67% (> 50%), 90%/72% for TP53 altered, 81%/75% for CNS involved, 89%/79% for BTKi-exposed, 91%/83% for BTKi-naïve, and 89%/78% for those not meeting ZUMA-2 eligibility criteria. The median duration of response was not reached and at 6-month was 67% (95% CI 57-75). With a median follow-up of 5.6 months (range 0.2-15.3), median PFS was not reached, the 6-month PFS rate was 63% (95% CI 54-71), and median OS was 15.3 months and the 6-month OS rate was 85% (95% CI 77-90). Conclusions: This multicenter retrospective study demonstrated encouraging safety and efficacy data of BA in R/R MCL in the real-world practice. Despite 78% of the pts being ineligible for ZUMA-2, the responses, CRS, ICANS and outcomes were comparable to ZUMA-2 data. Long term safety and efficacy will be reported.

7573 Background: While most patients (pts) with follicular lymphoma (FL) usually have favorable outcomes, those with refractory disease after first-line anti-CD20 based immunochemotherapy (IC), or progression within 24 months of diagnosis (POD24) have higher risk of premature death. There are no standard approaches for treating this vulnerable group and studies testing novel agents are ongoing in this setting. We sought to investigate clinical practice treatment choices and efficacy for pts with POD24 that align with eligibility criteria for the randomized SWOG1608 which compares IC with novel agents in this population. Methods: This was a multicenter observational cohort study from the LEO Consortium. Eligible pts had grade 1-3a FL diagnosed between 1/1/2002 and 2/1/2019, and initiated therapy after POD24 to first-line bendamustine or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) based IC. Observation, radiotherapy, or rituximab monotherapy were permitted prior to IC and pts with transformation prior to the subsequent therapy after IC were excluded as per S1608. Outcomes of interest were overall and complete response rate (ORR/CR), progression-free survival (PFS), and overall survival (OS). Results: We identified 196 eligible pts with early progression to IC (39% antiCD20 Benda; 61% antiCD20 CHOP) who received subsequent therapy. Median age at post IC treatment was 57 years, 78% grade 1-2 FL. Treatments for pts with POD24 included CHOP- or Benda-based in 31%, salvage/hematopoietic stem cell transplant (HSCT) in 27%, novel therapies in 10% (including phosphatidylinositol 3-kinase inhibitors), antiCD20 monotherapy in 9%, and lenalidomide-based treatment in 8% (table); 21% of pts were treated on clinical trials. Across all treatments, ORR (CR) was 63% (37%) (95% CI: 55-70). At a median follow up of 6.2 years, 2 year PFS was 22% (95% CI: 17%-29%) and 5 year OS was 71% (95% CI: 65-79). Outcomes by regimen are shown in the table. Conclusions: Pts with FL experiencing POD24 following first-line IC are treated heterogeneously, with many pts still receiving IC as subsequent therapy. Despite modest CR rates and low 2-year PFS, 5-year OS appear to be improving compared to historical outcomes. This supports the ongoing need to investigate novel treatments in this population. [Table: see text]