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Treatment paradigms for B-cell non-Hodgkin lymphomas (B-NHL) have shifted dramatically in the last 2 decades following the introduction of highly active immunotherapies such as rituximab. Since then, the field has continued to witness tremendous progress with the introduction of newer, more potent immunotherapeutics, including chimeric antigen receptor T-cell therapy, which have received regulatory approval for and currently play a significant role in the treatment of these diseases. Bispecific antibodies (BsAb) are a novel class of off-the-shelf T-cell redirecting drugs and are among the most promising immunotherapeutics for lymphoma today. BsAb may target various cell-surface antigens and exist in different formats. Anti-CD20xCD3 BsAb have demonstrated remarkable single-agent activity in patients with heavily pretreated B-NHL with a manageable toxicity profile dominated by T-cell overactivation syndromes. Much work remains to be done to define the optimal setting in which to deploy these drugs for B-NHL treatment, their ideal combination partners, strategies to minimize toxicity, and, perhaps most importantly, pharmacodynamic biomarkers of response and resistance. In this review, we provide an update on BsAb development in B-NHL, from discovery to clinical applications, highlighting the achievements, limitations, and future directions of the field.

Persistence or recurrence of large B-cell lymphoma after CD19-CAR-T is common, yet data guiding management are limited. We describe outcomes and features following CAR-T treatment failure. Of 305 adults who received CD19-CAR-T, 182 experienced disease recurrence or progression (1-year cumulative incidence 63% [95%CI: 57–69]). Of 52 post-CAR-T biopsies evaluated by flow cytometry, 49 (94%) expressed CD19. Subsequent anti-cancer treatment was administered in 135/182 (74%) patients with CAR-T treatment failure. Median OS from the first post-CAR-T treatment was 8 months (95%CI 5.6–11.0). Polatuzumab-, standard chemotherapy-, and lenalidomide-based treatments were the most common approaches after CAR-T. No complete responses (CRs) were observed with conventional chemotherapy, while CR rates exceeding 30% were seen following polatuzumab- or lenalidomide-based therapies. Factors associated with poor OS among patients treated post-CAR-T were pre-CAR-T bulky disease (HR 2.27 [1.10–4.72]), lack of response to CAR-T (2.33 [1.02–5.29]), age >65 years (HR 2.65 [1.49–4.73]) and elevated LDH at post-CAR-T treatment (HR 2.95 [1.61–5.38]). The presence of ≥2 of these factors was associated with inferior OS compared to ≤1 (56% vs. 19%). In this largest analysis to date of patients who progressed or relapsed after CD19-CAR-T, survival is poor, though novel agents such as polatuzumab and lenalidomide may have hold promise.

Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets (MSK-IMPACT) next-generation sequencing (NGS) panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with increased risk of progression (by multivariate analysis) were advanced-stage disease (HR, 5.1; 95% CI, 1.1-22.5, P=.03) and bone marrow involvement (HR, 3.0; 95% CI, 1.1-8.4; P=.04). The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations (HR, 3.1; 95% CI, 1.4-6.8; P=.005) and TP53/17p deletions (HR, 4.1; 95% CI, 1.1-15.0, P=.03). PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5 months (95% CI, 3.8-13.9) for PTCL with a TP53 mutation (n=21) vs 10.5 months (95% CI, 7.8-18.1; P

With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

Next-generation sequencing of cell-free DNA (cfDNA) can be used to noninvasively assess and monitor patients with lymphoma. Here, we describe the preliminary validation of MSK-ACCESS Heme (Memorial Sloan Kettering-Analysis of Circulating cfDNA to Examine Somatic Status), a cfDNA assay that employs unique molecular indexing and ultra-deep sequencing to detect somatic alterations in 117 genes related to hematologic malignancies. To our knowledge, this is the first report of a clinical-grade cfDNA assay developed specifically for hematologic malignancies. Overall assay performance was assessed using 53 validation samples (26 normal samples and 27 cfDNA samples with somatic variants). Initial accuracy studies showed excellent correlation with the reference next-generation sequencing method (MSK-ACCESS Solid), detecting 32/32 (100%) of expected variants with a variant allele frequency over 1%. The limit of detection was assessed using standard samples, with detection of variants down to 0.5% variant allele frequency. Results were highly concordant in both inter- and intra-assay reproducibility studies. Overall, these data indicate that MSK-ACCESS Heme is a robust cfDNA-based assay that can be used to detect variants at low frequency with high reproducibility. Future work sequencing additional samples will be performed to further assess the performance of the panel. Citation Format: Sara E. DiNapoli, Coleman Spence, Erika Gedvilaite, Anita Bowman, Monica Diosdado, Anna Razumova, Dana Tsui, Gilles A. Salles, Connie Batlevi, Gottfried von Keudell, Ryan Ptashkin, Ahmet Zehir, Michael Berger, A Rose Brannon, Ryma Benayed, Maria Arcila. MSK-ACCESS Heme: A cell-free DNA next-generation sequencing assay to identify somatic alterations in patients with lymphoma [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 56.

7560 Background: Tafasitamab (tafa) + lenalidomide (LEN) demonstrated efficacy in adult patients (pts) with R/R DLBCL ineligible for autologous stem-cell transplant in the pivotal Phase II study L-MIND (NCT02399085) and received accelerated approval in the United States in 2020 and conditional marketing authorization in Europe and Canada in 2021 in this setting. RE-MIND2 (NCT04697160), an observational, retrospective cohort study, compared pt outcomes from L-MIND with matched pt cohorts treated with other NCCN/ESMO recommended therapies. Methods: Methodology for RE-MIND2 has been presented previously. Hypothesis-generating analyses were conducted for pt subgroups of number of extranodal sites (ENS) (0–1 vs ≥2) and elevated lactate dehydrogenase (LDH) (yes vs no) in matched cohorts of pts receiving tafa + LEN vs systemic therapies pooled (STP), polatuzumab vedotin + bendamustine + rituximab (pola-BR), rituximab + LEN (R2), and CD19 CAR-T therapies (CAR-T). The primary endpoint was overall survival (OS). Results: Of 3,454 pts enrolled, 961, 106, 106, and 149 were treated with STP, pola-BR, R2, and CAR-T, resulting in 76, 24, 33, and 37 matched pairs for pts receiving tafa + LEN, respectively. Hazard ratios (HR) for OS show a trend toward favoring tafa + LEN in most pt subgroups (Table). Conclusion: These analyses suggest that tafa + LEN may be associated with improved OS vs selected systemic therapies for certain pts with high-risk disease and may further inform physicians’ treatment choices for pts with R/R DLBCL. These analyses are not powered for statistical comparison; small sample sizes in some subgroups result in wide confidence intervals (CI) and so results must be interpreted with caution. Data for other treatment cohorts, pt subgroups, and endpoints will be presented. Funding: MorphoSys AG. Clinical trial information: NCT04697160. [Table: see text]