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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]

Background: Less than 20% of patients with follicular lymphoma (FL) present with Ann Arbor Stage I or II disease at diagnosis. Numerous therapeutic options exist, however radiation therapy is considered the standard of care for early-stage disease based on single-institution or retrospective series. Our aim was to revisit the outcome of patients with localized FL in the rituximab era. Patients and Methods. We analyzed the characteristics and outcomes of 145 early-stage FL patients, who were retrospectively divided into six groups according to their initial treatment: watchful waiting (WW), chemotherapy alone (CT), radiotherapy alone (RT), combined radiotherapy and chemotherapy (RT-CT), rituximab alone (Ri), and immunochemotherapy (Ri-CT). Results: Of the 145 patients, 84 (57.9%) had stage I disease and 61 (42.1%) stage II. The complete response (CR) rate varied from 57% for the Ri group to 95% for the RT-CT group. Overall survival (OS) at 7.5 y of patients treated after 2000 was better than that of those treated prior to 2000. OS did not significantly differ from one treatment to another. In contrast, a significant difference was found for progression-free survival (PFS) at 7.5 y, which favored Ri-CT (60%) therapy versus the others (p=0.00135). Conclusion: Delayed therapy initiation was associated with a similar OS than that observed in patients receiving immediate intervention. The "watchful waiting" strategy may thus be proposed as first-line therapy, similar to stage III and IV FL patients with a low tumor burden. However, when treatment is required, immunochemotherapy appears to be the best option. © 2013 Michallet et al.; licensee BioMed Central Ltd.

Genomic alterations play a crucial role in the development and progression of diffuse large B-cell lymphomas (DLBCLs). We determined gene copy number alterations (GCNAs) of TP53, CDKN2A, CDKN1B, BCL2, MYC, REL, and RB1 with a single polymerase chain reaction (PCR) assay (quantitative multiplex PCR of short fragments [QMPSF]) in a cohort of 114 patients with DLBCL to assess their prognostic value and relationship with the gene expression profile. Losses of TP53 and CDKN2A, observed in 8% and 35% of patients, respectively, were significantly associated with a shorter survival after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment, independently of the International Prognostic Index and of the cell of origin. Analysis of the 9p21 genomic region indicated that transcripts encoding p14ARF and p16INK4A were both disrupted in most patients with CDKN2A deletion. These patients predominantly had an activated B-cell profile and showed a specific gene expression signature, characterized by dysregulation of the RB/E2F pathway, activation of cellular metabolism, and decreased immune and inflammatory responses. These features may constitute the molecular basis sustaining the unfavorable outcome and chemoresistance of this DLBCL subgroup. Detection of TP53 and CDKN2A loss by QMPSF is a powerful tool that could be used for patient stratification in future clinical trials.

TPS8601 Background: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non-Hodgkin lymphomas (iNHL) and account for approximately 22% and 10%, respectively, of all NHLs. Althoug...

Introduction Alkylating agent-rituximab combinations are a current standard of care for patients with iNHL. Most iNHL will eventually become refractory to current therapies. Particularly, once iNHL becomes “double-refractory” to rituximab + alkylating agents, there are few data available on beneficial therapeutic options and development of novel therapies is essential for this patient population. PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kδ, demonstrated considerable activity in recurrent iNHL in a phase 1 trial (Kahl, ICML 2011). We thus evaluated idelalisib in a phase 2 trial for patients with double-refractory iNHL, an area of unmet medical need. We present mature response data and extended follow-up of this study. Methods Eligible iNHL patients (pts) included those with measurable disease who were refractory to both rituximab and an alkylating agent. Refractory status was defined as lack of response to, or progression of lymphoma within 6 months of completion of therapy, documented by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007). The new data cutoff date for this analysis was June 2013, 8 months after the last patient enrolled. Results Enrolled pts (N=125) had a median age of 64 years [range 33-87] and were 64% male. Indolent NHL subtypes included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12], most common regimens included bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and 14 pts (11%) had a prior autologous transplant. 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. Median time since completion of last regimen was 3.9 months. At baseline, pts had elevated LDH (30%), bulky disease >7 cm (26%), anemia ≥grade 1 (51%), neutropenia ≥ grade 1 (24%), and thrombocytopenia ≥grade 1 (34%). With a median follow up 9.4 months, the overall response rate (ORR) was 57% (95% CI = 47.6, 65.6) with 71 responders, comprising 7 CRs (6%), 63 PRs (50%), and 1 minor response (MR) in a WM pt. There were 42 pts with stable disease (SD) (33%). 90% of pts experienced some decrease in tumor burden (Figure 1). Median time to response was 1.9 months (range 1.6-8.3), median time to CR was 3.7 months (range 1.9-12). ORR for iNHL subtypes was: FL (54%), SLL (61%), LPL/WM (80%), and MZL (47%). ORR for bendamustine refractory pts was 59%. ORR for pts with The most common adverse events were (total%/≥ grade 3%) diarrhea (43/13), fatigue (30/2), nausea (30/2), cough (29/0), pyrexia (28/2), dyspnea (18/3), rash (13/2), and pneumonia (11/7). Based on central laboratory measurements, Grade ≥3 ALT/AST elevations occurred in 16 pts (13%). Drug was held for these pts, and 11/14 pts (79%) were re-treated without recurrence of ALT/AST elevation. Grade ≥3 neutropenia occurred in 27%, thrombocytopenia in 6%, and anemia in 2%. 20% of pts have discontinued therapy due to adverse events. Conclusions Idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in this double-refractory iNHL population with an ORR of 57%. The ORR was consistent across all subgroups, regardless of disease histology, number of prior regimens, refractoriness to bendamustine, or tumor bulk. With continued administration of idelalisib, responses were durable beyond one year, substantially exceeding the median DOR for the last prior therapy. Mature response data demonstrate that idelalisib can provide clinical benefit to patients with the unmet medical need of double-refractory iNHL. Disclosures: Gopal: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. Kahl:Gilead Sciences: Advisory Board Other, Research Funding. De Vos:Gilead Sciences: Advisory Board Other, Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Schuster:Gilead Sciences: Research Funding. Blum:Gilead Sciences: Research Funding. Jurczak:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Flowers:Gilead Sciences: Research Funding. Martin:Gilead Sciences: Research Funding. Viardot:Gilead Sciences: Research Funding. Goy:Gilead Sciences: Research Funding. Davies:Gilead Sciences: Research Funding. Zinzani:Gilead Sciences: Research Funding. Dreyling:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment. Li:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment. Godfrey:Gilead Sciences: Employment. Salles:Gilead Sciences: Research Funding.

Introduction The B-cell receptor (BCR) pathway plays a central role in signal transduction pathways that regulate survival, activation, proliferation and differentiation of B-lineage lymphoid cells. Bruton’s tyrosine kinase (Btk) is a critical kinase in BCR signal transduction and recent studies support that targeting Btk is effective in the treatment of B-cell malignancies. ONO-4059 is a highly potent and selective oral Btk inhibitor with an IC50 in the sub-nmol/L range that has demonstrated anti-tumour activity in several pre-clinical models (Yasuhiro T et al, AACR 2013). Methods This Phase I study was initiated to determine the safety, tolerability, dose-limiting toxicity (DLT), pharmacokinetics and pharmacodynamics of ONO-4059 given as monotherapy to patients with relapsed/refractory NHL for whom no therapy of higher priority was available. In this safety-driven, dose-escalating 3+3 design, ONO-4059 was administered as an oral, daily dose (flat dose) given continuously initially for up to 6 months, with the option of additional dosing up to 2 years. We present the safety and efficacy data on 14 evaluable patients (mantle cell lymphoma n=7, follicular lymphoma n=3, plasmablastic DLBCL n=1, ABC-DLBCL n=1, small lymphocytic lymphoma n=1 and Waldenstrom’s macroglobulinaemia n=1), with a median age 64 yrs (range 48-88), median baseline tumour burden 5,668 mm2 [1,582-19,509]. Patients received a median of 3 prior therapies [range 2-8], with all patients having prior exposure to a rituximab-containing regimen 93% (13/14) and 29% of patients (4/14) had prior ASCT. Patients received ONO-4059 at doses ranging from 20mg-160mg (cohorts 1-4) and the study is currently ongoing with additional dose escalation cohorts to be completed. Results ONO-4059 was found to be well tolerated, with no dose limiting toxicities (DLTs). A total of 18 ONO-4059-related adverse events were reported in 6 out of 14 patients; CTCAE-V4.0 G1 (n=10 [n=6 in 1 patient]) and G2 (n=5). Three ONO-4059-related G3 haematological toxicities were reported in 2 patients; thrombocytopenia (x2) and anemia. No ONO-4059-related G4 events, or related SAEs or infections were reported. The pharmacokinetics of ONO-4059 reflects rapid absorption and elimination, a half-life of ∼6 hours, a dose dependent increase in exposure with no accumulation of ONO-4059 exposure and low inter- or intra-patient variability; with Btk occupancy in peripheral blood (as measured by phosphorylated Btk) being maintained for at least 24 hours across all dose levels. Responses have occurred at doses of 40, 80 and 160mg, with a best overall response rate of 42% [based on CT-scan and physical examination for 5/12 evaluable patients]; with 5 PR, 4 SD, 2 PD (both MCL) and one ABC-DLBCL patient was withdrawn due to non-related SAE during Cycle 1. Of the 6 evaluable MCL patients, 3 have achieved PR resulting in a best ORR of 50% (median reduction of lymph nodes was 73% [45%-84%]). Almost all patients experienced clinically meaningful rapid reductions in lymphadenopathy observed within the first cycle. Ten of the fourteen patients are currently still on study with a median progression-free survival of 93.5 days [Range 8-268]. In conclusion, ONO-4059 is a highly potent and selective oral Btk inhibitor that shows a favourable safety profile along with promising efficacy in this difficult-to-treat patient population. Disclosures: Salles: Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria. Karlin:Janssen: Honoraria; Celgene: Honoraria. Morschhauser:ONO Pharma: Honoraria; Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Dyer:Ono Pharma: Honoraria, Research Funding. Hutchinson:Ono Pharma: Research Funding. Fegan:ONO Pharma: Honoraria. Cartron:ONO Pharma: Honoraria. Knurowski:ONO Pharma: Consultancy. Wright:ONO Pharma: Consultancy. Saunders:ONO Pharma: Consultancy; Pharmacyclics: Consultancy. Honda:ONO Pharma: Employment. Mazur:ONO Pharma: Consultancy. Yoshizawa:Ono Pharma: Employment. Kawabata:Ono Pharmaceutical Co., Ltd.: Employment. Birkett:Ono Pharma UK: Employment.

Background The (14;18) translocation constitutes both a genetic hallmark and critical early event in the natural history of Follicular Lymphoma (FL). However, t(14;18) is also detectable in the blood of otherwise healthy persons, and the relationship with progression to disease remains unclear. A key gap in our understanding is whether such t(14;18)+ cells in healthy individuals constitute committed FL precursors, and if high t(14;18) frequencies in blood represent a suitable predictive biomarker of FL development. Methods Among 520,000 healthy participants enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we identified 100 subjects who developed FL 2-161 months after enrolment. Blinded Prediagnostic blood from these and 218 controls were screened for t(14;18) by sensitive PCR-based assays. Results were subsequently validated on an independent cohort (65 cases, 128 controls). Clonal relationships between t(14;18) cells and FL biopsy were also assessed by molecular backtracking of paired prediagnostic/tumor samples. Results Clonal analysis of t(14;18) junctions in paired prediagnostic blood vs. tumor demonstrated that progression to FL occurred from t(14;18)+ committed precursors. Furthermore, we show that the prevalence of t(14;18) was significantly higher in individuals that subsequently develop FL compared to the controls (56% vs. 28.9%, p Conclusion We demonstrated that high t(14;18) frequencies in blood from healthy individuals discriminates commitment to FL development up to 15 years before diagnosis and define the first predictive biomarker for FL. Providing they represent bona fide precursors, this molecular blood-based biomarker could therefore be of great value in identifying groups of at-risk individuals and their detailed geno-phenotypic characterization should provide important insights into the factors and kinetics of events driving early FL progression. Disclosures: No relevant conflicts of interest to declare.