Zinzani, Pier Luigi

Purpose: In RE-MIND2 (NCT04697160), patient-level outcomes from the L-MIND study (NCT02399085) of tafasitamab plus lenalidomide were retrospectively compared with patient-level matched observational cohorts treated with National Cancer Care Network (NCCN)/European Society for Medical Oncology (ESMO)-listed systemic therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients and Methods: Data were collected from health records of eligible patients aged ≥18 years with histologically confirmed DLBCL who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients from L-MIND were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest-neighbor matching, balanced for nine covariates. The primary analysis compared tafasitamab plus lenalidomide with patients who received any systemic therapy for R/R DLBCL (pooled in one cohort) or bendamustine plus rituximab (BR) or rituximab plus gemcitabine and oxaliplatin (R-GemOx; as two distinct cohorts). The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and time-to-event outcomes. Results: In RE-MIND2, 3,454 patients were enrolled from 200 sites in North America, Europe, and Asia-Pacific. Strictly matched pairs of patients consisted of tafasitamab plus lenalidomide versus systemic therapies pooled (n = 76 pairs), versus BR (n = 75 pairs), and versus R­GemOx (n = 74 pairs). Significantly prolonged OS was reported with tafasitamab plus lenalidomide versus systemic pooled therapies [hazard ratios (HR): 0.55; P = 0.0068], BR (HR: 0.42; P < 0.0001), and R-GemOx (HR: 0.47; P = 0.0003). Conclusions: RE-MIND2, a retrospective observational study, met its primary endpoint, demonstrating prolonged OS with tafasitamab plus lenalidomide versus BR and R-GemOx. See related commentary by Cherng and Westin, p. 3908

TPS7586 Background: EO2463 is a therapeutic vaccine designed to activate existing commensal bacteria-specific memory T cells that cross-react with B cell markers in order to drive anti-tumor immune activity against B-cell malignancies. The four microbial-derived, synthetically produced peptides contained in EO2463 (OMP72, OMP64, OMP65, and OMP66), correspond to cytotoxic CD8 T cell HLA-A2 restricted epitopes, and exhibit molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor), respectively. In pre-clinical models, these peptides can generate strong immune responses and specifically stimulate cross-reactive cytotoxic CD8 T cells to recognize the chosen B cell targets. EO2463 also contains a CD4 helper peptide referred to as universal cancer peptide 2, derived from the human telomerase reverse transcriptase catalytic subunit. The present study is a first-in-human clinical trial of this microbiome-derived peptide therapeutic cancer vaccine approach in patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods: This four-cohort phase 1/2 trial will investigate EO2463 monotherapy, and combinations of EO2463/lenalidomide (EL), EO2463/rituximab (ER), and EO2463/lenalidomide/rituximab (ER2), for treatment of patients with FL and MZL. Cohort 1 is a safety lead-in dose-finding in patients with relapsed/refractory (RR) disease, with a 3-by-3 design to establish the recommended phase 2 dose (RP2D) for EO2463 monotherapy and to confirm the safety of the RP2D for combination schedules of EL, and ER2. After the recommended EO2463 monotherapy dose is established, cohorts 2, 3, and 4 will open to accrual. Cohort 2 will investigate EO2463 monotherapy in patients with newly diagnosed FL/MZL who are not in need of treatment; cohort 3 will investigate EO2463 monotherapy, followed by ER in patients with limited tumor burden who need treatment, and cohort 4 will further investigate EL, followed by ER2 in the RR setting. EO2463 will be administered SC 4 times at 2-week intervals, followed by continued booster administrations every 4 weeks for 9 (Cohorts 2 and 3) or 12 (Cohorts 1 and 4) months. Inclusion/exclusion criteria, and the design and schedule of the intense immune and safety monitoring will be presented. The safety lead-in dose-finding is currently ongoing, and no safety concerns have been observed thus far. Clinical trial information: NCT04669171.

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]

7559 Background: Patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who relapse after or are ineligible for hematopoietic stem cell transplant (HSCT) or chimeric antigen receptor T cell (CAR-T) therapy generally have poor outcomes. Preclinical data provide the rationale for combining brentuximab vedotin (BV), lenalidomide (len), and rituximab for the treatment of R/R DLBCL. BV+len showed promising clinical activity in a Phase 1 trial with a 57% overall response rate (ORR), 10.2-month median progression-free survival, and 14.3-month overall survival (Ward 2021). We report the results of the open-label safety run-in that was conducted prior to the randomized portion of the study. Methods: ECHELON-3 (NCT04404283) is a randomized, double-blind, placebo-controlled, active-comparator, multicenter Phase 3 study. Prior to randomization, an open-label safety run-in was conducted; pts received BV (1.2 mg/kg) and rituximab (375 mg/m2) both q3w, and len 20 mg qd. Pts must have received ≥2 prior lines of therapy and be previously treated with or were ineligible for HSCT or CAR-T, ECOG score ≤2, and PET-avid, bidimensional measurable disease ( > 1.5 cm by CT). Pts with negligible CD30 expression ( < 1%) were eligible. Response was assessed by the investigator according to the Lugano Classification Revised Staging System (Cheson 2014). Results: 10 pts with R/R DLBCL were enrolled. Median age was 70.5 years, 7 pts were male, and all had an ECOG ≤1. Median prior lines of therapy was 3 (range, 2 to 6); no pts received prior HSCT and 6 pts received prior CAR-T. At a median follow-up of 6.9 months (range, 2.3 to 14.1), the most common treatment emergent adverse events (TEAE) were fatigue (n = 5), anemia (n = 4) and constipation (n = 4). Grade ≥3 events were experienced by 8 pts, most commonly anemia and pneumonia (n = 3 each), and neutropenia and thrombocytopenia (n = 2 each). Serious adverse events were observed in 7 pts. Seven pts each had BV and rituximab dose modifications, and 6 pts had a len dose modification. The most common reasons for any dose modification were anemia (n = 3), neutropenia, peripheral neuropathy, or pneumonia (n = 2 each). 4 pts discontinued treatment due to an AE, 2 of which were treatment related (n = 1 each of Grade 2 fatigue; Grade 3 anemia). There was 1 death due to a TEAE that was not treatment related. The ORR (best response) was 70%, including 4 pts with a complete metabolic response, 2 pts with a partial metabolic response, and 3 pts with progressive disease. Responses were seen in both CD30 (+) and (-) pts, as well as in 4 pts who received prior CAR-T. Conclusions: This novel triplet regimen appears active in R/R DLBCL with an acceptable safety profile. The randomized portion of the study is currently enrolling. Clinical trial information: NCT04404283.

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.