Savage, Kerry J.

Abstract Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression–based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx’s utility for routine diagnostic purposes and therapeutic decision making.

TPS7577 Background: Nivolumab (nivo) is a PD-1 immune checkpoint inhibitor that augments T-cell activation and host anti-tumor responses. PD-1 blockade has shown promise in B- and T-cell non-Hodgkin lymphoma (NHL),1 but many patients (pts) with NHL do not respond or progress after response. Combination therapy using anti-tumor agents with complementary mechanisms of action and low immunosuppressive impact may result in more frequent and durable responses. Brentuximab vedotin (BV) is an anti-CD30 antibody–drug conjugate that induces cell cycle arrest and apoptosis, with activity in a range of NHL tumors.2,3 Tumor cells undergoing BV-induced apoptosis have shown subsequent immune-mediated anti-tumor cytotoxicity.4 Therefore, nivo and BV may synergize if combined for relapsed/refractory (RR) NHL. Methods: CheckMate 436 (NCT02581631) is a phase 1–2, open-label, international, single-arm study evaluating nivo + BV for CD30-expressing RR NHL (study start: Dec 2015) in pts with RR diffuse large B-cell lymphoma, peripheral T-cell lymphoma (excluding anaplastic large cell lymphoma), and cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome); cohorts with primary mediastinal B-cell lymphoma (PMBL) and mediastinal gray zone lymphoma were made eligible in Sept 2016. Pts with PMBL must be aged ≥15 y (≥18 y for other histologies). All pts must have CD30-expressing disease, defined by CD30 on ≥1% of tumor cells or tumor-infiltrating lymphocytes by immunohistochemistry. In the phase 1 component, 6 pts will receive nivo and BV until disease progression or unacceptable toxicity. In the phase 2 component, ~130 more pts across the 5 histologies will be enrolled and treated at the recommended dose. Primary endpoints: safety, tolerability, and investigator-assessed objective response rate; secondary endpoints: duration of response and complete response (CR), CR rate, and progression-free and overall survival. Accrual is ongoing. References: 1. Lesokhin A et al. JCO 2016;34:2698–704 2. Jacobsen E et al. Blood 2015;125:1394–402 3. Horwitz S et al. Blood 2014;123:3095–100 4. Gardai S et al. Cancer Res 2015;75(15 Suppl):2469 [abstract]. Clinical trial information: NCT02581631.

Purpose Peripheral T-cell lymphomas (PTCLs) have aggressive clinical behavior. We have previously shown that event-free survival (EFS) at 24 months (EFS24) is a clinically useful end point in diffuse large B-cell lymphoma. Here, we assess EFS24 and subsequent overall survival (OS) in large, multinational PTCL cohorts. Patients and Methods Patients with systemic PTCL newly diagnosed from 2000 to 2012 and treated with curative intent were included from the United States and Sweden (initial cohorts) and from Canada (replication cohort). EFS was defined as time from date of diagnosis to progression after primary treatment, retreatment, or death. Subsequent OS was measured after achieving EFS24 or from the time of progression if it occurred within 24 months. OS rates were compared with the age-, sex-, and country-matched general population. Results Seven hundred seventy-five patients were included in the study (the median age at diagnosis was 64 years; 63% were men). Results were similar in the initial and replication cohorts, and a combined analysis was undertaken. Sixty-four percent of patients progressed within the first 24 months and had a median OS of only 4.9 months (5-year OS, 11%). In contrast, median OS after achieving EFS24 was not reached (5-year OS, 78%), although relapses within 5 years of achieving EFS24 occurred in 23% of patients. Superior outcomes after achieving EFS24 were observed in younger patients (≤ 60 years of age: 5-year OS, 91%). Conclusion EFS24 stratifies subsequent outcome in PTCL. Patients with PTCL with primary refractory disease or early relapse have extremely poor survival. However, more than one third of patients with PTCL remain in remission 2 years after diagnosis with encouraging subsequent OS, especially in younger patients. These marked differences in outcome suggest that EFS24 has utility for patient counseling, study design, and risk stratification in PTCL.

Key Points A total of 38% of patients who achieved CR (13 of 34) on brentuximab vedotin have remained in remission for >5 years and may be cured. Nine of the 13 patients (9% of all enrolled patients) have remained in long-term remission without a consolidative allogeneic transplant.