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Background With increased understanding of the unique entities, subtype-specific approaches for peripheral T-cell lymphoma (PTCL) are emerging, and more precise diagnoses are becoming increasingly important. Patients and Methods We analyzed the approach to the histopathologic diagnosis of PTCL using data from the comprehensive oncology measures of peripheral T-cell lymphoma (COMPLETE) study. The COMPLETE trial is a large prospective cohort study of patients with newly diagnosed PTCL in the United States. Results A total of 499 patients were enrolled from 40 academic and 15 community-based centers. Baseline assessment forms were collected for 493 patients, of which 435 (88%) were available for analysis. The most common diagnoses were PTCL, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, and angioimmunoblastic T-cell lymphoma (AITL). A mean of 10 markers (range, 0-21) was assessed per patient. CD30 was assessed frequently but not uniformly in cases that were not anaplastic large cell lymphoma. Only 17% of PTCL-NOS cases were assessed for PD1. CXCL13 was a relatively sensitive marker in AITL, expressed in 84% of tested cases; however, only 3% of PTCL-NOS cases were tested. T follicular helper cell marker assessment differed between academic and community practices, with PD1 more often evaluated by academic centers in cases of AITL (62% vs. 12%; P = .01). Conclusion The diagnostic workup for PTCL in the United States varies widely and often lacks important phenotypic information to fully characterize the lymphoma. Gaps in testing of selected markers should be filled, given the impending revision to the World Health Organization classification. The accuracy of diagnosis will become increasingly important as we enter the era of targeted treatment for PTCL.

Summary Background A new generation of biological and targeted agents might potentially replace traditional cytotoxic agents in lymphoma. Lenalidomide plus rituximab was felt to be a safe and promising backbone based on available data. Idelalisib is an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor that has promising activity as a monotherapy in refractory indolent lymphomas. The primary objective of these two trials was to determine the maximum tolerated dose of lenalidomide in combination with rituximab and idelalisib in relapsed follicular and mantle cell lymphoma. Methods A051201 (mantle cell lymphoma) and A051202 (follicular lymphoma) were phase 1 trials. Patients with histologically documented relapsed mantle cell lymphoma who had not received previous lenalidomide or idelalisib (A051201) were started with oral lenalidomide 15 mg on days 1–21 in a 28 day cycle, oral idelalisib 150 mg twice a day with continuous 28-day cycles, and intravenous rituximab 375 mg/m 2 weekly during cycle 1. Patients with histologically documented relapsed follicular lymphoma and time to progression 6 months or longer from last rituximab-containing regimen (A051202) were started with oral lenalidomide 10 mg on days 1–21 every 28 days and oral idelalisib 150 mg twice a day with continuous 28-day cycles, and intravenous rituximab 375 mg/m 2 on cycle 1, day 8, day 15, day 22, and cycle 2, day 1. The primary endpoints of the studies were safety and tolerability of combining idelalisib with lenalidomide and rituximab in patients with relapsed mantle cell lymphoma (A051201) and relapsed follicular lymphoma (A051202). All analyses were by intention to treat. The trials were registered at ClinicalTrials.gov, number NCT01838434 (A051201) and number NCT01644799 (A051202). Findings Between July 9, 2013, and Sept 30, 2014, 11 patients (three with mantle cell lymphoma and eight with follicular lymphoma) were enrolled. Among the first eight patients, four experienced unexpected dose-limiting toxicities: grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash. Symptom onset was 9–20 days after treatment initiation, coinciding with rituximab infusions. Both studies were amended to remove rituximab, but two of three additional patients had grade 3 rashes and one had grade 3 AST elevation. Both trials were permanently closed. The most common grade 3–4 adverse events were ALT elevation (two [67%] of three) and rash (two [67%] of three) for patients with mantle cell lymphoma and neutropenia (five [63%] of eight) and rash (four [50%] of eight) for patients with follicular lymphoma. The primary endpoint of safety and tolerability was not met. Interpretation The combination of idelalisib, lenalidomide, and rituximab in these trials is excessively toxic, and these trials serve as cautionary notes as new combinations are proposed. Off-target effects, drug–drug interactions, and emerging toxicities should be carefully assessed when investigating biological agents in combination and should never be done outside of a clinical trial setting. Funding National Cancer Institute of the National Institutes of Health.

Background Autologous stem cell transplant (ASCT) is frequently used as a consolidative therapy option after induction treatment in fit patients with mantle cell lymphoma (MCL) with the goal of prolonging the initial response duration. Despite recent advances there remains a subset of patients who experience early disease relapse after ASCT. We examined predictors of shortened progression-free survival (PFS) and post-relapse overall survival (OS) in a cohort of patients completing ASCT in first remission. Methods We evaluated MCL patients treated at 10 US academic medical centers. Eligible patients were treated from 2000 through 2017, and we collected information on demographic, clinical, and treatment-related variables of interest. Patients were then categorized into three post-ASCT PFS groups: 0-2 years, 2-5 years, and > 5 years, with PFS determined from the date of ASCT until progression or death from any cause. Patients followed for at least 5 years post-ASCT who were relapse free were included in the > 5 sub group. Associations were examined between groups and collected characteristics using chi-squared tests for categorical patient characteristics and ANOVA for numeric patient characteristics. The Kaplan-Meier method was used to estimate overall survival (OS) for each group, using time of relapse after ASCT as the starting point. Results Of 968 total MCL patients, 242 patients completed ASCT in first remission and either had a PFS event or were relapse-free for at least 5 years post-ASCT. Patients were 80% male, and the median age was 59 (Range: 29-83). The patients were divided into groups of post-ASCT PFS 0-2 years (n=74), 2-5 years (n=75), and more than 5 years (n=93). Post-ASCT PFS was shorter in patients with stage 4 disease (p=0.022), splenomegaly at baseline (p=0.005), and a lymph node size > 5 centimeters at baseline (p=0.043). Other variables were not significantly associated with PFS, including time to transplant and use of intensive therapy. Patients with 0-2 year PFS had a shorter median OS (22.1 months, 95% CI: 13.1- 38.1 months) in comparison to 2-5 year PFS (132 months, 95% CI: 36-132 months) and 5+ year PFS not reached (95% CI: 41.2 – N.A; Figure). Conclusion Patients with higher tumor burden at baseline have a shorter post-ASCT PFS and are more likely to relapse within 2 years. As has been seen in other lymphoma subtypes, early relapse is associated with shorter OS. This represents a patient group requiring improved therapies and perhaps are the best candidates for post-ASCT maintenance or consolidation approaches. Further studies integrating minimal residual disease and molecular risk-stratification may better identify patients at high risk for early progression.

Introduction Treatment with chimeric antigen receptor modified T cells targeting CD30 (CD30.CAR-Ts) without lymphodepletion was found to be safe with preliminary efficacy in patients (pts) with relapsed/refractory (r/r) CD30+ lymphomas (Ramos et al., JCI 2017). We report the results of a phase 1b/2 trial of CD30.CAR-Ts infused after lymphodepletion in pts with r/r CD30+ Hodgkin (HL) and Non-Hodgkin lymphoma (NHL). Objectives The primary objective of the phase Ib portion of the study was to determine the phase 2 dose of CD30.CAR-Ts using a standard 3+3 design. Methods Pts ≥ 18 years with r/r CD30+ HL or NHL having failed ≥2 prior therapies were eligible. Two dose levels were tested: 1 × 108 CAR-Ts/m2 (DL1) and 2 × 108 CAR-Ts/m2 (DL2). The first 8 pts (including the 3 pts on DL1) received bendamustine (benda) 90 mg/m2 × 2 days and the remaining 16 pts received benda 70 mg/m2 and fludarabine (flu) 30 mg/m2 × 3 days. Results At the time of data cut off (10/1/2018), 24 pts had been treated and undergone response assessment. The median age was 35.5 years (range: 23-70). 22 pts had HL, 1 had enteropathy associated T cell lymphoma and 1 had Sezary syndrome. Pts had undergone a median of 7.5 prior lines of therapy (range: 3-17). 23 pts had received prior brentuximab vedotin. 15 pts had prior autologous stem cell transplant (SCT) and 7 had prior allogeneic SCT. As there were no dose limiting toxicities, DL2 was administered as the phase 2 dose. 3 pts developed grade 1 cytokine release syndrome (CRS) and 1 pt had grade 2 CRS which responded to tocilizumab. 19 out of 24 pts had evidence of disease prior to lymphodepletion and were included in efficacy analysis. 10 pts had a CR at the 6 week assessment (53%, all in benda/flu cohort), 2 had partial response (11%), 2 had stable disease (11%), and 5 had progressive disease (26%, including all 3 pts treated at DL1). At median follow up of 180 days, the median PFS was 164 days. The median PFS for the 14 evaluable pts who received benda/flu at DL2 was 389 days. Using peripheral blood PCR, CD30.CAR-Ts peaked at wk 2 post infusion, with increasing CAR-Ts in pts receiving a higher dose or more robust lymphodepletion (3.4 × 103 ± 2.9 × 103 copies/ug of DNA for DL1-beda vs. 61 × 103 ± 41 × 103 for DL2-benda vs. 49 × 103 ± 16 × 103 for benda/flu). These differences were confirmed by flow cytometry (CD3+CAR+ cells = 13%±9% for DL1-benda vs 21%±10% for DL2-benda vs 35%±8% for benda/flu). There was also improved persistence at wk4 for higher dose and with addition of flu to lymphodepletion (0.06 × 103 ± 0.01 × 103 vs. 0.44 × 103 ± 0.41 × 103 vs. 25 × 103 ± 11 × 103/ug of DNA at wk 4 for DL1-benda, DL2-benda, and benda/flu, respectively). Conclusion CD30.CAR-Ts administered with lymphodepletion with benda/flu are safe and have promising anti-tumor activity for pts with r/r CD30+ lymphomas. A higher dose of CD30.CAR-Ts and the addition of flu to lymphodepletion increased T cell expansion and persistence and translated to improved efficacy.