Bartlett, Nancy L

PURPOSE Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma. PATIENTS AND METHODS Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety. RESULTS Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; P = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; P = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common ( P < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% v 10.7%, respectively), febrile neutropenia (35.0% v 17.7%, respectively), mucositis (8.4% v 2.1%, respectively), and neuropathy (18.6% v 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm. CONCLUSION In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.

Abstract Serum soluble chemokines/cytokines produced by Hodgkin cells and the tumor microenvironment might be of value as biomarkers in classic Hodgkin lymphoma (cHL). We assessed serum thymus and activation-related chemokine (TARC), macrophage-derived chemokine (MDC), interleukin-10 (IL-10), and soluble CD163 (sCD163) levels at baseline, time of interim fluorodeoxyglucose positron emission tomography (PET), and after therapy in cHL patients treated on S0816, an intergroup phase 2 response-adapted study evaluating escalated therapy for interim PET (PET2)–positive patients (www.clinicaltrials.gov #NCT00822120). Epstein-Barr virus (EBV) status was assessed, and 559 serum samples were evaluated for TARC, MDC, IL-10, and sCD163 by immunoassay. EBV positivity correlated with higher sCD163 and IL-10 levels but lower TARC levels. While baseline biomarker levels were not associated with outcome, sCD163 levels at the time of PET2 were associated with favorable progression-free survival (PFS), adjusting for PET2 status. After therapy TARC, MDC, and IL-10 correlated with PFS and overall survival (OS) on univariable analysis, which remained significant adjusting for international prognostic score. When also adjusting for end-of-therapy PET results, TARC and IL-10 remained significantly associated with shorter PFS and OS. Exploratory analysis in PET2-negative patients showed that elevated posttherapy TARC and IL-10 levels were associated with PFS. Serum cytokine levels correlate with outcome in cHL and should be investigated further in risk-adapted cHL trials.

Abstract Purpose: To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA). Patients and Methods: ECHELON-1 is a global, open-label, randomized phase III study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD + bleomycin) as first-line therapy in subjects with stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. Results: The NA subgroup consisted of 497 subjects in the A+AVD (n = 250) and ABVD (n = 247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint [modified progression-free survival (PFS) per independent review] demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR = 0.60; P = 0.012). For PFS, the risk of progression or death was also reduced (HR = 0.50; P = 0.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared with ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD. Conclusions: The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for patients with stage III or IV cHL.

7512 Background: Outcomes in activated B cell subtype diffuse large B cell lymphoma (ABC-DLBCL) and r-NHL are poor (Sehn Blood 2015, Crump ASCO 2016). ZUMA-1 is the first, multicenter trial of anti-CD19 chimeric antigen receptor (CAR) T cells, axi-cel, in r-NHL. Methods: Dosing and eligibility were per Neelapu ASH 2016. The primary endpoint was objective response rate (ORR); secondary endpoints were duration of response (DOR), overall survival (OS), and safety. Cell of origin (COO) and CD19 status were assessed centrally using Lymphoma Subtyping Test NanoString (Wallden JCO 2015) and a validated immunohistochemistry assay, respectively. Results: As of Jan 27, 2017, 111 patients (pts) were enrolled; the manufacturing success rate was 99% with an average 17-d turnaround time; 101 pts (modified intent-to-treat [mITT] population) received axi-cel. In the mITT population, the ORR was 82% (complete response [CR], 54%). With 8.7 m median follow-up, 44% remain in response and 39% in CR. The median DOR was 8.1 m and not reached (NR) for pts with CR. Median OS was NR. Results for clinical and biologic covariates are listed in the table. In pts who received tocilizumab (n = 43) and/or steroids (n = 27) for cytokine release syndrome (CRS) and/or neurologic events (NE), ORR was 84% and 78%, respectively. Most common grade ≥3 adverse events (AEs) were neutropenia (66%), leukopenia (44%), anemia (43%), febrile neutropenia (31%), thrombocytopenia (24%), and encephalopathy (21%). Rates of grade ≥3 CRS and NE were 13% and 28%, respectively. There were 3 grade 5 AEs (Neelapu ASH 2016). Conclusions: Axi-cel induced an ORR of 82% in pts with r-NHL, response is ongoing in 44% of pts at 8.7 m. Similar clinical responses were observed in pts with r-ABC-DLBCL. AEs were manageable and the use of tocilizumab/steroids did not appear to impact ORR. Drs Locke and Neelapu contributed equally. Funding source: Kite Pharma and Leukemia & Lymphoma Society Therapy Acceleration Program Clinical trial information: NCT02348216. [Table: see text]

3025 Background: Axi-cel is an autologous anti-CD19 CAR T cell therapy. ZUMA-1 is a multicenter, registrational trial of axi-cel in patients (pts) with refractory/aggressive B-cell non-Hodgkin lymphoma (NHL). In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with 76% objective response rate and 47% complete response (Blood 2016;128:LBA-6). We describe, for the first time, a tumor microenvironment immune gene signature associated with CAR T cell treatment (tx) of NHL pts. Methods: Paired biopsies, pre- and within 3 weeks post-axi-cel tx, were analyzed by digital gene expression followed by a pre-specified bioinformatics algorithm applied to IGES15 and IGES21 genes involved in immune-mediated tumor regression (Immunosign; Galon Immunity 2013). Immunosign profiles expression of a pre-defined set of effector T cell, Th1, chemokine, and cytokine genes. Expression analysis and hierarchical clustering were used to define an axi-cel-related tumor immune gene signature. Wilcoxon signed rank test with multiple test correction by FDR (Benjamini-Yekutieli) was used. Results: Gene expression profile comparisons of pre- and post-axi-cel tx biopsies from 14 pts showed profound changes in gene expression within the tumor environment after infusion. The most upregulated genes post-axi-cel tx were CCL5 (RANTES), CTLA4, and GZMA (log2 fold change > 2, P< 0.05, FDR < 0.050). Immune checkpoints PD-L1 and LAG3 were also upregulated post-axi-cel (log2 fold change > 1.6, P< 0.05, FDR < 0.055). Other genes associated with T cell proliferation, homing, and effector function were also upregulated: IL-15, GZMK, CXC3CL1 (Fractalkine), CD8A, and STAT4 (log2 fold change > 1.6; P< 0.05, FDR < 0.074). Additional baseline tumor characteristics and associative analysis will be presented. Conclusions: We define a mechanistic tumor immune gene signature in NHL pts associated with axi-cel tx. This signature comprises upregulation of T cell activation, effector, chemokine, and immune checkpoint genes. These data will potentially lead to rational optimization of T cell interventions in cancer Clinical trial information: NCT02348216.

Key Points BV and Nivo were well-tolerated in patients with R/R HL, with less than 10% of patients treated with systemic steroids for immune-related AEs. The complete response rate was 61% (82% objective response rate), and patients were able to undergo stem cell transplant without adverse impact.

Key Points Ibrutinib has modest activity in FL with low response rates in rituximab-refractory patients. CARD11 mutations predict for lack of response to ibrutinib.