Friedberg, Jonathan W.

7573 Background: While most patients (pts) with follicular lymphoma (FL) usually have favorable outcomes, those with refractory disease after first-line anti-CD20 based immunochemotherapy (IC), or progression within 24 months of diagnosis (POD24) have higher risk of premature death. There are no standard approaches for treating this vulnerable group and studies testing novel agents are ongoing in this setting. We sought to investigate clinical practice treatment choices and efficacy for pts with POD24 that align with eligibility criteria for the randomized SWOG1608 which compares IC with novel agents in this population. Methods: This was a multicenter observational cohort study from the LEO Consortium. Eligible pts had grade 1-3a FL diagnosed between 1/1/2002 and 2/1/2019, and initiated therapy after POD24 to first-line bendamustine or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) based IC. Observation, radiotherapy, or rituximab monotherapy were permitted prior to IC and pts with transformation prior to the subsequent therapy after IC were excluded as per S1608. Outcomes of interest were overall and complete response rate (ORR/CR), progression-free survival (PFS), and overall survival (OS). Results: We identified 196 eligible pts with early progression to IC (39% antiCD20 Benda; 61% antiCD20 CHOP) who received subsequent therapy. Median age at post IC treatment was 57 years, 78% grade 1-2 FL. Treatments for pts with POD24 included CHOP- or Benda-based in 31%, salvage/hematopoietic stem cell transplant (HSCT) in 27%, novel therapies in 10% (including phosphatidylinositol 3-kinase inhibitors), antiCD20 monotherapy in 9%, and lenalidomide-based treatment in 8% (table); 21% of pts were treated on clinical trials. Across all treatments, ORR (CR) was 63% (37%) (95% CI: 55-70). At a median follow up of 6.2 years, 2 year PFS was 22% (95% CI: 17%-29%) and 5 year OS was 71% (95% CI: 65-79). Outcomes by regimen are shown in the table. Conclusions: Pts with FL experiencing POD24 following first-line IC are treated heterogeneously, with many pts still receiving IC as subsequent therapy. Despite modest CR rates and low 2-year PFS, 5-year OS appear to be improving compared to historical outcomes. This supports the ongoing need to investigate novel treatments in this population. [Table: see text]

7503 Background: To date, an overall survival (OS) benefit from upfront treatment for new treatment combinations over existing approaches has rarely been shown in first-line classical Hodgkin lymphoma (cHL). With the introduction of newer active therapies for relapsed/refractory disease, demonstration of improved OS with first-line therapy has been challenging. In ECHELON-1 (NCT01712490), 5-year follow-up analyses supported the long-term progression-free survival (PFS) benefit with first-line brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients (pts) with stage III/IV cHL, independent of interim positron emission tomography status. A+AVD had a manageable long-term safety profile, with numerically fewer second malignancies and a greater number of pregnancies reported vs ABVD (Connors et al, NEJM 2018; Straus et al, Lancet Haematol 2021). We report a prespecified OS analysis after approximately 6 years’ follow-up (cut-off, June 1, 2021). Methods: Pts were randomized 1:1 to receive up to 6 cycles of A+AVD (n = 664) or ABVD (n = 670) on day 1 and 15 every 28 days. OS was the key secondary endpoint and was an event-driven, pre-specified, alpha-controlled analysis in the intention to treat population. Results: At a median follow-up of 73 months, 39 and 64 OS events occurred in A+AVD and ABVD arms, respectively: OS significantly favored A+AVD vs ABVD (HR 0.590; 95% confidence interval [CI] 0.396–0.879; p = 0.009). Estimated 6-year OS rates (95% CI) were 93.9% (91.6–95.5) vs 89.4% (86.6–91.7) with A+AVD vs ABVD, respectively. There was a consistent OS benefit for A+AVD vs ABVD across prespecified subgroups. The 6-year PFS estimate was 82.3% (79.1–85.0) vs 74.5% (70.8–77.7) with A+AVD vs ABVD, respectively (HR 0.678 [95% CI 0.532–0.863]). Overall, A+AVD had a comparable long-term safety profile to ABVD. Treatment-emergent peripheral neuropathy continued to resolve or improve in both arms, with 86% (379/443) and 87% (249/286) of cases in the A+AVD and ABVD arms either completely resolving (72% vs 79%) or improving (14% vs 8%) by last follow-up. Fewer second malignancies were reported in the A+AVD vs ABVD arm (23 vs 32). More female patients reported pregnancy (49 vs 28) or live births (42 vs 19 in females) in the A+AVD vs the ABVD arm; no stillbirths were reported. No new safety signals were identified. Conclusions: A+AVD treatment resulted in a statistically significant 41% reduction in the risk of death vs ABVD, with a manageable safety profile consistent with prior reports. These outcomes confirm A+AVD as a preferred option for pts with previously untreated stage III/IV cHL. Clinical trial information: NCT01712490.

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.

Abstract Recent first-line randomized controlled trials (RCTs) for patients with diffuse large B-cell lymphoma (DLBCL) have shown negative results, which may be due in part to onerous eligibility criteria limiting enrollment of poor-risk patients who require immediate treatment. We conducted a Delphi-method survey with lymphoma experts in the United States to define recommendations for essential and potentially unnecessary enrollment criteria for modern first-line DLBCL RCTs aimed at increasing clinical diversity of ensuing study groups. We first tabulated enrollment criteria from 19 DLBCL RCTs spanning the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) era to identify common eligibility criteria from prior DLBCL RCTs for inclusion in the Delphi-method survey. We tabulated 451 total eligibility criteria comprising 51 criterion categories across 19 first-line DLBCL RCTs in the R-CHOP era. We then surveyed lymphoma clinical trial experts representing 8 academic medical centers in the United States regarding essential and unnecessary eligibility criteria for modern DLBCL RCTs. Seventeen of 29 invited clinical investigators completed the round-1 questionnaire (response rate, of 58.6%), 15 of 17 round-1 participants (88.2%) completed the round-2 survey, and all round-1 participants reviewed finalized recommendations for eligibility criteria for modern first-line DLBCL RCTs. We defined consensus recommendations for 31 modernized eligibility criteria including threshold values for 10 quantitative eligibility criteria aimed at facilitating enrollment of a clinically diverse study population in first-line DLBCL RCTs designed to improve standard-of-care therapy.

Abstract Background: Differences in outcomes between clinical trial and real-world populations in follicular lymphoma (FL) may be partially explained by differences in characteristics between clinical trial and real-world patients. We hypothesized that certain eligibility criteria may be responsible for populations with distinct demographic/clinical characteristics. In this study, we compiled a list of eligibility criteria from front-line FL trials and evaluated their impact on the potentially eligible FL patients derived from two national cohort studies. We also evaluated whether criteria were duplicative and whether liberalizing criteria might enlarge the pool of eligible patients. Methods: Eligibility criteria were abstracted from 21 first-line clinical trials in FL in the FLASH database. We identified FL patients in two prospective cohort studies: Molecular Epidemiology Resource (MER) and Lymphoma Epidemiology of Outcomes (LEO). Descriptive statistics were used to characterize patients included and excluded by various eligibility criteria. Chi-square tests and two-sample t-tests were used to compare categorical and continuous variables, respectively. To study the relative impact of individual criteria, we used a step-wise approach to quantify the number of additional patients excluded with each individual criterion after applying other criteria. Results: Eligibility criteria included in at least one-third of studies included stage (present in all 21 trials), renal function (18), HIV/AIDS status (17), performance status (16), history of other malignancies (16), hepatic function (16), and cardiac function (15), other serious health conditions (13), pregnancy status (10), neuro/psych function (10), age (10), metabolic disease status (9), CNS involvement (9), birth control (8), pulmonary function (8), WBC count (8), HBV status (8), platelet count (7), measurable disease (7), HCV status (7), active infection status (7), and CD20 status (7). We included 738 patients with newly diagnosed FL undergoing first-line therapy from MER and 703 patients from LEO. In MER, the median age was 60 years; 87% were White vs 2% non-White, 80% were non-Hispanic vs 2% Hispanic, and 68% were stage III/IV. In LEO, the median age was 60 years; 88% were White vs 11% non-White, 87% were non-Hispanic vs 11% Hispanic, and 67% were stage III/IV. Exclusion criteria impacting more than 10% of patients included stage (31 in LEO vs 29% in MER), self-reported serious health conditions (17 vs 31%), prior cancer diagnosis (14 vs 11%), performance status (10%), and platelet count (10%). Patients excluded due to the following criteria tended to be older: renal function (median 70 vs 60 years in MER), prior malignancy (67 vs 58 years), and self-reported serious health conditions (66 vs 58 years). This pattern was consistent in LEO (Table). No eligibility criteria significantly impacted race/ethnicity. Given the potential for multiple eligibility criteria to exclude the same patients, we used a step-wise approach to evaluate the impact of individual criteria on patients remaining after exclusion by the larger group of criteria, and whether liberalizing criteria impacted patient numbers and/or demographics. We found that only self-reported serious health conditions significantly impacted numbers (excluding 43% of patients), whereas hematologic parameters and performance status excluded only 5 and 1% of patients, respectively, with no impact on age or race/ethnicity. We also found that liberalizing stage requirement from III-IV to II-IV could increase enrollment by 14% in MER (12% in LEO), and liberalizing platelet requirement from ≥150,000 to ≥100,000 could increase enrollment by 11% (15% in LEO). Moreover, liberalizing eligibility criteria had no impact on age or race/ethnicity of the patient pool or on EFS (Figure). Conclusions: We found that excluding patients with prior malignancies, poor renal function, and self-reported serious health conditions appears to inadvertently exclude older patients. Other serious health conditions appeared to exclude a significant number of patients but did not impact patient demographics. Liberalizing certain criteria, including stage and platelet requirement, could potentially increase trial accrual, but would not likely correct the older patient deficit. These findings may serve in developing consensus eligibility criteria for future first-line FL trials. Figure 1 Figure 1. Disclosures Flowers: Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; National Cancer Institute: Research Funding; Allogene: Research Funding; Biopharma: Consultancy; Cellectis: Research Funding; EMD: Research Funding; Genentech/Roche: Consultancy, Research Funding; Epizyme, Inc.: Consultancy; Genmab: Consultancy; Iovance: Research Funding; Guardant: Research Funding; Burroughs Wellcome Fund: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Spectrum: Consultancy; Gilead: Consultancy, Research Funding; Amgen: Research Funding; Xencor: Research Funding; Nektar: Research Funding; SeaGen: Consultancy; Ziopharm: Research Funding; TG Therapeutics: Research Funding; 4D: Research Funding; Acerta: Research Funding; Denovo: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Morphosys: Research Funding; Adaptimmune: Research Funding; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; Kite: Research Funding; Janssen: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding. Link: MEI: Consultancy; Novartis, Jannsen: Research Funding; Genentech/Roche: Consultancy, Research Funding. Friedberg: Acerta: Other: DSMC ; Bayer: Other: DSMC ; Novartis: Other: DSMC . Cohen: Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding; Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. Lossos: Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; Stanford University: Patents & Royalties; Seattle Genetics: Consultancy; NCI: Research Funding; Verastem: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; NIH grants: Research Funding; University of Miami: Current Employment. Nastoupil: Bayer: Honoraria; Gilead/Kite: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; ADC Therapeutics: Honoraria; IGM Biosciences: Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Janssen: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; Caribou Biosciences: Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; MorphoSys: Honoraria. Maurer: Nanostring: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; BMS: Research Funding. Cerhan: NanoString: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding. Martin: ADCT: Consultancy.

Abstract Background: High grade B-cell Lymphoma with rearrangements of MYC and BCL2 and/or BCL6, also known as double hit lymphoma (DHL), and double expressing lymphomas (DEL; DLBCL with IHC expression of MYC and BCL2, but without double hit cytogenetics) are highly aggressive B cell non-Hodgkin lymphomas and patients (pts) often develop relapsed/refractory disease following standard first-line chemoimmunotherapy. DA-EPOCH-R is widely used in patients with DHL, and a phase 1 trial of venetoclax + DA-EPOCH-R established the dose of 600 mg for 5 days with each cycle as the recommended phase 2 dose (Rutherford, et al. Proc ASCO 2020). A051701 is a phase II/III randomized trial evaluating chemoimmunotherapy +/- the BCL2 inhibitor venetoclax in a DHL cohort (pts with DHL with BCL2 rearrangement and/or expression), and a DEL cohort. Here we report the initial results from the DHL cohort of A051701. Methods: Pts age ≥ 18 years with newly diagnosed DHL were stratified on International Prognostic Index (IPI) score and receipt of a single cycle of chemotherapy prior to registration, which was permitted, and randomized 1:1 to receive DA-EPOCH-R (Arm 1) or DA-EPOCH-R with venetoclax (Arm 2). Enrollment was based on local pathology results which were centrally confirmed. DA-EPOCH-R was administered as previously published. Venetoclax was dosed at 600 mg po daily on days 4-8 of cycle 1 and on days 1-5 of subsequent cycles for up to 6 total cycles. All cycles were supported by GCSF or peg-GCSF. For the interim analysis at the end of phase II, 53 events ensured 90% power to detect an improvement in 24-month progression-free survival (PFS) from 40% in Arm 1 to 60% in Arm 2 (HR=0.557) using a one-sided stratified log-rank test with type I error rate of 20%. The Alliance Data and Safety Monitoring Board approved the data release after accrual was stopped early due to excess toxicity in Arm 2. These data were frozen July 8, 2021. Results: 73 pts were registered (36 in Arm 1 and 37 in Arm 2) between 8/7/19 and 9/18/20. Analyses were performed for the modified intent-to-treat (mITT) population, defined as eligible pts with DHL histology confirmed (n=66; 30 Arm 1, 36 Arm 2). Median age was 65 years in both arms (range 37-80) and baseline demographic factors were well balanced. An allowed pre-protocol chemoimmunotherapy cycle was administered in 60% and 56% of Arm 1 and Arm 2 pts, respectively. The majority of pts had advanced stage disease (Arm 1 87%, Arm 2 86%), GCB immunophenotype (Arm 1 100%, Arm 2 88%), ECOG PS 0-1 (Arm 1 90%, Arm 2 86%), and high-intermediate/high risk IPI score (Arm 1 63%, Arm 2 64%). Therapy was completed per protocol in 70% and 47% of pts, respectively, for Arm 1 and 2, and disease progression on therapy occurred in 10% and 3%. Treatment was discontinued due to adverse events in 7% of pts in Arm 1 and 11% of pts in Arm 2. Consent was withdrawn after beginning treatment in 3% and 11% in Arm 1 and 2, respectively. Death on treatment occurred in 1 patient (3%; PJP pneumonia) in Arm 1 and 6 pts (17%; sepsis (n=4), cardiac arrest (n=2)) in Arm 2. The observation of excess deaths on Arm 2 prompted suspension of accrual to the DHL cohort. Treatment was discontinued for other reasons in 3 (10%) and 4 (11%) pts in Arms 1 and 2, respectively. Venetoclax was dose-reduced and/or omitted in 15 (42%) pts. Grade 4 neutropenia was not significantly different between arms (Arm 1 67%, Arm 2 71%), nor was grade ≥3 neutropenic fever (Arm 1 36%, Arm 2 40%). Sepsis occurred more frequently in Arm 2 (14% vs. 23%). The end of treatment overall and complete response rates in the mITT population were 73% and 67% in Arm 1, and 58% and 50% in Arm 2. The end of treatment overall and complete response rates among only pts evaluated for response (n=52) were 79% and 71% in Arm 1, and 88% and 75% in Arm 2. With a median follow-up of 7.4 months, the median PFS was not reached (NR) in Arm 1 (95% CI 6.1-NR) and was 6.7 months in Arm 2 (95% CI 4.5-NR) (two-sided p=0.13). The median OS was NR in Arm 1 and was 8.5 months in Arm 2 (95% CI 5.2-NR) (two-sided p=0.004). Conclusions: DA-EPOCH-R plus venetoclax in DHL pts resulted in excess treatment-related mortality compared to DA-EPOCH-R alone, prompting early discontinuation of accrual and venetoclax treatment for the study cohort. Based on these data, we recommend against combining venetoclax with DA-EPOCH-R in DHL. Robust accrual to this study shows that prospective trials are feasible in DHL, and the favorable outcome thus far in the DA-EPOCH-R arm may serve as a benchmark for future trials Figure 1 Figure 1. Disclosures Abramson: Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Kymera: Consultancy; Bluebird Bio: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Ruppert: Telios Pharma: Consultancy. Hsi: Seattle Genetics: Honoraria; Cytomx: Honoraria; Eli Lilly: Research Funding; AbbVie: Research Funding. Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Friedberg: Acerta: Other: DSMC ; Novartis: Other: DSMC ; Bayer: Other: DSMC . Bartlett: Millennium: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Bristol Myers Squibb: Research Funding; Roche/Genentech: Consultancy; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Consultancy, Research Funding. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. OffLabel Disclosure: venetoclax in double hit lymphoma

7503 Background: Optimal initial therapy for mantle cell lymphoma (MCL) remains uncertain. The randomized phase 2 NCTN trial E1411 tested if progression-free survival (PFS) is prolonged by addition of bortezomib (V) (1.6 mg/m2 SC/IV days 1, 8) to bendamustine-rituximab (BVR vs BR) induction and/or by addition of lenalidomide (L) to rituximab (LR vs R) consolidation. Here we report efficacy and toxicity of induction BVR vs BR. Methods: 373 pts, accrued 2012–16, stratified by MIPI and age (≥60) received 1 of 4 arms: A) BR induction x 6 followed by R x 2 yrs, B) BVR followed by R, C) BR followed by LR or D) BVR followed by LR. Eligible pts had untreated MCL, ≥ age 18 (amended from ≥60 when S1106 for < 65 closed), ECOG PS 0-2 and adequate hematologic and organ function. Pts without progressive disease during induction proceeded to consolidation. Primary induction objective was whether adding bortezomib (BVR) (Arms B + D) to BR (Arms A + C) improves PFS, irrespective of consolidation R vs LR. Design of 360 eligible treated pts would provide 93.8% power to detect 10% improvement in 2-yr PFS from 70% hypothesized for BR, corresponding to 37.4% reduction in hazard using stratified log-rank test at 1-sided 10% alpha. Efficacy population was 179 (BVR) and 180 (BR), induction treatment completed in 144 vs 153, progressive disease during induction 6 vs 7 and registration to consolidation 140 vs 145. Results: Baseline demographics did not differ between the groups, with median age 67 (range 42-90) and 13% < 60 yr, 73% men, ECOG PS 0-1 97%, MIPI Low/Med/Hi 37/29/34%. Estimated PFS at 2 yrs 79.6% BVR (95% CI 73.8-85.9) vs 74.5% BR (95% CI 68.2-81.4) (1-sided stratified log-rank p = 0.268). With median PFS follow-up 51 mos, median PFS estimated at 64.1 and 64.0 mos. Overall response rate (ORR) for BVR was 88.9% (CR 65.5%) vs 89.5% (CR 60.5%) BR (z-test 1 sided p = 0.577 for ORR). Treatment related deaths during induction were 2 in BVR (cardiac arrest, hepatitis) and 1 in BR (tumor lysis). Grade ≥ 3 toxicities were 88.1% (163/185) BVR vs 77.5% (145/187) BR. For BVR vs BR grade ≥ 3 neutropenia occurred in 52 vs 39 pts, though febrile neutropenia (7 vs 6), anemia (7 vs 8) and thrombocytopenia (18 vs 16) did not differ. Peripheral neuropathy (PN) grade 2 was 8 sensory for BVR vs 2 sensory/1 motor for BR, while grade 3 PN was 6 sensory/1 motor for BVR vs 0 with BR. The only non-hematologic grade ≥ 3 toxicity in > 5% of pts was rash (9 vs 12 pts). Conclusions: Bortezomib did not significantly improve the primary endpoint of PFS when added to BR as initial MCL therapy. ORR and CR rates at end of induction were also similar. Follow-up continues to assess the entire treatment regimen, including consolidation R vs LR, but the PFS > 5 yrs, high ORR and MRD negativity rate (Smith et al ASH 2019) in this BR-based trial support BR as a platform for MCL induction therapy. Clinical trial information: NCT01415752.

PURPOSE Lenalidomide combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) in untreated diffuse large B-cell lymphoma (DLBCL) has shown promising activity, particularly in the activated B-cell–like (ABC) subtype. Eastern Cooperative Oncology Group (ECOG)-ACRIN trial E1412 was a randomized phase II study comparing R2CHOP versus R-CHOP in untreated DLBCL. PATIENTS AND METHODS Patients with newly diagnosed DLBCL, stage II bulky-IV disease, International Prognostic Index (IPI) ≥ 2, and ECOG performance status ≤ 2 were eligible and randomly assigned 1:1 to R2CHOP versus R-CHOP for six cycles. Tumors were analyzed using the NanoString Lymph2Cx for cell of origin. The primary end point was progression-free survival (PFS) in all patients with the co-primary end point of PFS in ABC-DLBCL. Secondary end points included overall response rate (ORR), complete response (CR) rate, and overall survival (OS). RESULTS Three hundred forty-nine patients were enrolled; 280 patients (145 R2CHOP and 135 R-CHOP) were evaluable: 94 were ABC-DLBCL, 122 germinal center B-cell–like-DLBCL, 18 unclassifiable, and 46 unknowns. Baseline characteristics were well-balanced between arms, and the median age was 66 (range, 24-92); 70% of patients had stage IV disease; 34%, 43%, and 24% had IPI 2, 3, and 4 or 5, respectively. Myelosuppression was more common in the R2CHOP arm. The ORR and CR rate were 92% and 68% in R-CHOP and 97% ( P = .06) and 73% ( P = .43) in the R2CHOP arm, respectively. The median follow-up was 3.0 years; R2CHOP was associated with a 34% reduction in risk of progression or death versus R-CHOP (hazard ratio [HR], 0.66 95% CI, 0.43 to 1.01) and 3-year PFS of 73% versus 61%, one-sided P = .03, and an improvement in OS (83% and 75% at 3 years; HR, 0.67; one-sided P = .05). The PFS HR for R2CHOP was 0.67 for ABC-DLBCL, one-sided P = .1. CONCLUSION In this signal-seeking study, the addition of lenalidomide to R-CHOP (R2CHOP) improved outcomes in newly diagnosed DLBCL including patients with ABC-DLBCL.

Abstract Approximately one‐third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high‐risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4–7, enrolled in the ECHELON‐1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first‐line therapy after a median follow‐up of 37.1 months. Among patients treated with A + AVD ( n = 664) or ABVD ( n = 670), 64% had Stage IV disease and 26% had an IPS of 4–7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537–0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4–7 (HR, 0.588; 95% CI, 0.386–0.894; p = 0.012). The most common adverse events (AEs) in A + AVD‐treated versus ABVD‐treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4–7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high‐risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON‐1 shows a favorable benefit‐risk balance in high‐risk patients.

The recent development and clinical implementation of novel immunotherapies for the treatment of Hodgkin and non-Hodgkin lymphoma have improved patient outcomes across subgroups. The rapid introduction of immunotherapeutic agents into the clinic, however, has presented significant questions regarding optimal treatment scheduling around existing chemotherapy/radiation options, as well as a need for improved understanding of how to properly manage patients and recognize toxicities. To address these challenges, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in lymphoma to develop a clinical practice guideline for the education of healthcare professionals on various aspects of immunotherapeutic treatment. The panel discussed subjects including treatment scheduling, immune-related adverse events (irAEs), and the integration of immunotherapy and stem cell transplant to form recommendations to guide healthcare professionals treating patients with lymphoma.