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Abstract Background: Autologous stem cell transplantation (ASCT) in multiple myeloma (MM) has been shown to improve survival compared to conventional chemotherapy alone. However, the ability to perform ASCT relies, in part, on collecting a sufficient number (#) of CD34+ hematopoietic stem cells (HSCs), typically from peripheral blood. The ideal HSC mobilization regimen would enable collection of optimal #s of HSCs (5-6x10 6 CD34+ cells/kg) within the minimum # of apheresis sessions possible. Yet, despite currently available G-CSF (G) based mobilization regimens and multiple apheresis days, many remain unable to collect optimal #s of HSCs. Motixafortide (M) is a novel CXCR4 inhibitor, with high affinity (IC 50 0.54-4.5 nM) and long receptor occupancy (>48 hours). Methods: In this prospective, phase 3, double blind, placebo controlled, multicenter trial, 122 patients were randomized (2:1) to receive either M+G or placebo (P)+G for HSC mobilization prior to ASCT for MM. All patients received G (10 mcg/kg) on days 1-5 (and 6-8, if needed). Patients received either M (1.25 mg/kg, subcutaneous injection) or P on day 4 (and 6, if needed). Apheresis began day 5, with the primary (PEP) and secondary (SEP) endpoints of collecting ≥6x10 6 CD34+ cells/kg in up to 2 apheresis days or 1 day, respectively. Apheresis continued on days 6-8 if needed. Total CD34+ cells/kg were analyzed on site to determine if patients mobilized to the goal and all samples were subsequently sent for assessment by central laboratory. Patients that did not collect ≥2x10 6 CD34+ cells/kg by day 8 proceeded to rescue mobilization. The # of CD34+ cells infused was determined independently by each investigator according to local practice (minimum ≥2x10 6 CD34+ cells/kg). Analyses of the PEP/SEPs were performed on an intent-to-treat basis. Results: Demographics between the 2 treatment arms were similar. Mobilization with M+G resulted in 92.5% of patients collecting ≥6x10 6 CD34+ cells/kg within 2 apheresis days vs 26.2% with P+G (Odds Ratio (OR) 53.3, 95% CI 14.12-201.33, p<0.0001). Furthermore, 88.8% of patients with M+G collected ≥6x10 6 CD34+ cells/kg in 1 apheresis day vs 9.5% with P+G (OR 118.0, 95% CI 25.36-549.35, p<0.0001); and 96.3% with M+G collected ≥2x10 6 CD34+ cells/kg within 1 apheresis day vs 64.3% with P+G (OR 18.9, 95% CI 4.47-80.04, p<0.0001). The PEP and SEPs were confirmed as statistically significant by central laboratory (all respective p-values <0.0001). The median # of HSCs mobilized in 1 apheresis day with M+G was 10.80x10 6 CD34+ cells/kg vs 2.14x10 6 CD34+ cells/kg with P+G. The # of cells infused was determined independently by each investigator according to local practice. Median time to neutrophil engraftment was 12 days in both arms (HR 0.94, 95% CI 0.62-1.41, p=0.75). Median time to platelet engraftment was 18 days (range: 17-19) with M+G and 17 days (range: 17-18) with P+G (HR 0.89, 95% CI 0.59-1.34, p=0.57). Graft durability at day 100 post-ASCT was 92.2% in the M+G arm and 91.9% in the P+G arm (OR 1.04, 95% CI 0.2-4.5, p=0.96). Overall, adverse events were reported in 98.8% (Grade 3/4: 68.8%) of patients with M+G vs 95.2% (Grade 3/4: 42.9%) with P+G, with cytopenias in the post-ASCT period prior to engraftment accounting for the majority of Grade 3/4 AEs in both arms, as expected. The most common AEs related to M included: local injection site reactions (any grade: 70.0%, Grade 3/4: 11.3%); and systemic reactions such as pruritis (33.8%), flushing (32.5%) and urticaria (12.5%). Additionally, mobilization with M+G resulted in a 10.5x increase in mean absolute # of CD34+CD45RA-CD123loCD38-CD90+CD49f+ primitive HSCs collected vs P+G (p<0.0001). Multicolor FACS and scRNA sequencing of CD34+ HSCs from both arms will be reported in a separate ASH abstract. Conclusions: A single injection of M on top of G significantly increased the proportion of patients mobilizing ≥6x10 6 CD34+ cells/kg for ASCT (92.5%) vs G (26.2%) in up to 2 apheresis days (p<0.0001), while enabling 88.8% to collect ≥6x10 6 CD34+ cells/kg in just 1 apheresis (p<0.0001, Figure 1A). Despite the higher # of cells mobilized by M+G, the # of CD34+ cells/kg infused was determined independently by each investigator according to local practice with comparable engraftment kinetics and graft durability between the 2 arms. Finally, M+G mobilized 10.5x more immunophenotypically primitive CD34+ HSCs capable of durable multilineage hematopoietic engraftment vs P+G (p<0.0001, Figure 1B). Figure 1 Figure 1. Disclosures Crees: BioLineRx Ltd.: Research Funding. Larson: TORL biotherapeutics: Current holder of individual stocks in a privately-held company; Bioline: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Celgene: Research Funding; GSK: Research Funding; Janssen: Research Funding; Juno: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. Illés: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stiff: Incyte: Research Funding; Cellectar: Research Funding; Seagen: Research Funding; Gamida Cell: Research Funding; Cellectar: Research Funding; Actinium: Research Funding; Bristol Myers Squibb: Research Funding; BioLineRX: Research Funding; Macrogenics: Research Funding; CRISPR Therapeutics: Consultancy, Honoraria; Amgen: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Karyopharm: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Sborov: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; SkylineDx: Consultancy. Pereira: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Mikala: Novartis: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Krka: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Holtick: Celgene: Honoraria; Sanofi: Honoraria. Qazilbash: Amgen: Research Funding; Oncopeptides: Other: Advisory Board; Bristol-Myers Squibb: Other: Advisory Board; Biolline: Research Funding; Angiocrine: Research Funding; NexImmune: Research Funding; Janssen: Research Funding. Hardy: American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; InCyte: Membership on an entity's Board of Directors or advisory committees. Vainstein: BioLineRx LTD: Current Employment. Sorani: BioLineRx LTD: Current Employment. Gliko-Kabir: BioLineRx Ltd.: Current Employment. Goldstein: BioLineRx Ltd.: Current Employment. Kadosh: BioLineRx Ltd.: Current Employment.

Abstract Background: CD34+ hematopoietic stem and progenitor cell (HSPC) dose during hematopoietic cell transplantation (HCT) remains one of the most reliable clinical parameters to predict quality of engraftment. A minimum HSPC dose of 2-2.5x10 6 CD34+ cells/kg is considered necessary for reliable engraftment, while optimal doses of 5-6x10 6 CD34+ cells/kg are associated with faster engraftment, as well as fewer transfusions, infections, and antibiotic days. CXCR4 inhibition significantly improves the number (#) of CD34+ HSPCs mobilized for HCT, when added to G-CSF (G). Motixafortide (M), a novel CXCR4 antagonist, is a potent mobilizer of HSPCs recently evaluated in the phase 3, double blind, placebo controlled, multicenter GENESIS Trial as a mobilizing agent prior to autologous HCT (ASCT) in multiple myeloma (MM). Methods: Patients received G (10 mcg/kg) on days 1-5 (and days 6-8, if needed). On day 4 (and day 6, if needed), patients received either M (1.25 mg/kg) or placebo (P). Apheresis began day 5, with up to 4 days of apheresis if needed. The primary and secondary endpoints were collection of ³6x10 6 CD34+ cells/kg in up to 2 days of apheresis or 1 day, respectively. The # of CD34+ cells/kg infused was determined independently by each investigator according to local practice, but a minimum of ³2x10 6 CD34+ cells/kg was required. A post-hoc analysis was performed pooling data from both arms to evaluate time to platelet engraftment (TPE) (≥20x10 9/L without transfusions x7 days) and neutrophil engraftment (TNE) (ANC ≥0.5x10 9/L x3 days) based on total # of CD34+ cells/kg and # of specific CD34+ HSPC subsets infused. CD34+ HSPC immunophenotyping was performed via multicolor fluorescence-activated cell sorting (FACS). TPE/TNE was analyzed using Kaplan-Meier curves and Cox proportional hazards model. Results: 114 MM patients underwent apheresis, ASCT and were evaluable (M+G N=77; P+G N=37). M+G mobilization yielded a median of 10.8x10 6 CD34+ cells/kg collected in 1 apheresis vs 2.3x10 6 CD34+ cells/kg with P+G (p<0.0001). M+G also resulted in mobilization of higher #s of relevant CD34+ HSPC subsets vs P+G, including 5.6 fold more HSCs (CD45RA-CD123loCD38+CD90+CD49f+) (p<0.0001), 3.5 fold more multipotent progenitors (MPPs) and common myeloid progenitors (CMPs) (CD45RA-CD123loCD38+CD90-CD49f+) (p=0.0004) and 5.6 fold more granulocyte and macrophage progenitors (GMPs) (CD45RA+CD123loCD38+/-CD10-) (<0.0001). The median # of infused HSPCs in both arms was <6x10 6 CD34+ cells/kg (Table 1), with similar TPE of 17-18 days (HR 0.89, 95% CI 0.59-1.34, p=0.57) and TNE of 12 days (HR 0.94, 95% CI 0.62-1.41, p=0.75). However, pooled analysis of all patients (N=114) revealed infusion of ³6x10 6 CD34+ cells/kg was associated with faster median TPE of 16 days vs 18 days with <6x10 6 CD34+ cells/kg (HR 0.63, 95% CI 0.41-0.96, p=0.03) (Figure 1A). Further analysis demonstrated an inverse correlation between increasing CD34+ cells/kg infused and TPE (Pearson r=-0.2789, p=0.0027). In addition, pooled analysis of 36 patients (M+G N=24; P+G N=12) using extended multicolor FACS revealed infusion of higher #s (>75 th percentile) of combined CD34+ HSC, MPP, CMP and GMP subsets was associated with faster TPE of 12 days vs 19 days with lower #s of these subsets (p=0.003) (Figure 2A). Furthermore, higher #s (>75 th percentile) of GMPs was individually associated with faster TPE of 13 days vs 19 days with lower GMP cell doses (p=0.0116) (Figure 2C). TNE was not impacted by increasing doses of total CD34+ HSPCs or any specific CD34+ HSPC subset (all p>0.05) (Figures 1B, 2B and 2D). Conclusions: M+G mobilization enabled significantly more CD34+ cells to be collected in 1 apheresis (median 10.8x10 6 CD34+ cells/kg) vs P+G (2.3x10 6 CD34+ cells/kg), as well as 3.5-5.6 fold higher #s of HSCs, MPPs, CMPs and GMPs (all p-values <0.0004). This high # of CD34+ cells/kg mobilized with M+G enables the potential infusion of ≥6x10 6 CD34+ cells/kg and cryopreservation of cells for later use. A dose response was observed with significant correlation between faster TPE and infusion of higher #s of total CD34+ HSPC doses (³6x10 6 CD34+ cells/kg) and combined HSC, MPP, CMP and GMP subsets. Additionally, infusion of higher #s of CD34+ GMP subsets was independently associated with faster TPE, suggesting these more committed progenitors may play a critical role in early engraftment. Figure 1 Figure 1. Disclosures Crees: BioLineRx Ltd.: Research Funding. Retting: BioLineRx Ltd.: Research Funding. Larson: TORL biotherapeutics: Current holder of individual stocks in a privately-held company; Abbvie, Bioline, BMS, Celgene, GSK, Janssen, Juno, Novartis, Pfizer, Takeda: Research Funding. Illes: Novartis, Janssen, Pfizer, Roche: Other: Travel, Accommodations, Expenses; Takeda, Seattle Genetics: Research Funding; Janssen, Celgene, Novartis, Pfizer, Takeda, Roche: Consultancy. Stiff: CRISPR: Consultancy; Gamida-Cell, Atara, Amgen, Incyte, Takeda, Macrogenetics, Eisai: Research Funding. Sborov: SkylineDx: Consultancy; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pereira: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Mikala: Abbvie: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Krka: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Holtick: Sanofi: Honoraria; Celgene: Honoraria. Qazilbash: Janssen: Research Funding; Oncopeptides: Other: Advisory Board; Biolline: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Amgen: Research Funding; Angiocrine: Research Funding. Hardy: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees; InCyte: Membership on an entity's Board of Directors or advisory committees. Sorani: BioLineRx LTD: Current Employment. Shemesh-Darvish: BioLineRx LTD: Current Employment. Vainstein: BioLineRx LTD: Current Employment; Enlivex: Consultancy. Kadosh: StatExcellence: Current holder of individual stocks in a privately-held company; BioLineRx: Honoraria.

PURPOSE Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL). METHODS Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee–assessed noninferiority of progression-free survival (PFS). RESULTS Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients. CONCLUSION In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.

7500 Background: Increased selectivity of the Bruton tyrosine kinase inhibitor (BTKi) acalabrutinib (Aca) vs ibrutinib (Ib) may improve tolerability. We conducted an open-label, randomized, noninferiority, phase 3 trial to compare Aca vs Ib in patients (pts) with chronic lymphocytic leukemia (CLL). Methods: Previously treated CLL pts with del(17p) or del(11q) by central lab were randomized to receive oral Aca 100 mg BID or Ib 420 mg QD (stratified by del(17p) status, ECOG PS [2 vs ≤1], and number of prior therapies [1–3 vs ≥4]) until progression or unacceptable toxicity. Primary endpoint was progression-free survival (PFS) as assessed by IRC; secondary endpoints of all grade atrial fibrillation (AF), grade ≥3 infection, Richter transformation, and overall survival (OS) were assessed in hierarchical order. Results: 533 pts (Aca, n=268; Ib, n=265) were randomized (median age 66 y; median 2 prior therapies; del(17p) 45.2%; del(11q) 64.2%). At a median follow-up of 40.9 mo (range 0.0–59.1), Aca was noninferior to Ib with a median PFS of 38.4 mo in both arms (HR 1.00; 95% CI 0.79–1.27). Aca was statistically superior to Ib in all-grade AF incidence (9.4% vs 16.0%; P=0.023). Among the other secondary endpoints, incidences of grade ≥3 infection (Aca: 30.8%, Ib: 30.0%) and Richter transformation (Aca: 3.8%, Ib: 4.9%) were comparable between arms. Median OS was not reached in either arm (HR 0.82 [95% CI 0.59–1.15]), with 63 (23.5%) deaths in the Aca arm and 73 (27.5%) in the Ib arm. Among any-grade AEs in ≥20% of pts in either arm, Aca was associated with a lower incidence of hypertension (9.4%, 23.2%), arthralgia (15.8%, 22.8%), and diarrhea (34.6%, 46.0%) but a higher incidence of headache (34.6%, 20.2%) and cough (28.9%, 21.3%). AEs led to treatment discontinuation in 14.7% of Aca- vs 21.3% of Ib-treated pts. Among any-grade events of clinical interest, cardiac, hypertension, and bleeding events were less frequent with Aca (Table). Conclusions: In this first head-to-head trial of BTKis in CLL, Aca demonstrated non-inferior PFS with less cardiotoxicity and fewer discontinuations due to AEs vs Ib. Clinical trial information: NCT02477696. [Table: see text]

Background Panobinostat (Pano), a pan-histone deacetylase inhibitor, is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (RRMM) in combination with bortezomib and dexamethasone (FVd) in patients who have received ≥2 prior lines of therapy, including bortezomib and an immunomodulatory agent (IMiD). The pivotal phase 3 PANORAMA 1 trial, which used intravenous (i.v.) bortezomib, demonstrated significant progression-free survival benefit with FVd compared with placebo-Vd; however, adverse events (AEs) were also more frequent (San-Miguel J. et al., Lancet Oncol. 2014). The randomized phase 2 PANORAMA 3 study was conducted to optimize FVd by comparing three regimens with varying dose and schedule of Pano and by incorporating subcutaneous (s.c.) bortezomib. Methods PANORAMA 3 (NCT02654990) was a randomized, open-label, international, multicenter phase 2 study conducted in compliance with the Declaration of Helsinki. Eligible patients were ≥18 years old with 1‒4 prior lines of therapy, including an IMiD. Patients refractory to bortezomib were excluded. Patients were randomized 1:1:1 to Pano 20 mg three times weekly (TIW; the currently approved dosing regimen; Days 1, 3, 5, 8, 10, 12), Pano 20 mg twice weekly (BIW; Days 1, 4, 8, 11), or Pano 10 mg TIW (Days 1, 3, 5, 8, 10, 12), all administered in 21-day cycles. Randomization was stratified by number of prior treatment lines (1 vs 2 vs 3 or 4) and by age at screening (≤75 vs >75 years). For Cycles 1-4, all patients ≤75 years old received s.c. bortezomib 1.3 mg/m2 BIW (Days 1, 4, 8, 11) and oral dexamethasone 20 mg (Days 1, 2, 4, 5, 8, 9, 11, 12). Patients aged ≤75 years from Cycle 5 onwards, and patients >75 years for all cycles, received bortezomib 1.3 mg/m2 weekly (Days 1 and 8) and dexamethasone 20 mg on Days 1, 2, 8, and 9. Patients were treated until progressive disease or death, or until discontinuation due to toxicity or withdrawal of consent. The primary endpoint was overall response rate (ORR; IMWG 2011 criteria) after up to 8 treatment cycles by Independent Review Committee assessment. Secondary endpoints included best response, time to response (TTR), duration of response (DOR) and safety. Results In total, 248 patients were randomized (Pano: 20 mg TIW, N=82; 20 mg BIW, N=83; 10 mg TIW, N=83) and 241 patients received treatment (Pano: 20 mg TIW, N=79; 20 mg BIW, N=82; 10 mg TIW, N=80). Mean (SD) age was 65 (9) years; 55% of patients were male. Overall, patients had a median (range) time since diagnosis of 49 months (7‒242) and a median (range) of 2 (1-4) prior lines of therapy; 17% and 2% of patients were refractory to lenalidomide and pomalidomide, respectively. In total, 68% of patients had relapsed and 32% had relapsed/refractory disease. High-risk molecular findings were present in 15% of patients, with either del(17p) or t (4;14) at screening by fluorescence in situ hybridization. For the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, median (range) number of treatment cycles completed was 9 (1; 50), 8 (1; 40) and 7 (1; 39); ORR (95% CI) after up to 8 treatment cycles was 62% (51; 73), 65% (54; 75), and 51% (39; 62); median TTR was 1, 2, and 3 months, with a median (95% CI) DOR of 22 (14, not estimable), 12 (9, 21), and 11 (6, 14.5) months. Best responses are presented in Table 1. In the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, treatment-related AEs Grade ≥3 were reported in 78%, 72%, and 54% of patients; serious AEs were reported in 54%, 48%, and 44% of patients; and discontinuations due to AEs occurred in 29.5%, 28%, and 15% of patients, respectively. Most common treatment-emergent AEs (≥20% patients) are presented in Table 2. Grade ≥3 diarrhea occurred in 11.5%, 10%, and 5% of patients, respectively. There were 14 (6%) on-treatment deaths during the study (20 mg TIW, n=5; 20 mg BIW, n=3; 10 mg TIW, n=6), with none causally related to therapy and with 12 of 14 directly attributable to progressive disease. Conclusion In patients with RRMM, the 20 mg TIW and 20 mg BIW dosing regimens provided favorable outcomes, with most durable and deepest responses observed in the 20 mg TIW arm. The rate of AEs, including diarrhea, with Pano 20 mg TIW was lower than those observed with the same dosing regimen in PANORAMA 1, suggesting s.c. administration of bortezomib improves tolerability compared with i.v. administration. Moreover, all three regimens of FVd proved generally manageable; Pano 20 mg TIW had greatest efficacy, while 10mg TIW proved best tolerated. Disclosures Schjesvold: Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Oncopeptides: Consultancy. Wróbel:Roche: Honoraria, Research Funding; Takeda, Celgene, Janssen, Amgen, AbbVie, Teva, Sandoz: Consultancy, Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Beksac:Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goncalves:Janssen, Takeda, Amgen, Bayer, Novartis, Merck, Bayer, Celgene, GSK, BMS: Research Funding; Janssen: Consultancy, Speakers Bureau. Bladé Creixenti:Celgene: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Chari:Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Novartis: Honoraria; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Adaptive Biotechnology: Honoraria; Array BioPharma: Honoraria; Karyopharm: Consultancy; Glaxo Smith Kline: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; The Binding Site: Honoraria. Lonial:JUNO Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria. Spencer:Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; Secura Bio: Consultancy, Honoraria; Pharmamar: Other; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TheraMyc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Other: Grant/Research Support; Takeda: Honoraria, Other, Speakers Bureau; Antegene: Consultancy, Honoraria. Maison-Blanche:Chiesi Pharmaceutical, Sanofi, Novartis: Honoraria. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction Historically, nearly all relapses in classical Hodgkin lymphoma (cHL) occur within the first 5 years (Radford et al, BMJ 1997). In the phase 3 ECHELON-1 study (NCT01712490), treatment with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) significantly improved modified progression-free survival (PFS) in patients (pts) with newly-diagnosed Stage III/IV cHL compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (Connors et al, NEJM 2018). 3- and 4-year follow-up (Straus et al, Blood 2020; Bartlett et al, Blood 2019) reported durable PFS benefit with A+AVD vs ABVD in the intent-to-treat (ITT) population that was consistent across most key pt subgroups, irrespective of interim positron emission tomography (PET) scan status, disease stage, and baseline disease risk factor score. We report updated efficacy and safety results for pts in the ECHELON-1 study after a median follow-up of 55.6 months. Methods In this evaluation of longer follow-up, an exploratory analysis of PFS (time from randomization to relapse, progression, or death from any cause) per investigator (INV) was conducted, with a cutoff date of May 18, 2020. Pts with previously untreated Stage III or IV cHL were randomized 1:1 to receive up to six cycles of A+AVD (n=664) or ABVD (n=670) intravenously on days 1 and 15 of a 28-day cycle. An interim PET scan after cycle 2 (PET2) was required. Resolution and improvement (defined as improvement by ≥1 grade from worst grade as of the latest assessment) of peripheral neuropathy (PN) in pts with ongoing symptoms at the end of treatment (EoT) were monitored during the extended follow-up period. The rate of secondary malignancies, and the incidence and outcomes of pregnancies among pts and their partners were also assessed. Results With extended follow-up (median 55.6 months; 95% CI 55.2-56.7) estimated 5-year PFS rates were 82.0% (95% CI 78.7-84.8) for A+AVD and 75.2% (95% CI 71.5-78.4) for ABVD. Overall, PFS per INV favored A+AVD over ABVD (HR 0.691; 95% CI 0.543-0.880; p=0.003) (Table). Exploratory subgroup analyses by PET2 status and age demonstrated PFS benefits regardless of PET2 status (Table); estimated 5-year PFS per INV with A+AVD vs ABVD in the ITT population was 84.7% vs 78.8% in PET2-negative pts (HR 0.676; 95% CI 0.512-0.892; p=0.005), and 60.6% vs 45.9% in PET2-positive pts (HR 0.703; 95% CI 0.393-1.256; p=0.230). PFS benefit with A+AVD over ABVD was also independent of the number of International Prognostic Factors Project (IPFP) risk factors (Figure). After a median follow-up of almost 5-years, 84% (370/442) and 86% (245/286) of pts with treatment-emergent PN reported complete resolution or improvement of symptoms in the A+AVD and ABVD arms, respectively. Median time to complete resolution of PN events that were ongoing at EoT was 30 weeks (range 0-262) in the A+AVD arm and 16 weeks (range 0-267) in the ABVD arm; median time to improvement was 49 weeks (range 8-270) and 12 weeks (range 2-70) , respectively. Of the 132 (30%) pts with ongoing PN in the A+AVD arm, 77 (17%), 39 (9%), 15 (3%) and 1 (<1%) experienced a maximum severity of grade 1, 2, 3 or 4, respectively. In the ABVD arm, PN was ongoing in 61 pts (21%); maximum severity was grade 1, 2, 3 or 4 in 40 (14%), 17 (6%), 4 (1%) and 0 pts, respectively. A total of 124 pregnancies were reported among pts and their partners (40 female and 30 male pts in the A+AVD arm; 26 female and 28 male pts in the ABVD arm). The proportion of live births was similar between arms for female pts (26/40 in the A+AVD arm and 17/26 in the ABVD arm, 65% in each arm) and for male pts' partners (19/30 [63%] in the A+AVD arm and 20/28 [71%] in the ABVD arm). No stillbirths were recorded. Additional follow-up at an estimated median of ~5 years and secondary malignancy data will be presented. Conclusions After a median follow-up of 55.6 months, A+AVD continues to demonstrate a robust and durable treatment benefit independent of disease stage, risk factor score, and PET2 status. In addition, compared with ABVD, treatment adaptation by interim PET2 status is not required and bleomycin exposure is avoided. The sustained PFS benefit with A+AVD is coupled with a manageable safety profile with symptoms of PN improving or resolving over time and similar pregnancy rates in both treatment arms. The benefits observed with A+AVD at this important milestone suggest that A+AVD is an attractive treatment option for all pts with previously untreated Stage III or IV cHL. Disclosures Straus: Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Imedex, Inc.: Speakers Bureau; Targeted Oncology: Consultancy, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; OncLive: Speakers Bureau; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Connors:Seattle Genetics: Other: Sponsorship to educational presentations; Takeda: Other: Sponsorship to educational presentations. Illés:Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy. Lech-Marańda:Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy; Roche, Amgen, Gilead: Speakers Bureau. Feldman:KITE: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Morphosis: Other: Ad board; AstraZeneca: Other: Ad board; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Smolewski:Roche Poland: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sandoz: Honoraria; Morphosis: Honoraria. Savage:Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy; BeiGene: Other: Steering Committee; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria. Bartlett:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding. Walewski:Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Research Funding. Ramchandren:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Zinzani:Eusapharma: Consultancy, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hutchings:Celgene, Genmab, Janssen, Novartis, F. Hoffmann-La Roche, Takeda: Research Funding; Genmab, F. Hoffmann-La Roche, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Munoz:Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Millenium: Research Funding; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau. Kim:JJ: Research Funding; Celltrion: Research Funding; Kyowa Kirn: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; Pfizer: Research Funding; F. Hoffmann-La Roche: Research Funding. Advani:Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy; Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding. Ansell:Bristol Myers Squibb: Research Funding; Takeda: Research Funding; ADC Therapeutics: Research Funding; AI Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding. Younes:HCM: Consultancy; Daiichi Sankyo: Consultancy; Curis: Consultancy; BMS: Consultancy; Novartis: Consultancy; Epizyme: Consultancy; BioPath: Consultancy; AstraZeneca: Current Employment; Janssen: Consultancy; Takeda: Consultancy. Gallamini:Takeda: Other: Speaker. Liu:Takeda Pharmaceuticals: Current Employment. Little:Takeda: Current Employment, Current equity holder in publicly-traded company. Fenton:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Radford:GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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.

Abstract The phase 3 ECHELON-1 study demonstrated that brentuximab vedotin (A) with doxorubicin, vinblastine, and dacarbazine (AVD; A+AVD) exhibited superior modified progression-free survival (PFS) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for frontline treatment of patients with stage III/IV classical Hodgkin lymphoma (cHL). Maturing positron emission tomography (PET)-adapted trial data highlight potential limitations of PET-adapted approaches, including toxicities with dose intensification and higher-than-expected relapse rates in PET scan after cycle 2 (PET2)-negative (PET2−) patients. We present an update of the ECHELON-1 study, including an exploratory analysis of 3-year PFS per investigator. A total of 1334 patients with stage III or IV cHL were randomized 1:1 to receive 6 cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET2 was required. At median follow-up of 37 months, 3-year PFS rates were 83.1% with A+AVD and 76.0% with ABVD; 3-year PFS rates in PET2− patients aged <60 years were 87.2% vs 81.0%, respectively. A beneficial trend in PET2+ patients aged <60 years on A+AVD was also observed, with a 3-year PFS rate of 69.2% vs 54.7% with ABVD. The benefit of A+AVD in the intent-to-treat population appeared independent of disease stage and prognostic risk factors. Upon continued follow-up, 78% of patients with peripheral neuropathy on A+AVD had either complete resolution or improvement compared with 83% on ABVD. These data highlight that A+AVD provides a durable efficacy benefit compared with ABVD for frontline stage III/IV cHL, consistent across key subgroups regardless of patient status at PET2, without need for treatment intensification or bleomycin exposure. This trial was registered at www.clinicaltrials.gov as #NCT01712490 (EudraCT no. 2011-005450-60).

Introduction: As previously reported, the combination of brentuximab vedotin with doxorubicin, vinblastine and dacarbazine (A+AVD) demonstrated a statistically significant improvement in modified progression free survival (modified PFS) compared with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with newly diagnosed Stage III or IV classical HL in the phase 3 ECHELON-1 trial (NCT01712490). The benefit of A+AVD in the ITT population observed in the primary analysis was maintained at 3-years median follow-up [3-year PFS: A+AVD: 83.1% (79.9-85.9), ABVD: 76% (72.4-79.2)] and appears independent of interim PET status, disease stage, and prognostic risk factors. Here we present the efficacy and safety results of longer follow-up at a median 43.3 months. Methods: Newly diagnosed patients with Stage III or IV cHL were randomized 1:1 to receive A+AVD (n=664) or ABVD (n=670) intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. The primary endpoint of the study was modified PFS per independent central review. The present follow-up PFS analysis is exploratory and per investigator assessment, with a cutoff date of June 17th, 2019. Patients with ongoing peripheral neuropathy (PN) at end of treatment were followed for resolution or improvement (defined as improved by ≥1 grade from worst grade as of the latest assessment) during the post-treatment follow-up period. Results: With a median follow-up of 43.3 months, the 42-month PFS per investigator for all patients was 82.4% (95% CI, 79.1-85.2) on the A+AVD arm and 76.2% (95% CI, 72.6-79.4) on the ABVD arm [overall HR 0.697 (95% CI, 0.547-0.890)]. Exploratory subgroup analyses of PET2(+) and PET2(-) patients showed a treatment effect in favor of A+AVD. The 42-month PFS in PET2(-) patients was 85.0% (95% CI, 81.6-87.7) for A+AVD and 79.6% (95% CI, 75.9-82.8) for ABVD [overall HR 0.695 (95% CI, 0.526-0.919)]; in PET2(+) patients 42-month PFS was 68.3% (95% CI, 54.5-78.7) for A+AVD and 51.5% (95% CI, 38.2-63.4) for ABVD [overall HR 0.552 (95% CI, 0.308-0.989)]. Upon continued follow-up, 81% (356/442) of patients with PN in the A+AVD arm had either complete resolution (64%, 283/442) or improvement (17%, 73/442) of their PN events compared with 83% (236/286) with either complete resolution (74%, 212/286) or improvement (8%, 24/286) in the ABVD arm. Among patients with ongoing PN after continued follow-up, the majority were Grade 1/2 events, with 89% (141/159; 59% Grade 1) and 95% (70/74; 65% Grade 1) on the A+AVD and ABVD arms, respectively. Overall survival data are not yet mature; per protocol, the final analysis will be performed after 112 deaths have occurred. Additional follow-up at an estimated median of ~4 years, including data from prespecified subgroups, will be presented. Conclusions: With a median follow-up of 43.3 months, A+AVD continues to provide a robust, durable benefit for patients with previously untreated Stage III or IV cHL compared with ABVD; the benefit is evident regardless of patient status at interim PET [PET2(+) or PET2(-)] and without the need for treatment intensification. PN continued to completely resolve or improve in patients on the A+AVD and ABVD arms. Together, these data further support the clinical advantages of A+AVD versus ABVD as treatment for patients with previously untreated Stage III or IV cHL. Disclosures Bartlett: Affimed Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Dynavax: Research Funding; Forty-Seven: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medimmune: Research Funding; Merck: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Dlugosz-Danecka:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Macrogenomics: Research Funding; Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Illes:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Feldman:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Cell Medica: Research Funding; Amgen: Research Funding; Viracta: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Eisai: Research Funding; Corvus: Research Funding; Roche: Research Funding; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Trillium: Research Funding. Smolewski:Roche: Other: Travel Expenses. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding; BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria. Walewski:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Takeda: Honoraria, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Gilead: Other: Travel Expenses; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Hutchings:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Radford:AstraZeneca: Equity Ownership, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; GSK: Equity Ownership. Munoz:AstraZeneca: Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Kim:Roche: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Celltrion: Research Funding; Donga: Research Funding. Advani:Cell Medica, Ltd: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Kura: Research Funding; Infinity Pharma: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; Stanford University: Employment, Equity Ownership; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Regeneron: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Gallamini:Takeda: Consultancy; Roche: Consultancy. Miao:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Liu:Takeda: Employment. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Forero-Torres:Seattle Genetics: Employment, Equity Ownership, Honoraria, Research Funding.