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INTRODUÇÃO: As ataxias cerebelares são um extenso grupo de doenças, que causam diversos distúrbios na marcha e no equilíbrio que comprometem seriamente a qualidade de vida, sem opções de tratamento eficazes. A cinesioterapia é a base de programas multifacetados que incorporam mais de um enfoque, como o treinamento de coordenação e equilíbrio. Recentemente, a estimulação transcraniana por corrente contínua (tDCS) sobre o cerebelo surgiu como uma intervenção para melhorar os distúrbios do equilíbrio. OBJETIVO: Descrever a aplicação simultânea de tDCS anódica cerebelar e cinesioterapia, em sessões múltiplas diárias para reabilitação da ataxia cerebelar. MATERIAIS E MÉTODOS: Este relato de caso incluiu um paciente do sexo masculino, de 34 anos, com história de ataxia espinocerebelar há 10 anos. Seus principais objetivos eram melhorar a marcha e o equilíbrio. Ele apresentava ataxia axial e apendicular, dificuldades na marcha e no equilíbrio. O protocolo de estimulação do cerebelo consistiu na aplicação de tDCS por 20 minutos, 2mA, diariamente, durante duas semanas, com ânodo posicionado sobre o ínion e cátodo sobre o músculo deltóide direito. A cinesioterapia simultânea incluiu exercícios funcionais progressivos com objetivo principal de treinamento de equilíbrio. RESULTADOS: A melhora clínica foi particularmente evidenciada por uma redução de 4 pontos na Escala para Avaliação e Graduação da Ataxia após 10 sessões, enquanto a literatura recomenda a eficácia de uma nova terapia que retardaria a progressão da ataxia em 1 ponto por ano. CONCLUSÃO: Nossos resultados sugerem que a associação entre tDCS e cinesioterapia foi eficaz neste paciente; as sessões de tDCS foram seguras e bem toleradas e podem ter desempenhado um papel na melhora nos testes funcionais. Novos estudos controlados envolvendo um número maior de pacientes são necessários para analisar os benefícios destas técnicas combinadas para maximizar a reabilitação motora nesta população.

PURPOSE Nivolumab, an anti–programmed death-1 monoclonal antibody, has demonstrated frequent and durable responses in relapsed/refractory classic Hodgkin lymphoma (cHL). We report results from Cohort D of the CheckMate 205 trial, which assessed nivolumab monotherapy followed by nivolumab plus doxorubicin, vinblastine, and dacarbazine (N-AVD) for newly diagnosed cHL. METHODS Patients 18 years of age or older with untreated, advanced-stage (defined as III to IV and IIB with unfavorable risk factors) cHL were eligible for Cohort D of this multicenter, noncomparative, phase II trial. Patients received nivolumab monotherapy for four doses, followed by 12 doses of N-AVD; all doses were every 2 weeks, and nivolumab was administered at 240 mg intravenously. The primary end point was safety. Efficacy end points included objective response rate and modified progression-free survival, defined as time to disease progression/relapse, death, or next therapy. Chromosome 9p24.1 alterations and programmed death-ligand 1 expression were assessed in Hodgkin Reed-Sternberg cells in evaluable patients. RESULTS A total of 51 patients were enrolled and treated. At diagnosis, 49% of patients had an International Prognostic Score of 3 or greater. Overall, 59% experienced a grade 3 to 4 treatment-related adverse event. Treatment-related febrile neutropenia was reported in 10% of patients. Endocrine immune-mediated adverse events were all grade 1 to 2 and did not require high-dose corticosteroids; all nonendocrine immune-mediated adverse events resolved (most commonly, rash; 5.9%). At the end of therapy, the objective response rate (95% CI) per independent radiology review committee was 84% (71% to 93%), with 67% (52% to 79%), achieving complete remission (five patients [10%] were nonevaluable and counted as nonresponders). With a minimum follow-up of 9.4 months, 9-month modified progression-free survival was 92%. Patients with higher-level Hodgkin Reed-Sternberg programmed death-ligand 1 expression had more favorable responses to N-AVD ( P = .041). CONCLUSION Nivolumab followed by N-AVD was associated with promising efficacy and safety profiles for newly diagnosed, advanced-stage cHL.

Background: Patients (pts) with classical Hodgkin lymphoma (cHL) frequently experience reduced health-related quality of life (HRQoL) (Oerlemans et al, Ann Hematol 2011). Nivolumab, a fully human IgG4 anti-programmed death-1 (PD-1) immune checkpoint inhibitor monoclonal antibody, demonstrated efficacy and clinically meaningful improvement in pt-reported outcomes (PROs) in pts with relapsed/refractory cHL in cohorts A, B, and C of CheckMate 205 (NCT02181738) (Armand et al, J Clin Oncol 2018; Engert et al, ASH 2017). Nivolumab monotherapy followed by nivolumab + doxorubicin, vinblastine and dacarbazine (N-AVD) demonstrated an objective response rate of 84% in newly diagnosed cHL (cohort D of CheckMate 205; Ramchandren et al, EHA 2018). We present PROs in CheckMate 205 cohort D. Methods: Pts ≥18 years of age with untreated, advanced-stage cHL, with ECOG performance status (PS) of 0–1 received 4 doses of nivolumab monotherapy (240 mg IV Q2W) followed by N-AVD for 6 cycles (12 doses). Pts then entered the follow-up (FU) period. PROs were an exploratory endpoint, assessed using the EuroQol 5 Dimensions-3 level (EQ-5D-3L) and associated visual analog scale (EQ-VAS) in all treated pts who had both a baseline (monotherapy cycle 1) and post-baseline assessment. EQ-VAS ranges from 0–100, with higher scores indicating better HRQoL. In EQ-5D-3L, pts can report no, some, or extreme problems in each of 5 dimensions (mobility, self-care, activity, pain, and anxiety). Results: 51 pts were treated. At baseline, median age was 37 years, 63% were male, 59% had ECOG PS of 0. 49 pts (96%) completed baseline EQ-VAS. Mean EQ-VAS scores exceeded the mean baseline score at the end of monotherapy, after 2 combination cycles, at the end of therapy, and during follow-up (Table 1). The proportion of pts reporting some or extreme problems in EQ-5D-3L was numerically lower than or similar to baseline after monotherapy for all dimensions, but was numerically higher than baseline (dimensions of mobility and activity) after 2 combination cycles, and remained close to or numerically below baseline during follow-up (dimensions of self-care, activity, pain, and anxiety). Conclusions: Pt-reported HRQoL, as assessed by observed mean EQ-VAS scores, did not deteriorate from baseline during treatment with nivolumab followed by N-AVD. Proportions of pts reporting problems in individual EQ-5D-3L dimensions were generally similar to baseline during treatment and follow-up.

This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2 to 4. In part 3, both study drugs were dosed, same day, for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (ORR; N = 91) was 85%, with 67% achieving a complete response (CR). At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI], 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow-up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns. This trial was registered at www.clinicaltrials.gov as #NCT02572167.

Introduction: Mediastinal gray zone lymphoma (MGZL) is an extremely rare form of non-Hodgkin lymphoma with a predominance in young men and with features that are intermediate between nodular sclerosis classical Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBL). Shared features of these tumor types include tumor CD30 expression and the presence of 9p24.1 chromosomal alterations with expression of programmed death 1 (PD-1) ligand. Compared with PMBL, patients (pts) with MGZL have inferior survival outcomes when treated with conventional chemotherapy (Wilson et al. Blood 2014). Nivolumab is a fully human immunoglobulin G4 anti-PD-1 immune checkpoint inhibitor monoclonal antibody; brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate. In the CheckMate 436 study, the combination of nivolumab and BV demonstrated a high objective response rate (ORR; 73%) and complete response (CR) rate (37%) in pts with relapsed/refractory (R/R) PMBL (Zinzani et al. J Clin Oncol 2019). A separate study in R/R cHL also showed impressive efficacy (ORR: 82%; CR: 61%), suggesting some complementary action between the two agents (Herrara et al. Blood 2018). A case series highlighted the clinical activity of PD-1 inhibitor monotherapy in R/R MGZL (Melani et al. N Engl J Med 2017). Given the overlapping features of MGZL with PMBL and cHL, we evaluated the efficacy and safety of nivolumab + BV in a separate MGZL cohort in CheckMate 436. Methods: The expansion cohort of the open-label, phase 1/2 CheckMate 436 (NCT02581631) study enrolled pts ≥ 18 years old with ECOG performance status of 0 or 1, and with confirmed R/R MGZL after autologous hematopoietic cell transplantation (auto-HCT) or, if ineligible for auto-HCT, after ≥ 2 multi-agent chemotherapy regimens. Pts received 240 mg nivolumab (on Day 8 of Cycle 1, then Day 1 of following cycles) and 1.8 mg/kg BV (on Day 1 of each cycle) every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were investigator-assessed ORR per the Lugano 2014 criteria and safety. Key secondary endpoints included CR rate, overall survival (OS), duration of response (DOR), and progression-free survival (PFS). Results: A total of 10 pts were treated and evaluable. Median age (range) was 35 (25-72) years, with only 1 pt aged > 65 years (72 years). Six pts (60%) were male; all pts had a mediastinal mass. Pts had a median of 2 prior lines of systemic cancer therapy, and none had received prior auto-HCT. At database lock, 8 months after the last pt received the first treatment, all pts had discontinued treatment (5 due to disease progression, 3 due to maximum clinical benefit, 1 due to allogenic [allo]-HCT, and 1 due to auto-HCT). Pts received a median of 7 doses of nivolumab and 7 doses of BV. ORR per investigator was 70% (80% CI, 45-88), with 5 pts (50%) achieving CR (Table). The time to CR was 1.2-1.3 months and the duration of CR was 1.5-3.2 months before pts were censored for subsequent therapy. The 5 pts who achieved CR were bridged to hematopoietic cell transplantation (4 allo- and 1 auto-HCT) and censored (all were alive at database lock). Eight pts (89%) who were evaluable for response had tumor reduction of > 25% (Figure). At a median follow-up of 12.4 (range, 0.1-25.5) months, the 6-month OS rate was 80.0% (95% CI, 40.9-94.6). DOR and PFS could not be estimated due to earlier censoring of pts who received subsequent therapies. Nine pts (90%) experienced any grade treatment-related adverse events (TRAEs); the most common any grade TRAEs were neutropenia (n = 3; 1 grade 1, 1 grade 2, 1 experienced 4 grade 1/2 events and 1 grade 3 event) and paresthesia (n = 3; all grade 1). Three pts (30%) had grade 3-4 TRAEs. Infusion-related reaction occurred in 1 pt (grade 1). One pt had an immune-mediated AE (grade 2 maculo-papular rash, which resolved without systemic steroids). A serious drug-related AE occurred in 1 elderly pt (grade 3 febrile neutropenia). There were 3 deaths, all caused by disease progression. Conclusions: Nivolumab + BV demonstrated a high investigator-assessed ORR of 70%, with a 50% CR rate and a tolerable safety profile in pts with R/R MGZL, similar to findings in PMBL. The regimen represents a potential option for bridging to hematopoietic cell transplantation based on the brisk and frequent responses and a safety profile that compares favorably with historic data using standard chemotherapy regimens. Study support: BMS. Writing support: Jane Cheung, Caudex, funded by BMS. Figure 1 Disclosures Santoro: Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD: Speakers Bureau; Arqule, Sanofi: Consultancy; Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, MSD: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy; Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD: Speakers Bureau; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy, Speakers Bureau. Moskowitz:Merck: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Miragen Therapeutics: Consultancy; Incyte: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Consultancy. Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Boehringer Ingelheim and Sanofi: Consultancy; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Francis:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Sacchi:Bristol-Myers Squibb Company: Current Employment. 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. OffLabel Disclosure: Nivolumab was used in combination with brentuximab vedotin (BV) for evaluation of its efficacy and safety in patients with relapsed/refractory mediastinal gray zone lymphoma.

Background Outcomes for younger patients with R/R cHL are poor, particularly for those without complete metabolic response (CMR) before autologous transplant (auto-HCT). CheckMate 744 ( NCT02927769 ) is an ongoing phase 2 study for CAYA with R/R cHL, evaluating a risk-stratified, response-adapted approach using nivolumab plus BV, and for patients without CMR, BV plus bendamustine. In the initial analysis of the standard-risk cohort (R2), the regimen was well tolerated with high CMR rates before consolidation with high-dose chemotherapy plus auto-HCT. We report primary analysis data. Patients 5–30 years old; had first-line treatment without auto-HCT. Design Risk stratification has been described (Harker-Murray, ASH 2018). Patients received 4 induction cycles of nivolumab plus BV; patients without CMR by blinded independent central review (BICR) received BV plus bendamustine intensification. Patients with CMR at any time could proceed to consolidation off study. Response was per Lugano 2014 criteria. Primary endpoint: CMR rate (Deauville ≤3) per BICR any time before consolidation. Results 44 patients were treated in R2 (median follow-up: 20.9 months); 43 received 4 induction cycles and 11 received intensification. Median age was 16 years (range, 9–30); 24 (55%) patients had primary refractory cHL. CMR rate (90% CI) any time before consolidation was 88% (77–95) and 89% (78–95) per BICR and investigator, respectively; objective response rate (ORR) was 98% by either assessment. After 4 cycles of induction, CMR was 59% and 66% per BICR and investigator, respectively; ORR (90% CI) was 82% (70–91) and 89% (78–95), respectively. One-year progression-free survival rate by BICR was 91% (90% CI, 77–96). During induction, 8 patients (18%) experienced grade (G) 3–4 treatment-related adverse events (TRAEs); the most common any-grade TRAEs were nausea and hypersensitivity (20% each). One TRAE led to discontinuation (G3 anaphylaxis). Most treatment-related immune-mediated AEs were G1–2 (1 patient had 2 G3 infusion-related reactions). Conclusions This risk-stratified, response-adapted approach offers a well-tolerated salvage strategy with high CMR rates and no new safety signals for CAYA with R/R cHL. Most patients avoided bendamustine prior to consolidation. Further follow-up may confirm durability of disease control. Funding BMS. Previous presentation ASCO 2020

In this study, we evaluated homeostatic and functional disorders of the spleen in mice inoculated with Toxoplasma gondii. The kinetics of megakaryocyte and leukocyte production, body and spleen mass and certain histopathological aspects were analyzed. There was increased (P

This work constitutes an integration of geological, archaeological and palynological data from Santa Cruz Province, Argentina, for assessing the influence of paleogeographic and paleoclimatic changes in relation to the dynamics of human occupation during the Holocene. In order to carry out its objectives, we surveyed different archaeological sites, we collected pollen samples from two archaeological sites, and described, sampled and dated stratigraphic profiles of lake levels. A digital elevation model was also developed to reconstruct old flooded areas. Given the obtained results, we observe the influence that paleogeographic changes could have had on human occupational dynamics. These changes may have opened up new areas for both settlement and mobility. Pollen records suggest a vegetation change from grass steppe to shrub steppe during the Middle Holocene, most likely related to climate changes identified at a regional scale. Fil: Horta, Luis Rubén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Estudios Sociales. Universidad Nacional de Tucumán. Instituto Superior de Estudios Sociales; Argentina. Universidad Nacional de La Rioja; Argentina Fil: Marcos, Maria Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencia Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina Fil: Bozzuto, Damian Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Secretaría de Cultura de la Nación. Dirección Nacional de Cultura y Museos. Instituto Nacional de Antropología y Pensamiento Latinoamericano; Argentina Fil: Mancini, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencia Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina Fil: Sacchi, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Secretaría de Cultura de la Nación. Dirección Nacional de Cultura y Museos. Instituto Nacional de Antropología y Pensamiento Latinoamericano; Argentina

8013 Background: Outcomes for younger patients (pts) with R/R cHL are poor, particularly for those without complete metabolic response (CMR) before autologous transplant (auto-HCT). Nivolumab + BV has shown 67% CMR and a high 2-y PFS rate as first salvage in adults with R/R cHL. CheckMate 744 (NCT02927769) is an ongoing phase 2 study for CAYA with R/R cHL, evaluating a risk-stratified, response-adapted approach using nivolumab + BV and, for pts without CMR, BV + bendamustine. In the initial analysis of the standard-risk cohort (R2), the regimen was well tolerated with high CMR rates before consolidation with high-dose chemotherapy plus auto-HCT. We report data from the primary analysis. Methods: Pts were aged 5–30 y and had first-line treatment (tx) without auto-HCT. Risk stratification has been described previously (Harker-Murray, ASH 2018). Pts received 4 induction cycles of nivolumab + BV; pts without CMR by blinded independent central review (BICR) received BV + bendamustine intensification. Pts with CMR at any time could proceed to consolidation off study. Response was per Lugano 2014 criteria. Primary endpoint: CMR rate (Deauville ≤3) per BICR any time before consolidation. Results: At database lock, 44 pts were treated in R2 (median follow up: 20.9 mo); 43 received 4 induction cycles and 11 received intensification. Median age was 16 y (range 9–30); 24 (55%) pts had primary refractory cHL and 20 had relapsed cHL. CMR rates and ORR any time before consolidation and after induction are shown in Table. 1-y PFS rate by BICR was 91% (90% CI 77–96). During induction, 8 (18%) pts experienced grade (G) 3–4 tx-related adverse events (TRAEs); the most common any grade TRAEs were nausea and hypersensitivity (20% each). 1 TRAE led to discontinuation (G3 anaphylaxis). Most tx-related immune-mediated AEs were G1–2 (1 pt had 2 G3 infusion-related reactions). Conclusions: This risk-stratified, response-adapted approach offers a well-tolerated salvage strategy with high CMR rates and no new safety signals for CAYA with R/R cHL. Most pts avoided alkylator exposure prior to consolidation. Further follow up may confirm durability of disease control. Clinical trial information: NCT02927769 . [Table: see text]

This paper discusses different aspects related to the andesite and obsidian availability and circulation routes in different moments of the occupation sequence in the Pueyrredón-Posadas-Salitroso (PPS) Lake Basin in the north, and the Burmeister-Belgrano (BB) Lake Basin to the south (north-west Santa Cruz province, Argentinian Patagonia). The distribution of raw materials - both in space and time - allows us to assert that potential regional circulation routes would have been affected differentially by the palaeolakes present from the Pleistocene up until the mid-Holocene. We are taking into account three sites: Cueva Milodón Norte 1 (CMN1), located in the northeast coast of the Pueyrredón Lake, Cerro de los Indios 1 (CI1) (central portion of the PPS Basin), and Cerro Casa de Piedra 7 (CCP7) (near to the Burmeister Lake). This investigation considers six periods, based on the calibrated ranges from 73 radiocarbon dates: 17 from CI1, 14 from CMN1, and 42 radiocarbon dates from CCP7. As a result of this analysis we can conclude that, in sites with a higher density of occupation such as CI1 and CCP7, the use of obsidian (non-local rock) and andesite or basalt did not vary over time. In the case of CMN1, access to the sources of these raw materials varied according to the presence of large bodies of water, although it does not seem to have influenced the procurement of these rocks.

Purpose Safe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP. A phase I study determined suitable dosing for children with Philadelphia chromosome–positive (Ph+) leukemias. Methods CA180-226/NCT00777036 is a phase II, open-label, nonrandomized prospective trial of patients < 18 years of age receiving dasatinib. There are three cohorts: (1) imatinib-resistant/intolerant CML-CP, (2) imatinib-resistant/intolerant CML in accelerated/blast phase or Ph+ acute lymphoblastic leukemia (n = 17), and (3) newly diagnosed CML-CP treated with tablets or powder for oral suspension. Major cytogenetic response > 30% for imatinib-resistant/intolerant patients and complete cytogenetic response (CCyR) > 55% for newly diagnosed patients were of clinical interest. Results Of 113 patients with CML-CP, 14 (48%) who were imatinib-resistant/intolerant and 61 (73%) who were newly diagnosed remained on treatment at time of analysis. Major cytogenetic response > 30% was reached by 3 months in the imatinib-resistant/intolerant group and CCyR > 55% was reached by 6 months in the newly diagnosed CML-CP group. CCyR and major molecular response by 12 months, respectively, were 76% and 41% in the imatinib-resistant/intolerant group and 92% and 52% in newly diagnosed CML-CP group. Progression-free survival by 48 months was 78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP groups, respectively. No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary arterial hypertension were reported. Bone growth and development events were reported in 4% of patients. Conclusion In the largest prospective trial to date in children with CML-CP, we demonstrate that dasatinib is a safe, effective treatment of pediatric CML-CP. Target responses to first- or second-line dasatinib were met early, and deep molecular responses were observed. Safety of dasatinib in pediatric patients was similar to that observed in adults; however, no cases of pleural or pericardial effusion or pulmonary arterial hypertension were reported.

Introduction Brentuximab vedotin (BV) targets CD30, a receptor expressed on the Reed-Sternberg cells of classic Hodgkin lymphoma (cHL). Nivolumab (Nivo) restores antitumor immunity by blocking the PD-1 receptor on activated T-cells. In this phase 1/2 study, combination treatment (tx) with BV + Nivo demonstrated durable efficacy in patients (pts) with relapsed/refractory (R/R) cHL (Herrera, Blood 2018; NCT02572167). Biomarkers consistent with innate and adaptive immune activation were observed in the peripheral blood of pts treated with the combination regimen. Herein, we associate biomarkers in the peripheral blood with clinical response, and present follow-up results for pts who received BV + Nivo under staggered and concurrent dosing schedules. Methods Enrolled pts had cHL that relapsed or was refractory to frontline chemotherapy. In Parts 1 and 2 (staggered dosing), pts received up to 4 cycles of BV 1.8 mg/kg and Nivo 3.0 mg/kg given on Days 1 and 8 of Cycle 1, respectively, and together on Day 1 of Cycles 2-4. Pts in Part 3 (concurrent dosing) received the same dose of both agents on Day 1 of all 4 cycles. After investigators assessed response (Cheson 2014, with the incorporation of LYRIC [Cheson 2016] for pts in Part 3), pts could undergo ASCT. Results Demographics and baseline characteristics were similar across all treated pts (N=91) in the staggered and concurrent dosing cohorts; median age 34 years (yrs, range; 18-69), 42% with primary refractory disease, and 30% with relapse within 1 yr of frontline therapy. All 91 pts are off-tx and have been observed through the 100-day safety reporting period. A total of 86 pts (92%) completed all 4 cycles of BV + Nivo. Early tx discontinuations were due to; AE (peripheral neuropathy and increased GGT [1 pt each]), progressive disease (PD), investigator decision, and pt decision (1 pt each). Most common AEs prior to ASCT or additional salvage therapy were nausea (52%) and infusion-related reactions (IRRs, 43%). Excluding IRRs, 14% of pts had immune-related AEs requiring tx with systemic steroids, including rash (8%), pneumonitis (4%), and AST increased, diarrhea, and Guillain-Barre syndrome (1% each). The ORR for all-treated pts was 85%, with 67% complete response (CR). A total of 67 pts (74%) underwent ASCT after tx with BV + Nivo. There were 22 pts who received additional salvage therapy after BV + Nivo (7 PD, 6 partial response, 5 stable disease, and 4 CR at EOT), 17 of whom later underwent ASCT. At a median of 22.6 months (range; 1.2, 41.2) from the start of tx, the estimated 2-yr PFS rate in all treated pts was 78%, and for pts who underwent ASCT after tx with BV + Nivo was 91% (Figure 1). At 2 years, the estimated OS rate for all treated pts was 93%. Staggered and concurrent dosing of BV + Nivo resulted in increased levels of activated and dividing CD4+ T cells, activated and dividing CD8+ T cells (concurrent dosing-only), regulatory T cells (Tregs), and circulating plasmablasts in blood. We did not observe any associations between the magnitude of these changes and clinical response. Pts with CR exhibited trends for higher pre-tx blood levels of CD30+ Tregs and CD30+ Th subsets compared to pts without CR, suggesting BV depletion of these populations may have a role in the clinical mode of action of BV + Nivo. Although pre-tx levels of cytotoxic lymphocytes (CTLs) in blood did not differentiate pts with CR from other pts, pts in the lower quartile of pre-tx CTL levels showed significantly shorter PFS than other pts, suggesting a potential association between CTLs and disease control. Changes in blood cytokine and chemokine levels were observed after BV + Nivo, including increased levels of IL-18, IP-10, I-TAC, and sCD30, and decreased levels of TARC, IL-2Ra, and IL-6. Our analyses support strong correlations between pre-tx cytokine/chemokine levels and clinical benefit including trends linking lower pre-tx levels of IL-18, I-TAC, and IL-2RA to achieving CR and longer PFS. Conclusion BV + Nivo, both staggered and current dosing, showed tolerability and high CR rates with durable remissions among pts with R/R cHL. Analysis of blood biomarkers identified trends potentially linking baseline levels of CD30+ immune cells and the baseline pt inflammatory state with the activity of BV + Nivo. Together, these encouraging results support further investigation of BV + Nivo as initial salvage therapy in pts with R/R cHL. Figure 1 Disclosures Moskowitz: Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Merck: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Incyte: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding. Advani:Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Forty-Seven: Research Funding; Infinity Pharma: Research Funding; Pharmacyclics: 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; Regeneron: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Merck: Research Funding; Kura: Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; Cell Medica, Ltd: Consultancy; Stanford University: Employment, Equity Ownership; Seattle Genetics: Consultancy, Research Funding; Millennium: Research Funding; Janssen: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. 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. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria. Ramchandren:Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Pharmacyclics LLC, an Abbvie company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Sandoz-Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Feldman:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding. LaCasce:BMS: Consultancy; Research to Practice: Speakers Bureau; Humanigen: Consultancy; Seattle Genetics: Consultancy, Research Funding. Christian:Bristol-Myers Squibb: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Research Funding; Janssen: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Triphase: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Merck: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding. Moskowitz:ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding. Brown:Seattle Genetics, Inc.: Employment, Equity Ownership. Taft:Seattle Genetics, Inc.: Employment, Equity Ownership. Ansari:Seattle Genetics, Inc.: Employment, Equity Ownership. Zak:Seattle Genetics, Inc.: Employment, Equity Ownership. Sacchi:Seattle Genetics, Inc.: Research Funding. Manley:Seattle Genetics: Employment, Equity Ownership. Herrera:Merck: Consultancy, Research Funding; AstraZeneca: Research Funding; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.

Introduction: Classical Hodgkin lymphoma (cHL) is among the most common malignancies in adolescents and young adults. High-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation (ASCT) are standard for most patients with relapsed/refractory (R/R) disease. Current salvage therapies are associated with excessive toxicity and variable complete remission rates (Harker-Murray et al, Pediatr Blood Cancer 2014). Novel regimens that increase remission rates and reduce late effects of therapy are needed, particularly for young patients. Nivolumab (nivo) is a fully human IgG4 anti-programmed death-1 monoclonal antibody. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate. In a phase 1/2 study of adults with R/R cHL, the combination of nivo + BV was well tolerated, with a high response rate as first salvage regimen (Herrera et al, Blood 2018). CheckMate 744 (AHOD1721; NCT02927769) is the first risk-stratified, response-adapted, phase 2 study of nivo + BV, followed by BV + bendamustine for suboptimal response, in children, adolescents, and young adults with R/R cHL with low or standard risk of relapse. Here we report preliminary, investigator (INV)-assessed results from the standard-risk (R2) cohort. Methods: This open-label study enrolled patients aged 5-30 years with pathologically confirmed cHL, excluding nodular lymphocyte-predominant HL, after failure/non-response to first-line therapy and without prior ASCT. Stratification to R2 was based on refractory disease or early relapse; B symptoms, extranodal disease, or extensive disease with radiation therapy (RT) contraindicated at relapse; relapse in a prior RT field; or stage IIIB or IV at initial diagnosis. Patients in R2 received induction (IND) with 4 cycles of nivo + BV. Patients without complete metabolic response (CMR; Deauville score 1-3) received intensification (INT) with 2-4 cycles of BV + bendamustine. Patients with CMR after IND or INT discontinued study treatment, proceeded to HDCT/ASCT, and entered follow-up. Tumors were assessed by INV and blinded independent central review (BICR) per Lugano 2014 criteria (Cheson et al, J Clin Oncol 2014) every 2 treatment cycles. Treatment decisions were based on BICR assessment. The primary endpoint was CMR rate by BICR prior to HDCT/ASCT. Secondary endpoints included INV-assessed response and safety. Results: At database lock (DBL), 32 patients in R2 had entered IND. Median age was 16 y (range 9-30), 78% were aged Conclusion: For children, adolescents, and young adults with standard-risk R/R cHL prior to ASCT, this risk-stratified, response-adapted approach using nivo, BV, and bendamustine resulted in high CMR rates and was well tolerated, making it a promising novel salvage therapy. Most evaluated patients achieved CMR with IND (nivo + BV); all 6 who went to INT (BV + bendamustine) achieved CMR. Updated results based on a planned interim analysis including more patients and BICR-assessed response data will be presented. Study support: Sponsored by Bristol-Myers Squibb in collaboration with Children's Oncology Group (COG) and EuroNet group. Disclosures Leger: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Brugieres:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Other: Financial support for SIOP meeting in 2016. Galderisi:Seattle Genetics: Employment, Equity Ownership. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Jou:Bristol-Myers Squibb: Employment, Other: company stock ownership.

Introduction: Genetic alterations at 9p24.1 resulting in overexpression of programmed death-1 (PD-1) ligands are near-universal in cHL (Roemer et al, J Clin Oncol 2016); cHL may thus be uniquely sensitive to PD-1 blockade. Nivolumab (nivo), an anti-PD-1 monoclonal antibody, was associated with an objective response rate (ORR) of 69% in relapsed/refractory (R/R) cHL after auto-HCT and irrespective of prior brentuximab vedotin (BV) in the phase 2 CheckMate 205 study (Armand et al, J Clin Oncol 2018; NCT02181738). Whether some patient (pts) can derive very long clinical benefit, whether depth of response predicts long-term outcome, whether treatment (Tx) can be interrupted in complete remission (CR), and whether the safety profile of nivo in R/R cHL changes with prolonged Tx all remain unclear. We therefore present an updated analysis of CheckMate 205, focusing on long-term efficacy and safety. Methods: This international, single-arm, multi-cohort study enrolled pts aged ≥18 y with R/R cHL after auto-HCT. Pts were BV naïve (Cohort A), had prior BV failure after auto-HCT (Cohort B), or had received BV before and/or after auto-HCT (Cohort C). Pts received nivo 3 mg/kg every 2 wk until disease progression (PD)/unacceptable toxicity. Pts in Cohort C discontinued nivo after 1 y in CR and could resume if they relapsed within 2 y of the last dose. Primary endpoint was ORR per independent radiology review committee (IRC); additional endpoints included duration of response (DOR) per IRC, progression-free survival (PFS) per IRC, overall survival (OS), and safety. Time to next Tx (TTNT: time from first dose to next systemic Tx or death) was an exploratory post-hoc analysis. Responses were assessed using International Working Group 2007 criteria. Results: In total, 243 pts were enrolled to Cohorts A (n=63), B (n=80), and C (n=100). Baseline characteristics have been previously described (Armand et al, J Clin Oncol 2018). At data cut-off, minimum follow-up was 31 mo and 49 pts (20%) were still on Tx; the most common reason for discontinuation was PD (35%). Median duration of Tx was 14 mo. ORR per IRC was 71% (65%, 71%, 75% in Cohorts A, B, C, respectively) with a best overall response (BOR) of CR in 21% (32%, 14%, 20% in Cohorts A, B, C, respectively). Among 51 pts who achieved CR, 20 had CR as the first response and 31 improved from partial remission (PR), mostly (n=28/31) within 1 year of first PR. Median time to response was 2 mo, and to CR was 4 mo. Within the first 6, 12, and 18 mo, 68%, 71%, and 71% of pts, respectively, achieved a response. Median DOR was 18 mo overall, and was 32 and 13 mo in pts with a BOR of CR and PR, respectively. Among responders, 64%, 44%, 31%, and 21% of pts had a DOR of at least 6, 12, 18, and 24 mo, respectively. Overall, 11 pts in Cohort C discontinued with persistent investigator-assessed CR; 2 reinitiated nivo due to PD. Median (95% CI) PFS per IRC among all pts was 15 (11-19) mo (Figure A), and was 17, 12 and 15 mo in Cohorts A, B, and C, respectively. Median OS was not reached in any cohort; 24-mo OS rates were 90%, 86%, and 86% in Cohorts A, B, and C, respectively, and were similar among pts in CR, PR, or with stable disease (SD; Figure B). Median TTNT was 29, 27, and 20 mo in Cohorts A, B, and C, respectively. The most common Tx-related adverse events (AEs) of any grade (G) were fatigue (24%), diarrhea (16%), and rash (12%), each Conclusions: With the longest phase 2-3 study follow-up of a checkpoint inhibitor in R/R cHL to date, nivo was associated with frequent and durable responses regardless of BV Tx history. More than 1 in 5 responders remained in response ≥2 years later. With extended follow-up, additional pts achieved CR in all cohorts. Pts with CR had longer PFS than pts with PR or SD. However, pts with both PR and SD had prolonged OS, unlike pts with PD, which may suggest that clinical benefit duration is not well predicted by conventional response criteria. Nivo continued to be well tolerated, with no new safety signals. Characteristics of long-term responders will be presented. Study support: BMS. Medical writing: A Gill, Caudex, funded by BMS Figure. Figure. Disclosures Armand: Infinity: Consultancy; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Otsuka: Research Funding; Adaptive: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Younes:Celgene: Honoraria; Genentech: Research Funding; Janssen: Honoraria, Research Funding; Bayer: Honoraria; Novartis: Research Funding; J&J: Research Funding; Astra Zeneca: Research Funding; BMS: Honoraria, Research Funding; Merck: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria, Research Funding; Sanofi: Honoraria; Incyte: Honoraria; Curis: Research Funding; Pharmacyclics: Research Funding. Zinzani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: 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; PFIZER: 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, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celltrion: Honoraria, 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; Bayer: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Merck: 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; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Collins:ADC Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Celgene Corporation: Research Funding; BMS: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Amgen: Research Funding. Ramchandren:Merck: Research Funding; Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cohen:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees. De Boer:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; EISA: Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Lundbeck: Honoraria; Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Leukemia and Lymphoma Society Canada: Research Funding; Abbvie: Consultancy; Merck: Consultancy, Honoraria; Karyopharm: Honoraria; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Trněný:F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Sandoz: Honoraria; Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Abbvie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Shipp:Merck: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Sumbul:Bristol-Myers Squibb: Employment. Ansell:Trillium: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding.

Introduction: In recently-reported interim results from a phase 1/2, open-label, multicenter study (NCT02572167), we showed that 61% of relapsed/refractory Hodgkin Lymphoma (HL) patients achieved complete responses (CRs) after treatment with Brentuximab Vedotin (BV) in combination with Nivolumab (Nivo) (Herrera et al., 2018). To gain insight into tumor microenvironment driven disease characteristics associated with CRs after combined BV+Nivo therapy, we performed RNA sequencing (RNA-Seq) transcriptome analysis of formalin-fixed paraffin-embedded tumor biopsies obtained from 37 study participants (23 CR, 14 PR/SD/PD) prior to the start of treatment. Results: Within a set of 132 candidate genes comprised of BV+Nivo therapeutic targets (CD30, PD-1, PD-L1), the markers for immune cells, inflammatory response factors, and potential resistance mechanism factors within the tumor microenvironment, the gene most strongly associated with CRs was the BV target CD30 (TNFRSF8) (p=4x10-4, FDR=5%). Baseline tumor expression of CD30 above 16 counts per million mapped reads (CPM) was strongly associated with achieving CR after BV+Nivo (65% sensitivity and 93% specificity). CRs were associated with several other factors, including higher baseline tumor expression of macrophage markers CD14 and CD163 and lower expression of the Nivo target PD-1 (PDCD1) and multidrug resistance-associated protein 2 (MRP2/ABCC2) in the tumor microenvironment. Both PD-1 and MRP2 were significantly complementary to CD30 for discriminating CRs from the other patients on the basis of baseline gene expression profiling in tumor microenvironment (p Conclusions: The CR rate for combination therapy of BV+Nivo in relapsed/refractory HL is nearly double the rate reported for this patient population for either agent individually, suggesting the possibility of complementary mechanisms between BV-targeted and Nivo-targeted pathways. By performing RNA-Seq analysis of patient baseline tumor biopsies from the BV+Nivo trial (NCT02572167), we were able to identify specific tumor characteristics that are associated with favorable responses to treatment. In particular, the gene expression ratio of CD30/PD-1 was an accurate discriminator for patients that would achieve CRs. This result suggests that BV+Nivo efficacy may be observed in tumors in which the potential for BV-driven immunogenic cell death (ICD) - as indicated by CD30 expression - exceeds a threshold set by the immunosuppressive potential of the tumor (as indicated by PD-1 expression). This hypothesis is supported by the deconvolution analysis results that implicated a favorable role for macrophages (which may become activated in response to BV-induced ICD) in the tumor and a detrimental role for immunosuppressive tumor T cells. Immunohistochemical analyses of biopsies from the study are underway to quantify target abundance and to further characterize the TMEs. These data will be integrated with the transcriptomics to validate and refine the model for BV+Nivo efficacy in relapsed/refractory HL. Disclosures Zak: Seattle Genetics: Employment, Equity Ownership. Ogden:Seattle Genetics: Employment, Equity Ownership. Herrera:Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Research Funding; Immune Design: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck, Inc.: Consultancy, Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Gilead Sciences: Research Funding. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Onsum:Seattle Genetics: Employment, Equity Ownership.

Introduction This phase 1/2 study evaluated the safety and antitumor activity of brentuximab vedotin (BV) administered in combination with nivolumab (Nivo) in adult patients (pts) with relapsed/refractory classic Hodgkin lymphoma (R/R cHL) who have failed frontline therapy (NCT02572167). Results from Parts 1 & 2 have been previously reported, wherein safety, efficacy, and biomarkers consistent with immune activation were observed in pts with R/R cHL (Herrera et al., Blood 2018). In Part 3, patients were treated with BV + Nivo on Day 1 of each cycle. In contrast, pts in Parts 1 & 2 received BV on C1D1 and Nivo on C1D8 with concurrent admin on subsequent cycles. Herein we present safety, efficacy, and biomarker results for Part 3 and updated progression free survival (PFS) from Parts 1 & 2. Methods Pts in Parts 1 & 2 received up to four 21-day cycles of staggered dosing (day 1 BV 1.8 mg/kg, day 8 Nivo 3 mg/kg in Cycle 1) and concurrent thereafter, with steroid and antihistamine premedication. Pts in Part 3 received up to four 21-day cycles of concurrent BV + Nivo on Day 1 with antihistamine premedication. Following Cycle 4 response assessment (Lugano Classification Revised Staging System with the incorporation of the Lymphoma Response to Immunomodulatory Therapy Criteria [LYRIC, 2016]) responding pts were eligible to undergo autologous stem cell transplant (ASCT). Results 30 pts were treated in Part 3 and all were evaluable for efficacy. Pt characteristics included the following: median age 31.5 yrs (range; 20 - 66), 63% female, 93% prior ABVD, 37% primary refractory HL, 30% relapsed within 1year of frontline therapy, 30% with extranodal disease and 17% with bulky disease at enrollment. 28 pts completed all 4 cycles. 1 pt discontinued treatment (tx) due to an adverse event (AE; Grade 3 [G3] elevated Gamma-Glutamyltransferase) and 1 pt due to progressive disease (PD). The latter pt eventually died due to PD. All pts are off tx and have been observed through the safety reporting period. 37% of pts experienced a G3 or higher tx emergent AE prior to ASCT. 30% of the pts experienced infusion related reactions (IRRs), which occurred most frequently during Cycle 2. Potential G3 or higher immune-related AEs (IRAEs), excluding IRRs, occurred in 2 pts, one of whom required steroids for G4 pneumonitis, which subsequently resolved. Among the 30 efficacy evaluable pts, the complete response (CR) rate was 80% (24/30), with an objective response rate (ORR) of 93%. 47% of pts (14) had a Deauville ≤2, and 17% (5) had Deauville 3. 5 pts with CR had a Deauville >3 and met LYRIC criteria for IR-2. 4/5 pts had a negative follow-up biopsy that confirmed CR and in 1 pt the PET finding was considered to be a false positive as contrast enhanced CT did not reveal any abnormality. All 5 pts proceeded directly to ASCT and remain in CR at follow-up. Among all treated patients, 25 went directly to ASCT after completing BV + Nivo tx with a median 6.8 x 106 CD34+ cells/kg (range 1-20) collected. Median times to neutrophil and platelet engraftment were 12 and 14 days, respectively. 4 pts required additional salvage therapy subsequent to study tx. Patients were followed for a median of 6 months from ASCT (N=25, range 0.8-8.8) and 10 months from first dose (N=30, range 1.8-12.7). The estimated 9-month PFS rate in all-treated pts was 88%. This is comparable to all-treated pts in Parts 1 & 2, whose estimated 9 and 15 month PFS were 86% and 82%, respectively (Fig 2). Biomarker testing was performed on peripheral blood samples, included immunophenotyping, serum cytokine analysis, and TCRβ sequencing. Concurrent dosing of BV+ Nivo resulted in increased levels of both activated and dividing CD4+ and CD8+ T cells, as well as increased regulatory T-cells and circulating plasmablasts. Cytokines and chemokines associated with innate and adaptive immune activation, including Type I and Type II interferons, IL-18, and IP-10, were significantly upregulated following BV + Nivo, while TARC levels were significantly diminished following therapy. TCRβ sequencing revealed clonal expansion in the periphery following BV + Nivo. Conclusion A concurrent dosing schedule of BV + Nivo was well tolerated with a high CR rate of 80%. Biomarkers evaluated in Part 3 indicate immune activation in the periphery following BV + Nivo. Cumulatively, the results in Part 3, along with the durable remissions noted in Parts 1 & 2, support BV + Nivo combination as an encouraging first salvage therapy prior to ASCT in pts with R/R cHL. Disclosures Advani: Forty Seven: Research Funding; Infinity: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Merck: Research Funding; Agensys: Research Funding; Millenium: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding. Moskowitz:Bristol Myers-Squibb: Consultancy, Research Funding; Incyte: Research Funding; Takeda: Honoraria; Merck: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Bartlett:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vose:Celgene: Research Funding; Legend Pharmaceuticals: Honoraria; Bristol Myers Squibb: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Incyte Corp.: Research Funding; Roche: Honoraria; Novartis: Honoraria, Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta Pharma: Research Funding; Abbvie: Honoraria; Epizyme: Honoraria; Kite Pharma: Research Funding. Ramchandren:Merck: Research Funding; Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Feldman:Johnson and Johnson: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Portola: Research Funding; Janssen: Speakers Bureau; KITE: Speakers Bureau. LaCasce:Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria. Christian:Acerta: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:LAM Therapeutics: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Takeda: Research Funding. Moskowitz:Celgene: Consultancy; Merck & Co: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Ogden:Seattle Genetics, Inc: Employment, Equity Ownership. Taft:Seattle Genetics: Employment, Equity Ownership. Zak:Seattle Genetics: Employment, Equity Ownership. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Galderisi:Seattle Genetics: Employment, Equity Ownership. Herrera:Immune Design: Research Funding; Merck, Inc.: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences: Research Funding.

Introduction: Nivolumab (nivo), an immune checkpoint inhibitor targeting the programmed death-1 (PD-1) receptor, augments T-cell activation and restores antitumor T-cell function. In the phase 2 CheckMate 205 study (NCT02181738), nivo demonstrated frequent (65-73%) and durable objective responses across 3 cohorts of patients (pts) with relapsed/refractory (R/R) cHL after failure of autologous hematopoietic cell transplantation (Fanale M et al. ICML 2017 [oral 125]). While most pts with cHL are cured with first-line therapy, those with advanced-stage disease are more likely to relapse or progress. More aggressive regimens (eg, BEACOPPesc., Borchmann P et al. Lancet Oncol 2017) are associated with improved progression-free survival (PFS) but are hampered by excessive toxicities and have limited applicability in elderly pts.PD-1 ligand gene amplification has been linked to poorer outcomes in cHL pts treated with standard induction regimens (Roemer MG et al. J Clin Oncol 2016) but is associated with improved responses to nivo in R/R cHL (Younes A et al. Lancet Oncol 2016), suggesting that PD-1 blockade may benefit pts in the frontline setting. We therefore assessed the safety and efficacy of nivo as a single-agent lead-in treatment followed by nivo in combination with chemotherapy, excluding bleomycin due to potential overlapping pulmonary toxicity, for pts with previously untreated advanced-stage cHL. Methods: Cohort D of CheckMate 205 enrolled untreated pts (aged ≥18 y) with advanced-stage newly diagnosed cHL (stage III, IV, or II with B symptoms and extranodal or bulky disease) and ECOG score 0-1. Pts received 4 biweekly doses of nivo monotherapy (240 mg IV flat dose) followed by nivo plus chemotherapy (nivo 240 mg IV, doxorubicin, vinblastine, dacarbazine [N-AVD]) for 6 cycles (12 doses). The primary endpoint was safety and tolerability: proportion of pts with ≥1 grade (G) 3-5 treatment-related adverse event (TRAE) ≤30 d after last dose. Additional endpoints included rates of discontinuation and of independent radiologic review committee-assessed complete remission (CR). Results: At database lock (June 2017), 51 pts had been treated, with a median (range) follow-up of 8 (1-11) mo. Median (range) age was 37 (18-87) y; 29 (57%) pts had stage IV disease, and 41 (80%) had B symptoms. At baseline, 7 (14%) pts had bulky disease and 17 (33%) had extranodal involvement. International prognostic score was ≥3 in 25 (49%) pts. At analysis, 49 (96%) pts had completed nivo monotherapy treatment, receiving all 4 doses; 1 pt discontinued due to disease progression and 1 due to study drug toxicity (G1-2 hyperthyroidism), subsequently receiving AVD only. TRAEs for both treatment phases are shown in the Table. During nivo monotherapy, 2 pts had 1 dose delay each due to an AE; 2 (4%) pts had serious AEs (SAEs; 1 G1-2 hyperthyroidism; 1 G1-2 polyneuropathy); an immune-mediated AE (IMAE), G1-2 hyperthyroidism, was reported in 2 (4%) pts. Fifty pts started combination therapy; at database lock, 35 (70%) had completed therapy, with 34 (69%) receiving 12 N-AVD doses. With N-AVD, 10 (20%) pts had SAEs, 6 G3-4; the most common G3-4 SAE was febrile neutropenia in 2 (4%) pts; IMAEs occurring in >1 pt were hypothyroidism in 8 (16%) pts and increased ALT in 2 (4%). AEs leading to discontinuation of N-AVD occurred in 2 pts: G1-2 hepatic abnormality, and G3-4 febrile neutropenia (FN) and Klebsiella bacteremia. The pt who developed FN and Klebsiella bacteremia died 38 d after the first dose of his fifth cycle of N-AVD due to study drug toxicity of acute respiratory insufficiency. Important primary, secondary, and exploratory endpoints (including CR and objective response rates at end of monotherapy, after 2 combocycles and end of therapy, and PFS) will be presented at the meeting. Conclusions: Nivo monotherapy followed by N-AVD combination therapy was well-tolerated in pts with newly diagnosed, untreated, advanced-stage cHL. Nearly all pts completed nivo monotherapy treatment and started combination therapy with N-AVD. The safety profile was consistent with historical experience of nivo and AVD separately, with no new safety signals. Nivo followed by N-AVD may provide a tolerable alternative treatment option to standard-of-care multi-agent chemotherapy for pts with newly diagnosed advanced-stage cHL. Study support: BMS. Writing support: Matthew Thomas, PhD, Caudex, funded by BMS. Disclosures Ramchandren: Janssen: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy. Fanale: CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC THERAPEUTICS: Research Funding; GENENTECH: Research Funding; MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; MOLECULAR TEMPLATES: Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; ONYX: Research Funding. Rueda: Bristol-Myers Squibb: Consultancy. Armand: Roche: Research Funding; Genmab: Consultancy; Infinity: Consultancy; Sigma Tau: Research Funding; Tensha: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Otsuka: Research Funding; Pfizer: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Sequenta/Adaptive: Research Funding. Trněný: Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Feldman: Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Bristol-Myers Squibb: Consultancy; Kite Pharma: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Janssen: Speakers Bureau. Ansell: Merck: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Affimed: Research Funding. Jaeger: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Cohen: Bioinvent: Consultancy, Membership on an entity's Board of Directors or advisory committees; LAM Therapeutics, Inc: Research Funding; Abbvie: 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; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takada: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees. Savage: Bristol-Myers Squibb: Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche: Research Funding; Celgene: Consultancy; Merck: Honoraria. Willenbacher: Bristol-Myers Squibb: Consultancy, Honoraria. Sacchi: Bristol-Myers Squibb: Employment. Sumbul: Bristol-Myers Squibb: Employment.

10511 Background: Safe and effective treatment options for newly diagnosed (ND) or imatinib (IM) resistant/intolerant (R/I) pediatric CML pts are limited, and a large prospective study is needed. DAS has proven safety and efficacy in adults with ND or IM-R/I CML and is now being evaluated in a phase II trial of pediatric pts. Methods: CA180-226/NCT00777036 is an open-label nonrandomized prospective study of pts aged 2 QD, (2) IM-R/I CML-AP/BP or Ph+ ALL (enrollment closed early due to poor response), and (3) ND CML-CP treated with DAS tablets 60 mg/m2 or DAS 72 mg/m2powder for oral suspension (PFOS) QD. Primary objectives were major cytogenetic response (MCyR) for CML-CP R/I to IM and complete cytogenetic response (CCyR) for ND CML-CP (MCyR >30% and CCyR >55% considered of clinical interest). Results: 113 pediatric CML-CP pts were treated. Cumulative rate of MCyR >30% was reached as early as 3 mo (55%; [95% CI 36, 74]) for IM-R/I CML-CP. Cumulative rate of CCyR >55% was reached as early as 6 mo (64% [95% CI 53, 74] for ND CML-CP; 61% [95% CI 46, 74] for pts on tablets and 70% [95% CI 51, 84] for pts on PFOS). Estimated PFS by 48 mo was >75% for CML-CP R/I to IM and >90% for ND CML-CP. One CML-CP pt R/I to IM died 1 y after stopping DAS from gastrointestinal bleeding. AEs were consistent with those observed in adults, except no DAS-related pleural/pericardial effusion or pulmonary arterial hypertension (PAH) were reported here. Conclusions: In the largest prospective trial of pediatric pts with CML-CP, target responses were met early and increased over time with DAS treatment. The efficacy and safety of DAS were consistent with previous reports in adults, except no cases of pleural/pericardial effusion or PAH were observed. These results suggest DAS is safe and highly effective in the first- or second-line treatment of pediatric CML-CP. Clinical trial information: NCT00777036. [Table: see text]

Introduction: The phase 2 CheckMate 205 study (NCT02181738) of nivolumab (nivo) has demonstrated high objective response rates, durable efficacy, and acceptable safety profiles in patients (pts) with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after failure of autologous hematopoietic cell transplantation (auto-HCT) regardless of prior brentuximab vedotin (BV) treatment (Younes A et al. Lancet Oncol 2016; Fanale M et al. ICML 2017 [Oral 125]). Recently proposed new response criteria aim to account for atypical patterns of response with checkpoint inhibitors which may not be fully captured by conventional response criteria (Cheson BD et al. Blood 2016; Younes A et al, Ann Oncol 2017). Studies in solid tumors have shown that pts may continue to derive clinical benefits from nivo beyond disease progression as defined by conventional criteria (George S et al, JAMA Oncol 2016; Long GV et al, JAMA Oncol 2017). Here we report outcomes among pts with R/R cHL treated beyond progression (TBP) in CheckMate 205. Methods: This single-arm, multicenter study enrolled pts (age ≥18 y) with R/R cHL after failure of auto-HCT into 3 independent cohorts (A: BV naïve, B: BV after auto-HCT, C: BV before and/or after auto-HCT). Nivo 3 mg/kg IV every 2 wk was given until disease progression or unacceptable toxicity. Response was assessed by 2007 International Working Group criteria. Best overall response (BOR) was assessed per investigator. A protocol amendment in July 2014 allowed pts to be TBP (investigator-assessed) if they met prespecified criteria, including deriving clinical benefit, stable performance status, and non-rapid progression. Pts TBP were required to discontinue in the event of further progression (≥10% increase in tumor burden). Tumor burden after initial progression was assessed in a prespecified analysis. Exploratory analyses assessed overall survival (OS) and time to next therapy (TTNT) in pts TBP. Results: In total, 70/243 (29%) pts were TBP: 19 in Cohort A, 23 in B, and 28 in C. Demographics were similar to the overall study population: 57% had stage IV disease at study entry, median (range) age was 37 (18-72) y, and median number of prior therapies was 3 (2-5). BOR prior to progression was complete remission (CR) in 5 (7%) pts, partial remission (PR) in 31 (44%), stable disease (SD) in 20 (29%), and progressive disease in 13 (19%) (BOR was non-evaluable in 1 pt). Among pts TBP, the initial cause of progression was a ≥50% increase in total tumor burden in 13 (19%) pts, non-target lesion progression in 17 (24%), and new lesions in 47 (67%) (pts could have multiple findings as reasons for progression). The median time to initial progression in pts TBP was 6 mo; 11 mo in pts with initial BOR of CR and 7 mo in pts with initial PR or SD. At December 2016 database lock, median (range) doses of nivo beyond progression were 8 (1-43), and median duration of treatment beyond progression was 5 (0-19) mo. Overall, 21 (30%) pts TBP remained on treatment; the most common reason for discontinuation was further disease progression (80%). The majority of pts TBP demonstrated stable reductions in tumor burden with continued treatment. Median (95% CI) TTNT from first study dose of nivo was 17 (14, not estimable) mo (Figure). Median OS from date of initial progression was not reached in pts TBP and OS was 84% (95% CI 70, 92) at 1 y. Treatment-related adverse events (TRAEs) occurred in 46% of pts (13% grade [G] 3-4) after progression, vs 64% (9% G3-4) prior to progression. Serious TRAEs after progression were aspartate aminotransferase increase (n=1) and hypercalcemia (n=1), both G3-4. Ten deaths occurred in pts TBP; 7 were due to disease progression and none were considered related to study drug. Conclusions: In total, 29% of pts from CheckMate 205 Cohort A/B/C were TBP. New lesions were the most common reason for initial progression in pts TBP. Stable reductions in tumor burden were seen with continued treatment in pts TBP, and median TTNT and OS remained high. Proposed updates to response criteria may help to better assess the long-term efficacy of checkpoint inhibitors. These data suggest that pts considered to show stable performance status, non-rapid progression, and clinical benefits despite progression according to conventional response criteria may derive long-term benefits from continued nivo treatment. Study funding: BMS. Writing support: Simon Wigfield, Caudex, funded by BMS. Disclosures Cohen: Bioinvent: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takada: Research Funding; Bristol Myers Squibb: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: 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, Research Funding; LAM Therapeutics, Inc: Research Funding. Engert: Amgen: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Affimed: Consultancy, Honoraria, Research Funding. Ansell: Merck: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding. Younes: Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Bayer: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Research Funding; Janssen: Honoraria; Merck: Honoraria; Curis: Research Funding; Sanofi: Honoraria; Takeda Millenium: Honoraria; Johnson & Johnson: Research Funding; Seattle Genetics: Honoraria; Incyte: Honoraria; Celgene: Honoraria. Trneny: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Savage: Roche: Research Funding; Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Merck: Honoraria; Celgene: Consultancy. Ramchandren: Seattle Genetics: Consultancy; Janssen: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Collins: ADC Therapeutics: Research Funding; Roche: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Celgene: Research Funding; Celleron: Consultancy; MSD: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding. Fanale: AMGEN: Membership on an entity's Board of Directors or advisory committees; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; ONYX: Research Funding; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MOLECULAR TEMPLATES: Research Funding; MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GENENTECH: Research Funding; ADC THERAPEUTICS: Research Funding. Armand: Bristol-Myers Squibb: Consultancy, Other: research funding (institutional); Merck: Consultancy, Other: research funding (institutional); Infinity: Consultancy; Pfizer: Consultancy, Other: research funding (institutional); Affimed: Other: research funding (institutional); Otsuka: Other: research funding (institutional); Sequenta: Other: research funding (institutional); Sigma Tau: Other: research funding (institutional); Roche: Other: research funding (institutional); Tensha: Other: research funding (institutional). Zinzani: Bayer: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. De Boer: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Other: Non-restricted grant for research in head and neck cancer; Eisai: Membership on an entity's Board of Directors or advisory committees; Astellas: Other: member of Independent Data Monitoring Committee. Shipp: Cell Signaling: Honoraria; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Other: Scientific Advisory Board; Merck: Other: Scientific Advisory Board; Gilead: Other: Scientific Advisory Board; AstraZeneca: Honoraria. Santoro: Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Timmerman: Seattle Genetics: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genmab: Consultancy, Equity Ownership; Kite Pharma: Research Funding; ImmuneGene: Research Funding. Sacchi: Bristol-Myers Squibb: Employment. Sy: Bristol-Myers Squibb: Employment. Kuruvilla: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy; Hoffman LaRoche: Consultancy; Seattle Genetics: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen: Honoraria; Lundbeck: Honoraria; Merck: Honoraria; Karyopharm: Research Funding; Roche: Research Funding; Celgene: Honoraria, Research Funding.