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Fludarabine, cyclophosphamide, and rituximab (FCR) is highly effective initial therapy for younger patients with chronic lymphocytic leukemia (CLL); however, most eventually relapse. Duvelisib is a delta/gamma PI3K inhibitor approved for relapsed/refractory CLL. We conducted an investigator-initiated, phase 1b/2 study of duvelisib + FCR (DFCR) as initial treatment for CLL patients aged ≤65. A standard 3 + 3 design included two dose levels of duvelisib (25 mg qd and 25 mg bid). Duvelisib was given for 1 week, then with standard FCR added for up to six 28-day cycles, then up to 2 years of duvelisib maintenance. Thirty-two patients were enrolled. The phase 2 dose of duvelisib was identified as 25 mg bid. Hematologic toxicity was common, and all-grade non-hematologic toxicities included transaminitis (28%), febrile neutropenia (22%), pneumonia (19%), and colitis (6%). The best overall response rate by ITT was 88% (56% CR/CRi and 32% PR). The best rate of bone marrow undetectable minimal residual disease (BM-uMRD) by ITT was 66%. The rate of CR with BM-uMRD at end of combination treatment (primary endpoint) was 25%. Three-year PFS and OS are 73 and 93%, respectively. DFCR is active as initial therapy of younger CLL patients. Immune-mediated and infectious toxicities occurred and required active management.

Allogeneic hematopoietic cell transplantation (alloHCT) can cure previously treated high-risk chronic lymphocytic leukemia (CLL) patients if they are suitable for transplant through the graft-versus-leukemia effect. However, since the emergence of targeted therapies, the role of alloHCT for high-risk CLL is less clear. To address this question, we evaluated 108 high-risk CLL patients who underwent alloHCT from 2010 to 2018. Thirty patients from the period of 2013 to 2018 received targeted therapy prior to alloHCT. The median age for the targeted therapy cohort was 60 years (range, 30-71 years), and 20% and 73% had complete and partial remission, respectively: 76% had del(17p), 46.2% had 5 or more cytogenetic abnormalities, and 78.9% were IGHV unmutated. The median number of prior therapies was 4 (range, 1-9). With a median follow-up time of 36 months (range, 10-72 months), the 3-year overall (OS) and progression-free survival (PFS) were 87% and 69%, respectively. The 3-year cumulative incidence of nonrelapse mortality and relapse was 7% and 24%, respectively. For the control cohort of 78 patients who underwent alloHCT from 2010 to 2014 and received only chemoimmunotherapy prior to transplant, the 3-year OS and PFS were 69% and 58%, respectively. Patients treated with targeted therapy prior to alloHCT had a significantly higher number of circulating T and B cells and a lower ratio of CD4 regulatory T cells to CD4 conventional T cells early after transplant. In summary, despite multiple high-risk features, the clinical outcome of CLL patients who receive targeted therapy prior to transplant is excellent and alloHCT should be offered while the disease is under control.

Patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) have limited options for salvage, and checkpoint blockade therapy (CBT) has little efficacy. Usage in solid malignancies suggests that CBT sensitises tumours to subsequent chemotherapy. We performed the first analysis of CBT on subsequent NHL treatment. Seventeen North American centres retrospectively queried records. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment. Secondary aims included progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Fifty-nine patients (68% aggressive NHL, 69% advanced disease) were included. Patients received a median of three therapies before CBT. Fifty-three (90%) discontinued CBT due to progression. Post-CBT regimens included chemotherapy (49%), targeted therapy (30%), clinical trial (17%), transplant conditioning (2%) and chimeric antigen receptor T cell (CAR-T) therapy (2%). The ORR to post-CBT treatment was 51%, with median PFS of 6·1 months. In patients with at least stable disease (SD) to post-CBT, the median DOR was significantly longer than to pre-CBT (310 vs. 79 days, P = 0·005) suggesting sensitisation. Nineteen patients were transplanted after post-CBT therapy. Median overall survival was not reached, nor affected by regimen. Prospective trials are warranted, as this may offer R/R NHL patients a novel therapeutic approach.

Classical Hodgkin lymphoma (cHL) is characterized by nearly universal genetic alterations at 9p24.1, resulting in increased expression of PD-1 ligands and immune evasion. Disruption of the PD-1 pathway with anti-PD-1 monoclonal antibodies (mAbs) can restore an antitumor immune response in many patients. Based on high overall response rates in cHL patients with relapsed or refractory (R/R) disease, two PD-1 mAbs, nivolumab and pembrolizumab, received accelerated approval in North America and Europe. Currently, numerous ongoing trials are combining PD-1 mAbs with rationally selected agents in the R/R setting and testing PD-1 blockade earlier in the treatment paradigm with potentially curative therapies. These trials and a rapidly improving understanding of mechanisms of immune resistance to PD-1 blockade have the potential to further improve outcomes for patients with cHL.

The KEYNOTE-013 study was conducted to evaluate pembrolizumab monotherapy in hematologic malignancies; classical Hodgkin lymphoma (cHL) was an independent expansion cohort. We present long-term results based on >4 years of median follow-up for the cHL cohort. The trial enrolled cHL patients who experienced relapse after, were ineligible for, or declined autologous stem cell transplantation and experienced progression with or did not respond to brentuximab vedotin. Patients received IV pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points were safety and complete response (CR) rate by central review. Enrolled patients (N = 31) had received a median of 5 therapies (range, 2 to 15). After a median follow-up of 52.8 months (range, 7.0 to 57.6 months), CR rate was 19%, and median duration of response (DOR) was not reached; 24-month and 36-month DOR rates were both 50% by the Kaplan-Meier method. Median overall survival was not reached; 36-month overall survival was 81%. Six patients (19%) experienced grade 3 treatment-related adverse events (AEs); there were no grade 4 or 5 treatment-related AEs. With long-term follow-up among a heavily pretreated cohort, pembrolizumab had a favorable safety profile; some patients maintained long-term response with pembrolizumab years after end of treatment. This trial was registered at www.clinicaltrials.gov as #NCT01953692.

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The idea that the immune system could be co-opted to treat cancer is not new; it has existed for centuries. However, what is new is the advancement of our understanding of how the immune system is regulated and how a tumor evolves to evade an immune response. This knowledge, combined with modern technologies to manipulate the immune system, both pharmacologically and genetically, has led to the realization of immuno-oncology as a new frontier in cancer therapeutics. This review will focus on pharmacologic immunotherapies in aggressive B cell lymphomas: checkpoint inhibition and bispecific antibodies. The success of checkpoint inhibitors in this heterogenous collection of diseases has largely been limited to those that genetic aberrations involving genes for checkpoint ligands, whereas bispecific antibodies appear to be more broadly efficacious but responses are short-lived. Investigation into the tumor microenvironment for each of the aggressive B cell lymphoma histologies, and interrogation of mechanisms of resistance as well as predictors of response to these immunotherapy approaches, will undoubtedly identify rational combinations as well as new therapeutic targets such that outcomes can be improved across these diseases.

Nivolumab, an anti–programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to further evaluate its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least 2 prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4 of 92 patients). Median progression-free survival (PFS) was 2.2 months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946. Key Points: • Nivolumab monotherapy was associated with very limited activity in patients with R/R FL. • Understanding the tumor microenvironment may be necessary to develop effective checkpoint-based strategies in FL.

Dose-adjusted rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) has produced good outcomes in primary mediastinal B-cell lymphoma (PMBCL), but predictors of resistance to this treatment are unclear. We investigated whether [18F]fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) findings could identify patients with PMBCL who would not respond completely to DA-R-EPOCH. We performed a retrospective analysis of 65 patients with newly diagnosed stage I to IV PMBCL treated at 2 tertiary cancer centers who had PET-CT scans available before and after frontline therapy with DA-R-EPOCH. Pretreatment variables assessed included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Optimal cutoff points for progression-free survival (PFS) were determined by a machine learning approach. Univariate and multivariable models were constructed to assess associations between radiographic variables and PFS. At a median follow-up of 36.6 months (95% confidence interval, 28.1-45.1), 2-year PFS and overall survival rates for the 65 patients were 81.4% and 98.4%, respectively. Machine learning-derived thresholds for baseline MTV and TLG were associated with inferior PFS (elevated MTV: hazard ratio [HR], 11.5; P = .019; elevated TLG: HR, 8.99; P = .005); other pretreatment clinical factors, including International Prognostic Index and bulky (>10 cm) disease, were not. On multivariable analysis, only TLG retained statistical significance (P = .049). Univariate analysis of posttreatment variables revealed that residual CT tumor volume, maximum standardized uptake value, and Deauville score were associated with PFS; a Deauville score of 5 remained significant on multivariable analysis (P = .006). A model combining baseline TLG and end-of-therapy Deauville score identified patients at increased risk of progression.

Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are associated with resistance to frontline and salvage immunochemotherapy, as well as autologous stem cell transplantation (SCT). We hypothesized that allogeneic SCT (alloSCT) could overcome the chemoresistance associated with DEL/DHL. We retrospectively studied the impact of DEL/DHL status in a multicenter cohort of patients who underwent alloSCT for relapsed/refractory (rel/ref) aggressive B cell non-Hodgkin lymphoma (B-NHL). Seventy-eight patients transplanted at 3 centers in whom tumor tissue was available for immunohistochemistry and fluorescence in situ hybridization were enrolled; 47% had DEL and 13% had DHL. There were no significant differences in 4-year progression-free (PFS) or overall survival (OS) between patients with DEL compared with patients without DEL (PFS 30% versus 39%, P = .24; OS 31% versus 49%, P = .17) or between patients with DHL compared with patients without DHL (PFS 40% versus 34%, P = .62; OS 50% versus 38%, P = .46). The lack of association between DEL or DHL and outcome was confirmed in multivariable models, although inadequate sample size may have limited our ability to detect significant differences. In our cohort alloSCT produced durable remissions in patients with rel/ref aggressive B-NHL irrespective of DEL and DHL status, justifying its consideration in the treatment of patients with rel/ref DEL/DHL.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.

Large, multicenter studies comparing commonly used reduced-intensity conditioning (RIC) approaches in follicular lymphoma (FL) have not been performed. Using the Center for International Blood and Marrow Transplant Research database, we report the outcomes of the 2 most commonly used RIC approaches, fludarabine and busulfan (Flu/Bu) versus fludarabine, cyclophosphamide, and rituximab (FCR) in FL patients. We evaluated 200 FL patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who received RIC with either Flu/Bu (n = 98) or FCR (n = 102) during 2008 to 2014. All patients received peripheral blood grafts, and graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor–based approaches. Median follow-up of survivors in the Flu/Bu and FCR groups was 48 months and 46 months, respectively. On univariate analysis in the Flu/Bu and FCR groups, the 3-year rates of nonrelapse mortality (11% versus 11%, P = .94), relapse/progression (18% versus 15%, P = .54), progression-free survival (PFS) (71% versus 74%, P = .65), and overall survival (OS) (73% versus 81%, P = .18) were not significantly different. On multivariate analysis no difference was seen between the FCR and Flu/Bu cohorts in terms of grades II to IV (relative risk [RR], 1.06; 95% confidence interval [CI], .59 to 1.93; P = .84) or grades III to IV (RR, 1.18; 95% CI, .47 to 2.99; P = .72) acute GVHD, nonrelapse mortality (RR, .83; 95% CI, .38 to 1.82; P = .64), relapse/progression (RR, .99; 95% CI, .49 to 1.98; P = .97), PFS (RR, .92; 95% CI, .55 to 1.54; P = .76), or OS (RR, .70; 95% CI, .40 to 1.23; P = .21) risk. However, RIC with FCR was associated with a significantly reduced chronic GVHD risk (RR, .52; 95% CI, .36 to .77; P = .001). RIC with either Flu/Bu or FCR in patients with FL undergoing allo-HCT provides excellent 3-year OS, with acceptable rates of nonrelapse mortality. FCR-based conditioning was associated with a lower risk of chronic GVHD.

Standard methods for disease response assessment in patients with lymphoma, including positron emission tomography and computed tomography scans, are imperfect. In other hematologic malignancies, particularly leukemias, the ability to detect minimal residual disease (MRD) is increasingly influencing treatment paradigms. However, in many subtypes of lymphoma, the application of MRD assessment techniques, like flow cytometry or polymerase chain reaction–based methods, has been challenging because of the absence of readily detected circulating disease or canonic chromosomal translocations. Newer MRD detection methods that use next-generation sequencing have yielded promising results in a number of lymphoma subtypes, fueling the hope that MRD detection may soon be applicable in clinical practice for most patients with lymphoma. MRD assessment can provide real-time information about tumor burden and response to therapy, noninvasive genomic profiling, and monitoring of clonal dynamics, allowing for many possible applications that could significantly affect the care of patients with lymphoma. Further validation of MRD assessment methods, including the incorporation of MRD assessment into clinical trials in patients with lymphoma, will be critical to determine how best to deploy MRD testing in routine practice and whether MRD assessment can ultimately bring us closer to the goal of personalized lymphoma care. In this review article, we describe the methods available for detecting MRD in patients with lymphoma and their relative advantages and disadvantages. We discuss preliminary results supporting the potential applications for MRD testing in the care of patients with lymphoma and strategies for including MRD assessment in lymphoma clinical trials.

Introduction CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has been transformative in B-cell lymphoid malignancies. CD30 is a validated target for classical Hodgkin Lymphoma (cHL), as demonstrated by the activity of the anti-CD30 antibody drug conjugate, brentuximab vedotin (BV), making it an attractive target for CAR-T therapy in this disease. In two Phase 1/2 clinical studies, autologous CD30-directed CAR-T-cell (CD30.CAR-T) therapy was well tolerated, with significant clinical activity (72% overall response rate [ORR] and 59% complete response [CR] rate) in relapsed or refractory (R/R) cHL patients after fludarabine-based lymphodepleting (LD) chemotherapy (Ramos et al., 2020). We report here the results of the Pilot segment of a Phase 2 Pivotal trial of autologous CD30.CAR-T in patients with R/R cHL (NCT#04268706). Methods This is a Phase 2 single arm, multi-center, multi-national study (U.S. and Europe), enrolling patients (12-75 years) with cHL who have progressed after at least 3 lines of therapy, including chemotherapy, BV, and anti-programmed cell death (PD)-1 antibodies. Previous autologous and/or allogeneic hematopoietic stem cell transplantation (HSCT) is allowed. The study is divided into two parts: a Pilot segment including at minimum 12 patients (for which accrual is complete) and a Pivotal segment planned to enroll approximately 82 patients to obtain at least 67 CD30.CAR-T-treated patients. Eligible patients undergo leukapheresis for manufacture of CD30.CAR-T cells, followed by LD chemotherapy using bendamustine and fludarabine, prior to infusion of CD30.CAR-T with an allowable dose range of 2.0 to 2.7 × 10 8 CD30.CAR-T cells per m 2. Bridging therapy was allowed. Safety is the primary endpoint in the Pilot portion, while ORR as assessed by an Independent Radiology Review Committee per the Lugano criteria (Cheson et al., 2014) is the primary endpoint in the Pivotal segment. Results As of 15 July 2021, 17 patients were screened and 15 patients enrolled in the Pilot segment (median age: 35 years [21-57], 66.7% male). The median number of prior therapies was 6, with a range of 4 to 19. Bridging therapy was given in 33.3% of patients. CD30.CAR-T product was successfully manufactured for all patients with a median manufacturing time of 6.3 weeks (5.9-8.0). Of 15 patients enrolled, 14 patients were eligible for treatment with CD30.CAR-T. To date, 12 patients have been treated, with CD30.CAR-T doses ranging from 2.2 to 2.7 × 10 8 cells/m 2. CD30.CAR-T treatment was well tolerated with the most common toxicities reported being hematologic adverse events (AEs)-related to LD chemotherapy. Majority of the AEs were Grade 1-2 anemia, neutropenia and thrombocytopenia. 12.5% of patients had Grade 3 anemia, neutropenia or thrombocytopenia. Other LD-related toxicities include Grade 1-2 nausea, anemia, fatigue, anorexia, gastrointestinal disorder and headache. CD30.CAR-T-related toxicities include Grade 1 cytokine release syndrome and maculopapular rash (reported in the same patient), and Grade 2 ventricular tachycardia in 1 patient. The ORR at Day 42 after CD30.CAR-T infusion, as assessed by investigators, was 100% (5/5). CR and partial response (PR) rates were observed in 4 (80%) and 1 (20%) patients, respectively. Pharmacokinetic analyses of CD30.CAR-T are ongoing. Conclusion Preliminary data from the Pilot segment of this study confirms favorable safety profile and excellent anti-tumor responses of CD30.CAR-T in heavily-treated R/R cHL patients. The efficacy and safety of CD30.CAR-T will be further evaluated in the Pivotal segment of this Phase 2 study. Figure 1 Figure 1. Disclosures Ahmed: Xencor: Research Funding; Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding. Flinn: Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Mei: Epizyme: Research Funding; TG Therapeutics: Research Funding; BMS: Research Funding; GlaxoSmithKline: Honoraria; Morphosys: Honoraria; EUSA: Honoraria; Janssen: Honoraria. Riedell: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calibr: Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Research Funding; Tessa Therapeutics: Research Funding; MorphoSys: Research Funding. Armand: Infinity: Consultancy; Pfizer: Consultancy; Kite: Research Funding; Tensha: Research Funding; IGM: Research Funding; Genentech: Consultancy, Research Funding; Roche: Research Funding; Epizyme: Consultancy; AstraZeneca: Consultancy; Regeneron: Consultancy; Enterome: Consultancy; C4: Consultancy; GenMab: Consultancy; Miltenyi: Consultancy; Tessa Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; Otsuka: Research Funding; Sigma Tau: Research Funding; ADC Therapeutics: Consultancy; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Grover: Novartis: Consultancy; ADC: Other: Advisory Board; Genentech: Research Funding; Kite: Other: Advisory Board; Tessa: Consultancy. Engert: Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Tessa Therapeutics: Consultancy; Hexal: Honoraria; ADC Therapeutics: Consultancy; Amgen: Honoraria; MSD: Honoraria. Lapteva: Tessa Therapeutics: Consultancy. Nadler: Tessa Therapeutics: Consultancy; Symphogen: Consultancy; Iksuda: Consultancy; Karyopharm: Consultancy. Myo: Tessa Therapeutics: Current Employment. Heslop: Novartis: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kuur Therapeutics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Current equity holder in publicly-traded company; Allovir: Current equity holder in publicly-traded company; Gilead: Membership on an entity's Board of Directors or advisory committees; Fresh Wind Biotherapies: Membership on an entity's Board of Directors or advisory committees.

Background: Autologous stem cell transplantation (ASCT) can be curative for a subset of patients (pts) with relapsed/refractory classical Hodgkin lymphoma (cHL). Post-ASCT maintenance therapy with brentuximab vedotin (BV) improves progression-free survival (PFS) among pts with high-risk clinical features, and PD-1 blockade is also being investigated in this setting. Ideally, novel biomarkers could be used to guide pt selection for these post-ASCT therapies. We hypothesized that the presence of minimal residual disease (MRD), quantified using immunoglobulin-based next generation sequencing (IgNGS), could predict post-ASCT relapse. As a preliminary test of this hypothesis, we analyzed a cohort of cHL pts who had serial peripheral blood mononuclear cell (PBMC) and plasma samples collected before or after ASCT. Methods: Samples from 2 cohorts (n=36) were analyzed. 28 pts were prospectively enrolled on a biobanking protocol and underwent ASCT at Dana-Farber Cancer Institute between 2014-2016 (biobank cohort). In addition, 8 pts underwent ASCT between 2015 and 2016 and subsequently participated in a multicenter phase II trial of post-ASCT pembrolizumab maintenance (PM) (trial cohort) (Armand, Blood 2020). Tumor tissue and serial post-ASCT plasma and PBMC samples were collected for all pts, and some pts also had pre-ASCT PB samples available for analysis. NGS of Ig receptor sequences (IgNGS) (clonoSEQ Ò, Adaptive Biotechnologies) was used to identify and track tumor clonotypes, as previously described (Ching, BMC Cancer 2020). MRD testing was not used for clinical decision making. Results: The 36 enrolled pts received a median of 2 lines of therapy, and 30 pts (83%) achieved a complete response (CR) on pre-ASCT positron emission tomography (PET). In total, 19 pts received post-ASCT treatment - PM (n=8, all on trial), radiation therapy (n=5), BV maintenance (n=4), and allogeneic stem cell transplantation as part of a planned tandem transplant (n=2). Among 36 enrolled pts, 12 (33%) had an identifiable clonotype (11/28 biobank and 1/8 trial). Higher rates of clonotype detection were seen in pts aged The 12 clonotyped pts had a median of 4 (range 1-13) post-ASCT plasma and 3 (range 1-17) post-ASCT PBMC samples. Among the 4 pts who relapsed, 3 had MRD detected within plasma samples with lead times of 0, 11, and 909 days (Figure 1). The pembrolizumab trial pt had detectable MRD early after ASCT which cleared within 9 weeks of starting pembrolizumab therapy, remained undetectable for the duration of pembrolizumab treatment, and became detectable again 5 months after completing PM in conjunction with clinical relapse. All pts with detectable MRD in a post-ASCT plasma sample subsequently relapsed (100% specificity). One pt relapsed without detectable MRD, but had a long interval (312 days) from last plasma sample to relapse. IgNGS testing from PBMC samples did not correlate with clinical outcomes; only two PBMC samples had detectable MRD and both were from a pt who did not relapse. 3 pts had pre-ASCT plasma samples collected concurrently with post-salvage PET scans. One pt achieved a partial response (PR) after 2 cycles of bendamustine and BV (Benda-BV), progressive disease after 4 cycles of Benda-BV, and a CR after pembrolizumab. MRD was detected after two cycles of Benda-BV (6.52 counts per million), was rising after 4 cycles of benda-BV (8.99 counts per million) and was undetectable after pembrolizumab. The pt remains in remission after a tandem transplant. Pre-ASCT samples were MRD negative in two other pts (1 CR, 1 PR) following salvage chemotherapy, both of whom remain in remission after ASCT. Conclusions: The clonotype detection rate among pts with cHL was considerably lower than has been reported for other B-cell lymphomas, likely due to the scarcity of Reed Sternberg cells within cHL tumor samples. Novel MRD techniques for cHL should be investigated. In this pilot study, among pts with a detectable clonotype, MRD was a dynamic marker of response to different therapies and was a specific indicator of impending relapse, suggesting that additional studies of MRD in cHL are warranted. Figure 1 Figure 1. Disclosures Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy. Crombie: Roche: Research Funding; Incyte: Consultancy; Karyopharm: Consultancy; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding. Davids: TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Takeda: Consultancy; Surface Oncology: Research Funding; AbbVie: Consultancy; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy. Jacobsen: Takeda: Consultancy; Syros: Consultancy; Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding. Jacobson: Lonza: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau; Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Humanigen: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support. LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Dahi: Kite / Gilead: Membership on an entity's Board of Directors or advisory committees. Chen: Gamida: Consultancy; Incyte: Consultancy. Herrera: ADC Therapeutics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Tubulis: Consultancy; Kite, a Gilead Company: Research Funding; Seagen: Consultancy, Research Funding; Takeda: Consultancy; Gilead Sciences: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Armand: IGM: Research Funding; Tensha: Research Funding; Roche: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; Enterome: Consultancy; Daiichi Sankyo: Consultancy; Miltenyi: Consultancy; Tessa Therapeutics: Consultancy; GenMab: Consultancy; C4: Consultancy; Kite: Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Otsuka: Research Funding; Sigma Tau: Research Funding; Morphosys: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding.

Introduction FCR remains the only therapy other than allo transplant proven to provide a significant chance of functional cure with very long term follow-up for young, fit patients with mutated IGHV CLL. Given the excellent efficacy and tolerability of ibrutinib in a broad population of young, fit CLL patients, we designed the frontline iFCR study to investigate whether time-limited novel agent plus chemoimmunotherapy could provide durable remission for CLL patients irrespective of IGHV status. We previously reported that with a median follow-up of 16.5 months, the rate of CR with bone marrow undetectable minimal residual disease (BM-uMRD) 2 months post-FCR (primary endpoint) was 33%, and that 84% of patients achieved BM-uMRD as best response (Davids et al., Lancet Haem, 2019). Here, we report updated data with longer follow-up, with all patients having had the opportunity to complete 2 years of ibrutinib maintenance following iFCR. Methods This is a multicenter, single arm, phase 2 investigator sponsored trial (NCT02251548) which enrolled CLL patients age ≤65 years without restriction by IGHV mutation status, all of whom met iwCLL treatment criteria. Ibrutinib 420 mg daily was given for 7 days, then combination ibrutinib with FCR for up to 6 cycles. Responders continued on ibrutinib maintenance, and patients with BM-uMRD after 2 years of maintenance discontinued therapy. Response was assessed by 2008 iwCLL criteria, and toxicity by CTCAE v4.03 and iwCLL criteria. The primary objective was to determine the rate of CR/CRi with BM-uMRD 2 months after iFCR combination. Secondary objectives were to assess response rates, PFS/OS, rates of BM-uMRD after 2 years of ibrutinib maintenance, and safety/tolerability. Results Between October, 2014, and April, 2018, 85 patients were enrolled at 9 US sites.As previously reported, the median age was 55 years (range 38-65). IGHV was unmutated in 46/79 patients (58.2%). Deletion of 17p and TP53 mutation were present in 4/83 (4.8%) and 3/81 (3.7%) patients, respectively; 2 of these patients had both. The median number of FCR cycles completed was 6 (range 1-6). Median follow-up is now 40.3 months (range 3.1-76). Median number of ibrutinib maintenance cycles is 24 (range 0-81). By ITT analysis, the rate of CR with BM-uMRD at any point on study is now 55% (47/85 patients), and best rate of BM-uMRD remained 84% (71/85). After 2 years of ibrutinib maintenance, the rates of CR/CRi, BM-uMRD, and PB-uMRD in patients with available data were 77% (44/57), 81% (50/62), and 81% (55/68), respectively, with no differences based on IGHV status. At the median follow-up time of 40 months, PFS and OS for all patients were 97% and 99%, respectively (see Figure, below). Thirteen of 61 patients (21.3%) who completed iFCR and started ibrutinib maintenance in a BM-uMRD state have had recurrent BM-MRD, with median time to MRD recurrence not yet reached. Seven patients underwent retreatment with ibrutinib monotherapy (5 due to clinical progression and 2 due to recurrent BM-MRD without clinical progression), and all 7 achieved PR with re-treatment. Median time on re-treatment is 12.8 months (range 4.2-26.2), and none of these 7 patients have progressed on re-treatment. One patient died 17 months into ibrutinib maintenance due to presumed sudden cardiac death. In the updated safety analysis, the most common treatment-emergent Gr 3/4 adverse events were hematologic, including neutropenia 40% (up from 35%), thrombocytopenia 32% (unchanged), and anemia 11% (unchanged). Ten patients (12%, up from 9%) experienced Gr ≥3 febrile neutropenia, and 20 patients (24%, up from 11%) had Gr ≥3 infection. Any Gr atrial fibrillation was observed in 8%, and ventricular arrhythmia in 1 patient. No major bleeding events occurred. Two patients developed MDS, and both are now in CR for CLL and MDS after undergoing allo transplant. No patients developed Richter's syndrome. Conclusions With longer term follow-up (median of 40.3 months), most patients treated with iFCR have continued to maintain deep responses, including patients with unmutated IGHV. The safety profile remains consistent with the individual toxicities of ibrutinib and FCR. Among the few patients with recurrence after this time-limited therapy, all have responded to re-treatment with ibrutinib monotherapy. iFCR is worthy of exploring in comparative studies in younger, fit CLL patients who desire the possibility of functional cure with time-limited therapy. Figure 1 Figure 1. Disclosures Davids: Ascentage Pharma: Consultancy, Research Funding; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; BeiGene: Consultancy; Adaptive Biotechnologies: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy. Brander: NCCN: Other: panel member; Verastem: Consultancy; MEI Pharma: Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; ArQule: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; DTRM: Research Funding; ArQule/Merck: Consultancy; LOXO: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Genentech: Consultancy, Research Funding; Ascentage: Research Funding; BeiGene: Research Funding. Montegaard: AbbVie: Consultancy; AstraZeneca*-: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy. Alencar: Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Epizyme: Consultancy; Celgene: Consultancy; BeiGene: Consultancy; Amgen: Consultancy. Jacobson: Humanigen: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Axis: Speakers Bureau; Lonza: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria. Armand: Infinity: Consultancy; Pfizer: Consultancy; Kite: Research Funding; Tensha: Research Funding; IGM: Research Funding; Roche: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Epizyme: Consultancy; Enterome: Consultancy; Regeneron: Consultancy; C4: Consultancy; GenMab: Consultancy; Tessa Therapeutics: Consultancy; Miltenyi: Consultancy; Morphosys: Consultancy; Daiichi Sankyo: Consultancy; Otsuka: Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy; ADC Therapeutics: Consultancy; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Crombie: Roche: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding; Karyopharm: Consultancy; Incyte: Consultancy. LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Arnason: Juno/BMS: Honoraria. Hochberg: Trapelo Health: Consultancy; Leuko: Consultancy. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; Kite Pharma: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; C4 Therapeutics: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy. OffLabel Disclosure: Ibrutinib being used to enhance the efficacy of FCR

Introduction: Prognosis remains poor for patients (pts) with R/R cHL who relapse after or are ineligible for autologous stem cell transplant (ASCT). Programmed death 1 (PD-1) inhibitors are an effective therapeutic option for such pts. Previous analyses from the phase 2 KEYNOTE-087 (NCT02453594) trial demonstrated that monotherapy with the PD-1 inhibitor pembrolizumab (pembro) had effective antitumor activity and acceptable safety in pts with R/R cHL, leading to FDA approval for adult and pediatric pts with R/R cHL who relapsed after ≥3 prior lines of therapy. However, durability of response after pembro, its relationship with response depth, and safety of treatment discontinuation for pts achieving complete response (CR) remain salient clinical questions. We present efficacy and safety from KEYNOTE-087 after ~5 y of follow-up. Methods: Pts with R/R cHL that progressed after ASCT and subsequent brentuximab vedotin (BV, cohort 1), progressive disease (PD) after salvage chemotherapy and BV therapy without ASCT (cohort 2), or PD after ASCT without subsequent BV therapy (cohort 3) received pembro 200 mg every 3 wks for up to 2 y. Pts who discontinued treatment after initial CR and relapsed were eligible to receive up to 17 additional cycles (~1 y) of pembro (2nd course). Primary end points: ORR per blinded independent central review (BICR), and safety. Additional end points: ORR per Lugano classification, DOR, and PFS by BICR; OS and 2nd-course ORR per investigator. DOR, PFS, and OS were estimated by Kaplan-Meier (K/M) method. Data cutoff was March 15, 2021. Results: At data cutoff, median time from first dose to date of death or data cutoff was 62.9 mo (range, 1.0-68.7). In the total population (N=210), 46 pts completed 2 y of treatment and 164 pts discontinued (primarily due to progressive disease [n=86]). ORR was 71.0% (95% CI, 64.8-77.4; CR, 27.6%; partial response [PR, 43.8%]); results were similar per Lugano classification (ORR, 73.3% [95% CI, 66.8-79.2]; CR, 32.9%; PR, 40.5%). ORR was 84.1% (CR, 36.2%; PR, 47.8%) in cohort 1 (n=69), 67.9% (CR, 28.4%; PR, 39.5%) in cohort 2 (n=81), and 68.3% (CR, 35.0%; PR, 33.3%) in cohort 3 (n=60). In the total population, median DOR was 16.6 mo (95% CI, 11.8-27.1). Four pts (24.8% per K/M method; cohort 1, n=1; cohort 2, n=0; cohort 3, n=3) had response ≥60 mo. In the total population, median PFS was 13.7 mo (95% CI, 11.1-19.4) and the 5-y PFS rate was 14.2%: 16.4 mo (95% CI, 11.3-27.6) in cohort 1, 11.1 mo (95% CI, 7.5-13.7) in cohort 2, and 19.7 mo (95% CI, 10.8-27.3) in cohort 3. In the total population, median OS was not reached (NR) and the 5-y OS rate was 70.7%: 71.3% in cohort 1, 69.2% in cohort 2, and 71.5% in cohort 3. Of 58 pts in the total population who achieved CR (Table), median DOR was NR (95% CI, 16.1-NR) and 4 pts (51.6% per K/M method; cohort 1, n=1; cohort 2, n=0; cohort 3, n=3) had a response ≥60 mo. Median PFS was 56.5 mo (95% CI, 21.7-NR) and 5-y PFS rate was 44.3%; median OS was NR and 5-y OS rate was 82.8%. Ten pts with CR received allogeneic stem cell transplant (allo-SCT) and 48 pts with CR did not undergo allo-SCT. Of 20 pts who received 2nd-course treatment (cohort 1, n=10; cohort 2, n=7; cohort 3, n=3), 10 pts (cohort 1, n=2; cohort 2, n=6; cohort 3, n=2) completed 17 additional cycles of treatment; 1 pt each from cohort 1 and cohort 3 were mid-treatment. ORR based on 19 evaluable pts from cohorts 1-3 was 73.7% (95% CI, 48.8-90.9). Median DOR for 2nd course was 15.2 mo (95% CI, 3.9-32.9), and 1 pt (13.7%) had a second response ≥36 mo. Treatment-related adverse events (AEs) of any grade occurred in 72.9% of pts; most common (>10%) were hypothyroidism (14.3%), pyrexia (11.4%), and fatigue (11.0%). Grade 3-4 treatment-related AEs occurred in 12.9% of pts; neutropenia (n=5), diarrhea and pericarditis (n=2, each) occurred in ≥2 pts. All-cause grade 5 AEs (n=3) were due to acute graft-versus-host disease, infection, and septic shock; these AEs were not considered treatment related. Conclusions: With median of follow-up >5 y, pembro monotherapy demonstrated sustained antitumor activity in pts with R/R cHL. ORRs were high and responses durable in the overall population and in those with varied treatment histories. Pts with CR had especially durable responses, and in those relapsing from CR, 2nd-course pembro frequently re-induced sustained response. Safety was manageable with no new signals. Figure 1 Figure 1. Disclosures Armand: Merck & Co., Inc.: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Affimed: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Infinity: Consultancy; ADC Therapeutics: Consultancy; Celgene: Consultancy; Morphosys: Consultancy; Daiichi Sankyo: Consultancy; Miltenyi: Consultancy; Tessa: Consultancy; GenMab: Consultancy; C4: Consultancy; Enterome: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; IGM: Research Funding; Kite: Research Funding. Zinzani: Celgene: Consultancy, 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; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: 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; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, 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; Sandoz: Consultancy, 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; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lee: Oncternal: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Seagen: Research Funding; Century Therapeutics: Consultancy; Guidepoint: Honoraria; Aptitude Health: Honoraria; BMS: Honoraria, Research Funding; Janssen: Honoraria; Pharmacyclics: Research Funding. Johnson: AbbVie: Consultancy, Research Funding; Merck: Consultancy; Roche: Consultancy, Honoraria; BMS: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy. Brice: MSD: Research Funding; Amgen: Other: Travel/accommodations/expenses; Takeda: Research Funding; Roche: Other: Travel/accommodations/expenses. Radford: Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company; ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; BMS: Honoraria. Ribrag: Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Molin: Roche: Honoraria; MSD: Honoraria; BMS: Honoraria; Takeda: Honoraria. Vassilakopoulos: AbbVie: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Other: Travel; Amgen: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Merck: Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel; Roche: Consultancy, Honoraria, Other: Travel; Takeda: Consultancy, Honoraria, Other: Travel, Research Funding; Integris: Honoraria; AstraZeneca: Honoraria; Pfizer: Research Funding; Dr. Reddy's: Research Funding; Karyopharm: Research Funding. Tomita: Kyowa Kirin: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Nippon Shinyaku: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria; Zenyaku Kogyo: Honoraria; AbbVie GK: Honoraria; Bristol Myers Squibb: Honoraria; SymBio Pharmaceutical: Consultancy, Honoraria; Otsuka Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding; Shionogi: Research Funding; Suitomo Dainippon Pharma: Research Funding; Taiho Pharmaceutical: Research Funding; Teijin: Research Funding; Pfizer Japan: Research Funding; Mochida Pharmaceutical: Research Funding; Yakult Honsya: Research Funding; Perseus Proteomics: Research Funding. von Tresckow: Pentixafarm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; AstraZeneca: Honoraria, Other: congress and travel support; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding; BMS-Celgene: Consultancy, Honoraria, Other: congress and travel support; Novartis: Consultancy, Honoraria, Other: congress and travel support, Research Funding; Kite-Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other: congress and travel support, Research Funding; AbbVie: Other: congress and travel support. Shipp: Bristol Myers Squibb: Research Funding; Merck: Research Funding; AstraZeneca: Consultancy, Research Funding; Immunitas Therapeutics: Consultancy; Abbvie: Other: Institution: Research Grant/Funding; Bayer: Other: Institution: Research Grant/Funding. Herrera: Genentech: Consultancy, Research Funding; Karyopharm: Consultancy; Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; Gilead Sciences: Research Funding; Merck: Consultancy, Research Funding; Tubulis: Consultancy. Lin: Merck (MSD): Current Employment. Kim: Merck: Current Employment, Other: Current Stockholder. Chakraborty: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Marinello: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Moskowitz: Merck & Co., Inc.: Research Funding.

Introduction: Although anti-CD19 autologous chimeric antigen receptor (CAR) T-cell therapy has transformed the management of relapsed/refractory non-Hodgkin lymphoma (NHL), the majority of patients will ultimately relapse. The prognostic implications of early (1-month) metabolic response on ultimate outcome are still poorly defined, yet would have significant implications on the development of consolidation strategies. Methods: We conducted a multi-center, retrospective study of patients with NHL who received commercial anti-CD19 CAR T-cell therapy at 5 academic medical centers between 7/2018-5/2021. All patients had a PET scan 30 (+/- 15) days following CAR T-cell infusion. Imaging responses were per investigator assessment using Lugano criteria. Cox proportional hazards models were used to identify predictors of progression free survival (PFS). Results: A total of 193 patients were identified who received axicabtagene ciloleucel (axi-cel, n=180) or tisagenlecleucel (tisa-cel, n=13). Histologies included diffuse large B-cell lymphoma (DLBCL), NOS, n= 134 (69%), DLBCL transformed from an indolent lymphoma, n=47 (24%), primary mediastinal B-cell lymphoma (PMBCL), n=8 (4%), and Richter's syndrome (RS), n=4 (2%). The median age was 62 (range 19-80) years; 66% of patients were male; IPI was low in 28%, intermediate in 27%, and high in 42%; median prior therapies was 3 (range 1-9); 44% had an elevated LDH prior to lymphodepletion; 30% had an elevated CRP prior to CAR T-cell infusion; 10% had bulky disease (≥10 cm) prior to lymphodepleting therapy; and 40% received bridging therapy. The median follow-up of the entire cohort was 22 months (m). Responses at 1m included complete response (CR), n= 101 (52%), partial response (PR), n=53 (27%), stable disease (SD), n=4 (2%), and progressive disease (PD), n=35 (18%). The median PFS of the entire cohort was 11m (95% CI: 6-not reached) (Figure 1B) and median overall survival (OS) was not reached. PFS for the entire cohort was 57% (95% CI: 50-65) at 6m and 49% (95% CI: 42-58) at 12m; and OS was 79% (95% CI: 73-85) at 6m and 67% (95% CI: 61-75) at 12m. The 12m PFS and OS for patients with CR at 1m was 70% (95% CI: 61-80) and 82% (95% CI: 74-91), respectively, and was 38% (95% CI: 26-55) and 69% (95% CI: 57-84) for patients with PR/SD (Figure 1C). The 12m PFS and OS based on 1m PET (Figure 1D) was 72% (95% CI: 61-85) and 82% (95% CI: 72-93), respectively, for Deauville 1/2, 68% (95% CI: 53-88%) and 82% (CI: 69-98) for Deauville 3, 55% (95% CI: 39-79) and 83 (95% CI: 69-100) for Deauville 4, and 12% (95% CI: 3-46) and 56% (95% CI: 27-56) for Deauville 5 with PR/SD. Indicators of shorter PFS across the entire cohort included elevated LDH at lymphodepletion (HR: 2.11 (95% CI: 1.41-3.16, p Discussion: We demonstrate that PFS is improved in patients with a CR at day +30 PET as compared to patients with a PR or SD. Furthermore, patients with Deauville 1/2 appear to have similar outcomes as those with a Deauville 3. No independent clinical variables were able to predict which patients with a PR/SD were likely to progress at the time of their next scan. Novel biomarkers such a minimal residual disease (MRD), may be necessary to further guide treatment modification in this setting. Figure 1 Figure 1. Disclosures Crombie: Karyopharm: Consultancy; Incyte: Consultancy; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding; Roche: Research Funding. Chow: AstraZeneca: Research Funding; ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding. Gauthier: Janssen: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Multerra Bio: Consultancy; Larvol: Consultancy; JMP: Consultancy; Eusapharma: Consultancy. Shouse: Beigene: Honoraria; Kite Pharma: Speakers Bureau. Herrera: Kite, a Gilead Company: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Takeda: Consultancy; Seagen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy; Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding. Jacobson: Lonza: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Axis: Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Clinical Care Options: Speakers Bureau. Armand: Otsuka: Research Funding; Sigma Tau: Research Funding; Infinity: Consultancy; Kite: Research Funding; Pfizer: Consultancy; IGM: Research Funding; Tensha: Research Funding; Roche: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Epizyme: Consultancy; Regeneron: Consultancy; Enterome: Consultancy; C4: Consultancy; GenMab: Consultancy; Tessa Therapeutics: Consultancy; Miltenyi: Consultancy; Daiichi Sankyo: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hess: BMS: Speakers Bureau; ADC Therapeutics: Consultancy.

Introduction : IGM-2323 is the first engineered high-affinity, high-avidity bispecific IgM monoclonal antibody TCE to be tested in the clinic. It has 10 binding domains for CD20 and a single binding domain for CD3 and is designed to bind irreversibly to CD20-high and low-expressing cells with more physiologic stimulation to T cells, which may mitigate cytokine release syndrome (CRS)-related toxicity and broaden the therapeutic window. IGM-2323 may act by multiple mechanisms: T-cell dependent cytotoxicity, complement dependent cytotoxicity, and enhanced immune modulation via IFNγ-dominant cytokine stimulation. This phase 1 study is exploring the safety and activity of IGM-2323 using a dose titration schedule intended to optimize repeatable immune stimulation while minimizing toxicity. Methods : This first-in-human Phase 1 study is a global, multicenter, open-label, dose escalation evaluating safety, tolerability, PK, and preliminary efficacy (NCT04082936). Adults with relapsed or refractory CD20 + B-cell NHL with ≥ 2 prior systemic therapies, adequate organ function, and ECOG 0-1 are eligible. IGM-2323 is given IV on Days 1, 8, and 15 of 21-day cycles until disease progression or unacceptable toxicity. Treatment can continue beyond progression if the patient (pt) has benefitted from treatment and intra-patient dose escalation is allowed. This study also utilizes a dose titration scheme where a starting dose is given on Day 1, then higher subsequent doses are given up to a plateau dose. If a pt has symptoms of CRS, the same dose may be repeated, and a higher dose is not given until the dose is well tolerated. Results : As of April 30, 2021, 29 pts have been enrolled: 12 at 5 fixed dose levels (0.5, 2.5, 10, 30, 100 mg) and 17 at 5 dose titration levels (50/100, 50/200, 50/300, 50/600, 50/1000 mg)*. NHL subtypes include: 13 follicular (FL), 11 diffuse large B-cell (DLBCL), 3 mantle cell (MCL), and 2 marginal zone (MZL). Median age is 66 (range, 36-84) and median prior therapies is 3 (range, 2-7). 2 pts had prior autologous transplant and 7 had prior CAR-T. All 29 pts received at least one dose and are safety evaluable. There were no DLTs and no neurotoxicity AEs. No pts discontinued due to AE. There were 3 drug-related SAEs (1 each Gr1/2/3 CRS by ASTCT). 16 pts discontinued treatment: 2 pt/investigator decision and 14 PD. The 13 pts still on treatment have received a median of 9 doses (range, 1-42). At fixed dose levels, 5 of 12 pts had a CRS event, primarily grade 1 (fever). Only 1 of 17 titration pts had CRS (Gr3 in a pt with prior experimental CAR-T and baseline circulating B-cells). The most common drug-related AEs in titration pts were hypophosphatemia (29%), IRR (29%; the distinction between IRR and CRS was determined by the investigator), and nausea (24%). 23 pts were evaluable for efficacy; there were 8 responses (5 CR, 3 PR). 5 responses were in FL/MZL and 3 in DLBCL/MCL. Response kinetics varied, with some CRs at the first scan (Week 6) and others after biopsy-confirmed pseudo-progression or prolonged SD (up to 69 weeks). 7 of 8 responses were ongoing as of the data cut. 5 of 11 evaluable patients in dose titration cohorts responded (3 CR, 2 PR), with a median time to response of 6 weeks. In the titration cohort with the longest follow-up (50/100), there were 2 CR and 1 PR in 4 evaluable pts. Repeatable IFNγ stimulation is detectable in nearly all pts with measurable cytokine elevations, while polycytokine response was observed in CRS cases (Table). Preliminary IHC data in matched baseline and on-treatment biopsies (n=3) shows decrease of CD20 + tumor cells and increase of CD3 + T cells in tumor tissue upon treatment, regardless of clinical response. Conclusions : Preliminary results from this first-in-human study of IGM-2323 show an excellent safety and tolerability profile at up to 1000 mg, with reduced CRS when IGM-2323 was given using a dose titration scheme. Response patterns included rapid responses, deepening responses and pseudo-progression. IGM-2323 also has evidence of an IFNγ-dominant repeatable T-cell activation and preservation of T cell function over time. The MTD of IGM-2323 has not been reached. Clinical activity was observed across multiple histologies. Updated safety, PK, biomarker, and efficacy data, including complete dose escalation data, will be presented at the meeting. * starting and plateau dose referenced Figure 1 Figure 1. Disclosures Budde: Mustang Bio, Inc: Research Funding; Roche: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; AstraZeneca: Research Funding; IGM Biosciences: Research Funding; Merck, Inc: Research Funding; Amgen: Research Funding; Gilead: Consultancy. Gopal: Agios: Research Funding; MorphoSys: Honoraria; Bristol Meyers Squibb: Research Funding; Incyte: Honoraria; Acrotech: Consultancy, Honoraria; Servier: Consultancy, Honoraria; IGM Biosciences: Research Funding; Nurix Inc: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Astra-Zeneca: Research Funding; Takeda: Research Funding; Teva: Research Funding; ADC Therapeutics: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Cellectar: Consultancy, Honoraria; Genetech: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; I-Mab bio: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; SeaGen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding. Kim: Dong-A Pharmaceutical: Research Funding; Eisai: Research Funding; Celltrion: Research Funding; Johnson & Johnson: Research Funding; Kyowa Kirin: Research Funding; Roche: Research Funding; Sanofi: Research Funding; IGM Biosciences: Research Funding. Flinn: Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Cheah: Ascentage Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Nastoupil: Bayer: Honoraria; Denovo Pharma: Other: DSMC; Novartis: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; IGM Biosciences: Research Funding; Caribou Biosciences: Research Funding; Gilead/Kite: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Janssen: Honoraria, Research Funding; MorphoSys: Honoraria. Matasar: Daiichi Sankyo: Consultancy; TG Therapeutics: Consultancy, Honoraria; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Juno Therapeutics: Consultancy; Rocket Medical: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Merck: Consultancy; IGM Biosciences: Research Funding; Pharmacyclics: Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Diefenbach: Janssen: Consultancy, Honoraria, Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Gilead: Current equity holder in publicly-traded company; Trillium: Research Funding; IGM Biosciences: Research Funding; Celgene: Research Funding; AbbVie: Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; Incyte: Research Funding; MEI: Consultancy, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; IMab: Research Funding. Gregory: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy. Qazi: IGM Biosciences: Current Employment. Pang: IGM Biosciences: Consultancy. Leabman: IGM Biosciences: Current Employment. Hernandez: IGM Biosciences: Current Employment. Sison: IGM Biosciences: Current Employment. Keyt: IGM Biosciences: Current Employment. Chen: IGM Biosciences: Ended employment in the past 24 months. Armand: Enterome: Consultancy; C4: Consultancy; GenMab: Consultancy; Infinity: Consultancy; Otsuka: Research Funding; Regeneron: Consultancy; Pfizer: Consultancy; Morphosys: Consultancy; Daiichi Sankyo: Consultancy; Epizyme: Consultancy; Affimed: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding; IGM: Research Funding; Kite: Research Funding; ADC Therapeutics: Consultancy; BMS: Consultancy, Honoraria, Research Funding; Sigma Tau: Research Funding; Merck: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Miltenyi: Consultancy; Tessa Therapeutics: Consultancy.

Introduction: Similar to classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma (PMBCL) expresses high level of the programmed cell death 1 (PD-1) ligands: PD-L1 and PD-L2. Prior analyses of the phase 2 KEYNOTE-170 (NCT02576990) study demonstrated that monotherapy with the PD-1 inhibitor pembrolizumab had effective antitumor activity and acceptable safety in relapsed/refractory (R/R) PMBCL, leading to FDA approval for adult patients with R/R PMBCL after ≥2 prior therapies. Long-term durability of response with PD-1 blockade in patients with PMBCL, especially those who achieve complete remission (CR), remains a critical clinical question. Here we present updated efficacy and safety of patients with R/R PMBCL in KEYNOTE-170 after ~4 years of follow-up. Methods: Patients with R/R PMBCL who progressed after or were ineligible for autologous stem cell transplant and received ≥2 prior therapies received pembrolizumab 200 mg every 3 weeks (Q3W) for up to 35 cycles (~2 years). Response assessments were Q12W per 2007 Revised Response Criteria for Malignant Lymphomas. End points included overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR) by investigator assessment; as well as overall survival (OS) and safety. Data cutoff date was October 23, 2020. Results: At data cutoff, the median duration of follow-up was 48.7 months (range,41.2-56.2). Baseline characteristics of the patients have been previously described (Armand P, et al. J Clin Oncol. 2019; 37(34): 3291-3299). Among all treated patients (N=53), 13 completed 2 years of treatment and 40 patients discontinued, primarily due to progressive disease (n=18). ORR per investigator assessment was 41.5% (95% CI, 30.0-53.7), with 20.8% complete response rate and 20.8% partial response rate. Median DOR was not reached (NR) and 80.6% of patients had a response ≥48 months. Median PFS was 4.3 months (95% CI, 2.8-13.8) and the 48-month PFS rate was 33.0%. Median OS was 22.3 months (95% CI, 7.3-NR) and the 48-month OS rate was 45.3%. At data cutoff, treatment-related adverse events (AEs) of any grade occurred in 30 patients (56.6%); the most commonly reported (incidence >5%) were neutropenia (18.9%), asthenia (9.4%), hypothyroidism (7.5%), and fatigue and pyrexia (5.7% each). Grade 3-4 treatment-related AEs occurred in 22.6% of patients; only neutropenia (n=7) occurred in ≥2 patients. No grade 5 treatment-related AEs occurred. Conclusions: With 48.7 months of follow-up in heavily pretreated participants with R/R PMBCL, treatment with pembrolizumab monotherapy continued to demonstrate sustained antitumor activity. PFS and OS demonstrated promising trends for long-term survival with no new safety signals identified. Disclosures Zinzani: Novartis: 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; Incyte: Consultancy, 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; Verastem: Consultancy, Honoraria, 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; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: 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; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Thieblemont: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Bouabdallah: Sandoz: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Abbvie: Honoraria; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Waleswski: Roche: Consultancy, Honoraria, Other: Institution: Research Grant/Funding; Takeda: Consultancy, Honoraria; Servier: Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Novartis: Consultancy, Honoraria; GSK/Novartis: Other: Institution: Research Grant/Funding; Abbvie: Consultancy, Honoraria. Fogliatto: AstraZeneca: Speakers Bureau. Martin Garcia-Sancho: Celgene: Honoraria, Other: travel; Celgene/BMS: Consultancy; Janssen: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Gilead: Consultancy, Honoraria; Morphosys: Consultancy; Kyowa Kirin: Consultancy; Clinigen: Consultancy; Eusa Pharma: Consultancy; Novartis: Consultancy; Takeda: Honoraria; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Incyte: Consultancy; Kern Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Christian: Celgene/BMS: Other: Institution: Research Grant/Funding; Acerta: Other: Institution: Research Grant/Funding; Seattle Genetics: Consultancy, Other: Institution: Research Grant/Funding; Genentech: Consultancy, Other: Institution: Research Grant/Funding; AstraZeneca: Consultancy; VeraStem: Consultancy; Morphosys: Consultancy, Other: Institution: Research Grant/Funding; Triphase: Other: Institution: Research Grant/Funding; Millenium: Other: Institution: Research Grant/Funding; Immunomedics: Other: Institution: Research Grant/Funding; Merck: Other: Institution: Research Grant/Funding. Özcan: Amgen: Honoraria, Other: Travel/Accommodations/Expenses; Janssen: Other: Travel/Accommodations/Expenses, Research Funding; Celgene: Research Funding; Archigen: Research Funding; Roche: Other: Travel/Accommodations/Expenses, Research Funding; Bayer: Research Funding; AstraZeneca: Research Funding; Takeda: Honoraria, Other: Travel/Accommodations/Expenses, Research Funding; Pfizer: Research Funding; BMS: Other: Travel/Accommodations/Expenses; Abbvie: Other: Travel/Accommodations/Expenses, Research Funding; Jazz: Other: Travel/Accommodations/Expenses; Abdi Ibrahim: Other: Travel/Accommodations/Expenses; Sanofi: Other: Travel/Accommodations/Expenses; MSD: Research Funding. Perini: Takeda: Speakers Bureau; Roche: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Abbvie: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Salles: Debiopharm: Consultancy; Incyte: Consultancy; Morphosys: Consultancy, Honoraria; Janssen: Consultancy; Epizyme: Consultancy, Honoraria; Rapt: Consultancy; Loxo: Consultancy; Ipsen: Consultancy; Miltneiy: Consultancy; Regeneron: Consultancy, Honoraria; Allogene: Consultancy; Velosbio: Consultancy; Takeda: Consultancy; Genmab: Consultancy; Genentech/Roche: Consultancy; Kite/Gilead: Consultancy; Novartis: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Shipp: Bayer: Other: Institution: Research Grant/Funding; AstraZeneca: Consultancy, Research Funding; Abbvie: Other: Institution: Research Grant/Funding; Immunitas Therapeutics: Consultancy; Merck: Research Funding; Bristol Myers Squibb: Research Funding. Thompson: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Chakraborty: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Marinello: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Armand: Merck: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Affimed: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Infinity: Consultancy; ADC Therapeutics: Consultancy; Celgene: Consultancy; Morphosys: Consultancy; Daiichi Sankyo: Consultancy; Miltenyi: Consultancy; Tessa: Consultancy; GenMab: Consultancy; C4: Consultancy; Enterome: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; IGM: Research Funding; Kite: Research Funding.

Introduction: Allogeneic stem cell transplant (allo-SCT) and checkpoint blockade both have efficacy in some lymphoid malignancies. However, the safety of allo-SCT after programmed cell death 1 (PD-1) blockade in these patients (pts) remains a question of high clinical interest. We present data from an analysis from 4 KEYNOTE phase 1-3 studies to assess the incidence and severity of complications in pts who received allo-SCT following pembrolizumab therapy. Methods: The analysis included pts with a known transplant date who received an allo-SCT within 2 years of the last dose of study pembrolizumab from the KEYNOTE-013 (NCT01953692, n=20), KEYNOTE-087 (NCT02453594, n=31), KEYNOTE-170 (NCT02576990, n=5), and KEYNOTE-204 (NCT02684292, n=14) trials. Descriptive statistics were used for prespecified complications of interest following allo-SCT. The cumulative incidence of acute grade 2-4 graft versus host disease (GVHD), acute grade 3-4 GVHD, and chronic GVHD was estimated. The corresponding competing risk events were death without acute grade 2-4 GVHD, death without acute grade 3-4 GVHD, and death without chronic GVHD, respectively. In addition, the cumulative incidence of transplant related mortality (TRM) post-allo-SCT was estimated with relapse as a competing risk. The Kaplan-Meier method was used for estimation of progression-free survival (PFS) and overall survival (OS). Results: Seventy patients were evaluable for this analysis. Median age was 30 y (range, 18-65), 57 (81.4%) had classical Hodgkin lymphoma, and the rest had non-Hodgkin lymphoma. Sixty-nine pts (98.6%) received pembrolizumab monotherapy and the remainder received pembrolizumab in combination with lenalidomide. Median duration on study treatment was 5.34 months (range, 0.72-29.60) and median time from last pembrolizumab dose to first allo-SCT was 4.6 months (range, 1-20). Post-pembrolizumab and before allo-SCT, 49 pts (70.0%) had intervening anticancer regimen; 34 (48.6%) had active disease, 31 pts (44.3%) were in remission at time of transplant, and 5 pts (7.1%) had unknown disease status. Forty-four pts (62.9%) received reduced-intensity conditioning, 25 pts (35.7%) received full-intensity conditioning, and 1 pt (1.4%) had missing data. In terms of donor source, 31.4% were haploidentical, 25.7% matched sibling, 31.4% matched unrelated. A total of 55 pts (78.6%) developed GVHD, 54.3% with acute GVHD and 24.3% with chronic GVHD. The estimated cumulative incidence was 0.41 (95% CI, 0.30-0.53) for grade 2-4 acute GVHD and 0.20 (95% CI, 0.12-0.30) for grade 3-4 acute GVHD, both at 6 months post-allo-SCT and was 0.21 (95% CI, 0.12-0.31) for chronic GVHD at 1 year post-allo-SCT. Common sites affected by chronic GVHD were skin, liver, and oral mucosa. Other predetermined complications, including critical illness, immune-mediated adverse events, pulmonary complications, and venoocclusive liver disease, occurred in 32 pts (45.7%). With a median follow-up, defined as the time from allo-SCT to data cutoff or death, of 30.9 months (range, 0.85-71.2) , the post-allo-SCT median PFS was not reached (NR) (95% CI, 14.5-NR) and the 30-month post-allo-SCT PFS rate was 56.8% (95% CI, 42.9-68.5) (Figure A); median overall survival (OS) was NR (95% CI, NR-NR) and the OS rate at 12 months was 82.2% (Figure B). The estimated cumulative incidence for TRM at 18-month post-allo-SCT was 0.11 (95% CI, 0.05-0.21). Conclusions: The incidence of acute and chronic GVHD in this population seems similar to that from historical data (40%-72% and 30%-70%, respectively), although the incidence of severe acute GVHD may be higher than a typical modern allo-SCT series. Despite this, the TRM was low. Furthermore, PFS in the subgroup of pts with cHL was favorable compared to historical series of pts without prior PD-1 blockade, which is consistent with other studies in this population. Altogether, this analysis provides reassurance that allo-SCT is feasible for pts after PD-1 blockade, with PFS and OS outcomes that may in fact be better than historical benchmarks. Figure 1 Figure 1. Disclosures Armand: Merck: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Affimed: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Infinity: Consultancy; ADC Therapeutics: Consultancy; Celgene: Consultancy; Morphosys: Consultancy; Daiichi Sankyo: Consultancy; Miltenyi: Consultancy; Tessa: Consultancy; GenMab: Consultancy; C4: Consultancy; Enterome: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; IGM: Research Funding; Kite: Research Funding. Kuruvilla: Incyte: Honoraria; Gilead: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; TG Therapeutics: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Janssen: Honoraria, Research Funding; Merck: Honoraria; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; AstraZeneca: Honoraria, Research Funding; Antengene: Honoraria; Medison Ventures: Honoraria. Herrera: ADC Therapeutics: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Research Funding; Seagen: Consultancy, Research Funding; Tubulis: Consultancy; Takeda: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy. Ribrag: Argen-X: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; GSK: Research Funding; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Nanostring: 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; Astex Pharmaceuticals: Research Funding; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Brice: Takeda: Research Funding; Amgen: Other: Travel/accommodations/expenses; Roche: Other: Travel/accommodations/expenses; MSD: Research Funding. Thieblemont: Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: 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 , Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Von Tresckow: Pentixafarm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Congress and travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: congress and travel support, Research Funding; AstraZeneca: Honoraria, Other: congress and travel support; Amgen: Consultancy, Honoraria; AbbVie: Other: congress and travel support; Kite-Gilead: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Other: congress and travel support; MSD: Consultancy, Honoraria, Other: congress and travel support, Research Funding. Kim: Merck: Current Employment, Other: Current Stockholder. Orlowski: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Chakraborty: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Marinello: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Zinzani: Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, 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; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: 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; TG Therapeutics Inc: Consultancy, Honoraria, 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; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, 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; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Classical Hodgkin lymphoma (cHL) is uniquely vulnerable to PD-1 blockade. This is likely related, at least in part, to the near-universal genetic amplification events at 9p24.1, the locus of the genes for the PD-1 ligands (PD-L1 and PD-L2). Several phase 2 studies have shown that single-agent monoclonal antibodies targeting the PD-1 pathway yield objective responses in approximately two-thirds of patients with relapsed/refractory (R/R) cHL, although only a minority of patients achieve complete responses (CR). Furthermore, these remissions may be long-lasting, with a median duration of approximately 1.5 years. These results have made PD-1 blockade a cornerstone of the treatment for patients with R/R cHL, at least in the third line.

Non-Hodgkin Lymphomas (NHLs) are a heterogeneous group of tumours with distinct treatment paradigms, but in all cases the goal of treatment is to maximize quality and duration of remission while minimizing therapy-related toxicity. Identification of persistent disease or relapse is most often the trigger to intensify or re-initiate anti-neoplastic therapy, respectively. In the current era of NHL treatment, this determination is mostly based on imaging and clinical evaluations, tools with imperfect sensitivity and specificity. The availability of minimal residual disease (MRD) monitoring could transform treatment paradigms by allowing intensification of treatment in at-risk patients or early intervention for impending relapse. Novel methods based on polymerase chain reaction and next-generation sequencing are now being studied in NHL with promising results. This review outlines the current status of the field in the use of MRD techniques for diffuse large B-cell lymphoma, mantle cell lymphoma and follicular lymphoma. Specifically, we address their demonstrated and potential clinical utility in risk stratification, monitoring of remission status, and guiding interim and post-treatment escalation. Future applications of these techniques could identify novel markers of MRD, improve initial treatment selection, guide treatment escalation or de-escalation, and allow for real-time monitoring of patterns of clonal evolution, which together could redefine NHL treatment paradigms.

CD4+Foxp3+ regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after hematopoietic stem cell transplantation. We previously reported that low-dose interleukin-2 (IL-2) therapy increased circulating Tregs and improved clinical symptoms of chronic graft-versus-host-disease (cGVHD); however, the mechanisms that regulate Treg homeostasis during IL-2 therapy have not been well studied. To elucidate these regulatory mechanisms, we examined the role of inhibitory coreceptors on Tregs during IL-2 therapy in a murine model and in patients with cGVHD. Murine studies demonstrated that low-dose IL-2 selectively increased Tregs and simultaneously enhanced the expression of programmed cell death 1 (PD-1), especially on CD44+CD62L+ central-memory Tregs, whereas expression of other inhibitory molecules, including CTLA-4, LAG-3, and TIM-3 remained stable. PD-1-deficient Tregs showed rapid Stat5 phosphorylation and proliferation soon after IL-2 initiation, but thereafter Tregs became proapoptotic with higher Fas and lower Bcl-2 expression. As a result, the positive impact of IL-2 on Tregs was completely abolished, and Treg levels returned to baseline despite continued IL-2 administration. We also examined circulating Tregs from patients with cGVHD who were receiving low-dose IL-2 and found that IL-2-induced Treg proliferation was promptly followed by increased PD-1 expression on central-memory Tregs. Notably, clinical improvement of GVHD was associated with increased levels of PD-1 on Tregs, suggesting that the PD-1 pathway supports Treg-mediated tolerance. These studies indicate that PD-1 is a critical homeostatic regulator for Tregs by modulating proliferation and apoptosis during IL-2 therapy. Our findings will facilitate the development of therapeutic strategies that modulate Treg homeostasis to promote immune tolerance.

Although venous thromboembolism rates and risk factors are well described in patients with cancer, there are limited data on the incidence, risk factors and outcomes of thrombosis after allogeneic stem cell transplantation, a curative therapy for patients with hematologic malignancies. We aimed to determine the incidence and risks associated with venous thrombosis in allogeneic stem cell transplants. We studied 2276 recipients of first transplant between 2002–2013 at our institution with a median follow up of 50 months (range 4–146). Using pharmacy records and subsequent chart reviews, 190 patients who received systemic anticoagulation for venous thrombosis were identified. The 1-and 2-year cumulative incidence of all venous thrombotic events were 5.5% (95% confidence interval (CI) 4.6–6.5%) and 7.1% (95% CI 6.1–8.2%), respectively. There was no difference in age, sex, body mass index, diagnosis, disease risk index, conditioning intensity, donor type or graft source between transplant recipients with and without subsequent thrombosis. In multivariable models, both acute and chronic graft-versus-host disease were independently associated with thrombosis occurrence (Hazard ratio (HR)=2.05, 95% CI 1.52–2.76; HR=1.71, 95% CI 1.19–2.46, respectively). Upper extremity thrombosis differed from all other thromboses in terms of timing, risk factors and clinical impact, and was not associated with non-relapse mortality (HR=1.15; 95% CI 0.69–1.90), unlike all other thromboses which did increase non-relapse mortality (HR=1.71; 95% CI 1.17–2.49). In subgroup analysis evaluating conventional thrombosis predictors by comparing patients with and without thrombosis, a history of prior venous thrombosis was the only significant predictor. Venous thromboembolism has a high incidence after allogeneic stem cell transplant and is associated with graft-versus-host disease and non-relapse mortality.

Purpose Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are subtypes of diffuse large B-cell lymphoma (DLBCL) associated with poor outcomes after standard chemoimmunotherapy. Data are limited regarding outcomes of patients with relapsed or refractory (rel/ref) DEL or DHL who undergo autologous stem-cell transplantation (ASCT). We retrospectively studied the prognostic impact of DEL and DHL status on ASCT outcomes in patients with rel/ref DLBCL. Methods Patients with chemotherapy-sensitive rel/ref DLBCL who underwent ASCT at two institutions and in whom archival tumor material was available were enrolled. Immunohistochemistry for MYC, BCL2, and BCL6 and fluorescence in situ hybridization (FISH) for MYC were performed. In cases with MYC rearrangement or copy gain, FISH for BCL2 and BCL6 was also performed. Results A total of 117 patients were included; 44% had DEL and 10% had DHL. DEL and DHL were associated with inferior progression-free survival (PFS), and DHL was associated with poorer overall survival (OS). The 4-year PFS in patients with DEL compared with those with non-DEL was 48% versus 59% ( P = .049), and the 4-year OS was 56% versus 67% ( P = .10); 4-year PFS in patients with DHL compared with those with non-DHL was 28% versus 57% ( P = .013), and 4-year OS was 25% versus 61% ( P = .002). The few patients with concurrent DEL and DHL had a poor outcome (4-year PFS, 0%). In multivariable models, DEL and DHL were independently associated with inferior PFS, whereas DHL and partial response ( v complete response) at transplant were associated with inferior OS. Conclusion DEL and DHL are both associated with inferior outcomes after ASCT in patients with rel/ref DLBCL. Although ASCT remains a potentially curative approach, these patients, particularly those with DHL, are a high-risk subset who should be targeted for investigational strategies other than standard ASCT.

Background: While most patients (pts) with follicular lymphoma (FL) have excellent outcomes with frontline chemoimmunotherapy (CIT), a subset of pts will experience early progression, which is associated with inferior survival. Earlier identification of high-risk FL pts could allow for intervention with novel treatments to forestall early progression. Current prognostic tools are imperfect, particularly for pts receiving bendamustine-based regimens, and novel biomarkers are needed. In Hodgkin lymphoma, interim positron emission tomography (iPET) evaluated based on Deauville score (DS) is highly prognostic and is used to guide response-adapted therapy. The prognostic value of iPET using DS has not yet been assessed in a large population of FL pts receiving frontline CIT. We hypothesized that iPET would predict progression-free survival (PFS) in this population which could support PET-guided treatment approaches. Methods: We retrospectively identified pts with a diagnosis of FL (grade 1-3B) who initiated frontline CIT at Dana-Farber Cancer Institute from 1/2005-3/2019 and underwent an iPET after 2-4 cycles of CIT. Pts who received radiation (XRT) prior to CIT were included. Baseline, interim, and (when available) end-of-treatment (EOT) PET scans were reviewed by a nuclear medicine radiologist in a blinded fashion and assigned a DS of 1-5. Results: 118 pts were identified. The median age was 55 (range 26-82). 73 pts (62%) had grade 1-2 FL, 17 pts (14%) grade 3A, 15 pts (13%) grade 3B, 12 pts (10%) grade 3 NOS, and 1 pt (1%) grade not reported. FLIPI score was low for 32%, intermediate for 42% and high for 26%. In total, 5 pts (4%) received XRT before CIT. The most common CIT regimens were RCHOP (54%) and BR (42%) (Table 1). 107 pts (91%) received 6 cycles of CIT and 4 pts (3%) received 8 cycles, while 7 pts (6%) discontinued CIT after 4-5 cycles due to cytopenias (4), heart failure (1), infection (1), or pt decision (1). 88% of iPETs were performed after 3 cycles. iPET DS was 1 for 18%, 2 for 57%, 3 for 13%, 4 for 9%, and 5 for 3%. EOT PET was available for review for 112 pts (95%) and demonstrated DS of 1 for 32%, 2 for 56%, 3 for 3%, 4 for 4%, and 5 for 5%. After CIT, 29 pts (25%) received a median of 9 doses (range 1-13) of rituximab maintenance (RM) and 2 pts (2%) received consolidative XRT. With a median follow-up of 54 months (range 5-186), the 4-year (yr) PFS and overall survival (OS) for the entire cohort were 69% (95% CI 58-77%) and 94% (95% CI 87-98%), respectively. iPET was a significant predictor of PFS (p=0.0011 for 5 categories). Compared to pts with an iPET DS of 1-2, pts with a DS of 3 (HR 3.0, p=0.006) or a DS of 4-5 (HR 3.4, p=0.004) had inferior PFS (Figure 1) and were grouped together in a +iPET group (n=30) for all analyses. The 4-yr PFS for DS 1-2 and DS 3-5 pts were 77% and 46%, respectively (HR 3.2, p EOT PET was also a significant predictor of PFS (p Conclusions: Our study suggests that iPET may be a useful prognostic marker in FL. Additionally, iPET interpretation may be different in FL compared to other lymphomas. In this cohort, pts with a DS of 3 on iPET had inferior PFS with outcomes similar to those of pts with a DS of 4-5. A DS of 3-5 on iPET appears to predict earlier progression independent of EOT PET while providing response-driven prognostic information earlier in a patient's treatment course. If validated, these results suggest that iPET could be investigated as a tool for response-adapted treatment strategies in FL. Disclosures Salles: BMS/Celgene: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; Epizyme: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; Genmab: Honoraria, Other; Karyopharm: Honoraria; Takeda: Honoraria. Zelenetz:MEI Pharma: Research Funding; Celgene: Research Funding; Sandoz: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Celgene: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Consultancy; MorphoSys: Research Funding; Gilead: Consultancy; Genentech/Roche: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Roche: Research Funding. Brown:Janssen, Teva: Speakers Bureau; Gilead, Loxo, Sun, Verastem: Research Funding; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy. Crombie:AbbVie: Research Funding; Bayer: Research Funding. Davids:Ascentage Pharma: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Merck: Consultancy; Research to Practice: Honoraria; Syros Pharmaceuticals: Consultancy; Zentalis: Consultancy; Sunesis: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Fisher:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Jacobsen:Merck: Consultancy; Acerta: Consultancy; Astra-Zeneca: Consultancy; Pharmacyclics: Research Funding; F. Hoffmann-LaRoche: Research Funding; Novartis: Research Funding; Takeda: Honoraria. LaCasce:BMS: Consultancy; Research to Practice: Speakers Bureau; UptoDate: Patents & Royalties. Armand:Sigma Tau: Research Funding; Tensha: Research Funding; Pfizer: Consultancy; Affimed: Consultancy, Research Funding; IGM: Research Funding; Adaptive: Consultancy, Research Funding; Celgene: Consultancy; Merck & Co., Inc.: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Infinity: Consultancy; ADC Therapeutics: Consultancy; Genentech: Research Funding.

Background: While autologous stem cell transplantation (ASCT) can be curative for patients (pts) with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapse remains common. With the emergence of novel effective therapies, it is even more important to identify pts at high risk of treatment failure who may not benefit from ASCT, and pts with impending post-ASCT relapse who may be candidates for pre-emptive interventions. We assembled cohorts of DLBCL pts who underwent ASCT and had apheresis stem cell (ASC) samples or serially collected post-ASCT peripheral blood mononuclear cell (PBMC) and plasma samples. We hypothesized that circulating tumor DNA (ctDNA) identified using immunoglobulin-based next generation sequencing (IgNGS) in ASC or PB samples could predict relapse. Methods: Samples from 3 cohorts were analyzed. Pts in cohort 1 (C1) underwent ASCT at Dana-Farber Cancer Institute (DFCI) from 2003-2013 (Herrera, ASH 2015). Archival tumor tissue and ASC samples were retrospectively collected for analysis. Pts in cohort 2 (C2) were prospectively enrolled on a banking protocol at DFCI and underwent ASCT from 2014-2016. Pts in cohort 3 (C3) underwent ASCT from 2015-2016 and participated in a multicenter phase II trial of post-ASCT pembrolizumab maintenance (PM) (Frigault, Blood Adv 2020). Pts in C2/C3 had tumor tissue and serially collected post-ASCT PBMC and plasma samples as mandated by protocol, and a subset had available pre-ASCT PB or ASC samples. Because PM did not demonstrate a clear benefit in the trial, all cohorts were analyzed together. IgNGS (Adaptive Biotechnologies; Seattle, WA) was performed, as previously described (Armand, BJH 2013). In all cases, ctDNA testing was not performed in real-time or used to drive clinical decisions. Results: 152 pts were enrolled. Among 141 pts with sufficient DNA for testing, a clonotype was identified in 112 (78%) with a higher detection rate in more recent cohorts - C2 (93%) and C3 (90%) vs C1 (67%). Among 97 pts with an available ASC sample, 23 (24%) were ctDNA-positive (pos). With a median follow-up among survivors of 69 months (m) (range 13-185), the 5-year (y) progression-free survival (PFS) for ASC ctDNA-pos and ASC ctDNA-negative (neg) pts were 13% (95% CI 3-30%) and 52% (95% CI 40-63%), respectively (HR 2.8, p 56 pts had a median of 3 (range 1-8) post-ASCT plasma samples available for analysis. Within this cohort, 25 pts relapsed and 2 pts died in remission. 21 pts (38%) had detectable ctDNA in a median of 2 post-ASCT samples (range 1-5); among them, 18 (86%) relapsed with a median lead time from first ctDNA detection to relapse of 52 days (range 0-518). Among the 3 ctDNA-pos pts who did not relapse, 2 had detectable ctDNA at a single time point and subsequently became ctDNA-neg, and 1 developed acute myeloid leukemia and underwent allogeneic transplantation. Among 20 pts who relapsed and had ≥1 plasma sample available within 100 days of relapse, 18 (90%) had detectable ctDNA. PBMC testing had inferior performance characteristics (Table). Conclusions: Identification of ctDNA using IgNGS within an ASC sample is a powerful predictor of post-ASCT relapse and provides (at least in this cohort) a better way to predict relapse than pre-ASCT PET. Detection of ctDNA in pre-ASCT plasma also appears to be predictive of relapse. In ctDNA-pos pts, given the dismal PFS, strong consideration could be given to alternative treatment strategies, e.g. CAR-T cell therapy. Furthermore, detection of ctDNA in post-ASCT plasma samples is closely associated with impending relapse, which provides an attractive platform for pre-emptive therapeutic intervention. Figure Disclosures Brown: Dynamo Therapeutics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Octapharma: Consultancy; Pfizer: Consultancy; Acerta: Consultancy; Sun: Research Funding; Genentech: Consultancy; Rigel Pharmaceuticals: Consultancy; Eli Lilly and Company: Consultancy; Juno/Celgene: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Gilead: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Janssen: Honoraria; Sunesis: Consultancy; Novartis: Consultancy; Loxo: Consultancy, Research Funding; Nextcea: Consultancy; MEI Pharma: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy; AbbVie: Consultancy; Catapult: Consultancy; BeiGene: Consultancy; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy. Crombie:AbbVie: Research Funding; Bayer: Research Funding. Davids:Gilead Sciences: Consultancy; Zentalis: Consultancy; Sunesis: Consultancy; Syros Pharmaceuticals: Consultancy; Research to Practice: Honoraria; Merck: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Eli Lilly: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; Novartis: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Fisher:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Jacobsen:Merck, Pharmacyclics, F. Hoffmann-LaRoche, Novartis: Research Funding; Takeda: Honoraria; Acerta, AstraZeneca, Merck: Consultancy. LaCasce:BMS: Consultancy; Research to Practice: Speakers Bureau; UptoDate: Patents & Royalties. Dahi:Kite: Consultancy. Nieto:Secura Bio: Other: Grant Support; Novartis: Other: Grant Support; Affimed: Consultancy, Other: Grant Support; Astra Zeneca: Other: Grant Support. Chen:Incyte Corporation: Consultancy; Takeda: Consultancy; Magenta: Consultancy; Kiadis: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member; Equillium: Other: Data and Safety Monitoring Board Member; AbbVie: Other: Data and Safety Monitoring Board Member. Herrera:Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Karyopharm: Consultancy; Merck: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; AstraZeneca: Research Funding. Armand:IGM: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Affimed: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Infinity: Consultancy; Otsuka: Research Funding; Genentech: Research Funding; Roche: Research Funding; Tensha: Research Funding; Merck: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy, Research Funding; Sigma Tau: Research Funding.

Background Despite active frontline regimens including venetoclax (V) plus obinutuzumab (O) and continuous BTK inhibitors (BTKi), the outcomes for some CLL patients (pts) remain suboptimal. The ibrutinib (I) plus V doublet and IVO triplet are active (Jain et al., NEJM, 2019, Huber et al., EHA, 2020), but are associated with cardiac and infectious toxicities. We hypothesized that a time-limited triplet with a more specific BTKi acalabrutinib (A) with V and O (AVO) would be well-tolerated and active. We report updated data from a phase 2 trial of AVO in previously untreated CLL pts enriched for high risk disease. Methods This ongoing phase 2 investigator-initiated study (NCT03580928) initially enrolled unselected pts with previously untreated CLL. A recent protocol amendment restricted additional enrollment to pts with TP53 aberrant CLL. Additional eligibility: treatment required per iwCLL criteria, ECOG PS ≤ 2, CrCl ≥50ml/min, ANC ≥500/mm3, and platelets ≥30,000/mm3. A, V, and O are started sequentially, with a 28-day lead-in with A at 100 mg bid, then 2 cycles of AO (with O at standard dosing), then AO plus a 4-week V ramp-up beginning C4D1 with 20 mg, then 50 mg on C4D2, then weekly ramp-up to 400 mg qd. After 3 more AVO cycles (6 total cycles of O), AV continues from C8-C15; pts with bone marrow undetectable MRD (BM-uMRD) CR after C15 may discontinue therapy, while all others continue AV until completing C24, with the option to discontinue if BM-uMRD then. Response by 2018 iwCLL criteria, with central MRD testing by 8-color flow cytometry in peripheral blood (PB) and BM at 10-4. Primary endpoint: rate of BM-uMRD CR at C16D1. Non-heme AEs by CTCAE v5.0, and heme toxicity by iwCLL criteria. Results As of July 24, 2020, 44 pts were accrued. Median age: 63 yrs (range: 41-78), 68% male. Baseline prognostics: TP53 aberrant (either del(17p) and/or TP53 mutation) in 17 (39%) pts, del(11q) in 12 (27%) pts, complex karyotype (3 or more changes) in 9 (20%) pts, unmutated IGHV in 29 (66%) pts. With a median follow-up of 19 mo. (range 6-26), 43 pts remain on study (1 withdrew consent after 6 mo. due to GI symptoms). Of 36 pts with at least 16 mo. of follow-up, the overall response rate is 100% (43% CR/CRi, 57% PR [in most cases due to small residual lymph nodes]), with 31% BM-uMRD CR at C16 (primary endpoint). By ITT at C16, 84% PB-uMRD and 78% BM-uMRD. In the 10 pts with TP53-aberrant disease who have reached C16 to date, 4 had CR and 6 had PR, with 9/10 pts PB-uMRD and 7/10 pts BM-uMRD. Response and uMRD did not differ based on IGHV status. Eleven pts in BM-uMRD CR discontinued therapy as allowed per protocol after 15 cycles. Median time off therapy for these pts is 4 mos (range: 1-10). No pts have progressed to date. The most frequent non-heme AEs have been headache (80%, 61% gr1, 16% gr2, 2% gr3), fatigue (77%, 75% gr 1+2, 2% gr3), bruising (57%, 55% gr1, 2% gr2), nausea (45%, all gr 1/2), hypocalcemia (34%, 32% gr 1+2, 2% gr3), rash 32% (30% gr1, 2% gr2), and diarrhea (27%, 18% gr1, 9% gr2). Gr 3/4 heme toxicities: neutropenia (34%), thrombocytopenia (23%), and anemia (4.5%). G-CSF was used in 5 pts (11%). Infusion-related reactions occurred in 11 pts (25%, 23% gr1+2, 2% gr3). One case of gr3 afib (2%) and no cases of major bleeding or febrile neutropenia were observed. 6 pts required dose reductions, including 4 who reduced both A and V, and 1 pt each who reduced A or V alone. SAEs: gr4 neutropenia (n=4), and 1 pt each with gr3 lung infection, cardiac troponin increase, thrombocytopenia, and hyperkalemia. Gr≥3 infection occurred in 1 pt (2.3%). Transient lab TLS occurred in 2 pts (4.5%), both gr3 just after starting O (prior to any V). 41/44 pts (93%) were medium or high risk for TLS at baseline, but only 3 pts (7%) were medium risk at V initiation on C4D1. Five low or medium risk pts were admitted at investigator discretion for V initiation. Conclusion The AVO triplet is highly active, with 78% achieving BM-uMRD after 15 months of time-limited therapy in a frontline CLL population that included nearly 40% pts with TP53 aberrant disease. No pts have progressed, with a median of 19 months follow-up. The safety profile is favorable, with a 2% rate of ≥Gr3 infection and afib, and no TLS due to V, which was given with a more convenient 4-week ramp-up. AVO is now being studied in a registrational phase 3 trial CL-311 (NCT03836261) with the potential to define a new standard frontline therapy option for CLL pts. Disclosures Davids: TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Sunesis: Consultancy; Research to Practice: Honoraria; Janssen: Consultancy; Merck: Consultancy; Surface Oncology: Research Funding; AbbVie: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; Zentalis: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy, Research Funding; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Eli Lilly: Consultancy; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Syros Pharmaceuticals: Consultancy; Bristol Myers Squibb: Research Funding. Crombie:Bayer: Research Funding; Abbvie: Research Funding. Montegaard:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: KOL lecture seires guest lecturer. LaCasce:Research to Practice: Speakers Bureau; BMS: Consultancy; UptoDate: Patents & Royalties. Armand:Adaptive: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Research Funding; Affimed: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Genentech: Research Funding; IGM: Research Funding; Infinity: Consultancy; Otsuka: Research Funding; Pfizer: Consultancy; Roche: Research Funding; Sigma Tau: Research Funding; Tensha: Research Funding. Arnason:Regeneron: Consultancy; Juno: Consultancy. Fisher:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Brown:BeiGene: Consultancy; Catapult: Consultancy; Dynamo Therapeutics: Consultancy; Eli Lilly and Company: Consultancy; Juno/Celgene: Consultancy; Kite: Consultancy; MEI Pharma: Consultancy; Nextcea: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Rigel Pharmaceuticals: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Sun: Research Funding; Acerta: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Gilead: Consultancy, Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy. OffLabel Disclosure: Although acalabrutinib, venetoclax, and obinutuzumab are each approved for frontline CLL, the AVO combination is not approved and therefore considered off-label.

Introduction : Bispecific antibodies that bridge lymphoma cells to T-cells have shown promise in treating B-cell malignancies. However, existing T cell engaging antibodies are associated with toxicity, especially cytokine release syndrome (CRS), which may limit dose intensity and efficacy. CRS results from overstimulation of T cells, which can also lead to subsequent downregulation of T cell function. IGM-2323 is a novel type of bispecific antibody, based on an engineered pentameric IgM framework, with a recombinant J-chain that is fused to an anti-CD3 scfv. The resulting construct has 10 high-affinity binding domains for CD20 and one binding domain for CD3. In preclinical studies, IGM-2323 has been shown to bind irreversibly to CD20-expressing cells and deplete them in human PBMC cell cultures with limited cytokine secretion. This first-in-human Phase 1, open-label, multicenter, dose escalation study was designed to evaluate the safety, tolerability, biomarkers and preliminary anti-tumor activity of IGM-2323 in adults with B- cell malignancies. Methods : Patients with relapsed or refractory CD20-positive B-cell NHL who had received >= 2 prior systemic therapies, acceptable organ function and ECOG 0-1 are eligible for enrollment. IGM-2323 is administered as an IV infusion on Days 1, 8, and 15 of a 21-day cycle, for up to 8 cycles, or longer if there is evidence of clinical benefit. The study utilized an accelerated titration design, with single patient cohorts for the first two dose levels, followed by traditional 3+3 design with further dose levels. The primary objectives are to evaluate the safety and tolerability of IGM-2323, and to determine a recommended phase 2 dose and schedule. Results : As of June 12, 2020, 8 patients have been treated at 4 dose levels (0.5, 2.5, 10, and 30 mg). NHL subtypes include 3 follicular lymphoma (FL), 2 mantle cell lymphoma, 2 marginal zone lymphoma, and 1 diffuse large B-cell lymphoma. Median age is 65 (range 47-81), median number of prior therapies is 4 (range 2-6). 2 patients had prior autologous transplant (ASCT). All 8 patients have completed at least one cycle and are evaluable for safety and dose limiting toxicities (DLT). 6/8 patients remain on active treatment at the time of the database cutoff. Two patients have discontinued at 25 and 7 weeks, due to patient and investigator decision. Six patients remain on study at 37, 27, 18, 9, 6, and 5 weeks ongoing. Median number of doses is 14. There were no DLT observed and no drug-related SAE. Two patients experienced Grade 3-4 treatment-emergent adverse events of transient neutropenia (0.5 mg cohort G4 Two patients in the 30 mg cohort experienced transient low-grade fever (one grade 1, one grade 2), with neither requiring treatment with steroids. Analysis of pharmacodynamic biomarkers shows measurable levels of circulating B cells at baseline in 1/8 patients, where B cell depletion was observed with treatment. Furthermore, there is evidence of cytokine secretion consistent with repeatable T cell responses over successive doses in both 10 mg and 30 mg cohorts. When cytokines were detectable following dosing, they were transient and were mostly gone at less than 6-12 hours. Interferon-gamma (IFNg) was the primary cytokine observed, with significant levels of IL-6 detected in only one patient. Conclusions : IGM-2323 is the first engineered high-affinity, high-avidity bispecific IgM monoclonal antibody to be tested in the clinic, and is designed to bind irreversibly to CD20-expressing cells while providing a more physiologic stimulation to T cells. Preliminary results from this first in human T-cell engaging antibody study show an improved safety and tolerability profile at higher doses. There is also evidence of a novel mechanism of action based on repeatable T cell activation and preservation of T cell function compared with other T cell engaging antibodies. The study continues to enroll patients in dose escalation. Updated safety, pharmacokinetic, biomarker, and efficacy data will be presented at the meeting. This study is registered with clinicaltrials.gov identifier NCT04082936. Disclosures Budde: F. Hoffmann-La Roche, Kite Pharma: Consultancy; Merck, Amgen, AstraZeneca, Mustang Therapeutics: Research Funding; AstraZeneca: Speakers Bureau. Gopal:Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding; IgM bio, BMS, merck: Research Funding; Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy. Flinn:BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Research Funding; Kite Pharma: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; IGM Biosciences: Research Funding; Calithera Biosciences: Research Funding; Loxo: Research Funding; ArQule: Research Funding; Agios: Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Novartis: Research Funding; Nurix Therapeutics: Consultancy; Curis: Research Funding; MorphoSys: Consultancy, Research Funding; Curio Science: Consultancy; Constellation Pharmaceuticals: Research Funding; Merck: Research Funding; Forty Seven: Research Funding; Iksuda Therapeutics: Consultancy; Genentech, Inc.: Research Funding; Great Point Partners: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Gilead Sciences: Consultancy, Research Funding; Forma Therapeutics: Research Funding; F. Hoffmann-La Roche: Research Funding; Incyte: Research Funding; Takeda: Consultancy, Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy, Research Funding. Nastoupil:Gilead/KITE: Honoraria; Bayer: Honoraria; Pfizer: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Novartis: Honoraria, Research Funding; LAM Therapeutics: Research Funding; TG Therapeutics: Honoraria, Research Funding; Merck: Research Funding; Janssen: Honoraria, Research Funding; Gamida Cell: Honoraria. Keyt:IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Carroll:IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Leabman:IGM Biosciences: Current Employment. Hernandez:IGM Biosciences: Current Employment. Sison:IGM Biosciences: Current Employment. Chen:IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Godfrey:IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Armand:Adaptive: Consultancy, Research Funding; IGM: Research Funding; Otsuka: Research Funding; Roche: Research Funding; Celgene: Consultancy; Affimed: Consultancy, Research Funding; Genentech: Research Funding; ADC Therapeutics: Consultancy; Sigma Tau: Research Funding; Infinity: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Merck & Co., Inc.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Tensha: Research Funding.

Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, is characterized by both clinical and molecular heterogeneity. Despite efforts to tailor therapy for individual patients, treatment remains uniform and a subset of patients have poor outcomes. The past decade has witnessed a dramatic expansion of our understanding of the genomic underpinnings of this disease, especially with the application of next-generation sequencing. In this review, the authors highlight the current genomic landscape of DLBCL and how this information provides a potential molecular framework for precision medicine-based strategies in this disease.

Clinical disease caused by BK virus reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Because of the lack of effective antiviral agents, BK virus–specific T cells are emerging as a potential therapy for BK virus disease, but the immune response to BK virus after allogeneic HCT has not been well characterized. Our study describes reconstitution of BK virus–specific T-cell immunity in 77 adult patients after HCT. All patients had urinary symptoms, and urine was tested for BK virus replication; 33 patients were positive for BK virus (cases), and 44 were negative (controls). In BK virus cases, the median time to first positive test was 75 days (range, 2-511). BK virus cases had lower CD4 T-cell counts 3 to 9 months after transplant, but CD8 T-cell counts were similar in cases and controls. BK virus–specific T cells were identified by cytokine flow cytometry in cryopreserved samples collected prospectively. BK virus–specific CD4 T cells producing T helper 1 (Th1) cytokines recovered quickly after HCT. BK virus–specific T cells were detected more frequently in patients with BK virus reactivation at most time points, and CD4 T cells producing Th1 cytokines were more frequent than BK virus–specific cytolytic CD8 T cells. Early detection of interferon-γ+ and cytolytic BK virus–specific CD4 T cells was associated with lower rates of hematuria among cases. Overall, our study describes recovery of BK virus–specific T cells after HCT and the distinct roles for BK virus–specific T cells in the development and resolution of clinical symptoms.

Classical Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive, but ineffective, inflammatory/immune cell infiltrate. HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands. To define genetic mechanisms of response and resistance to PD-1 blockade and identify complementary treatment targets, we performed whole-exome sequencing of flow cytometry–sorted HRS cells from 23 excisional biopsies of newly diagnosed cHLs, including 8 Epstein-Barr virus–positive (EBV(+)) tumors. We identified significantly mutated cancer candidate genes (CCGs) as well as somatic copy number alterations and structural variations and characterized their contribution to disease-defining immune evasion mechanisms and nuclear factor κB (NF-κB), JAK/STAT, and PI3K signaling pathways. EBV(–) cHLs had a higher prevalence of genetic alterations in the NF-κB and major histocompatibility complex class I antigen presentation pathways. In this young cHL cohort (median age, 26 years), we identified a predominant mutational signature of spontaneous deamination of cytosine- phosphate-guanines (“Aging”), in addition to apolipoprotein B mRNA editing catalytic polypeptide-like, activation-induced cytidine deaminase, and microsatellite instability (MSI)–associated hypermutation. In particular, the mutational burden in EBV(–) cHLs was among the highest reported, similar to that of carcinogen-induced tumors. Together, the overall high mutational burden, MSI-associated hypermutation, and newly identified genetic alterations represent additional potential bases for the efficacy of PD-1 blockade in cHL. Of note, recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1 mutations and 2p/2p15, 6p21.32, 6q23.3, and 9p/9p24.1 copy number alterations, were also identified in >20% of primary mediastinal B-cell lymphomas, highlighting shared pathogenetic mechanisms in these diseases.

Background Although classical Hodgkin lymphoma (cHL) is highly curable, 20%-30% of patients will not be cured with conventional treatments. The programmed death-1 (PD-1) inhibitors (PD-1i) nivolumab and pembrolizumab have been Food and Drug Administration-approved for relapsed/refractory (R/R) cHL. There is limited data on the real-world experience with PD-1i in cHL and it is unknown whether fewer selected patients treated with PD-1i derive benefits similar to those observed in published trials. Materials and methods We performed a multicenter, retrospective analysis of R/R cHL patients treated with PD-1i in the nontrial setting. The primary objective was to describe progression-free survival (PFS) and overall survival (OS) in this population. Secondary objectives were to characterize response rates, toxicities, discontinuation patterns, and post-PD-1i therapies. Results The study included 53 patients from nine U.S. centers. Overall response rate (ORR), complete response (CR), and partial response (PR) to PD-1i were 68%, 45%, and 23%, respectively. Twelve-month OS and PFS were 89% and 75%, respectively; median PFS was 29 months. Ninety-six percent of patients with CR continue to respond at a median follow-up of 20 months. Toxicities were similar to those previously described. Seventy percent of patients treated with systemic therapy after PD-1i demonstrated objective responses. Conclusion To our knowledge, this analysis is the first describing real-world experience with PD-1i in cHL patients in the U.S. Here, we demonstrate similar response rates compared to prior studies. The toxicity profile of PD-1i was similar to that seen in previous studies; we further describe toxicity patterns in those with prior autoimmune disease or allogeneic transplant. Post-PD-1i systemic therapies appear active. These results support the effectiveness and tolerability of PD-1i therapy in R/R cHL in a real-world setting. Implications for practice Two PD-1 inhibitors have recently been approved for patients with relapsed/refractory classical Hodgkin lymphoma based on results from nonrandomized clinical trials. However, to date, there have been no studies evaluating the effectiveness and toxicity profile of these drugs in the real-world setting in the U.S. The present study demonstrates that patients treated in a real-world context experience similar rates of overall effectiveness compared with published clinical trials. Patients who discontinue PD-1 inhibitors may experience clinical responses to subsequent treatment with systemic chemotherapy or targeted therapy. This study provides clinicians with further insight into the effectiveness and tolerability of PD-1 inhibitors and suggests that when patients progress while on these drugs, conventional systemic chemotherapy may be an effective treatment option.

Classic Hodgkin lymphoma (cHL) is a tumor composed of rare, atypical, germinal center-derived B cells (Hodgkin Reed-Sternberg [HRS] cells) embedded within a robust but ineffective inflammatory milieu. The cHL tumor microenvironment (TME) is compartmentalized into "niches" rich in programmed cell death-1 ligand (PD-L1)-positive HRS cells and tumor-associated macrophages (TAMs), which associate with PD-1-positive T cells to suppress antitumor immunity via PD-L1/PD-1 signaling. Despite the exquisite sensitivity of cHL to PD-1 checkpoint blockade, most patients eventually relapse and need therapeutic alternatives. Using multiplex immunofluorescence microscopy with digital image analysis, we found that cHL is highly enriched for non-T-regulatory, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-positive T cells (compared with reactive lymphoid tissues) that outnumber PD-1-positive and lymphocyte-activating gene-3 (LAG-3)-positive T cells. In addition, T cells touching HRS cells are more frequently positive for CTLA-4 than for PD-1 or LAG-3. We further found that HRS cells, and a subset of TAMs, are positive for the CTLA-4 ligand CD86 and that the fractions of T cells and TAMs that are CTLA-4-positive and CD86-positive, respectively, are greater within a 75 μm HRS cell niche relative to areas outside this region (CTLA-4, 38% vs 18% [P = .0001]; CD86, 38% vs 24% [P = .0007]). Importantly, CTLA-4-positive cells are present, and focally contact HRS cells, in recurrent cHL tumors following a variety of therapies, including PD-1 blockade. These results implicate CTLA-4:CD86 interactions as a component of the immunologically privileged niche surrounding HRS cells and raise the possibility that patients with cHL refractory to PD-1 blockade may benefit from CTLA-4 blockade.

Low-dose interleukin-2 (IL-2) therapy for chronic graft-versus-host disease (cGVHD) generates a rapid rise in plasma IL-2 levels and CD4+CD25+CD127−Foxp3+ regulatory T-cell (CD4Treg) proliferation, but both decrease over time despite continued daily administration. To test whether IL-2 dose escalation at the time of anticipated falls in plasma levels could circumvent tachyphylaxis and enhance CD4Treg expansion, we conducted a phase 1 trial in 10 adult and 11 pediatric patients with steroid-refractory cGVHD (www.clinicaltrials.gov: NCT02318082). Daily IL-2 was initiated in children and adults (0.33 × 106 and 0.67 × 106 IU/m2 per day, respectively). Dose escalations were scheduled at weeks 2 and 4 to a maximum dose of 1 × 106 IU/m2 per day in children and 2 × 106 IU/m2 per day in adults. Patients continued at their maximum tolerated dose (MTD) until week 8. Children tolerated IL-2 dose escalation with partial responses (PRs) in 9 of 11 patients (82%) at multiple cGVHD sites, including lung. Patient-reported outcome scores for skin and lung improved significantly in pediatric patients. In contrast, 5 of 10 adults required dose reduction, and only 2 of 7 evaluable patients (29%) had PRs at week 8. CD4Tregs and natural killer cells expanded in both cohorts without significant changes in conventional CD4+ T cells (Tcons) or CD8+ T cells. Children achieved a higher median CD4Treg/Tcon ratio at week 8 (0.4 vs 0.18, P = .02) despite lower IL-2 doses. We show for the first time that low-dose IL-2 is safe and effective in children with advanced cGVHD. In adults, escalation above the previously defined MTD did not improve CD4Treg expansion or clinical response.

Monoclonal antibodies (mAbs) against programmed cell death 1 (PD-1), such as nivolumab and pembrolizumab, are associated with high response rates in patients with relapsed or refractory classic Hodgkin lymphoma (HL). To date, no prognostic factor for overall survival (OS) has been established with these agents in HL. We examined whether the first early response assessment evaluated using

In this multicenter Phase 2 single arm study, we substituted low dose total body irradiation (TBI) for antithymocyte globulin (ATG) in a reduced intensity conditioning regimen with the intent to lower the risk for viral infections after double umbilical cord blood (UCB) transplantation. The conditioning regimen consisted of fludarabine (30 mg/m2/day, Day −7 to −2), melphalan (100 mg/m2/day, Day −1), and TBI (200cGy, Day 0). Graft-versus-host disease prophylaxis was sirolimus and tacrolimus. Thirty-one patients were treated on the protocol. The median time of follow-up for survivors was 24 months (range, 3.3–55.1). Nineteen patients experienced a total of 24 clinically significant viral reactivations or infections, with 1-year cumulative incidence rate of first significant viral event as 64% (95% CI, 43–79%), compared with our historical control of 53%. Within the context of these 24 clinically significant viral reactivations, there were a total of 10 infections with organ involvement. Nonrelapse mortality was 28% (95% CI 13–45%) at 2 years. The 2-year overall and progression-free survivals were 53% (95% CI 33–69%) and 47% (95% CI 28–64%), respectively. In conclusion, the substitution of low dose TBI for ATG did not decrease the incidence of significant viral events after UCB transplantation.

Summary Background Fludarabine, cyclophosphamide, and rituximab (FCR) can improve disease-free survival for younger (age ≤65 years) fit patients with chronic lymphocytic leukaemia with mutated IGHV. However, patients with unmutated IGHV rarely have durable responses. Ibrutinib is active for patients with chronic lymphocytic leukaemia irrespective of IGHV mutation status but requires continuous treatment. We postulated that time-limited ibrutinib plus FCR would induce durable responses in younger fit patients with chronic lymphocytic leukaemia. Methods We did a multicentre, open-label, non-randomised, single-arm phase 2 trial at seven sites in the USA. We enrolled patients aged 65 years or younger with previously untreated chronic lymphocytic leukaemia. Our initial cohort (original cohort) was not restricted by prognostic marker status and included patients who had del(17p) or TP53 aberrations. After a protocol amendment (on March 21, 2017), we enrolled an additional cohort (expansion cohort) that included patients without del(17p). Ibrutinib was given orally (420 mg/day) for 7 days, then up to six 28-day cycles were administered intravenously of fludarabine (25 mg/m2, days 1–3), cyclophosphamide (250 mg/m2, days 1–3), and rituximab (375 mg/m2 day 1 of cycle 1; 500 mg/m2 day 1 of cycles 2–6) with continuous oral ibrutinib (420 mg/day). Responders continued on ibrutinib maintenance for up to 2 years, and patients with undetectable minimal residual disease in bone marrow after 2 years were able to discontinue treatment. The primary endpoint was the proportion of patients who achieved a complete response with undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR. Analyses were done per-protocol in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov ( NCT02251548 ) and is ongoing. Findings Between Oct 23, 2014, and April 23, 2018, 85 patients with chronic lymphocytic leukaemia were enrolled. del(17p) was detected in four (5%) of 83 patients and TP53 mutations were noted in three (4%) of 81 patients; two patients had both del(17p) and TP53 mutations. Median patients' age was 55 years (IQR 50–58). At data cutoff, median follow-up was 16·5 months (IQR 10·6–34·1). A complete response and undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR was achieved by 28 (33%, 95% CI 0·23–0·44) of 85 patients (p=0·0035 compared with a 20% historical value with FCR alone). A best response of undetectable minimal residual disease in bone marrow was achieved by 71 (84%) of 85 patients during the study. One patient had disease progression and one patient died (sudden cardiac death after 17 months of ibrutinib maintenance, assessed as possibly related to ibrutinib). The most common all-grade toxic effects were haematological, including thrombocytopenia in 63 (74%) patients, neutropenia in 53 (62%), and anaemia in 41 (49%). Grade 3 or 4 non-haematological serious adverse events included grade 3 atrial fibrillation in three (4%) patients and grade 3 Pneumocystis jirovecii pneumonia in two (2%). Interpretation The proportion of patients who achieved undetectable minimal residual disease in bone marrow with ibrutinib plus FCR is, to our knowledge, the highest ever published in patients with chronic lymphocytic leukaemia unrestricted by prognostic marker status. Ibrutinib plus FCR is promising as a time-limited combination regimen for frontline chronic lymphocytic leukaemia treatment in younger fit patients. Funding Pharmacyclics and the Leukemia & Lymphoma Society.

Bendamustine-rituximab (BR) is a standard therapy in CLL, and lenalidomide has single-agent activity. This phase 1 study evaluated lenalidomide-BR as initial CLL therapy. Thirteen patients were treated at three dose levels (DL), and an additional 10 were treated at the MTD. The MTD was DL3: lenalidomide 5 mg daily D8-21 of C1, then 10 mg D1-21 of C2-6. One DLT occurred at DL2 (pulmonary embolus). Grade ≥3 toxicities included neutropenia (52.2%), rash (26.1%), anemia (21.7%), thrombocytopenia (21.7%), and febrile neutropenia (13.0%). Of 13, 9 treated at the MTD required dose modification, most for neutropenia (5). OR and CR rates were 87% and 39%, respectively. Lenalidomide-BR could be safely administered and was active as initial CLL therapy, although frequent dose modification at the MTD suggests that lenalidomide 10 mg is too high for most patients. Given the current treatment landscape, lenalidomide combinations warrant evaluation in CLL patients who are chemonaïve but have been failed by the approved targeted therapies.

Chronic graft-versus-host disease (cGVHD) affects >50% of hematopoietic stem cell transplant patients. Extracorporeal photopheresis (ECP), an immunomodulatory therapy, provides clinical benefit in steroid-refractory (SR) cGVHD, possibly via regulatory T (Treg) and natural killer (NK) cell expansion. We demonstrated that low-dose interleukin-2 (IL2) led to clinical improvement in SR-cGVHD and stimulated preferential Treg and NK-cell expansion with minimal effect on conventional T (Tcon) cells. We evaluated the effect of ECP (weeks 1-16) plus IL2 (1 × 106 IU/m2, weeks 9-16) in 25 adult patients with SR-cGVHD in a prospective phase 2 trial. Objective responses occurred in 29% and 62% of evaluable patients at weeks 8 (ECP alone) and 16 (ECP plus IL2), respectively. Eight weeks of ECP alone was associated with a marked decline in CD4+ Tcon (P = .03) and CD8+ T cells (P = .0002), with minimal change in Treg cells, Treg:Tcon cell ratio, or NK cells. Adding IL2 induced an increase in Treg cells (P < .05 at weeks 9-16 vs week 8), Treg:Tcon cell ratio (P < .0001 at weeks 9-16 vs week 8), and NK cells (P < .05 at weeks 9-16 vs week 8). Patients responding to ECP alone had significantly fewer CD4+ Tcon and CD8+ T cells at baseline compared with patients who responded after IL2 addition and patients who did not respond; neither Treg nor NK cells were associated with response to ECP alone. Altogether, ECP plus IL2 is safe and effective in patients with SR-cGVHD. ECP and IL2 have distinct immunologic effects, suggesting different therapeutic mechanisms of action. This trial was registered at www.clinicaltrials.gov as #NCT02340676.

Programmed death-1 inhibitors are approved for patients with relapsed or refractory classic Hodgkin lymphoma (RRcHL). We present the 2-year follow-up of the phase 2 KEYNOTE-087 study of pembrolizumab in 210 patients, based on HL progression after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV; cohort 1); salvage chemotherapy and BV, with ineligibility for SCT owing to chemorefractory disease (cohort 2); and progression after SCT without BV (cohort 3). With a median follow-up of 27.6 months, the objective response rate (ORR) by blinded independent central review was 71.9% (95% CI, 65.3-77.9), the complete response rate (CRR) was 27.6%, and the partial response (PR) rate was 44.3%. Median duration of response was 16.5 months (range, 0.01 to 27.01 [1, no progressive disease at last assessment]) in all patients, 22.1 months in cohort 1, 11.1 months in cohort 2, and 24.4 months in cohort 3. Median progression-free survival was not reached in all patients with CR: 13.8 months (95% CI, 12.0-22.1) for patients with PR and 10.9 months (95% CI, 5.6-11.1) for patients with stable disease. Median overall survival was not reached in all patients or in any cohort. Treatment-related adverse events (TRAEs) of any grade occurred in 153 (72.9%) patients; grades 3 and 4 occurred in 25 (12.0%) patients; none resulted in death. Results confirmed effective antitumor activity, durability of response, and manageable safety of pembrolizumab monotherapy in RRcHL, regardless of prior treatment and including chemoresistant cHL. This trial was registered at www.clinicaltrials.gov as #NCT02453594.

Background With the rising number of rectal cancer survivors, more patients with sphincter-preserving surgery are having to live with a potentially impaired quality of life. The survey aimed to assess bowel and genitourinary sequelae and their impact on quality of life in an unselected registry-based population of rectal cancer survivors. Methods This cross-sectional cohort survey (registered at ClinicalTrials.gov ; ID: NCT03459235 ) included patients with rectal cancer who underwent curative surgery with sphincter-preserving surgery from January 1, 2007 to January 31, 2015. Patients with recurrent disease, intestinal stoma, or cognitive disorders were excluded. Validated scoring system included the Urinary Symptom Profile in women and the International Prostate Symptom Score in men for urinary function, International Index for Erectile Function 5 in men and Female Sexual Function Index in women for sexual function, and Core 30/ Colo Rectal 29 questionnaires for quality of life and Low Anterior Resection Syndrome score for bowel function. The impact of functional sequelae on global quality of life was evaluated by multiple linear regression. Results Responders (45.3%, 92/203 patients) and nonresponders were comparable according to sex, age, tumor stage, and neoadjuvant chemoradiation. With a mean follow-up of 6.5 years, 65.2% of the rectal cancer survivors had bowel dysfunction, of whom 41.3% experienced major Low Anterior Resection Syndrome and 80% of rectal cancer survivors experienced genitourinary dysfunction. In multiple linear regression, poor bowel function was a significant predictor of global quality of life in men (P = .04) and women (P = .0003). Conclusion This survey highlights the importance of sexual and bowel dysfunction in rectal cancer survivors and the strong correlation between high Low Anterior Resection Syndrome score and inferior quality of life. Further studies are needed to improve knowledge on how to predict bowel dysfunction and how to best support patients with bowel dysfunction.

There is no Food and Drug Administration-approved treatments for ocular chronic graft-versus-host disease (oGVHD) to date, and current therapeutic options are limited. Forehead application of 1% progesterone gel provides corneal antinociception in preclinical models, suggesting it may be useful in alleviating ocular irritations. This study was conducted to evaluate the efficacy and safety of 1% progesterone gel in treating moderate to severe symptomatic oGVHD. Thirty-three patients with oGVHD following allogeneic stem cell transplantation were enrolled in this single-center, sponsor-initiated, prospective exploratory randomized double-masked placebo-controlled phase II clinical trial. The inclusion criteria included a National Institutes of Health consensus score of ≥2, moderate to severe ocular discomfort level, and receipt of a stable immunosuppression regimen. Twenty-one of the 22 patients in the progesterone arm and all 11 patients in the placebo arm completed the course of twice-daily forehead drug application for 10 weeks. The changes from baseline of self-reported ocular symptom scores and physician-recorded cornea fluorescein staining scores were analyzed using mixed-model repeated-measures regression model in an intention-to-treat population. The 33 patients included 12 women and 21 men, with a median age of 66 years (range, 24 to 75 years). At 10 weeks, there was a significant reduction in ocular symptoms from baseline in the progesterone group compared with the placebo group in symptom frequency (-30.7 versus -2.2; P.001) and severity (-19.8 versus +1.6; P = .005). At 10 weeks, there was also greater reduction of cornea fluorescein staining centrally (-1.2 versus +.1; P = .001) and inferiorly (-1.4 versus -0.2; P = .005). No difference was noted in superior cornea staining. There were no severe adverse events in the progesterone group. Forehead application of 1% progesterone gel significantly improved ocular signs and symptoms within 10 weeks. It appears to be a safe and effective new therapy for oGVHD, and a novel mechanism for neuroaxis drug delivery. A multicenter phase III clinical trial is planned for further validation.

The objective of this study was to evaluate the safety and efficacy of single-agent dexamethasone or tacrolimus topical solution as first-line treatment for symptomatic oral chronic graft-versus-host disease (cGVHD). This was a prospective, single-center, open-label, randomized phase II trial of patients with symptomatic oral cGVHD without prior topical therapy. Subjects were randomly assigned 1:1 to either topical dexamethasone (.5 mg/mL) or tacrolimus (.5 mg/mL) solution and instructed to rinse with 5 mL for 5 minutes, 4 times a day, for 4 weeks. Oral cGVHD assessments (National Institutes of Health [NIH] criteria) were completed at baseline and end of treatment (NIH criteria, global response, and tolerability). The primary endpoint was the response rate defined as ≥3-point reduction in patient-reported sensitivity score (range, 0 to 10). A parallel 2-stage design was employed so that a less efficacious arm could be terminated early. The accrual goal was 60 evaluable patients; 30 in each arm), accruing 14 in the first stage and 16 in the second stage. If both arms were regarded as efficacious, a "pick-the-winner" method would be employed to choose a better treatment for future investigation. Forty-six subjects were randomized to receive either dexamethasone (n = 28) or tacrolimus (n = 18). Six subjects were excluded from the analysis because of changes in systemic immunosuppression (dexamethasone = 1, tacrolimus = 3) or lack of end-of-treatment visit (1 per arm). After the first stage evaluation, the tacrolimus arm was terminated because of lack of activity (3 of 14 responses; response rate, 21%). Twenty-six subjects in the dexamethasone arm completed both study visits and were included in the response analysis, with a 58% (15 of 26) response rate, compared with 21% (3 of 14) in the tacrolimus arm (P = .05). The response rates according to the NIH score in the dexamethasone and tacrolimus arms were 50% (13 of 26) and 2% (2 of 14), respectively (P = .04). From the onset of therapy, 31% versus 21% patients reported feeling "much better" and 38% versus 36% reported feeling "slightly better," giving an overall global response rate ("much better" or "slightly better") of 81% (21 of 26) versus 71% (10 of 14), in the dexamethasone and tacrolimus arms, respectively. Dexamethasone rinses were well tolerated and taste was reported as "very pleasant" or "tolerable" in most subjects (96%). Intensive topical therapy with dexamethasone solution is effective for managing patients with new-onset symptomatic oral cGVHD and should be considered for first-line therapy. Topical tacrolimus solution appears less effective, at least for first-line therapy.

Next-generation sequencing (NGS)-based circulating tumour DNA (ctDNA) detection is a promising monitoring tool for lymphoid malignancies. We evaluated whether the presence of ctDNA was associated with outcome after allogeneic haematopoietic stem cell transplantation (HSCT) in lymphoma patients. We studied 88 patients drawn from a phase 3 clinical trial of reduced-intensity conditioning HSCT in lymphoma. Conventional restaging and collection of peripheral blood samples occurred at pre-specified time points before and after HSCT and were assayed for ctDNA by sequencing of the immunoglobulin or T-cell receptor genes. Tumour clonotypes were identified in 87% of patients with adequate tumour samples. Sixteen of 19 (84%) patients with disease progression after HSCT had detectable ctDNA prior to progression at a median of 3·7 months prior to relapse/progression. Patients with detectable ctDNA 3 months after HSCT had inferior progression-free survival (PFS) (2-year PFS 58% vs. 84% in ctDNA-negative patients, P = 0·033). In multivariate models, detectable ctDNA was associated with increased risk of progression/death (Hazard ratio 3·9, P = 0·003) and increased risk of relapse/progression (Hazard ratio 10·8, P = 0·0006). Detectable ctDNA is associated with an increased risk of relapse/progression, but further validation studies are necessary to confirm these findings and determine the clinical utility of NGS-based minimal residual disease monitoring in lymphoma patients after HSCT.

Summary Background Malignant cells of classical Hodgkin's lymphoma are characterised by genetic alterations at the 9p24.1 locus, leading to overexpression of PD-1 ligands and evasion of immune surveillance. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed and refractory classical Hodgkin's lymphoma, with an acceptable safety profile. We aimed to assess the clinical benefit and safety of nivolumab monotherapy in patients with classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin. Methods In this ongoing, single-arm phase 2 study, adult patients (aged ≥18 years) with recurrent classical Hodgkin's lymphoma who had failed to respond to autologous stem-cell transplantation and had either relapsed after or failed to respond to brentuximab vedotin, and with an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled from 34 hospitals and academic centres across Europe and North America. Patients were given nivolumab intravenously over 60 min at 3 mg/kg every 2 weeks until progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response following a prespecified minimum follow-up period of 6 months, assessed by an independent radiological review committee (IRRC). All patients who received at least one dose of nivolumab were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02181738. Findings Among 80 treated patients recruited between Aug 26, 2014, and Feb 20, 2015, the median number of previous therapies was four (IQR 4–7). At a median follow-up of 8·9 months (IQR 7·8–9·9), 53 (66·3%, 95% CI 54·8–76·4) of 80 patients achieved an IRRC-assessed objective response. The most common drug-related adverse events (those that occurred in ≥15% of patients) included fatigue (20 [25%] patients), infusion-related reaction (16 [20%]), and rash (13 [16%]). The most common drug-related grade 3 or 4 adverse events were neutropenia (four [5%] patients) and increased lipase concentrations (four [5%]). The most common serious adverse event (any grade) was pyrexia (three [4%] patients). Three patients died during the study; none of these deaths were judged to be treatment related. Interpretation Nivolumab resulted in frequent responses with an acceptable safety profile in patients with classical Hodgkin's lymphoma who progressed after autologous stem-cell transplantation and brentuximab vedotin. Therefore, nivolumab might be a new treatment option for a patient population with a high unmet need. Ongoing follow-up will help to assess the durability of response. Funding Bristol-Myers Squibb.

Purpose Cancer cells can exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity. In part, this may occur through overexpression of PD-1 and PD-1 pathway ligands (PD-L1 and PD-L2) in the tumor microenvironment. PD-1 blockade has produced significant antitumor activity in solid tumors, and similar evidence has emerged in hematologic malignancies. Methods In this phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma, T-cell lymphoma, and multiple myeloma received the anti–PD-1 monoclonal antibody nivolumab at doses of 1 or 3 mg/kg every 2 weeks. This study aimed to evaluate the safety and efficacy of nivolumab and to assess PD-L1/PD-L2 locus integrity and protein expression. Results Eighty-one patients were treated (follicular lymphoma, n = 10; diffuse large B-cell lymphoma, n = 11; other B-cell lymphomas, n = 10; mycosis fungoides, n = 13; peripheral T-cell lymphoma, n = 5; other T-cell lymphomas, n = 5; multiple myeloma, n = 27). Patients had received a median of three (range, one to 12) prior systemic treatments. Drug-related adverse events occurred in 51 (63%) patients, and most were grade 1 or 2. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma, diffuse large B-cell lymphoma, mycosis fungoides, and peripheral T-cell lymphoma, respectively. Median time of follow-up observation was 66.6 weeks (range, 1.6 to 132.0+ weeks). Durations of response in individual patients ranged from 6.0 to 81.6+ weeks. Conclusion Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.

Chronic graft-versus-host disease (cGVHD) is associated with inadequate reconstitution of tolerogenic CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs). Previous phase 1 studies identified a low daily dose of interleukin-2 (IL-2) that was well tolerated, did not exacerbate alloimmunity, augmented Treg in vivo, and was associated with improvement of active cGVHD. In the current phase 2 study, 35 adults with steroid-refractory cGVHD received daily IL-2 (1 × 10(6) IU/m(2)) for 12 weeks. Median time from transplantation and cGVHD onset was 616 days (range, 270-2145 days) and 317 days (range, 28-1880 days), respectively. Two patients withdrew and 5 required IL-2 dose reductions due to side effects. Twenty of 33 evaluable patients (61%) had clinical responses at multiple cGVHD sites (liver, skin, gastrointestinal tract, lung, joint/muscle/fascia). Three patients (9%) had progressive cGVHD. Compared with pretreatment levels, Treg and natural killer cell counts rosefivefold (P.001) andfourfold (P.001), respectively, without significant change in conventional CD4 T cells (Tcons) or CD8 T cells. The Treg:Tcon ratio rosefivefold (P.001). Clinical responders initiated IL-2 earlier (508 vs 917 days after transplantation, P = .005; 249 vs 461 days after cGVHD onset; P = .03). Treg:Tcon ratios ≥0.07 at baseline and ≥0.2 at week 1 also predicted clinical response (P = .003; P = .0003, respectively). After a 4-week treatment hiatus, clinical responders were eligible to continue IL-2 therapy indefinitely. During 2 years of extended IL-2 therapy, clinical and Treg immune responses persisted, while Tcon count and Treg:Tcon ratio gradually normalized. Low-dose IL-2 provides durable clinical improvement in active cGVHD and extended therapy is well-tolerated.