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PURPOSE Axicabtagene ciloleucel (axi-cel) was approved by the Food and Drug Administration for relapsed aggressive B-cell non-Hodgkin lymphoma in part on the basis of durable remission rates of approximately 40% in a clinical trial population. Whether this efficacy, and the rates of toxicity, would be consistent in a postcommercial setting, with relaxed eligibility criteria and bridging therapy, is unknown. This study describes the efficacy and safety correlates and outcomes in this setting. PATIENTS AND METHODS One hundred twenty-two patients from 7 medical centers in the United States were treated with axi-cel and were included in a modified intent-to-treat (mITT) analysis. Seventy-six patients (62%) were ineligible for the ZUMA-1 trial. Response and toxicity rates, duration of response (DOR), survival, and covariates are described on the basis of the mITT population. Correlative studies on blood and tumor samples were performed to investigate potential biomarkers of response and resistance. RESULTS Median follow-up was 10.4 months. In the mITT population, the best overall and complete response (CR) rates were 70% and 50%, respectively. Median DOR and progression-free survival (PFS) were 11.0 and 4.5 months in all patients and were not reached (NR) in CR patients. Median overall survival (OS) was NR; 1-year OS was 67% (95% CI, 59% to 77%). Although response rates were similar in the ZUMA-1–eligible and ZUMA-1–ineligible groups (70% v 68%), there was a statistically significant improvement in CR rate (63% v 42%, P = .016), DOR (median, NR v 5.0 months; P = .014), PFS (median, NR v 3.3 months; P = .020), and OS (1-year OS, 89% v 54%; P < .001) in patients who were ZUMA-1 eligible. Rates of grade ≥ 3 cytokine release syndrome and neurotoxicty were 16% and 35%, respectively. CONCLUSION Axi-cel yields similar rates of overall response and toxicity in commercial and trial settings, although CR rates and DOR were more favorable in patients eligible for ZUMA-1.

PURPOSE Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692 ) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990 ) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.

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

Purpose Treatment options are limited for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Tumor cells can exploit the programmed death-1 checkpoint pathway to evade immune surveillance. In the current study, we evaluated the efficacy and safety of programmed death-1 blockade by nivolumab in patients with relapsed/refractory DLBCL. Methods In this phase II, open-label study, patients with relapsed/refractory DLBCL who were ineligible for autologous hematopoietic cell transplantation (auto-HCT) or who had experienced failure with auto-HCT received nivolumab 3 mg/kg every 2 weeks. We assessed the efficacy and safety of nivolumab as well as genetic alterations of 9p24.1. Results Among 121 treated patients, patients in the auto-HCT–failed cohort (n = 87) received a median of four nivolumab doses and a median of three doses were administered to those in the auto-HCT–ineligible cohort (n = 34). At a median follow-up of 9 months in the auto-HCT–failed cohort and 6 months in the auto-HCT–ineligible cohort, independently assessed objective response rates were 10% and 3%, and median durations of response were 11 and 8 months, respectively. Median progression-free survival and overall survival were 1.9 and 12.2 months in the auto-HCT–failed cohort and 1.4 and 5.8 months in the auto-HCT–ineligible cohort respectively. All three patients with complete remission—3% of the auto-HCT–failed cohort—had durable response (11 or more, 14 or more, and 17 months). Treatment-related grade 3 and 4 adverse events were reported in 24% of patients. The most common were neutropenia (4%), thrombocytopenia (3%), and increased lipase (3%). Of all evaluable samples for 9p24.1 analysis, 16% exhibited low-level copy gain and 3% had amplification. Conclusion Nivolumab monotherapy is associated with a favorable safety profile but a low overall response rate among patients with DLBCL who are ineligible for auto-HCT or who experienced failure with auto-HCT. Genetic alterations of 9p24.1 are infrequent in DLBCL.

TPS7585 Background: Classical Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBCL) frequently harbor amplifications at 9p24.1, leading to overexpression of PD-L1 and PD-L2, suggesting a genetically driven vulnerability to programmed death 1 (PD-1) blockade. The PD-1 inhibitor pembrolizumab, dosed at 200 mg every 3 weeks (Q3W), demonstrated strong antitumor activity and acceptable safety that led to approvals for adult and pediatric patients with relapsed or refractory (R/R) cHL and R/R PMBCL. Efficacy, safety, and pharmacokinetic (PK) results from studies in solid tumors have since led to accelerated approval for the pembrolizumab 400 mg Q6W regimen for all indications in adults; however, further efficacy and safety data are needed for hematologic indications. The open-label, single-arm, multisite, global, phase 2 KEYNOTE-B68 study (NCT04875195) evaluates the safety, efficacy, and PK profile of pembrolizumab 400 mg Q6W in patients with R/R cHL or PMBCL. Methods: Patients must have histologically confirmed R/R cHL (cohort 1) or R/R PMBCL (cohort 2) per WHO classification and radiographically measurable disease per the Lugano 2014 classification criteria and must not have previously received treatment with anti–PD-1 therapy. Eligible patients must have failed to respond to or relapsed after receiving an autologous stem cell transplant (ASCT) or must be ineligible for ASCT and must have failed to respond or relapsed after ≥1 (cHL) or ≥2 (PMBCL) prior lines of therapy; patients with PMBCL must have received ≥1 line of therapy containing rituximab. Approximately 60 patients will be enrolled. They will receive pembrolizumab 400 mg IV Q6W for up to 18 cycles. Disease assessments will occur Q12W by investigator per the Lugano 2014 response criteria. Local radiographic assessments will be collected by computed tomography Q12W and by positron emission tomography at weeks 12 and 24 and to confirm complete response. Adverse events will be monitored and assessed by investigators throughout the study, and their severity will be graded per NCI Common Terminology Criteria for Adverse Events, version 5.0 guidelines. Patients who receive an allogeneic SCT within 2 years of the last dose of study treatment will be monitored for 18 months after SCT for events of clinical interest. The primary end point (assessed per cohort) is objective response rate by investigator per the Lugano 2014 classification criteria. Secondary end points (assessed per cohort) include duration of response by investigator assessment, characterization of the PK profile and immunogenicity for pembrolizumab 400 mg Q6W, and safety. Exploratory end points assessed per cohort include overall survival, progression-free survival per the Lugano 2014 criteria, and molecular biomarker analyses. Clinical trial information: NCT04875195.

7516 Background: PD-1 inhibitors are a standard of care in pts with R/R cHL but new approaches are still needed to deepen and lengthen responses. Dual blockade of PD-1 and LAG-3 has demonstrated antitumor activity in preclinical models. The multicohort phase 1/2 MK-4280-003 study (NCT03598608) evaluated the safety and efficacy of favezelimab (MK-4280), a humanized IgG4 LAG-3 inhibitor, plus pembrolizumab (pembro; a PD-1 inhibitor) in pts with R/R hematologic malignancies. This analysis focused on anti–PD-1–naïve pts with R/R cHL (cohort 1). Methods: This study included a safety lead-in phase (part 1) to determine the recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible pts in cohort 1 must have R/R cHL after autologous stem cell transplantation (ASCT) or be ineligible for ASCT and have had no prior anti–PD-1 therapy. In part 1, patients from all cohorts received pembro IV 200 mg Q3W and favezelimab IV 200 mg or 800 mg Q3W. Dose escalation followed the mTPI design. In part 2, pts received pembro + favezelimab at the established RP2D for up to 35 cycles. Primary end point was safety. Secondary end point was ORR. DOR, PFS, and OS were exploratory end points. Results: Only 1 dose-limiting toxicity (DLT; autoimmune hepatitis [grade 4]) was identified among the first 6 pts from all cohorts in part 1 at the favezelimab 200 mg dose; thus, the dose was escalated to 800 mg. No DLTs were observed in the 15 additional pts treated at the 800 mg dose. The RP2D for the combination was defined as 800 mg Q3W + pembro 200 mg Q3W. In cohort 1, 30 pts were enrolled; median age was 40 years, 53% had ECOG PS 0, and 80% had ≤3 prior lines of therapy. After a median follow-up of 13.5 mo, ORR for cohort 1 was 73% (95% CI, 54-88; CR, 7 pts [23%]; PR, 15 pts [50%]). 28 of 30 pts (93%) had reduction from baseline in target lesions. Median DOR was not reached (NR; 95% CI, 0+ to 23+ mo); 6 pts (51%) had response ≥12 mo. Median PFS was 19 mo (95% CI, 8-NR); 12-mo PFS rate was 57%. Median OS was NR (95% CI, NR-NR); 12-mo OS rate was 94%. As of the database cutoff (Nov 1, 2021), 9 of 30 pts had discontinued (3 AEs; 6 PD). Treatment-related AEs (TRAE) occurred in 26 pts (87%); most common (≥10%) were hypothyroidism (27%), fatigue (20%), infusion-related reactions (20%), headache (17%), and arthralgia, hyperthyroidism, myalgia, and nausea (10% each); grade 3 or 4 TRAEs occurred in 6 pts (20%). 10% of pts discontinued due to TRAEs. No treatment-related deaths occurred. Conclusions: Favezelimab 800 mg + pembrolizumab 200 mg Q3W demonstrated a tolerable safety profile and effective antitumor activity in pts with anti–PD-1–naïve R/R cHL. Further studies will be useful to compare its activity to that of pembrolizumab alone. Clinical trial information: NCT03598608.

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.

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.

7536 Background: Axi-cel is an autologous anti-CD19 CAR T-cell therapy approved for patients (pts) with relapsed/refractory LBCL after ≥2 prior systemic therapies. In the pivotal ZUMA-1 study, pts with high pretreatment (preTx) TB (estimated by sum of product diameters [SPD]) had lower peak CAR T-cell expansion normalized to TB and less frequent durable response rates vs pts with low TB ( < 30% vs > 60%, respectively; Blood Adv. 2020;4:3268). The number of CD8+ and CCR7+CD45RA+ product T cells infused and favorable immune contexture in preTx TME were also associated with axi-cel response ( Blood Adv. 2020;4:3268; Galon et al. ASCO 2020. #3022). As potential barriers to axi-cel efficacy are not fully elucidated, we systematically analyzed preTx TME characteristics, including myeloid-related biomarkers and product attributes, to identify such challenges in ZUMA-1 pts with high TB. Methods: Samples from evaluable pts in ZUMA-1 Phase (Ph) 1 and Ph2 Cohorts (C) 1–3 were analyzed (NCT02348216; Ph1 and Ph2 C1+2, ≥2-y follow-up; C3, ≥6-mo follow-up). PreTx immune TME was analyzed by multiplex immunohistochemistry (n = 18) and gene expression analysis (n = 30) as previously described (Rossi et al. AACR 2018. #LB-016; Galon et al. ASCO 2020. #3022). CAR T-cell product characteristics and other covariates were evaluated as previously described ( Blood Adv. 2020;4:3268). Correlative analyses of these covariates with clinical outcomes were performed by Wilcoxon or Kruskal-Wallis test. Median TB (by SPD) from ZUMA-1 Ph1 and Ph2 C1+2 was used as a cutoff for high ( > 3721 mm2) vs low (≤3721 mm2) TB. Durable response refers to pts in ongoing response at time of data cutoff. Results: PreTx immune TME features related to suppressive myeloid-related activity, most notably ARG2, TREM2, and IL-8 gene expression, were elevated in pts who failed to respond or relapsed without documented loss of CD19 expression. ARG2 and TREM2 levels in preTx biopsies were negatively associated with CD8+ T-cell density. Pts with high TB who achieved durable response had low preTx ARG2 and TREM2 levels in TME and enhanced CAR T-cell expansion after axi-cel compared to pts with high TB who relapsed. High ratio of T-cell to suppressive myeloid cell markers (T/M ratio) in preTx biopsies associated positively with CAR T-cell expansion (peak and peak normalized to TB) and durable response in pts with high TB. Conclusions: Axi-cel may overcome high TB in pts with a favorable immune TME alongside robust CAR T-cell expansion. Favorable immune TME is characterized by reduced suppressive myeloid cell activity (low ARG2 and TREM2 expression) and increased T/M ratio. These data suggest possible actionable strategies to overcome high TB in the context of CAR T-cell therapy. [JC and VP contributed equally] Clinical trial information: NCT02348216.

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.

Purpose HLA-mismatched unrelated donor (MMUD) hematopoietic stem-cell transplantation (HSCT) is associated with increased graft-versus-host disease (GVHD) and impaired survival. In reduced-intensity conditioning (RIC), neither ex vivo nor in vivo T-cell depletion (eg, antithymocyte globulin) convincingly improved outcomes. The proteasome inhibitor bortezomib has immunomodulatory properties potentially beneficial for control of GVHD in T-cell-replete HLA-mismatched transplantation. Patients and Methods We conducted a prospective phase I/II trial of a GVHD prophylaxis regimen of short-course bortezomib, administered once per day on days +1, +4, and +7 after peripheral blood stem-cell infusion plus standard tacrolimus and methotrexate in patients with hematologic malignancies undergoing MMUD RIC HSCT. We report outcomes for 45 study patients: 40 (89%) 1-locus and five (11%) 2-loci mismatches (HLA-A, -B, -C, -DRB1, or -DQB1), with a median of 36.5 months (range, 17.4 to 59.6 months) follow-up. Results The 180-day cumulative incidence of grade 2 to 4 acute GVHD was 22% (95% CI, 11% to 35%). One-year cumulative incidence of chronic GVHD was 29% (95% CI, 16% to 43%). Two-year cumulative incidences of nonrelapse mortality (NRM) and relapse were 11% (95% CI, 4% to 22%) and 38% (95% CI, 24% to 52%), respectively. Two-year progression-free survival and overall survival were 51% (95% CI, 36% to 64%) and 64% (95% CI, 49% to 76%), respectively. Bortezomib-treated HLA-mismatched patients experienced rates of NRM, acute and chronic GVHD, and survival similar to those of contemporaneous HLA-matched RIC HSCT at our institution. Immune recovery, including CD8+ T-cell and natural killer cell reconstitution, was enhanced with bortezomib. Conclusion A novel short-course, bortezomib-based GVHD regimen can abrogate the survival impairment of MMUD RIC HSCT, can enhance early immune reconstitution, and appears to be suitable for prospective randomized evaluation.

Purpose Classical Hodgkin lymphomas (cHLs) include small numbers of malignant Reed-Sternberg cells within an extensive but ineffective inflammatory/immune cell infiltrate. In cHL, chromosome 9p24.1/PD-L1/PD-L2 alterations increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and their further induction through Janus kinase 2–signal transducers and activators of transcription signaling. The unique composition of cHL limits its analysis with high-throughput genomic assays. Therefore, the precise incidence, nature, and prognostic significance of PD-L1/PD-L2 alterations in cHL remain undefined. Methods We used a fluorescent in situ hybridization assay to evaluate CD274/PD-L1 and PDCD1LG2/PD-L2 alterations in 108 biopsy specimens from patients with newly diagnosed cHL who were treated with the Stanford V regimen and had long-term follow-up. In each case, the frequency and magnitude of 9p24.1 alterations—polysomy, copy gain, and amplification—were determined, and the expression of PD-L1 and PD-L2 was evaluated by immunohistochemistry. We also assessed the association of 9p24.1 alterations with clinical parameters, which included stage (early stage I/II favorable risk, early stage unfavorable risk, advanced stage [AS] III/IV) and progression-free survival (PFS). Results Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci (polysomy, 5% [five of 108]; copy gain, 56% [61 of 108]; amplification, 36% [39 of 108]). There was an association between PD-L1 protein expression and relative genetic alterations in this series. PFS was significantly shorter for patients with 9p24.1 amplification, and the incidence of 9p24.1 amplification was increased in patients with AS cHL. Conclusion PD-L1/PD-L2 alterations are a defining feature of cHL. Amplification of 9p24.1 is more common in patients with AS disease and associated with shorter PFS in this series. Further analyses of 9p24.1 alterations in patients treated with standard cHL induction regimens or checkpoint blockade are warranted.

7555Background: Patients (pts) with cHL who relapse after autologous stem-cell transplant (ASCT) or progress after brentuximab vedotin (BV) have a poor prognosis. The PD-1 ligands PD-L1 and PD-L2 a...

TPS7576Background: Nivolumab (nivo) is a fully-human immunoglobulin G4 monoclonal antibody immune checkpoint inhibitor that targets programmed death receptor-1 (PD-1) to restore active T-cell immun...

TPS7573Background: Nivo is a human IgG4 monoclonal antibody immune checkpoint inhibitor that targets programmed death receptor-1 (PD-1) on activated immune cells and disrupts engagement of the rece...

7535Background: cHL is characterized by amplification at 9p24.1, causing overexpression of PD-1 ligands. Thus, cHL may be uniquely sensitive to PD-1 blockade. Nivo is a fully human IgG4 immune checkpoint inhibitor targeting PD-1 that showed promising results in a phase 1b study (NCT01592370) in pts with relapsed/refractory cHL (Ansell SM et al NEJM 2015;372:311–9), who currently have limited treatment options. Methods: This study evaluated the efficacy and safety of nivo in pts with cHL who had received BV after failed ASCT, as Cohort B of the larger Phase 2 Checkmate 205 study (NCT02181738). Nivo was given at 3 mg/kg IV q2w. Response was assessed by independent radiologic review committee (IRRC) and investigators (Inv), using 2007 IWG criteria. Primary endpoint was IRRC ORR. Results: The main characteristics of 80 treated cHL pts were: median age 37 y, median (range) 4 prior regimens (3–15). 90% of pts had drug-related AEs: 25% G3–4, 1% G5 (multi-organ failure). Most common drug-related AEs were fatigue ...

3053Background: PD-1 inhibitor-related pneumonitis is an uncommon but serious immune-related adverse event (irAE). Details of radiographic patterns of this entity remain to be investigated. Methods...

8579 Background: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma (MM) (Colla, Leukemia 2010). Evofosfamide (EVO; formerly TH-302) is a nov...

7082 Background: Lenalidomide is an immunomodulator with activity in CLL. Bendamustine-rituximab (BR) is a widely used upfront regimen. We conducted a phase I trial combining lenalidomide (len) wit...

TPS3113 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported with various hematologic malignancies and may prevent the host immune response from exerting an antitumor effect on the malignant cells. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, has demonstrated antitumor activity in pts with solid tumors including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. We hypothesized that nivolumab could also mediate antitumor activity in pts with hematologic malignancies, a significant area of unmet medical need. We describe a phase I study to evaluate the effects of nivolumab in pts with select hematologic malignancies. Methods: This open-label, two-part study will enroll approximately 100 pts. During dose escalation, successive cohorts of pts with relapsed or refractory hematologic malignancies will be treated using a 6+3 escalation design. Pts will receive 1 or 3 mg/kg nivolumab IV every 2 weeks (wks) (the first dose will be followed by a 3-wk evaluation period), for 2 years, with the potential for an additional year of therapy for pts who progress during the follow-up period. Subsequently, 5 tumor-specific cohorts of 16 pts will be enrolled at the maximum tolerated dose (MTD) for multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma/primary mediastinal B-cell lymphoma, and chronic myelogenous leukemia. Response will be assessed at wks 4, 8, 16, 24, and every 16 wks thereafter. The primary study objective is to establish dose limiting toxicities, the MTD, and the recommended phase II nivolumab dose. Secondary objectives are to characterize nivolumab pharmacokinetics, immunogenicity, preliminary antitumor activity, and the potential association between PD-L1 expression on tumor cells and clinical efficacy. Exploratory objectives include investigation of the immunoregulatory effects of nivolumab in peripheral blood, bone marrow, and/or tumor. Pts are currently being enrolled at 3 mg/kg. Clinical trial information: NCT01592370.

8602 Background: TH-302 is an investigational 2-nitroimidazole prodrug of the DNA alkylator Br-IPM designed to be selectively activated in hypoxia. In multiple myeloma (MM) mouse models, diseased animals demonstrate a marked expansion of areas of hypoxia in the bone marrow. TH-302 exhibited anti-tumor activity against MM in vitro and in vivo and synergism was seen when combined with bortezomib (Hu et al, Blood 2010; Chesi et al, Blood 2012). Based on these findings, a phase I/II study of TH-302 plus dexamethasone (dex) was initiated for patients (pts) with relapsed/refractory MM. Methods: Eligible pts in the study (NCT01522872) had ECOG PS ≤ 2, receipt of at least two prior therapies, and acceptable hepatorenal function and hematologic status. A standard 3+3 dose escalation design was used with a fixed oral 40 mg dose of dex and 40% dose increments of TH-302. TH-302 was administered IV with dex on days 1, 4, 8, and 11 of a 21-day cycle. The objectives were to determine DLTs and the MTD; assess the safety, tolerability and preliminary clinical activity of TH-302 plus dex; and study the relationship between hypoxia within the bone marrow and response to TH-302. Results: Eleven pts have been treated: 7M/4F with a median age 61 years (range: 53 – 86) and 6 prior therapies (range: 3 – 10). All received both bortezomib and lenalidomide/thalidomide containing regimens. TH-302 was dosed at 240 (n=5), 340 (n=4), and 480 (n=2) mg/m² for a median of 5 cycles. No DLTs were reported at 240 or 340 mg/m². Two pts treated at 480 mg/m² had DLTs of grade 3 mucositis, exceeding the definition of MTD. A dose expansion is thus ongoing at 340 mg/m2. Two patients had SAEs related to TH-302 (pneumonia). Five pts continue on study after a median of 7 cycles (range: 2–11). Nine pts have had efficacy evaluations: 2 pts with partial responses, 2 pts with minimal responses, and 5 pts with stable disease, for an overall response rate (of MR or better) of 44%. Conclusions: TH-302 can be administered at 340 mg/m2 biweekly + dex, with dose limiting mucositis seen at higher doses. Initial clinical activity has been noted with an ORR of 44% in heavily pretreated MM pts who are relapsed/refractory to both bortezomib and lenalidomide. Clinical trial information: NCT01522872.