ALBERT

Description: Background: Despite advances in chemotherapy, relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge and an unmet medical need. HL has a unique biology in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment. We hypothesized that using immune checkpoint inhibitor therapy to activate the immune cells in the tumor microenvironment, and concurrently targeting HRS cells with the CD30 antibody-drug conjugate brentuximab vedotin (BV), could overcome tumor cell resistance. E4412 is a Phase 1 ECOG-ACRIN sponsored study of the combination of BV and ipilimumab (IPI) and nivolumab (Nivo) in patients with R/R HL. Here we present the preliminary safety and response data on the patients treated with BV + Nivo (Arms D and E). Methods: Patients with confirmed R/R HL were treated with Nivo 3mg/kg and BV 1.2mg/kg (Arm D: Dose Level 1) or 1.8mg/kg (Arm E: Dose Level 2) in dose escalation with a 3+3 design and an expansion cohort (Arm F) of 9 patients. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional year (total 2 years of Nivo therapy). Dose limiting toxicity (DLT) was defined for purposes of dose escalation within the first cycle of therapy. Patients are followed for toxicity up to 30 days beyond their last treatment. Results: As of 7/20/2016 10 patients (1 ineligible) have been treated with BV + Nivo. We report the data on the dose escalation population: 3 patients: Arm D, 7 patients: Arm E. Data will be updated to include the full BV + Nivo dose escalation and dose expansion cohorts (Arms D, E & F) (N = 19) by the time of the Annual Meeting. Median age was 46; (range: 25-53). Six patients were male. Patients were heavily pretreated with a median of 3 prior therapies. Six patients had prior SCT (5 autologous, 1 allogeneic); 2patients had prior treatment with BV. Safety: Ten of 10 patients are evaluable for safety. Overall safety profiles show that the regimen of BV + Nivo was extremely well tolerated. One patient out of 7 in dose level 2 experienced a DLT (pneumonitis grade 3 with grade 3 dyspnea and hypoxia, and typhilits grade 3), this patient had received a prior SCT, and made a full recovery from his toxicities. Per protocol he discontinued further therapy. No other DLTs were noted for the remaining 9 patients. Common and relevant toxicities considered at least possibly related to drug during any cycle of treatment are shown in Table 1. There were no Grade 4 treatment related adverse events (AEs). The only additional grade 3 AEs noted were one each grade 3 rash and puritis. The most common grade 1-2 treatment related adverse events were: transaminitis (9), peripheral sensory neuropathy (6), and rash (3). Other AEs of interest included: diarrhea (3), blurry vision (2), and myalgias (2). One grade 1-2 infusion reaction was noted, this patient was able to receive subsequent therapy with pre-medication. Response: Eight of 10 patients are evaluable for response. One patient is not yet evaluable. For the 8 evaluable patients the overall response rate (ORR) for the combination of BV + Nivo was 100%, with a CR rate of 62.5% (5/8), with 95% CI of 0.25-0.91. One patient was ineligible for laboratory studies that were out of range at screening, however this patient continues on therapy, and also had a response. One of 5 CRs occurred at in dose level 1 (BV 1.2 mg/kg). Both patients who had been treated with prior BV achieved CRs. The progression free survival (PFS) to date is 100% with a median follow-up of 0.3 years. Conclusion: In this first reported study of the combination of the checkpoint inhibitor Nivo and the ADC BV therapy was well tolerated with one DLT, and primarily grade 1 and 2 toxicities. In a heavily pretreated patient population, 20% of whom had had prior BV and 60% of whom were s/p ASCT, the ORR of 100% and CR rate of 62.5% suggests a deepening of response compared to either therapy alone. Optimization of this combination strategy is planned with ongoing accrual to cohorts receiving BV + Nivo, and BV + Ipi + Nivo. Data will be updated to include the full BV + Nivo cohort (N = 19) by the time of the Annual Meeting. Disclosures Diefenbach: Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Genentech: Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Molecular Templates: Research Funding; Oncomed: Research Funding; This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Hong:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Cohen:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Advani:Stanford University: Employment; Juno: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Honoraria; Sutro: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Kura: Research Funding; Merck: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Pharmacyclics: Research Funding; Infinity: Research Funding; Millennium: Research Funding; FortySeven: Consultancy, Honoraria; Kyowa Hakko Kirin: Consultancy, Honoraria. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Description: Survival outcome for elderly patients with newly diagnosed diffuse large B-cell lymphoma remains suboptimal in the rituximab era. In this systematic review, we summarize available evidence relevant to the inclusion of anthracycline in upfront chemoimmunotherapy for these elderly patients and highlight the need of prospective clinical trials. With limited prospective data, we find that pretreatment comprehensive geriatric assessment accurately predicts survival and treatment-related toxicities, suggesting its potential role in guiding overall treatment decision-making.

Description: Background The international prognostic score (IPS) (Hasenclever et al., NEJM 1988) uses 7 factors (age〉 45, male sex, hemoglobin 15,000, and lymphopenia〈 600) to predict a 5 year freedom from progression (FFP) of 42%-84% and overall survival (OS) of 56%-89% for patients with advanced HL. Constructed from a retrospective analysis of patients treated before 1992, the IPS continues to be the most commonly used risk stratification index for advanced HL. Recent studies suggest that the predictive range of the IPS has narrowed due to improved outcomes of patients treated with current therapy (Moccia et al. JCO 2012). In this report we prospectively evaluated the ability of the individual components of the IPS to predict outcome in patients enrolled on the US Intergroup trial E2496. Methods All seven IPS (IPS-7) variables were recorded for all patients at study entry. FFP was defined as the time from study entry to disease progression or relapse; deaths that occurred during remission that were not preceded by disease progression/relapse were censored. OS was defined as the time from study entry to death from any cause. Kaplan-Meier methodology was used to construct survival curves. Univariate and multivariate analysis (MVA) was performed using Cox proportional-hazards models. We subsequently constructed an alternative prognostic score utilizing the factors which were significant on MVA (PS-3). Results From 1996-2006, 854 patients with advanced HL, were randomized to treatment with either ABVD or Stanford V, with no significant differences in outcome (Gordon et al, JCO 2013). While the IPS-7 remained prognostic it did not stratify the lowest risk patients (0-1 risk factor) or patients with 3-5 risk factors, as its predictive range was narrowed due to improved clinical outcomes (Fig 1a and 2a). Table 1 shows the univariate and multivariate analysis for IPS-7 and outcomes. In contrast to the original IPS-7, on MVA, only two factors, hemoglobin and stage were significant for FFP, and three factors for OS: hemoglobin, stage, and age. We then evaluated a new 3 factor score (PS-3) utilizing variables significant on the MVA. The PS-3 was significant for both FFP (p=0.0001) and OS (p

Description: Abstract 3737 Background: Hodgkin lymphoma (HL) is among the most curable lymphomas, however 20%-30% of patients relapse after initial chemotherapy, or have primary refractory disease. While 30–50% of these patients may be cured with second line chemotherapy and autologous stem cell transplant, patients who do not obtain a complete response (CR) prior to transplantation, or who relapse after second line therapy have few effective therapeutic options. Novel treatment strategies for these patients are needed. It has been previously shown that in patients with classical HL the malignant Hodgkin Reed-Sternberg cells (HRS) express a high level of the Interleukin-3 receptor (IL-3R). Therefore, we hypothesized that SL-401, a novel biologic conjugate consisting of IL-3 linked to diphtheria toxin, which targets IL-3R, may be an effective approach for selectively targeting and killing HRS cells. Methods: We first assessed the expression of the IL-3R α-chain (CD123) on two nodular sclerosing (HDLM-2 and L-428) and two mixed cellularity (KM:H2 and L-1236) HL cell lines by flow cytometry. Cells were washed with PBS and stained with CD123 PE (BD Pharmingen) as well as other antibodies, including CD15 FITC (BD Pharmingen), for 20 minutes at 4°C and again washed with PBS. Stained cells were acquired using the LSR II (BD) and data were analyzed using Flow Jo (Tree Star). We then tested the sensitivity of these cell lines to SL-401 using a CellTiter Glo in vitro cytotoxicity assay. A CD123 positive eyrthroleukemic cell line (TF-1/H-ras) with known sensitivity to SL-401 was used as a positive control. The cell lines were cultured in the presence or absence of SL-401 for 48 h and assessed for cell viability at concentrations ranging from 3×10−7 to 1.3 μg/ml. Results: We found high expression of CD123 on HDLM-2 and L-428 HL lines (99% and 89%, respectively) and low-to-moderate expression of the receptor on the L1236 and KM-H2 lines (19.5% and 1%, respectively). Based on CD123 expression, we assessed the sensitivity of these cell lines to SL-401. The L428 and HDLM2 cell lines, which exhibited a high expression of CD123, showed sensitivity to SL-401 relative to control starting at approximately 0.3 ng/ml. Cell viability was reduced to 64.8 ± 5% for L-428 and 68.2 ± 8% for HDLM2 when incubated at the highest concentration of drug (1 μg/ml (L428) and 0.7 μg/ml (HDLM2)). The low CD123 expressing cell lines L1236 and KM:H2 were less sensitive to SL-401 and did not exhibit a significant reduction in cell viability even at the highest concentration of SL-401 tested (1.3 ug/ml; 100 ± 2% and 88.4 ± 6%, respectively). Other lymphoid malignant cell lines with CD123 expression reported in the literature were also tested. Interestingly, the T Acute Lymphocytic Leukemia (T-ALL) cell lines DND41 and P12 showed marked sensitivity to SL-401, with a reduction in cell viability to 55.9 ± 4% and 47.9 ± 6%, respectively, in the presence of 1.3 μg/ml of drug. Conclusion: These results suggest that CD123 expression may vary as a function of HL histology, and that sensitivity to SL-401 may correlate with CD123 expression. Based on these results, SL-401, which is currently being evaluated in clinical trials of patients with acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia, may be a potential treatment strategy in refractory HL, and warrants further exploration in T-ALL. Exploration of CD123 expression in primary and relapsed/refractory patients with lymphoid malignancies as well as in vivo studies with SL-401 in this setting is currently underway. Disclosures: Brooks: Stemline Therapeutics, Inc: Employment, equity options. Cirrito:Stemline Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Bergstein:Stemline Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. O'Connor:Merck: Research Funding; Spectrum: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding.

Description: Background: Despite advances in chemotherapy, R/R HL remains a significant clinical problem with over 1,000 primarily young lives lost annually. HL is a unique tumor in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment that augments HRS growth and survival. We hypothesized that immune checkpoint inhibitor therapy could activate the tumor immune microenvironment, while the CD30 expressing HRS cells could be targeted by brentuximab vedotin (BV), thereby overcoming tumor cell resistance and deepening clinical responses. E4412 is a phase 1 ECOG-ACRIN sponsored study of the combination of BV and the checkpoint inhibitors ipilimumab (IPI) and nivolumab (NIVO) in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). Here we report the data on the patients treated with BV + IPI, the first cohort of the study. Methods: Patients with biopsy proven R/R HL were treated with BV 1.8mg/kg and two escalating doses of IPI: 1 mg/kg or 3mg/kg. After safety was determined an expanded cohort was treated with BV 1.8mg/kg IV and IPI 3mg/kg IV. The schedule consisted of BV administered every 21 days for 16 cycles and IPI every 21 days x 4 doses and thereafter every 3 months for up to a year. Dose limiting toxicity (DLT) was defined for purposes of dose escalation within the first cycle of therapy. Patients are followed for toxicity up to 30 days beyond their last treatment. Results: As of 7/2015 19 of 23 planned patients have been treated with BV + IPI. We report the data on the full dose escalation population (13 patients: Dose level 1 (6), Dose level 2 (7)). The median age was 33 years (range: 20-49). Seven patients were male. Patients were heavily pretreated with a median of 4 prior therapies (2-13). Fourpatients had prior treatment with BV; 8 patients had prior SCT (7 autologous, 1 allogeneic). Safety: Overall the regimen of BV + IPI was extremely well tolerated with no DLTs noted during dose escalation. Toxicities considered at least possibly related to drug during any cycle of treatment are shown according to grade in Table 1. The most common treatment related adverse events were: diarrhea, rash, and peripheral sensory neuropathy. Other AEs of interest included: alopecia, transaminitis, and uveitis. Grade 3 and 4 treatment related adverse events (AEs) included: Dose level 1: one grade 3 infusion reaction, which led to a protocol amendment to include premedication, no further grade 3 infusion reactions were noted; Dose level 2: one each: grade 3 rash, vomiting, and peripheral sensory neuropathy, and one grade 4 thrombocytopenia in patient with pre-existing thrombocytopenia. Response: For the 12 evaluable patients, the overall response (ORR) for the combination of BV + IPI was 67% with a complete response (CR) rate of 42% (5 of 12 patients). An additional 2 patients had stable disease (SD) giving a clinical benefit rate of 83%. Three of 5 of the CRs occurred at dose level 1 (1mg dose of IPI). The median progression free survival (PFS) is 0.74 years with a median follow-up of 0.66 years. Conclusion: In this first reported study of the combination of checkpoint inhibitor and ADC, toxicity was low, primarily grades 1 and 2. In a heavily pretreated patient population, 33% of whom had had prior BV and 67% of whom were s/p ASCT, the ORR of 67% and CR rate of 42% suggests a potential deepening of response compared to monotherapy. More than half of these CRs occurred at 1mg of IPI suggesting that in combination with ADC, low doses of immune stimulation may be highly active. Optimization of this combination strategy is planned with ongoing accrual to cohorts receiving BV + NIVO, and BV + IPI + NIVO. Data will be updated to include the full BV + IPI cohort by the time of the annual meeting. Table 1. Common and Immune Toxicities Toxicity Type Dose Level 1 (n=6) Dose Level 2 (n=7) Grade Grade 1,2 3 4 5 1,2 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) Fatigue 5 - - - 3 - - - Fever 1 - - - 3 - - - Pain 2 - - - 3 - - - Alopecia 2 - - - 1 - - - Pruritus 1 - - - 2 - - - Rash maculo-papular 4 - - - 2 1 - - Diarrhea 4 - - - 4 - - - Dyspepsia 2 - - - 1 - - - Nausea 6 - - - 4 - - - Vomiting 3 - - - 2 1 - - Papulopustular rash 1 - - - 1 - - - Alanine aminotransferase increased 3 - - - 3 - - - Aspartate aminotransferase increased 3 - - - 2 - - - Platelet count decreased - - - - - - 1 - Anorexia 3 - - - - - - - Headache 2 - - - 2 - - - Peripheral sensory neuropathy 5 - - - 4 1 - - Dry eye 2 - - - - - - - Uveitis 1 - - - - - - - Cough 2 - - - 1 - - - Disclosures Diefenbach: Molecular Templates: Research Funding; Immunogen: Consultancy; Celgene: Consultancy; Idera: Consultancy; Jannsen Oncology: Consultancy; Gilead: Equity Ownership, Research Funding, Speakers Bureau; Incyte: Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Off Label Use: Presentation will discuss the experimental use of the checkpoint inhibitor Ipilimumab in relapsed/refractory Hodgkin lymphoma.. Cohen:Celgene: Consultancy; Millennium: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; BMS: Research Funding; Janssen: Research Funding. Robertson:Eli Lilly: Equity Ownership. Fenske:Pharmacyclics: Honoraria; Seattle Genetics: Honoraria; Millennium/Takeda: Research Funding; Celgene: Honoraria. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

Description: Background: Previously reported results from an ongoing study of polatuzumab vedotin (PoV) and pinatuzumab vedotin (PiV), antibody drug conjugates (ADC) containing the anti-mitotic MMAE targeting CD79b (PoV) and CD22 (PiV), showed clinical activity in combination with rituximab (R) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Here we report updated results of ADC + R at the RP2D of 2.4 mg/kg and initial results of PoV + R in r/r FL at the PoV dose of 1.8 mg/kg. Methods: Pts were randomized to receive PoV or PiV + R (ADC 2.4 mg/kg + R 375 mg/m2). In a separate non-randomized cohort (Cohort C), r/r FL pts were treated with PoV (1.8 mg/kg) + R. ADC + R was given every 21 days. Tumor assessments were performed every 3 months. Results: As of 21 February 2014, 59 pts received PoV + R (39 DLBCL; 20 FL), 63 PiV + R (42 DLBCL; 21 FL); 20 r/r FL pts were treated in Cohort C. Median time of follow-up was 10 mo. for PoV + R, 9 mo. for PiV + R, and 5 mo. for Cohort C. Median prior therapies [DLBCL, 3 (1-10); FL, 2 (1-8)] were balanced among the randomized treatment (tx) arms, median prior therapies in Cohort C was 2 (1-13); overall 44% were R refractory. Median tx cycles in DLBCL: 6 PoV (range 1-16) and 7 PiV (1-15); FL: 10 PoV (3-17), 7 PiV (1-14), and 6 Cohort C (2-10). Overall safety profiles of both regimens in the randomized arms receiving 2.4 mg/kg ADC were similar. The most common tx-emergent adverse events (AE) ≥25%: fatigue (55%), diarrhea (43%), nausea (37%), peripheral neuropathy (PN) (39%), neutropenia (27%), constipation (26%), sensory PN (25%), and decreased appetite (25%). Grade ≥ 3 AE 〉3%: neutropenia (24%), diarrhea (6%), dyspnea (5%), febrile neutropenia (4%), hyperglycemia (4%), fatigue (3%), and thrombocytopenia (3%). Serious AEs were reported in 43% and 36% of PiV and PoV treated pts, respectively. Discontinuation of study treatment for AE was reported in 49% and 41% of PiV and PoV treated pts, respectively. Thirty-five pts discontinued treatment due to PN with a median time to discontinuation of 5.6 mo. PN reversibility was observed following treatment interruptions and ADC dose modifications. Two of 9 Grade 5 AEs (sepsis, urosepsis) were attributed to CD22 ADC; no Grade 5 AEs were attributed to CD79b ADC. In Cohort C the most common tx-emergent AE ≥ 25%: fatigue (55%), nausea (45%), neutropenia (40%), sensory PN (30%), diarrhea (25%), constipation (25%) and pyrexia (25%). Grade ≥ 3 neutropenia was reported in 7 pts; no other Grade ≥ 3 AE was reported in 〉1 pt. Serious AE were reported in 5 pts. Two pts discontinued study treatment for AE. No Grade 5 AEs were reported. Overall response rate (ORR), complete (CR) and partial (PR) response rates, n (%) [95% CI], and median PFS in DLBCL (95% CI) are shown in the table. Median PFS in the FL cohorts are not reported due to insufficient follow-up duration. Table PoV (CD79b) + R PiV (CD22) + R PoV [1.8 mg/kg] + R (Cohort C) R/R DLBCL ORR CR PR mPFS (mo.) N=39 22 (56%) [41, 71] 6 (15%) [7, 30] 16 (41%) [26, 58] 5.4 (2.8-8.4) N=42 24 (57%) [41, 72] 10 (24%) [12, 39] 14 (33%) [20, 48] 5.2 (4.1-NR) N/A R/R FL ORR CR PR N=20 14 (70%) [47, 86] 8 (40%) [21, 64] 6 (30%) [14, 53] N=21 13 (62%) [40, 80] 2 (10%) [2, 30] 11 (52%) [30, 72] N=16 7 (44%) [20, 70] 0 7 (44%) [20, 70] Pharmacokinetic profiles were similar for both ADCs across DLBCL and FL with no free MMAE accumulation. Pts receiving PoV at 1.8 mg/kg had proportionately lower exposure of antibody conjugated MMAE compared to pts treated at the 2.4 mg/kg dose level. Conclusions: PoV and PiV + R were generally well-tolerated with similar toxicity profiles. Neutropenia, PN, and diarrhea were the principal toxicities. Similar efficacy was observed with both ADCs in heavily pretreated pts with DLBCL. The higher CR rate with PoV + R compared to PiV + R suggests greater clinical activity in r/r FL. Lower overall response rates were observed in r/r FL pts treated with a lower dose of PoV. Results based on longer follow-up to further assess differences in safety and tolerability between the two PoV doses in r/r FL will be presented. Additional data of pts who received crossover ADC + R treatment following documented disease progression on initial ADC + R treatment will also be presented. Combination studies of PoV + R with chemotherapy and with ADC schedules to reduce PN are ongoing or in planning. Disclosures Morschhauser: Genentech/roche: Honoraria, travel grants Other; Celgene: advisory boards, advisory boards Other, Honoraria. Off Label Use: obinutuzumab and lenlidomide in relapsed follicular lymphoma. Flinn:Genentech, inc.: Research Funding. Advani:Genentech, inc.: Research Funding. Diefenbach:Genentech, inc.: Research Funding. Press:Genentech, inc.: Research Funding. Chen:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Salles:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tilly:Genentech, inc.: Research Funding. Cheson:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Assouline:Roche: Honoraria, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hagenbeek:millenium: Membership on an entity's Board of Directors or advisory committees. Zinzani:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Yalamanchili:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Sharman:Gen: Research Funding.

Description: Background: In Hodgkin lymphoma (HL) the malignant Hodgkin Reed-Sternberg (HRS) cells comprise only a small fraction of the total cellular tumor population. These HRS cells orchestrate an inflammatory microenvironment of reactive cells that propagate a permissive milieu for HL growth, contributing to an ineffective local anti-tumor immune response. The peritumoral CD4 and CD8 T cells in HL patients show high expression of the receptor programmed death-1 (PD-1), involved in the functional impairment and “exhaustion” of T cells. Growing data suggests that this HL-mediated immune suppression may have effects that extend beyond the tumor microenvironment. High systemic levels of inflammatory cytokines and chemokines in HL patients has been reported. We characterized the systemic immune profile of HL patients with both newly diagnosed (ND) and relapsed (R) disease. Methods: Informed consent for correlative blood testing was obtained from patients with ND (n=8) or R (n=5) HL treated at the NYU Perlmutter Cancer Center or NY Presbyterian/Weil Cornell since January of 2013. Blood samples were drawn pre-treatment, and at sequential timepoints during and after therapy. Peripheral blood mononuclear cells (PBMC) were isolated using Ficoll separation method and cells were frozen for subsequent analysis. The frozen PBMC were then stained with fluorescent-conjugated antibodies against T cell surface molecules in 10-color FACS analysis. The analyses were performed after gating live cells for CD4, CD8 and memory and effector T cell markers. Patient samples were compared to normal controls matched for age and sex (n=18). Results: The median HL patient age was 32 (22-72), and 8 subjects were male. All ND HL patients were treated with ABVD (range 4-6 cycles) +/- consolidative radiation; R patients had median of 3 prior therapies. One patient out of 5 had prior autologous stem cell transplant (SCT), and 1 had prior allogeneic SCT, but was not on immunosuppression. Eight patients (6ND, 2R) responded to therapy (8 CR); 5 patients (1ND, 4R) progressed on therapy or had stable disease. HL patients displayed a high frequency of the exhaustion marker PD-1 on CD4 central memory T cells (CD4+CD45RO+CD27+) compared to normal matched controls (NC): mean 41, standard error (SE) 4.8 for HL patients vs. mean 22.2, SE 1.3 for NC (p = 0.0002) (Figure 1A). PD-1 expression was similarly elevated on CD8 central memory T cells (CD8+CD45RO+CD27+) of HL patients: mean 55, SE 3.3 vs. NC: mean 40, SE 3.3 (p = 0.003) (Figure 1B). HL patients also displayed an increased frequency of PD-1 expression on CD27 negative CD4 effector T cells: mean 43, SE 4, vs. NC: mean 28.5, SE 2.4 (p = 0.003) (Figure 2). In 4 of the HL patients who responded to therapy, PD-1 expression on central memory CD4+ cells declined after therapy: mean 30.1 vs. mean increase of +2.67 in 3 patients who progressed on therapy (p〈 0.009). A higher number of subjects in prospective analysis is underway, to confirm whether a response to therapy may be correlated with a reversal of the suppressed phenotype of T cells in these patients. Conclusion: HL patients have evidence of chronic activation/exhaustion in their central memory and effector T cells, suggesting that ineffective immune clearance of the HRS cells may be a systemic rather than local phenomenon. In patients with progressive disease for whom this phenotype persists it is worthy of investigation whether this immune dysfunction is a cause or consequence of resistance to therapy. This may be rationale for immune targeted therapy in patients with relapsed or resistant disease. Figure 1. Evidence for increased levels of T cell exhaustion in central memory T cells of HL patients. PBMC were stained with specific fluorescent conjugated antibodies against T cell markers (CD3, CD4, CD8) together with differentiation markers (CD45RO, CD27) and PD1 and analyzed using FACS (LSR-II). The proportion of PD1+ T cells were determined in: A) CD4+CD45RO+CD27+ and B) CD8+CD45RO+CD27+ T cells. Figure 1. Evidence for increased levels of T cell exhaustion in central memory T cells of HL patients. PBMC were stained with specific fluorescent conjugated antibodies against T cell markers (CD3, CD4, CD8) together with differentiation markers (CD45RO, CD27) and PD1 and analyzed using FACS (LSR-II). The proportion of PD1+ T cells were determined in: A) CD4+CD45RO+CD27+ and B) CD8+CD45RO+CD27+ T cells. Figure 2. Evidence for increased levels of T cell exhaustion in effector memory CD 4+ T cells of HL patients. PBMC were stained with specific fluorescent conjugated antibodies against T cell markers (CD3, CD4) together with differentiation markers (CD45RO, CD27) and PD1 and analyzed using FACS (LSR-II). The proportion of PD1+ T cells was determined in CD4+RO+CD27- T cells Figure 2. Evidence for increased levels of T cell exhaustion in effector memory CD 4+ T cells of HL patients. PBMC were stained with specific fluorescent conjugated antibodies against T cell markers (CD3, CD4) together with differentiation markers (CD45RO, CD27) and PD1 and analyzed using FACS (LSR-II). The proportion of PD1+ T cells was determined in CD4+RO+CD27- T cells Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

Description: Key Points INCB040093 was active across lymphoma subtypes, and the addition of itacitinib provided substantial activity in classic Hodgkin lymphoma. INCB040093 ± itacitinib had a manageable safety and tolerability profile; severe hepatic adverse effects were less common with the combination.

Description: Abstract 4863 Background: Hodgkin Lymphoma (HL) has a cure rate of 70% with chemotherapy or combined modality therapy. Despite this success, approximately 5–10% of patients have primary refractory disease, and 20–30% of patients will relapse after initial complete remission (CR). Second-line chemotherapy and autologous stem cell transplant (ASCT) approaches are curative for only 50% of patients with relapsed/refractory disease. Maximal cytoreduction prior to ASCT confers the greatest potential benefit, yet the current standard salvage chemotherapy regimens have a low CR rate despite a high overall response rate (ORR), and survival is poor for patients who relapse after ASCT. Allogeneic stem cell transplantation can induce durable remissions in some patients with relapsed and primary refractory HL; however the use of this modality is limited in part by the challenges of achieving adequate disease control prior to transplantation. Novel treatment platforms to maximally debulk these patients and allow them to proceed to successful transplantation are needed. Our group has treated multiply relapsed HL patients with the chemotherapy regimen of Ifosfamide, Etoposide, and Cytarabine (IVAC) and we report a retrospective chart review detailing our experience. Methods: Between January of 2011 and June of 2012, 4 patients with relapsed or primary refractory HL were treated with the chemotherapy regimen IVAC consisting of: Ifosfamide 1,500mg/m2 days 1–5; MESNA 1,500mg/m2 days 1–5, Etoposide 600mg/m2 days 1–5, and Cytarabine 2,000mg/m2 q 12hrs × 4 doses days 1–2 given every 21 days. All patients received growth factor support beginning 24hrs after completion of chemotherapy. All patients received prophylactic antifungal, antiviral, and PCP prophylaxis. Restaging PET/CT was performed after 2 cycles of therapy. All patients received 2 cycles of therapy prior to assessment for transplant. Results: Four patients have been treated to date on this regimen. The mean age of the 4 patients was 35.5 (range 32–43). All patients were male. All patients were heavily pre-treated with a mean of 8 prior chemotherapy regimens (range 7–9) including ICE (Ifosfamide, Carboplatin, Etoposide) and Brentuximab vedotin. Three of the 4 patients had prior stem cell transplant: autologous (n=2), allogneic with subsequent DLI (n=1). All patients tolerated the chemotherapy well. The most common significant adverse events were: grade 3 pneumonia (1/4 patient), grade 3 febrile neutropenia (1/4 patients), grade 3 neutropenia (4/4 patients), grade 3 anemia (4/4 patients), grade 3 thrombocytopenia (4/4 patients). All patients recovered to baseline before initiating cycle 2, and after the completion of therapy. Response was evaluated after 2 cycles of therapy in all patients. Three of 4 patients (75%) had a response giving an ORR rate of 75%. Two of the 3 responding patients had a CR giving a CR rate of 50%, 1 patient had a PR. Response duration was: 6 weeks (n=1), 3 months (n=1), 6 months (n=1). Conclusion: IVAC is highly active, even in heavily pre-treated HL patients, with an ORR of 75% and a CR rate of 50%. With close clinical monitoring hematologic and infectious toxicities were manageable in all patients. The regimen of IVAC may allow disease debulking for multiply relapsed HL patients prior to stem cell transplant. Prospective evaluation of this therapy is ongoing. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4860 Background: Programmed death-1(PD-1) and programmed death-1 ligand (PD-L) signaling are involved in the functional impairment and “exhaustion” of T cells in conditions such as chronic viral infection and in tumor immune evasion. The interaction of PD-1 with its ligand PD-L suppresses T cell function. Up-regulation of PD-L has been demonstrated both in Hodgkin lymphoma (HL) cell lines, and in primary Hodgkin Reed Sternberg (HRS) cells. PD-1 is markedly elevated in the tumor infiltrating lymphocytes of HL patients, leading to the hypothesis that T cell exhaustion and deficient anti-tumor immunity induced by the activation of the PD-1-PD-L signaling pathway may play a key role in creating a permissive milieu for HL. In this setting, elevated PD-1 expression in HL patient T cells may be a biomarker of disease activity. We investigated this hypothesis by examining PD-1 expression in the peripheral T cells of patients with relapsed/ refractory HL. Methods: Patients with relapsed or refractory HL who enrolled in a clinical trial of an HDAC inhibitor in combination with Niacinamide between December of 2010 and July of 2011 were eligible to participate. PD-1 levels were assessed pre-treatment, and at selected timepoints during therapy. The levels of PD-1 expression for 5 relapsed/refractory HL patients and 4 healthy control subjects were evaluated by flow cytometry. An aliquot of cells (1 × 106/mL) was washed and stained with: CD3 APC-H7, CD8 PerCP-Cy5.5, CD4 FITC and PD-1-APC, for 20 minutes at 4°C. Dead cells were excluded using the Live/Dead Fixable Staining Kit (Invitrogen), and stained cells were acquired using the LSR II flow cytometer (BD). Compensation (parallel controls using cells singly stained for each color) and data analysis were performed using FlowJo flow cytometry analysis software (TreeStar). The percentage and/or mean fluorescence intensity (MFI) of PD-1+ cells within the live CD3+CD4+ and CD3+CD8+ populations was compared to isotype controls to establish baseline values and to normal control subjects. Results: The median age of the 5 HL patients was 32 (range 25–73). The median age of the healthy control subjects was 43 (range 39–49). Three of the HL subjects were male; all 4 of the normal controls were female. All 5 of the HL patients were heavily pretreated with an average number of prior regimens of 7.8 (range 5–13). Three of the 5 patients underwent previous autologous stem cell transplant, and 2 had a prior allogeneic stem cell transplant. There was a clear shift of PD1+ cells within the CD4+ T cell population in the HL patients compared to normal controls. PD-1 was significantly elevated in the peripheral blood CD4+ cells of HL patients compared to normal volunteers (mean MFI 1034 vs 123, p 〈 0.025). PD-1 was also elevated on the CD8+ T cells of the HL patients compared to normal volunteers (MFI 808 vs 221), but did not reach significance. There was no correlation between the level of PD-1 elevation on CD4+ or CD8+ cells, and prior autologous or allogeneic transplantation. Conclusion: PD-1 expression in peripheral blood CD4+ T cells may be a potential biomarker of systemic immune dysregulation in heavily pre-treated HL patients. PD-1 warrants further exploration in relapsed/refractory HL both as a potential biomarker, and as a target for directed immunotherapy. Additional studies by our group, investigating the role PD-1 as a biomarker in relapsed/refractory HL are ongoing. Disclosures: O'Connor: Spectrum: Research Funding; Novartis: Research Funding; Merck: Research Funding; Celgene: Consultancy, Research Funding.