ALBERT

Description: Backgound Venetoclax (V) plus obinutuzumab (O) regimen is active as frontline CLL treatment; a little over half of patients (pts) will achieve undetectable minimal residual disease in the bone marrow (BM-uMRD) with one year of time-limited therapy (Fischer et al. NEJM 2019). Novel strategies may further augment the efficacy of VO. Ibrutinib was previously combined with VO, but relatively high rates of infusion reactions and neutropenia were observed, as were the characteristic toxicities of ibrutinib including diarrhea and bruising (Rogers et al. Blood 2018). Acalabrutinib (A), a more selective BTK inhibitor, is well-tolerated and active as monotherapy or with O, and we previously found that it sensitizes CLL cells to V (Deng et al. Leukemia 2017). We hypothesized that a time-limited triplet combination of A, V, and O (AVO) could achieve a high rate of BM-uMRD with good tolerability. For the first time we now report on the safety and preliminary efficacy data of AVO in previously untreated CLL pts. Methods This ongoing open-label, single arm, phase 2 investigator-initiated study (NCT03580928) enrolled pts with previously untreated CLL without restriction by prognostic marker status. Eligibility: requiring treatment by iwCLL criteria, ECOG PS ≤ 2, creatinine clearance ≥50ml/min, absolute neutrophil count ≥500/mm3, and platelets ≥30,000/mm3. A, V, and O are started sequentially (see figure), with one 28-day cycle lead-in with A at 100 mg bid, then 2 cycles of AO (with O at standard dosing), then V ramp-up beginning at C4, followed by 3 more cycles of triplet AVO therapy. After 6 months of O, the AV doublet continues through C15; pts with BM-uMRD-negative CR after C15 may discontinue therapy, while all others continue AV until completing C24, with the option to discontinue therapy if in BM-uMRD CR at that time. Response is assessed by 2018 iwCLL criteria, including bone marrow biopsy with MRD testing in the BM and peripheral blood (PB) by 8-color flow cytometry at a sensitivity of at least 10-4. The primary endpoint is the rate of BM-uMRD CR after 15 cycles. Non-hematologic adverse events (AEs) are assessed by CTCAE v5.0, with hematologic toxicity determined by iwCLL criteria. Results The data cut for this interim analysis was July 11, 2019. The study is fully accrued at 37 pts. Median age: 63 years (range: 41-78), 73% male. Baseline prognostic features: unmutated IGHV in 23 (62%) pts, TP53 aberrant disease (defined as either del(17p) and/or TP53 mutation) in 10 (27%) pts, del(11q) in 10 (27%) pts, and complex karyotype in 7 (19%) pts. Thirty-six pts remain on study drugs with a median time on therapy of 8 months (range: 2-11). One pt withdrew consent after 6 cycles due to gastrointestinal symptoms. The overall response rate for the 24 pts who have completed re-staging at C8 is 100%, 18 (75%) PR and 5 (25%) CR. At C8 restaging, 65% of pts were PB-uMRD, 50% of pts were BM-uMRD, and 3 pts (13%) had BM-uMRD CRs. In 8 pts with TP53-aberrant disease who have reached C8, 6 had PR and 2 had CR, with 3 pts BM-uMRD. The most frequent AEs have been fatigue (81% total, 78% gr 1+2, 3% gr ≥3) and headache (76% total, 73% gr 1+2, 3% gr ≥3). Bruising was reported by 16 pts (43%, all gr 1+2). The most frequent gr 3/4 AE has been neutropenia (68% total, 32% gr ≥3). Infusion-related reactions were seen in 8 pts (22%, 19% gr 1+2, 3% gr ≥3). Laboratory tumor lysis syndrome (TLS) occurred in 2 pts (5%), both gr 3 immediately after starting O and prior to any V; both pts continued O. Out of 32 pts, 31 (97%) were medium-to-high risk for TLS on C1D1 but only 3 (9%) were medium-to-high risk at V initiation on C4D1, with 4 medium-to-low risk pts electively admitted for V initiation. One case of gr 3 atrial fibrillation and no cases of hemorrhage or febrile neutropenia were observed. Conclusion Our preliminary data suggest that even at an early response evaluation after 8 cycles of therapy (including only 4 months of V), AVO as frontline CLL therapy leads to a high proportion of pts achieving BM-uMRD and CR, including pts with TP53-aberrant disease. The AE profile is favorable, with a low rate of infusion reactions and no significant cardiac or bleeding toxicities. Updated data will be presented at the meeting for this ongoing study. Based on our initial results we have opened an expansion cohort to further characterize the efficacy and safety of AVO. AVO will also be studied head-to-head against chemoimmunotherapy and the AV doublet in the phase 3 trial CL-311 (NCT03836261), which is currently enrolling. Figure Disclosures Montegaard: Pharmacyclics: Consultancy; Janssen: Consultancy. Jacobson:Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Pfizer: Consultancy, Research Funding; Humanigen: Consultancy, Other: Travel Expenses; Bayer: Consultancy, Other: Travel Expenses; Precision Biosciences: Consultancy, Other: Travel Expenses; Celgene: Consultancy, Other: Travel Expenses. Jacobsen:Astra-Zeneca: Consultancy; Novartis: Research Funding; F. Hoffmann-LaRoche: Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Acerta: Consultancy. LaCasce:Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy; Research to Practice: Speakers Bureau; Humanigen: Consultancy. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy; Celgene/Juno: Consultancy. Armand:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; Infinity: Consultancy; Genentech: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding. Brown:BeiGene: Consultancy; AbbVie: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Juno/Celgene: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; Research to Practice: Honoraria. OffLabel Disclosure: Acalabrutinib, venetoclax, obinutuzumab - combination therapy for previously untreated CLL

Description: Introduction: Classical Hodgkin lymphoma (cHL) is highly curable with front-line multi-agent chemotherapy with or without radiotherapy. The treatment landscape is rapidly evolving, with a continued focus on optimizing available therapies in order to improve outcomes and minimize toxicity. Randomized controlled trials provide valuable insights into new treatments and outcomes; however, real-world data describing treatment effectiveness, safety, and health-related quality of life (HRQoL) are limited. This analysis was conducted to understand patient-reported outcomes (PROs) in patients who were treated for newly diagnosed cHL across a range of academic and community settings. Methods: Study CA209655 is an ongoing, prospective, observational study (NCT02856646) at ~80 US oncology practices with a target enrollment of 500 patients and a planned follow-up of ≤ 5 years. Eligible patients are ≥ 18 years old with histologically confirmed cHL and are treatment naive or within ± 2 weeks of beginning any line of therapy at time of enrollment. HRQoL is a secondary endpoint and evaluated using the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) questionnaire. The FACT-Lym combines a generic cancer-related core consisting of the FACT-General (FACT-G; 27 items) that assesses physical (PWB; 7 items), social/family (SWB; 7 items), emotional (EWB; 6 items), and functional well-being (FWB; 7 items), and a 15-item disease-specific lymphoma subscale (LymS) that assesses lymphoma-specific symptoms. PROs were assessed using questionnaires at baseline (BL), every 3-6 months for ≤ 2 years, and annually thereafter. All patients with BL and ≥ 1 post-BL assessment were included in the PRO analysis. Completion rates and changes from BL scores were evaluated descriptively and analyzed based on published estimates for clinically important differences and individual responder definitions (Hlubocky et al. Lymphoma 2013; Carter et al. Blood 2008; Yost and Eton. Eval Health Prof 2005). High scores indicate better health/functioning for all scales/subscales. Results: Of 278 enrolled patients at data cutoff (Feb 2019), 226 (81%) were treatment naive; for those, the most common index therapy was chemotherapy (n = 210; 93%). The most common index chemotherapies were ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine; n = 187, 83%) and AAVD (adriamycin, brentuximab, vinblastine, dacarbazine; n = 10, 5%). Only patients receiving index chemotherapy were included in the full analysis set. In all, 89% (87/210) of patients had BL and ≥ 1 post-BL assessment and were included in the PRO analysis. PRO completion rate at BL was 97% (204/210) and remained 〉 70% up to 24 months for the expected population. Analysis of PROs was not feasible after 24 months owing to small patient numbers (≤ 10); therefore, PRO analyses were focused on the first 18 months. At BL, mean (SD) scores were: FACT-Lym total, 122 (24); FACT-G, 82 (15); PWB, 21 (6); SWB, 25 (3); EWB, 18 (4); FWB, 18 (6); and LymS, 40 (11). At 3 months there was a deterioration in mean scores from baseline in FACT-G (−3.8) and PWB (−3.0) (Figure A). Clinically meaningful improvement of mean scores was observed starting at 6 months in LymS (+4.4) and at 9 months in FACT-G (+7.1), PWB (+3.1), FWB (+2.8), and FACT-Lym total (+15.6). There were no clinically meaningful improvements in SWB and EWB. Based on individual responder definitions, ≥ 50% of patients had improvements in PWB (Figure B) and FACT-G from 12 months, and FACT-Lym total from 9 months. Conclusions: Initial data from this observational study suggest most patients receive multi-agent cytotoxic chemotherapy as first-line treatment of cHL. Patient-reported PWB initially declined with chemotherapy, but improved with time, and patients had a clinically meaningful improvement in HRQoL by 9 months. The timing of this improvement may be due to discontinuation of chemotherapy due to disease control. Future analyses will evaluate the relationship between improvements in HRQoL and other factors including response, use of immunotherapies versus chemotherapy, and the timing of treatment discontinuation. Study support: Bristol-Myers Squibb. Disclosures Svoboda: Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy; Celgene: Research Funding; Kyowa: Consultancy; Kite: Consultancy. Armand:Roche: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; Infinity: Consultancy; Genentech: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding. Taylor:Adelphi Values: Employment, Other: I am an employee of Adelphi Values, a consulting firm who has received payment from Bristol-Myers Squibb for statistical data analysis in Bristol-Myers Squibb's trials. Sun:Adelphi Values: Employment. Gajavelli:Bristol-Myers Squibb: Employment. Peterson:Bristol-Myers Squibb: Employment, Equity Ownership. Chen:Bristol-Myers Squibb: Employment.

Description: Disease type and status at the time of allogeneic hematopoietic stem cell transplantation (HSCT) dominantly influence HSCT outcome. It is therefore important to stratify patients by disease risk in any retrospective or prospective transplantation study that enrolls patients across multiple disease types or status. We previously proposed a Disease Risk Index for this purpose, based on a retrospective study of patients transplanted at 2 institutions (Armand et al, Blood 2012;120:905). Here we present the results of a study designed to validate and refine the DRI in a larger multicenter population. We included 13,131 adult patients who underwent HSCT for hematologic malignancies, excluding very rare diseases, between 2008 and 2010 and were reported to the CIBMTR. Their median age was 52 (range, 18-80) years. The cohort included a broad representation of diseases, disease status, donor types, and graft sources. 53% of patients were conditioned with a myeloablative regimen. The median follow-up for survivors was 24 months. The original DRI stratified patients into 4 groups with 2y OS of 64% in the low-risk, 51% in the intermediate, 34% in the high, and 24% in very high risk group (p

Description: Background: Induction chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for transplant eligible (TE) patients (pts) with untreated mantle cell lymphoma (uMCL); however, there is no consensus on the optimal induction regimen. The addition of rituximab + high-dose cytarabine (RC) to an RCHOP-like regimen is associated with better outcomes. In addition, two randomized trials have demonstrated superior efficacy and tolerability for rituximab/bendamustine (RB) compared to RCHOP for uMCL. Based on this, we conducted a phase 2 trial of 3 cycles of RB followed by 3 cycles of RC in 23 TE pts with uMCL, with encouraging preliminary results (Armand, BJH 2016). Pts continued to be followed for relapse and survival. Meanwhile, RB/RC became the standard frontline regimen at Dana-Farber Cancer Institute (DFCI). Simultaneously, investigators at Washington University in St. Louis (WUSTL) initiated a similar study of alternating cycles of RB/RC for uMCL. Herein, we report the results of both phase 2 trials as well as the off-trial experience. Methods: In the DFCI trial, TE pts (age 18-69) with uMCL were treated with 3 cycles of RB (R 375 mg/m2 d1, B 90 mg/m2 d1-2) followed by 3 cycles of RC (R 375 mg/m2 d1, C 3gm/m2 BID d1-2 with dose reductions for age, renal dysfunction, or pre-existing neurotoxicity). Off-trial pts treated with RB/RC at DFCI or in consulting community practices were retrospectively identified using clinical and pharmacy databases. In the WUSTL trial, TE pts (age 18-65) received alternating cycles of RB (cycles 1, 3, 5) and RC (cycles 2, 4, 6) (same dosing as above). Response assessments were made using CT scans for the DFCI trial and PET/CT for the WUSTL trial and DFCI off-trial pts. Results: In total, 86 pts (23 DFCI trial, 49 DFCI off-trial, 14 WUSTL trial) were treated with RB/RC. The median age was 57 (range 30-72). Pts in the WUSTL cohort were more likely to be male, have a high MIPI score, and have blastoid variant (Table). 94% of pts completed 6 cycles of RB/RC therapy. Off-trial pts were more likely to receive a lower starting dose (≤ 2gm/m2) of cytarabine (76%) compared to trial pts (38%). At the EOI, the overall response rate and CRR were 98% and 92%, respectively, with similar response rates across cohorts (Table). 73 pts (85%) subsequently underwent ASCT and 4 additional pts (5%) have ASCTs planned. 9 pts did not undergo ASCT because of persistent or PD (n=3), prolonged cytopenias (n=3), an incidentally identified ASXL1 mutation without cytopenias (n=1), pt preference (n=1), and inadequate stem cell collection (n=1). Delayed platelet engraftment after ASCT was seen for pts receiving alternating cycles of RB/RC compared to sequential RB/RC at day 30 (plts

Description: Abstract 4476 Chronic graft-versus-host disease (cGVHD) is a serious and frequent complication of allogeneic hematopoietic stem cell transplantation (HSCT). It is not known why some patients develop cGVHD and others do not, but identifying predictive biomarkers would facilitate the development of pre-emptive therapeutic strategies. Investigation into the pathophysiology of cGVHD has revealed different patterns of immune reconstitution in patients who develop cGVHD following HSCT. This suggests that the development of cGVHD occurs as a result of altered immune homeostasis and the inability to establish B and T cell tolerance. We prospectively examined 88 patients with hematologic malignancies following allogeneic HSCT at the Brigham and Woman's Hospital/Dana-Farber Cancer Institute between the years 2004 and 2008 and measured plasma cytokines known to modulate effector T cell, regulatory T cell, and B cell homeostasis and function. Seventy-six patients (86%) received reduced intensity conditioning; 84 (95%) received filgrastim-mobilized peripheral blood stem cells. Median follow-up for all patients was 5 years (range 2.9 to 7.3 years). Fifty-nine percent developed cGVHD. Plasma samples were collected at 1, 3, 6, and 12 months after HSCT and multiplex Luminex bead assays were used to measure levels of the following cytokines: Interferon-γ, IL-2, IL-7, IL-1β, IL-12, TNFα, IL-4, IL-5, IL-6, IL-10, and GM-CSF. Cytokine levels in patients who developed cGVHD were compared to patients who did not develop cGVHD. Results are shown in figure 1. Significantly higher levels of IL-4, IL-6, IL-12, and IL-1β were observed at 1 and/or 3 months after transplantation in patients who subsequently developed cGVHD. IL-4 and IL-6 are characteristic of T-helper-2 (TH2) cellular and humoral immune responses previously associated with cGVHD and fibrogenesis. IL-12 and IL-1β have heterogeneous functions including stimulating interferon-γ and TNFα production, enhancing cytotoxic and helper T cells, and promotion of autoimmunity. IL-1α also stimulates IL-6 production and activates fibroblasts. Finally, GM-CSF was significantly elevated in patients who do not develop cGVHD at 1 year following HSCT (2.5 v 1.46 pg/mL, p=0.017). As shown in figure 1, we observed a general pattern for many cytokines, including IFNγ, IL-2, IL-4, IL-5, IL-6, and IL-1β, in which these cytokines are initially similar in both groups, or lower in patients without cGVHD, but gradually increase over time in patients who do not develop cGVHD. In contrast, cytokine levels remain stable in patients with cGVHD and are generally lower 1 year after transplantation in these patients. These late differences may reflect immune suppressive therapies as well as persistent abnormalities of immune homeostasis. Taken together, these results support the hypothesis that alterations in immune homeostasis early after allogeneic HSCT are significantly associated with the subsequent development of cGVHD. Manipulation of the cytokine environment early after HSCT can modulate immune homeostasis and may be of potential prophylactic value. Administration of homeostatic cytokines late after HSCT may also have therapeutic benefit. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Autologous stem cell transplantation (ASCT) can be curative for patients (pts) with relapsed/refractory Hodgkin lymphoma (HL) who are sensitive to salvage therapy, particularly for pts who achieve a complete metabolic response (CMR) before ASCT. Pts who fail multiple salvage regimens have inferior outcomes and are generally considered poor candidates for ASCT. Recent studies suggest that anti-PD-1 monoclonal antibodies (mAbs) may restore sensitivity to cytotoxic therapy in HL pts with previously chemorefractory disease. We hypothesized that PD-(L)1 mAb-based salvage therapy may therefore also improve ASCT outcomes for HL pts who had failed salvage therapy. Methods: Medical records were reviewed at 13 US transplant centers to identify pts with a diagnosis of classic HL who failed at least 2 systemic therapies, were treated with a PD-1 or PD-L1 mAb (either alone or in combination) as 3rd line or later therapy, and subsequently underwent ASCT. Results: 44 eligible pts were identified. The median age was 33 (range 19-68). Pts received ABVD (39), AVD (2), brentuximab vedotin (BV) + AVD (1), Stanford V (1), or eBEACOPP (1) as 1st line therapy. 26 pts (59%) were refractory to 1st line treatment and 8 additional pts (18%) relapsed within 12 months. High-risk clinical features were observed frequently at 1st relapse including extranodal involvement (47%), B symptoms (27%), and advanced stage (64%). Pts received PD-(L)1 based treatment after failing 2 lines (32%), 3 lines (57%), or ≥4 lines (11%) of therapy. 32 pts (73%) were refractory to the line of therapy before PD-(L)1, 25 pts (57%) to 2 consecutive lines before PD-(L)1, and 10 pts (22%) to 3 consecutive lines before PD-(L)1. 16 pts (36%) were refractory to ≥2 salvage therapies immediately before PD-(L)1 therapy and 17 (39%) were refractory to all prior treatments. 39 pts (89%) received BV or a BV-based combination before ASCT. 67% were BV-refractory, including 86% of those receiving BV monotherapy. Pts received a median of 6 doses of a PD-(L)1 mAb (range 2-26) either as monotherapy (75%) or as part of a PD-1 based combination (25%). The median time from last dose of PD-(L)1 mAb to ASCT was 54 days (range 12-386). Best response to PD-(L)1-based therapy was CR (53%), PR (33%), SD (12%), or PD (2%). The median number of systemic therapies (including PD-(L)1) before ASCT was 4 (range 3-7) and 12 pts (27%) received intervening salvage therapy between PD-(L)1 treatment and ASCT. Pre-ASCT PET status was CR in 31 pts (70%), PR in 9 (18%), SD in 4 (9%), and PD in 1 (2%). There were no ASCT-related deaths. 2 pts developed BCNU pneumonitis and 1 developed engraftment syndrome. All 3 pts responded to steroids. 14 pts (32%) have received maintenance therapy with BV (4), a PD-1 mAb (8), or BV + PD-1 mAb (2). 4 pts (9%) received consolidative radiation. With a median post-ASCT follow-up of 12.2 months, progression-free survival (PFS) at 1 yr was 91% [95CI 75-97]. Notably, resistance to chemotherapy before PD-(L)1 therapy did not predict worse post-ASCT outcomes (see Table). 1-yr PFS was 90% for pts who were refractory to the 3 lines of therapy before PD-(L)1, 93% for pts refractory to ≥2 salvage therapies immediately before PD-(L)1, and 90% for pts refractory to all prior treatments. Favorable 1-yr PFS was also seen among pts who received PD-(L)1 as 4th or later line therapy (88% vs 100% for pts receiving PD-[L]1 as 3rd line, p=0.17) and among pts who failed to achieve a CMR on pre-ASCT PET (1-yr PFS 81% vs 96% for CMR pts, p=0.34). Lack of response to PD-(L)1 therapy (1-yr PFS 67% vs 96%, p=0.04), receipt of intervening salvage therapy (1-yr PFS 72% vs 100%, p=0.026), and increasing age (HR 1.11, p=0.015) were all significant predictors of inferior PFS. 1-yr overall survival was 100%. Conclusions: This high-risk cohort is heterogenous in terms of number of prior therapies and degree of chemoresistance, but excellent post-ASCT outcomes were observed among even the most heavily pre-treated, chemorefractory subgroups. Outcomes for PD-(L)1 responders were particularly favorable with a 1-yr PFS of 96%, suggesting that response to PD-(L)1 rather than prior chemotherapy may be the more important predictor of post-ASCT outcomes in this pt population. While longer follow-up is required to confirm the durability of these remissions, ASCT can be considered for HL pts responding to PD-(L)1 based salvage therapy, even if they have previously demonstrated a high degree of chemoresistance. Table Disclosures Nieto: Novartis: Research Funding; Astra-Zeneca: Research Funding; Affimed: Research Funding; Affimed: Consultancy. Byrne:Karyopharm: Research Funding. Maddocks:BMS: Research Funding; Novartis: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding. Svoboda:BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy; Celgene: Research Funding; Kyowa: Consultancy; Kite: Consultancy. McGuirk:Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Bellicum Pharmaceuticals: Research Funding. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Millennium: Research Funding; Janssen: Research Funding; Cell Medica, Ltd: Consultancy; Regeneron: Research Funding; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stanford University: Employment, Equity Ownership; Agensys: Research Funding; Kura: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Infinity Pharma: Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cohen:Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; ASH: Research Funding; Lymphoma Research Foundation: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Frigault:Xenetic: Consultancy; Foundation Medicine: Consultancy; Novartis: Consultancy; Nkarta: Consultancy; Juno/Celgene: Consultancy; Kite/Gilead: Honoraria; Incyte: Consultancy. Chen:Magenta: Consultancy; Takeda: Consultancy; Incyte: Consultancy; Kiadis: Consultancy; Abbvie: Consultancy. Lynch:Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Rhizen Pharmaceuticals S.A: Research Funding; Juno Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; T.G. Therapeutics: Research Funding. Smith:Seattle Genetics: Research Funding; Denovo Biopharma: Research Funding; Ayala (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Incyte Corporation: Research Funding; Ignyta (spouse): Research Funding; Genentech: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ho:Jazz Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy; Omeros Corporation: Membership on an entity's Board of Directors or advisory committees. Armand:Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sigma Tau: Research Funding; Infinity: Consultancy; Otsuka: Research Funding; Genentech: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding; Roche: Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Herrera:Merck: Consultancy; BMS: Consultancy; Genentech: Research Funding; Adaptive Biotechnologies: Consultancy; Gilead Sciences: Research Funding; KiTE/Gilead: Consultancy; Genentech: Consultancy; Merck: Research Funding; Astra-Zeneca: Research Funding; Seattle Genetics: Consultancy; BMS: Research Funding; Seattle Genetics: Research Funding.

Description: Abstract 1216 Poster Board I-238 Background: PD-1 (Program Death-1), an immune inhibitory receptor and its ligands PD-L1 and PD-L2, participate in peripheral tolerance and play a key role in immune suppression and evasion mechanisms in cancer and chronic infectious diseases. PD-1 inhibits activation signals and functions as a pro-apoptotic receptor in effector lymphocytes, and consequently regulates the extent and duration of specific adaptive and innate immune responses. CT-011, a humanized antibody, blocks the function of PD-1, resulting in increased activities of T and NK cells in vitro and in enhanced tumor immunity in experimental tumor models. At the molecular level, the antibody enhances PI3K-mediated survival and trafficking signals, attenuates cell death in effector/memory (CD4+CD45RO+) cells, and enhances trafficking in response to Stromal Cell-derived Factor-1 (SDF-1). We hypothesized that CT-011 would enhance effector/memory cells in patients with DLBCL after AuSCT and delay recurrence. Methods: We treated 41 patients (pts) with DLBCL from 30-90 days after AuSCT with CT-011 and now report data on effector/memory and memory lymphocytes in the first 30 pts. CT-011 was given at a dose of 1.5mg/kg for 3 doses, 6 weeks apart. The primary endpoint was to determine the proportion of patients who have not relapsed or died within 18 months following autologous PBSCT, and it is too early for that analysis. Our secondary endpoint was to measure the number of effector /memory and memory lymphocytes before and after treatment, and those data are the subject of this report. Results: Flow cytometry analyses (Table) on pre (baseline: BL) and post-treatment blood samples from the first 30 pts enrolled show elevated levels of specific effector/memory and memory CD4+ T lymphocytes following treatment with CT-011; the median absolute number (ABS) of effector/memory CD4+CD45RO+CD62L-CCR7- cells was increased by +49% from BL (p

Description: Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for nearly 3% of all newly diagnosed NHLs. Treatment of adult non-HIV-related BL with the intensive CODOX-M/IVAC regimen (modified Magrath regimen) produces complete responses (CR) in 75 to 86% of patients, with lower CR rates reported in HIV-related BL. The CD20-directed monoclonal antibody rituximab has never been reported in combination with CODOX-M/IVAC, and here we report the first series in BL patients, with or without HIV infection. A total of 24 patients were identified at our institutions who received rituximab plus CODOX-M/IVAC with curative intent. Rituximab was administered at 375mg/m2 on day 3 of cycle 1, and then on day 1 of subsequent cycles. Twenty-three patients received 4 alternating cycles of R-CODOX-M/R-IVAC for high risk disease, while 1 patient received 3 cycles of R-CODOX-M alone for low risk disease, defined as a single focus less than 10cm with a normal LDH. All patients received white cell growth factor support, and pneumocystis prophylaxis was included for all HIV+ patients. The median age was 45 years (17–67), advanced Ann Arbor stage 80%, LDH 〉 upper limit of normal 80%, extra nodal involvement 80% and ECOG PS

Description: Background: Outcomes to salvage therapy for patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) are suboptimal. Checkpoint blockade therapy (CBT) has been explored in the relapsed/refractory (R/R) NHL population, but response rates to single agent CBT therapy are modest. To date, there is no literature on whether treatment with CBT may sensitize NHL patients to subsequent therapy. We investigated the outcome of subsequent treatment in patients with R/R NHL who had received CBT in a large multicenter international retrospective analysis. Methods: Seventeen centers across the US and Canada are participating in this study to date. Medical records of each institution were queried to identify lymphoma patients who received CBT and were subsequently treated with an additional line of therapy. The primary aim of the current analysis was to determine the best response to post-CBT treatment in patients who discontinued CBT due to progression of disease (PD) or toxicity. Patients who discontinued CBT due to a complete response (CR), or patients whose best response to post-CBT therapy could not be determined due to death from another cause, were excluded from analysis. Responses were assessed using Lugano criteria. Survival status to date was analyzed for the entire study population and stratified by post-CBT treatment regimen categories and disease subgroups using the Kaplan-Meier method. Progression free survival (PFS) and overall survival (OS) were calculated for patients with at least stable disease (SD) to post-CBT treatment. Log rank tests were performed to test for statistical significance. Two-sided P

Description: Key Points CTLA-4 is enriched in the microenvironmental niche in cHL, and identifies a T-cell population largely distinct from PD-1 CD86, the natural ligand for CTLA-4, is enriched in the niche and expressed on HRS cells and a subset of TAMs that also express PD-L1