ALBERT

Description: Ibrutinib is a promising targeted therapy for chronic lymphocytic leukemia (CLL). However, a small subset of patients progress on ibrutinib either through progressive CLL or Richter's transformation. Patients responding to ibrutinib and then progressing with Richter's transformation do so most commonly within the first 2 years of treatment and have an extremely poor prognosis. Identifying biomarkers associated with this transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas; however, its incidence in CLL has not been described. We investigated the prevalence of near-tetraploidy in CLL patients prior to starting ibrutinib and identified it as a pre-treatment biomarker for Richter's transformation. We examined near-tetraploidy in a large series of CLL patients enrolled across four ibrutinib clinical trials at the Ohio State University, for which extensive correlative studies and follow up data are available (previously described by Maddocks et al., JAMA Oncol, 2015). We identified this abnormality in 9 of 300 patients (3.0%, 95% CI: 1.4-5.6) in blood or bone marrow samples taken prior to starting therapy. Near-tetraploidy was detected by the presence of four signals with four or more fluorescence in situ hybridization (FISH) probes and confirmed in the metaphase karyotype of each patient in at least one cell. Near-tetraploidy was associated with aggressive disease characteristics including: Rai stage 3/4 (p=0.03), deletion 17p (p=0.03), and complex karyotype (p=0.01), as well as trisomy 12 (p=0.05). With a median follow-up time of 40.5 months, in patients positive with near-tetraploidy, one patient (11%) progressed with CLL on ibrutinib, six patients (67%) progressed with Richter's transformation, and two patients (22%) were still on treatment. Cumulative incidence of Richter's transformation was significantly higher in patients with near-tetraploidy (Figure; p

Description: Overexpression of the oncomiR, miR-155, is known to be predictive of poor outcome in chronic lymphocytic leukemia (CLL) patients. Using NanoString Technologies’ nCounter platform, we interrogated the miR-155 expression levels in 109 previously untreated CLL patients receiving chemoimmunotherapy on CALGB 9712 or CALGB 10101. The data, dichotomized around median expression, showed that high expressers of miR-155 had shorter progression-free survival (p=0.005) and a higher risk of death after 4 years on study (p=0.004). The expression of miR-155 was not significantly associated with the majority of baseline demographic, clinical and cytogenetic characteristics, including age, Rai stage and high-risk cytogenetics [del(17p)/del(11q)] (p〉0.15). Association of high miR-155 expression with IGHV un-mutated disease(p=0.03) and ZAP70 methylation

Description: Background: Donor grafts with more naive T cells and plasmacytoid dendritic cells were associated with improved overall survival after unrelated donor bone marrow, but not peripheral blood stem cell (PBSC) transplants (Waller, E JCO 2014). Here we present results on influence of innate and adaptive immune subsets in G-CSF mobilized allografts on incidence of acute GVHD (aGVHD) and chronic GVHD (cGVHD) in 238 patients (pts). Methods: We analyzed the absolute numbers and percentages of T, NK, NKT and B cells along with an extensive immunophenotypic characterization of their activation status in consecutive PBSC allografts obtained from sibling and unrelated donors between 2010 - 2014 and studied their association with the incidence of aGVHD and cGVHD. Wilcoxon rank sum tests were used to screen differential marker expression between those who did vs. did not develop aGVHD and similarly for cGVHD. Significant markers were evaluated in the multivariable (m.v.) setting along with known prognostic factors, including: recipient age, related vs. unrelated donor, female donor vs. not, Anti-thymocyte globulin (ATG) use (yes vs. no), and Reduced-intensity conditioning (RIC) vs. not. Cutpoints for markers were generated using recursive partitioning algorithms and evaluated in m.v. models. Results: Of the 238 alloSCT pts evaluated, most (71%) had unrelated donors, 64% received ATG, where most pts with unrelated donors received ATG (83%), and 78% received RIC. The incidence of aGVHD and cGVHD was 58% and 38% respectively. A total of 107 pts had grade II-IV aGVHD reported (71 II, 28 III, 8 IV), and 92 of 192 evaluable for cGVHD (at least 100 days of f/u) had reported cGVHD. Median follow-up in living pts was 21 months (range: 1.4 to 41.1 months). Table 1 shows dichotomized markers most influential on aGVHD. Higher absolute numbers of T cells, activated T cells, CD8+ cells, CD8+ cells expressing IL-7 receptor and CD27 were associated with higher incidence of aGVHD. Higher number of Stage 4 NK cells expressing stem cell factor receptor, and T-regs were associated with a lower incidence of aGVHD. Similar analyses were done for cGVHD (Table 2). Higher absolute numbers of activated T lymphocytes, activated B lymphocytes, KIR expressing CD3+ cells, CD8+ lymphocytes and activated NK cells were associated with higher incidence of cGVHD. When the percent of these makers in relation to total lymphocytes was evaluated regarding association with aGVHD, higher percent of T-regs (OR: 0.204, p=0.0018), effector memory T cells (OR: 0.45, p=0.024) and NKG2D positive NK cells (OR: 0.38, p=0.0008) conferred protection from aGVHD . Similar analysis for cGVHD showed higher percent of naïve CD4+ T cells conferred protection from cGVHD (OR: 0.44; p=0.0062) while higher percent of CD8+ cells (OR: 3.93; p=0.0032) and activated NK cells (OR: 2.08; p=0.024) was associated with cGVHD. Conclusions: These results show a protective role of donor T-regs, CD4+ T cells and Stage 4 NK cells from aGVHD. Additionally, higher content of activated T cells, CD8+ cells and B lymphocytes are associated with higher incidence of cGVHD. Higher content of activated NK cells seems to protect from aGVHD, but not from cGVHD. Updated results including multivariable analyses will be presented. These findings showing the influence of specific subsets in the allograft on aGVHD and cGVHD may provide opportunities for therapeutic interventions for graft engineering or pharmacologic methods for targeting specific immune subsets to decrease incidence of aGVHD and cGVHD. Table 1 Univariate model results for aGVHD with dichotomized markers using cutpoints: Marker Absolute OR p-value CD3+/CD5616- (T lymphocytes) 3.07 0.0013 CD3+/HLA DR+ (Activated T lymphocytes) 3.26 0.012 CD8+/CD45RA- (CD 8+ lymphocytes) 2.56 0.012 CD8+/CD27+ (Effector Memory CD8 cells) 3.25 0.0082 CD8+/CD127+ ( CD8 cells expressing IL-7 receptor) 2.92 0.073 CD4+/CD25+/CD127-(T regs) 0.43 0.057 CD3-/CD16-/CD56+/CD117+ (Stage 4 NK cells expressing Stem cell factor receptor) 0.12 0.0007 Table 2 Univariate model results for cGVHD with dichotomized markers using cutpoints: Marker Absolute OR p-value CD3+/HLA DR+ (Activated T lymphocytes) 4.41

Description: Introduction Blocking Bruton tyrosine kinase (BTK) with ibrutinib has demonstrated efficacy in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) patients (pts). However, resistance to therapy is common. Preclinical data suggest selinexor (oral selective inhibitor of nuclear export) downregulates BTK (Hing 2015). We hypothesized that dual BTK blockade by combining ibrutinib and selinexor would be tolerable and efficacious in CLL/NHL pts. Herein, we report the phase I combination study with expansion cohorts. Methods Pts with histologically confirmed CLL/NHL were enrolled (n=33). Eligible pts were age ≥18 years (yrs), had ≥1 prior therapy and ECOG performance status of 0-1. CLL pts met iwCLL 2008 criteria for therapy. Pts received selinexor orally 1-2 times weekly (3 weeks of 4-week cycle) and daily oral ibrutinib (420mg) starting Cycle 1 Day 8. Treatment cycles were repeated until disease progression, intolerance, death or discontinuation of trial participation. Primary endpoint was determination of maximum tolerated dose (MTD). Dose-finding proceeded using a modified continual reassessment method targeting a probability of dose limiting toxicity (DLT)

Description: Background: Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR)-T cell therapy that is approved for adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). In the phase 2 JULIET trial, pts could receive bridging therapy (BT), when needed, to permit flexibility in scheduling and maintain disease control. Lymphodepleting chemotherapy (LDC) was started 5-14 days prior to CAR-T cell infusion. Here we present baseline characteristics, efficacy/safety outcomes, and cellular kinetics by BT and type of LDC used in the JULIET trial. Methods: Pts were categorized based on BT or no BT, as well as LDC (cyclophosphamide/fludarabine [Cy/Flu; 250 and 25 mg/m2 IV daily for 3 doses, respectively] or bendamustine [90 mg/m2 IV daily for 2 days]) or no LDC, received prior to tisagenlecleucel infusion. Cy/Flu was the proposed regimen for LDC, followed by bendamustine (if the pt experienced previous grade [G] 4 hemorrhagic cystitis with Cy or demonstrated resistance to a previous Cy-containing regimen). LDC was not required if white blood cell count was 8 weeks to ≤1 year post-infusion, 〉1 year post-infusion, and any time after infusion were generally consistent across BT and LDC groups for prolonged cytopenias, neurological events (NE), cytokine release syndrome (CRS), and infection (Table). Of note, among pts who did not receive BT, only 1 G3 CRS and 1 G3 NE were reported, and no G4 CRS or NE were reported. Additionally, the rate of cytopenias not resolved by day 28 post-infusion was lowest among pts who did not receive BT (1/11 pts). However, cytopenias resolved to ≤G2 by month 3 or month 6 in the majority of pts. Cmax, Tmax, and exposure (AUC0-28d) were similar between LDC groups (Table). Cmax and AUC0-28d were also similar between pts who received BT and those who did not. Additional analyses of subgroups will be presented at the congress. Conclusions: The majority of pts enrolled in the JULIET trial received BT and LDC, indicating high tumor burden and aggressive disease in this pt population with r/r DLBCL. Although the sample size is small (n=11), pts not requiring BT appeared to have less aggressive disease, achieved high response rates, and had no G4 CRS or NE. Pts who did not receive LDC (n=8) seemed to have low response rates, suggesting either the impact of prior therapy, the importance of LDC, or both. Further evaluation of the impact of BT and LDC on clinical outcomes on larger patient population will be possible with the availability of registry data. Clinical trial information: NCT02445248 Table Disclosures Andreadis: Genentech: Consultancy, Employment; Merck: Research Funding; Roche: Equity Ownership; Novartis: Research Funding; Celgene: Research Funding; Juno: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy; Kite: Consultancy; Jazz Pharmaceuticals: Consultancy. Tam:BeiGene: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie company: Honoraria; AbbVie: Honoraria, Research Funding. Borchmann:Novartis: Honoraria, Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. McGuirk:Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding. Holte:Novartis: Honoraria, Other: Advisory board. Waller:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy. Jaglowski:Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding. Bishop:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foley:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau. Westin:Curis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Unum: Research Funding; Kite: Other: Advisory Board, Research Funding. Fleury:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy. Ho:Novartis: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs. Mielke:DGHO: Other: Travel support; IACH: Other: Travel support; EBMT/EHA: Other: Travel support; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; ISCT: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution). Teshima:Novartis: Honoraria, Research Funding. Salles:Epizyme: Consultancy, Honoraria; Amgen: Honoraria, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Schuster:Novartis: Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors (royalties to Novartis); i3Health, Dava Oncology, Novartis, OncLive, PER Oncology: Speakers Bureau; AbbVie, Acerta, Celgene, DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, TG therapeutics: Research Funding; AbbVie, Celgene, Novartis, Nordic Nanovector, Pfizer: Other: steering committee; Acerta, AstraZeneca, Celgene, Juno, LoxoOncology, Novartis: Other: advisory board; i3Health, Acerta, AstraZeneca, Celgene, Dava Oncology, Juno, LoxoOncology, Novartis, Nordic Nanovector, OncLive, PER Oncology, Pfizer: Honoraria. Bachanova:Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Gamida Cell: Research Funding; GT Biopharma: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Maziarz:Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria; Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees. Van Besien:Miltenyi Biotec: Research Funding. Izutsu:Eisai, Chugai, Zenyaku: Honoraria; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Corradini:Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Gilead: Honoraria, Other: Travel Costs; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs. Tiwari:Novartis: Employment. Awasthi:Novartis: Employment. Lawniczek:Novartis: Employment. Eldjerou:Novartis Pharmaceuticals Corporation: Employment. Kersten:MSD: Other: Travel grants, honorarium, or advisory boards; Janssen/Cilag: Other: Travel grants, honorarium, or advisory boards; Kite: Consultancy, Other: Travel grants, honorarium, or advisory boards; Roche: Consultancy, Research Funding, Travel grants, honorarium, or advisory boards; Bristol Myers Squibb: Other: Travel grants, honorarium, or advisory boards; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel grants, honorarium, or advisory boards; Celgene: Other: Travel grants, honorarium, or advisory boards; Gilead: Other: Travel grants, honorarium, or advisory boards; Amgen: Other: Travel grants, honorarium, or advisory boards; Roche: Other: Travel grants, honorarium, or advisory boards; Celgene: Consultancy, Research Funding.

Description: BACKGROUND JULIET (NCT02445248) is a single-arm, open-label, multicenter, global, pivotal phase 2 trial of tisagenlecleucel, a chimeric antigen receptor (CAR)-T cell therapy targeting CD19, that has shown a high rate of durable complete responses (CR) and a manageable safety profile in adult patients with clinically active relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The primary objective was met at the interim analysis, with an overall response rate (ORR) of 59% (CR, 43%; partial response [PR], 16%). Here, we present an updated analysis of the JULIET trial, with a median of 19 months of follow-up, an additional 5 months since the previous report (Schuster et al. EHA 2018), demonstrating sustained activity in this patient population. METHODS Eligible patients were ≥18 years with r/r DLBCL, had received ≥2 lines of therapy, including rituximab and an anthracycline, and were ineligible for or had failed autologous stem cell transplant (ASCT). Tisagenlecleucel was centrally manufactured at 2 facilities (Morris Plains, NJ, USA [main cohort] and Leipzig, Germany [cohort A]) using cryopreserved apheresis material and provided to patients at 27 treatment sites across 10 countries on 4 continents using a global supply chain. The primary endpoint was ORR (CR + PR) per independent review committee. Efficacy results are reported for patients in the main cohort with ≥3 months of follow-up or earlier discontinuation; safety is reported for all infused patients. RESULTS At data cutoff (May 21, 2018), 167 patients were enrolled and 115 were infused (99 in the main cohort and 16 in cohort A) with a single dose of tisagenlecleucel (median, 3.0×108 [range, 0.1-6.0×108] CAR-positive viable T cells). 90% of infused patients received bridging therapy and 93% received lymphodepleting chemotherapy. Median time from infusion to data cutoff was 19.3 months. Median age was 56 years (range, 22-76 years); 23% were aged ≥65 years. At study entry, 77% of infused patients had stage III/IV disease and 17% had double/triple hit disease. 55% and 43% had germinal center and activated B-cell molecular subtypes, respectively. 51% of patients had received ≥3 prior lines of antineoplastic therapy (range, 1-6); 49% had undergone a prior ASCT. All 99 patients in the main cohort had ≥3 months of follow-up or discontinued earlier and were evaluable for efficacy. ORR was 54% (95% CI, 43%-64%), with 40% CR and 13% PR. ORR was consistent across prognostic subgroups (including prior ASCT and double/triple-hit lymphoma). Median duration of response (DOR) was not reached; the probability of being relapse free was 66% (95% CI, 51%-78%) at 6 months and 64% (95% CI, 48%-76%) at 12 and 18 months. DOR was similar by age group (≥ vs 〈 65 years) and by relapsed or refractory status (Figure). No relapses were observed beyond 11 months after infusion. Median OS for all infused patients was 11.1 months (95% CI, 6.6 months-NE) and not reached (95% CI, 21 months-NE) for patients in CR. OS probability was 48% (95% CI, 38%-57%) at 12 months and 43% (95%CI, 33%-53%) at 18 months (max follow-up, 29 months). No patients proceeded to allogeneic SCT or ASCT while in remission. Grade 3 or 4 adverse events (AEs) of special interest within 8 weeks of infusion included cytopenias lasting 〉28 days (34%), cytokine release syndrome (CRS; 23%, by the Penn scale), infections (19%), febrile neutropenia (15%), neurological events (11%; 1 case of grade 2 cerebral edema), and tumor lysis syndrome (2%). 16% of patients received tocilizumab for CRS management. 3 patients died within 30 days of infusion (all due to disease progression). No treatment-related mortality was reported. Since the previous report, no new deaths occurred due to causes other than disease progression. CONCLUSION Results from this longer-term follow-up show that tisagenlecleucel produced high response rates and durable responses in a cohort of heavily pretreated adult patients with r/r DLBCL. Efficacy was consistent in all predefined subgroups, including elderly patients, patients with r/r disease, and other clinical or biological subgroups expected to have a worse prognosis with available treatments, as demonstrated by similar and sustained DOR and OS following tisagenlecleucel treatment. Figure. Figure. Disclosures Schuster: Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Honoraria. Bishop:Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; United Healthcare: Employment; Novartis Pharmaceuticals Corporation: Speakers Bureau. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Beigene: Honoraria. Borchmann:Novartis: Consultancy, Honoraria. Jaeger:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Waller:Pharmacyclics: Other: Travel Expenses, EHA, Research Funding; Celldex: Research Funding; Kalytera: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cambium Medical Technologies: Consultancy, Equity Ownership. Holte:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Roche, Norway: Research Funding. McGuirk:Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding. Jaglowski:Kite Pharma: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Juno: Consultancy. Tobinai:Abbvie: Research Funding; SERVIER: Research Funding; Takeda: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Janssen: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Andreadis:Cellerant Therapeutics: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Research Funding; Incyte Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Genentech Inc.: Honoraria, Research Funding; Seattle Genetics: Honoraria; Gilead Sciences: Honoraria; Astellas: Honoraria. Fleury:F. Hoffmann-La Roche Ltd: Consultancy; Lundbeck: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy; Merck: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Celgene: Consultancy. Mielke:Celgene: Speakers Bureau; KIADIS Pharma: Speakers Bureau; Miltenyi Biotec: Speakers Bureau; DGHO: Speakers Bureau; EHA: Speakers Bureau. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Bachanova:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Research Funding; GT Biopharma: Research Funding. Foley:Celgene: Honoraria, Speakers Bureau; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel expenses ; Amgen: Honoraria; Janssen: Speakers Bureau; Jazz Pharma: Other: Travel expenses . Ho:Amgen: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: travel to meeting; Celgene: Other: travel to meeting. Wagner-Johnston:JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTEX: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Research Funding. Kersten:Millennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Kite/Gilead: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria. Chu:Novartis Pharmaceuticals Corporation: Employment. Jary:Novartis Pharma AG: Employment. Anak:Novartis Pharma AG: Employment. Salles:Celgene: Honoraria, Other: Advisory Board, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Servier: Honoraria, Other: Advisory Board; Merck: Honoraria; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria; Acerta: Honoraria; Morphosys: Honoraria; Servier: Honoraria; BMS: Honoraria, Other: Advisory Board; Epizyme: Honoraria; Abbvie: Honoraria. Maziarz:Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria; Kite Therapeutics: Honoraria; Athersys, Inc.: Patents & Royalties.

Description: Background: In the phase 2 JULIET trial, tisagenlecleucel, an anti-CD19 CAR-T cell therapy, demonstrated durable responses and manageable safety in adult patients (pts) with r/r DLBCL. Here, we examine the impact of key product cellular attributes of tisagenlecleucel on clinical outcomes. Methods: JULIET is a single-arm, global, phase 2 trial of tisagenlecleucel in adult pts with r/r DLBCL. Samples from 115 tisagenlecleucel individual products were examined at the end of manufacturing at the batch release testing for various product attributes (Table). Additional detailed immunophenotyping for 66 attributes was conducted on previously frozen product samples via flow cytometry (FC). For each cell population of CAR+ T cells, the percentage and absolute number of the subpopulation were analyzed. Univariate and multivariate analyses were performed to evaluate effects of product attributes and CAR+ T-cell phenotypes on efficacy (Month 3 response [M3R], duration of response [DOR], progression-free survival [PFS], overall survival [OS]) and safety (cytokine release syndrome [CRS] and neurological events [NE], grade 0-2 [low] vs 3-4 [severe]). Several exploratory approaches, including machine learning methods (eg, elastic net and random forest), were pursued in conjunction with logistic regression to identify a set of variables associated with clinical outcomes. We included clinically relevant characteristics evaluated at baseline per protocol (LDH, CRP, and tumor volume) with the product attributes in multivariate modeling. Logistic regression was used to model M3R, CRS, and NE. Cox regression was used to model DOR, PFS, and OS. Results: As of December 11, 2018, 115 pts were infused and evaluable. The median T-cell transduction efficiency by FC was 28% (range, 5.3-63.2%); no relationship of these attributes with efficacy (M3R, DOR, PFS, or OS) or safety (severe CRS or NE) was observed. The percentage of viable cells had no impact on efficacy or safety outcomes; this was anticipated since tisagenlecleucel dose is formulated based on the number of viable CAR+ T cells. Tisagenlecleucel demonstrated in vitro functional activity upon CD19-specific stimulation, as evidenced by IFNγ release, with a wide range among different batches (range, 23.7-938 fg/CAR+ cell). Durable responses were observed across the entire range of IFNγ release; high IFNγ release was not associated with severe CRS or NE. The median ratio of CAR+ CD4+ to CD8+ cells was 3.70 (range, 0.26-65.3); no relationship with clinical outcomes was observed (Figure). CAR+ T cells showed variability in T-cell phenotypes, with central memory (CM) cells as the predominant subpopulation of both CD4+ and CD8+ CAR+ T cells (Figure). The majority of CAR+ T cells were highly activated (co-expressing HLA-DR and CD38), as measured by FC. Relative and absolute number of less mature T cells (naive and CM T cells) in the product did not correlate with efficacy. There was no significant correlation between cell populations and efficacy on multivariate analyses. For CRS, the total number of certain CD4+ T cells expressing activation markers (HLA-DR+, CD25+, or HLA-DR+CD38+) and CM cells showed trends of correlation with more severe CRS, but none of these were significant after p-value adjustment; in a multivariate regression model adjusted for LDH and other clinically relevant factors, HLA-DR+ CD38+CD4+ T cells showed a correlation with severe CRS. Correlation analyses did not reveal product attributes significantly related to severe NE. Conclusions: In JULIET, tisagenlecleucel CAR-T cell product attributes had no significant impact on efficacy or NE; the total number of activated CD4+ cells infused positively correlated with higher-grade CRS. There is great variability in the product attributes, especially with respect to T-cell phenotypes, though this variability appears to play a minor role on efficacy. Additional analyses with larger data sets are required to confirm these findings. ClinicalTrials.gov Identifier: NCT02445248. Disclosures Bachanova: Novartis: Research Funding; Gamida Cell: Research Funding; GT Biopharma: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Incyte: Research Funding. Tam:BeiGene: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria; Novartis: Honoraria; AbbVie: Honoraria, Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. McGuirk:Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Holte:Novartis: Honoraria, Other: Advisory board. Waller:Amgen: Consultancy; Kalytera: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property . Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Andreadis:Celgene: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Roche: Equity Ownership; Pharmacyclics: Research Funding; Merck: Research Funding; Gilead: Consultancy; Kite: Consultancy; Genentech: Consultancy, Employment; Juno: Research Funding. Foley:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau. Westin:Unum: Research Funding; Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Kite: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Curis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding. Fleury:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy. Ho:Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Novartis: Other: Trial Investigator meeting travel costs. Mielke:Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; DGHO: Other: Travel support; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; EBMT/EHA: Other: Travel support; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; ISCT: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution); GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; IACH: Other: Travel support. Teshima:Novartis: Honoraria, Research Funding. Salles:Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria. Schuster:Celgene: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Maziarz:Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria; Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Besien:Miltenyi Biotec: Research Funding. Izutsu:Eisai, Chugai, Zenyaku: Honoraria; Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy. Kersten:Celgene: Consultancy, Research Funding; Kite: Consultancy, Other: Travel grants, honorarium, or advisory boards; Janssen/Cilag: Other: Travel grants, honorarium, or advisory boards; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel grants, honorarium, or advisory boards; Gilead: Other: Travel grants, honorarium, or advisory boards; Amgen: Other: Travel grants, honorarium, or advisory boards; Roche: Other: Travel grants, honorarium, or advisory boards; Celgene: Other: Travel grants, honorarium, or advisory boards; Roche: Consultancy, Research Funding, Travel grants, honorarium, or advisory boards; MSD: Other: Travel grants, honorarium, or advisory boards; Bristol Myers Squibb: Other: Travel grants, honorarium, or advisory boards. Wagner-Johnston:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Corradini:Celgene: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Amgen: Honoraria; Janssen: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria. Chu:Novartis: Employment. Gershgorin:Novartis: Employment. Choquette:Novartis: Employment. Bubuteishvili Pacaud:Novartis: Employment. Jeschke:Novartis: Employment.

Description: Introduction: Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course, with many patients (pts) experiencing relapse after initial treatment. Ibrutinib is a first-in-class once-daily, oral, inhibitor of Bruton's tyrosine kinase indicated for treatment of pts with CLL with ≥1 prior therapy and for pts with 17p deletion CLL. Extended follow-up of ibrutinib-treated pts has demonstrated an increase in complete response (CR) rate over time (Byrd, Blood 2015; Brown, Blood 2015). This ad hoc analysis examines baseline factors predictive of CR in pts with CLL/SLL treated with ibrutinib. Methods: Univariate and multivariate analyses were performed on pooled data from studies of pts treated with either single-agent ibrutinib (PCYC-1102, PCYC-1112), or in combination with ofatumumab (PCYC-1109), to assess the prognostic value of various baseline factors on a CR to ibrutinib treatment in CLL/SLL. CR criteria were met per iwCLL parameters, including bone marrow confirmation, which was not mandated at any standard timepoint in any protocol. Both treatment-naive (TN) and previously treated (R/R) pts were included. Factors with P

Description: Background: Patients undergoing allogeneic hematopoietic stem cell transplant with reduced-intensity conditioning (RIC-alloSCT) rely primarily on the graft-versus-tumor (GVT) effect to prevent relapse. Although relapse remains high in this setting, previous data suggest modifications of allograft composition could produce enhanced GVT effect and improve outcomes. Prior retrospective studies suggested higher total nucleated cell (TNC) and CD8 dose correlate with improved overall survival (OS) and a reduction in relapse among all patients undergoing RIC-alloSCT. The aim of our study was to further investigate this association by comparing transplant outcomes with detailed graft immunophenotyping data including T-cell and NK-cell activation and maturation status and CD34 cell doses in patients with AML and MDS undergoing RIC-alloSCT. Methods: We performed a retrospective analysis using data from consecutive patients with AML and MDS who underwent RIC-alloSCT at a single center from 2010-2015 who had graft immunophenotyping data available. We compared transplant outcomes with TNC per kilogram (kg) and dose of CD3, CD4, CD8, CD34, and NK cells along with selected activation and maturation subsets. A competing risk regression analysis was conducted to examine the association between cell dose/kg and risk of relapse and graft versus host disease (GVHD). Overall survival and relapse free survival (RFS) were assessed utilizing the Cox proportional hazard model. Estimates of survival probability were determined by the Kaplan-Meier survival function. The log-rank test was used to compare OS and RFS among patients. Univariable and multivariable regression analyses were performed. Disease Risk Index (DRI) was used to stratify risk among patients. To identify optimal cutoffs (OC) of continuous variables for a specific outcome, a Classification and Regression Tree (CART) algorithm was utilized. Results: Our study included 142 patients who underwent RIC-alloHSCT for AML (n=97, 68%) and MDS (n=45, 32%). The vast majority of patients (98%) received fludarabine and busulfan conditioning with 65% receiving anti-thymocyte globulin. All patients received tacrolimus-based GVHD prophylaxis. Overall relapse rate was 37% at 3 years. Overall survival was 49% with median follow-up of 3.2 years. Total Nucleated Cell Dose: In multivariable analysis controlling for disease, comorbidity index, and performance status, a high infused TNC dose (10.6 - 16.8 x 108 cells/kg) correlated with improved overall survival (HR 0.27, 95% CI [0.12 - 0.59], p=0.001) and relapse free survival (HR 0.31, 95% CI [0.15 - 0.64], p=0.002). However, a very high TNC dose (OC 〉16.8 x 108 cells/kg) correlated with significantly worse OS (HR 2.84, 95% CI [1.16 - 6.98], p=0.023) and trended toward worse RFS (HR 2.09, 95% CI [0.88 - 4.93], p=0.093). Higher TNC doses were also correlated with an increased risk of chronic GVHD (HR 2.16, 95% CI [1.28 - 3.67], p=0.004, OC 9.8 x 108 cells/kg). Cell Subsets: Very low CD3 cell doses (OC

Description: Abstract 1398 Poster Board I-420 Background: Splenectomy remains a standard treatment for ITP patients not responding to medical management, but anecdotal reports suggest that use of the procedure is in decline. We studied patterns of use and outcome of splenectomy performed for ITP at the population level. Methods: Using data from the Nationwide Inpatient Sample and ICD-9 diagnosis and procedure codes, we identified 39,543 splenectomies among hospital admissions including a diagnosis of ITP (ICD-9 287.3) from 1993-2005. Admissions were characterized by patient and hospital facility characteristics. Laparascopic procedures were identified by published procedure coding algorithms. Factors influencing in-hospital mortality for 2005 were further evaluated using multivariate logistic regression models. Results: Annual estimates for incidence of splenectomy are displayed in Figure 1. Between 1993 and 2005, there was a decrease in the total number of splenectomies performed for ITP, with the most significant drop occurring from 1997 to 2000, concurrent with the FDA approval of rituximab. Over the same period, there has been an increase in the proportion of splenectomies performed laparoscopically from 3.4% to 18.6%. Patient gender, age, presence of comorbid malignancy, and Charlson score were not significantly associated with type of splenectomy procedure. Among facility factors, only hospital teaching status was a statistically significant predictor of laparoscopic splenectomy use, early but not later in the observation period. On an annual basis, in-hospital mortality did not vary significantly over the observation period, with risks ranging from 1.5% (95% CI 0.83-2.86%) in 1993 to 4% (95% CI 2.8%-5.7%) in 1997. Annual mortality risk between open and laparoscopic procedures likewise did not significantly differ. However, over the total 13-year observation period there was a 〉60% increased risk of death with an open versus laparoscopic procedure (OR 1.669, p