Academic literature on the topic 'Ann Arbor No. 6 (Car ferry)'

Abstract INTRODUCTION: Circulating tumor DNA (ctDNA), a portion of circulating cell-free DNA (cfDNA), is released from tumor cells into the circulatory system, which contains mutations corresponding to the patient's tumour alleles. Detection of ctDNA may noninvasively signal the presence of minimal residual disease (MRD) and predict prognosis. In recent years, droplet digital PCR (ddPCR) has emerged as a sensitive and effective tool for detection of point mutations in cfDNA. In this work, by application of ddPCR, we monitored the mutated TP53 ctDNA levels in serial plasma samples of lymphoma patients with identified TP53 hotspot mutations in their tumor biopsies. These results may give clues about the prognostic implications of different mutation locations and therapeutic strategies. METHODS: Lymphoma-focused next-generation sequencing were performed in tumor biopsies from over 200 lymphoma patients. A total of 134 sequential plasma samples from 32 lymphoma patients with TP53 hotspot mutations were subsequently monitored. cfDNA was extracted from a median sample volume of 4.8 ml (range 3.5-7.0 ml) of plasma. Specific MGB probes were designed for each TP53 mutation site and were then validated by tumor biopsies as well as healthy plasma samples as positive and negative controls respectively. Patient samples were considered to be mutation-positive if the mutant concentration in the sample was higher than the 95% confidence interval of the assay-specific false positive rate. The ctDNA sequential samples were quantitatively tracked using the ddPCR system QX200 (Bio-Rad Laboratories). RESULTS: 30 different TP53 mutations in 134 plasma samples from 32 lymphoma patients were monitored. All the mutations are hotspot in tumors according to COSMIC database, and are predicted to make damaging effect on TP53 protein by SIFT prediction. The average TP53 mutation frequency in tumor biopsies is 40.41% (2.30~92.21%). A total number of 30 specific MGB probes were designed for each TP53 mutation site. Their average false positive rate is 0.0004 copies/ul (0~0.002 copies/ul). In our results, 6 out of 20 (30%) patients with mutations in Loop3 and LSH motifs within the DNA binding domain of TP53 had a clearance of ctDNA, while 6 of 12 (50%) patients with mutations outside of the Loop3 and LSH motifs had a clearance of ctDNA. Literatures reported that patients with non-detectable ctDNA in plasma have negative minimal residual disease (MRD). So these results suggested that Loop3 and LSH motifs, which were reported to interact with DNA groove directly, are more critical than other structures. To investigate the association between different Ann Arbor stages and prognosis in TP53 mutated patients, we divided all the patients according to their stages. We found that patients with earlier Ann Arbor stages were more likely to have their ctDNA cleared (stage I/II: 83.33%; stage III/IV: 28%). In addition, we also analyzed the prognostic implication of cytogenetic abnormality. We found that, in patients with del (17p) as well as TP53 mutation, 7 of 8 had persistent detectable TP53 mutated ctDNA, only 1 of 8 (12.5%) had a clearance of ctDNA, While among the patients carrying TP53 mutations but not accompanied del (17p), 11 of 24 (45.83%) patients had a clearance of ctDNA. These results suggested that it is more difficult to achieve remission in patients with no wide-type TP53 allele compared to those have one wide-type TP53 allele. We further evaluated CAR-T cell immunotherapy and chemotherapy alone to 30 refractory recurrent TP53 mutated lymphoma patients. After CAR-T cell immunotherapy, 11 of 21 (52.38%) patients have non-detectable TP53 mutated ctDNA, while only 2 of 9 (22.22%) patients who received chemotherapy alone have non-detectable ctDNA. It suggested that CAR-T cell immunotherapy is more effective than chemotherapy alone to clear TP53 mutated ctDNA. CONCLUSIONS: Circulating tumor DNA is a promising biomarker to noninvasively monitor tumor load and quantify MRD. By applying droplet digital PCR, ctDNA could be measured and monitored sensitively, specifically and fast. In this work, we designed and validated 30 TP53 probes and tracked 134 sequential plasma from 32 patients. We found that it is easier to clear ctDNA for earlier stages of lymphoma patients with TP53 mutations. CAR-T cell immunotherapy is more effective than chemotherapy alone to continuously clear ctDNA. DISCLOSURE: No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.

2507 Background: C-CAR039 has been developed as a novel 2nd generation 4-1BB bi-specific CAR-T targeting both CD19 and CD20 antigens with an optimized bi-specific antigen binding domain. C-CAR039 can eradicate CD19/CD20 single or double positive tumor cells in vitro and in vivo. The tissue cross reactivity and whole genome membrane proteome array studies further confirmed the specificity of C-CAR039. Methods: GMP manufacturing of C-CAR039 was carried out in a serum free and fully closed semi-automatic system. Dose escalation and expansion studies were conducted to evaluate the safety and efficacy of C-CAR039 in r/r B-NHL patients. C-CAR039 was administered as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen. Results: As of 1/31/2021, 28 patients were infused and 25 (DLBCL, n = 22; PMBCL, n = 1; tFL, n = 1; FL, n = 1) were evaluable for safety and efficacy at dose ranges of 1.0 x 106 to 5.0x106 CAR-T cells/kg. The median age was 54 (range, 28-71) years, median number of prior lines of therapy was 3 (range, 1–5), 76% (19/25) of patients were in Ann Arbor Stage III/IV, and 80% (20/25) were refractory to their last treatment. 5 patients (20%) received bridging therapy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. Of the 25 patients, 24 (96%) experienced CRS, 23 (92%) were grade 1 or 2, 1 patient was grade 3. Median time to onset of CRS was 3 days (range, 0-10), with median duration of 4 days (range, 1-25). 2 patients had a grade 1 ICANS. Grade≥3 neutropenia, anemia, thrombocytopenia and infection were reported in 88%, 40%, 16% and 0% of patients, respectively. The best overall response rate was 92%, complete response (CR) rate was 84% and median time to response was 1.0 month (range, 0.9-1.2). With a median follow-up of 5.3 months, 76% remained in CR. Kaplan Meyer estimation of PFS at 6 months was 87.3% (95% CI, 71.2 to 100.0). Median duration of response has not been reached. Furthermore, C-CAR039 showed an encouraging cellular kinetic profile. In 25 evaluable patients, the median Tmax was 11 day, the median Cmax was 139,497 copies/mg gDNA, and the median AUC0̃28DAY of 1,673,844 day*copies/μg gDNA. Conclusions: C-CAR039 demonstrated a favorable safety profile and promising efficacy in this early clinical trial in patients with r/r B-NHL that might allow it to differentiate from existing therapies. The early clinical efficacy signal is encouraging and compares favorably to anti-CD19 CAR-T and peer therapies. These findings will be evaluated in more patients with longer follow-up to confirm safety, efficacy and duration of response. Clinical trial information: NCT04317885 , NCT04655677 , NCT04696432 , NCT04693676 .

7512 Background: The combination of Pola-R-Len may enhance anti-tumor response in R/R DLBCL. We report the primary analysis of the R/R DLBCL cohort in a Phase 1b/2 study (GO29834; NCT02600897). Methods: Pts received induction with 6 x 28-Day (D) cycles (C) of: Pola 1.8mg/kg intravenous (IV; C1−6: D1); R 375mg/m2 IV (C1−6: D1) and oral Len 10–20mg (dose escalation) or recommended Phase 2 dose (RP2D) daily on D1–21. Pts with a response at end of induction (EOI) received 6 months (mo) consolidation with R 375mg/m2 (D1 every 2 mo) and Len 10mg (D1–21 monthly). Primary endpoints were safety/tolerability and positron emission tomography (PET)-complete response (CR) rate at EOI by independent review committee (IRC) by modified Lugano criteria. Results: At primary analysis (Sep 08, 2020), 57 pts were enrolled. Median age was 71 years (range 28–92); male (67%); Ann Arbor Stage III–IV (86%); International Prognostic Index 3–5 (60%); median 2 prior therapies; prior bone marrow transplant (11%); prior CAR-T therapy (5%); primary refractory (49%) and refractory to last therapy (65%). Grade 3–4 adverse events (AEs) were experienced by 75% of pts, most commonly, neutropenia (58%), thrombocytopenia (14%), infections (14%) and anemia (11%). AEs led to Len dose reduction in 25% and interruption in 63% of pts. One Grade 5 treatment-related AE (neutropenic sepsis) was reported. In total, 49 pts were treated at RP2D (Pola 1.8mg/kg + Len 20mg). IRC PET-CR rate at EOI was 29% (Table). A best overall response (BOR) assessed by investigator (INV) was seen in 36/49 (74%) pts with 17/49 (35%) pts achieving a CR; of these, 14/17 (82%) remain in remission at the cutoff date. Median duration of response (DOR) was 8.1 mo (95% confidence interval [CI]: 4.7–not evaluable [NE]). After a median follow-up of 9.7 mo, median progression-free survival (PFS) and overall survival (OS) were 6.3 mo (95% CI: 4.5–9.7) and 10.9 mo (95% CI: 7.4–NE), respectively. Conclusions: Our study of the novel triplet combination, Pola-R-Len, demonstrates a tolerable safety profile. This first efficacy report of Pola-R-Len shows promising activity in a difficult-to-treat R/R DLBCL population, particularly in pts achieving CR, a large proportion of whom remain in remission at the cutoff date. Further evaluation of Pola-R-Len and the impact of consolidation therapy is warranted to address the significant unmet need in this patient population. Clinical trial information: NCT02600897. [Table: see text]

Introduction: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has improved survival outcomes in patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL). However, many patients experience systemic toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) and about 60% relapse. Recent studies indicate that the gut microbiome can modulate tumor response and also influence toxicities associated with immune checkpoint inhibitor therapy. However, the influence of gut microbiome has not been well-studied in patients receiving CAR T-cell therapy. Here, we analyzed the association between gut microbiome composition and diversity metrics with survival outcomes and toxicities in r/r LBCL patients treated with anti-CD19 CAR T-cell therapy. Methods: Baseline stool samples were collected from r/r LBCL patients within 3 days of CAR T-cell infusion (days -3 to +3). Taxonomic profiling was performed on all samples using targeted ribosomal 16S RNA gene sequencing of the V4 region. The anti-tumor response was assessed as per Lugano 2014 criteria. Bacterial community alpha diversity was calculated using the inverse Simpson Index (ISI). Results were correlated with toxicity outcomes, including CRS and ICANS, as well as efficacy outcomes, including response, progression-free (PFS), and overall survival (OS). Results: We analyzed baseline stool samples from 33 r/r LBCL patients (24 DLBCL, 7 transformed follicular lymphoma, and 2 double-hit lymphomas) treated with standard of care axicabtagene ciloleucel (n =30) or tisagenlecleucel (n=3). The median age of the cohort (23 males, 10 females) was 54 (range 28 - 84) years. The number of patients with ECOG performance status (PS) 0-1, Ann-Arbor stage ≥3, and International Prognostic Index (IPI) of ≥3 at the time of apheresis were 29 (88%), 33 (100%), and 15 (46%), respectively. The median number of prior lines of therapy was 3 (range 2-6). The median follow-up from CAR-T infusion was 7.3 (range 0.8 -13.6) months. The best overall and complete response (CR) rates were 82% (27/33) and 58% (19/33), respectively. All patients were evaluable for toxicity assessment and 29 were evaluable for response assessment at 3 months (3 patients died of toxicity before 3 months and 1 was lost to follow-up). Since ongoing response at 3 months was previously shown to be associated with long-term durability (Locke et al, Lancet Oncol 2019), we analyzed differences in baseline gut microbiome markers in patients with or without ongoing CR at 3 months post-CAR-T infusion. ISI was significantly higher in patients with ongoing CR at 3 months (N=13) compared to those without ongoing CR (NoCR) group (N=16) (Fig.1A, p=0.045). However, beta diversity using weighted UniFrac distances by principal coordinate analysis was not significantly different. ISI did not correlate with age, sex, IPI score, ECOG PS, serum LDH, number of lines of therapy or disease status (primary refractory vs. relapsed). We found an increased relative abundance of several bacterial families in patients with ongoing CR vs. NoCR group. We also analyzed the impact of gut microbial diversity on PFS and OS by stratifying the patients according to the tertile of ISI. The PFS of patients in the highest tertile of ISI values (n=11, median PFS not reached) was significantly higher compared to those with intermediate (n=11, median PFS = 2.82 months, HR 12.7, 95% CI 3.61 to 44.77, log-rank, p=0.001) or low (n=11, median PFS = 2.43 months, HR 12.9, 95% CI 3.68 to 45.75, log-rank, p=0.001) ISI values (Fig. 1B). High ISI values also correlated positively and significantly with OS (Fig. 1C). We did not observe any significant association between microbial diversity, either alpha or beta, and toxicities including CRS [(grade 0-1 (N=22) vs ≥2 (N=11)] and ICANS [(grade 0-2 (N=23) vs ≥3 (N=10)]. Additional details including impact of microbial composition will be presented at the meeting. Conclusion: Our results suggest that the baseline gut bacterial diversity may serve as a predictive biomarker for efficacy of anti-CD19 CAR T-cell therapy in r/r LBCL patients, with high diversity favoring improved outcomes. If confirmed in larger studies, future investigations should explore if the microbiome could be a modulator of CAR T-cell response in order to determine whether developing therapeutic interventional strategies to favorably alter the microbiome are warranted. Disclosures Nastoupil: TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding; Gamida Cell: Honoraria; Gilead/KITE: Honoraria; Bayer: Honoraria; Pfizer: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Karus Therapeutics: Research Funding. Westin:Janssen: Consultancy, Research Funding; Amgen: Consultancy; Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; 47: Research Funding; Morphosys: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding. Lee:Guidepoint Blogal: Consultancy; Celgene: Research Funding; Seattle Genetics: Research Funding; Oncternal Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau; Takeda: Research Funding. Kebriaei:Kite: Other: Served on advisory board; Novartis: Other: Served on advisory board; Ziopharm: Other: Research Support; Amgen: Other: Research Support; Pfizer: Other: Served on advisory board; Jazz: Consultancy. Shpall:Takeda: Other: Licensing Agreement; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Jain:Cellectis: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Incyte: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Green:KDAc Therapeutics: Current equity holder in private company. Flowers:Kite: Research Funding; Pharmacyclics/Janssen: Consultancy; Spectrum: Consultancy; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; AbbVie: Consultancy, Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Karyopharm: Consultancy; V Foundation: Research Funding; National Cancer Institute: Research Funding; Bayer: Consultancy; Denovo Biopharma: Consultancy; Cancer Prevention and Research Institute of Texas: Research Funding; Millennium/Takeda: Consultancy, Research Funding; BeiGene: Consultancy; OptumRx: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; TG Therapeutics: Research Funding. Champlin:Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Omeros: Consultancy; Johnson and Johnson: Consultancy; Actinium: Consultancy; Takeda: Patents & Royalties. Wargo:Imedex, Dava Oncology, Omniprex, Illumina, gilead, PeerView, PET, MedImmune and Bristol-Myers Squibb: Honoraria, Speakers Bureau; Merck: Consultancy; Microbiome DX: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Astrazeneca: Consultancy; Biothera Pharmaceuticals: Consultancy. Neelapu:Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Novartis: Other: personal fees; N/A: Other; Precision Biosciences: Other: personal fees, Research Funding; Incyte: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties; Poseida: Research Funding; Cellectis: Research Funding; Karus Therapeutics: Research Funding; Calibr: Other; Legend Biotech: Other; Adicet Bio: Other; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Unum Therapeutics: Other, Research Funding.

Introduction: We have previously reported short-term efficacy of six courses of R-DA-EPOCH in patients with aggressive B cell lymphomas carrying concomitant MYC and BCL-2 and/or BCL-6 rearrangement (DHL/THL) or gene increase copy number (ICN) (Tucci et al. Blood S1: 4154, 2017). Further experience with the same program has been described in the meantime in patients with aggressive lymphoma and c-MYC rearrangement, either as single hit or DHL/THL (Dunleavy et al. Lancet Haematol, 2018). We report here long-term results in a larger unselected series of DHL/THL with the aim to confirm our preliminary results and to define the role of consolidation with autologous stem cell transplantation (ASCT) after R-DA-EPOCH remission induction. Methods: The study includes patients consecutively seen in four Italian centres. From January 2014, fit patients aged less than 80 years, with diffuse large B cell lymphoma (DLBCL), lymphoma with intermediate features between DLBCL and Burkitt (BCLU) or high grade lymphoma (HGBCL) histology, diagnosed as DHL or THL by fluorescent in situ hybridization (FISH), were treated with R-DA-EPOCH and central nervous system prophylaxis. Patients with MYC -ICN (three or more extra signals in more than 30% of nuclei, Schieppati et al. Haematologica, 2019) plus BCL-2 and/or BCL-6 gene rearrangement or ICN were also included. Pre-treatment with one cycle of R-CHOP was allowed in patients in need of urgent treatment, pending the results of FISH analysis. Consolidation with ASCT was planned in three of the four centres for stage II-IV patients aged less than 71 who reached at least a partial remission (PR) after six R-DA-EPOCH courses. Immunohistochemistry (IHC) was used to define cell of origin (COO) according to Hans' algorithm, double expressor cases (MYC and BCL-2 protein >40% and 50% respectively) and Ki67 expression. Results: Sixty-three patients were treated (51 DLBCL, 5 BCLU, 7 HGBCL, including 16 with histologic transformation from an indolent lymphoma). Their median age was 63 years (range 23-79) and 43 (68%) were males. Fifty-four (86%) had Ann-Arbor stage III/IV, 18 (28%) B symptoms and 41 (65%) high-intermediate/high risk score according to International Prognostic Index (IPI), with extranodal disease in 79% of patients, mainly in bone and gastrointestinal tract. According to FISH analysis, 34 cases were DHL, 10 THL and 19 c-MYC-ICN. According to IHC, 81% were of germinal center origin, 73% were double expressors and median Ki-67 was 91% (range 35-100%). Patients received a median of six courses of R-DA-EPOCH (range 1-6). Twelve patients were pre-treated with one R-CHOP course and 24 patients (17 in complete remission, 6 in PR and 1 with disease progression) received transplant consolidation (allogeneic SCT in one PR patient), according to the policy of the centre and eligibility criteria. In the entire cohort, the overall response rate was 81%, including 68% complete responses (CR) and 3y-PFS and OS were 67% and 69% respectively. Two patients died of infectious complications during chemotherapy. Of the 10 chemo-refractory patients, all have died of lymphoma. Median length of follow-up was 32 months. At univariate analysis, IPI > 3 and THL were significantly associated with a worse outcome while cMYC-ICN and ASCT with a better OS. At multivariate analysis, only ASCT remained significantly associated with better survival (HR 0.146, IC 95% 0.032-0.667, p 0.013). Focusing on patients who achieved CR with R-DA-EPOCH, all 17 patients who underwent transplantation (100%) are alive (after a median of 27 months from transplant), versus 19 out of 24 patients (79%) who did not. Only one patient relapsed after ASCT and is alive after receiving CAR-T cells. 3y-OS and PFS of patients in CR after induction therapy who received or not ASCT consolidation were 100% vs 76% and 94% vs 72% respectively (Fig.1). Clinical characteristics of the two subgroups were similar except for median age that was lower in the former one (59 vs 69 years). Conclusions: These results confirm the favourable outcome of patients with MYC and BCL-2 and/or BCL-6 rearrangements or gene ICN with R-DA-EPOCH therapy. The role of consolidative ASCT and its usefulness seems encouraging, but remains to be proven by prospective randomized studies. The poor outcome of chemo-refractory patients represents an unmet need and greater expansion of CAR-T cell programs could improve these results in the near future. Disclosures Tucci: Amgen: Consultancy. Carlo-Stella:Boehringer Ingelheim and Sanofi: Consultancy; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding. Corradini:Takeda: Consultancy, Honoraria, Other; BMS: Other; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Rossi:Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

Introduction: The type II anti-CD20 monoclonal antibody, obinutuzumab (OBI) is an effective therapy approved for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL). Data are limited for use of OBI as monotherapy in CLL/SLL as well as across other lymphoma subtypes, other than the GAUSS, GADOLIN, and GAUGUIN trials. We describe our experience of OBI as monotherapy without chlorambucil in the CLL/SLL population and OBI as monotherapy or in combination regimens across non-Hodgkin lymphomas (NHLs). Patients and Methods: We conducted a retrospective cohort study of all adult pts who received OBI for CLL/SLL and NHL at the University of Pennsylvania between 2/2013 and 6/2019. Demographics, overall response, survival, and toxicities were examined. The primary endpoints were progression-free survival (PFS; defined as time from OBI start to disease progression or regimen change, death due to CLL/SLL or NHL or last-follow-up in remission), and overall survival (OS) using the Kaplan-Meier method. All other analyses were descriptive. Indolent lymphomas included follicular, marginal zone, and mantle cell lymphomas. Aggressive lymphomas included diffuse large B-cell lymphoma, Richter transformation, transformed follicular lymphoma, and transformed marginal-zone lymphoma. Results: We identified 78 pts for this analysis. Disease subtypes included CLL/SLL (58%; n=45), follicular lymphoma (13%; n=10), MZL (8%; n=6), MCL (5%; n=5), DLBCL/transformed disease (15%; n=12). Median age of OBI start was 67 years (27-89); CLL/SLL patients (pts) were median Rai Stage 2 and ECOG performance 0. NHL pts were median Ann Arbor Stage IV and ECOG performance 1. Median number of prior therapies was 1 (Range 1-7) in CLL/SLL and 3 in NHL (Range 0-9) with a median time to OBI initiation from last therapy of 12 months (mos) and 1 mos respectively. Of the CLL/SLL population 60% were rituximab naïve and 18% were rituximab refractory; 9% of NHL pts were rituximab naïve and 52% were rituximab refractory. Overall response rate (ORR) for the CLL/SLL cohort was 91%, 80% for FL, 83% for marginal zone lymphoma (n=6), 80% for mantle cell lymphoma (n=5), and 25% for aggressive lymphomas (n=12). For NHL, 50% received OBI as monotherapy, with 33% ORR. Median PFS subdivided by histologic cohorts were: 35 mos for CLL/SLL, not reached in indolent lymphomas, and 4 mos for aggressive lymphomas. Median overall survival divided by histologic subtype were 17 mos for CLL/SLL, 14 mos in indolent lymphoma and 45 mos in aggressive lymphomas. (Figure 1). OBI monotherapy in the indolent lymphoma group (n=8) had a 75% ORR and aggressive lymphoma group (n=6) had a 33% ORR. Of note, 2 aggressive lymphoma pts were successfully bridged to CAR T-cell therapy. Adverse events (AEs) occurred in approximately 91% of CLL/SLL pts and 61% of NHL pts. AEs for the CLL/SLL group included: infusion related reactions (IRRs) (62%), neutropenia (16%), thrombocytopenia (40%), infection (22%), neutropenic fever (7%), and diarrhea (9%). AEs for the NHL group included: IRRs (24%), neutropenia (18%), thrombocytopenia (27%), infection (9%), and diarrhea (24%). In the CLL/SLL population 62% experienced an IRR on the first dose and 6 of those pts experienced a second infusion reaction in the first cycle of OBI. Despite a high rate of reactions in this population, most were confined to grade 2 reactions (93% grade 2; 7% grade 3). In the NHL population, all 8 pts (24%) experienced an infusion reaction on the first dose of OBI and one patient experienced a subsequent infusion reaction on the second dose. Conclusion: We describe our experience of OBI therapy across histological subtypes of NHL outside the setting of a clinical trial, including OBI used as part of multi-agent salvage therapy in indolent and aggressive NHL. We observed high ORRs and durable PFS and OS in both CLL/SLL and indolent lymphoma cohorts. As expected, the aggressive lymphoma cohort had an ORR of 25% with a median PFS of 4 mos. Neutropenia and thrombocytopenia were manageable with close supportive care, yet are critical parameters to monitor while on OBI regimens. IRRs were high in the CLL/SLL cohort and mainly confined to grade 2 reactions. OBI remains an effective and well tolerated agent in NHL and should continue to be considered for utilization in clinical trials to develop novel combination regimens for aggressive NHL as well as a partner to cellular therapy. Figure 1 Disclosures Hughes: Acerta Pharna/HOPA: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees. Schuster:Pfizer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Nordic Nanovector: Consultancy, Honoraria; Loxo Oncology: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Triphase: Research Funding; Takeda: Research Funding; Takeda: Research Funding; Seattle Genetics: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Celgene: Research Funding. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Chong:Tessa: Consultancy; Novartis: Consultancy; Merck: Research Funding. Rhodes:DAVA Oncology: Honoraria. Stadtmauer:Celgene: Consultancy; Abbvie: Research Funding; Takeda: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Amgen: Consultancy. Dwivedy Nasta:Debiopharm: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Millenium/Takeda: Research Funding; Roche: Research Funding; 47 (Forty Seven): Research Funding; Rafael: Research Funding. OffLabel Disclosure: Obinutuzumab was investigated as a monotherapy agent as opposed to in combination for CLL. Additionally, obinutuzumab was only studied in follicular lymphoma and chronic lymphocytic leukemia. This retrospective analysis includes lymphomas outside of specified indications.

Abstract BACKGROUND: The cell of origin (COO) of diffuse large B cell lymphoma (DLBCL), germinal center (GC) or non-germinal center (NGC), may have prognostic significance for treatment outcome in first-line and relapsed settings (Lenz et al NEJM 2008; Thieblemont et al JCO 2011). "Double hit" DLBCL (DHL), defined by chromosomal breakpoints affecting the MYC/8q24 locus and BCL2/18q21 and/or BCL6/3q27 loci and arising either from transformation of follicular lymphoma (tFL) or de novo, has no standard effective therapy in the relapsed setting. Since new therapies are needed for poor prognostic groups of relapsed DLBCL patients (pts), we examined the efficacy of treatment with autologous T cells genetically modified to express a chimeric antigen receptor consisting of an external anti-CD19 single chain murine antibody domain with CD3ζ and 4-1BB signaling domains (CTL019 cells) in pts with relapsed/refractory GC and NGC DLBCL, DHL, and tFL as part of an ongoing phase IIa clinical trial (NCT02030834). METHODS: Eligible pts had CD19+ DLBCL with measurable residual disease after primary and salvage therapies, were not eligible for autologous stem cell transplant (ASCT) or had relapsed/residual disease after ASCT, and had responsive or stable disease with most recent therapy. COO of DLBCL was defined immunohistochemically using the Hans algorithm (Hans et al Blood 2004) and included the DLBCL subtypes DHL and tFL that met this definition. Fluorescence in-situ hybridization was performed on diagnostic tissue using Vysis MYC (8q24), BCL2 (18q21) and BCL6 (3q27) break apart probes to determine DHL. DHL was defined by a MYC locus chromosomal translocation with a second translocation involving either BCL2 or BCL6. After steady state apheresis to collect peripheral blood leukocytes, pts received lymphodepleting chemotherapy based on clinical features and past therapies. 1 to 4 days after chemotherapy, pts received a single dose of CTL019 cells. Following CTL019, pts received no further therapy for DLBCL. Initial tumor response assessment was performed 3 months (mo) after CTL019 using IWG criteria. Enrollment started in Feb 2014; data are reported through 24 Jul 2016. RESULTS: 13 pts with DLBCL are enrolled and evaluable for response (7 pts GC, 5 pts NGC, 1 undetermined). The median age is 59 years (range: 25-77), male:female ratio 10:3, median number of prior therapies 5 (range: 2-8), and number of pts with prior transplant 7 (54%). At enrollment, Ann Arbor stages were: Stage IV 8 pts (61%), Stage III 1 pt (8%), and Stage II 3 pts (23%) Stage IE 1 pt (8%); 3 pts (23%) had bone marrow involvement. LDH was increased in 8 pts (62%). ECOG PS was 0 in 4 pts (31%) and 1 in 9 pts (69%).Lymphodepleting chemotherapy regimens were bendamustine (90 mg/m2 x 2; 1 pt), cyclophosphamide (1 gm/m2; 2 pts), radiation-cyclophosphamide (4,000cGy-750 mg/m2; 1 pt), modified-EPOCH (3 pts), and hyper-fractionated cyclophosphamide (300 mg/m2 q12 hours x 6; 6 pts). 12 pts received 5.00E+08 (5.10 - 6.75E+06 cells/kg) CTL019 cells; 1 pt received 1.93E+08 (3.10E+06 cells/kg).Median peak CTL019 cell expansion in blood occurred 7 days after infusion (range: 2-28 days); there is no difference in peak expansion between responders and non-responders or pts with GC or NGC DLBCL.Cytokine release syndrome occurred in 9 pts (8 grade 2; 1 grade 3) and did not predict response. Transient neurotoxicity included delirium in 2/13 pts (1 grade 2; 1 grade 3) and cognitive disturbance in 1/13 pts (1 grade 1). At 3 mo post CTL019, overall response rate (ORR) is 52% (7/13 pts); ORR at 3 mo for GC 71% (5/7 pts) and NGC 40% (2/5 pts). Complete response rate (CR) at 3 mo is 38% (5/13 pts); CR at 3 mo for GC 43% (3/7 pts) and NGC 40% (2/5 pts). Best response for all pts is CR in 6 of 13 pts (46%); CR for GC 57% (4/7 pts) and NGC 40% (2/5 pts). 3 of 7 pts with GC DLBCL had tFL and all 3 achieved CR; 2 of 7 pts with GC DLBCL had DHL and both achieved CR. To date, no pt achieving CR has relapsed. Median progression-free survival is 5.8 mo for all pts, 3.0 mo for NGC pts, and not reached for GC pts (57.1% [95%CI: 17.2%-83.7%] progression-free at median follow-up 21.9 mo). At median follow-up 23.3 mo for responding pts, 85.7% [95%CI: 33.7-97.9%] maintain response. CONCLUSIONS: A single treatment with CTL019 cells can achieve durable remissions in pts with relapsed/refractory GC and NGC DLBCL, DHL and transformed FL. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Schuster: Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Honoraria; Merck: Research Funding; Janssen Research & Development: Research Funding; Hoffman-LaRoche: Research Funding; Gilead: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Svoboda:Pharmacyclics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding. Nasta:Millennium Pharmaceuticals: Research Funding. Porter:Genentech/Roche: Employment; Genentech/Roche: Equity Ownership; Incyte: Honoraria; Novartis: Consultancy; Novartis: Research Funding; University of Pennsylvania: Patents & Royalties; Immunovative Therapies: Other: Travel, Accommodations, Expenses. Mato:ProNAi: Research Funding; TG Therapeutics: Research Funding; Acerta Pharma: Research Funding; Theradex: Research Funding; Gilead Sciences: Research Funding; Abbvie: Research Funding; TG Therapeutics: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Abbvie: Consultancy. Wasik:Gilead Sciences: Equity Ownership; Seattle Genetics: Honoraria; Novartis: Research Funding; University of Pennsylvania: Patents & Royalties: NPM-ALK as an omncogene; University of Pennsylvania: Patents & Royalties: CAR T-cells; Gilead Sciences: Research Funding; Pharmacyclics: Research Funding. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Patents & Royalties: Novartis, Research Funding. Chew:Novartis: Research Funding. Hasskarl:Novartis: Employment. Marcucci:Novartis: Research Funding. Levine:GE Healthcare Bio-Sciences: Consultancy; Novartis: Patents & Royalties, Research Funding. June:Pfizer: Honoraria; Johnson & Johnson: Research Funding; University of Pennsylvania: Patents & Royalties; Tmunity: Equity Ownership, Other: Founder, stockholder ; Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; Celldex: Consultancy, Equity Ownership; Immune Design: Consultancy, Equity Ownership.

Introduction: Acalabrutinib (acala), a Bruton's Tyrosine Kinase inhibitor (BTKi), received accelerated FDA approval for treatment of mantle cell lymphoma (MCL) in 2017. Since approval, there has been limited "real world" data, especially in the setting of off-label utilization. We performed an analysis of the safety and efficacy of acala in non-Hodgkin lymphoma (NHL) at our institution for both on- and off-label indications. Methods: We performed a retrospective analysis of all patients (pts) who had received acala for NHL at the University of Pennsylvania between 1/2017 and 5/2019. We examined best response to therapy, duration of response, and progression free survival. Response assessments were determined by treating physician using standard, disease-specific criteria. We collected clinical and demographic data such as genetic risk factors, staging, previous and concomitant therapies. We analyzed adverse events (AEs) and toxicities associated with acala. Survival analyses were completed as described by Kaplan and Meier; all other analyses were descriptive in nature. Results: We identified 23 pts treated with acala at our institution. The cohort consisted of 83% males (n=19). Diagnoses were chronic lymphocytic leukemia (CLL) (n=10; 44%), MCL (n=9; 39%), and diffuse large B-cell lymphoma (DLBCL) (n=4; 17%). One DLBCL was GCB subtype and three were ABC subtype; two of four DLBCL pts were transformed from marginal zone lymphoma and two were de novo. The median age at diagnosis was 61 years, median age at acala start was 69 years. Sixteen (70%) of the pts were Ann Arbor or Rai stage III or IV at diagnosis. The median number of therapies prior to acala was 3 (range 0-12). Of note, the GCB-DLBCL patient had previously undergone both allogeneic (alloSCT) and autologous (autoSCT) stem cell transplants and four of the MCL patients (44%) also had prior allo and/or autoSCTs. The majority (65%) of pts received acala 100 mg twice daily, with the rest of the patients receiving 100 mg once daily. The median time to best response was 2 months (mos). All CLL pts (n=10; 100%) had at least a partial response (PR), including 1 complete response (CR) by iwCLL criteria. In the MCL cohort of 9 pts, 8 (88%) had at least a PR (including 1 CR), and one patient (11%) had stable disease (SD). One MCL pt achieved a CR and moved to alloSCT. One (25%) of the DLBCL pts had a PR (pt was ABC subtype), and three (75%) had SD (one GCB and two ABC-DLBCL pts.) At the time of last follow up, two DLBCL pts had SD and remain on acala, one progressed after 10 months on acala and was switched to obinutuzumab, and one died due to disease progression. The 12 mo progression free survival (PFS) was 89% for CLL and 83% for MCL; 12 mo overall survival (OS) was 89% for CLL and 100% for MCL respectively. (Figure 1). Of note, 16 pts (70%) had been on ibrutinib previously and all pts discontinued (d/c) ibrutinib due to intolerance. Acala related toxicities included: 26% (n=6) arthralgias/myalgias, 13% (n=3) infection, 13% (n=3) bruising/ bleeding, 9% (n=2) rashes, and 4% (n=1) diarrhea. Two pts required dose adjustment of acala and one patient had to d/c acala due to fatigue and bleeding/bruising. Ten (43%) of pts tolerated acala without any side effects. Of note, there were 6 pts with a history of atrial fibrillation (afib) or an afib-related toxicity of ibrutinib, and none of our pts experienced new afib while on acala. In total, six pts d/c acala: 1 patient moved to alloSCT, 3 had disease progression, 1 d/c due to toxicity, and 2 pts died. One death was unrelated to lymphoma progression (renal cancer). Conclusion: Our "real world" experience with acala demonstrates its efficacy and tolerability in the setting of NHL, supporting previously published literature (ACE-LY-004 and ACE-CL-001 trials). In our analysis of 23 patients, the response rates in our CLL and MCL cohorts were 100% and 88% respectively and only one patient discontinued acala for intolerance. There is limited information on the off-label utilization of acala in the relapsed/refractory DLBCL setting. However, the response in our cohort may warrant further evaluation of acala as a possible therapeutic agent in this aggressive/refractory patient population. Acala continues to demonstrate a favorable toxicity profile, especially in pts who were unable to tolerate ibrutinib. Our experience with acala supports pilot data showing efficacy and thus further research in other B-cell malignancies, especially DLBCL, is warranted. Figure 1 Disclosures Hughes: Genzyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding. Schuster:Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Chong:Merck: Research Funding; Novartis: Consultancy; Tessa: Consultancy. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Barta:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria. Dwivedy Nasta:Rafael: Research Funding; Millenium/Takeda: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Roche: Research Funding; 47 (Forty Seven): Research Funding; Debiopharm: Research Funding. OffLabel Disclosure: FDA label indication for acalabrutinib is only for patients with CLL. Utilization in DLBCL and CLL populations is beyond the specified indication.

Abstract Introduction: Venetoclax (VEN) is a highly effective agent for chronic lymphocytic leukemia (CLL) that targets BCL-2. Thus, it has been hypothesized to have efficacy in NHL and tested in phase-1/2 studies (Gerecitano JF, Blood 2015; de Vos S, Blood 2015; Davids MS, J Clin Oncol 2017). Overall response rates (ORR) observed in r/r NHL were 44% for all subtypes combined, 38% for follicular lymphoma (FL), 75% for mantle cell lymphoma (MCL), and 18% for diffuse large B-cell lymphoma (DLBCL). The adverse effect profile was consistent with the labeling despite dose escalation to doses higher than used in CLL. Additionally, VEN is a potential option in the r/r NHL setting, potentially providing less T cell toxicity compared to other agents used as bridging to T-cell therapies (Cummins NW, mBio, 2016; Dzhagalov I, J Immunol, 2008). We performed an analysis of all NHL patients (pts) treated with VEN at our institution to assess efficacy and safety of VEN in r/r NHL. Patients and Methods: We conducted a retrospective cohort study of all adult pts who received VEN for r/r NHL at the University of Pennsylvania between 4/2016 and 6/2018. Demographics, tumor lysis syndrome (TLS; events, prophylaxis and management), duration of therapy, reason for discontinuation, overall response, survival, and toxicities were examined. The primary endpoints were progression-free survival (PFS; defined as time from VEN start to disease progression or regimen change, death due to NHL or last-follow-up in remission), and overall survival using the Kaplan-Meier method. All other analyses were descriptive. Results: We identified 23 NHL pts for this analysis. NHL subtypes included DLBCL (35%; n=8), MCL (30%; n=7), Richter transformation (RT) (9%; n=2), transformed FL (tFL) (12%; n=4), post-transplant lymphoproliferative disease (PTLD) (4%; n=1), and marginal zone lymphoma (MZL; n=1) (4%). Median age at VEN start was 65 years; most pts were Ann Arbor stage IV (87%) and ECOG performance 2-4 (57%). NHL characteristics were MYC rearrangement (35%), BCL2 rearrangement (22%), double-hit lymphoma (26%), BCL2 IHC+ (22%), non-germinal center phenotype (13%). Median number of prior therapies was 4 (range: 2-13) with 17% having a prior autologous stem cell transplant. Median time to VEN initiation from prior therapy was 1 month (range, 0.5-9). Median VEN dose achieved was 400 mg (Range, 100-1200). Data for TLS are in Table 1. Median time on VEN was 2 months. While on VEN, 17% received radiation and 43% were on other anti-neoplastic therapy. Overall response rate (ORR) for the entire cohort was 26% (100% Partial Response [PR]). Subtypes with PR included MCL (13%), DLBCL (9%), and RT (4%). No PRs were observed with tFL, PTLD, nor MZL. Pts most commonly discontinued VEN for disease progression (74%); 2 pts (9%) remain on VEN therapy (range: 2-11 months). Median PFS and OS for the entire cohort were 2 months and 3 months, respectively, (Figure 1). Analyzed as histologic cohorts, large B-cell lymphomas (DLBCL, RT, PTLD, tFL) had similar median PFS and OS. However, small B-cell lymphomas (MCL, MZL) had median PFS and OS of 2.5 and 4 months, respectively. Two pts subsequently received CAR T-cell therapy post-VEN; one collected T-cells during VEN therapy and one collected T-cells prior to VEN start. Adverse events (AEs) occurred in approximately 65% while on VEN. AEs included: neutropenia (48%), thrombocytopenia (43%), TLS (30%), infection (26%), neutropenic fever (26%), and diarrhea (22%). One pt had an opportunistic infection (Pneumocystis jiroveci pneumonia) while on VEN and concurrent high-dose steroids. Conclusion: VEN monotherapy appears effective for NHL in phase I clinical trials. We describe our experience outside the setting of a clinical trial, including VEN used as part of multi-agent salvage therapy. Median PFS for our entire cohort is 2 months; AEs, while expected, were observed frequently, reflecting comorbidities. Clinical TLS events are attributed to pre-existing renal dysfunction (61% below 80 mL/min) during VEN escalation. The wide heterogeneity of VEN dose escalation, multi-agent combinations, and timing of initiation of VEN therapy are factors that require further investigation best designed as prospective clinical trials using other agents in combination with VEN. Disclosures Landsburg: Takeda: Consultancy; Curis: Consultancy, Research Funding. Schuster:Genentech: Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Merck: Consultancy, Honoraria, Research Funding; OncLive: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Consultancy, Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Physician's Education Source, LLC: Honoraria. Svoboda:Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; TG Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Regeneron: Research Funding; KITE: Consultancy; Kyowa: Consultancy; Merck: Research Funding. Gill:Novartis: Research Funding; Extellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Carisma Therapeutics: Equity Ownership. Mato:TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy; Portola: Research Funding; Johnson & Johnson: Consultancy; Regeneron: Research Funding; Acerta: Research Funding; Celgene: Consultancy; Prime Oncology: Honoraria; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Medscape: Honoraria. Altman:Epizyme: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Pfizer: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Other; GSK: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Bayer: Other: payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work; Cyclacel: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genetech: Other: Payment to the institution to conduct clinical trial work; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Dwivedy Nasta:Pharmacyclics: Research Funding; Incyte: Research Funding; Roche: Research Funding; Aileron: Research Funding; Rafael/WF: Research Funding; Debiopharm: Research Funding; Merck: Other: DSMC; Takeda/Millenium: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees.

"So which is the most authentic experience for an end-user steeped in car culture? Real, made-in-Japan Type R? Or virtual, programmed-in-Japan Type-R. Each Type-R is equally enjoyable, equally wieldy, equally consistent -- and precisely fulfils the sporting intent of Honda's Type-R sub-brand. Car culture, then, is so broad, so diverse, that we might now have got to a point where actual driving, all the bum-on-seat, wind-in-hair, aphid-in-teeth, tradly, dadly stuff we were weaned on is peripheral... Who needs reality, anyway?" -- Russell Bulgin, Car Magazine, August 1998 (53) "Such would be the successive phases of the image: it is the reflection of a profound reality; it masks and denatures a profound reality; it masks the absence of a profound reality; it has no relation to any reality whatsoever: it is its own pure simulacrum." (Baudrillard 6) A Personal Prehistory of Racing Sims The very first racing sim I used was an arcade machine on the Gold Coast sometime during the mid-seventies. A coin-operated cabinet where a boy and his dad could stand and move a plastic steering wheel from side to side. This controlled a plastic model racing car attached to a stick. I kid you not. Youth was further misspent on large four-up machines, with a simple overhead view of a square-cornered, maze-like track. Each driver had a certain coloured 'car' to control round the electronic labyrinth in real time. The revolution moved into the living room, and a Hanimex TV game. Something of a poor man's Atari 2600, the driving sim was the overhead view of an endless straight track -- 'driving' was the act of jabbing a joystick left or right to avoid oncoming traffic. Addictive until the repetitive pattern of avoidance was committed to memory. Finally, there was an Apple II --and perhaps my first true racing sim. No overhead imagery, or even representations of cars. Just a first-person view down an imaginary winding road, as the view shuffled left or right using a knob-shaped controller. A Coming of Age Today, reputable motoring journalists dare to compare driving a Honda sports car on a Sony Playstation with driving a Honda Integra in real life, and deriving similar levels of satisfaction from each. This, mind you, on a two-generations-old, soon to be superseded piece of hardware with relatively chunky graphics hooked up to a mildly archaic television screen. Using a couple of buttons as a controller. When the immersion becomes more complete -- when graphics chips render more and more polygons at ever faster speeds, when the visual virtual is displayed on a wrap-around plasma in a real racing helmet, where control is provided by a force-feedback steering wheel in a vibrating bucket seat, what then... The latest racing sim I used was at Sega World in Sydney. Eight IndyCar machines, all giant 50" screens, mechanical vibrating seats and shuddering steering wheels. The physics engines sucked. Purists would call it more of a game, and less of a sim; but I still walked away with sweaty palms, shaky legs and a moment of nausea. But you ain't seen nothing yet... indeed the Nascar Silicon Motor Speedway in the USA has taken the concept to the next appropriate level -- a dozen real Nascar racers mounted on rocking. rolling motion generators in front of enormous projection screens. And So to the Network The crazies buy fibreglass tubs and strap themselves into racing seats. Jacques Villeneuve apparently learnt the layout of F1 tracks from his PC, before he scored a Formula One drive, and promptly went out and won the world championship in his second season. And the real crazies do it to each other. There are dial-in racing boards all over the USA and the racing mob have taken to the Internet in a big way. Nascar runs a league for on-line racers, who participate in a season of speedway much like that of their heroes. Indeed, the official body of V8 metal munchers in the good old USA is talking about running hybrid races -- inserting virtual images onto real races, and allowing online competitors to compete against their heroes in real time. We're a little way from that technologically -- V90 modems and Voodoo II cards may do the job for the moment, but utopian racing simulations will require Moore's Laws for a few more years yet. Nevertheless, it's way less than a single human generation since playing with a car glued to a stick was considered pretty cool. What of It? It may indeed be time to invoke the appropriate french philosopher. Whilst anecdotal evidence exists of world champions learning formula one race tracks using PC simulators, the reality is that racing sims are a simulacrum for most of us. Few of us have the opportunity, let alone the courage, to partake in the act of driving cars fast. Either on the road, on on a race track. Indeed, when it can take 15 minutes to move a mile in peak hour traffic, it is tempting to suggest that the entire notion of car-culture, which this society holds dear to its heart, be moved to simulation, so that the rest of us can just get on with the job of getting from A to B as efficiently as possible. As participants, racing sims -- even driving sims -- don't exist in real life. A daily commute across the harbour bridge is, in reality, nothing like we imagine the real thing should be. Crawling, foot riding on clutch, through slow-moving traffic, is as far from the dream of freedom that the motorcar suggests as, well, as sitting in front of a Playstation or PC. In fact, the computer does more than represent a simulation of driving. It represents the new freedom. The question is though, in Baudrillard's precession of simulacra, where exactly are we at? If one accepts that the reality represented by a racing sim does not exist; then does this new escapism mask the absence of a profound reality? Is the hyperreality that is the sweaty palm on plastic wheel merely a confirmation that we live in a hyperreality? As he describes Disneyland, "it is no longer a question of a false representation of reality ... but of concealing the fact that the real is no longer real" (12). There is no escape machine for the overworked stressed young executive; there is no sports car or highway that can give you a day's respite from the pressures of consumption; there is no road to Tijuana, no Corvette summer, no Highway 66. There is no Bathurst 1000, Le Mans or Monte Carlo where men can be men and leave behind the grinding reality. There is, in fact, no escape at all -- there is only cyberspace! References Jean Baudrillard. "The Precession of Simulacra." Simulacra and Simulation. Ann Arbor: U of Michigan P, 1994. Citation reference for this article MLA style: Sherman Young. "Racing Simulacra?" M/C: A Journal of Media and Culture 1.5 (1998). [your date of access] <http://www.uq.edu.au/mc/9812/racing.php>. Chicago style: Sherman Young, "Racing Simulacra?" M/C: A Journal of Media and Culture 1, no. 5 (1998), <http://www.uq.edu.au/mc/9812/racing.php> ([your date of access]). APA style: Sherman Young. (1998) Racing simulacra? M/C: A Journal of Media and Culture 1(5). <http://www.uq.edu.au/mc/9812/racing.php> ([your date of access]).