Academic literature on the topic 'Ann Arbor No. 7 (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.

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.

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: 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.

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.

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.


 
 
 Perhaps nothing in media culture today makes clearer the connection between people’s bodies and their homes than the Emmy-winning reality TV program Extreme Makeover: Home Edition. Home Edition is a spin-off from the original Extreme Makeover, and that fact provides in fundamental form the strong connection that the show demonstrates between bodies and houses. The first EM, initially popular for its focus on cosmetic surgery, laser skin and hair treatments, dental work, cosmetics and wardrobe for mainly middle-aged and self-described unattractive participants, lagged after two full seasons and was finally cancelled entirely, whereas EMHE has continued to accrue viewers and sponsors, as well as accolades (Paulsen, Poniewozik, EMHE Website, Wilhelm). That viewers and the ABC network shifted their attention to the reconstruction of houses over the original version’s direct intervention in problematic bodies indicates that sites of personal transformation are not necessarily within our own physical or emotional beings, but in the larger surround of our environments and in our cultural ideals of home and body. One effect of this shift in the Extreme Makeover format is that a seemingly wider range of narrative problems can be solved relating to houses than to the particular bodies featured on the original show. Although Extreme Makeover featured a few people who’d had previously botched cleft palate surgeries or mastectomies, as Cressida Heyes points out, “the only kind of disability that interests the show is one that can be corrected to conform to able-bodied norms” (22). Most of the recipients were simply middle-aged folks who were ordinary or aged in appearance; many of them seemed self-obsessed and vain, and their children often seemed disturbed by the transformation (Heyes 24). However, children are happy to have a brand new TV and a toy-filled room decorated like their latest fantasy, and they thereby can be drawn into the process of identity transformation in the Home Edition version; in fact, children are required of virtually all recipients of the show’s largess. Because EMHE can do “major surgery” or simply bulldoze an old structure and start with a new building, it is also able to incorporate more variety in its stories—floods, fires, hurricanes, propane explosions, war, crime, immigration, car accidents, unscrupulous contractors, insurance problems, terrorist attacks—the list of traumas is seemingly endless. Home Edition can solve any problem, small or large. Houses are much easier things to repair or reconstruct than bodies. Perhaps partly for this reason, EMHE uses disability as one of its major tropes. Until Season 4, Episode 22, 46.9 percent of the episodes have had some content related to disability or illness of a disabling sort, and this number rises to 76.4 percent if the count includes families that have been traumatised by the (usually recent) death of a family member in childhood or the prime of life by illness, accident or violence. Considering that the percentage of people living with disabilities in the U.S. is defined at 18.1 percent (Steinmetz), EMHE obviously favours them considerably in the selection process. Even the disproportionate numbers of people with disabilities living in poverty and who therefore might be more likely to need help—20.9 percent as opposed to 7.7 percent of the able-bodied population (Steinmetz)—does not fully explain their dominance on the program. In fact, the program seeks out people with new and different physical disabilities and illnesses, sending out emails to local news stations looking for “Extraordinary Mom / Dad recently diagnosed with ALS,” “Family who has a child with PROGERIA (aka ‘little old man’s disease’)” and other particular situations (Simonian). A total of sixty-five ill or disabled people have been featured on the show over the past four years, and, even if one considers its methods maudlin or exploitive, the presence of that much disability and illness is very unusual for reality TV and for TV in general. What the show purports to do is to radically transform multiple aspects of individuals’ lives—and especially lives marred by what are perceived as physical setbacks—via the provision of a luxurious new house, albeit sometimes with the addition of automobiles, mortgage payments or college scholarships. In some ways the assumptions underpinning EMHE fit with a social constructionist body theory that posits an almost infinitely flexible physical matter, of which the definitions and capabilities are largely determined by social concepts and institutions. The social model within the disability studies field has used this theoretical perspective to emphasise the distinction between an impairment, “the physical fact of lacking an arm or a leg,” and disability, “the social process that turns an impairment into a negative by creating barriers to access” (Davis, Bending 12). Accessible housing has certainly been one emphasis of disability rights activists, and many of them have focused on how “design conceptions, in relation to floor plans and allocation of functions to specific spaces, do not conceive of impairment, disease and illness as part of domestic habitation or being” (Imrie 91). In this regard, EMHE appears as a paragon. In one of its most challenging and dramatic Season 1 episodes, the “Design Team” worked on the home of the Ziteks, whose twenty-two-year-old son had been restricted to a sub-floor of the three-level structure since a car accident had paralyzed him. The show refitted the house with an elevator, roll-in bathroom and shower, and wheelchair-accessible doors. Robert Zitek was also provided with sophisticated computer equipment that would help him produce music, a life-long interest that had been halted by his upper-vertebra paralysis. Such examples abound in the new EMHE houses, which have been constructed for families featuring situations such as both blind and deaf members, a child prone to bone breaks due to osteogenesis imperfecta, legs lost in Iraq warfare, allergies that make mold life-threatening, sun sensitivity due to melanoma or polymorphic light eruption or migraines, fragile immune systems (often due to organ transplants or chemotherapy), cerebral palsy, multiple sclerosis, Krabbe disease and autism. EMHE tries to set these lives right via the latest in technology and treatment—computer communication software and hardware, lock systems, wheelchair-friendly design, ventilation and air purification set-ups, the latest in care and mental health approaches for various disabilities and occasional consultations with disabled celebrities like Marlee Matlin. Even when individuals or familes are “[d]iscriminated against on a daily basis by ignorance and physical challenges,” as the program website notes, they “deserve to have a home that doesn’t discriminate against them” (EMHE website, Season 3, Episode 4). The relief that they will be able to inhabit accessible and pleasant environments is evident on the faces of many of these recipients. That physical ease, that ability to move and perform the intimate acts of domestic life, seems according to the show’s narrative to be the most basic element of home. Nonetheless, as Robert Imrie has pointed out, superficial accessibility may still veil “a static, singular conception of the body” (201) that prevents broader change in attitudes about people with disabilities, their activities and their spaces. Starting with the story of the child singing in an attempt at self-comforting from Deleuze and Guattari’s A Thousand Plateaus, J. MacGregor Wise defines home as a process of territorialisation through specific behaviours. “The markers of home … are not simply inanimate objects (a place with stuff),” he notes, “but the presence, habits, and effects of spouses, children, parents, and companions” (299). While Ty Pennington, EMHE’s boisterous host, implies changes for these families along the lines of access to higher education, creative possibilities provided by musical instruments and disability-appropriate art materials, help with home businesses in the way of equipment and licenses and so on, the families’ identity-producing habits are just as likely to be significantly changed by the structural and decorative arrangements made for them by the Design Team. The homes that are created for these families are highly conventional in their structure, layout, decoration, and expectations of use. More specifically, certain behavioural patterns are encouraged and others discouraged by the Design Team’s assumptions. Several themes run through the show’s episodes: Large dining rooms provide for the most common of Pennington’s comments: “You can finally sit down and eat meals together as a family.” A nostalgic value in an era where most families have schedules full of conflicts that prevent such Ozzie-and-Harriet scenarios, it nonetheless predominates. Large kitchens allow for cooking and eating at home, though featured food is usually frozen and instant. In addition, kitchens are not designed for the families’ disabled members; for wheelchair users, for instance, counters need to be lower than usual with open space underneath, so that a wheelchair can roll underneath the counter. Thus, all the wheelchair inhabitants depicted will still be dependent on family members, primarily mothers, to prepare food and clean up after them. (See Imrie, 95-96, for examples of adapted kitchens.) Pets, perhaps because they are inherently “dirty,” are downplayed or absent, even when the family has them when EMHE arrives (except one family that is featured for their animal rescue efforts); interestingly, there are no service dogs, which might obviate the need for some of the high-tech solutions for the disabled offered by the show. The previous example is one element of an emphasis on clutter-free cleanliness and tastefulness combined with a rampant consumerism. While “cultural” elements may be salvaged from exotic immigrant families, most of the houses are very similar and assume a certain kind of commodified style based on new furniture (not humble family hand-me-downs), appliances, toys and expensive, prefab yard gear. Sears is a sponsor of the program, and shopping trips for furniture and appliances form a regular part of the program. Most or all of the houses have large garages, and the families are often given large vehicles by Ford, maintaining a positive take on a reliance on private transportation and gas-guzzling vehicles, but rarely handicap-adapted vans. Living spaces are open, with high ceilings and arches rather than doorways, so that family members will have visual and aural contact. Bedrooms are by contrast presented as private domains of retreat, especially for parents who have demanding (often ill or disabled) children, from which they are considered to need an occasional break. All living and bedrooms are dominated by TVs and other electronica, sometimes presented as an aid to the disabled, but also dominating to the point of excluding other ways of being and interacting. As already mentioned, childless couples and elderly people without children are completely absent. Friends buying houses together and gay couples are also not represented. The ideal of the heterosexual nuclear family is thus perpetuated, even though some of the show’s craftspeople are gay. Likewise, even though “independence” is mentioned frequently in the context of families with disabled members, there are no recipients who are disabled adults living on their own without family caretakers. “Independence” is spoken of mostly in terms of bathing, dressing, using the bathroom and other bodily aspects of life, not in terms of work, friendship, community or self-concept. Perhaps most salient, the EMHE houses are usually created as though nothing about the family will ever again change. While a few of the projects have featured terminally ill parents seeking to leave their children secure after their death, for the most part the families are considered oddly in stasis. Single mothers will stay single mothers, even children with conditions with severe prognoses will continue to live, the five-year-old will sleep forever in a fire-truck bed or dollhouse room, the occasional grandparent installed in his or her own suite will never pass away, and teenagers and young adults (especially the disabled) will never grow up, marry, discover their homosexuality, have a falling out with their parents or leave home. A kind of timeless nostalgia, hearkening back to Gaston Bachelard’s The Poetics of Space, pervades the show. Like the body-modifying Extreme Makeover, the Home Edition version is haunted by the issue of normalisation. The word ‘normal’, in fact, floats through the program’s dialogue frequently, and it is made clear that the goal of the show is to restore, as much as possible, a somewhat glamourised, but status quo existence. The website, in describing the work of one deserving couple notes that “Camp Barnabas is a non-profit organisation that caters to the needs of critically and chronically ill children and gives them the opportunity to be ‘normal’ for one week” (EMHE website, Season 3, Episode 7). Someone at the network is sophisticated enough to put ‘normal’ in quotation marks, and the show demonstrates a relatively inclusive concept of ‘normal’, but the word dominates the show itself, and the concept remains largely unquestioned (See Canguilhem; Davis, Enforcing Normalcy; and Snyder and Mitchell, Narrative, for critiques of the process of normalization in regard to disability). In EMHE there is no sense that disability or illness ever produces anything positive, even though the show also notes repeatedly the inspirational attitudes that people have developed through their disability and illness experiences. Similarly, there is no sense that a little messiness can be creatively productive or even necessary. Wise makes a distinction between “home and the home, home and house, home and domus,” the latter of each pair being normative concepts, whereas the former “is a space of comfort (a never-ending process)” antithetical to oppressive norms, such as the association of the home with the enforced domesticity of women. In cases where the house or domus becomes a place of violence and discomfort, home becomes the process of coping with or resisting the negative aspects of the place (300). Certainly the disabled have experienced this in inaccessible homes, but they may also come to experience a different version in a new EMHE house. For, as Wise puts it, “home can also mean a process of rationalization or submission, a break with the reality of the situation, self-delusion, or falling under the delusion of others” (300). The show’s assumption that the construction of these new houses will to a great extent solve these families’ problems (and that disability itself is the problem, not the failure of our culture to accommodate its many forms) may in fact be a delusional spell under which the recipient families fall. In fact, the show demonstrates a triumphalist narrative prevalent today, in which individual happenstance and extreme circumstances are given responsibility for social ills. In this regard, EMHE acts out an ancient morality play, where the recipients of the show’s largesse are assessed and judged based on what they “deserve,” and the opening of each show, when the Design Team reviews the application video tape of the family, strongly emphasises what good people these are (they work with charities, they love each other, they help out their neighbours) and how their situation is caused by natural disaster, act of God or undeserved tragedy, not their own bad behaviour. Disabilities are viewed as terrible tragedies that befall the young and innocent—there is no lung cancer or emphysema from a former smoking habit, and the recipients paralyzed by gunshots have received them in drive-by shootings or in the line of duty as police officers and soldiers. In addition, one of the functions of large families is that the children veil any selfish motivation the adults may have—they are always seeking the show’s assistance on behalf of the children, not themselves. While the Design Team always notes that there are “so many other deserving people out there,” the implication is that some people’s poverty and need may be their own fault. (See Snyder and Mitchell, Locations 41-67; Blunt and Dowling 116-25; and Holliday.) In addition, the structure of the show—with the opening view of the family’s undeserved problems, their joyous greeting at the arrival of the Team, their departure for the first vacation they may ever have had and then the final exuberance when they return to the new house—creates a sense of complete, almost religious salvation. Such narratives fail to point out social support systems that fail large numbers of people who live in poverty and who struggle with issues of accessibility in terms of not only domestic spaces, but public buildings, educational opportunities and social acceptance. In this way, it echoes elements of the medical model, long criticised in disability studies, where each and every disabled body is conceptualised as a site of individual aberration in need of correction, not as something disabled by an ableist society. In fact, “the house does not shelter us from cosmic forces; at most it filters and selects them” (Deleuze and Guattari, What Is Philosophy?, qtd. in Frichot 61), and those outside forces will still apply to all these families. The normative assumptions inherent in the houses may also become oppressive in spite of their being accessible in a technical sense (a thing necessary but perhaps not sufficient for a sense of home). As Tobin Siebers points out, “[t]he debate in architecture has so far focused more on the fundamental problem of whether buildings and landscapes should be universally accessible than on the aesthetic symbolism by which the built environment mirrors its potential inhabitants” (“Culture” 183). Siebers argues that the Jamesonian “political unconscious” is a “social imaginary” based on a concept of perfection (186) that “enforces a mutual identification between forms of appearance, whether organic, aesthetic, or architectural, and ideal images of the body politic” (185). Able-bodied people are fearful of the disabled’s incurability and refusal of normalisation, and do not accept the statistical fact that, at least through the process of aging, most people will end up dependent, ill and/or disabled at some point in life. Mainstream society “prefers to think of people with disabilities as a small population, a stable population, that nevertheless makes enormous claims on the resources of everyone else” (“Theory” 742). Siebers notes that the use of euphemism and strategies of covering eventually harm efforts to create a society that is home to able-bodied and disabled alike (“Theory” 747) and calls for an exploration of “new modes of beauty that attack aesthetic and political standards that insist on uniformity, balance, hygiene, and formal integrity” (Culture 210). What such an architecture, particularly of an actually livable domestic nature, might look like is an open question, though there are already some examples of people trying to reframe many of the assumptions about housing design. For instance, cohousing, where families and individuals share communal space, yet have private accommodations, too, makes available a larger social group than the nuclear family for social and caretaking activities (Blunt and Dowling, 262-65). But how does one define a beauty-less aesthetic or a pleasant home that is not hygienic? Post-structuralist architects, working on different grounds and usually in a highly theoretical, imaginary framework, however, may offer another clue, as they have also tried to ‘liberate’ architecture from the nostalgic dictates of the aesthetic. Ironically, one of the most famous of these, Peter Eisenman, is well known for producing, in a strange reversal, buildings that render the able-bodied uncomfortable and even sometimes ill (see, in particular, Frank and Eisenman). Of several house designs he produced over the years, Eisenman notes that his intention was to dislocate the house from that comforting metaphysic and symbolism of shelter in order to initiate a search for those possibilities of dwelling that may have been repressed by that metaphysic. The house may once have been a true locus and symbol of nurturing shelter, but in a world of irresolvable anxiety, the meaning and form of shelter must be different. (Eisenman 172) Although Eisenman’s starting point is very different from that of Siebers, it nonetheless resonates with the latter’s desire for an aesthetic that incorporates the “ragged edge” of disabled bodies. Yet few would want to live in a home made less attractive or less comfortable, and the “illusion” of permanence is one of the things that provide rest within our homes. Could there be an architecture, or an aesthetic, of home that could create a new and different kind of comfort and beauty, one that is neither based on a denial of the importance of bodily comfort and pleasure nor based on an oppressively narrow and commercialised set of aesthetic values that implicitly value some people over others? For one thing, instead of viewing home as a place of (false) stasis and permanence, we might see it as a place of continual change and renewal, which any home always becomes in practice anyway. As architect Hélène Frichot suggests, “we must look toward the immanent conditions of architecture, the processes it employs, the serial deformations of its built forms, together with our quotidian spatio-temporal practices” (63) instead of settling into a deadening nostalgia like that seen on EMHE. If we define home as a process of continual territorialisation, if we understand that “[t]here is no fixed self, only the process of looking for one,” and likewise that “there is no home, only the process of forming one” (Wise 303), perhaps we can begin to imagine a different, yet lovely conception of “house” and its relation to the experience of “home.” Extreme Makeover: Home Edition should be lauded for its attempts to include families of a wide variety of ethnic and racial backgrounds, various religions, from different regions around the U.S., both rural and suburban, even occasionally urban, and especially for its bringing to the fore how, indeed, structures can be as disabling as any individual impairment. That it shows designers and builders working with the families of the disabled to create accessible homes may help to change wider attitudes and break down resistance to the building of inclusive housing. However, it so far has missed the opportunity to help viewers think about the ways that our ideal homes may conflict with our constantly evolving social needs and bodily realities. References Bachelard, Gaston. The Poetics of Space. Tr. Maria Jolas. Boston: Beacon Press, 1969. Blunt, Alison, and Robyn Dowling. Home. London and New York: Routledge, 2006. Canguilhem, Georges. The Normal and the Pathological. New York: Zone Books, 1991. Davis, Lennard. Bending Over Backwards: Disability, Dismodernism & Other Difficult Positions. New York: NYUP, 2002. ———. Enforcing Normalcy: Disability, Deafness, and the Body. New York: Verso, 1995. Deleuze, Gilles, and Felix Guattari. A Thousand Plateaus: Capitalism and Schizophrenia. Tr. B. Massumi. Minneapolis: University of Minnesota Press, 1987. ———. What Is Philosophy? Tr. G. Burchell and H. Tomlinson. London and New York: Verso, 1994. Eisenman, Peter Eisenman. “Misreading” in House of Cards. 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