ALBERT

Description: The success of B cell depletion therapies and identification of leptomeningeal ectopic lymphoid tissue (ELT) in patients with multiple sclerosis (MS) has renewed interest in the antibody-independent pathogenic functions of B cells during neuroinflammation. The timing and location of B cell antigen presentation during MS and its animal model experimental autoimmune encephalomyelitis (EAE) remain undefined. Using a new EAE system that incorporates temporal regulation of MHCII expression by myelin-specific B cells, we observed the rapid formation of large B cell clusters in the spinal cord subarachnoid space. Neutrophils preceded the accumulation of meningeal B cell clusters, and inhibition of CXCR2-mediated granulocyte trafficking to the central nervous system reduced pathogenic B cell clusters and disease severity. Further, B cell-restricted very late antigen-4 (VLA-4) deficiency abrogated EAE dependent on B cell antigen presentation. Together, our findings demonstrate that neutrophils coordinate VLA-4–dependent B cell accumulation within the meninges during neuroinflammation, a key early step in the formation of ELT observed in MS.

Description: Abstract 2475 Poster Board II-452 Introduction: Non-Hodgkin Lymphoma (NHL) is the fifth most common type of malignancy in Canada. The most common subtype of NHL is diffuse large B-cell lymphoma (DLBCL). Initial standard treatment for DLBCL includes combination immuno-chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This regimen is typically administered every 21 days for a total of 6 cycles. Febrile neutropenia (FN) is a serious toxicity of lymphoma chemotherapy and patients with this condition must be treated aggressively as it could lead to complications such as prolonged hospitalization and death. Granulocyte-colony stimulating factors such as filgrastim and pegfilgrastim are efficacious in preventing FN, yet their cost-effectiveness has not been evaluated in the publicly funded Canadian healthcare system. Methods: A Markov model was constructed to evaluate the cost-effectiveness (cost-utility) of filgrastim and pegfilgrastim as primary prophylaxis versus no primary prophylaxis against FN in DLBCL patients receiving induction chemotherapy. Health states included in the model were hospitalization for FN, and receiving chemotherapy with no FN. It was assumed that patients in the no primary prophylaxis arm of the model who experienced a FN episode would receive secondary prophylaxis with filgrastim for all subsequent chemotherapy cycles. The time horizon of the model was 18 weeks, the time period over which the six cycles of chemotherapy are administered. The analysis was conducted from the hospital perspective. Costs are reported in 2009 Canadian dollars and outcomes in quality-adjusted life years (QALY). One-way sensitivity analyses were done on model parameters. A probabilistic sensitivity analysis was done to evaluate overall uncertainty in the model. Results: In the base case analysis costs associated with the no primary prophylaxis, filgrastim and pegfilgrastim interventions were $6044, $9450 and $15899, respectively. Quality-adjusted life years associated with the three interventions were 0.198, 0.200, and 0.202 respectively (over the 18-week model time horizon). The incremental cost-effectiveness ratio (ICER) of filgrastim compared to no primary prophylaxis was estimated to be $1.7 million (M)/QALY [95% confidence interval: -14M/QALY (dominated) to $15M/QALY]; for pegfilgrastim compared to filgrastim the ICER was estimated to be $4.4M/QALY [95% confidence interval: -25M/QALY (dominated) to $22.7M/QALY]. All one-way sensitivity analyses yielded ICERs of greater than $1M/QALY. Conclusions: The ICERs for filgrastim and pegfilgrastim when used as primary prophylaxis against FN in DLBCL patients receiving induction chemotherapy are well above the usually accepted cost-effectiveness threshold of $50,000/QALY. Disclosures: Mittmann: Amgen Canada: Unrestriced educational grant.

Description: The treatment of ARL is complicated by the numerous immuno-chemotherapy, antiretroviral, and prophylactic options available to lymphoma specialists. The optimal management in the era of combination antiretroviral therapy (cART) is unclear. We administered a survey instrument to determine physician preferences and perceptions in the management of ARL and to assess the variability in treatment in Canada. The survey was developed with items grouped into key domains of ARL management (physician demographics, attitudes, and treatment preferences) and piloted for content validity and clarity. The final questionnaire was administered to lymphoma physicians with valid contact information in the provinces of Ontario (ON; n=155) and British Columbia (BC; n=48). The Dillman Tailored Design Method was followed for multi-modality (internet and standard mail) survey administration. Of 196 physicians, 131 either responded by completing the questionnaire (n=117; 60% response rate) or declining to participate (n=14; 7%). Most responders were male (63%), white (70%), practicing in an academic setting (63%), and belonged to a median age group range of 41–50 years. The majority (98%) had a positive attitude towards the treatment of ARL, as measured by a previously validated 2-item attitude scale. However, barriers to adequate care were still identified; 84% of physicians agreed that uncontrolled human immunodeficiency virus infection represented a major barrier to ARL care and 54% agreed that a patient’s concurrent intravenous drug abuse impaired care. Most physicians recommended the concomitant use of cART in the care of their patients with ARL (n=72 of 109 responses; 66%). Similarly, a majority of respondents recommended CHOP-like regimens (cyclophosphamide, doxorubicin, vincristine, and prednisone; n=92 of 108 responses; 85%) to form the backbone of chemotherapy. The addition of the rituximab was preferred by 41% physicians but not by 40% others, with remaining respondents unsure of the agent’s role. In logistic regression analysis, use of rituximab was predicted only by location of practice (province), after adjusting for other potential predictors including physician age, race, gender, practice environment (academic vs. community), years of experience, ARL patient volume, and modality of survey response. Physicians from BC were much more likely to administer rituximab than ON practitioners (OR 44.5; 95% CI: 7.76–255.0, p

Description: Key Points A key transition from the prealveolar macrophage precursor to mature alveolar macrophage is impaired in neonatal mice lacking LPL. Genetic impairment of neonatal alveolar macrophage development associates with impaired clearance of a pulmonary pathogen in adult animals.

Description: Introduction: Sezary syndrome is a rare, aggressive and advanced stage of cutaneous T cell lymphoma where patients exhibit total body erythroderma and peripheral blood involvement. Patients can progress from preexisting mycoses fungoides or present de-novo. Historically median survival has been less than two years however with current combinations of skin directed and immunomodulatory therapy median survival has been documented up to 3–4 years, however randomized trials are lacking given the rarity of this disorder. We describe the outcomes 23 patients followed in our centre diagnosed with sezary syndrome based on peripheral blood involvement and erythroderma who have been treated primarily with combination skin and immunomodulatory therapy. Methods: A review of all patients diagnosed with sezary syndrome in our centre was conducted. Base line characteristics, survival, number and type of therapies as well as responses to treatments were recorded Results: 23 patients were identified. 11 male, 12 female, average age at diagnosis 64.7 yrs (range 47–85). Therapies included total skin electron beam (TSEB), PUVA, Interferon, oral retinoids, and extracorporeal photophoresis (ECP). 5 patients had received prior traditional chemotherapy including CHOP, chlorambucil and purine analogues with either no or transient responses. 19 patients received a combination of all 5 therapies. 19 patients received IFN, 13 TSEB, 21 PUVA, 18 ECP and 16 oral retinoids. 7 patients received 3 or fewer therapies (3 in process of escalating therapy, 1 CR to TSEB, 3 pts refused multiagent therapy as elderly and stable on PUVA +/− retinoids). 6 patients achieved a durable complete remission while on therapy (4 received IFN/TSEB/PUVA/ECP, 1 IFN/PUVA/ECP, 1 TSEB alone), 3 patients had progressive disease, and the remainder either had partial responses or stable disease. Median follow-up was 44 months (range 9–127). Median survival of the entire cohort was 37 months (mean 52 months, range 6–108 months, 5 patients have been diagnosed in the last 12 months). There have been 5 deaths to date, median 43 months (range 33–101) from the time of diagnosis. Cause of death included 2 cardiac, 1 renal, 1 infection, and 1 progressive disease. There was no correlation between survival and LDH at presentation, sezary cell count or number of therapies. There was a modest correlation between survival and age at diagnosis (R2=0.1263). Patients who received TSEB had an average of 57 months survival vs. 33.5 months than those who did not, however this was not statistically significant. Reasons not to receive TSEB included 5 patient refusal, 3 still escalating therapy, 2 had adequate response to other therapies. Patients who achieved a CR to therapy had a median survival of 63 months (average 65 months) vs. those who did not achieve a CR had a median survival of 22 months (average 65 months). Conclusions: Patients receiving combination immunotherapy and skin based treatments for sezary syndrome appear to be living longer than historical series. Given the small number of this cohort it was not possible to statistically determine variables predictive of prolonged survival, however patients who received TSEB and or achieved a CR to treatment had median survival of approximately 5 years. The majority of patients received maintenance immunotherapy to sustain disease control.

Description: Hodgkin lymphoma (HL) occurs in HIV-infected individuals more frequently than in the HIV-negative population and the incidence is rising. Patients (pts) with non-Hodgkin’s lymphoma in HIV appear to have improved outcomes if they receive HAART with chemotherapy (CT). ABVD is standard CT for HL and is frequently administered with HAART in pts with HIV-HL. However, some components of the ABVD regimen may interact with antiretroviral (ARV) medications to alter metabolism and increase toxicity. In particular, vinblastine (VBL) is metabolized by CYP3A4 and protease inhibitors, particularly ritonavir (RTV), appear to inhibit this cytochrome potentially leading to higher VBL exposure. Little definitive information is available regarding how interactions might affect clinical outcome. We conducted a retrospective review of 36 pts with HIV-related HL to identify the frequency of neurotoxicity (NT), hematologic toxicity (HT), and lung toxicity (LT), to identify risk factors for severe (grade III–IV) toxicity, and to determine its clinical significance. Clinical data were collected from the CFE database and by chart review from 3 centers. The median age at HL diagnosis (dx) was 41 (range 29–66) years and 34 (94%) were male. HL was advanced stage in 28 (78%). Hasenclever score could be calculated in 23 pts and was 0–4 and ≥5 in 15 and 8 pts respectively. ECOG PS was 0–1 in 13 and ≥2 in 8 (n=21). HIV risk factor was: sexual, n=21 and other, n=5 (n=26). Median CD4 count at HL dx was 210 (2–660) cells/ul (n=31). Median HIV viral load (VL) was undetectable (

Description: Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and is characterized by its genetic and clinical heterogeneity. Patients can develop DLBCL de novo or as a transformation from other lymphoid malignancies, most commonly follicular lymphoma. For patients with relapsed/refractory DLBCL (rrDLBCL), prognosis is extremely poor with 2-year overall survival of 20-40%. While numerous treatments are under investigation to improve patient outcomes, the success of these treatments has been limited as the genetic mechanisms underpinning treatment resistance are largely unknown. Identifying genomic alterations which contribute to relapse may improve salvage therapy for patients with rrDLBCL or allow patients to be stratified prior to frontline treatment. Methods To identify genomic alterations which contribute to R-CHOP resistance, we previously collected samples from patients enrolled in four clinical trials exploring candidate salvage therapies for patients with rrDLBCL as well as a retrospective rrDLBCL cohort, totalling 193 cases (133 de-novo DLBCL, 60 transformed). Plasma samples were collected from each patient upon relapse along with diagnostic tissue biopsies where available. A combination of exome sequencing and target-panel sequencing of lymphoma associated genes was performed on circulating tumour DNA and tissue biopsies (if available). Mutations implicated in R-CHOP resistance were identified through two complimentary strategies. First, the mutation frequency of recurrently mutated genes across de novo rrDLBCL samples was compared to a cohort of unrelated diagnostic DLBCL cases (n=1691) to identify genes enriched for mutations. Second, the genomic landscape and tumor clonal structure was compared prior to and following R-CHOP to identify mutations in each patient that underwent clonal expansion following therapy. Anti-CD20 antibody binding affinity of MS4A1 mutants was evaluated using flow cytometry on transfected CHO-S cells. Results We have identified five genes enriched for mutations in our rrDLBCL cohort relative to diagnostic DLBCL: KMT2D (Mutated in 49%, Q=0.0385), TP53 (47%, Q=1.07x10-9), FOXO1 (11%, Q=0.0727), NFKBIE (11%, Q=0.0385), and MS4A1 (8%, Q=0.0522). Consistent with its characterization as a poor prognostic marker, mutations in TP53 were typically present at diagnosis and remained stable following R-CHOP therapy for both de novo and transformed DLBCL (23/27 cases, 85%). Recurrent mutations affecting Arg248 of TP53 (6.8%, Q=0.0413) were also clonally stable and have previously been associated with poor overall survival across several cancer types. The histone methyltransferase KMT2D is dominated by nonsense and frameshift mutations which were stable or underwent clonal expansion following R-CHOP (17/19, 89%). Recurrent missense mutations in MS4A1 targeted the small loop and adjacent transmembrane domains of CD20, including several patients with a Tyr86 mutation. Transfected cells carrying Tyr86Cys or Leu66Arg mutations were not bound by rituximab or other anti-CD20 antibodies including obinituzumab and ofatumumab. Subclonal populations containing MS4A1 mutations underwent clonal expansion (6 cases) or were stable (1 case) following treatment, including one case with multiple MS4A1 mutations in distinct subclonal populations which both underwent clonal expansion. In another unique case, a series of ctDNA samples were available prior to and following R-CHOP and salvage therapy, where we again observed convergent evolution of two mutually exclusive clonal subpopulations containing MS4A1 mutations. The first subpopulation underwent clonal expansion following frontline therapy but was extinguished following salvage therapy, while the other subpopulation underwent clonal expansion following salvage therapy and harboured a transmembrane domain mutation. Conclusion Mutations in TP53 and truncating mutations in KMT2D are generally present prior to treatment and will be investigated as biomarkers of treatment failure. Additional mutations are not always present at diagnosis, but their emergence can be detected in ctDNA and relapsed tissue, specifically mutations in MS4A1. As mutations in MS4A1 attenuate rituximab binding and are recurrently associated with clonal expansion, they likely impart a selective advantage and lead to resistance against anti-CD20 antibodies. Disclosures Michaud: Epizyme: Employment. Daigle:Epizyme: Employment. Jain:Kite/Gilead: Consultancy. Kuruvilla:Roche: Honoraria; Astra Zeneca: Honoraria; Novartis: Honoraria; Merck: Honoraria; Karyopharm: Honoraria; Gilead: Honoraria; Celgene: Honoraria; BMS: Honoraria; Amgen: Honoraria; Seattle Genetics: Consultancy; Roche: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy; Janssen: Research Funding; Roche: Research Funding; BMS: Consultancy; Abbvie: Consultancy; Seattle Genetics: Honoraria; Janssen: Honoraria. Assouline:Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Scott:NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Celgene: Consultancy; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding. Johnson:BD Biosciences: Other: Provided a significant proportion of the antibodies used in this project free of cost.; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Seattle Genetics: Honoraria; Lundbeck: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding.

Description: Key Points Patients with relapsed or refractory transformed indolent lymphoma and DLBCL have similar outcomes with salvage therapy and ASCT. This therapy should be considered the standard of care for previously treated transformed indolent lymphoma.