ALBERT

Description: Introduction. The VES-13 is a simple, self-reported, function based tool originally developed to screen community-dwelling populations to identify persons age 65 years and older at risk of death and functional decline, including death in the next 12 months. The VES-13 items include patient's age, self-rated overall health status, functional limitations in physical activity, and functional disabilities in more complex activities of daily living. As part of the Lymphoma Epidemiology of Outcomes (LEO) cohort study, we collected self-reported VES-13 data at study enrollment on all participants regardless of age, and here we report on the prevalence of vulnerable status defined by the VES-13 and its association with 1-year mortality, overall, stratified at age 65 years, and in the subset of diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy. Methods. From 7/2015 to 6/2017, 3253 participants with NHL were enrolled within 6 months of their diagnosis into the LEO cohort. 2004 were evaluable on VES-13, and 1183 (59%) completed it before the initiation of therapy. VES-13 scores range from a minimum of 0 (low risk for decline) to a maximum of 10 (greatest risk for decline), and a score ≥3 was classified as vulnerable. Clinical, pathology and treatment data were abstracted using a standard protocol, and participants were contacted every 6 months for the first three years and then annually thereafter to identify outcomes. Medical records were reviewed by LEO clinicians to classify cause of death according to a standard protocol. Therapy was determined by the treating physician, and this was independent of knowledge of the VES-13 score. The association of VES-13 with 1-year mortality from date of diagnosis was estimated using odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models, which also provided model c-statistics. Results. The median age of the 2004 participants in this analysis was 62 years (range 18-94); 57% were male; 54% were ≥65 years; and 28% had a normal body mass index (BMI), 1% were underweight, 35% were overweight, and 36% were obese. Clinically, 59% of participants had an aggressive subtype, 65% were stage III-IV, 24% had B-symptoms, and 11% had a performance status (PS) of ≥2. Overall, 28% of participants were classified as vulnerable (95% CI 26%-30%), with a higher prevalence among those completing the survey after initiation of therapy (38%, 95% 34%-41%) versus before initiation of therapy (22%, 95% CI 20%-24%), and a higher prevalence for those ≥65 years (32%, 95% CI 29%-34%) versus

Description: Abstract 2686 Background: DLBCL is the most commonly occurring form of non-Hodgkin lymphoma and is a highly curable disease, but one that is universally fatal if untreated or improperly treated. In a series of studies, we have reported racial disparities in the clinical presentation and the treatment outcomes for patients (pts) with DLBCL in the United States (Shenoy Cancer 2010; Flowers CEBP 2012). These studies showed that black pts with DLBCL are diagnosed at an age a decade younger than whites, are more likely to have advanced stage disease, and are less likely to survive 5 years. One explanation is that black patients in the US less often receive standard of care therapy (Flowers CEBP 2012). However, in a cohort study of 533 white and 144 black patients with DLBCL managed at Emory and University of Alabama-Birmingham (UAB) black race predicted worse overall survival (OS) even when black and white pts received the same therapy (CHOP; Hazard ratio [HR] 1.8, p 60 years of age (p=0.04), 73% had stage III/IV disease vs. 56% (p=0.03), and 77% had an LDH〉ULN vs. 51% (p=0.04). There were no significant differences between the two racial groups in terms of sex, ECOG PS, presence of B-symptoms (38% vs. 29%p=0.46), extranodal sites (50% vs. 78% ≤ 1, p=0.27), IPI risk, or treatment received (RCHOP 46% vs. 40% p=0.93). By the Hans, Natkunam, Tally, and Choi algorithms black patients more commonly presented with the poor-risk ABC/non-GCB subtype (by Choi black 64% ABC vs. white 37%; p= 0.01, Table). After controlling for clinical confounders including age, sex, stage, LDH, performance status, presence of B-symptoms, race, treatment (RCHOP vs. other), and ABC subtype, being 〉60 years of age [HR 3.1 95% CI 1.3–7.2], being black (HR 3.5 95% CI 1.5–8.2), and receiving treatment other than RCHOP (HR 12.8, 95% CI 3.2–50.6) were associated with inferior OS. Conclusions: The rate of ABC DLBCL is significantly higher in black pts compared to white pts in this university-based cohort from the Southern United States. Additional studies confirming these findings in larger populations and examining the mutations associated with these differences are underway to address biological differences intrinsic to DLBCL that may in part explain comparatively adverse features and outcomes for black pts with DLBCL. Disclosures: Flowers: Celgene, Spectrum, Millennium, Gilead, Janssen: Research Funding; Genentech/Roche (unpaid), Millennium (unpaid), Celgene: Consultancy. Bernal-Mizrachi:Empire Genomics (not related to current work): Patents & Royalties. Sinha:Celgene: Research Funding. Jaye:Millenium Pharmaceuticals (For single lecture on immunohistochemical subtyping of large B cell lymphomas): Honoraria.

Description: Abstract 144 In MHC-mismatched allogeneic hematopoietic stem cell transplantation (allo-HSCT), host antigen specific donor T cells mediate acute and chronic graft-versus-host disease (GvHD). Based upon the radio-protective effects of flagellin, a TLR5 agonist protein (∼50 kDa) extracted from bacterial flagella, we reasoned that flagellin might modulate donor T cells immune responses toward host antigens, reduce GvHD, and improve immune responses to CMV infection in experimental models of allogeneic HSCT. Two 50mg/mouse i.p doses of highly purified flagellin were administered 3 hrs before irradiation and 24 hrs after allo-HSCT in H-2b ^ CB6F1 and H-2k ^ B6 models. GvHD scores were obtained with weekly clinical examination and with histological scoring of intestine, colon, liver and skin at necropsy. Flagellin treatment successfully protected allo-HSCT recipients from acute and chronic GvHDs after transplantation of 5×106 splenocytes and 5×106 T cell depleted (TCD) BM, and significantly increased survival compared to PBS-treated control recipients. Reduced acute GvHD was associated with significant reduction of a) early post-transplant proliferation of donor CD4+ and CD8+ T cells measured by Ki67 and CFSE staining, b) fewer CD62L+, CD69+, CD25+, ICOS-1+ and PD-1+ donor CD4+ and CD8+ T cells compared with the PBS-treated control recipients. Decreased numbers of activated and proliferating donor T cells were associated with significantly reduced pro-inflammatory serum IFN-g, TNF-a, and IL-6 on days 4–10 post transplant in flagellin-treated recipients compared with the PBS-treated recipients. Interestingly, both flagellin-treated recipients and PBS-treated recipients had over 99% donor T cell chimerism at 2 months post transplant. Moreover, MCMV infection on 100+ days post-transplant flagellin-treated mice significantly enhanced anti-viral immunity, including more donor MCMV-peptide-tetramer+ CD8+ T cells in the blood (p

Description: Abstract 2947 Poster Board II-923 Introduction: DLBCL occasionally presents in leukemic phase, and the prognostic significance of circulating lymphoma cells is unknown. We herein report characteristics and outcomes of newly diagnosed DLBCL presenting in leukemic phase at 2 Institutions. Methods: Flow cytometry database analysis and retrospective chart reviews were carried out with IRB-approval for cases accrued between 2001 and 2008. Leukemic phase DLBCL patients were matched on a 3:1 basis with control DLBCL with no circulating lymphoma cells based on IPI, year of diagnosis, and age ± 10 years. Results: 18 patients, median age 48 years (range 34-80), ECOG PS-1 (22%), 2(38%) and 3(40%), and IPI - 3(56%), 4(40%) and 5(4%) presented in leukemic phase. Extranodal sites included bone marrow (100%), spleen (83%), pleura (61%) and CSF (22%). 61% had B symptoms, and LDH was 6xULN (range, 1-56). WBC was 13,000/microL (range, 7,100-127,400), with 50% lymphoma cells (range, 2-92); these cells were immunophenotypically similar to those in the histologically confirmed DLBCL node, and co-expressed CD19, CD20, CD22, CD38, CD45, HLA-DR and FMC7 in 〉90% of cases, and kappa or lambda light chain restriction in 〉 50%. Karyotype was abnormal and complex in 61%. One patient expired before treatment began. Treatment consisted of R-CHOP (10), R-HCVAD (6), and single agent rituximab (1). 8 (44%) achieved CR (5 R-HCVAD and 3 R-CHOP), 5 (28%) PR, and 4 (22%) had resistant disease. 1 patient was autografted in CR1 and remains in remission. With a median follow-up of 32 months, 2 relapsed in leukemic phase, 1 of whom achieved CR2, but relapsed at the time of conditioning for a consolidative allograft. 10 (56%) patients died from progressive disease, 2 (11%) were lost to follow-up and 6 (33%) remain alive in remission. Overall (Panel A) and progression-free (Panel B) survival curves the 18 leukemic (solid line) and 54 non-leukemic phase (dashed line) DLBCL are depicted in the Figure. Conclusion: DLBCL presenting with circulating lymphoma cells is associated with chemo-resistance (44% CR) and poor outcomes with the exception of those who achieve complete remission. These patients are candidates for alternative therapies. Disclosures: Kaufman: Millenium: Consultancy; Genzyme: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Armitage:Eisa: Consultancy; Allo: Consultancy; Ziopharm: Consultancy.

Description: Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with both malignant and non-malignant hematologic disorders. But life-threatening graft-vs-host diseases (GvHD) caused by alloreactive donor T cells limits its clinical use. Alloreactive T cells are also required for graft-vs-leukemia (GvL) and to fight opportunistic infections. Hence, a method that modulates donor T cells activity to reduce GvHD but to retain GvL effect is highly desirable. The inhibitory receptor programed cell death-1 (PD-1) reduces T cell activation through binding with its ligand PD-L1 or PD-L2. Interaction between PD-1 and PD-L1 induces cardiac allograft tolerance and expression of PD-L1 is upregulated in presence of inflammatory stimuli. Here, we studied the role of PD-L1 expression on hematologic and non-hematologic tissues and PD-1 - PD-L1 binding in the development of GvHD. Methods Wild type C57BL/6 (WT B6), PD-L1 knock out B6 (KO) and PD-L2 KO B6 mice were transplanted with 2 x106 splenic T cells and bone marrow (BM) cells from H-2K B10.BR donors. The average acute GvHD scores were determined by combining the GvHD scores obtained from the histological tissue sections of small intestine, large intestine and liver, and weight-loss, posture, activity, fur texture and skin integrity data following standard published procedures. The activation status of splenic T cells was analyzed by flow cytometry. Serum cytokines were determined by using 26 plex Luminex assay. The requirement of hematopoietic and or non-hematopoietic tissues expressing PD-L1 to reduce GvHD was investigated by generating radiation chimeras using WT B6 mice engrafted with PD-L1 KO BM and vice versa. Two months later radiation chimeras were transplanted again with 2 x106 splenic T cells along with 2 x106 BM cells from congenic na•ve H-2K donors. The role of PD-L1 expressing donor hematopoietic cells on the development of acute GvHD was tested by transplanting B10.BR mice with donor PD-L1 KO B6 and WT B6 splenocytes. Results PD-L1 KO B6 recipients had significantly increased acute GvHD (scores 1.68 ± 0.07) compared with WT B6 GvHD (0.78 ± 0.024, p

Description: Host antigen-presenting cells (APC) persist after high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT) and initiate graft-versus-host disease (GvHD) in mouse models of HSCT. The role for donor APC on transplant outcomes is less clear. In clinical allogeneic HSCT from HLA-matched siblings, larger numbers of donor plasmacytoid dendritic cell (DC) precursors were associated with more relapse, and worse survival. Depletion of CD11b+ cells from bone marrow (containing CD11b+ DC) modestly augmented graft-versus-leukemia (GvL) activity in murine allogeneic HSCT. In this study, using allogeneic MHC mis-matched HSCT (C57BL/6→B10.BR) of mice bearing a lymphoblastic leukemia (LBRM), recipients of FACS–purified CD11b− donor DC plus FACS–purified HSC and T-cells had dramatically improved long-term survival (45% alive at 〉100 days) compared to d 5% survival among recipients of HSC and T-cells, or HSC, T-cells and CD11b+ DC (p

Description: Introduction: In patients (pts) with relapsed/refractory CLL, responses achieved with conventional salvage chemotherapy may have limited durability, likely due to the presence of residual disease remaining in the bone marrow (BM) or peripheral blood (PB). The anti-CD52 monoclonal antibody alemtuzumab (Campath®) demonstrates single-agent efficacy in relapsed/refractory CLL and has been shown to induce MRD-negative (-) responses in 20% of pts (Moreton et al J Clin Oncol2005;23:2971–2979). A recent phase 2 study reported that treatment with SC alemtuzumab with or without the addition of oral fludarabine in pts with relapsed/refractory CLL resulted in a 49% overall response (OR) rate and 16% complete response (CR) rate; MRD(-) CR was achieved in 10% of pts (Sayala et al Blood2006;108: abstract 34). We evaluated the safety and efficacy of SC alemtuzumab combined with intravenous (IV) fludarabine in pts with previously treated CLL and report the responses and results from MRD analysis. Methods: Eligible pts had active CLL requiring therapy and had relapsed after at least 1 prior therapy. SC alemtuzumab 30 mg days 1–5 and IV fludarabine 25 mg/m2 days 1–5 were administered on a 28-day cycle for 4 cycles. Pts with

Description: Background: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) in adults is an aggressive bone marrow malignancy that historically has a poor prognosis. Hyper-CVAD/methotrexate-cytarabine (hyper CVAD) regimen is a commonly used induction regimen following the protocol developed at MD Anderson Cancer center. Recent reports from Swedish Cancer Registry showed that relapse rates were much higher than expected with this regimen. We report our retrospective experiences across three different centers, Winship Cancer Institute of Emory University (Atlanta), University of Alabama Cancer Center (Birmingham) and Moffitt Cancer Center, (Tampa), with the use of this regimen for management of T-ALL/LBL. Methods: We conducted a retrospective chart review of all adult T-ALL/T-LBL cases at three large cancer centers between the years 2005-2015, treated at the physician's discretion. Data collected included patient demographics, tumor characteristics (white count at diagnosis, flow cytometry, FISH, cytogenetics, bone marrow involvement), treatment regimens and patient outcomes. Since hyper CVAD is a commonly used regimen outside of clinical trials, we focused our analysis on outcomes with this regimen. This regimen consisted of 4 courses of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone; the odd courses 1, 3, 5, 7); and 4 courses of MTX-Ara-C (methotrexate-cytarabine; the even courses 2, 4, 6, 8). CNS prophylaxis was given to all patients as per standard of care recommendations. All patients eligible for maintenance received 2 years of POMP (6 mercaptopurine, methotrexate, vincristine and prednisone) maintenance. Relapse-free survival (RFS) and overall survival (OS) were examined looking at medians and interquartile ranges of times to events. Kaplan Meier curves provided a graphical representation of the survival probability. Results: The final analysis included 95 adult patients with 64/95 (67%) patients receiving hyper-CVAD induction. Among the hyper-CVAD patients the median age at diagnosis was 30 (range 17-74). 71% of patients were male. Median white cell count (WBC) was 13.6/mm3 (1.7-500). Cytogenetic analysis revealed diploid in 36, complex (1 or more abnormalities in 16) and was not available in 12. WBC count was 〉 100,000/mm3 in 9 patients. 14 patients had mediastinal disease while 7 had CNS disease at diagnosis. Hyper-CVAD was the primary induction regimen in 56/64. Other patients either started on non-hyper CVAD induction prior to switching (n=3) or had asparaginase added to induction (n=5). The median number of cycles given as 7 (range 2-10) with 27(45%) patients receiving the planned 8 cycles. 37 patients did not complete 8 cycles due to stem cell transplant in remission (n=12), progressive disease (n=10) and unclear reasons (n=15). After induction therapy, remission status was unknown in 3 patients while 43/61 patients (70%) achieved remission. Maintenance with POMP was started in 21 patients that were in remission while 12 patients were taken to transplant without starting on maintenance. At the time of analysis, 23/64 (35%) patients are alive. The median relapse free survival was 387 days (12.9 months) and the median overall survival was 536 days (17.6 months). Excluding one patient lost to follow up, 44/63 (69.8%) relapsed. There was no difference in relapse versus non relapse patients in terms of median age (30 vs 33 years), median WBC at diagnosis (13.2 vs 13.6 mm3). Relapse rate was lower in patients with diploid karyotype (22/36, 61%) as compared to those with complex karyotype (14/16). Median survival in patients post relapse was 150 days. Only 9 patients were able to go for transplant after relapse with post transplant survival also being low (6 deaths). For the entire group, the two year survival was 35%. Conclusion: Our multi-institutional retrospective review shows that outcomes are poor across various centers in patients outside of clinical trials. This is the largest reported series of patients with adult T-ALL/T-LBL treated with hyper-CVAD outside of clinical trials. This data warrants investigation with newer agents to improve outcomes in this disease. Figure 1. Relapse free survival and overall survival in patients treated with hyper-CVAD (n=64) Figure 1. Relapse free survival and overall survival in patients treated with hyper-CVAD (n=64) Disclosures Kota: Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hathaway:OnQ Health: Research Funding. Shah:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acetylon: Membership on an entity's Board of Directors or advisory committees; PLexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Spectrum: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria; Rosetta Genomics: Research Funding; Seattle Genetics: Research Funding. Jillella:Seattle Genetics, Inc.: Research Funding. Borate:Genoptix: Consultancy; Seattle Genetics: Research Funding; Gilead: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau.

Description: Abstract 4909 Introduction: The proteasome inhibitor bortezomib and the histone deacetylase inhibitor (HDACi) romidepsin are both able to induce tumor cell death in single-agent clinical studies. In vitro studies using the combination of bortezomib and romidepsin have demonstrated synergistic activity against tumor cell lines, and clinical trials using both classes of agents have demonstrated efficacy. Bortezomib and romidepsin induce thrombocytopenia that is transient and reversible. It is thought that these agents temporarily disrupt the process of platelet budding from megakaryocytes, in contrast to long-term thrombocytopenia induced by classical cytotoxic chemotherapeutic agents that deplete the megakaryocyte population. However, thrombocytopenia has been a dose-limiting factor when proteasome inhibition is combined with HDACi. We have previously shown that platelet recovery after bortezomib exposure in mice results in transient high elevation of circulating platelets and that the megakaryocyte population is preserved, with increased numbers of immature forms suggesting a rebound effect (Lonial et al., Blood, 2005). Here, we conducted additional murine studies to determine whether combination bortezomib + romidepsin induces increased thrombocytopenia compared to the single-agent drugs, examine platelet recovery kinetics, and test effects on bone marrow megakaryocytes. Methods: Six groups of 12 female BALB/c mice were used: Control, 1mg/kg bortezomib, 2mg/kg bortezomib, 1mg/kg romidepsin, 2mg/kg romidepsin, and the combination of 1mg/kg bortezomib + 1mg/kg romidepsin. Only one injection timepoint was used (d1, via tail vein) to narrow the focus of thrombocytopenic effects. Three mice per group were bled on subsequent days (to d11) for CBC including WBC and platelet counts. Plasma samples were frozen for batch analysis of thrombopoietin (TPO) levels by ELISA. Subgroups of 2–3 mice were sacrificed at d3, 5, and 8 for analysis of bone marrow megakaryocyte ploidy. Bone marrow cells were fixed in ethanol and analyzed by flow cytometry to determine the representation of CD41-positive megakaryocytes in the different 7-AAD ploidy categories based upon 7-AAD-stained DNA content. Bone marrow H&E histological analysis of marrow megakaryocyte content is ongoing. Results: WBC counts for controls and mice treated with bortezomib alone were at baseline values or greater during the course of the experiment. Mice treated with romidepsin, or the combination of bortezomib + romidepsin, showed an initial drop in d2 WBC counts to 50% of baseline. The platelet nadir for most groups was at d3, with very similar counts for all single-agent groups near 500 × 103 per mcL (Figure 1, bars represent standard deviation). Counts for the groups treated with 2mg/kg bortezomib or romidepsin were only slightly lower than for groups treated with 1mg/kg. However, the average day 3 platelet count for the combination group was significantly lower at 250 × 103 per mcL (Figure 1, * indicates p=0.0018). Platelet recovery was very rapid in the mice that received bortezomib alone, with d6 levels 150% of baseline. Platelets remained low in romidepsin-treated mice until d5 and then began increasing. Interestingly, platelet counts in the combination group also remained low until d5, similar to romidepsin alone, but then rose rapidly with kinetics reminiscent of the rebound seen in the bortezomib-treated groups (Figure 1). On d3, thrombocytopenia was associated with an increase in plasma TPO, especially in the bortezomib + romidepsin group, indicating that platelet reduction induced by the combination of both agents is not the result of TPO suppression. At d5 and d8, drug-treated groups had lower percentages of 8N/16N megakaryocytes and corresponding increases in the 2N/4N category, suggesting a megakaryocyte rebound effect in response to thrombocytopenia. Conclusions: The combination of bortezomib + romidepsin induces more profound thrombocytopenia in mice compared to either drug alone, but platelets recover to baseline levels or greater by 7 days after treatment. The platelet recovery phase is characterized by a rapid increase in platelet counts exceeding baseline values, similar to the rebound effect induced by bortezomib alone. This suggests that the platelet-producing megakaryocyte population is maintained after bortezomib + romidepsin treatment. Disclosures: Nix: Gloucester, Celgene: Consultancy, Employment. Lonial: Gloucester, Celgene: Consultancy, Research Funding.