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Evidence regarding the effectiveness of COVID-19 vaccine in patients with impaired immunity is limited. Initial observations suggest a lower humoral response in these patients. We evaluated the relative effectiveness of the mRNA BNT162b2 vaccine in patients with hematological neoplasms compared with matched controls. Data on patients with hematological neoplasms after 2 vaccine doses were extracted and matched 1:1 with vaccinated controls. Subpopulation analyses focused on patients receiving therapy for hematological neoplasm, patients without treatment who were only followed, and recipients of specific treatments. The analysis focused on COVID-19 outcomes from days 7 through 43 after the second vaccine dose in these areas: documented COVID-19 infection by polymerase chain reaction; symptomatic infection; hospitalizations; severe COVID-19 disease; and COVID-19–related death. In a population of 4.7 million insured people, 32 516 patients with hematological neoplasms were identified, of whom 5017 were receiving therapy for an active disease. Vaccinated patients with hematological neoplasms, compared with vaccinated matched controls, had an increased risk of documented infections (relative risk [RR] 1.60, 95% CI 1.12-2.37); symptomatic COVID-19 (RR 1.72, 95% CI 1.05-2.85); COVID-19–related hospitalizations (RR 3.13, 95% CI 1.68-7.08); severe COVID-19 (RR 2.27, 95% CI 1.18-5.19); and COVID-19–related death (RR 1.66, 95% CI 0.72-4.47). Limiting the analysis to patients on hematological treatments showed a higher increased risk. This analysis shows that vaccinated patients with hematological neoplasms, in particular patients receiving treatment, suffer from COVID-19 outcomes more than vaccinated individuals with intact immune system. Ways to enhance COVID-19 immunity in this patient population, such as additional doses, should be explored.

Background: Murine models of myelodysplastic syndromes (MDS) exhibit lower bone mass (B-Mass), and several reports suggest increased incidence of osteoporosis and fractures in MDS patients. Whether MDS is associated with lower B-Mass is unknown. Aims: 1) to develop a simple method to estimate trabecular B-Mass from bone marrow biopsies (BMB); 2) to compare the trabecular B-Mass of MDS patients at diagnosis and non-MDS controls; 3) to develop an artificial intelligence (AI) algorithm for automated trabecular B-Mass assessment. Methods: In this study we included male patients age ≥ 65 years old with "lower-risk" (LR) MDS, diagnosed at Tel Aviv Sourasky Medical Center, between 2011 and 2019 and age-matched controls undergoing bone marrow (BM) biopsy for either unexplained anemia or as a part of staging work-up for newly diagnosed lymphoma. BM slides (H&E stain) were digitally scanned. The total relevant area (TRA, Figure 1A) was identified and bone trabeculae were manually contoured using Adobe Photoshop software. Bone area (BA, figure 1B) was calculated as the sum of all contoured pixels of bone, and B-Mass = BA/TRA(%). The manually annotated data were used to develop a preliminary AI algorithm to automatically detect the BA as well as BM fat for use in the current and future research in the field. The Sørensen-Dice similarity coefficient (DSC) was used to assess agreement between manual and AI annotations. Results: There were 43 MDS and 36 control patients with mean ages of 80 and 78 years (p>0.05), respectively. Comorbidities in both groups were similar. Notably, trabecular B-Mass of MDS was significantly lower than that of controls: 11.6% [95%CI 9.9-13.3] vs 18.3% [16.6-20.3], respectively (p Conclusions: We have developed a simple technique to estimate trabecular B-Mass based on available BM sections. Importantly, we found that trabecular B-Mass of LR-MDS patients is compromised already at diagnosis. In addition, automated (AI) assessment of B-Mass using available H&E-stained BM slides is feasible and clinically relevant for patients with MDS and other hematological malignancies. Future work will develop the AI technique and expand it to identify all components of the BM, including the cellular compartment. This will enhance our understanding of the osteohematological niche in such patients, and aid in diagnosis as well as treatment planning. This study was supported by a grant from the Dotan Hemato-oncology Fund, the Cancer Biology Research Center, Tel Aviv University to DN, MM and HSO. Figure 1: Bone marrow biopsy (BMB) slide of a representative patient showing (A) the total relevant area, and (B) the bone area - TRA and BA respectively. Demonstrating the artificial intelligence (AI) technique for the same patient, we compare (C) manual annotation to (D) AI-based annotation of both bone (red) and fat (green). Figure 1 Figure 1. Disclosures Mittelman: Janssen · Roche · Novartis · Takeda · Medison / Amgen · Neopharm / Celgene / BMS · Abbvie · Gilead: Research Funding; Novartis · Takeda · Fibrogen · Celgene / BMS · Onconova · Geron: Other: Clini; Onconova · Novartis · Takeda · Silence: Membership on an entity's Board of Directors or advisory committees; MDS HUB: Consultancy; Celgene / BMS · Novartis: Speakers Bureau.

'MDS with isolated del(5q)' is a subtype of Myelodysplastic Syndrome (MDS) with characteristic morphological and genomic features. Clinically, MDS with isolated del(5q) is uniquely responsive to immunomodulatory agents, with lenalidomide (LEN) approved for treating anemia in this indication. Erythropoiesis Stimulating Agents (ESA) and red cell transfusion (RBCT) are other options for anemia management. The EUMDS Registry is an international prospective registry of newly diagnosed patients (within 100 days of diagnosis) with IPSS Low/Int-1-risk MDS (plus higher-risk MDS from 2017) recruiting since 1 st April 2008, currently at 146 sites in 17 countries. We describe the largest prospective Registry series of 'MDS with del(5q)' patients, with data from diagnosis. Methods Comparative analyses of baseline characteristics for categorical variables compared different groups by chi 2 test, and for continuous variables by Kruskal-Wallis test. p values are given with Bonferonni correction applied. Results Baseline characteristics Of 2469 EUMDS patients, 197 (8%) met the WHO 2016 classification criteria for 'MDS with isolated del5q'. Median follow up is 4.3 yrs. 77% were female (34% for all EUMDS patients), and median age was 73y. In comparison to EUMDS patients lacking del(5q), patients with MDS with isolated del(5q) were lower risk at diagnosis (IPSS and IPSS-R, p Interventional management To date, 168/197 patients received active intervention and the following sequence of interventions was observed, in order of frequency of initial intervention, RBCT>ESA>LEN: RBCT (n=96), - then ESA (42) then LEN (21) - then LEN (32) then ESA (5) ESA (n=55), - then RBCT (30) then LEN (13) - then LEN (9) then RBCT (6) LEN (n=17), - then ESA (3) then RBCT (2) - then RBCT (2) then ESA (2) Ninety-two patients have received LEN. In comparison with those not (yet) treated with LEN, LEN treated patients were younger (mean 70y vs 75y, p Adverse events were considered but proved too difficult to evaluate from the Registry data. For example, anticoagulant treatment data was collected, but not the specific indication. Outcome No difference in outcome (OS or PFS) was noted for patients treated with LEN vs. not (Figure, OS - adjusted Hazard Ratio, age and sex, 95% Confidence Interval: 0.67 [95% CI:0.35-1.29], lenalidomide treatment as a time-dependent variable). Conclusion EUMDS is uniquely placed to describe 'real-world' management of patients with 'MDS with isolated del(5q)' from diagnosis. To date, the largest (retrospective) case series reported had a median age 5 years younger than EUMDS, most likely representing referral bias(1). EUMDS demonstrates that most patients with MDS with isolated del(5q) require interventional therapy, and that more than half of transfusion dependent patients have received LEN. Further analysis of interventions and response will be presented. 1. Germing U, Lauseker M, Hildebrandt B, Symeonidis A, Cermak J, Fenaux P, et al. Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): A multicenter study. Leukemia 2012;26(6):1286-92. Figure 1 Figure 1. Disclosures Fenaux: Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Symeonidis: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Demo: Research Funding; WinMedica: Research Funding; Astellas: Consultancy, Research Funding; Sanofi/Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GenesisPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kotsianidis: Novartis Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Abbvie: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Bristol Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Janssen Hellas: Consultancy, Other: NONE, Speakers Bureau; Genesis: Consultancy, Other: NONE; Astellas: Other: NONE, Research Funding, Speakers Bureau. Mittelman: Janssen · Roche · Novartis · Takeda · Medison / Amgen · Neopharm / Celgene / BMS · Abbvie · Gilead: Research Funding; Novartis · Takeda · Fibrogen · Celgene / BMS · Onconova · Geron: Other: Clini; Onconova · Novartis · Takeda · Silence: Membership on an entity's Board of Directors or advisory committees; MDS HUB: Consultancy; Celgene / BMS · Novartis: Speakers Bureau. Sanz: Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Gilead Sciences: Other: Travel, accommodations, and expenses; Abbvie: Consultancy, 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, Other: Travel, accommodations, and expenses, Research Funding. Stauder: Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Germing: Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Jazz Pharmaceuticals: Honoraria. van Marrewijk: EUMDS Registry: Current Employment; Novartis: Other: Educational Grants; BV Oncology Europe: Other: Educational Grants; Amgen Limited: Other: Educational Grants; Celgene International: Other: educational grants; Janssen Pharmaceuticals: Other: educational grants; Takeda Pharmaceuticals: Other: educational grants; MDS-RIGHT: Other: project budgets. de Witte: Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Janssen: Research Funding.

Background: Quality of life (QoL) is impaired in MDS. Aims: 1) To study QoL for various levels of anemia in MDS patients at diagnosis, 2) Compare with non-MDS controls. 3) Compare at MDS diagnosis to 1 year later. Methods: Patients in The Israel MDS registry fill out the EQ-5D QoL questionnaire. The evaluated parameters are: mobility, self-care, daily activities, pain/discomfort and anxiety/depression, each scored 0(normal), 1(mild/moderate), or 2(poor). They also evaluate their general health using a visual analogue scale (VAS), scoring from 0 (poor) to 100(excellent). Anemia was classified as none/normal (Hb≥12.5 g/dl), mild (10≤Hb For controls, we used VAS to assess QoL of patients admitted to the Department of Medicine. Results: In total, 126 MDS patients participated: 19, 40, 17, 21 and 29, from normal to very severe anemia, respectively. Fig.1 shows mean QoL of the 5-parameters for all patients (A), and for each individual (B), as well as the mean VAS score for all patients (C) and for each individual (D). Anemic MDS patients show a wide QoL variability (patients with the same Hb behave differently, Fig.1, B, D). Also, note the drop in QoL from moderate to severe anemia (below 9 g/dl, p=0.06, for 5-parameter; p=0.01, for VAS). In the non-MDS controls (n=141), there was impaired QoL in anemic patients as compared to those without anemia (VAS, Figure 2; p=0.02). However, there was no significant difference in QoL among patients with various degrees of anemia. Follow-up QoL data (1 year) were available for 61 MDS patients (Figure 3). 27 (44%) increased Hb. 32 (52%) decreased, and 2 (3%), had no change. Of the 32 who decreased Hb, average QoL deteriorated by -11.88 [95%CI: -17.96, -5.79]; 24 patients (75%, Figure 3, left-lower quadrant) had decreased VAS score; some still had improved QoL (16%), or stayed the same (9%). Of the 27 who increased Hb, average VAS still reduced by -6.48 [-14.08, 1.12]. The minority increased QoL (26%), or stayed the same (19%). Most (56%) still deteriorated in QoL (right-lower). The QoL results using the 5 parameters was consistent. Conclusions: In this preliminary study: 1) Poor QoL in anemic MDS is variable and not linear, suggesting that other factors, in addition to Hb, affect QoL. 2) The sharp drop in QoL with Hb Figure 1 Figure 1. Disclosures Mittelman: Janssen · Roche · Novartis · Takeda · Medison / Amgen · Neopharm / Celgene / BMS · Abbvie · Gilead: Research Funding; Novartis · Takeda · Fibrogen · Celgene / BMS · Onconova · Geron: Other: Clini; Onconova · Novartis · Takeda · Silence: Membership on an entity's Board of Directors or advisory committees; MDS HUB: Consultancy; Celgene / BMS · Novartis: Speakers Bureau.

Background and aims: Immunotherapy with anti-CD20-specific antibodies (e.g. rituximab), has become the standard of care for B cell lymphoproliferative disorders and many autoimmune diseases. Despite previously demonstrated role for B cells in bone metabolism, the effect of anti-CD20-mediated B cell depletion on bone mass in human patients has not been thoroughly studied. For example, in rheumatological patients the effect of rituximab on bone mass yielded conflicting results, while in lymphoma patients it has not yet been described. Here, we describe the effect of treatment with anti-CD20-specific antibodies on bone mass in a cohort of patients with follicular lymphoma and propose a plausible mechanism using murine model. Methods: To assess the effect of rituximab on bone mass in lymphoma patients, we retrospectively studied the bone mass in patients with follicular lymphoma (FL) during the maintenance phase of chemoimunotherapy, i.e. when rituximab is administered as monotherapy. FL patients on no maintenance (historical controls) or patients with marginal zone lymphoma were include as a control group. Cross-sectional X-ray imaging (CT/PET-CT), performed at the completion of the induction phase and 6-12 months thereafter, were used to serially assess bone density. Wild-type female C57BL/6J mice and mouse anti-mouse CD20 antibody (Genentech) were used for the animal experimental system. Murine bone structure was assessed by the microCT method. Immunophenotyping of the bone marrow (BM), spleen and peripheral blood cells was performed. ELISA and "real-time" quantitative PCR were used to measure the levels of key mediators of bone remodeling, e.g. RANKL, OPG and TNFα. Standard osteoclastogenic assay was used to assesses the osteoclastogenic potential of BM cells. Results: Rituximab treatment prevented the decline in bone mass observed in patients who did not receive active maintenance therapy, both in the lumbar spine (-2.6% vs -8%) and femoral head (-0.5% vs -5.1%) (n=12 patients in each group, p Conclusions: While many lymphoma patients may suffer from bone loss due to advanced age and glucocorticoid administration, our data suggest additional favorable effect of anti-CD20 treatment in bone preservation. Importantly, our murine studies indicate that B cell depletion has a direct effect on bone remodeling, primarily by reducing the osteoclastogenic signals, thus potentially diminishing bone resorption. This novel unrecognized effect should be taken into consideration when maintenance treatment is considered. MM and DN contributed equally to this work. Figure Disclosures No relevant conflicts of interest to declare.

Background and aims: Erythropoietin (EPO) is the key regulator of red blood cell production, commonly used in clinical practice to treat certain forms of anemia. Our studies and those of others have demonstrated that EPO administration induces substantial trabecular bone loss. We proposed that EPO-induced bone loss is partially mediated by subsets of bone marrow (BM) B cells that express EPO-R. Mechanistically, EPO upregulates the surface expression of RANKL by BM B cells and augments B cell-derived osteoclastogenesis in vitro. We showed that the latter is likely mediated by pro-B cells expressing the MCS-F receptor (CD115) and capable of transdifferentiation to osteoclasts (Abstract # 1007, EHA 2017). Here we address the role of B cell-specific EPO-R in EPO-induced bone loss (i.e. at supra-physiological EPO levels). Moreover, we demonstrate, for the first time, the occurrence of B cell-derived osteoclastogenesis in vivo, a finding of critical importance in the field of osteohematology. Methods: In order to trace the B cell lineage from its earliest precursors, we used the MB1-Cre mouse line combined with either the R26R-EYFP or the EPO-Rfl/fl mice for lineage tracing and B cell-specific EPO-R knockdown, respectively. Sequential fluorescence and light microscopy were used for the demonstration of B cell-derived osteoclastogenesis in vivo. Human recombinant EPO was administered in vivo at a dose of 180IU thrice weekly for two weeks. Immunophenotyping of BM B cell populations was assessed by multi-color flow cytometry. Results: Using female MB1-Cre; EPO-Rfl/fl (cKD) mice, we found that B cell-specific EPO-R knockdown attenuated the profound EPO-induced trabecular bone loss in the proximal part of the femoral distal metaphysis (proximal BV/TV 0.034±0.012% vs 0.007±0.003% in the cKD vs control mice, p Using the MB1-Cre;R26R-EYFP murine model for B cell lineage tracing, we could demonstrate that some of the TRAP+/ β3 integrin+ bone lining cells were also positive for EYFP (Figure 2). This demonstrates the B cell origin of some of the osteoclasts in vivo. Conclusions: Our work highlights B cells as an important extra-erythropoietic target of EPO-EPO-R signaling that regulates bone homeostasis and might also indirectly affect EPO-stimulated erythropoietic response. The relevance and the mechanisms of the latter phenomenon merits further investigation. Importantly, we present here, for the first time, histological evidence for B cell-derived osteoclastogenesis in vivo, thus opening novel research avenues. DN and YG Equal contribution Funded by the German Israel Foundation, Grant # 01021017 to YG, DN, MR and BW and by the Israel Science Foundation (ISF) Grant No. 343/17 to DN. Disclosures Mittelman: Novartis: Honoraria, Research Funding, Speakers Bureau.

Introduction: Most patients with newly diagnosed FL treated with rituximab (R) alone or R + chemotherapy will experience prolonged progression-free survival and overall survival (OS), but it remains unclear what factors have the greatest influence on FL-associated and other causes of death in this patient population. We utilized individual patient data from 13 first-line randomized clinical trials from the FLASH database to perform a comprehensive multistate survival analysis to examine and quantify the relationships between clinical characteristics, treatment response, and early, intermediate, and late FL outcomes. Methods: The multistate survival analysis model defined states for "Alive after beginning Induction Treatment (TX)", "Alive after beginning Maintenance TX", "Death due to FL", and "Death from Other Causes" (Figure 1). We used the Aalen-Johansen estimator, a generalization of the Kaplan-Meier estimator, to calculate the likelihood of being in each model state and estimate the course of FL over time. Making no assumptions on the probability distributions and capable of coping with censored observations, the Aalen-Johansen estimator is a convenient and reliable nonparametric estimator for clinical data. Results: Among 7,465 FL patients with median age 56 (range 18-90) years, 49.2% were female; 28.7% Stage I-III, 71.3% Stage IV, and FLIPI was 0-1 (20.0%), 2 (36.8%), ≥ 3 (43.2%). Following initiation of induction treatment, 2-, 5- and 10-year death rates were 1.7%, 3.8%, and 5.8% due to FL, and 0.7%, 2.1%, and 4.8% from other causes (Figure 2). Death rates at 2, 5, and 10 years due to FL and other causes for subgroups based on clinical characteristics and treatment response are shown in Table 1. Notably, patients > 70 years and patients with FLIPI ≥ 3 had worse outcomes and patients achieving CR at 18, 24, and 30 months experienced improved outcomes. Conclusion: This is the largest study using data from randomized trials to quantify the impact of clinical factors on early, intermediate and late mortality by cause of death. We demonstrated that age > 70 years and FLIPI ≥ 3 were linked to increased FL-associated death and response to TX distinguished patients with favorable and poor outcomes. Future analyses should quantify the impact of predictors on the rate/time of FL outcomes in multivariable models. Disclosures Salles: Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Hoster:Janssen: Research Funding; Roche Pharma AG: Other: Travel Support. Hiddemann:Bayer: Research Funding; Gilead: Consultancy, Honoraria; Vector Therapeutics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Herold:Roche: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Celgene: Honoraria. Morschhauser:Servier: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Roche/Genentech: Consultancy; BMS: Honoraria; Celgene: Honoraria. Rummel:Roche Pharma AG: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Kimby:AbbVie,: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Gilead: Other: educational lectures. Vitolo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gyan:Pfizer: Honoraria. Ladetto:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Acerta: Honoraria; Sandoz: Honoraria. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Flowers:AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; Optimum Rx: Consultancy; V Foundation: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding; Bayer: Consultancy; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding; Denovo Biopharma: Consultancy; Acerta: Research Funding; National Cancer Institute: Research Funding; Millenium/Takeda: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Spectrum: Consultancy

Background: Myelodysplastic syndromes (MDS) are diagnosed with a bone marrow examination (BME), an invasive procedure that patients (pts) would rather avoid. Earlier (Oster et al, Leuk Lymph 2018) we developed a logistic regression (LoR) model to diagnose MDS by incorporating 6 variables (age, gender, Hb, WBC, PLT, MCV) into a formula (Figure 1A). We improved the model using data from 178 MDS pts (47 from Tel Aviv, 131 from the EUMDS registry), and 178 controls (ASH 2017). Here we significantly improve the model using a much larger dataset (501 pts; 501 controls) and additional variables. Methods: The EUMDS registry contains data on 2600 BME-proven MDS pts. A random sample of 501 MDS pts from the registry was combined with 501 controls with no MDS (ruled out with BME). Gradient-boosted models (GBM) were used to predict having or not having MDS, using the variables age, gender, Hb, WBC, PLT, MCV, neutrophils, monocytes, glucose, and creatinine (Figure 1B). Area under the ROC curve (AUC), sensitivity and specificity were used to evaluate the models, and model performance was validated by using 100 times 5-fold cross-validation. Model stability was also assessed by repeating the fit of the models using different randomly chosen groups of 501 EUMDS pts as cases. Results: The AUC was 0.97 (95% CI 0.96-0.98, Figure 2), compared with an AUC of 0.87 (0.84-0.91) achieved previously. Under cross-validation, AUC was 89%. Maximizing the sum of sensitivity and specificity led to sensitivity of 88% and specificity of 95%. This means we can calculate a threshold "GBM score," assigning a subject to "MDS" or "no MDS" status with a specificity of 95% and a sensitivity of 88%. Alternatively, we can set two GBM score thresholds G1 & G2, where a GBM score > G2 provides 95% specificity and a score < G1 provides 95% sensitivity. A score between these two cutoffs gives an indeterminate probability of disease. Only 24% of our MDS patients and 15% of our control patients fall into this indeterminate region, compared with about 50% in our earlier model. The most influential variables were MCV, creatinine and neutrophils. Repeated random choice of cases from the EUMDS registry led to stable results. Conclusions: Using easily accessible parameters, MDS can be diagnosed or excluded non-invasively with high accuracy in a substantially large portion of patients. While the Logistic Regression model (Figure 1A) can be used with a relatively simple formula, the Gradient Boosted Model (Figure 1B) is more complex. The GBM combines the variables and the interactions among them, achieving an AUC that represents an excellent predictive ability and a considerable improvement over the previous model. Adding peripheral blood cytogenetic/genetic information could further improve non-invasive MDS diagnosis, and obviate the need for bone marrow examination in many patients. We continue to improve and validate the model. An on-line calculator/app for use in a clinical setting is being developed and will be presented. Disclosures Smith: Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Research Funding; Novartis: Research Funding; Gilead Sciences: Consultancy. Fenaux:Celgene: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Stauder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria.

Background: The immune system has been shown to be involved in the pathogenesis of myelodysplastic syndromes (MDS), and is also affected by the disease. Recombinant erythropoietin (rHuEPO), or in general, erythroid stimulating agents (ESAs) have become a standard treatment for anemic patients with MDS. They were found to improve anemia, quality of life, and possibly survival. We have previously demonstrated that EPO has effects on cellular and humoral immunity and specifically, on immune function in patients with multiple myeloma (MM). Here we report our findings demonstrating the effect of ESAs on T cell (CD4+, CD8+ and CD4+CD25+) number and function in patients with MDS. Patients and Methods: We examined three groups: healthy subjects ('Control', 20 participants), MDS patients without ESA treatment ('MDS', 13), and MDS patients treated with an ESA ('MDS+EPO', 17). All diagnosed patients gave informed consent as approved by our IRB. Cell numbers were evaluated with flow cytometry. In a subset of patients, cell activation was assessed in response to phytohemagglutinin (PHA) by examining CD69 expression in both CD4+ and CD8+ cells. The co-stimulatory marker, CD28, and the inhibitory marker CTLA-4 (CD152) were evaluated as well. We also examined World Health Organization (WHO) subgroups, refractory anemia (RA) and RA with ringed sideroblasts (RARS) versus more advanced disease. Results: CD4+ and CD8+ T cell levels are reduced and increased respectively in MDS patients compared to control, and these changes are reversed in MDS+EPO (Table 1, CD4+, p Conclusions: MDS patients display T-cell abnormalities that are improved upon EPO treatment. MDS is a heterogeneous disease where the immune system both affects and is affected by the disease. As such, treatment with ESAs might ameliorate not only the anemia, but also the immune deficiencies and perhaps the disease itself. Future studies will clarify the immunomodulatory role of ESA in the various stages of MDS. Disclosures No relevant conflicts of interest to declare.

Background: Limited data exist to describe the clinical features and outcomes for elderly pts with FL. The FLASH group performed a prospectively planned pooled analysis of IPD from first-line RCTs and examined associations between age ( 70 years), clinical characteristics and FL outcomes. Methods: We identified 18 randomized controlled multicenter clinical trials in the FLASH database which enrolled elderly pts (> 70 yrs). From these 18 studies, 5922 previously untreated FL pts were included for this analysis. Complete response (CR) at 24 and 30 months were defined as whether the pt achieved and remains in CR at 24 months and 30 months after initiation of induction treatment. PFS24 is defined as proportion of pts progression-free and alive at 24 months post-randomization. Time to progression (TTP) and overall survival (OS) were defined as time from randomization to the date of progression (censoring for death without progression) and date of death due to any cause, respectively. Progression-free survival (PFS) was defined as time from randomization to the date of progression or death, due to any cause, whichever comes first. Non-lymphoma death was defined as death without prior progression. Early disease outcomes, i.e. CR24, CR30, and PFS24 were primary outcomes; secondary outcomes were TTP, OS, and PFS. For time-to-event outcomes, Kaplan-Meier method and log-rank test were used for univariate estimation and comparison; stratified Cox proportional hazard modeling was used for multivariable analyses. Cumulative incidence methods were used to model PFS while treating disease progression as the primary event of interest and non-lymphoma death as a competing risk. For binary outcomes, multivariable logistic regression was used to estimate the association between age groups and outcomes. Variable adjusted in the regression models are FLIPI score without the age component, ECOG performance status (>= 2 vs < 2), and rituximab use. Results: Among 5922 previously untreated FL pts from 18 RCTs, 63% (n = 3728) were 70 yrs. Pts age > 70 (vs. = 2 (8.8% vs 5.0%, p = 0.0004), and elevated β2-microglobulin (68% vs 49%, p < 0.001), less often had > 4 lymph nodes involved (54% vs 65%, p < 0.001), and had similar FLIPI scores without age component (p = 0.17). There were no significant differences between groups in: Ann Arbor stage (94% vs 95% stage III/IV) or rituximab use (62% vs 58%). Median survival follow-up was 5.6 yrs. Pts > 70 yrs did not differ from pts 70 and 70 and 70 and 70 with no difference in disease progression (Figure). In regression models, adjusting for rituximab use, ECOG PS >= 2, and FLIPI score without the age component, age > 70 was a significant predictor of OS and PFS (due to higher incidence of non-lymphoma death), but not PFS24, CR24 or CR30 (Table). Conclusions: FL pts > 70 yrs treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs. Disclosures Flowers: Genentech: Consultancy, Research Funding; NIH: Research Funding; Mayo Clinic: Research Funding; TG Therapeutics: Research Funding; Millenium/Takeda: Research Funding; ECOG: Research Funding; Acerta: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Roche: Consultancy, Research Funding; AbbVie: Research Funding; Infinity: Research Funding; Gilead: Consultancy, Research Funding. Ou:Mayo Clinic: Employment. Shi:Mayo Clinic: Employment. Hochster:Genentech: Consultancy, Other: Consultancy fees for advisory boards for GI cancer and bevacizumab with amounts within Yale University de minims guidelines. Brice:Roche: Honoraria; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Bristol Myers-Squibb: Honoraria; Gilead: Honoraria; Seattle Genetics: Research Funding. Hiddemann:Roche: Other: Grants; Roche: Membership on an entity's Board of Directors or advisory committees; Genentech: Other: Grants. Marcus:Takeda: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Kimby:Abbvie: Consultancy, Honoraria; Jansen: Consultancy, Honoraria; Celgene: Honoraria; Baxalta: Consultancy; Gilead: Honoraria. Herold:Gilead: Other: Personal fees from member advisory board; Celgene: Honoraria; Genentech: Other: Grants; Roche: Honoraria, Other: Grants. De Bedout:Celgene: Employment. Nielsen:Hoffmann-La Roche: Employment. Morschhauser:Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria. Rummel:Mundipharma GmbH: Other: Personal fees, Research Funding; Roche Pharma AG: Other: Personal fees, Research Funding. Vitolo:Gilead: Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures. Salles:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria. Sargent:Celgene: Research Funding.

Bone turnover is regulated by the coupled actions of osteoblasts, the bone-forming cells, and monocyte-derived osteoclasts, which mediate bone resorption. B cells were also shown to regulate bone metabolism, chiefly via paracrine signals. Depending on their state and/or mode of activation, B cells may inhibit or enhance osteoclastogenesis. In mammals, B cell development and maturation occurs in the bone marrow (BM), spleen, and other peripheral lymphoid tissues. In the BM, Pro-B cells sequentially differentiate into Pre-B and immature B cells. Whether BM B cells can transdifferentiate into osteoclasts remains controversial, since osteoclast differentiation from residual monocytic precursors in the cultures was not excluded in the earlier studies. Osteoclasts and B cells arise from distinct myeloid and lymphoid progenitors, respectively, which are downstream of a common multipotent progenitor cell. Monocyte differentiation into osteoclasts relies on monocyte-macrophage colony-stimulating factor (M-CSF) and the receptor activator of nuclear factor kappa B ligand (RANKL). Here, we investigated the possibility that BM B-cells contribute to bone loss by transdifferentiating into bone-resorbing osteoclasts. We found that B220+CD19+ cells can transdifferentiate into multinucleated tartrate-resistant acid phosphatase (TRAP) positive osteoclasts in the presence of RANKL and M-CSF. Our results show that Pro-B cells (B220+CD19+CD43HighIGM-), but not Pre-B cells (B220+CD19+CD43LowIGM-), nor immature B cells (B220+CD19+CD43-IGM+), could transdifferentiate into osteoclasts (16%±3.7 vs. 0.79%±0.28 and 0.48%±0.13 osteoclasts area, respectively). Moreover, among the Pro-B cells, only those expressing M-CSF receptor (CD115) could transdifferentiate into functional osteoclasts (18%±6.55 vs. 0.11%±0.05 osteoclasts area, respectively, Figure 1A and B). To unequivocally establish the generation of osteoclasts from B-cells, we next utilized a mouse model in which all B cell lineage-derived progenies express EYFP. We found that B cells isolated from BM of CD19-Cre:EYFP mice differentiated into TRAP+ multinucleated osteoclasts that were also positive for EYFP (Figure1C). Erythropoietin (EPO) is a crucial kidney-derived hormone responsible for erythropoiesis. Once thought to act solely on the erythroid compartment to potentiate red blood cell production, it became evident that EPO receptors are also found on the monocytic lineage (monocytes, macrophages and dendritic cells). In that respect, we have reported that EPO directly stimulates bone loss via activation of EPO-R signaling in the monocytic lineage (Hiram-Bab et al., 2015). Here we report that B cells express EPO-R, and that EPO enhances Pro-B cell differentiation into osteoclasts by 70% (p Conceivably, in other scenarios, e.g., sex hormone deficiency, certain hematological cancers, and treatment with anti-CD20, increased B cell lymphocytes contribute to the bone loss phenotype due to transdifferentiation of B-cell precursors into osteoclasts. Taken together, our data suggest a new physio-pathological role for BM B cell precursors in bone metabolism, via their capacity to differentiate into functional osteoclasts, and a possible role for EPO in this process. Figure 1 Osteoclastogenesis in vitro from sorted B cells. (A) TRAP staining of osteoclasts derived from the indicated sorted cells originating from BM (10,000 cells per well) and cultured with M-CSF and RANKL. Left - Pro-B cells expressing CD115 (B220+CD19+CD43HighIgM-CD115+). Right - Pro-B cells not expressing CD115 (B220+CD19+CD43HighIgM-CD115-). Data are mean±SEM of osteoclast area, n=5 mice in each group; *p Disclosures No relevant conflicts of interest to declare.

Background: "Choosing wisely" strategies have been applied in Tel Aviv Sourasky Medical Center (TASMC). Limiting red blood cell (RBC) transfusions according to the 1999/2005 guidelines, without compromising patient care, has been selected as a major goal. Our preliminary single center experience is described. Methods : We initiated a program including physician education, inspection and feedback. We retrospectively reviewed the inpatient charts and the hospital RBC transfusion data from 2011-2015. Results: Approximately 80,000 non-surgical patients are admitted yearly to TASMC, primarily to the Department of Medicine (350 beds). The percentage of transfused patients declined from 4.6% in 2011 to 4.2% in 2013. Most transfused patients were older than 80 years with cardiovascular disease or other co-morbidities. The % of patients requiring RBC transfusions who had pre-transfusion Hb ≥ 9 g/dL was reduced from 23.8% (2011) to 21.9% (2012) and 14.4% (2013). Those with pre-transfusion Hb ≥ 8g/dL declined from 62.9% (2011) to 59.6% (2012) and 51.8% (2013). The total number of RBC units transfused declined from 2982 in 2012 to 2404 in 2015, a 19.4% reduction. Summary : An active policy including education, awareness, and feedback from blood bank to physician, using a lower Hb threshold, resulted in a dramatic reduction of RBC transfusions. Disclosures Kirgner: Tel Aviv Sourasky Medical Center: Consultancy. Avivi:Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche.

Background and rationale: Identifying risk factors for bone loss is of utmost importance in the prevention of osteoporotic bone fractures. We and others have recently described the dramatic erythropoietin (EPO)-induced bone loss. Recombinant EPO and its long-acting derivative, darbepoetin alpha (DA), are frequently and interchangeably used in clinical practice for similar indications including diseases (e.g. multiple myeloma) in which bone mass may be compromised already, as a part of the disease process. Here, we examined in a murine model, the dose response to the erythroid stimulating agents (ESA) EPO and DA, in the erythroid and bone compartments. Methods:C57B6/JRcchsd 9-week old female mice were treated for two weeks with either EPO or DA using two dose intensities. EPO and DA were administered subcutaneously thrice or once weekly, respectively, for a total weekly dose of 27IU/mouse or 540IU/mouse, hereafter defined correspondingly as intermediate (ID) and high dose (HD) subgroups. Bone morphometry of the distal femoral metaphysis was assessed using microCT. Flow cytometry was used for immunophenotyping of bone marrow (BM) cells. One-way ANOVA was used to compare variables among the treatment groups. Results: First, we found that ID-DA induced bone loss to a similar extent as ID-EPO as reflected by a significant (p0.05 for EPO versus DA groups). In view of the established role of B cells in bone metabolism, we determined the effects of EPO and DA on BM B cell compartment. HD-EPO but not ID-EPO induced a "maturation arrest"-like state in the bone marrow B cell population, increasing the proportion of B220+/CD19-/CD43high/IgM- pre-pro-B two-fold and B220+/CD19+/CD43high/IgM- pro-B cells 2.8-fold (p Conclusion:Applying clinically comparable dosing regimen, both recombinant EPO and DA exert a similar, dose-dependent bone loss, not directly proportional to the erythroid response. However, DA, in contrast to EPO, spares the preosteoblast and bone marrow B cell populations. These finding suggest a different mechanism of action of these closely related ESA preparations on the skeletal and immune systems thus warranting further exploration. Finally, our findings advocate for initiating and maintaining patients with the lowest possible doses of EPO/DA to minimize untoward skeletal and other extra-erythropoietic effects, while achieving the desired correction of anemia. This study was supported by a grant from the Israel Cancer Association to DN, YG and MM. Disclosures No relevant conflicts of interest to declare.

Introduction: Recombinant human erythropoietin (EPO) treats anemia, but EPO also has non-erythroid effects. We have previously shown that EPO has anti-neoplastic immunomodulating effects in both patients and mice (Mittelman PNAS 2001; Mittelman Eur J Haematol 2004). EPO effects were demonstrated in both the cellular and humoral immune systems (Katz Acta Haematol 2005; Katz Eur J Immunol 2007; Prutchi-Sagiv Br J Haematol 2006; Prutchi-Sagiv Exp Hematol 2008; Lifshitz Mol Immunol 2009, Hassan Ren Fail 2003). In a previous study we found that EPO was associated with an improved antibody response to the seasonal influenza vaccine in patients (Oster Exp Hematol 2013). B-cell maturation begins in the bone marrow (BM), and continues primarily in the spleen. The cells mature either to marginal zone (MZ) or to Follicular B-cells, both of which can progress to antibody producing plasma cells (PC). This study evaluates EPO's effects on B-cell maturation and antibody production. Methods and Results: Two murine models: 1) Mice were injected (INJ) with either recombinant human EPO (rHuEPO 180units) or saline 3 times over one week (9+8 mice respectively). 2) Transgenic mice from the Tg6 line (TG), with constitutively increased levels of EPO from birth vs wild type (9+8) mice. The total B220+ (a pan B marker) cell number in EPO mice of both murine models was significantly reduced in the BM (similar to Singbrant Blood 2011; see Table). In the spleen, the total number of B220+ cells was similar, irrespective of EPO exposure. However, some B-cell populations were different (Table): splenic MZ precursor (MZP, B220+/CD21hi/CD24mid/CD23hi) as well as MZ B-cell (B220+/CD21hi/CD24mid/CD23lo) numbers were significantly smaller in EPO mice compared with controls. Splenic PC (B220-/CD138+) were tested in TG mice and their number was greater than in the WT controls (5+6 mice, respectively; see Table). Finally, serum antibodies and light chains were studied and found to be increased in TG compared with WT mice (3+4 mice). IgA: 140±14.1 vs 47±5.0 (x104 ng/ml), p Conclusions: Our findings demonstrate a multistep process, with reduced BM B-cells, reduced splenic MZP and MP cells, followed by increased splenic PC and increased antibody production. EPO may be involved in stimulating this dynamic process and as such may have the additional clinical application of augmenting the humoral immune response in patients.Table.Injected (EPO vs Saline) miceTransgenic vs Wild Type mice(mean%±SEM)EPOSalineTGWTBM B220+, total10.9 ±0.6**28.6 ±1.717.7 ±1.8**30.2 ±1.8Spleen MZP2.1 ±0.2**4.8 ±0.24. 9 ±0.6**9.4 ±1.2Spleen MZ2.2 ±0.4**4.4 ±0.43.8 ±0.5*6.4 ±0.9Spleen PCN/A2.5 ±0.4**0.5 ±0.1*depicts p Disclosures Mittelman: XTL Biotech company, interested in EPO: Consultancy.

Background Hypomethylating agents are the standard therapy for higher-risk (HR, Int-2 and high-risk) myelodysplastic syndromes (MDS). Lenalidomide is effective in lower-risk (LR) MDS, with or without 5q-, in HR-MDS and in acute leukemia. Many patients remain resistant to a single agent. A potential synergistic effect of both agents has been shown [Sekeres M et al, Am J Hemat 2010; Blood 2012]. Thus, the MDS Israel group has designed a phase II clinical trial (NIH trial #: TASMC-10-MM-0437-09-CTIL). Protocol The ViLen-01 protocol consists of 3 phases. The induction phase includes 6 monthly cycles of SC azacitidine (Aza), 75 mg/m daily, days 1-5, and PO lenalidomide (Len) 10 mg daily, days 6-21, followed by a 7-day (days 22-28) respite. The consolidation consists of 6 monthly cycles of Aza only for 5 days each, followed by 12 months of maintenance with Len only. Response is evaluated by the IWG criteria [Cheson B et al, Blood 2006]. Results As of July 2013, 7 medical centers have enrolled 18 patients. Patients had been diagnosed with either HR-MDS, or LR-MDS with transfusion-dependence, erythropoietin resistance and poor cytogenetics. Adverse events (AE) were as expected in these elderly HR-MDS patients. The common AEs were grade IV transient cytopenias, requiring dose modification in 15 patients. Only 2 patients stopped the protocol due to AE. Thirteen patients completed the induction, 8 continued to consolidation, and 5 patients continued to maintenance. Eight of the 18 enrolled patients (44%, 8 of the 13, 61.5%) who had completed the induction, achieved CR. Three of the 8 patients in CR also attained cytogenetic response. The other 5 had normal karyotype on study initiation. Five other patients obtained erythroid response and became transfusion-free, and another patient achieved platelet response, for a total of 14 (78%) responders. It is still too early to evaluate response duration and survival. One patient is in early induction, and 4 are still being treated. The others have either died or have discontinued for various reasons (patient refusal, progressive disease, transplant). Conclusions These preliminary data in a small group of patients with HR-MDS and expected poor prognosis, demonstrate a high response rate and a reasonable safety profile. The study is ongoing. If these results are confirmed in randomized trials, it may set new standards for the treatment of this disease. Disclosures: No relevant conflicts of interest to declare.

Background Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells and monoclonal gammopathy. It is associated with various clinical manifestations including bone disease and anemia. Clinical introduction of recombinant human erythropoietin (rHuEPO) and its derivatives has been a breakthrough in treating patients with anemia, mainly those with chronic kidney disease and cancer patients on chemotherapy. EPO was found to have additional biological effects, including potentiation of both humoral and cell-mediated immune responses. Our studies and those of others, have shown that EPO treatment for anemia in MM patients was associated with general improved immunological functions and immune-mediated modulation (suppression) of MM. A role for EPO in bone metabolism was previously suggested, but its effects were often controversial and the underlying mechanisms remain to be resolved. Objectives To determine the immunological and skeletal effects as well as the underlying mechanisms of EPO signaling in the 5T33 MM mouse model. Results EPO administration led to a 50% decrease in the levels of the MM pathological κ light chain while attenuating the decrease in normal IgA. These immunoglobulin changes were accompanied by a 70% elevation (p=0.015) of B220+IGM+IgD- immature B cells in the BM of EPO-treated MM mice, compared to diluent-injected MM mice (9.8%±0.91 versus 5.68%±1.19 of B220-gated cells, respectively). We also found a 45% increase (p=0.01) in the level of BM macrophages (F4/80+CD11b+) following EPO administration in both healthy and MM mice. Moreover, stimulation in vitro of purified BM-derived macrophages with EPO, led to a 33% increase (p=0.01) in phagocytosis of the 5T33 MM cells. Th17 cells play an important role in MM pathobiology. Our data demonstrate that in MM mice, rHuEPO administration induces a 70% decrease (p=0.021) in the expression level of RORγt, a Th17 hallmark transcription factor. These findings were associated with a 4-fold increase (p Bone disease is a major component of MM and is associated with significant morbidity. High-resolution CT analysis of the distal femurs confirmed bone loss in 5T33 MM mice. The femur bone density of 5T33 MM mice was 30% lower (p=0.04) than that of their healthy counterparts (3.1%±0.003 versus 4.4%±0.008, respectively). Unexpectedly, EPO treatment of MM mice, in comparison to diluent-injected MM mice, induced a 35% reduction (p=0.004) in trabecular bone density (3.1%±0.003 and 2%±0.007, respectively) and 41% (p Conclusions We show that in MM, EPO acts as a double-edged sword, by stimulating the immune response against MM on one hand, but also accelerating bone resorption on the other, which further alters the already compromised bone tissue. A better understanding of the osteoimmunological roles of EPO may advocate for the use of rHuEPO along with targeted bone protective treatment in MM patients, to attenuate the anemia and MM progression, while also preventing bone damage. ND-U and SH-B have contributed equally. Supported by the Multiple Myeloma Research Foundation (DN). Disclosures: No relevant conflicts of interest to declare.

Abstract 3705 Improved outcomes were reported in USA studies in DLBCL (Habermann et al. J Clin Oncol 2006) in a two-staged randomized study of R-CHOP (rituximab, cyclophosphamide, Adriamycin, vincristine, and prednisone) versus CHOP with a second randomization assignment to maintenance rituximab (MR) or observation (OBS) (E4494) and in follicular lymphoma (FL) in patients in a trial with CVP (cyclophosphamide, vincristine, and prednisone) followed by randomization to MR versus OBS in advanced-stage indolent lymphoma (E1496) (Hochster et al. J Clin Oncol 2009). The details of the treatment regimens have been previously described. The German High Grade Lymphoma Study Group has reported differences between men and women in outcomes in DLBCL with improved outcomes in women treated with rituximab (Müller et al. Blood 2012). Methods: Survival outcomes by sex were analyzed using a stratified weighted cox regression, removing the effect of maintenance rituximab in DLBCL (E4494), and a log-rank test in patients with follicular histology (E1496). A Cox regression model was used to evaluate the differences between males and females together with weight (below or above the median). Wilcoxon test and Fisher's exact test were used to compare medians and proportions, respectively. Results: In DLBCL, there were 273 eligible males and 273 females. The median age was 69 in males and 70 in females. There were no differences in baseline patient characteristics among the male and female populations. 138 males and 129 females were treated with R-CHOP. There was no difference in treatment received, with 83% females and 75.3% males receiving 6 cycles or more of R-CHOP treatment (p=0.14). The complete remission (CR) and partial remission (PR) rates after RCHOP were higher in females (82.6%) versus males (71.5%) (P = 0.04). With a median follow-up of 9.45 years, the failure free survival (FFS) and overall survival (OS) were improved in females (P = 0.02, 0.002; HR=0.63, 0.54) compared with males in the R-CHOP group. The outcomes were not different in the CHOP group for FFS (P = 0.81) or OS (P= 0.57) between males and females. Within the R-CHOP group, the failure free survival (FFS) was significantly different between women and men (P = 0.002) and body weight (P = 0.03), but only female sex (P = 0.001) was significant and not weight (P = 0.26) for OS. Of 282 evaluable patients with advanced-stage follicular lymphoma who received initial treatment with CVP, 115 patients were randomly assigned to MR and 113 to OBS. 120 patients were male, and 108 were female. The median age was 58 years in the MR arm and 54 years in the OBS arm. At a median follow-up of 8.04 years, MR markedly improved the PFS (P=0.003) compared with OBS. There were no differences in PFS (P= 0.17) between males and females treated with MR or OS (P = 0.27). In conclusion, in induction therapy with rituximab in DLBCL there is a sex dependent effect with rituximab with males benefiting less than females. In contrast, in patients with follicular lymphoma treated with chemotherapy followed by maintenance rituximab, there were no differences. The differences in outcomes in patients of different sex with DLBCL treated with immunochemotherapy and FL treated with maintenance rituximab will require further analysis of multiple clinical and biologic variables. Disclosures: Fisher: Roche: Advisory Board Other. Cheson:Genentech: Consultancy. Kahl:Genentech, Roche: Consultancy, Research Funding. Horning:Genetech, Roche: Employment, stock (Roche) Other.

Abstract 4793 Introduction: Erythropoietin (EPO) is the major hormone which enhances proliferation and maturation of the red cell lineage, and its recombinant form (rHuEPO) is used extensively to treat various types of anemia. rHuEPO has also been found to exert effects in other organ systems, and our previous work has demonstrated an immunomodulatory role for EPO. Recently, we have also found that mice exposed to high levels of EPO (either rHuEPO injections or transgenic mice overexpressing human EPO), have significantly lower levels of blood glucose than those of their respective controls (Katz et al., J Endocrinol 2010;205:87-95). The current retrospective study was designed to determine whether rHuEPO treatment in hematologic patients, is associated with decreased blood glucose levels. Methods: Patients receiving rHuEPO were examined, comparing glucose levels (morning blood tests, assumed to be fasting) while on rHuEPO treatment to those off treatment. All patients served as their own controls. To test the association between rHuEPO treatment and blood glucose levels, we employed a mixed-model repeated-measures analysis of variance (ANOVA). Results: The charts of 19 patients were reviewed to determine the starting date of rHuEPO and the levels of blood glucose in relation to rHuEPO treatment. Mean age: 77 (range: 54–93). Thirteen patients had myelodysplastic syndrome, and six had multiple myeloma. Two patients had diabetes mellitus. Average glucose levels (mean±95%CI) without rHuEPO treatment were 116.07±4.98. Glucose measurements were available for a median of 9.23 (interquartile range: 7.90–16.80) months after the initiation of rHuEPO treatment. The average glucose level over that period of time was 101.77±4.86 (p Conclusions: Treatment of hematologic patients with rHuEPO is associated with significantly lower blood glucose levels, and might serve in the future to improve glucose control in anemic patients with hyperglycemia. Further studies with both diabetic and non-diabetic patients are currently underway to clarify this association. Disclosures: No relevant conflicts of interest to declare.