Citations

Abstract Context Several studies have reported increased risk of fragility fractures in patients with mild autonomous cortisol secretion (MACS), discordant to the degree of bone density deterioration. Objective To evaluate the effect of MACS on bone metabolism in patients with adrenal adenomas. Design Cross-sectional study with prospective enrollment, 2014-2019 Setting Referral center. Patients 213 patients with adrenal adenomas: 22 Cushing syndrome (CS), 92 MACS and 99 nonfunctioning adrenal tumors (NFAT). Main Outcome Measures Osteocalcin, procollagen I intact N-terminal (PINP), C-terminal telopeptide (CTX), sclerostin. Results Patients with CS demonstrated lower markers of bone formation compared with patients with MACS and NFAT (CS vs MACS vs NFAT: mean osteocalcin 14.8 vs 20.1 vs 21.3 ng/mL [P < 0.0001]; mean PINP 34.8 vs 48.7 vs 48.5 µg/L [P = 0.003]). Severity of cortisol excess was inversely associated with sclerostin (CS vs MACS vs NFAT: mean sclerostin 419 vs 538 vs 624 ng/L, [P < 0.0001]). In a multivariable model of age, sex, body mass index, cortisol, and bone turnover markers, sclerostin was a significant predictor of low bone mass in patients with MACS (OR 0.63 [CI 95%, 0.40–0.98] for each 100 ng/L of sclerostin increase). After adrenalectomy, osteocalcin, CTX, and sclerostin increased by a mean difference of 6.3 ng/mL, 0.12 ng/mL, and 171 pg/mL (P = 0.02 for all), respectively. Conclusions Lower sclerostin level in patients with MACS reflects a reduction in osteocyte function or number associated with exposure to chronic cortisol excess. Increase in bone turnover markers after adrenalectomy suggests restoration of favorable bone metabolism.

AbstractBackgroundAdvanced glycation end products (AGEs) are formed via the nonenzymatic glycation of sugars with amino acids. Two AGEs, Nε-(1-carboxymethyl)-L-Lysine (CML) and pentosidine, have been observed to be elevated in subjects suffering from a multitude of chronic disease states, and accumulation of these compounds may be related to the pathophysiology of disease progression and aging.MethodsWe describe here the development and validation of a specific and reproducible LC-MS/MS method to quantify CML and pentosidine in human serum with lower limits of quantitation of 75 ng/mL and 5 ng/mL, respectively. The analyte calibration curve exhibited excellent linearity at a range of 0–10 900 ng/mL for CML and 0–800 ng/mL for pentosidine. High-low linearity of 5 serum pairs was assessed, with a mean recovery of 103% (range 94—116%) for CML, and 104% (range 97—116%) for pentosidine.ResultsSerum concentrations of CML and pentosidine were quantified in 30 control and 30 subjects with chronic renal insufficiency. A significant increase in both analytes was observed in renal failure compared to control subjects (2.1-fold and 8.4-fold, respectively; P < 0.001 for both). In a separate cohort of 49 control versus 95 subjects with type 2 diabetes mellitus (T2DM), serum CML but not serum pentosidine, was significantly elevated in the T2DM patients, and CML was also correlated with glycemic control, as assessed by hemoglobin A1c (r = 0.34, P < 0.001).ConclusionsThese mass spectroscopy-based assays for serum CML and pentosidine should be useful in accurately evaluating circulating levels of these key AGEs in various disease states.

ABSTRACTCell‐based therapies, defined here as the delivery of cells in vivo to treat disease, have recently gained increasing public attention as a potentially promising approach to restore structure and function to musculoskeletal tissues. Although cell‐based therapy has the potential to improve the treatment of disorders of the musculoskeletal system, there is also the possibility of misuse and misrepresentation of the efficacy of such treatments. The medical literature contains anecdotal reports and research studies, along with web‐based marketing and patient testimonials supporting cell‐based therapy. Both the American Society for Bone and Mineral Research (ASBMR) and the Orthopaedic Research Society (ORS) are committed to ensuring that the potential of cell‐based therapies is realized through rigorous, reproducible, and clinically meaningful scientific discovery. The two organizations convened a multidisciplinary and international Task Force composed of physicians, surgeons, and scientists who are recognized experts in the development and use of cell‐based therapies. The Task Force was charged with defining the state‐of‐the art in cell‐based therapies and identifying the gaps in knowledge and methodologies that should guide the research agenda. The efforts of this Task Force are designed to provide researchers and clinicians with a better understanding of the current state of the science and research needed to advance the study and use of cell‐based therapies for skeletal tissues. The design and implementation of rigorous, thorough protocols will be critical to leveraging these innovative treatments and optimizing clinical and functional patient outcomes. In addition to providing specific recommendations and ethical considerations for preclinical and clinical investigations, this report concludes with an outline to address knowledge gaps in how to determine the cell autonomous and nonautonomous effects of a donor population used for bone regeneration. © 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:485–502, 2020

ABSTRACT Multiple myeloma is caused by abnormal plasma cells that accumulate in the bone marrow and interact with resident cells of the bone microenvironment to drive disease progression and development of an osteolytic bone disease. Bone marrow adipocytes (BMAds) are emerging as having important endocrine functions that can support myeloma cell growth and survival. However, how BMAds respond to infiltrating tumor cells remains poorly understood. Using the C57BL/KaLwRij murine model of myeloma, bone marrow adiposity was found to be increased in early stage myeloma with BMAds localizing along the tumor-bone interface at later stages of disease. Myeloma cells were found to uptake BMAd-derived lipids in vitro and in vivo, although lipid uptake was not associated with the ability of BMAds to promote myeloma cell growth and survival. However, BMAd-derived factors were found to increase myeloma cell migration, viability, and the evasion of apoptosis. BMAds are a major source of adiponectin, which is known to be myeloma-suppressive. Myeloma cells were found to downregulate adiponectin specifically in a model of BMAds but not in white adipocytes. The ability of myeloma cells to downregulate adiponectin was dependent at least in part on TNF-α. Collectively our data support the link between increased bone marrow adiposity and myeloma progression. By demonstrating how TNF-α downregulates BMAd-derived adiponectin, we reveal a new mechanism by which myeloma cells alter the bone microenvironment to support disease progression. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Abstract Background: Vitamin D insufficiency (VDI) has been associated with inferior outcomes in patients with follicular lymphoma (FL) treated with chemotherapy and an anti-CD20 monoclonal antibody (immunochemotherapy; IC), but whether this association holds for other FL treatment strategies is not known. Furthermore, the subset of FL patients who experience clinical failure (progression, treatment failure) within 12 months of diagnosis have an inferior outcome compared to those achieving event-free status at 12 months (EFS12). We tested the hypothesis that VDI is predictive of early clinical failure (failure to achieve EFS12), overall survival (OS), and lymphoma-specific survival (LSS) among FL patients overall and in subgroups who were initially observed, treated with IC, rituximab monotherapy, or other therapies. Methods: We evaluated this hypothesis in a prospective cohort study of 642 newly diagnosed patients with grade 1-3a FL enrolled from 2002-2012 in the Molecular Epidemiology Resource of the Iowa/Mayo Lymphoma SPORE. Serum 25-hydroxyvitamin D [25(OH)D] was measured by liquid chromatography-tandem mass spectroscopy, and VDI was defined as serum total 25(OH)D <20 ng/mL (per Institute of Medicine criteria) determined within 120 days of diagnosis. We used logistic regression to estimate Odds Ratios (ORs) and 95% confidence intervals (CIs) and Cox regression to estimate hazard ratios (HRs) and 95% CIs. We adjusted for FLIPI, body mass index, and month of blood draw; for the full cohort, we additionally adjusted for treatment. Results: The mean age at diagnosis was 60 years (range 23-93); 19% of patients had VDI. The median follow-up period was 59 months (range 1-144), with 297 events and 78 deaths (42 due to lymphoma). Treatment included IC (N=252), observation (N=218), rituximab monotherapy (N=76), or other (N=96). OS and EFS curves are shown in figures 1 and 2. In the full cohort, VDI was associated with inferior EFS12 (OR=2.05; 95% CI 1.18-3.54), OS (HR=2.35; 95% CI 1.37-4.02), and LSS (HR=2.97; 95% CI 1.52-5.80). In the IC subset, VDI was associated with inferior EFS12 (OR=3.00; 95% CI 1.26-7.13), OS (HR=2.86; 95% CI 1.39-5.85), and LSS (HR=2.96; 95% CI 1.29-6.79). VDI was associated with inferior OS in patients who were observed (HR=2.25; 95% CI 1.20-6.76) or received other therapies (HR=3.06; 95% CI 1.01-9.24). VDI was positively but not statistically significantly associated with inferior EFS12 in the patients who were observed (OR=1.71; 95% CI 0.70-4.17) or received other therapies (OR=2.31; 95% CI 0.41-13.07), with low power for these associations; LSS could not be estimated due to lack of deaths. There were too few events (N=10) and deaths (N=5) in the R-monotherapy group for analysis. Conclusions: We confirm previous findings that vitamin D insufficiency is associated with adverse long-term prognosis among patients with FL treated with IC, and extend these findings to patients who are initially observed or treated with other therapies. For the first time, we observed an association of vitamin D insufficiency with early clinical failure, suggesting a potentially modifiable factor to address in this subset of patients with poor outcomes. Whether treating VDI improves outcomes in FL warrants assessment. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Nowakowski:Celgene: Research Funding; Morphosys: Research Funding; Bayer: Consultancy, Research Funding.

Introduction: Vitamin D deficiency is common, with 25-50% of the population having levels below the optimal range (<20 ng/mL). Aside from its role in maintaining serum calcium and skeletal homeostasis, vitamin D has been shown to play an important role in regulation of differentiation, proliferation, apoptosis, metastatic potential and angiogenesis in a variety of malignancies. Low serum 25(OH)D levels have been associated with a worse prognosis in several malignancies, including colorectal and breast cancer, chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Almost no data have been reported on vitamin D levels in light chain (AL) amyloidosis. We therefore measured vitamin D levels among AL patients and correlated levels at presentation to explore if vitamin D deficiency has any effect or association in this disease. Methods: Stored serum samples from 90 patients with newly diagnosed AL amyloidosis were obtained for vitamin D studies, which included 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D] and vitamin D binding protein (DBP). All vitamin D measurements were made by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total 25(OH)D and 1,25(OH)2D was assessed as the additive sum of the 25(OH)D2/25(OH)D3 and 1,25(OH)2D2/1,25(OH)2D3 components, respectively. Clinical data was extracted from the electronic medical records. All calculations were made using JMP software (SAS, Cary, NC). Results: All patients were seen between June 2004 and September 2013. Median age was 63 [IQR 57-70]. Heart, kidney, nerve, liver and gastrointestinal amyloidosis was seen in 80%, 60%, 19%, 17% and 13% of patients, respectively. The median dFLC and bone marrow plasma cells were 28 (IQR 12-84) mg/dL and 10% (IQR 5-20%), respectively. The median serum 25(OH)D level was 20 ng/mL (IQR 10-29; normal >20 ng/mL), while the median serum level of 1,25(OH)2D was 23 pg/mL (IQR 14-37; normal 16-64 pg/mL for men; 16-78 pg/mL for women). 25(OH)D levels <20 ng/mL were strongly associated with renal involvement (84% renal involvement vs 42% of renal involvement for levels ≥20 ng/dL, P<0.001; Table). No other association with organ involvement was seen. Among all patients, heavy proteinuria (>5 gr/24-h) was strongly associated with low 25(OH)D, (P<0.001, Table). A weaker association was seen between 25(OH)D levels and estimated glomerular filtration rate (eGFR) (P=0.06). Seventy-eight percent of patients with 1,25(OH)2D levels below 20 pg/mL had renal involvement versus 48% in those with levels above 20 pg/mL (P=0.01). While heavy proteinuria was associated with 1,25(OH)2D (P=0.008), the association was stronger for eGFR, as no patient with an eGFR <30 ml/min/1.73 m2 had a 1,25(OH)2D level above 20 pg/mL (P<0.001). An association between vitamin D levels and low serum albumin was also seen, mainly in relation to 25(OH)D (Table). The median level of serum DBP was 58 μg/mL (IQR 36 - 120 μg/mL), significantly lower than the normal range (168-367 μg/mL). Low levels of 25(OH)D or 1,25(OH)2D were not associated with lower DBP levels. Surprisingly, patients with renal involvement had higher levels of DBP versus those without renal involvement (median 70.9 vs 48 μg/mL; P=0.03), although median levels were below normal in both groups. FISH data was available in 47 of patients (52%). Patients with 25(OH)D levels <20 ng/dL were less likely to harbor t(11;14) versus patients with 25(OH)D levels above this threshold (26% vs 64%, respectively; P=0.0095). A similar, but less significant association was seen between 1,25(OH)2D levels at a 20 pg/mL threshold and t(11;14) (35% vs 59%, P=0.09). Other associations between vitamin D and FISH abnormalities were not seen. Conclusions: Hypovitaminosis D is common among AL amyloidosis patients with renal involvement. In the general cohort, heavy proteinuria, reduced eGFR and low serum albumin were all associated with low circulating vitamin D levels. Although the majority of AL patients had low levels of DBP, urinary loss of DBP does not explain the low levels of vitamin D. Hypovitaminosis D is associated with non-t(11;14) disease, a finding which warrants further exploration. Disclosures Dispenzieri: Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Dingli:Rigel: Consultancy; Karyopharm: Research Funding; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Kapoor:Cellectar: Consultancy; Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding; Glaxo Smith Kline: Research Funding. Leung:Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Russell:Imanis: Equity Ownership. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Gertz:Ionis/Akcea: Consultancy; Alnylam: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Annexon: Consultancy; Prothena Biosciences Inc: Consultancy; Spectrum: Consultancy, Research Funding.

Abstract Introduction: MGUS is generally an incidental finding in the diagnostic work-up for clinical signs and symptoms suggestive of lymphoplasmacytic malignancies (multiple myeloma, light chain amyloidosis, and Waldenström macroglobulinemia), which are relatively rare (<35,000 annual new cases in the US). While much is known about the natural history of MGUS, information regarding the pre- and post-diagnostic part of MGUS patient care is lacking. Our study objectives were to determine the following: 1) indications for monoclonal protein testing; 2) subsequent diagnoses found for those indications; 3) specialty of ordering clinicians; 4) follow-up patterns after MGUS diagnosis. Methods: We identified MGUS patients residing in southeastern Minnesota who were diagnosed from 2011-2014 and followed at the Mayo Clinic. Medical records were reviewed to confirm the diagnosis and obtain relevant clinical data. Laboratory tests and visits were identified using Current Procedural Terminology-4th edition (CPT-4) codes from billing data. We defined a follow-up visit as: 1) any face-to-face encounter linked to MGUS diagnosis 30 days after the date of MGUS diagnosis regardless of whether ancillary test was performed or not; and 2) MGUS-specific tests or laboratory tests linked to an MGUS diagnosis claim performed without a face-to-face encounter. Based on the Mayo Clinic MGUS risk stratification model, we classified our cohort into either low-risk or non-low risk. Criteria for low-risk used were: serum monoclonal protein <1.5 g/dL, IgG subtype, and normal serum free light chain ratio. Follow-up patterns were analyzed according to year of diagnosis, demographics, and the specialty of clinicians performing the follow-up. Results: 330 MGUS patients were included in the study. The median age at diagnosis was 73 years (range, 21-98) and most were males (59.7%). The common indications for monoclonal protein studies were neuropathy (19.6%), kidney disease (13.6%), anemia (12.7%), bone symptoms/signs (12.7%), cutaneous disorders (5.8%), congestive heart failure (4.8%), and hypercalcemia (2.7%). The most common subsequent diagnoses for these indications were neuropathy not otherwise specified (NOS;100%), chronic kidney disease NOS (35.5%), anemia of chronic kidney disease (19%), osteopenia/osteoporosis (45.2%), congestive heart failure NOS (57.1%), and dermatitis NOS (100%), respectively. The practice specialties that most commonly diagnosed MGUS were internal medicine (31.3%), neurology (13.7%), nephrology (10.3%), family medicine (6.1%), and hematology (5.8%). Low risk MGUS comprised 44.8% of the cohort. After a median follow-up of 53.5 months (range, 13.0-77.4; IQR, 40.8-77.4), the total number of follow-up visits was 937. Majority (85.5%) of the visits were a combination of office visit with laboratory testing, while the rest were either office visit (11.2%) or laboratory tests (3.3%) only. The distribution of patients by mean interval between visits was: every <6 months (7.9%); every 6-12 months (19.4%); every 13-24 months (15.2%), and every >24 months or no follow-up at all (57.6%). The follow-up patterns did not change significantly (Kruskal Wallis; P=0.6759) over time (Figure 1) and were similar when age groups were compared (Figure 2; P=0.1328). However, males were followed more frequently than females (P=0.0365). Among patients 80 years and older, 32.1% continued to be followed at least once every 2 years (Figure 2). Hematologists were more likely than non-hematologists to follow MGUS patients regardless of the risk category (Figures 3-4). Among low risk patients, 31.1%, 22.2%, 20.7%, and 19.1% had at least one follow-up during years 2, 3, 4, and 5, after MGUS diagnosis (Figure 3). Conclusions: Approximately 1/3 of MGUS diagnoses were made during the evaluation of signs and symptoms not related to lymphoplasmacytic malignancies. The subsequent diagnoses found were a wide variety of common diseases. Most MGUS diagnoses were made by general internists, neurologists, and nephrologists. Follow-up practices varied between hematologists and non-hematologists. Nearly 1/3 of the oldest old patients continued to have follow-up, despite limited life expectancy. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 5158 Background: Vitamin D insufficiency is commonly observed in clinical practice. Observational studies have suggested an association of vitamin D insufficiency with increased risk of cancer development. Further, vitamin D insufficiency has been associated with poorer prognosis in solid tumors as well as hematologic malignancies, including non-Hodgkin lymphoma and chronic lymphocytic leukemia. In this study, we examined the clinical and prognostic correlates of low plasma levels of 25-hydroxyvitamin D (25[OH]D), which reflects whole-body vitamin D stores, in a cohort of myeloproliferative neoplasm (MPN) and myelodysplastic syndrome (MDS) patients. Methods: We studied a total of 409 patients: 247 (60%) had primary myelofibrosis (PMF), 74 (18%) de novo MDS, 63 (15%) polycythemia vera (PV) and 25 (6%) essential thrombocythemia (ET). Inclusion criteria required availability of archived plasma, bone marrow aspirate and biopsy and cytogenetic information at the time of first referral to our institution. Vitamin D measurements were performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). For the purposes of this study, plasma 25(OH)D levels <10 ng/mL indicated severe deficiency, <25 ng/mL insufficiency, and 25–80 ng/mL optimal levels. Results: Patient characteristics were as follows: (i) PMF: median age=63 years, >65 years=41%, males=68% and serum creatinine above the upper normal limit (UNL)=15%; (ii) MDS: median age=72 years, >65 years=77%, males=69% and creatinine >UNL=12%; (iii) PV median age=61 years, >65 years=37% and males=50%; and (iv) ET: median age=48 years, >65 years=10% and males=28%. Median (range) plasma 25(OH)D levels (ng/mL) were as follows: PMF 25 (0–60), PV 27 (6.8–51), ET 31 (6–50) and MDS 30 (7.7–72) (p=0.005). The proportion of patients with 25(OH)D insufficiency were: PMF 48%, PV 43%, ET 28% and MDS 28% (p=0.01). Similarly, the proportion of patients with severe 25(OH)D deficiency were: PMF 9%, PV 3%, ET 12% and MDS 1% (p=0.05). In PMF and MDS, 25(OH)D insufficiency was not significantly correlated with age (≤65 vs. >65 years), gender, red cell transfusion need, DIPSS-plus/IPSS category, hemoglobin (<10 vs. ≥10 g/dL), thrombocytopenia (<100 vs. ≥100 × 109/L), circulating blasts, unfavorable karyotype, serum creatinine >UNL, or JAK2V617F (PMF only) (p>0.05). 25(OH)D insufficiency was not predictive of inferior overall survival (OS) in PMF, MDS, PV, or ET (p>0.05). Similarly, in PMF and MDS, 25(OH)D insufficiency was not predictive of inferior leukemia-free survival (LFS) (p>0.05). Severe 25(OH)D deficiency was infrequently observed in MDS or PV patients; in PMF or ET patients, there was no prognostic impact of severe 25(OH)D deficiency on OS or LFS (p>0.05). Conclusions: Vitamin D insufficiency is relatively common in PMF, PV, ET and de novo MDS however this finding had no prognostic value for OS in the aforementioned patients. In PMF and MDS patients, low 25(OH)D levels had no clearly identifiable clinical correlates and further did not have prognostic value for LFS. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2408 Purpose: Vitamin D insufficiency is common globally and in the United States. Approximately 25–50% of patients seen in routine clinical practice have vitamin D levels below the optimal range with low levels linked to higher cancer incidence. Although vitamin D insufficiency is also related to inferior prognosis in some cancers, no data exists for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Patients and Methods: To test the hypothesis that vitamin D levels predict outcome in patients with CLL, we evaluated the relationship of 25 (OH)D serum levels with time-to-treatment (TTT) and overall survival (OS) in 390 newly diagnosed CLL patients participating in a prospective cohort study (discovery cohort) and separate cohort of 153 previously untreated patients participating in an observational study (confirmation cohort). 25 (OH)D levels were measured by liquid chromatography-tandem mass spectrometry. Intra- and inter-assay coefficients of variation were all <7% (data not shown). All vitamin D assays were performed on stored research samples; results were not included in the clinical record and were not known to the treating physicians in either study. Vitamin D insufficiency was defined as a serum 25 (OH)D level <25 ng/mL (62.5 nmol/L), an accepted level3 for the establishment of hypovitaminosis D and the threshold used in routine clinical practice to identify individuals with 25 (OH)D insufficiency by our laboratory in routine clinical practice (http://www.mayomedicallaboratories.com). Results: We evaluated the relationship of 25 (OH)D serum levels with time-to-treatment (TTT) and overall survival (OS) in newly diagnosed CLL patients participating in a prospective cohort study (discovery cohort) and a separate cohort of previously untreated patients participating in an observational study (confirmation cohort). Of 390 CLL patients in the discovery cohort, 119 (30.5%) were 25 (OH)D insufficient. 25 (OH)D insufficiency had no relationship with CD38, ZAP-70, CD49d or IGHV mutation status and had no relationship with FISH risk category as classified using the Dohner system. After median follow-up of 3 years, TTT (hazard ratio [HR]=1.66; p=0.005) and OS (HR=2.39; p=0.01) were shorter for 25 (OH)D insufficient patients (figure). We next attempted to validate these findings in an independent group of previously untreated CLL patients. In the validation cohort, 61 of 153 patients (39.9%) were 25 (OH)D insufficient. After median follow-up of 9.9 years, TTT (HR=1.59; p=0.05) and OS (HR 1.63; p=0.06) were again shorter for 25 (OH)D insufficient patients. On pooled multivariable analysis of patients in both cohorts adjusting for age, sex, stage, CD38, ZAP-70, IGHV, CD49d, and FISH, 25 (OH)D insufficiency remained an independent predictor of TTT (HR=1.47; p=0.008). On multivariable analysis for OS, the HR for death associated with 25 (OH)D insufficiency was similar to univariate findings although the p value did not reach the threshold of statistical significance (HR=1.47; 95% CI=0.97–2.23; p=0.07). Conclusion: 25 (OH)D insufficiency is associated with inferior TTT and OS in CLL patients. Whether normalizing vitamin D levels in deficient CLL patients would improve outcome merits clinical testing. Disclosures: Zent: Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; G.S.K.: Research Funding.

Abstract Abstract 1952 Poster Board I-975 Background: Vitamin D is a naturally occurring steroid hormone. In addition to its well-established role in maintaining serum calcium homeostasis, vitamin D has effects on cellular differentiation, proliferation, apoptosis, and angiogenesis. Vitamin D3 is naturally produced in skin in response ultraviolet-B (UVB) radiation from the sun. Several recent studies, however, have shown that a high proportion of community-dwelling subjects in both tropical and temperate climates are deficient in vitamin D, and that subjects in northern latitudes often require dietary supplementation to maintain vitamin D sufficiency. Further, several reports now suggest that vitamin D sufficiency is protective against the development of several cancers, including non-Hodgkin lymphoma (NHL). However, it is not known whether vitamin D impacts prognosis in diffuse large B-cell lymphoma (DLBCL), the most common NHL subtype. Methods: We evaluated serum vitamin D concentrations in two cohorts of DLBCL patients. The first cohort consisted of 374 patients newly diagnosed from September 2002-February 2008 who were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource, an observational study in which neither therapeutic nor diagnostic management is prescribed. All serum was obtained within 120 days of diagnosis, and was prior to treatment in 221 (59%). In the second study, 62 patients newly diagnosed from February 2006-August 2007 were enrolled on NCCTG clinical trial N0489, and all serum was obtained before the first course of therapy. Central pathology review was performed on all patients to confirm the diagnosis of DLBCL. Serum 25-hydroxyvitamin (25-OH-VitD) levels were measured by the gold standard method for vitamin D determination: liquid chromatography tandem mass spectroscopy (LC-MS/MS). Vitamin D deficiency was defined as total serum 25-OH-VitD < 25 ng/mL (62.5 nmol/L). SPORE patients were followed per a standard protocol for event-free (progression, retreatment, or death due to any cause) and overall survival (EFS and OS, respectively); N0489 patients were followed in a similar way per the clinical trial protocol. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results: SPORE patients were primarily treated with immunochemotherapy (83%); all N0489 patients were treated with epratuzumab + R-CHOP21. The median age at diagnosis was 62 years (range, 19-93) for SPORE patients and 61 years (range, 21-82) for N0489 patients. Median follow-up for SPORE patients was 36 months (range, 1-77) with 95 deaths and 131 events; median follow-up for N0489 patients was 24 months (range, 7-39) with 13 deaths and 18 events. Vitamin D deficiency was identified in 188 SPORE patients (50%) and 15 N0489 patients (24%). There were no differences in the prevalence of vitamin D deficiency by age, IPI, or whether serum was obtained prior to starting treatment (all p > 0.28). Vitamin D deficiency was associated with inferior overall (HR=2.33, 95% CI 1.53-3.57, logrank p = 0.0001) and event-free survival (HR=1.71, 95% CI 1.20-2.44, logrank p = 0.003) in the SPORE cohort. These associations remained significant after adjusting for IPI and treatment: OS HR=1.97, 95% CI 1.27-3.07; EFS HR=1.47, 95% CI 1.02-2.21. These results were similar for the subset of SPORE patients who were treated with R-CHOP. The HRs for vitamin D deficiency and event-free survival were consistent in the N0489 patients (HR=1.63, 95% CI 0.61-4.35, IPI adjusted HR=1.43, 95% CI 0.53-3.85), although these results lacked precision due to a smaller sample size. We were unable to evaluate OS in N0489 due to the small number of deaths. Conclusions: Approximately 50% of all DLBCL patients in this northern US latitude population are vitamin D deficient at the time of diagnosis and treatment. Vitamin D deficient patients have an inferior event-free and overall survival compared to patients with vitamin D levels within the normal range. Vitamin D supplementation during treatment of DLBCL patients with vitamin D deficiency should be evaluated in a clinical trial setting. Disclosures: No relevant conflicts of interest to declare.