Higher Beta 2-microglobulin Levels Research Articles

Survival Outcomes of Patients with Primary Plasma Cell Leukemia in the Era of Proteasome Inhibitors and Immunomodulatory Agents: A Real-Life Multicenter Analysis.

In this study, we aimed to obtain real-life data on the use of antimyeloma agents, which significantly increase overall survival (OS) in multiple myeloma (MM) patients, in primary plasma cell leukemia (pPCL) patients with a poor prognosis. Data from 53 patients who were diagnosed with pPCL between 2011-2020 and who used at least one proteasome inhibitor (PI) and/or immunomodulatory (IMID) agent were analyzed retrospectively. Depending on the year of pPCL diagnosis, 20% leukocytes or ≥2×109/L plasma cells in the peripheral blood were used. The median age of the patients was 58 years, and 23 (43.4%) patients were over 65 years of age. For first-line treatment, PI or IMID alone was used in 31 (58.5%) patients, and PI and IMID were used simultaneously in 15 (28.3%) patients. Additionally, 21 (39.6%) patients received transplantation, and 13 (24.5%) patients received maintenance treatment. The median progression-free survival was 4 (1-42) months. When patients whose primary disease was refractory to first-line therapy were excluded, the duration of treatment was 6.5 months. The median OS was 15 months, with a median follow-up of 15 months. Only 7 (13.2%) of the patients were alive at the last follow-up visit. Those with higher beta-2 microglobulin levels and ISS stage 3 and nontransplant patients receiving first-line treatment had shorter OS (p=0.005, p=0.02 and p=0.008, respectively). Otherwise, the concomitant use of PIs and IMIDs, the addition of chemotherapy to induction therapy, and the response to induction therapy or maintenance therapy did not affect OS. In our study, as in previous similar studies, we could not see the increased survival trend in pPCL which is observed in MM. New studies are needed for pPCL patients, which is likely to increase with the new diagnostic criteria, based on current agents and information in MM.

Hodgkin lenfoma hastalarında maksimum tümör çapı ve 18F-FDG PET/BT görüntüleme durumunun genel sağkalıma etkisi

Aims: This research aims to determine the impact of maximum tumor diameter and FDG PET CT status at the time of diagnosis on survival outcomes and to identify prognostic factors that influence treatment response and survival. 
 Methods: 239 patients with a diagnosis of Hodgkin lymphoma participated in the study. Clinical characteristics, treatment responses, and prognostic factors influencing survival were retrospectively analyzed from patient medical records.
 Results: There were 136 (56.9%) male patients and 103 (43.1%) female patients, who participated in the study. Of these patients, 202 (84.5%) survived, while 37 (15.5%) died during the study period. When surviving patients and non-survivor patients were compared, the deceased patients had a higher mean age (p = 0.003), a higher prevalence of spleen involvement and B symptoms (p = 0.011 and p = 0.001, respectively), lower albumin levels (p = 0.008), higher beta-2 microglobulin levels (p = 0.001), and more bone marrow involvement (p = 0.006). A fourfold increase in mortality was seen in patients with beta-2 microglobulin levels > 2920 mg/L, and a 3.188-fold increase in mortality was seen in patients with spleen involvement.
 Conclusion: In conclusion, beta-2 microglobulin > 2920 mg/L, the presence of spleen involvement, the presence of relapse, and the presence of progressive or refractory disease in FDG PET CT were significant prognostic factors for 1st, 3rd, and 5th-year survival rates in patients with Hodgkin lymphoma. In addition, there was no correlation between survival rate and maximum tumor diameter as measured by FDG-PET or CT.

LncRNA CRNDE is downregulated and associated with poor prognostic markers in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by a very heterogeneous clinical outcome. Thus, a plethora of prognostic factors and systems has been identified to place patients into different risk categories and to guide therapy decisions. The classic clinical staging models by Rai and Binet have been the cornerstone of patient management for several years. The greater insight into the molecular biology of CLL facilitated the advent of prognostic genetic biomarkers that are expected to impact clinical practice soon in the future. Therefore, we aimed to investigate the expression of long non-coding RNA (lncRNA) CRNDE in patients with CLL, and to analyze its relationship with the clinicopathological parameters of CLL. In this study, 40 untreated CLL patients and 30 age- and gender-matched controls were enrolled. The analysis of lncRNA CRNDE expression was determined using reverse transcription-quantitative polymerase chain reaction technique. Our result confirmed the downregulated expression of LncRNA CRNDE in CLL patients compared to controls (p < 0.001). The low expression of CRNDE was significantly associated with poor prognostic markers including advanced stage of CLL, high levels of serum beta-2 microglobulin and lactic dehydrogenase, and the presence of del17p (p = 0.029, p = 0.013, p = 0.003, p = 0.028; respectively). Our study demonstrated that LncRNA CRNDE is significantly downregulated and associated with poor prognostic markers in CLL. It provides a rationale to assess its biological and prognostic impact in CLL.

Diagnosing anaplastic large cell lymphoma: A challenging case

A 61-year-old man with multiple comorbidities was hospitalized following urosepsis. Broad-spectrum antibiotic therapy was initiated. Blood testing on admission revealed high levels of lactate dehydrogenase and beta-2 microglobulin, along with an important neutrophilic leukocytosis (25,310/μL) that persisted over its hospitalization. A blood smear revealed no morphologic findings, but flow cytometry showcased the presence of that could not be completely characterized. A total body scan was performed, revealing multiple lymphadenopathies above and below the diaphragm that raised suspicion on a lymphoproliferative disease. The histologic samples obtained through endoscopically guided biopsies of the lesions were non-evaluable for pathological characterization. Meanwhile, the patient quickly developed multiorgan failure and was taken into intensive care ten days after admission.

#3255 BETA2 MICROGLOBULIN IS AN INDEPENDENT PARAMETER RELATED WITH DYSFUNCTION OF NATURAL KILLER CELL ACTIVITY IN HEMODIALYSIS PATIENTS

Abstract Background and Aims End-stage renal disease patients are characterized by immune dysfunction. Natural killer (NK) cells area lymphocytes of innate immune system that play a key role in an immune response towards viral infections and tumors. We aimed to analyze clinical factors related to the NK cell activity in chronic hemodialysis (HD) patients. Method Clinically stable 196 patients who were treated by HD for more than 3 months were enrolled from 4 outpatient HD clinics. NK cell activity was assessed using NK Vue assay (NKMAX, Sungnam, Korea) that uses serum of ex-vivo stimulated whole blood to detect interferon (IFN)-γ secreted from NK cells as an indicator of NK cell activity. All patients were stratified as abnormal (&amp;lt;250 pg/ml) and normal (≥250 pg/ml) groups according to NK cell activity. Results Mean age of the HD patients was 62.7 years [range 31 to 95 years] and mean HD duration was 49.2 months [range 3 to 221 months]. In total, 68 (35%) of HD patients showed abnormal NK cell activity. The abnormal NK cell activity group showed significantly increased age and shorter HD duration compared to the normal NK cell activity group (66.7 ± 11.9 vs. 60.6 ± 13.4 years, p = 0.001; 33.8 ± 33.0 vs. 57.5 ± 48.5 months, p&amp;lt;0.001, respectively). The serum albumin and parathyroid hormone levels were significantly lower in the abnormal NK cell activity group (3.7 ± 0.4 vs. 3.9 ± 0.3 g/dL, p = 0.005 and 176 ± 153 vs. 240 ± 260 pg/mL, respectively). In contrast, hemoglobin, blood urea nitrogen, urea reduction ratio, and C-reactive protein levels were comparable between the two groups. In multivariate regression analysis, old age, short dialysis duration, low serum albumin and high beta2 microglobulin levels were independent risk factors of abnormal NK cell activity in HD patients (adjusted odd ratio [AOR], 1.033; 95% confidence interval [CI], 1.005-1.062, p = 0.02; AOR, 0.981; 95% CI, 0.971-0.992; p&amp;lt;0.001, AOR, 0.395; 95% CI, 0.157-0.995; p = 0.049, and AOR, 1.042; 95% CI, 1.011-1.075; p = 0.008, respectively). Conclusion Our results suggest that young age and good nutrition as well as lower burden of middle molecule uremic toxin is associated with greater NK cell activity in HD patients.

Prognostic Value of the Expression of Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR-1) in Chronic Lymphocytic Leukemia.

Background: The transmembrane receptor tyrosine kinase-like orphan receptor 1 (ROR1) has acted on the causation and sustentation of mature B-cell lymphomagenesis for chronic lymphocytic leukemia (CLL) cells.The study attempted to show whether there is a relationship between the level of ROR1 surface expression in CLL cells and disease findings. Materials and Methods: The level of ROR1 cell surface expression was determined in accordance with the flow cytometric analysis of CLL patients at the first diagnosis time. Two groups were formed according to the high and low ROR1 levels. The cut-off point for the ROR1 level was calculated for advanced-stage disease using receiver operating characteristic (ROC) curves. A two-sided p-value <0,05 was considered statistically significant. Results: 108 CLL cases with a median age of 60 were enrolled. The median percentage of ROR1 cell surface marker positivity in the CD5/CD19 positive leukemic cell was 62%.The CLL cases with high ROR1 levels have thrombocytopenia (p=0.042), anemia (p=0.028), and high beta-2 microglobulin value ≥3 mg/dL (p=0.002) and the need for first-line treatment (p=0.043). Conclusion: The poor prognostic parameters such as splenomegaly, anemia, higher beta-2 microglobulin levels, intermediate/advanced RAİ stage disease, and need for first-line treatment had associated high-level ROR 1 expression of our CLL patients. It needs to be investigated for its effect on predicting disease burden and aggressiveness with more comprehensive studies on ROR1 expression levels in CLL cases.

Idecabtagene Vicleucel Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma with Renal Insufficiency: Real World Experience

Introduction: Idecabtagene vicleucel (ide-cel) is an autologous BCMA directed chimeric antigen receptor therapy T (CAR-T) cell therapy approved for relapsed/refractory multiple myeloma (RRMM). However, patients with renal insufficiency (RI) were excluded from the registrational KarMMa clinical trial. RI impacts a significant proportion of patients with multiple myeloma and the safety and efficacy profile of CAR-T remains unknown in this patient population. We evaluated the real-world outcomes of patients with RI treated with standard of care ide-cel. Methods: RI was defined as creatinine clearance (CrCl) < 50 ml/min at the time of CAR-T therapy. CrCl of < 30 ml/min or being on dialysis was defined as severe RI. Dosing of lymphodepletion chemotherapy and grading/management of toxicities was per institutional guidelines, while responses were graded based on the IMWG response criteria. Results: The study cohort includes 211 patients receiving ide-cel from 11 medical centers, of which 28 (13%) patients had RI at the time of CAR-T therapy with CrCl < 50 ml/min. Among these, 11 (39%) patients had severe RI including one patient on dialysis. Table 1 describes baseline and treatment characteristics of patients with and without RI. Patients with RI were older (69 vs 63 years, p=0.003) and more likely to be female (68% vs 35%, p=0.001). They had lower albumin, higher beta-2-microglobulin (B2M) and higher likelihood of having revised ISS stage 3 disease, driven primarily by high B2M levels. Median prior lines of therapy in patients with and without RI was 8 vs 6, respectively. Fludarabine was dose reduced in 82% patients with RI and amongst this group 61% of patients had > 20% dose reduction. There was no difference in CAR-T cell dose infused (median: 416 vs 408 million cells). Cytokine release syndrome (CRS) was seen in 89% vs 84%, p=0.7 of patients with and without RI, including grade ≥ 2 CRS in 14% vs 20%, p=0.6 of patients, respectively. Neurotoxicity was observed in 21% vs 19%, p=0.7 of patients, respectively. Patients with RI had a longer hospital stay (median 13 vs 9 days, p=0.05), although ICU admission rates were similar (14% vs 7%, p=0.3). Infections were seen in 43% vs 32%, p=0.2 of patients, respectively. At one month, any ≥ grade 3 cytopenia was more common in patients with RI (86% vs 55%, p=0.001), including grade ≥ 3 neutropenia (54% vs 33%, p=0.04) and grade ≥ 3 thrombocytopenia (75% vs 41%, p<0.001). By 90 days post CAR-T, there was no difference in > grade 3 cytopenias amongst the 2 groups. Renal function did not significantly change after CAR-T in most patients. Amongst patients with paired baseline and day 30 data, no patient with CrCl 30-49 ml/min experienced worsening of CrCl to < 30 ml/min at day 30. Amongst 10 patients with CrCl < 30 ml/min, 3 patients experienced improvement in CrCl to 30-49 ml/min, while 7 patients had similar CrCl at day 30. New need for dialysis post CAR-T was observed in two patients, both with baseline CrCl > 50 ml/min; in one patient at 1 week post CAR-T in the setting of critical illness/severe CRS and in another patient 8 months post CAR-T in the setting of salvage therapy for relapse and critical illness. 34 patients have died by last follow-up, of which 8 were due to CAR-T related toxicities including infections (1 patient with RI, 7 without RI, p=0.9). 189 patients were evaluable for response. Patients with RI had an overall response rate of 96% comparted to 83% in patients without RI, p=0.045. Complete response (58% vs 65%, p=0.1) and very good partial response rates (77% vs 65%, p=0.2) were similar. At a median follow-up of 6 months, the median progression-free survival (PFS) in the two groups was 6.5 vs 8.1 months, p=0.6 (Fig 1). On multivariable analysis incorporating RI, age, cytogenetics and prior BCMA-directed therapy, RI was not an independent predictor for PFS (HR 1.4, 95% CI: 0.7-2.7, p=0.4), while high-risk disease, prior BCMA therapy, and age < 65 years were independent adverse prognostic factors. Conclusions: This multicenter retrospective study supports the feasibility of ide-cel CAR-T cell therapy in RRMM patients with RI. CRS, neurotoxicity and non-relapse mortality were comparable in patients with or without RI, although patients with RI had a longer hospital stay and were more likely to experience short-term high-grade cytopenias. Importantly, patients with RI experienced similar benefit in terms of response rates and PFS. S.S & L.P: co-first authors. L.S, K.K.P & D.K.H: joint senior authors Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lactate dehydrogenase, Beta-2 Microglobulin Levels and CD4/CD8 Lymphocyte Ratio in Patients with Mycosis Fungoides in Stage 1A

Objective: Mycosis fungoides is the most common type of primary cutaneous T-cell lymphomas. In this study, we aimed to investigate the biochemical parameters of beta-2 microglobulin, lactate dehydrogenase, CD4/CD8 lymphocyte ratio determined by flow cytometry, and T cell clonality in patients with MF and to correlate these parameters in stage 1A and other stages.&#x0D; Materials and Methods: A hundred sixty-one (87 Male, 74 Female) patients followed-up between January 1995 and January 2019 were retrospectively evaluated. Patients’ demographics, stage of the disease, peripheral lymph node and organ involvement, peripheral blood beta-2-microglobulin, lactate dehydrogenase levels, CD4/CD8 + lymphocyte ratio and presence of T cell clonality in biopsy samples were evaluated.&#x0D; Results: Median beta-2 microglobulin levels were 1608.5 ng/ml for stage 1A and 1970.5 ng/ml for other stages. Peripheral blood median CD4/CD8 lymphocte ratio was 1.60 for stage 1A and 1.85 for other stages. We found statistically significant difference between two groups in terms of beta-2 microglobulin levels and peripheral blood median CD4/CD8 lymphocte ratio (p=0.001, p=0.04). No statistically significant difference was found between two groups in terms of lactate dehydrogenase levels and T-cell clonality (p=0.234, p=0.525).&#x0D; Conclusion: Our study supports that high peripheral blood beta-2 microglobulin level and CD4/CD8 lymphocyte ratio at the time of diagnosis may imply advanced stage and poor prognosis in Mycosis Fungoides.

A prognostic score for survival in patients older than 65 years with Diffuse Large B-Cell Lymphoma.

Available prognosis scores for patients with diffuse large B-cell lymphoma (DLBCL) included a limited number of patients ≥ 65 years of age, and most of them did not include comorbidities. Here, we propose a prognostic score for overall survival (OS) for this group of patients. Patients ≥ 65 years with DLBCL treated at a single national reference center were included. Clinical features including comorbidities and biochemical parameters were analyzed. We included 141 patients. Response rate in the whole group was 77%. Based on multivariate analysis, the presence of the European Cooperative Oncology Group (ECOG) > 2, elevated levels of beta-2 microglobulin, bulky disease, and anemia (hemoglobin < 10 g/dL) had a significant effect on OS. These parameters were considered when computing the prognostic score, which identified three groups with differential survival: Low, intermediate, and high risk of death, with a probability of survival at 60 months of 80.05%, 55.5%, and 29.84%, respectively. This score may select patients to optimize treatment. The presence of high levels of beta-2 microglobulin, bulky disease, and hemoglobin < 10 g/dL, and ECOG > 2 was associated with poor OS in elderly patients with DLBCL.

Cytogenetic Profiling of Myelomas, Association With Complete Blood Count: Study of 180 Patients.

To analyze the most common primary and secondary cytogenetic events in myelomas using a probe panel designed in our laboratory, and to associate those events with hematological and biochemical findings. Blood specimens from patients diagnosed with myeloma were processed to determine complete blood count and levels of albumin, creatinine, and beta-2 microglobulin. We evaluated bone-marrow specimens for plasma-cell percentage by light microscopy and for cytogenetic abnormalities by fluorescence in situ hybridization (FISH). The Mann-Whitney U test was used to compare hematological and biochemical parameters. We observed immunoglobulin heavy chain (IgH) gene translocations in 43.3% and t(4;14) in 21% of specimens; t(11;14) was observed in 7.7% of specimens. Gain of chromosomes was observed in 67.2% and loss observed in 16.6% of specimens. Gains of chromosomes were observed in two-thirds of patients with myeloma. The most common IgH translocation was t(4;14); del13/monosomy13 was the most common secondary cytogenetic abnormality. Partial or complete tetrasomies were associated with higher beta-2 microglobulin levels.

Oxidative Stress Is Associated with Poor Prognosis in Patients with Follicular Lymphoma

[Introduction] Follicular lymphoma (FL) is an indolent non-Hodgkinfs lymphoma (NHL), with a highly variable clinical course that can range from indolent to rapidly progressive disease, including the transformation to aggressive NHL. Oxidative stress caused by the increased production of reactive oxygen species (ROS) or decreased efficacy of the antioxidant system is implicated in the pathogenesis of various disease entities, such as atherosclerosis, cardiovascular disease, renal failure, malignant tumors, and autoimmune diseases. Recent observations suggested that oxidative stress is closely related to all aspects of cancer. Oxidative stress markers are prognostically important in various cancers including diffuse large B-cell lymphoma (DLBCL). However, the prognostic role of oxidative stress in FL is still unknown. The objective of this study is to evaluate the role of oxidative stress in patients with FL.[Methods] 8-hydroxy-2-deoxyguanosine (8-OHdG), which originates from damaged DNA repaired by non-specific endonucleases and specific glycosylates and is eliminated into urine, is widely used as a sensitive biomarker of oxidative stress. Urinary 8-OHdG levels have been reported to be elevated in patients with various malignancies. In the present study, urinary 8-OHdG levels were prospectively examined in 30 patients with FL by using a novel automatic oxidative stress analyzer, ICR-001. We also evaluated serum d-ROMs (the derivatives of Reactive Oxygen Metabolites) levels by using the Free Radical Analytical System 4 (FRAS 4, Wismerll Co. Ltd., Tokyo, Japan). The d-ROMs test has been successfully used to evaluate oxidative stress in a very large number of studies on humans and animals. The d-ROMs test essentially determines the concentration of hydroperoxides in the blood, which are substances that belong to a broad class of reactive oxygen metabolites. The d-ROMs concentration is expressed in Carratelli Units (1 CARR U = 0.08mg hydrogen peroxide/dl). The study protocol and sampling were approved by the Institutional Review Board of Yokohama Municipal Citizen's Hospital, and it was carried out in accordance with the Declaration of Helsinki.[Results] Median age at diagnosis was 70 years (range, 43-84 years) and 53% were male. According to the WHO pathological grading, grade 1 FL was observed in 16 patients (53%), grade 2 FL in 8 patients (27%), and grade 3 FL in 6 patients (20%). FLIPI scores were 0 to 1 in 27%, 2 in 27%, and 3 to 5 in 46%.The urinary 8-OHdG levels in patients with FL (N=30) were elevated compared with normal controls (N=20) (19.7+/-10.3 vs. 13.7+/-3.4 ng/mg/Cr, P=0.01). In 30 FL patients, patients with high urinary 8-OHdG levels (over 23.9 ng/mg/Cr) had significantly shorter overall survival (OS) than those with low urinary 8-OHdG levels (under 23.9 ng/mg/Cr) (3-year OS, 33.3% versus 90.5%, respectively; P<0.001) (Figure. 1). The serum d-ROMs levels in patients with FL were significantly elevated compared with normal controls (543.9+/-199.4 vs. 281.1+/-25.9 CARR U, P<0.001). Patients with high serum d-ROMs levels (over 519 CARR U) had significantly shorter overall survival (OS) than those with low serum d-ROMs levels (under 519 CARR U) (3-year OS, 41.7% versus 94.4%, respectively; P<0.001) (Figure. 2). In univariate analysis, high 8-OHdG levels, high d-ROMs levels, high PS, high LDH levels, high tumor burden (GELF criteria), high beta-2 microglobulin levels, and high FLIPI score were associated with poor OS in patients with FL. In multivariate analysis, parameters having independent adverse significance for OS were: high serum d-ROMs levels (over 519 CARR U) (p=0.01, HR 15.68), high LDH levels (p=0.02, HR 12.25).[Conclusion] In the present study we demonstrated that elevated urinary 8-OHdG levels and serum d-ROMs levels are associated with poor prognosis in patients with FL. In particular, our data proved that a high serum d-ROMs level is an independent prognostic factor for survival in patients with FL. These results suggest that oxidative stress may have an important role in FL and also may be a useful prognostic biomarker. Since our results are based on a small-sized analysis, further large prospective studies are warranted to verify this conclusion. [Display omitted] [Display omitted] DisclosuresNakazato:Mundipharma KK: Research Funding.

Abstract P319: Prospective Association Between Beta-2 Microglobulin and the Risk of Ischemic Stroke in Women

Introduction: Elevated beta-2 microglobulin (B2M) is associated with total stroke. Previous studies have not examined the association between B2M and ischemic stroke risk or ischemic stroke subtypes. We hypothesized that women with higher B2M levels would be at increased risk of experiencing ischemic stroke events. Methods: We performed a nested case-control study among women enrolled in the Nurses’ Health Study who provided blood samples at baseline (1989-1990) and were free of cardiovascular disease and cancer. We measured B2M levels in 460 ischemic strokes cases which occurred between 1989-2008 confirmed by medical record review and classified as thrombotic or embolic, and in 460 controls matched 1:1 to the cases on age, race, date of blood collection, menopausal status, postmenopausal hormone use, and smoking status. We analyzed the association between B2M and ischemic stroke using multivariable conditional logistic regression conditional on the matching factors and adjusted for physical activity, body mass index, aspirin use, alcohol consumption, log transformed total cholesterol to HDL cholesterol ratio, and history of diabetes, high blood pressure, and coronary heart disease or revascularization. Results: The mean age at baseline was 60.5 years with a median of 9.0 years to stroke event. Median levels of B2M were higher among cases (1.86 mg/L) than controls (1.80 mg/L; p-value for Wilcoxon rank sum test=0.009). Those in the highest B2M quartile had a multivariable adjusted increased risk of ischemic stroke compared to those in the lowest quartile (OR=1.68; 95% CI: 1.08, 2.62) (Table). Other quartiles were not associated with an increased risk of ischemic stroke compared to those in the lowest quartile. The association between B2M and thrombotic ischemic stroke was similar to the overall ischemic stroke results. However, we observed no association between B2M and embolic ischemic stroke risk. Conclusion: High levels of B2M were associated with an increased risk of ischemic strokes of thrombotic origin among women.

High Thymidine Kinase Activity and CD5 Positivity Predict Poor Prognosis Of DLBCL Treated With R-CHOP

IntroductionThymidine kinase (TK) activity has been investigated as a prognostic factor in hematological malignancies, and several studies have demonstrated that high TK activity correlates with the disease stage and provides prognostic information on overall survival (OS) and progression-free survival (PFS). We have reported that high thymidine kinase activity (TK) predicts poor prognosis for diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP. In addition, CD5 positivity was reported as a poor predictor for DLBCL. The purpose of this retrospective study was to investigate the prognostic value of high TK activity and CD5 positivity compared with other laboratory findings in evaluating OS in patients undergoing R-CHOP for previously untreated DLBCL. MethodsWe retrospectively analyzed 176 patients newly diagnosed with DLBCL and treated with R-CHOP from September 2003 to October 2008 in our institute, and followed them until December 2012. The values of TK activity, CD5, non-germinal center type, C-reactive protein, lactate dehydrogenase, and beta2 microglobulin before R-CHOP were evaluated as prognostic factors for overall survival (OS). The cut-off of TK activity was defined as 14 IU/L because the median level of TK activity was 14.0 IU/L. CD5 positivity was defined if CD5 expression was detected by flow cytometry. Excluded were those positive for cyclin D1 or those with a history of chronic lymphocytic leukemia/small lymphocytic lymphoma. Germinal center type was defined by Hans classifier. The primary endpoint was OS. First, the OS and PFS were analyzed by the Kaplan-Meier method, and biological prognostic factors for OS were evaluated by Cox regression analysis. Second, we classified the patients into three risk groups due to significant poor predictors. All reported p-values were two-sided, and statistical significance was defined as p < 0.05. ResultsMedian age of the evaluable patients was 65.2 years old. The number of CD5+ patients was 19 (10.8%). The median levels of TK activity, CRP, LDH, and Hb were 14.0 IU/L (range, 3.0–1,100), 0.3 IU/L (range, 0.1–21.2), 254.5 IU/L (range, 111.0–44,432), and 13.1 g/dL (range, 7.7–17.0), respectively. Median follow-up was 60.0 months. Five-year OS rate of all patients was 51.1%. The OS was significantly worse in patients with high TK activity, CD5 positivity (CD5+), and high beta2 microglobulin level by univariate analysis. Five-year OS rates of the high-TK-activity arm and the low-TK-activity arm were 39.1% and 62.9%, respectively (p = 0.001). Five-year OS rates of the CD5+ arm and the CD5-negative arm were 21.1% and 53.8%, respectively (p = 0.002). The OS was significantly worse in patients with high TK activity and CD5+ by Cox regression analysis (hazard ratios 2.595 and 2.585; p = 0.044 and 0.026, respectively). We classified the patients into three groups based on the numbers with high TK activity and CD5+. There was a significant difference of OS in the three risk groups: five-year OS rates were 8.3% in the high-risk arm (two factors), 43.9% in the intermediate-risk arm (one factor), and 64.6% in the low-risk arm (zero factors) (p < 0.001). This prognostic model was suitable for PFS. Five-year PFS rates were 8.3% in the high-risk arm (two factors), 31.7% in the intermediate-risk arm (one factor), and 59.6% in the low-risk arm (zero factors) (p < 0.001). According to the chi square test and Fisher's exact test, there was no significant relationship between high TK and CD5+ (p = 0.153). ConclusionsHigh TK activity and CD5+ were strong predictors of short OS in patients with newly diagnosed DLBCL treated with R-CHOP. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Evaluation of beta‐2 microglobulin and alpha‐2 macroglobulin levels in patients with different periodontal diseases

Beta-2 microglobulin (B2M) and alpha-2 macroglobulin (A2M) play key roles in the immune system. The aim of this study was to compare B2M and A2M levels in patients with different periodontal diseases. Eighty patients (20 periodontally healthy, 20 with gingivitis, 20 with chronic periodontitis and 20 with generalized aggressive periodontitis) were enrolled in the study. The analysis of B2M and A2M was performed on gingival crevicular fluid (GCF) using an enzyme-linked immunosorbent assay in GCF. The total levels of B2M and A2M were statistically lower in the periodontally healthy group than in the other groups (p < 0.05) and significantly higher in the generalized aggressive periodontitis group compared to the other groups (p < 0.05). B2M and A2M play key roles in the balance between periodontal health and disease. It is proposed that tissues release B2M and A2M to stop inflammation and inhibit the proliferation of microorganisms and this may be the reason for the high levels of B2M and A2M in the generalized aggressive periodontitis and chronic periodontitis groups. B2M and A2M are assumed to be user-friendly and cost-effective markers for periodontal disease to identify asymptomatic diseases.

Plasma beta-2 microglobulin is associated with cardiovascular disease in uremic patients

Since beta-2 microglobulin (B2M) is a surrogate marker for middle molecular weight uremic toxins and the major protein component in dialysis-related amyloidosis, it has been frequently studied in dialysis patients. It is not known, however, whether B2M has an impact in patients with chronic kidney disease (CKD) not yet on dialysis. Here we studied the relationship of plasma B2M levels to clinical and cardiovascular outcomes in 142 patients (mean age of 67 years) at different stages of CKD. B2M levels increased with CKD stage and thus were highest in hemodialysis patients. Baseline B2M levels were associated with vascular calcification but not with arterial stiffness or bone density. During a mean follow-up of 969 days, 44 patients died and 49 suffered a cardiovascular event. Higher B2M levels were independently associated with overall and cardiovascular mortality and cardiovascular events in the whole cohort and with cardiovascular events in the predialysis cohort. Moreover, B2M appeared to be a better predictor than well-established factors associated with outcomes in this population, such as estimated glomerular filtration rate ((eGFR), only for predialysis patients), inflammation biomarkers, and other factors included in a propensity score. Thus, we confirm the strong relationship between B2M levels and eGFR and confirm the power of B2M to predict overall and cardiovascular mortality and cardiovascular events in patients at different stages of CKD.

Early death in patients diagnosed with non-Hodgkin’s lymphoma

This study sought to identify risk factors for early death in non-Hodgkin's lymphoma (NHL). The databases of a tertiary medical center were reviewed for adult patients diagnosed with NHL since 1985 who died within 4 months of diagnosis. Comprehensive background, disease-related data, and treatment-related data were collected and analyzed by descriptive statistics. Ninety-two patients (7 % of the patient registry) met the inclusion criteria: 40 men and 52 women of mean age 74 years. Most (86 %) had B cell NHL; the most frequent pathologic classification was diffuse large B cell lymphoma (75 %). Rates of other disease-related factors were as follows: aggressive disease, 90 %; stage IV, 73 %; bulky disease, 66 %; extranodal involvement, 86 % (usually >1 site); performance score 2-4, 76 %; international prognostic index 3-5, 89 %; and B symptoms, 84 %. Mean Ki-67 proliferation index was 71 %. Additionally, 80 % of patients had a high lactose dehydrogenase level, 89 % a high beta-2 microglobulin level, and 47 % serosal (mainly pleural) effusion. A history of other cancer or organ transplantation was documented in 24 %. Chemotherapy was administered to 59 %, mostly CHOP. In conclusion, early death occurs in at least 7 % of patients with newly diagnosed NHL. This patient group is characterized by older age, aggressive lymphoma, poor performance status, advanced-stage disease, extranodal disease, B symptoms, bulky disease, elevated lactate dehydrogenase and beta-2 microglobulin levels, and serosal effusion. These early death resulted from sepsis, severe underlying disease, disease progression, or gastrointestinal perforation. The selection of appropriate treatment modalities for these patients with poor prognostic features is a real challenge. They should undergo comprehensive geriatric assessment and receive individualized tailored treatments with protocol adjustment to their condition, strict clinical surveillance, best supportive care, and maybe, as recently suggested, a prephase treatment.

Transformation of Chronic Lymphocytic Leukemia Into Diffuse Large B-Cell Lymphoma (Richter's Syndrome): Large Retrospective Analysis From a Single Institution.

AbstractAbstract 2902 Background:Although chronic lymphocytic leukemia (CLL) is a low grade B-cell malignancy, 2–8% of patients (pts) are reported to undergo transformation to diffuse large B-cell lymphoma (DLBCL; Richter’s syndrome [RS]). Whether the risk of transformation is related to the underlying biology of CLL or is a consequence of treatment for CLL is uncertain. Also, the role of prognostic markers such as immunoglobulin heavy chain (IGHV) gene mutation status, ZAP-70 and CD38 expression, and genetic abnormalities detected by fluorescence in situ hybridization (FISH) in predicting the development of RS is not well defined. The available data on stem cell transplant (SCT) in pts with RS is based on retrospective case series of selected RS pts and is of uncertain relevance to the majority of CLL pts experiencing RS. Therefore, we conducted a cohort study of newly diagnosed CLL pts to explore the incidence and natural history of RS. Methods:The Mayo Clinic CLL database includes all consenting pts with a pathologic diagnosis of CLL. Information on date of diagnosis, treatment history, and disease-related complications is abstracted from clinical records on all pts and then maintained prospectively. We used this database to identify newly diagnosed pts with CLL from January 2000 through July 2011, who were seen at our institution within 12 months of diagnosis. Pts with biopsy-confirmed RS were included in this analysis. For pts referred from an outside institution, pathology review at Mayo Clinic was mandatory to be included in this study. The Mayo Clinic Institutional Review Board approved the study. Results:Between January 2000 and July 2011, 1641 pts with newly diagnosed CLL were seen at Mayo Clinic within 12 months of diagnosis, and this cohort had a median follow-up of 4.0 yrs (range, 0–12.3 yrs). Of these pts, 37 (2.3%) were diagnosed with RS. The median time to development of RS after a diagnosis of CLL was 1.8 yrs (range, 0–11.7 yrs). The incidence of RS at 2 and 5 yrs post CLL diagnosis were 1.3% and 2.1% respectively (Figure).Pts who developed RS had more advanced (Rai III/IV) stage disease (22% vs. 6%; p<0.001) and higher beta 2-microglobulin levels (median 3.1 mg/dL vs. 2.3 mg/dL; p=0.003) at diagnosis of their CLL compared to pts without RS. Pts who developed RS were also more likely to be positive for ZAP-70 (58% vs. 33%; p=0.03), CD49d (77% vs. 31%; p=0.0004), and CD38 (57% vs. 29%; p=0.001), have unmutated IGHV (76% vs. 44%; p=0.003) and have either del(11q22.3) or del(17p13) on FISH analysis (46% vs. 13%; p<0.0001).RS transformation occurred prior to treatment of CLL in 17 (46%) pts and after treatment of CLL in 20 pts (54%). Treatment for CLL was associated with an increased risk of RS (92% vs 34%; p<0.0001). The odds ratio (OR) of RS was increased for pts who received purine nucleoside analogues (OR=3.0; 95%CI=[1.6, 5.9]; p=0.001), alkylating agents (OR=2.5; 95% CI=[1.3, 4.9]; p=0.004), or both (OR=3.3; 95% CI=[1.7, 6.4]; p=0.0003) for treatment of their CLL.Median overall survival after development of RS was 2.1 yrs. Most pts (29/37, 78%) received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. Two (5%) pts underwent an autologous SCT and 5 (14%) underwent an allogeneic SCT. Additionally, 1 (3%) patient received an autologous SCT followed by an allogeneic SCT. By the end of the study period, 17 (46%) pts with RS had died. Conclusion:The overall rate of biopsy-proven RS in this large cohort of pts with newly diagnosed CLL was 2.3% (5 year incidence: 2.1%). Clinical characteristics (Rai stage III/IV) and biologic characteristics of the CLL B-cell (positive expression of ZAP-70, CD38 and CD49d; unmutated IGHV; and either del(11q22.3) or del(17p13) on FISH) at the time of diagnosis were associated with future risk of RS. Exposure to purine nucleoside analogues and/or alkylating agents for treatment of CLL was also associated with increased risk of RS. [Display omitted] Disclosures:Zent:GlaxoSmithKline: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Genzyme: Research Funding; Biothera: Research Funding. Shanafelt:Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.

Survival trends among 1,325 patients with chronic lymphocytic leukemia seen over the past 40 years in Israel

In the light of recent data showing survival improvement of patients with chronic lymphocytic leukemia (CLL), we investigated clinical characteristics and survival patterns of patients with CLL over the last 40 years in Israel. Demographic and clinical data collected in the database of the Israeli CLL Study Group were analyzed. Of the 1,325 patients, 221 were diagnosed during the time period 1968-1989, 456 during 1990-1999, and 639 during 2000-2010. There was shift toward older age (median, 71 vs. 68 vs. 66 years) and a higher proportion of patients at Binet stage A at diagnosis (77.6% vs. 66.7% vs. 60.3%) in the more recent time periods. Median survival for the entire cohort was 10.9 years; 12.2 years for patients diagnosed at Binet stage A, 8.5 years for stage B, and 6.4 years for stage C patients. Older age, high-beta 2-microglobulin level, and expression of ZAP-70 predicted shorter survival. There were no apparent changes over time regarding gender, age or different clinical stages. Young patients with Binet stage A had lower life expectancy than the general population; but, in older ages, the survival rates were comparable. There were increased proportions of CLL patients diagnosed in early stages, and, at older age, during the last decades, however, survival rates according to sex, age, or stage remained stable. CLL continues to be an incurable disease affecting survival even in patients diagnosed at early stages. Survival benefit shown in recent trials using chemoimmunotherapy has still to be proven in wider general practice.

Clinical Relevance of Circulating Poly-Ubiquitin as a Prognostic Indicator in Chronic Lymphocytic Leukemia.

Abstract 1240Poster Board I-262The ubiquitin-proteasome pathway is implicated in the pathogenesis of many hematological malignancies. We have reported that proteasome activities in plasma samples can be detected in patients with chronic lymphocytic leukaemia (CLL). Here we examined the correlation of plasma ubiquitin protein levels with clinical behavior in CLL patients. Using the Meso Scale Discovery (MSD) platform, we quantified poly-ubiquitin levels in plasma samples from 138 patients with CLL and 101 healthy control subjects, and examined the associations of ubiquitin levels with various clinical and laboratory variables and overall survival. Patients with CLL had significantly higher levels of poly-ubiquitin proteins (median=158.2; range=35.0-281.2) than did normal control subjects (median=57.3; range=22.0-160.2) (P<0.001). Poly-ubiquitin levels showed no correlation with Rai stage, performance status, beta-2 microglobulin (B2M), or the mutation status of IgVH. However, when considered as a continuous variable, poly-ubiquitin levels correlated negatively with survival. Higher levels of poly-ubiquitin were associated with longer survival (P=0.04). In a multivariate model incorporating poly-ubiquitin, B2M, and IgVH mutation status only B2M (P=0.00004) and poly-ubiquitin P=0.04) levels, but not IgVH mutation status (P=0.12), were independent predictors of survival. When a cut- point corresponding to the upper quartile was used, patients with poly-ubiquitin levels >193 ng/mL had significantly better survival than did those with lower levels. Using B2M and poly-ubiquitin in combination allowed us to stratify patients into 3 different groups : survival was greatest in patients with high poly-ubiquitin and low B2M levels, lowest in those with low poly-ubiquitin and high B2M levels, and intermediate in those with high levels of B2M and ubiquitin or low levels of both (P<0.00001). In conclusion, these findings confirm the importance of the proteasome-ubiquitin system in the pathophysiology of CLL. Moreover, our data also suggest that plasma levels of poly-ubiquitin, along with B2M, should be explored as a prognostic factor in CLL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Beta-2 Microglobulin Is a Strong Prognostic Marker in Patients with Chronic Lymphocytic Leukemia Submitted to Allogeneic Stem Cell Transplantation.

Abstract 1244Poster Board I-266Allogeneic stem cell transplantation (SCT) is the only curative treatment for chronic lymphocytic leukemia (CLL). Advanced age, extensive prior therapy, lack of response to treatment, and T-cell depletion of the graft are poor prognostic factors which have been identified in many studies. Beta-2 microglobulin (B2M) has important prognostic value in patients treated with chemotherapy or chemoimmunotherapy, but has been scarcely investigated in the context of allogeneic SCT. In two studies (Khouri et al. Cytotherapy 2002; Sorror et al. J Clin Oncol 2008) no correlation was found between B2M and transplant outcome. Against this background, we analyzed the influence of B2M and other prognostic parameters in 32 patients (median age 50 yrs [range, 29-63], 20 males) who received an allogeneic SCT in our institution between 1991 and 2006. Interval between diagnosis and transplantation was 44 months (range, 6-116). Median number of prior therapies was 2 (range, 1-6). Six patients had previously received an autologous SCT. Most patients had adverse biologic features (high ZAP-70 expression, unmutated IGHV, poor cytogenetics). Serum B2M was increased (≥2.5 mg/L) in 13 out of 29 patients prior to transplant. Creatinine levels and glomerular filtration rate were normal. Median follow-up after transplantation was 7 years (range, 1.8- 16.9). The relapse risk (RR) at 5 and 10 years was 5 % (95% CI, 0-14%) and 23% (95% CI, 2-44), respectively. At one and 10 years the cumulative non-relapse mortality (NRM) was 34% (95% CI, 17-51) and 38% (95% CI, 20-55), respectively. Five and 10-year progression free survival (PFS), event free survival (EFS) and overall survival (OS) were 85% (CI, 66-100) and 65% (CI, 35-94), 58% (CI, 40-76) and 40% (CI, 19-62), and 62% (CI, 45-79) and 57% (CI, 38-75). In the univariate analysis, factors associated with a higher NRM were prior autologous SCT (p=0.006), chemorefractory disease (p=0.04), and high serum B2M levels at the time of SCT (p=0.03). Parameters associated with EFS and OS were high B2M levels (p=0.001 and p=0.002), prior autologous SCT (p<0.001 and p=0.001), and number of prior lines of chemotherapy (≤ 1 vs. ≥ 2) (p=0.018 and p=0.042). In the multivariate analysis, prior autologous SCT (RR=4.4, CI: 1.2-16.3; p=0.02) and chemorefractory disease (RR=3.82, CI: 1.06-13.7; p=0.04) were associated with a higher NRM whereas B2M at the time of SCT was a strong independent factor associated with EFS (RR=5.34, CI: 1.7-16.6; p=0.004) and OS (RR=6.20, CI: 1.6-23; p=0.006). The figure shows the impact of B2M on survival after allogeneic SCT.In contrast, IGHV mutational status, high ZAP-70 expression, > 30% bone marrow infiltration, and disease status (CR vs. no CR) at the time of SCT were not associated with outcome. In summary, this study indicates that, as in patients treated with chemo or chemoimmunotherapy, B2M is a strong predictor of clinical outcome in patients with CLL submitted to allogeneic SCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.