Elevated Beta-2 Microglobulin Research Articles

Unusual course of glyphosate-induced acute kidney injury: a case report of tubulointerstitial nephritis treated with steroids.

Glyphosate is a widely used herbicide that is generally considered safe; however, acute kidney injury (AKI) caused by glyphosate ingestion can be severe and require hemodialysis. We present a unique case of a 68-year-old Japanese man who developed AKI after accidental ingestion of glyphosate and required hemodialysis. Based on the clinical presentation and findings, the patient was diagnosed with renal AKI with severe tubulointerstitial damage. However, the precise pathogenesis of the tubulointerstitial damage remained unclear. An elevated beta-2 microglobulin level discovered by the urinalysis during admission raised the suspicion of tubulointerstitial nephritis caused by glyphosate. Gallium scintigraphy revealed accumulation in both kidneys. A renal biopsy revealed acute tubulointerstitial nephritis rather than acute tubular necrosis, which is commonly observed with glyphosate-induced renal injury. After initiating steroid therapy, his kidney function gradually improved and he was weaned from hemodialysis. This report is the first to describe glyphosate-induced acute tubulointerstitial nephritis that was successfully treated with immunosuppressive therapy. Furthermore, this report highlights the importance of steroid therapy for cases of persistent kidney injury after the discontinuation of agents associated with acute tubulointerstitial nephritis.

Dal rene all'occhio: che cos'è la TINU?

An eight-year-old boy presenting with interstitial nephritis (abdominal pain, microhematuria, glycosuria, proteinuria, elevated urinary beta2-microglobulin levels) was eventually diagnosed with TINU syndrome (tubulointerstitial nephritis associated with uveitis) following the late onset of uveitis.

Elevated concentration of beta2-microglobulin among patients with carpal tunnel syndrome in the course of primary Sjögren syndrome – a prospective observational study on 50 patients

IntroductionSjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltrates in the exocrine glands. Carpal tunnel syndrome (CTS) is suggested to be more frequent among SS patients than in the general population. The aim of this study was to seek associations between the CTS and the laboratory and clinical findings of SS patients.MethodsFifty patients diagnosed with primary SS (pSS) were examined. Clinical evaluation by a rheumatologist and electrophysiological studies were conducted. Data on laboratory tests results was collected. Control group consisted of 50 sex and age-matched individuals with osteoarthritis (OA).ResultsOut of 50 patients in the study group 27 (54%) were diagnosed with CTS. The prevalence of CTS among 50 individuals in the control group was 8%. Among pSS patients with CTS the joint involvement was not more common than in those from the non-CTS group [15 vs. 13 (p = 0.945)]. There was an expected difference in sleep disorders [18 vs. 9 (p = 0.012)] and paresthesia [23 vs. 13 (p = 0.024)]. The major finding was a significant difference in elevated beta2-microglobulin (B2MG) [23 vs. 13 (p = 0.024)]. Other studied factors, suggested in the literature as significant in the pSS-related neuropathy, were not statistically different between the groups.ConclusionOur study confirms that CTS is more prevalent among pSS patients than in the general population and suggests that a new approach is required towards the pathogenesis of this phenomenon. We hypothesize that CTS is more associated with an overall disease activity than joint involvement as such.

Serum beta2-microglobulin acts as a biomarker for severity and prognosis in glioma patients: a preliminary clinical study

BackgroundGliomas are the deadliest malignant tumors of the adult central nervous system. We previously discovered that beta2-microglobulin (B2M) is abnormally upregulated in glioma tissues and that it exerts a range of oncogenic effects. Besides its tissue presence, serum B2M levels serve as biomarkers for various diseases. This study aimed to explore whether serum B2M levels can be used in the diagnosis and prognosis of gliomas.MethodsMedical records from 246 glioma patients were retrospectively analyzed. The relationship between preoperative serum B2M levels and clinicopathological features was examined. Kaplan-Meier analysis, alongside uni- and multivariate Cox regression, assessed the association between B2M levels, systemic inflammatory markers, and glioma patient prognosis. Receiver operating characteristic (ROC) curve analysis evaluated the diagnostic significance of these biomarkers specifically for glioblastoma (GBM).ResultsPatients with malignant gliomas exhibited elevated preoperative serum B2M levels. Glioma patients with high serum B2M levels experienced shorter survival times. Multivariate Cox analysis determined the relationship between B2M levels (hazard ratio = 1.92, 95% confidence interval: 1.05–3.50, P = 0.034) and the overall survival of glioma patients. B2M demonstrated superior discriminatory power in distinguishing between GBM and non-GBM compared to inflammation indicators. Moreover, postoperative serum B2M levels were lower than preoperative levels in the majority of glioma patients.ConclusionsHigh preoperative serum B2M levels correlated with malignant glioma and a poor prognosis. Serum B2M shows promise as a novel biomarker for predicting patient prognosis and reflecting the therapeutic response.

Development and Validation of a Machine-Learning Model to Predict POD24 Risk of Follicular Lymphoma

Background: Disease progression or relapse within 24 months after starting treatment (POD24) has been considered as an independent unfavorable factor in follicular lymphoma (FL). This study was to explore the discriminative accuracy of a machine learning-based (ML) model within different ethnic groups for identifying FL1-3a patients at higher risk for POD24. Methods: 1938 FL1-3a patients were enrolled from a Chinese multicenter cohort and randomly subdivided into a training cohort and an internal validation cohort. An external validation cohort included 1145 patients from the GALLIUM Study within different ethnicity. Univariable regression analysis with backward selection for inclusion of predictor variables and nonlinear analysis based on the XGBoost algorithm were used to develop a ML model for predicting POD24. For internal and external validation, the time-dependent area under the receiver operating characteristic curve (AUROC) was used to investigate the model's predictive performance, compared with established traditional models such as Follicular Lymphoma International Prognostic Index (FLIPI), FLIPI-2 and PRIMA-PI. The calibration and clinical usefulness of the ML model were evaluated using calibration plots and decision curve analyses, respectively. Results: During the follow-up period, 383 (19.7%) and 405 (36.3%) of patients who experienced POD24 were identified in the Chinese cohort and the GALLIUM Study, respectively. In the training cohort, important features of POD24 based on the XGBoost algorithm were ranked by SHAP analysis. Increased lymphocyte-to-monocyte ratio (LMR>10) ranked first (scoring 2), followed by elevated lactate dehydrogenase (LDH), hemogolobin reduction (HGB<12g/dl), elevated beta-2 microglobulin (B2-MG), higher maximum standardized uptake value (SUVmax>10), and 4 or more involved lymph nodes (each scoring 1) were incorporated into the new ML model, referred to as FLIPI-C. The new model performed well in predicting PFS as well as OS, and stratified patients into low- (0-3) and high-risk groups (4-7). In internal validation, FLIPI-C demonstrated a higher AUROC of 0.764 (95%CI:0.721-0.806) for POD24 prediction compared with 0.648 (95%CI: 0.599-0.696) of FLIPI, 0.706 (95%CI: 0.658-0.754) of FLIPI-2 and 0.716 (95%CI: 0.669-0.763) of PRIMA-PI. In external validation with GALLIUM Study, FLIPI-C demonstrated a higher AUROC of 0.701 (95%CI: 0.659-0.741) for POD24 prediction compared with 0.578 (95%CI: 0.531-0.625) of FLIPI, 0.600 (95%CI: 0.554-0.645) of FLIPI-2 and 0.593 (95%CI: 0.547-0.639) of PRIMA-PI. In addtion, the FLIPI-C model had adequate calibration with similar predicted and observed risk of POD24. In decision curve analysis, FLIPI-C yielded improved net benefits compared with FLIPI, FLIPI-2 and PRIMA-PI. Conclusions: TheFLIPI-C model generated using a machine learning approach exhibited greater discriminative accuracy than prior established traditional models for predicting POD24 and is valuable for treatment selection and prognostic assessment of FL.

Comparison of International Prognostic Indices and Validation Study for Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era

ABSTRACT In diffuse large B-cell lymphoma (DLBCL), patients needing new alternative regimens in first-line treatment should be selected with better risk classification. After International Prognostic Index (IPI), Revised-IPI (R-IPI), National Comprehensive Cancer Network (NCCN)-IPI, and Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea (GELTAMO)-IPI, have been developed to improve risk predictions. This study compared performances of four prognostic indices concerning differentiation of overall survival (OS), the most critical endpoint. The study was conducted on 116 patients diagnosed with DLBCL. Patients with primary nervous system and testicular DLBCL, and post-transplant lymphoproliferative disorders, were excluded. The fitting of prognostic indices for database and the prediction of patient discrimination were compared using Akaike’s information criterion and concordance index. Of the study cohort, 63.8% were male, the median age was 56 (18-88), and median follow-up term was 45.6 (0.3-75.2) months. All factors, constituting IPI and R-IPI scores, demonstrated a significant difference in OS. Involvements of the extranodal regions specified in NCCN-IPI and elevated serum beta-2 microglobulin levels in GELTAMO-IPI had prognostic significance (p= 0.005 and p= 0.040, respectively). Each of the four prognostic indices, resulted in risk groups with significantly different OS. R-IPI provided the best fit for database, while NCCN-IPI provided the best discrimination between patients with high and low OS. Although NCCN-IPI provides the best discrimination between patients with short and long OS, using original IPI still seems acceptable in the rituximab era. Integration of tumor molecular characteristics into NCCN-IPI may better characterize high-risk group in new treatment approaches. Keywords: International Prognostic Index, National Comprehensive Cancer Network, Validation, Diffuse Large B-Cell Lymphoma, Rituximab

Impact of Hyper- and Hypo-Uricemia on Kidney Function.

Uric acid (UA) forms monosodium urate (MSU) crystals to exert proinflammatory actions, thus causing gout arthritis, urolithiasis, kidney disease, and cardiovascular disease. UA is also one of the most potent antioxidants that suppresses oxidative stress. Hyper andhypouricemia are caused by genetic mutations or polymorphism. Hyperuricemia increases urinary UA concentration and is frequently associated with urolithiasis, which is augmented by low urinary pH. Renal hypouricemia (RHU) is associated with renal stones by increased level of urinary UA, which correlates with the impaired tubular reabsorption of UA. Hyperuricemia causes gout nephropathy, characterized by renal interstitium and tubular damage because MSU precipitates in the tubules. RHU is also frequently associated with tubular damage with elevated urinary beta2-microglobulin due to increased urinary UA concentration, which is related to impaired tubular UA reabsorption through URAT1. Hyperuricemia could induce renal arteriopathy and reduce renal blood flow, while increasing urinary albumin excretion, which is correlated with plasma xanthine oxidoreductase (XOR) activity. RHU is associated with exercise-induced kidney injury, since low levels of SUA could induce the vasoconstriction of the kidney and the enhanced urinary UA excretion could form intratubular precipitation. A U-shaped association of SUA with organ damage is observed in patients with kidney diseases related to impaired endothelial function. Under hyperuricemia, intracellular UA, MSU crystals, and XOR could reduce NO and activate several proinflammatory signals, impairing endothelial functions. Under hypouricemia, the genetic and pharmacological depletion of UA could impair the NO-dependent and independent endothelial functions, suggesting that RHU and secondary hypouricemia might be a risk factor for the loss of kidney functions. In order to protect kidney functions in hyperuricemic patients, the use of urate lowering agents could be recommended to target SUA below 6 mg/dL. In order to protect the kidney functions in RHU patients, hydration and urinary alkalization may be recommended, and in some cases an XOR inhibitor might be recommended in order to reduce oxidative stress.

Tubulointerstitial Nephritis and Uveitis Syndrome in the United Arab Emirates

ABSTRACT Purpose To report the first series of tubulointerstitial nephritis (TINU) syndrome from the Middle East. Methods We retrospectively included patients with elevated urine beta-2 microglobulin, and a diagnosis of TINU based on anterior uveitis with or without posterior involvement. Multimodal imaging, duration of follow-up, local and systemic treatment used were recorded. Results 24 eyes of 12 patients (8 male, mean age 20.3 years) met the criteria for TINU. The most common posterior segment clinical finding was optic nerve head edema (41.7%), while on fluorescein angiography 58.3% and 75% of eyes had peripheral vascular and optic disc leakage, respectively. The mean follow-up was 2.5 years and all patients required immunomodulatory treatment. Conclusions Middle Eastern patients with TINU seem to have a male predominance, a bimodal distribution in terms of age, and present with ocular involvement first. Multimodal imaging is paramount in detecting subclinical inflammation and tailoring immunomodulatory treatment.

The Short-Term Efficacy and Safety of Obinutuzumab Plus Chemotherapy in B-NHL with High Tumor Burden: A Real-World, Retrospective Study

Introduction: The prognosis of patients with B-cell non-Hodgkin's lymphoma (B-NHL) in high tumor burden is significant poor and patients frequently occur tumor lysis syndrome (TLS) during chemotherapy. There are no standard treatment regimens at present, so it is very crucial to explore effective treatment options to improve prognosis. The aim of present study is to analysis the short-term efficacy and safety of obinutuzumab plus chemotherapy in B-NHL with high tumor burden. Methods: We retrospectively investigated the records of 19 patients of B-NHL with high tumor burden and received obinutuzumab treatment at the First Hospital of Jilin University from November 2021 to July 2022, including 9 marginal zone lymphoma (MZL), 7 chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL), 2 mantle cell lymphoma (MCL), 1 B-prolymphocytic leukemia (B-PLL). All patients received obinutuzumab at a dose of 1000 mg (on days 1, 8, and 15 of cycle 1 and on day 1 of subsequent cycles). The primary endpoint was objective response rates (ORR), and secondary endpoints was incidence of adverse events (AEs). Results: This study enrolled 19 patients completed ≥ 1cycles obinutuzumab plus chemotherapy, including 8 patients with initial treatment and 11 with relapsed and refractory (R/R). Among them, 15 received obinutuzumab with bendamustine (BG), 3 with Bruton tyrosine kinase inhibitors (G-BTKi), 1 with COP (cyclophosphamide, vincristine, and prednisone; G-COP). The median age was 65 years (range, 41-83 years); 12 males and 7 females. In addition, 94.7% patients (18/19) were identified with advanced stage; 73.7% (14/19) with B symptoms; 52.6% (10/19) with ECOG ≥ 2; 57.9% (11/19) with elevated lactate dehydrogenase (LDH) levels; 100% with elevated beta-2 microglobulin (β2MG) levels. 94.7% patients could quickly relieve the high tumor burden status after 1cycle obinutuzumab treatment (Figure 1A). Furthermore, there are 6 patients with hyperleukocytosis (blood cell count greater than 100,000/mL), all reduce to normal level on day 4 of obinutuzumab treatment (Figure 1B); 12 patients with splenomegaly, including 11 massive splenomegaly (long axis >20 cm), all significantly decreased after obinutuzumab treatment, and 7 patients has returned to normal level, and patients with enlarged lymph nodes also significantly reduced after obinutuzumab treatment (Figure 1C). Besides, 8 patients measured minimal residual disease (MRD) in peripheral blood and 6 (75%) achievement of undetectable MRD. Significantly, the ORR was 94.7% (18/19), and 57.9% (11/19) achieved complete remission by evaluation of images. (Figure 1D). The most common AE of any grade were infusion-related reactions 7/19 (36.8%); expiratory dyspnea 2/19 (10.5%); nausea 1/19 (5.3%). In addition, 9/19(47.4%) neutropenia, which may also associate with chemotherapy. There was no incidence of AEs leading to treatment withdrawal or death under obinutuzumab plus chemotherapy treatment. Conclusions: Obinutuzumab could quickly relieve the high tumor burden status and decrease the occurrence of TLS. Thus, obinutuzumab is a promising treatment in patients of B-NHL with high tumor burden. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Total Metabolic Tumor Volume Is Confirmed As Independent Prognostic Factor in Treatment Naïve Follicular Lymphoma Patients and Can be Combined with FLIPI2 to Improve Prognostic Accuracy. a FOLL12 Substudy By the Fondazione Italiana Linfomi

Aim/Introduction: The prognostic role of FDG PET/CT parameters before first line therapy in patients with Follicular Lymphoma (FL) remains unclear, with conflicting data published in the literature. To this end we evaluated the prognostic value of baseline Total Metabolic Tumor Volume (TMTV) in a large cohort of treatment-naïve FL patients enrolled in the FOLL12 trial (NCT02063685). Materials and Methods: FOLL12 is a multicenter, randomized, phase III trial that compared standard (Arm A) vs response adapted maintenance (Arm B) in patients with grade 1-3a advanced stage FL who achieved complete (CR) or partial response (PR) to induction rituximab based immunochemotherapy (R-ICT). In the current study we included patients for whom baseline FDG PET/CT was available and centrally reviewed. The TMTV was obtained by expert nuclear physicians from baseline scans by summing the metabolic volumes of all individual nodal and extra nodal lesions, using the 41% SUVmax threshold method. Univariate and multivariate analyses were performed using Cox proportional hazard model. Main study endpoint was Progression Free Survival (PFS). Results: starting from the FOLL12 trial population, 692/807 patients were included in this study; 48% were older than 60 years, 89% had stage III-IV disease and 40% had a high-risk FLIPI-2 score(3-5 risk factors). Overall, the 5-year PFS was 79% (95% CI, 76 to 82%) and the median TMTV was 242 mL (IQR=446). The optimal cutoff identified for TMTV was 200ml. TMTV values were higher in association with unfavorable prognostic features (Hb <12 g/dl, LoDLIN > 6cm, elevated beta2 microglobulin and LDH, and number of nodal areas >4) whereas were similar between study arms, and ICT regimens. In univariate analysis, 5-year PFS was significantly lower for patients with high vs low TMTV (60% vs 75%; HR=1.87 [95%CI: 1.41-2.49], p<0.001). The correlation between TMTV and PFS was confirmed both in the standard maintenance arm and in the response adapted arm of the FOLL12 trial and the independent prognostic role of TMTV was confirmed when adjusted by study arm, FLIPI-2, and type of ICT. In multivariate analysis, high TMTV (HR 1.47 (1.09 - 2.00); p=0.012) and high risk FLIPI2 (3-5 RFs: HR2.05 (1.54 - 2.73) p<0.001) retained their independent prognostic role for predicting PFS. Three groups of patients were identified which were associated with different 5-year PFS rates; TMTV < 200ml and intermediate FLIPI2: N=241 (35%), 5yr PFS 78% (95% CI 71-83); TMTV > 200ml or high risk FLIPI2: N=237 (34%), 5yr PFS 68% (60-74), HR 1.53 (1.06 - 2.22); TMTV >200ml and high risk FLIPI2: N=214 (31%) 5-yr PFS 51% (43-58), HR 2.96 (2.10-4.19). The combined TMTV + FLIPI2 model was internally validated with 1000 bootstrap resampling (c-Harrel 0.616) Conclusion: Pre-treatment TMTV is confirmed as a strong independent predictor of PFS in patients with FL receiving frontline R-based ICT The combination of TMTV and FLIPI2 may contribute to improve risk stratification in guiding risk adapted therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hyperphosphatemia: A Clue to Diagnosis

Serum phosphate level reference range in adults is 2.5 mg/dL to 4.5 mg/dL and in children is 3 mg/dL to 6 mg/dL. The causes of hyperphosphatemia fall into four categories. These are decreased renal excretion of phosphorus, exogenous phosphorus administration, redistribution of phosphorus, and pseudohyperphosphatemia. We report a 69-year-old gentleman presented with the history of swelling of feet and facial puffiness of 1 month duration. He had renal failure with normal sized kidneys. Serum phosphorus was high. Advanced investigations revealed plasma cell proliferative disorder (clonal bone marrow plasma cells &gt;10%) on bone marrow examination, presence of M band at the junction of beta-2 and gamma region, and elevated serum IgG and serum beta-2 microglobulin. Hyperphosphatemia in multiple myeloma may be true, or pseudohyperphosphatemia. Diligent history, examination, and investigations have yielded the possibility of pseudohyperphosphatemia owing to multiple myeloma in our patient. The interference with the phosphomolybdate ultraviolet assay for serum phosphorus estimation is one of the reasons of pseudohyperphosphatemia in multiple myeloma. The other mechanism of pseudohyperphosphatemia could be the direct binding of paraprotein to phosphorus.

Autologous Hematopoietic Stem Cell Transplantation for AL Amyloidosis Refractory to Induction Therapy

Background:There has been an increased use of novel agents in the induction therapy for transplant-eligible AL amyloidosis over past decade. Hematologic response after an autologous hematopoietic stem cell transplantation (ASCT) is predictive of better outcomes, including organ response and overall survival. However, limited data exist about the outcomes of patients who are refractory to induction chemotherapy but proceed with upfront ASCT). We present here the outcomes of AL amyloidosis refractory to induction therapy.Methods:This retrospective study included all consecutive AL patients who had their ASCT at our institution between 01/2008 and 12/2018 and received induction therapy. We excluded patients who were untreated at the time of transplant. Primary objective: assess the hematologic response, progression-free survival (PFS) and overall survival (OS). Secondary objective: compare PFS and OS of AL amyloidosis by response to induction therapy (refractory vs sensitive). Refractory disease was defined as patient who had stable disease (SD) or progressive disease (PD) after at least 1 line of induction therapy. Hematologic response was defined per the 2012 consensus criteria. Survival estimates were calculated using Kaplan-Meier method.Results:One-hundred-and-eleven patients with a median age of 61 (range, 27-77) years met eligibility criteria. Thirty-three (30%) were refractory and 78 (70%) were sensitive to induction therapy. Table 1 summarizes patient and disease characteristics of all study patients and for the refractory vs sensitive groups. Overall, the two groups were comparable except for significantly more kidney involvement in the refractory group (97% of patients). Induction therapies were similar in the two groups, with bortezomib/cyclophosphamide/dexamethasone (VCD) being the most commonly used regimen (46%). With a median follow-up of 3.11 (range, 0.18-11.15) years, the 3-year PFS and OS for all study patients were 67% and 78%, respectively. At 3 months after transplant, 74% of the patients in the refractory group achieved an objective hematologic response (OHR; defined as PR or better). Of these, 29% achieved VGPR/CR and 45% achieved PR. As expected, more patients in the sensitive group achieved OHR (97%) and VGPR/CR (76%). The respective 3-year PFS and OS were 49% and 73% in the refractory group compared to 75% and 83% in the sensitive group (p=0.0068 for PFS; p=0.0790 for OS). Univariate analysis (UVA) was performed for the variables listed in Table 1 and multivariable analyses included only factors with p value<0.1 in in the UVA. In MVA, in addition to increased risk for refractory patients (HR 2.885, 95% CI:1.237-6.729; p=0.0142), only elevated beta-2 microglobulin (HR 3.899, 95% CI:1.039-14.629; p=0.0437) was associated with inferior PFS. Regarding OS, age ≥60 (HR 3.812, 95% CI:1.038-14.002; p=0.0438) and revised Mayo stage III/IV (HR 3.886, 95% CI: 1.029-14.679; p=0.0453) were associated with inferior survival. In a subgroup analysis comparing PFS and OS stratifying patients by their response to induction (refractory vs sensitive) and their 3-month hematologic response after transplant, we found no significant differences in the 3-year PFS (86% for refractory vs 80% for sensitive group; p=0.7284) for those with VGPR or better but significantly inferior PFS for refractory patients who achieved <VGPR (27% compared to 74% for the sensitive group; p=0.0196).Conclusion:AL amyloid patients refractory to induction therapy seem to benefit from high-dose chemotherapy and ASCT in terms of both response rates and survival. Durable responses for refractory disease are notable in patients who achieved >VGPR after ASCT. Prospective studies comparing transplant versus non-transplant approaches are warranted for these high-risk patients. [Display omitted] DisclosuresHosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Lee: Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy; Legend Biotech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Oncopetides: Consultancy; Takeda Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Regeneron: Research Funding. Orlowski: Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria. Qazilbash: Janssen: Research Funding; Biolline: Research Funding; Angiocrine: Research Funding; Amgen: Research Funding; NexImmune: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; Oncopeptides: Other: Advisory Board.

Development of second primary multiple myeloma five years after treatment for limited-stage small cell lung cancer: a rare case report

Introduction. The development of a second primary malignancy (SPM) following small cell lung cancer (SCLC) has been previously reported in the literature. Especially smoking-related malignancy coupling is well known. The development of multiple myeloma (MM) in long-term survivors after treatment for SCLC is unknown. Here, we report the first case in the literature who developed MM 5 years after treatment for limited-stage SCLC. Case report. A 67-year-old male patient was diagnosed with limited-stage SCLC. After he received chemotherapy and radiotherapy, he was followed up without medication. He was admitted to the hospital with back pain and dyspnea 5 years after the diagnosis of small cell lung cancer. MRI revealed osteolytic lesions in the vertebrae. Laboratory testing revealed a markedly elevated serum IgA and an elevated serum beta-2 microglobulin level. Serum immunofixation revealed IgA lambda-type M-protein. Lambda excretion in urine immunofixation electrophoresis was observed. Bone marrow aspiration revealed the frequency of plasma cells to be 80% of all nucleated cells. Hence, the final diagnosis revealed IgA lambda free light chain MM. Treatment was given for multiple myeloma. In the follow-up, the patient experienced increased dyspnea and developed bilateral pleural effusion. The cytology sent from thoracentesis sampling was reported as plasmocyte-rich material. The patient fell into a coma and died in an intensive care unit. Conclusion. We presented the development of MM 5 years after treatment in a patient with SCLC who were treated for one year and then followed up with stable findings. It should be kept in mind that a patient with SCLC who is a long-term survivor and presents with back pain may have developed a primary malignancy originating from bone marrow rather than a bone metastasis. Patients should be advised smoking cessation after the treatment and diagnosis of SCLC. Also, the patients with SCLC who are long-term survivors should be closely monitored for the development of SPM.

Prognostic value of beta-2 microglobulin on mortality in chronic kidney disease patients: A systematic review and meta-analysis.

The aim of this study was to delve into whether beta-2 microglobulin could assess all-cause mortality in patients with chronic kidney disease. PubMed and Embase were systematically searched. Hazard risk and 95%CI were pooled using random-effect models. A total of eight studies were involved according to the inclusion and exclusion criterions. By meta-analysis, each 1mg/L increase in beta-2 microglobulin displayed positive relationships to the risk of all-cause mortality (hazard risk 1.03, 95%CI=1.02-1.03) and cardiovascular events (hazard risk 1.04, 95%CI=1.00-1.08) in patients with dialysis. However, the relationship between elevated level of serum beta-2 microglobulin as a categorical variable and mortality was not significant. The prognostic value of elevated beta-2 microglobulin might be significant in ESRD patients with dialysis and a proper cutoff value to predict mortality should be determined in the future.

Abnormal Karyotype (Not Only Complex) at Diagnosis Is an Independent Prognostic Factor for Overall Survival in Early Stage Chronic Lymphocytic Leukemia Patients. Results of a Prospective Study with a Median Follow-up of More Than 7-Years

Introduction: Only few studies have prospectively dealt with the prognostic impact on survival of both clinical and laboratory abnormalities in patients with early stage chronic lymphocytic leukemia (CLL) at diagnosis. In our previously published analyses including a prospective cohort of 307 CLL (Oliveira et al, Leuk Lymphoma. 2011; 52:429-35, Oliveira et al, Ann Hematol. 2015; 94:627-32), patients with atypical lymphocyte morphology, 11q deletion, and elevated beta-2 microglobulin had a shorter progression-free survival (PFS) and treatment-free survival (TFS). Abnormal karyotype (AK), 1 or more abnormalities at diagnosis, was not an independent prognostic factor at that time. Complex karyotype (CK), 3 or more abnormalities, despite having been described as an important prognostic marker in retrospective studies, was a rare finding at diagnosis in early stage CLL patients. The aim of this study is to evaluate prognostic factors at diagnosis in patients with early stage CLL for PFS, TFS and also OS, with a longer follow-up.Patients and methods: 307 patients were prospectively enrolled in the study from 2003 to 2010 in a single center. All clinical and laboratory data were homogeneously collected at diagnosis. Analysis of prognostic factors for survival was performed in 231 patients presenting early stage disease: lymphocytosis without other signs or symptoms of CLL (CLL Rai 0 and monoclonal B lymphocytosis, MBL). Survival curves were plotted using Kaplan-Meier's method and log-rank test was used to identify differences in survival between subgroups. Multivariate analysis was performed with Cox regression model. Variables included in the univariate analysis were: age, gender, LDH, beta-2 microglobulin, lymphocyte morphology, CD38, ZAP-70, deletions of 13q, 11q and 17p, trisomy 12, normal FISH and AK. The significant variables in the univariate analysis were included in the multivariate regression model.Results: Eighty-one patients had MBL and 150 were diagnosed with CLL Rai 0, 145 (62.8%) patients were male with a median age at diagnosis of 68 years (limits 27-93). One hundred sixteen patients presented a normal karyotype at diagnosis, 54 (23.3%) an AK [7 (3%) of them a CK], in 9 (3.9%) patients no metaphases were obtained for karyotype analysis and in 52 (22.5%) karyotype was not performed. With a median follow-up of 7.8 yrs (range 0.7-13.6), 37 (16%) patients died, 73 (31.6%) presented CLL progression and 60 (26%) required treatment. OS was 84%. AK was an independent prognostic factor for OS (OR 2.2, 95%CI: 1.0-4.6, p=0.038), TFS (OR 2.9, 95%CI: 1.4-6.0, p=0.003), and PFS (OR 2.4, 95%CI: 1.3-4.6, p=0.005). Atypical lymphocyte morphology was also an independent prognostic factor for OS (OR 2.7, 95%CI: 1.3-5.8, p=0.008) and elevated beta-2 microglobulin for PFS (OR 2.1, 95%CI:1.1-3.9, p=0.018).Conclusions: Abnormal karyotype (not only complex) at diagnosis in early stage CLL (CLL Rai 0 or MBL), is an independent prognostic factor for OS, PFS and TFS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical and molecular characteristics and treatment patterns of adolescent and young adult patients with chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) rarely presents in adolescent and young adult (AYA) patients (patients aged 15-39years). Disease characteristics and outcomes of AYA patients with CLL are not well understood, particularly in the era of novel oral targeted therapies. We analysed outcomes of 227 AYA patients with CLL diagnosed in the last two decades and evaluated at our institution. Median time to first treatment (TTFT) was 2·2years, and five- and 10-year overall survival (OS) were 90% and 78%, respectively. Pre-treatment elevated beta 2-microglobulin, advanced Rai stage, del(11q) or del(17p) by FISH, unmutated IGHV and CD38 positivity were associated with both shorter TTFT and OS. Within the subgroup of patients who received oral targeted therapy at any time, del(11q) or del(17p) and complex karyotype were associated with shorter OS. First-line treatment choice was significantly associated with time to second treatment (P<0·001). Patients harbouring del(11q) or del(17p) experienced shorter time to Richter transformation and were more likely to undergo an allogeneic stem cell transplant. There was a significant association between age and both OS and time to Richter transformation. Our study is the first analysis of AYA patients with CLL with a large number of patients treated with oral targeted therapies.

Bone Marrow Infiltration at Diffuse Large B-Cell Lymphoma NOS Diagnosis: Comparative Study between PET, Histology and Flow Cytometry

Introduction Bone marrow (BM) examination at diffuse large B-cell lymphoma (DLBCL) diagnosis is essential in staging and has prognostic implication. According to the last recommendations (Cheson, et al. JCO 2014) BM biopsy (BMB) is only needed for those patients with a negative BM infiltration by positron emission tomography (PET) for whom identification of occult discordant histology - whose biological and prognostic implications are unknown - is clinically important. Despite its greater sensitivity, flow cytometry (FC) is secondary in BM assessment. Our aim was to compare PET, BMB and FC in the study of BM infiltration at DLBCL diagnosis. Methods Retrospective study in two hospitals in Madrid of patients diagnosed with DLBCL NOS from January 2014 to January 2020. A complete BM assessment including PET, BMB and FC was performed in all included patients. The hole series (n=102) was analysed separately according with BM infiltration by each technique, differences between biological, clinical and laboratory variables were studied applying descriptive statistics tests when appropriate (Fisher's exact test, chi-square test, Student's T test and Mann-Witney U test). Event-free survival (EFS) and overall survival (OS) were analysed with Kaplan-Meier estimator according to BM infiltration positive vs negative for each technique, using Cox proportional-hazard model for comparisons. Results BM infiltration was not assessed in 2 patients by BMB and in 4 patients by FC due to technical reasons. Analysing separately the series according to BM infiltration by each technique (PET+ 25 vs PET- 77, BMB+ 15 vs BMB- 85 and FC+ 16 vs FC- 82) the basal characteristics were comparable between groups, except from extranodal sites ≥2, Ann Arbor III-IV and elevated LDH level in groups with positive BM infiltration. The variables associated with worsen EFS in univariate analysis were age ≥80 years (HR 2.31; CI 95% 1.1-5.1), cell-of-origin (COO) non-GCB (HR 2.33; CI 95% 1.1-4.9), extranodal sites ≥2 (HR 2.39; CI 95% 1.2-4.7), Ann Arbor III-IV (HR 4.55; CI 95% 2.0-10.5), and elevated LDH level (HR 2.32; CI 95% 1.1-4.7). The variables statistically related with worsen OS were COO non-GCB (HR 2.91; CI 95% 1.2-6.8), extranodal sites ≥2 (HR 2.61; CI 95% 1.2-5.5), Ann Arbor III-IV (HR 5.97; CI 95% 2.1-17.3), elevated LDH level (HR 2.36; CI 95% 1.1-5.4), and elevated beta-2 microglobulin level (HR 3.82; CI 95% 1.1-12.9). Double-expressor phenotype did not demonstrated association with EFS or OS. Median infiltration by FC analysis was 0.9% (0.05-27). The series distribution among BM infiltration is presented in Figure 1. Median follow-up was 25 months (0.3-90). Survival curves according to BM infiltration by PET, BMB and FC are presented in Figure 2. Univariate analysis among the type of infiltration by each technique are presented in Table 1. Multivariate analysis included age ≥80 years, COO non-GCB, BM FC+ and IPI score 3-5; BM infiltration by FC demonstrated no association with EFS (HR 2.2; CI 95% 0.9-5.3) or OS (HR 2.5; CI 95% 0.9-6.5). Conclusions BM infiltration by PET at DLBCL NOS diagnosis has not survival implication, contrary to infiltration demonstrated by BMB or FC. Cases with positive infiltration by PET but negative by BMB and FC could be false positive in PET or false negative in BMB/FC. According to our results the patients with discordant lymphoproliferative disorder BM infiltration presented worse prognosis and FC is probably the most important technique in this regard. Disclosures No relevant conflicts of interest to declare.

Pretransplant serum beta-2 microglobulin level is a potential novel prognostic marker of overall survival after allogeneic hematopoietic cell transplantation - a retrospective observational study.

Although elevated serum beta-2 microglobulin (BMG) has been reported as a poor prognostic marker for various hematological malignancies, no study has assessed its prognostic significance in allogenec hematopoietic cell transplantation (allo-HCT). Therefore, we conducted this retrospective observational study in 227 consecutive patients with available pretransplant serum BMG levels between April 2010 and September 2017 at our institute. We also collected and retrospectively analyzed various pretransplant variables likely related to transplant outcomes. Multivariable analysis, including major prognostic variables, such as the disease risk index and the hematopoietic cell transplant-comorbidity index, showed a significant association between higher serum BMG levels and poorer overall survival (OS) in all three adjusted models [hazard ratio (HR) per its standard deviation (SD) (SD=1.094): 1.67 (1.35-2.03; P<0.001), HR per SD: 1.46 (1.14-1.86; P=0.002), HR per SD: 2.03 (1.62-2.55; P<0.001)], respectively, due to the significant association between higher serum BMG levels and relapse/progression [HR 1.52 (1.20-1.94; P<0.001)] instead of nonrelapse mortality [HR 1.06 (0.70-1.60; P=0.780)]. Moreover, DRI and serum BMG had statistically significantly higher c-statistic estimates for OS compared with DRI alone (c-index 0.74 and 0.68, respectively; P<0.001). In conclusion, pretransplant serum BMG level may serve as a useful prognostic marker and help clinical decision in allo-HCT.

“Real-World” Peripheral T-Cell Lymphomas Experience in Portugal: Is There Reason for Optimism?

Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell neoplasms with aggressive behavior and dismal outcomes. Anthracycline-based chemotherapy is commonly used upfront; hematopoietic stem-cell transplantation (HSCT) is employed as consolidation by some groups. Refractory/relapsed cases (R/R) have a median survival of less than 6 months. Our objective was to analyze the outcomes of all consecutive PTCLs diagnosed and treated in a single center during 16 years according to histological subtype, disease phase (first line and R/R) and treatment strategies. Patients and methods: All adult PTCL patients referred to our center between 2003 and 2019 were included. All cases were locally diagnosed based on the current WHO classification by an expert hemato-pathologist. Initial clinical features, treatment and outcomes were analyzed, as well as salvage strategies. Results: A total of 188 patients were included (118 male, 70 female; median age 62 years). Median OS was 22.7 months, with a median follow up of 54 months. Histological subtypes, initial features, response to treatment and survival are detailed in table 1. Briefly, most cases were diagnosed at advanced stages, with extranodal involvement in 69% and elevated beta-2 microglobulin (B2m) in 77%; half had B symptoms. OS according to different subtypes is shown in figure 1. Of note, anaplastic large cell lymphoma (ALCL)-ALK+ patients had a 5-year OS of 88%. Interestingly, fifteen patients had circulating lymphoma cells (12 PTCL not otherwise specified [NOS], 2 hepatosplenic lymphoma and 1 angioimmunoblastic lymphoma [AITL]), with no impact on outcome. PTCL-NOS was the most prevalent subtype (40%) followed by AITL; unexpectedly, the proportion of PTCL-NOS cases increased while AITL cases decreased after 2008. Seven cases belonging to the recently recognized nodal PTCL with T follicular helper (TFH) phenotype were observed, with baseline characteristics and outcome similar to other PTCLs. IPI score index stratified patients into 4 groups with 24-month OS of 71%, 55%, 42% and 16% for low, int-low, int-high and high risk patients, respectively (P=.049). Only B2m and IPI score maintained independent significance for OS (HR= 3.2 and 1.8, respectively, P&lt;.01) in a multivariate analysis that also included histologic subtype and frontline treatment. Most patients were treated with CHOP (75%), although other regimens were increasingly used in recent years, including CHOEP (9%). Young (&lt;65 years) PTCL-NOS patients had a better outcome when treated with CHOEP compared to CHOP (24-month OS of 100% vs. 37%, P=.04); this difference was not noted in ALCL-ALK- and in AITL cases. Twenty-three patients (21% of transplant-eligible cases) underwent HSCT (18 autologous, 5 allogeneic), mostly (16/23) in first remission. As expected, patients not responding to frontline therapy or relapsing after CR showed a dismal outcome (median OS of 4.1 months from R/R date). Intensive platinum-based salvage treatments (26 cases) led to a median OS from relapse of only 6 months. In contrast, single-drug Gemcitabine at first relapse showed a median OS 17.4 months in 5 elderly patients. Of 76 R/R transplant eligible patients, only 7 underwent HSCT(4 allogeneic, 3 autologous), with a 5-year OS of 86%. Eight patients (4 AITL, 4 ALCL) received Brentuximab-Vedotin (BV) at first or later relapse, with improved outcomes compared to other regimes (24-month OS of 63% vs. 22%, P=.03). Conclusion: Initial features, treatments and outcomes for PTCL have not significantly changed in a 16-year period. Only a minority of cases underwent HSCT or received new agents. Ideal salvage regimens are not defined and, in our experience, single agent Gemcitabine or BV performed better than more aggressive combinations. Although promising new drugs have been recently approved for PTCL, their impact on outcome is still not clear. Recent progresses in molecular characterization of the disease may translate into better outcomes through prospective collaborative efforts in the near future. Disclosures Silva: Gilead Sciences: Consultancy, Other: Travel support, Research Funding; Janssen Cilag: Consultancy, Other: Travel support; Abbvie: Consultancy, Other: Travel support; Celgene: Consultancy; Roche: Consultancy, Other: Travel support.

Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group