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Introduction: Serum lipid profiles play a crucial role in diagnosing and evaluating cardiovascular diseases. However, the presence of paraprotein can lead to inaccurate dyslipidemia results on automated analyzers., Case Report: A 65-year-old woman whose combined concentrations of HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) consistently surpassed her total serum cholesterol levels over a period of three months presented with unusual lipid component detection. Further analysis revealed the presence of a monoclonal paraprotein, identified as an IgMλ band, with a concentration of 28.0 g/L. The patient was subsequently diagnosed with Waldenström macroglobulinemia. The use of abnormal reaction kinetic curves and the β quantification method, along with an alternative method that did not suffer from interference, revealed that the monoclonal paraprotein interfered with the measurements of HDL-C, LDL-C, apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB) when using the Roche detection system. This interference led to spurious elevated HDL-C concentrations and falsely decreased apoA-I and apoB concentrations, while the LDL-C results were minimally affected. Although diluting the sample normalized the HDL-C and LDL-C measurements, the interference with the apoA-I and apoB assays persisted. No other common biochemical tests were interfered with this paraprotein., Conclusion: Caution is advised when using a homogenous method for direct measurement of HDL-C and LDL-C in patients with monoclonal paraprotein. Techniques to recognize and eliminate this interference are available. However, immunoturbidimetric detection of apoA-I and apoB levels is also susceptible to this interference, which is not readily removable., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Waldenström macroglobulinemia (WM) is a type of B-cell lymphoma that produces IgM. Our study aimed to investigate the role of CXCL13, a chemokine essential for B lymphocytes, in the evaluation of treatment response and prognosis in WM. We collected serum samples and clinical data from 72 WM patients, with 69 patients receiving systemic therapy and 3 patients opting not to receive treatment. Serum CXCL13 levels at baseline and after six months of treatments were measured by enzyme-linked immunosorbent assay. The median serum level of CXCL13 was 1 539.2 pg/ml (range 10.0-21 389.9) at baseline and significantly decreased to 123.1 pg/ml (range 0.0-6 741.5) after 6 months of treatments. At baseline, higher CXCL13 levels were associated with lower hemoglobin levels (p = 0.001), higher β2-microglobulin levels (p = 0.001), lower albumin levels (p = 0.046), and higher IPSS-WM scores (p = 0.013). After 6 months of treatment, patients who achieved PR/VGPR had significantly lower CXCL13 levels compared to those with SD (70.2 pg/ml vs 798.6 pg/ml, p = 0.002). The median follow-up period was 40 months (range 4.2-188). Eight patients died during the follow-up period. Overall survival differed based on CXCL13 levels. When grouped by baseline CXCL13 levels, the median OS was 60.0 months in patients with serum CXCL13 > 2 000 pg/ml, while it was not reached in patients with low CXCL13 levels (p < 0.001). Based on CXCL13 levels after the treatments, the median OS was 74.0 months in patients with serum CXCL13 > 200 pg/ml, while it was not reached in patients with CXCL13 ≤ 200 pg/ml. In a subgroup of 28 patients with a series of serum samples, the increase of serum CXCL13 level was associated with disease progression or the start of next-line therapy (p < 0.001). Our study concludes that serum CXCL13 levels decrease in WM patients treated with various regimens and correlate with treatment response. Detecting serum CXCL13 at baseline or after treatment help in predicting prognosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Patients with asymptomatic/smouldering Waldenström macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow-up of 9·5 [8·1-11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and β 2 -microglobulin (β 2 M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time-to-progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88 WT ) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7-8·7) vs. 4·7 (2·4-7·7) years for the MYD88 L265P cohort, n = 42; P = 0·11]. The presence of C-X-C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4 WT vs. 5·6 years for CXCR4 MUT , P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age-, sex- and calendar year-matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and β 2 M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre-emptive intervention in this patient population., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Waldenstrom macroglobulinemia (WM) is a rare type of non-Hodgkin lymphoma with great heterogeneity, and the data of peripheral blood T-lymphocyte subsets in WM are limited. This study aimed to investigate the clinical correlation and distribution of circulating T-lymphocyte subsets in newly diagnosed WM patients. We retrospectively searched medical records for 86 newly diagnosed WM patients. Comparisons of the absolute CD3 + T-lymphocyte count (ACD3C), CD4 + T-lymphocyte count (ACD4C), CD8 + T-lymphocyte count (ACD8C), and CD4 + /CD8 + T-lymphocyte ratio (CD4 + /CD8 + ) as continuous parameters in different groups were calculated. Univariate and multivariate analyses were used to assess prognostic factors for overall survival (OS) and progression-free survival (PFS). Young patients (<65 years) had lower ACD8C levels and a higher CD4 + /CD8 + ratio. And the lower level of β2-microglobulin (<3 mg/L) was associated with a higher CD4 + /CD8 + ratio. With a median follow-up of 25 months, the univariate survival analysis showed that CD4 + /CD8 + ratio inversion (CD4 + /CD8 + <1.5) was associated with shorter OS and PFS, and multivariate analysis confirmed that inverted CD4 + /CD8 + ratio could be an independent adverse prognostic factor for OS and PFS. Additionally, initial treatment with rituximab or bortezomib significantly improved the PFS and OS of CD4 + /CD8 + inversion patients but did not affect normal CD4 + /CD8 + patients. We show that low circulating CD4 + /CD8 + ratio at diagnosis is an adverse prognostic factor in WM patients and that first-line therapy which included rituximab or bortezomib significantly improved PFS and OS for patients with CD4 + /CD8 + ratio less than 1.5.

Zanubrutinib is a potent, second-generation Bruton's tyrosine kinase inhibitor that is currently being investigated in patients with B-cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the PKs of zanubrutinib and identify the potential impact of intrinsic and extrinsic covariates on zanubrutinib PK. Data across nine clinical studies of patients with B-cell malignancies and data of healthy volunteers (HVs) were included in this analysis, at total daily doses ranging from 20 to 320 mg. In total, 4,925 zanubrutinib plasma samples from 632 subjects were analyzed using nonlinear mixed-effects modeling. Zanubrutinib PKs were adequately described by a two-compartment model with sequential zero-order then first-order absorption, and first-order elimination. A time-dependent residual error model was implemented in order to better capture the observed maximum concentration variability in subjects. Baseline alanine aminotransferase and health status (HVs or patients with B-cell malignancies) were identified as statistically significant covariates on the PKs of zanubrutinib. These factors are unlikely to be clinically meaningful based on a sensitivity analysis. No statistically significant differences in the PKs of zanubrutinib were observed based on age, sex, race (Asian, white, and other), body weight, mild or moderate renal impairment (creatinine clearance ≥ 30 mL/minute as estimated by Cockcroft-Gault), baseline aspartate aminotransferase, bilirubin, tumor type, or use of acid-reducing agents (including proton pump inhibitors). These results support that no dose adjustment is considered necessary based on the aforementioned factors., (© 2020 BeiGene. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Disease Overview: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity., Diagnosis: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in the majority of IgM MGUS patients., Risk Stratification: Age, hemoglobin level, platelet count, β 2 microglobulin, LDH and monoclonal IgM concentrations are characteristics that are predictive of outcomes., Risk-Adapted Therapy: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogues are active but usage is declining in favor of less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine., Management of Refractory Disease: Bortezomib, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection., (© 2020 Wiley Periodicals LLC.)

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance., (© 2020 by The American Society of Hematology.)

Ibrutinib may inhibit intestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B-cell malignancies received single doses of EE/LN (30/150 μg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single-dose ibrutinib plus single-dose midazolam). Systemic induction was assessed at steady-state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) were derived using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady-state, the C max and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion., (© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

We report the case of a man with a primary diagnosis of Waldenström macroglobulinemia. He secondarily presented a diffuse large B cell lymphoma (DLBCL) located in the nasal fossae, which relapsed later in the eye. The diagnosis of these two malignancies is based on a multidisciplinary biological approach using new sensitive and specific techniques. These techniques revealed that the two diseases harbor different B cell clones, indicating a distinct origin. This observation highlights the importance of targeted biological techniques for the diagnosis of these two rare hemopathies. It also shows that it is possible to prove the independent nature of the two tumor clones, thus allowing optimized therapeutic management.

We aimed to detect the MYD88 L265P and CXCR4 S338X mutations in cell-free DNA (cfDNA) in patients with Waldenström macroglobulinemia (WM). We collected peripheral blood and paired bone marrow aspirates from 27 WM patients (including 16 patients with newly diagnosed WM, 3 patients with WM in relapse and 8 patients with WM during treatment). cfDNA was extracted from peripheral blood using a QIAamp Circulating Nucleic Acid Kit. The MYD88 L265P and CXCR4 S338X mutations were detected by real-time allele-specific PCR (AS-PCR) in cfDNA and genomic DNA (gDNA) extracted from bone marrow aspirates. The sensitivity of real-time AS-PCR for detecting MYD88 L265P in cfDNA was determined using a serial dilution of 10%, 2%, 0.4% and 0.08% MYD88 L265P cfDNA in wild-type cfDNA. Among the 27 patients, MYD88 L265P was detected in 88.9% of them in gDNA and in 85.2% of them in cfDNA, with a concordance rate of 96.3%. The concordance rates were 93.8%, 100% and 100% in patients with newly diagnosed WM, patients with WM in relapse and patients with WM during treatment, respectively. The sensitivity of real-time AS-PCR for detecting MYD88 L265P in cfDNA was 0.4%. CXCR4 S338X was detected in 6.3% of the 16 newly diagnosed WM patients in both gDNA and cfDNA, with a concordance rate of 100.0%. It is feasible to apply cfDNA to detect MYD88 L265P and CXCR4 S338X in WM patients with a high concordance rate.

Introduction: After tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 were introduced for the treatment of chronic myeloid leukemia, clinical outcomes have improved dramatically. However, together with the increase in the survival rate, a more frequent occurrence of secondary malignancies has been observed as well. TKIs have been demonstrated to be a risk factor of malignancies such as non-Hodgkin lymphoma, prostate cancer, and skin cancer. However, lymphoplasmacytic lymphoma (LPL) has never been reported as a secondary malignancy after TKI treatment in chronic myeloid leukemia (CML)., Patient Concerns: An 81-year-old male patient diagnosed with CML and treated with TKIs for a long period (15 years) was admitted due to a chief complaint of abdominal pain. A large abdominal mass was detected by imaging that included computed tomography., Diagnosis: LPL was confirmed from biopsies after ultrasonography and sigmoidoscopy. Serum IgM level was increased and M protein and monoclonal gammopathy, IgM&#95;kappa light chain type were detected., Interventions: The patient received six cycles of R-CHOP chemotherapy., Outcomes: After chemotherapy, he showed response. The sizes of the abdominal mass and lymph nodes decreased; moreover, serum M protein and IgM levels decreased, as well., Conclusion: Herein, for the first time, we describe a patient who developed LPL as a secondary malignancy after administration of TKIs for the treatment of CML. Our observations indicate the importance of awareness of this secondary malignancy that can develop in CML patients treated with TKIs.

Rituximab-containing regimens are commonly used for frontline therapy in patients with symptomatic Waldenström macroglobulinemia (WM). We had observed that a portion of WM patients experienced deepening of response months to years after therapy completion. We carried a retrospective study aimed at describing this phenomenon. We gathered baseline data, and responses at end of induction, end of maintenance and best response. Deepening of response was defined as ≥25% decrease in serum IgM achieved at a later time from therapy completion. Of 178 patients included, 116 (65%) received maintenance therapy and 62 (35%) were observed. In patients who received maintenance, 44 (38%) had ≥25% decrease in serum IgM level after the end of maintenance with a median time from end of maintenance to lowest IgM level of 1.6 years (range 0.1-7.9 years). In patients who were observed, 19 (31%) had ≥25% decrease in serum IgM level after the end of induction with a median time from end of induction to lowest IgM level of 1.6 years (range 0.2-5.1 years). Baseline hemoglobin <11.5 g/dL, bone marrow involvement ≥50%, CXCR4 mutations and serum IgM ≥4000 mg/dL were associated with lower odds of deepening of response after therapy completion. Deepening of response was associated with better progression-free survival (PFS; HR 0.46, 95% CI 0.26-0.80; P = .006) and better survival after frontline treatment initiation (SAFTI; HR 0.21, 95% CI 0.06-0.73; P = .01). In conclusion, deepening of response occurs in one third of WM patients after completing rituximab-containing regimens and was associated with better PFS and SAFTI., (© 2019 Wiley Periodicals, Inc.)

Purpose: To image retinal blood vessels in patients with Waldenström's macroglobulinemia using optical coherence tomography (OCT)., Methods: Retrospective case series examining fundus photographs and OCT scans of 16 eyes in eight patients with Waldenström's macroglobulinemia. Analyses included intravascular OCT reflectivity profiles and vessel diameters, and their relation to total immunoglobulin M (IgM) levels., Results: In six out of eight patients, cross-sectional OCT scans of larger retinal vessels (diameter > 100 μm) showed normal intravascular reflectivity and retrovascular shadowing. In two patients with the highest total IgM > 60 g/l, altered intravascular reflectivity, distinct anterior and posterior vessel wall reflexes, and retrovascular hyposhadowing were seen. Normalization of the OCT reflectivity in these patients occurred after reduction of total IgM to < 17 g/l and was accompanied by decreasing venous tortuosity and disappearance of retinal haemorrhages and cotton wool spots., Conclusion: This study found that Waldenström's macroglobulinemia and total IgM > 60 g/l were associated with abnormal intravascular reflectivity and retrovascular shadowing on OCT. Awareness of these signs of hyperviscosity could potentially enable earlier detection of critical conditions in patients with Waldenström's macroglobulinemia and improve the assessment of severity and treatment effect., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Lymphoplasmacytic lymphoma (LPL) is usually associated with a serum IgM paraprotein, corresponding to Waldenström's Macroglobulinemia (WM). Cases presenting with IgG or IgA, or without a monoclonal protein are extremely rare. We analyzed clinical characteristics, frontline treatment, and the outcome of 45 patients with non-IgM LPL, and compared them with a control group of WM patients. The median age was similar, with significantly higher prevalence of females in non-IgM LPL, than in WM patients (60% vs 39%, P = .016). Patients with non-IgM LPL more frequently presented with lymphadenopathies (53% vs 15%, P < .001), splenomegaly (22% vs 8%, P = .015) or extranodal involvement (20% vs 8%, P = .05). In non-IgM LPL a serum monoclonal protein and bone marrow infiltration were less common than in WM patients (69% and 84% of cases respectively, P < .001 for both comparisons). The MYD88 (L265P) mutation was found in 8/19 patients using allele-specific polymerase chain reaction. A CXCR4 mutation was found in 4/17 cases using Sanger. In 16 patients we performed targeted next-generation sequencing of genes MYD88, CXCR4, ARID1-A, KMT2D, NOTCH2, TP53, PRDM1, CD79B, TRAF3, MYBBP1A, TNFAIP3. Seven patients (44%) had a MYD88 mutation (S219C in one), four (25%) a CXCR4 mutation, three (19%) a KMT2D mutation, one (6%) a TP53 mutation and one (6%) a TRAF3 mutation. With a median follow-up of 55.7 months, 36 non-IgM LPL patients (80%) were treated. Non-IgM LPL patients received more frequently anthracycline-containing regimens, as compared with WM patients, who mainly received alkylating-based therapies. Five-year overall survival (OS) was 84%, similar to that of WM patients., (© 2019 Wiley Periodicals, Inc.)

IgA-producing lymphoplasmacytic lymphoma (LPL) is rare and IgH/c-myc translocation is rare in LPL. This is the first report of a case of IgA-producing LPL carrying t(8;14). An 86-year-old woman presented inguinal and intra-abdominal lymph node swelling, and lytic bone lesions in the lumbar vertebrae. A diagnosis of IgA-producing LPL was immunohistochemically made by inguinal lymph node biopsy. The serum IgA level was 1,180 mg/dL, which was revealed to be composed of IgA-λ monoclonal protein. Bone marrow chromosomal analysis demonstrated a complex abnormal karyotype, including t(8;14)(q24;q32), which was confirmed by FISH analysis. Abnormal lymphocytes positive for CD19, CD20, cyIgA, and cyλ were detected on flow cytometry analysis of marrow cells. Best supportive care was selected because of dementia and refractory urinary tract infection. Circulating lymphoplasmacytic cells with the same phenotype and karyotype were observed, and increased in number. The aggressive clinical course, including lytic bone lesions, may have been due to IgH/c-myc translocation or the nature of IgA-producing LPL.

We investigated the feasibility of using next-generation sequencing (NGS) technique using molecular barcoding technology to detect MYD88 L265P mutation in unselected peripheral blood mononuclear cells (PBMCs) in 52 patients with Waldenström's macroglobulinemia [1] and 21 patients with IgM-monoclonal gammopathy of undetermined significance (MGUS). The NGS technique successfully detected the MYD88 L265P in unselected PBMCs at a sensitivity of 0.02%, which was ×5 higher than that of AS-PCR. All the results between paired BM and PB samples from 2 IgM MGUS and 4 untreated WM patients matched completely. MYD88 L265P mutation was detected in 14/21 (66.7%), 14/19 (73.7%), and 10/33 (30.3%) with the median mutant allele burden of 0.36% (range, 0.06-2.85%), 0.48% (range, 0.02-32.3%), and 0.16% (range, 0.02-33.8%), in IgM-MGUS, untreated WM, and previously treated WM, respectively. Multiple linear regression analysis identified an absolute peripheral lymphocyte count as the positive predictor of PB mutant allele burden (R2 = 0,72, P<0.0001). Our non-invasive, simple NGS method has the potential to detect MYD88 L265P mutations in PBMCs of IgM MGUS and WM patients, which may especially utilized for monitoring minimal residual tumor burden after treatment., Competing Interests: The authors have declared that no competing interests exist.

A 67 years old woman with a Waldenström disease was admitted in the intensive care unit for dyspnea and fever. During hospitalization, episodes of undetectable glycemia were observed without any hypoglycemia symptoms. Plasma glucose was determined with the hexokinase method (recommended). From this observation, a literature review on PubMed was performed to investigate similar cases. In patients with protides in excess (e.g. immunoproliferative syndrome), absorption measurements could be disrupted by the precipitation of excess protein (IgM in most cases). Other parameters could be affected: bilirubin, phosphate, HDL cholesterol, GGT, CRP and calcemia. In our case, the main difficulty was to identify the cause of the interference and then correct it. Using a series of dilution, we prevented protide precipitation allowing correct glucose determination. Those interferences are rare, but present a real analytical difficulty. Biologists should be aware of those interferences because of dramatics consequences.

Purpose: To explore the value of elevated CXCL13 levels in Waldenström macroglobulinemia (WM)., Methods: We collected serum samples from 41 patients and bone marrow tissues from 14 patients with newly diagnosed symptomatic WM. Serum and bone marrow samples from patients with other indolent B-cell lymphomas and MGUS were also collected for comparison. Serum CXCL13 levels were measured by enzyme-linked immunosorbent assay, and bone marrow tissues were examined by immunohistochemistry., Results: The median serum level of CXCL13 in patients with symptomatic WM was 2483.0 (range 36.8-5644.0) pg/ml, which was significantly higher than in patients with other indolent B-cell lymphomas with monoclonal IgM (median 380.9 pg/ml, range 23.8-5518.0 pg/ml) (p = 0.01). Serum CXCL13 >3250 pg/ml and serum M-protein >38 g/l diagnosed WM with a sensitivity of 98% and specificity of 85%. Serum CXCL13 was strongly correlated with hemoglobin levels (ρ=-0.46, p = 0.002), serum M-protein (ρ=0.47, p = 0.002), and IgM levels (ρ=0.30, p = 0.05) in patients with symptomatic WM. Immunohistochemistry analysis indicated that CXCL13 and activated mast cell levels were also higher in the bone marrow of WM patients compared to patients with IgM-MGUS or other indolent B-cell lymphomas with monoclonal IgM., Conclusions: Serum CXCL13 levels were significantly elevated in patients with WM and correlated with tumor load. Detection of serum CXCL13 may therefore be helpful in the differential diagnosis of WM., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The finding of an IgM monoclonal gammopathy often represents a diagnostic challenge. In fact, there are many pathological disorders associated with this condition, each of which has distinctive characteristics and requires specific clinical, instrumental, and laboratory assessments to set the appropriate treatment. This review has two aims. Firstly, to provide a framework of the broad spectrum of IgM-associated disorders: (1) monoclonal gammopathy of undetermined significance (MGUS); (2) Waldenström macroglobulinemia (WM); (3) IgM-related disorders (among which hyperviscosity syndrome, light chain amyloidosis, cold agglutinin disease, cryoglobulinaemia, IgM neuropathy, Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome, Castleman disease); (4) IgM-secreting multiple myeloma (IgM-MM); and (5) other lymphoproliferative disorders which may be associated with IgM (such as chronic lymphocytic leukemia, small lymphocytic lymphoma, and B-cell non Hodgkin lymphoma). Secondly, to give a detailed insight regarding diagnosis and treatment of WM., (© 2018 John Wiley & Sons, Ltd.)

Background: IgM monoclonal gammopathy can be present in a broad spectrum of diseases. We evaluated the value of serum markers in the differential diagnosis of Waldenstrom macroglobulinemia (WM) and other types of IgM monoclonal gammopathies., Methods: We included patients who were first admitted to hospital and identified as having IgM monoclonal gammopathy by serum immunofixation electrophoresis (sIFE). We evaluated basic clinical features, sIFE, diagnosis, and serum markers. Furthermore, we applied the receiver operating characteristic (ROC) curve to analyze the differential diagnosis value of serum markers for WM. Finally, we used logistic regression and ROC curve to analyze the differential diagnosis value of multimarker combinations to identify WM., Results: IgM monoclonal gammopathy was most frequently found in patients with Waldenstrom macroglobulinemia, followed by monoclonal gammopathy of undetermined significance (MGUS), B-cell non-Hodgkin Lymphoma (B-NHL), and multiple myeloma (MM). Serum markers showed significant differences among the four diseases. The diagnostic markers LDH, IgM, IgG, IgA, and serum light chain К had higher diagnostic efficiency. Among these markers, serum IgM provided the highest diagnostic efficiency. Additionally, the combined use of all five serum markers provided the most effective diagnosis., Conclusions: The five serum markers, LDH, IgM, IgG, IgA, and К, each yielded a specific efficacy in differential diagnosis of WM. The single marker with the highest diagnostic efficiency was the serum IgM level. However, a combination of multiple serum markers was better than the use of a single marker in diagnosing WM. The combined use of all five serum markers provided the most effective diagnosis, with an AUC of .952 and sensitivity and specificity of 87.8% and 86.9%, respectively., (© 2018 Wiley Periodicals, Inc.)

IgM secreting myelomas or lymphomas, including Waldenström macroglobulinemia, are associated with a varied spectrum of renal pathology, including intracapillary hyaline deposits, cryoglobulin, membranoproliferative glomerulonephritis, amyloid, monoclonal immunoglobulin deposition disease, cast nephropathy, and lymphoma infiltration. We report our single institution experience, and describe five cases with distinctive glomerular pathology: intracapillary IgM pseudothrombi and thrombotic microangiopathic change, with glomerular intracellular crystals in two biopsies. Two patients were hypocomplementemic at presentation. This series adds to the recent literature on paraprotein associated thrombotic microangiopathy.

Lymphoplasmacytic lymphoma is rare. Although most cases of LPL are Waldenström macroglobulinemia associated with an immunoglobulin M, there are exceptions. Indeed, few cases are immunoglobulin A-secreting or immunoglobulin G-secreting. These cases are poorly described and raise diagnostic difficulties. The purpose of this article is to describe an IgG lymphoplamacytic lymphoma case diagnosed recently in the hematology laboratory University Hospital of Toulouse.

Symptomatic hyperviscosity is a well-established phenomenon in Waldenström macroglobulinemia (WM). Monoclonal IgM can variably impact intrinsic serum viscosity, leading to widely disparate symptomatic thresholds for development of hyperviscosity-related symptoms. Data regarding the predictors of symptomatic hyperviscosity and outcomes related to this complication remain scarce and a recent study proposed that IgM >6000 mg/dL be considered a new criterion for initiating therapy in otherwise asymptomatic (smoldering) WM to pre-empt hyperviscosity-related injury. Herein, we attempt to identify predictors of the development of symptomatic hyperviscosity and its impact in patients with WM. Of 997 WM patients evaluated from January, 1996 through June, 2017, symptomatic hyperviscosity was observed in 130 (13%) patients. Overall survival (OS) of these 130 patients was similar to that of patients without symptomatic hyperviscosity (median: 11.5 vs 11.6 years; P = 0.63). On multivariate-analysis, only viscosity >1.8 cp (risk ratio: 4.0, P = 0.02) assessed at the time of WM diagnosis was an independent predictor for the development of subsequent symptomatic hyperviscosity. Among patients with smoldering WM and IgM >6000 mg/dL at diagnosis (n = 13) who were managed expectantly, the median time-to-initial therapy was 6.9 years and only 15% developed hyperviscosity-related symptoms subsequently. In summary, the occurrence of symptomatic hyperviscosity does not impact OS. Serum viscosity at diagnosis of WM, and not IgM concentration, represents the single most important independent predictor for development of subsequent hyperviscosity-related symptoms. Patients with smoldering WM and high serum IgM can be safely observed in the absence of any indications per the Consensus recommendations to initiate WM-directed therapy., (© 2018 Wiley Periodicals, Inc.)

We present a nationwide prospective Swedish registry-based study of Waldenström macroglobulinaemia (WM), that focuses on incidence and survival in relation to clinical prognostic factors and primary systemic therapies. A total of 1511 patients with WM and lymphoplasmocytic lymphoma (LPL) were registered in the Swedish Lymphoma Registry (SLR) between 1 January 2000 and 31 December 2014. The age-adjusted incidence of WM/LPL was 11·5 per million persons per year, three times higher than the reported incidence worldwide. Medical records were retrieved for 1135 patients (75%). A retrospective review showed that 981 (86·1%) of these patients fulfilled the World Health Organization diagnostic criteria for WM and these patients were analysed further. The overall survival (OS) improved between two periods - 2000-2006 and 2007-2014 - with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS, evaluated at the time of diagnosis, were age, elevated lactate dehydrogenase level and haemoglobin ≤115 g/l for patients receiving therapy 0-3 months after diagnosis, and age, poor performance status, haemoglobin ≤115 g/l, and female sex in "watch and wait" patients (multivariable analysis). The level of the IgM monoclonal immunoglobulin had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Waldenström Macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by disease progression from IgM MGUS to asymptomatic and then symptomatic disease states. We profiled exosomes from the peripheral blood of patients with WM at different stages (30 smoldering/asymptomatic WM, 44 symptomatic WM samples and 10 healthy controls) to define their role as potential biomarkers of disease progression. In this study, we showed that circulating exosomes and their miRNA content represent unique markers of the tumor and its microenvironment. We observed similar levels of miRNAs in exosomes from patients with asymptomatic (smoldering) and symptomatic WM, suggesting that environmental and clonal changes occur in patients at early stages of disease progression before symptoms occur. Moreover, we identified a small group of miRNAs whose expression correlated directly or inversely with the disease status of patients, notably the known tumor suppressor miRNAs let-7d and the oncogene miR-21 as well as miR-192 and miR-320b. The study of these miRNAs' specific effect in WM cells could help us gain further insights on the mechanisms underlying WM pathogenesis and reveal their potential as novel therapeutic targets for this disease., Competing Interests: Irene Ghobrial has a consulting/advisory role with Celgene, Takeda, Bristol-Myers Squibb (BMS), Janssen Pharmaceuticals, and Amgen. Outside of the present study, Irene Ghobrial received research funding/ honoraria from Celgene, Takeda, Bristol-Myers Squibb (BMS), Janssen Pharmaceuticals, and Amgen. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors declare that no competing interests exist.

Multiparameter flow cytometry (MFC) is valuable in the diagnosis and monitoring of most hematological malignancies. Although the assessment of cellular infiltrates in Waldenström macroglobulinemia (WM) relies on morphology and immunohistochemistry grounds, there is evidence pointing to the clinical significance of MFC in this disease. Herein, the authors review immunophenotypic patterns of B-cell development, the antigen profile of the WM clone and its normal B-cell counterpart, the clinical applicability of MFC in the differential diagnosis of immunoglobulin M-secreting lymphoproliferative disorders and monoclonal gammopathies, and its potential role in detecting minimal residual disease and monitoring treatment efficacy in WM., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Although immune checkpoint molecules regulate the progression of certain cancers, their significance in malignant development of Waldenstrom macroglobulinemia (WM), an incurable low-grade B-cell lymphoma, remains unknown. Recently, cytokines in the bone marrow (BM) microenvironment are shown to contribute to the pathobiology of WM. Here, we investigated the impact of cytokines, including interleukin-6 (IL-6) and IL-21, on immune regulation and particularly on the programmed death-1 (PD-1) and its ligands PD-L1 and PD-L2. We showed that IL-21, interferon γ, and IL-6 significantly induced PD-L1 and PD-L2 gene expression in WM cell lines. Increased PD-L1 and PD-L2 messenger RNA was also detected in patients' BM cells. Patients' nonmalignant BM cells, including T cells and monocytes, showed increased PD-L1, but minimal or undetectable PD-L2 surface expression. There was also very modest PD-L1 and PD-L2 surface expression by malignant WM cells, suggesting that ligands are cleaved from the cell surface. Levels of soluble ligands were higher in patients' BM plasma and blood serum than controls. Furthermore, IL-21 and IL-6 increased secreted PD-L1 in the culture media of WM cell lines, implying that elevated levels of soluble PD-1 ligands are cytokine mediated. Soluble PD-1 ligands reduced T-cell proliferation, phosphorylated extracellular signal-regulated kinase and cyclin A levels, mitochondrial adenosine triphosphate production, and spare respiratory capacity. In conclusion, we identify that soluble PD-1 ligands are elevated in WM patients and, in addition to surface-bound ligands in WM BM, could regulate T-cell function. Given the capability of secreted forms to be bioactive at distant sites, soluble PD-1 ligands have the potential to promote disease progression in WM., (© 2018 by The American Society of Hematology.)

We report here a case of lymphoplasmacytic lymphoma with IgA paraproteinemia and a case of concomitant Waldenström macroglobulinemia and monoclonal gammapathy of unknown significance. These rare cases show that the isotype of a monoclonal immunoglobulin does not allow to foresee every time the underlying pathology. Clinical data and medical imaging are essential. From a biological point of view, additional analysis such as immunophenotyping, cytogenetics and molecular biology are required in addition to the cytological features in order to make an accurate differential diagnosis between lymphoid and plasma cell malignancy.

The blood proteome has been studied extensively for identification of novel reliable disease biomarkers. In recent years, differential scanning calorimetry has emerged as a new tool for characterization of the thermodynamic properties of the major serum/plasma proteins and for the establishment of calorimetric markers for a variety of diseases. Here we applied calorimetry to monitor the effect of treatment of patients diagnosed with multiple myeloma and Waldenström's macroglobulinemia on the calorimetric profiles of patients' blood sera. The parameters derived from the calorimetric profiles were compared with the primary serum biomarkers, monoclonal immunoglobulin (M protein) concentration, and κ/λ free light chain ratio. For the secretory cases, the calorimetric parameters thermogram's shape similarity and weighted average center strongly depended on the M protein level but had lower sensitivity and specificity. By contrast, for non-secretory cases, the calorimetric parameters did not depend on the κ/λ free light chains ratio and exhibited significantly higher sensitivity and specificity than M protein levels. A combination of the immunological and calorimetric tests was found to greatly improve the sensitivity and specificity of the clinical status evaluation. The pronounced differences in blood sera thermograms before and during monitoring reflected the individual patients' response to treatment received and showed maintenance of heterogeneity during the disease course.

Background: Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence., Methods: We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples., Results: At 30 months, the progression-free survival rate was 82% with ibrutinib-rituximab versus 28% with placebo-rituximab (hazard ratio for progression or death, 0.20; P<0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P<0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P<0.001). The most common adverse events of any grade with ibrutinib-rituximab included infusion-related reactions, diarrhea, arthralgia, and nausea. Events of grade 3 or higher that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included atrial fibrillation (12% vs. 1%) and hypertension (13% vs. 4%); those that occurred less frequently included infusion reactions (1% vs. 16%) and any grade of IgM flare (8% vs. 47%). The major hemorrhage rate was the same in the two trial groups (4%)., Conclusions: Among patients with Waldenström's macroglobulinemia, the use of ibrutinib-rituximab resulted in significantly higher rates of progression-free survival than the use of placebo-rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib-rituximab, whereas infusion reactions and IgM flare were more common with placebo-rituximab. (Funded by Pharmacyclics and Janssen Research and Development; ClinicalTrials.gov number, NCT02165397 .).

Background: Serum receptor activator of nuclear factor κB ligand (sRANKL) and chemokine (C-C) motif ligand 3 (CCL-3) have been reported to be elevated in Waldenström macroglobulinemia (WM) patients. However, there are no published data regarding the prognostic value of these molecules in WM regarding progression-free and overall survival., Methods: To evaluate the effect of these markers of bone remodeling on survival parameters, we prospectively evaluated serum cytokines and biological markers in 55 patients with symptomatic WM before they received any kind of treatment. Serum levels of CCL-3 and bone remodeling markers were also evaluated in asymptomatic WM and IgM monoclonal gammopathy of undetermined significance. Furthermore, we assessed bone marrow biopsy samples from newly diagnosed WM patients for CCL-3 and RANKL expression., Results: High circulating sRANKL values predicted shorter median overall survival (46 months vs. not reached, P = .025). High serum levels of CCL-3 predicted shorter median progression-free survival (27 months vs. not reached, P = .048). At bone marrow biopsy evaluation, the whole number of the neoplastic cells revealed strong cytoplasmic positivity for CCL-3, while the neoplastic clone did not express RANKL., Conclusion: We conclude that WM cells produce CCL-3 and possibly enhance the production of RANKL in the bone microenvironment. The correlation of sRANKL and CCL-3 with survival reveals the importance of these cytokines in disease biology and highlights the significance of the interactions between WM and stromal cells for the development of WM. Finally, these findings provide the rationale for the use of anti-RANKL and anti-CCL-3 drugs in animal models of WM before their clinical evaluation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Waldenström macroglobulinemia is often an indolent disorder, and many patients are candidates for observation with careful monitoring. For symptomatic patients, one must distinguish between those patients whose symptoms are related to immunologic manifestations associated with the IgM monoclonal protein and those that have symptoms related to progressive marrow and nodal infiltration with lymphoplasmacytic lymphoma. In Waldenström macroglobulinemia, the driver for therapy in the majority of patients is progressive anemia, secondary to bone marrow replacement by lymphoplasmacytic lymphoma. Recent introduction of MYD88 mutational analysis has been very useful for diagnostic purposes but is unclear what effect it might have on the prognosis or response rate to therapy. An algorithm is provided on the management of asymptomatic individuals and the sequence used for chemotherapeutic intervention of symptomatic patients.

Hyperviscosity syndrome (HVS) develops most commonly in Waldenström's macroglobulinemia (WM) and multiple myeloma (MM). Plasmapheresis is the immediate therapy and very effective at relieving symptoms by removing paraprotein. The most commonly used replacement fluid is 4%-5% human albumin in physiologic saline. FFP may be used in patients with coagulation abnormalities. Plasmapheresis should be continued until acute symptoms abate. Hyperviscosity impairs the circulation in the retina and causes hemorrhages around the small retinal vessels. Early diagnosis and urgent plasmapheresis may reduce blindness caused by retinal hemorrhages and/or retinal detachment. In HCV related mixed cryoglobulinemias, plasmapheresis is indicated if rapidly evolving life-threatening disease with immunosuppressive agent exists. In non-infectious mixed cryoglobulinemia plasmapheresis is indicated when the disease manifestations are severe, as a second line option. In WM patients with hyperviscosity symptoms and IgM > 4 g/dL, preemptive plasmapheresis is recommended to prevent an IgM flare with rituximab. Certain IgG/A MGUS-associated neuropathy patients may benefit from plasmapheresis. For cast nephropathy (suspected or biopsy proven), plasmapheresis is recommended when the sFLC ≥ 500 mg/l and as early as possible (<1 month with kidney injury). Theoretically, extracorporeal removal alone, without efficient tumor killing, could not reduce sFLC due to high production by the tumor mass and rapid rebound between compartments., (Copyright © 2018. Published by Elsevier Ltd.)

In this brief review, we have examined some clinical disorders which are associated to an altered hemorheological profile and at times accompanied by skin ulcers. This skin condition may be, in fact, observed in patients with primary plasma hyperviscosity such as multiple myeloma, Waldenstrom macroglobulinemia, cryoglobulinemia, cryofibrinogenemia, dysfibrinogenemia and connective tissue diseases. It must be underlined that the altered hemorheological pattern is not the only responsible for this skin complication but, as it worsens the microcirculatory flow, it contributes to determine the occurrence of the skin ulcers., (Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)