High Serum IgM Research Articles

A 35-year-old male with Waldenstrom Macroglobulinemia

Waldenstrom macroglobulinemia is one type of non- Hodgkin lymphoma that presents with a wide range of clinical features mainly due to secretion of the IgM paraprotein and infiltration of lymphoplasmacytic cells. Patients with Waldenstrom macroglobulinemia may experience fatigue, unexplained weight loss, enlarged lymph nodes, abdominal swelling, weakness, nose bleeding, blurring of vision etc. Waldenstrom macroglobulinemia is a disease of elderly individuals. The median age at diagnosis is 65 years, with a slight male predominance. We reported a case of a 35-yearold male who presented with fever, abdominal pain, loose motion and epistaxis. Examination revealed cervical and inguinal lymphadenopathy with hepatosplenomegaly. Investigation revealed diffuse lymphocyte infiltration on bone marrow study . Protein electrophoresis showed monoclonal gammopathy with high serum IgM level. On the basis of clinical features and investigation reports finally we diagnosed that, this was a rare case of Waldenstrom macroglobulinemia in a young patient. The patient was transfused 5 units of whole blood and was treated following standard treatment protocol with dexamethasone, Bortezomib and G-CSF. Unfortunately, patient died 3 weeks after initiation of treatment. J Bangladesh Coll Phys Surg 2023; 41(4): 325-328

Expression kinetics of cytokines and the humoral antibody response concerning short-term protection induced by radiation-attenuated Trypanosoma evansi in bovine calves.

'Surra', an economically important disease of livestock, is caused by the parasitic blood protozoon Trypanosoma evansi. Both innate and adaptive immunity contribute to the protection against this infection. T-helper cells play a crucial role in the antibody-mediated clearance of T. evansi. We present here the data on the kinetics of expression of important Th1, Th2 and Th17 cytokines, vis-a-vis the dynamics of humoral response in bovine calves following immunization with γ-radiation-attenuated live T. evansi and later challenged with homologous virulent T. evansi. Significant upregulation of the pro-inflammatory Th1 and Th17 cytokines was correlated with the IgG2-mediated protection in the immunized bovine calves post-challenge. The calves were immunized with 5×106 500Gy γ-radiation-attenuated live T. evansi (horse isolate) thrice at 15days intervals through the subcutaneous route and subsequently, challenged with 1×103 virulent T. evansi on day 50. Significantly high serum IgG (1:1600) and IgM (1:800) titres were recorded on week 2 PC, whereas the peak serum IgG2 titre (1:800) was recorded on week 6 PC. Significant upregulation of IFN-γ, TNF, IL-1β, and IL-2 was recorded between days 1 to 3 PC, while the same for IL-17 was recorded on day 14 PC. The immunized calves were free from parasitemia post-challenge and were clinically healthy till the end of the experiment. Significant upregulation of IL-10 and IL-4 transcripts and a corresponding increase of serum IgG1 titre in the placebo group helped patency of the parasite in an anti-inflammatory environment and clinical exacerbation of the disease. The expression of the important Th1 cytokines was crucial for antibody-mediated short-term protection against a lethal challenge of T. evansi in cattle.

Preliminary Clinical Response Data from a Phase 1b Study of Mavorixafor in Combination with Ibrutinib in Patients with Waldenström's Macroglobulinemia with MYD88 and CXCR4 Mutations

Preliminary Clinical Response Data from a Phase 1b Study of Mavorixafor in Combination with Ibrutinib in Patients with Waldenström's Macroglobulinemia with MYD88 and CXCR4 Mutations

Acquired Von Willebrand Disease in Patients with Waldenström Macroglobulinemia

Introduction: Acquired von Willebrand disease (VWD) is uncommonly observed in patients with Waldenström Macroglobulinemia (WM), and necessitates treatment intervention. The clinical characteristics for WM patients with acquired VWD, as well as outcomes following therapy have not been well characterized.Methods: We carried a retrospective study in patients with new diagnosed diagnosed WM who were evaluated at our institution, and tested for the presence of VWD. The presence of any VWD was evaluated by measuring levels of VW factor antigen (VWFAG), VW factor activity (VWFACT) and factor VIII (FVIII). Low-level VWD was diagnosed if VWFAG, VWFACT and FVIII levels were between 30% and 50%. VWD was diagnosed if VFWAG, VWFACT and FVIII were <30%. Univariate and multivariate logistic regression models were fitted to evaluate association of clinical factors and presence of any VWD. We also evaluated the effect of response to therapy on VWFAG, VWFACT and FVIII levels.Results: A total of 320 patients with WM were tested for VWD, of whom 271 (85%) showed no evidence of deficiency, and 49 (15%) showed any VWD. Patients were tested because they provided a history of easy bruising or bleeding. Thirty patients had low-level VWD (61%) and 19 were VWD (39%). The median IgM level of patients with any VWD was 5,660 mg/dl (range 1,800-10,300 mg/dl) and 2270 mg/dl (95% CI 25-11,000 mg/dl) in patients without VWD. Patients with any VWD were more likely to have IgM levels 3,000-5,999 mg/dl and 6,000+ mg/dl (47% vs. 31%, and 45% vs. 6%, respectively; p<0.001) and less likely to have white blood cell count (WBC) >6 K/uL (29% vs. 50%; p=0.006) than patients without VWD. There were no differences in age, sex, hemoglobin levels, platelet count and bone marrow involvement between WM patients with any and without VWD. In the multivariate regression analyses, patients with IgM levels 3,000-5,999 mg/dl and 6,000+ mg/dl had OR 11.1 (95% CI 3.7-33.3; p<0.001) and OR 48.7 (95% CI 14.7-160.8; p<0.001), respectively, of having any VWD. WBC was not associated with presence of any VWD (p=0.34). In the subset of patients who had genomic testing performed (n=125), patients with any VWD were more likely to carry CXCR4 mutations (77% vs. 37%, p<0.001) than patients without VWD. There were no clinical or genomic differences between patients with low level VWD and actual VWD. Of 18 patients with any VWD who received therapy for WM, 6 patients (33%) received proteasome inhibitors + rituximab, 5 (28%) received alkylators + rituximab, 5 (28%) received ibrutinib and 2 (11%) received rituximab alone. Three patients (17%) achieved very good partial response (VGPR), 6 (33%) partial response, 8 (44%) minor response and 1 (11%) stable disease. At the moment of best response, the median IgM level had decreased from 6241 mg/dl to 2274 mg/dl, the median VWFAG level had increased from 21% to 64%, the median level VWFACT had increased from 23% to 58% and the median FVIII had increased from 21% to 57% (p<0.001 for all comparisons). Before therapy, 6 patients (33%) had low-level VWD and 12 (67%) had VWD. After therapy, 14 patients (78%) did not have VWD, 4 (22%) had low-level VWD and no patients had VWD. The depth of response to therapy (change in IgM) correlated with the percentage of change in VFWAG, VWFACT and FVIII (see Figure).Conclusion: Patients with WM can present with acquired VWD, which seems to strongly correlate with high serum IgM levels. VWD improves and in most cases resolves with response to WM therapy. The depth of response to therapy correlates with the degree of improvement in VWD. [Display omitted] DisclosuresCastillo:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Research Funding. Treon:Pharmacyclics: Consultancy, Research Funding.

Differential Diagnosis of Suspected MYD88 Wild-Type Waldenstrom's Macroglobulinemia Includes Other Malignant and Non-Malignant IgM Secreting Entities, Including Frequent Cases of IgM Myeloma

MYD88 mutations are present in 95% of patients with Waldenstrom's Macroglobulinemia (WM), and permit diagnostic discrimination from other overlapping IgM-secreting B-cell malignancies. However, such diagnostic discrimination can often be difficult among suspected WM patients with wild-type MYD88 (MYD88WT), and can result in either diagnostic misclassification or mistreatment. We therefore examined a relatively large cohort of patients with suspected MYD88WT WM, and performed a systematic review of their clinical, pathologic and laboratory studies. Sixty-four patients with suspected MYD88 wild-type WM were identified. All had a monoclonal IgM protein, and bone marrow (BM) disease involvement. AS-PCR testing for MYD88 L265P mutation, and exclusion of non-L265P mutations by Sanger sequencing was performed to confirm MYD88WT status utilizing CD19-selected and unselected BM mononuclear cells (Xu et al, Blood 2013). WHO and WM consensus guidelines were used to establish clinicopathological diagnosis.Forty-six (71.8%) patients fulfilled WHO and WM consensus criteria for WM. Their median BM involvement was 37.5% (range 5-95%), serum IgM was 2,980 (range 160-9,000 mg/dL), and hemoglobin was 11 (range 4-15.5 g/dL). Sixteen (35%) and 13 (28%) had adenopathy and splenomegaly, respectively. Principal reasons for diagnosis included anemia (50%), and/or other cytopenias (13%), peripheral neuropathy (13%), adenopathy (8%), symptomatic hyperviscosity (5%), and renal failure (5%). At a median follow-up of 5.4 years, 31 (67%) patients required therapy. Notably, 7 (15.2%) MYD88WT patients were diagnosed with diffuse large B-cell lymphoma (DLBCL) during the follow-up period. Eleven (24%) patients died, 4 due to DLBCL transformation. Among the other MYD88WT patients, 7 (10.9%) had IgM multiple myeloma (IgM MM). Their median BM disease involvement was 60% (range 10%-80%), with a predominant plasma cell infiltrate. In 3(43%) patients, both clonal B-cells and plasma cells were detected, while clonal plasma cells alone were observed in the other 4 patients. FISH testing of BM mononuclear cells showed t(11;14) in 5 patients; t(14;16) in one patient; and normal cytogenetics in one patient. The median serum IgM level was significantly higher at 8,375 (range 2,530-12,000 mg/dL) versus MYD88WT WM patients (p=0.016). One (14%) patient had both adenopathy and splenomegaly. Principal reasons for diagnosis included anemia (100%), and symptomatic hyperviscosity (43%). With a median follow-up of 2.4 years, all patients required treatment and one died of myeloma. Findings consistent with marginal zone lymphoma (MZL) were observed in 6 (9%) patients. Their median BM involvement was 10% (range 5-25%), and three (50%) had detectable clonal B-cells by BM flow cytometry. Their median serum IgM level was 1,642 (95-2,800 mg/dL), and was not significantly different versus MYD88WT WM patients. Adenopathy and splenomegaly were present in 4 (67%) and 2 (33%) patients. With a median follow-up of 3.8 years, 4 (67%) required therapy, and all remain alive. For 3 (4.6%) patients, the findings favored a diagnosis of IgM MGUS with plasma cell infiltration. The median BM involvement for these patients was 5% (range 5-8%) with flow cytometry demonstrating clonal plasma cells. The median serum IgM level for these patients was 1,846 (range 1,262-2,390 mg/dL), and did not differ versus MYD88WT WM patients. With a median follow-up of 2.5 years, none progressed or received treatment, and are alive. In one patient, the findings favored the diagnosis of CLL while another patient had intravascular DLBCL. The serum IgM level was 1,822 and 355 mg/dL respectively. The BM disease burden was 5% in both patients. The CLL patient remains alive without treatment, while the patient with DLBCL required therapy and remains alive. No DLBCL transformation was observed among non-WM cases. Our findings show that up to 30% of suspected MYD88WT WM cases have an alternative clinicopathological diagnosis that includes both malignant and non-malignant entities. IgM MM was frequently present among suspected MYD88WT WM cases, and presented with very high serum IgM levels, symptomatic hyperviscosity and chr. 14 translocations. Patients with MYD88WT WM disease had a high incidence of DLBCL transformation that contributed to a third of deaths. The findings highlight the importance of diagnostic discrimination among suspected MYD88WT WM cases. DisclosuresTreon:Pharmacyclics: Consultancy, Research Funding. Castillo:Abbvie: Research Funding; Millennium: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding.

Long-Term Anti-Bacterial Immunity against Systemic Infection by Salmonella enterica Serovar Typhimurium Elicited by a GMMA-Based Vaccine.

Salmonella Typhimurium (STm) represents the most prevalent cause of invasive non-typhoidal Salmonella (iNTS) disease, and currently no licensed vaccine is available. In this work we characterized the long-term anti-bacterial immunity elicited by a STm vaccine based on Generalized Modules of Membrane Antigens (GMMA) delivering O:4,5 antigen, using a murine model of systemic infection. Subcutaneous immunization of mice with STmGMMA/Alhydrogel elicited rapid, high, and persistent antigen-specific serum IgG and IgM responses. The serum was bactericidal in vitro. O:4,5-specific IgG were also detected in fecal samples after immunization and positively correlated with IgG observed in intestinal washes. Long-lived plasma cells and O:4,5-specific memory B cells were detected in spleen and bone marrow. After systemic STm challenge, a significant reduction of bacterial load in blood, spleen, and liver, as well as a reduction of circulating neutrophils and G-CSF glycoprotein was observed in STmGMMA/Alhydrogel immunized mice compared to untreated animals. Taken together, these data support the development of a GMMA-based vaccine for prevention of iNTS disease.

Infection Related Immunoglobulin-M Antibodies Cross Reactive with Human Leucocyte Antigens

Objective: The first required feature for the patients, who will undergo allotransplantation, is HLA compatibility between donor and the recipient. In this study, it was aimed to indicate whether IgM antibodies that are produced during acute infection phase affect crossmatch tests or not, in addition to hitches that can occur in HLA incompatible transplants. Methods: Eighty-two patients with acute infection due to only one infectious agent and high serum IgM antibody levels were involved in this study. The patients had no alloimmunization (blood transfusion, pregnancy, and/or previous transplants). Fifty-five healthy individuals were used as HLA antigen source in order to evaluate Ab-Ag lymphocytotoxicity reactions. Results: The infectious agent distribution in the sera samples were as 25.6% Anti-Epstein-Barr virus capsid antigen (EBV VCA), 14.6% Anti-Cytomegalovirus (CMV), 17.1% Anti-Toxoplasma, 11% Anti-Hepatitis A Virus (HAV), 7.3% Anti-Rubella, 7.3% Anti-Varicella zoster virus (VZV), 4.9% Anti-Brucella, 3.7% Anti-Mumps, 2.97% Anti-Parvovirus B19, 1.9% Anti-Herpes simplex virus (HSV)-1, and 3.7% Anti-HBc. IgM antibody and HLA antigen reactions were analyzed by lymphocytotoxicity method in terasaki plates using peripheral blood lymphocytes of 55 healthy individuals. Conclusion: In lymphocytotoxicity test, the distribution of reactions that IgM antibodies gave to HLA antigens without class I-II differentiation according to infections were identified as 50% Brucella, 50% VZV, 44.4% HAV, 41.7% CMV, 42.9% EBV, 35.7% Toxoplasma, and 33.3% Rubella.

Cell Surface Proteins of B Cells and Plasmacells Are Differently Expressed in Waldenström’s Macroglobulinemia (WM) Patients Vs. Subjects with Monoclonal Gammopathy of Uncertain Significance (IgMMGUS) Vs. Healthy Donors

We performed gene expression profiling (GEP) of 36 patients with Waldenström's Macroglobulinemia (WM), 13 subjects with Monoclonal Gammopathy of Uncertain Significance (IgMMGUS), and 7 healthy subjects (CTRLs) by Affymetrix GeneChip Human Genome U133 Plus 2.0. GEP was performed on 36 WM bone marrow (BM) CD19+ cells vs. 10 IgMMGUS BM CD19+cells vs. 7 CTRLs BM CD19+ cells. We analyzed 32 WM BM CD138+ cells vs. 10 IgMMGUS BM CD138+ cells vs. 7 CTRLs BM CD138+ cells by microarray. Data was preprocessed and normalized using RMA and ComBat and analyzed using Statistical Analysis for Microarrays (SAM) on 3 groups and a false discovery rate threshold of 5%, followed by a pair-wise SAM test. We found 2038 and 29 unique genes in the comparison between WM, IgMMGUS and CRTLs in CD19+ and CD138+ cells, respectively. There were 16 differently expressed (DE) genes in common between the CD19+ and the CD138+ cells. Genes were grouped accordingly to the following patterns of differential expression: 1) WM&amp;gt;MGUS&amp;gt;CTRL, 2) WM&amp;lt;MGUS&amp;lt;CTRL, 3) WM&amp;gt;MGUS but MGUS&amp;lt;CTRL, 4) WM&amp;lt;MGUS but MGUS&amp;gt;CTRL (Tab.1). Functional enrichment analysis and annotation clustering (DAVID) were run on each pattern. We demonstrated gene expression changes between WM, IgMMGUS and CTRLs in genes encoding hematopoietic cell lineage markers. We showed thatIL2RA, CD1D,andCD44were over expressed in WM vs. IgMMGS, and WM vs. CTRLs.CD25expression characterizes Waldenström's clone (García-Sanz et. al. Best Pract Res Clin Haematol 2016). The over expression ofCD1Don WM B cells compared to IgMMGUS and CTRLs, suggests its possible role as a marker in WM as previously shown in B-cell chronic lymphoproliferative disorders (Kotsianidis et. al. Am J Clin Pathol 2011). We found thatCD44,encoding a glycoprotein over expressed in cancer stem cells, was up regulated in WM B cells compared to the same cell counterpart of IgMMGUS and CTRLs (Chen et. al. J Hematol Oncol 2018). Functional clustering identified several genes encoding cell adhesion molecules (CAM) which are expressed on the surface of B lymphocytes and are involved in the binding with other cells, immune response (T cells), and inflammation. Class I histocompatibility genesHLA-A, HLA-C, HLA-B, HLA-E,andHLA-Gwere over expressed in WM vs. IgMMGUS, and WM vs. CTRLs. Previous studies demonstrated the higher levels of HLA-Gs in WM and IgMMGUS compared to CTRL. Moreover, HLA-G could represent a marker of clonality since high levels of HLA-Gs were observed in both IgG and IgA MGUS and MM patients (Moreau et. al. EJH 2008). CNTNAP2andADAM23were down regulated in WM vs. CTRLs.CNTNAP2,encoding CASPR2 protein, is expressed in CNS and PNS and is involved in neurodevolpmental disorders and the autoimmune disease Sjogren's syndrome (SS) (Xiao Clin Rheumatol 2017). In addition, Caspr2 and ADAM23 take part in the peripheral neuropathy by controlling the activity of potassium channels in neurological autoimmune diseases (Saint-Martin et al. Eur J Neurosci 2018). We can speculate the role of both genes in WM patients with Sjogren's syndrome. VWF(von Willebrand factor),TFPI, andSERPINE1belonging to the complement and coagulation cascade were under expressed in WM vs. IgMMGUS. Notably, some authors have demonstrated that a low level of VWF was associated with high serum IgM levels and withCXCR4mutations in WM patients, and that response to treatment improves VWF in WM patients (Castillo et. al. BJH 2019). Genes encoding zinc finger proteins (ZNF) (n=120) were deregulated in the comparison between WM vs. IgMMGUS, and vs. CTRLS CD19+ cells in all patterns. We suggest the possible role of ZNF in the transcription regulation and cancer progression in the comparison between the 3 groups of subjects. Of note,ZNF804AandZNF215were upregulated in WM vs. IgMGUS and WM vs. CTRLs with high FC (Guerrera et. al. Haemat 2018). TJP1was under expressed in WM CD19+ and WM CD138+ cells. We noted very high FC in CD138+ cells: WM vs. IgMMGUS (FC=-2,65), and WM vs. CTRLs (FC=-6,18). HighTJP1expression in myeloma plasma cells was associated to a better and longer response to protease Inhibitors (PI) suggesting this gene as a biomarker to identify patients which can benefit from PI-based therapy (Zhang et. al. Cancer Cell 2016). Our findings demonstrate that B cells show different gene expression levels in membrane adhesion and cell lineage pathways in WM compared to IgMMGUS and CTRLs, suggesting the possible role of these genes in the progression of IgMMGUS to WM. Disclosures Tedeschi: AstraZeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen spa:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;BeiGene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Department of Hematology Niguarda Hospital Milano:Current Employment;Sunesis:Consultancy.Montillo:F. Hoffmann-La Roche:Honoraria, Research Funding;Astra Zeneca:Honoraria;AbbVie:Honoraria, Speakers Bureau;Janssen:Honoraria, Speakers Bureau;Verastem:Honoraria;Gilead:Honoraria, Speakers Bureau.

Associations between circulating levels of natural antibodies, total serum immunoglobulins, and polymorphonuclear leukocyte function in early postpartum dairy cows

The objective of this study was to investigate the associations between natural antibodies (NAbs) and total serum immunoglobulins (Igs) concentrations (both from IgG and IgM isotypes), with variables of polymorphonuclear leukocytes (PMN) function of dairy cows in the early postpartum period. Seventy-five healthy postpartum dairy cows at 2 ± 1 days in milk were enrolled in a cross-sectional study. Natural and total antibodies in serum samples were measured by ELISA. Flow cytometry was used to determine the phagocytosis and oxidative burst capacities of PMN and the quantification of the adhesion molecule l-selectin. Leukocyte count and differentials, and serum haptoglobin were also measured. A positive correlation between NAbsIgM and total serum IgM and between NAbsIgM and NAbsIgG were found. Before performing the associations between circulating Igs concentrations and PMN function variables, cows were categorized into having low, medium or high circulating antibodies based on their NAbs and total Igs serum concentrations. None of the PMN variables assessed differed between low, medium, and high cows for both NAbsIgM and NAbsIgG. While associations between PMNs function and total IgG were not observed, some associations between total IgM concentrations and PMN activity were found. Cows with high serum IgM had greater phagocytic activity compared to cows in the low IgM group. Finally, the proportion of PMN that performed oxidative burst and PMN surface expression of l-selectin intensity was greater in high total IgM group when compared to medium and low groups. In conclusion, association between NAbs, and PMN activity variables were not observed, but total serum IgM was associated to some PMN function variables in early post-partum dairy cows.

Oral Administration of Lactobacillus Casei Expressing Flagellin A Protein Confers Effective Protection against Aeromonas Veronii in Common Carp, Cyprinus Carpio.

Aeromonas veronii is a pathogen capable of infecting humans, livestock and aquatic animals, resulting in serious economic losses. In this study, two recombinant Lactobacillus casei expressing flagellin A (FlaA) of A. veronii, Lc-pPG-1-FlaA (surface-displayed) and Lc-pPG-2-FlaA (secretory) were constructed. The immune responses in fish administered with recombinant L. casei were evaluated. The two recombinant L. casei were orally administered to common carp, which stimulated high serum IgM and induced higher ACP, AKP, SOD and LYZ activity. Using qRT-PCR, the expression of IL-10, IL-8, IL-1β, TNF-α and IFN-γ in the tissue of fish immunized with recombinant L. casei was significantly (p < 0.05) upregulated, which indicated that recombinant L. casei could activate the innate immune system to trigger the cell immune response and inflammatory response. Furthermore, recombinant L. casei was able to survive the intestinal environment and colonize in intestine mucosal. The study showed that after being challenged by A. veronii, fish administered with Lc-pPG-1-FlaA (70%) and Lc-pPG-2-FlaA (50%) had higher survival rates compared to Lc-pPG and PBS, indicating that recombinant L. casei might prevent A. veronii infection by activating the immune system to trigger immune responses. We demonstrated that flagellin as an antigen of vaccine, is acceptable for preventing A. veronii infection in fish. The recombinant L. casei expressing FlaA may be a novel mucosal vaccine for treating and controlling A. veronii.

Deepening of Response after Completing Rituximab-Containing Primary Therapy in Patients with Waldenstrom Macroglobulinemia

Introduction: Rituximab-containing regimens are commonly used for primary therapy in patients with symptomatic Waldenstrom macroglobulinemia (WM), and response is defined by decrease in serum IgM levels. In previous studies, we and others observed that in certain WM patients completing rituximab-based primary therapy, serum IgM levels continued to decline following completion of therapy, deepening the response to therapy. To further clarify the frequency and clinical characteristics, we evaluated a large population of treatment naïve patients treated at our WM center with rituximab-containing regimens.Methods: Patients with a clinicopathological diagnosis of WM requiring therapy based on criteria from the 2ndInternational Workshop for WM (IWWM) who received a rituximab-containing regimen as primary therapy in the WM center at our institution from 2005 to 2016 were included. Responses were defined per criteria from the 6thIWWM. Findings were stratified based on patients having received, or not, maintenance therapy after induction therapy. We gathered pertinent clinical data, including responses at the end of induction, at the end of maintenance, and at the lowest serum IgM level after completion of induction and/or maintenance. Response deepening was defined as 25% decrease in serum IgM at any point after completion of therapy.Results: 179 patients met eligibility criteria for this study. Induction therapy consisted of bortezomib, dexamethasone and rituximab (BDR) (N=86; 48%); bendamustine and rituximab (Benda-R) (N=57; 32%); cyclophosphamide, dexamethasone and rituximab (CDR) (N=36; 20%). 117 (65%) patients received maintenance therapy. There were no differences in baseline characteristics for age, gender, serum IgM, hemoglobin level, bone marrow involvement, hemoglobin, platelet count, beta-2-microglobulin level, MYD88 and CXCR4 mutation status, time to therapy, regimen, and receipt of maintenance therapy vs. observation status. At baseline, median serum IgM levels for patients who received maintenance was 4,445 mg/dl (range 289-8,100 mg/dl) and for those who were observed was 4,400 mg/dl (range 155-10,020 mg/dl) (p=0.37). Following induction therapy, median serum IgM levels declined to 969 mg/dl (range 33-5,940 mg/dl) and 1,366 mg/dl (114-7,108 mg/dl) for patients who subsequently received maintenance or were observed (p<0.001 for each group versus baseline; p=0.11 for serum IgM comparisons post-induction between groups). Following maintenance, median serum IgM level declined to 528 mg/dl (range 10-5,410 mg/dl; p<0.001 compared to end of induction). Further declines in serum IgM post-maintenance occurred, with best post-maintenance serum IgM level of 384 mg/dl (range 9-4,759 mg/dl; p<0.001 compared with end of maintenance, with 72/117 (62%) patients experiencing a lower serum IgM level and 44/117 (38%) having at least a 25% decrease in serum IgM levels. Median time from end of maintenance to lowest IgM level was 1.6 years (0.1-7.9 years). For patients observed after induction therapy, the median best serum IgM level was 1,253 mg/dl (11-7,108 mg/dl; p=0.01 compared to end of induction), with 29/62 (47%) patients having a lower serum IgM level than at completion of induction, and 18/62 (29%) had at least a 25% decrease in serum IgM level. Median time from end of induction to lowest IgM level for those observed was 1.6 years (0.2-5.1 years). Categorical responses are shown in Figure. Importantly, when analyzing all patients, hemoglobin level <11.5 g/dl (OR 0.44, 95% CI 0.23-0.88; p=0.02), bone marrow involvement ≥50% (OR 0.49, 95% CI 0.26-0.93; p=0.03), presence of CXCR4 mutations (OR 0.33, 95% CI 0.13-0.87; p=0.03) and serum IgM level ≥4,000 mg/dl (OR 0.53, 95% CI 0.29-0.99; p=0.04) were associated with lower odds of response deepening after completing therapy.Conclusion: A third of WM patients who receive primary therapy with rituximab-containing regimens experienced deepening of response following completion of therapy, with a median time to best response of 1.6 years. High serum IgM levels and bone marrow burden, low hemoglobin levels, and presence of CXCR4 mutations at primary therapy initiation were associated with lower odds of response deepening. [Display omitted] DisclosuresCastillo:Genentech: Consultancy; Beigene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Hunter:Pharmacyclics: Consultancy. Treon:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Johnson & Johnson: Consultancy; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding.

An X-Linked Hyper-IgM Patient Followed Successfully for 23 Years without Hematopoietic Stem Cell Transplantation

When caring for patients with life-limiting diseases, improving survival and optimizing quality of life are the primary goals. For patients with X-linked hyper-IgM syndrome (XHIGM), the treatment modality has to be decided for a particular patient regarding hematopoietic stem cell transplantation or intravenous immunoglobulin replacement therapy with P. jiroveci prophylaxis. A seven-year-old male patient was admitted with recurrent upper and lower respiratory tract infections and recurrent otitis media. His initial immunologic evaluation revealed low IgG and normal IgA and IgM levels with normal lymphocyte phenotyping and inadequate specific antibody responses. He was diagnosed as common variable immunodeficiency and began to receive intravenous immunoglobulin (IVIG) (0.5 gm/kg) with four-week intervals. During follow-up for 23 years under IVIG therapy, he was extremely well and never had severe infections. In 2017, targeted next generation sequencing was performed in order to understand his molecular pathology. A previously described hemizygous c.31C>T(p.Arg11Ter) mutation was found in CD40LG gene. The mother was heterozygous carrier for this mutation and his sister did not have any mutation. Flow cytometric analysis for CD40LG expression on activated T cells showed highly decreased, but not absent, CD40LG expression. In conclusion, diagnostic delay is a clinical problem for patients with CD40LG deficiency, because of low or normal IgM levels, showing that all the hypogammaglobulinemic patients, not only with high serum IgM levels, but also with normal to low IgM levels, have to be examined for CD40LG expression on activated T lymphocytes. Secondly, type of CD40LG mutations leads to enormous interpatient variations regarding serum IgM levels, CD40LG levels on activated T cells, age at diagnosis, severity of clinical findings, and follow-up therapies with or without hematopoietic stem cell therapy.

Predictors of symptomatic hyperviscosity in Waldenström macroglobulinemia.

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.

Tubulointerstitial Nephritis with IgM-Positive Plasma Cells.

Infiltration by IgG-positive plasma cells is a common finding in tubulointerstitial nephritis. Indeed, it has been thought that CD138-positive mature plasma cells secrete mainly IgG, and the occurrence of tubulointerstitial nephritis with CD138-positive plasma cells secreting IgM has rarely been reported. Routine immunofluorescence of fresh frozen sections is considered the gold standard for detection of immune deposits. However, the immunoenzyme method with formalin-fixed, paraffin-embedded sections is superior for detecting IgM- or IgG-positive cells within the renal interstitium, thus histologic variants may often go undetected. We recently discovered a case of tubulointerstitial nephritis showing IgM-positive plasma cell accumulation within the interstitium. To further explore the morphologic and clinical features of such cases, we performed a nationwide search for patients with biopsy-proven tubulointerstitial nephritis and high serum IgM levels. We identified 13 patients with tubulointerstitial nephritis and IgM-positive plasma cell infiltration confirmed with the immunoenzyme method. The clinical findings for these patients included a high prevalence of distal renal tubular acidosis (100%), Fanconi syndrome (92%), and anti-mitochondrial antibodies (82%). The pathologic findings were interstitial nephritis with diffusely distributed CD3-positive T lymphocytes and colocalized IgM-positive plasma cells, as well as tubulitis with CD3-positive T lymphocytes in the proximal tubules and collecting ducts. Additionally, levels of H+-ATPase, H+, K+-ATPase, and the HCO3--Cl- anion exchanger were markedly decreased in the collecting ducts. We propose to designate this group of cases, which have a common histologic and clinical form, as IgM-positive plasma cell-tubulointerstitial nephritis.

Serum IgM level as predictor of symptomatic hyperviscosity in patients with Waldenström macroglobulinaemia.

Symptomatic hyperviscosity is a common clinical manifestation in patients with Waldenström macroglobulinaemia (WM) and high serum IgM levels. Prompt intervention is required to prevent catastrophic events, such as retinal or central nervous system bleeding. Identifying patients at high risk of symptomatic hyperviscosity might support the decision to treat asymptomatic patients before irreversible damage occurs. We carried out a large retrospective study in 825 newly diagnosed WM patients, of who 113 (14%) developed symptomatic hyperviscosity. The median serum IgM level at the time of symptomatic hyperviscosity was 61·8g/l (range 31-124g/l). Forty-four patients (36%) had symptomatic hyperviscosity at the time of WM diagnosis. A serum IgM level >60g/l at diagnosis was associated with a median time to symptomatic hyperviscosity of 3months, whereas the median time for patients with serum IgM level of 50·01-60g/l was approximately 3years. Adjusting for other clinical factors, the odds of developing symptomatic hyperviscosity were 370-fold higher with serum IgM levels >60g/l, and showed an association with CXCR4 mutational status. Symptomatic hyperviscosity did not impact overall survival (P=0·12). The findings support the use of serum IgM level >60g/l as a criterion for initiation of therapy in an otherwise asymptomatic WM patient.

The High Risk for Symptomatic Hyperviscosity in Patients with High Serum IgM Levels Can be Used to Support Initiation of Treatment in Waldenström Macroglobulinemia

Introduction: Hyperviscosity syndrome (HVS) is a clinical feature associated with Waldenström macroglobulinemia (WM). The overproduction of an IgM paraprotein can increase serum viscosity and induce signs and symptoms of HVS, prompting the need for WM-directed therapy. Current consensus panel guidelines recommend initiating treatment only for symptomatic HVS rather than a specified serum IgM level (Kyle et al, 2003). However, many clinicians treat for an elevated IgM in the absence of hyperviscosity-related findings to pre-empt HVS and any associated sequelae. Empiric treatment for WM patients with high serum IgM levels has been proposed as a reasonable criterion for treatment initiation regardless of symptomatic status due to the risk of HVS (Treon, 2015). We therefore sought to determine the serum IgM level threshold for which the risk of HVS would be supportive of treatment initiation.Methods: We identified 825 untreated patients who met the consensus diagnosis for WM (Owen et al, 2003), and who received care in the WM clinic at our Institution between January 1999 and June 2016. The occurrence of symptomatic HVS was then determined, and serum IgM levels at the time of HVS diagnosis were stratified. For patients with an IgM >=3,000 mg/dL, a stratified hazard analysis was performed to compare the risk of HVS associated with increasing serum IgM levels. The outcome of interest was hazard ratio (HR) with 95% confidence interval (CI). P-values <0.05 were considered statistically significant.Results: Among 825 untreated patients, 112 (14%) cases of HVS were identified. The incidence of HVS in patients with serum IgM levels between 3000-3999, 4000-4999, 5000-5999, 6000-6999 and >=7000 mg/dl was 3%, 22%, 30%, 61% and 79%, respectively. The HR of HVS in patients with serum IgM levels 4000-4999, 5000-5999, 6000-6999 and >=7000 mg/dl was 7.5 (95% CI 3.4-16.8), 9.8 (95% CI 4.7-20.4), 28.2 (95% CI 13.2-60.3) and 26.8 (95% CI 12.5-57.7), respectively (IgM 3000-3999 was baseline; Figure 1A). When compared to patients with a serum IgM 3,000-5,999 mg/dL, patients with a serum IgM >=6,000 mg/dL had a 4.9-fold increased risk for development of HVS (HR 4.87, 95% CI 3.06-7.56; Figure 1B). No symptomatic HVS was observed among patients with a serum IgM <3,000 mg/dL. HVS patients with a serum IgM level >=6,000 mg/dL were significantly more anemic and thrombocytopenic, as well as more likely to have a serum B2M >3.0 mg/dL. HVS patients with a serum IgM >=6,000 mg/dL were also more likely to receive emergent plasmapheresis versus those HVS patients with a serum IgM 3,000-5,999 mg/dL (77% vs. 58%; p=0.04). All but one patient received WM-directed intervention in response to symptomatic HVS; one patient refused treatment.Conclusion: Patients with a serum IgM >=6,000 mg/dL are at a significantly increased risk for developing symptomatic HVS. Given the magnitude of the risk increase described herein for symptomatic HVS, a serum IgM >=6,000 mg/dL may reasonably be considered as a criterion for initiation of WM-directed therapy. [Display omitted] DisclosuresGhobrial:Amgen: Honoraria; Noxxon: Honoraria; BMS: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria. Castillo:Otsuka: Consultancy; Abbvie: Research Funding; Biogen: Consultancy; Janssen: Honoraria; Millennium: Research Funding; Pharmacyclics: Honoraria.

Waldenström Macroglobulinemia

Waldenström’s macroglobulinemia (WM) is a B-cell neoplasm manifested by the accumulation of clonal IgM secreting lymphoplasmacytic cells. MYD88 and CXCR4 WHIM-like somatic mutations are present in >90%, and 30-35% of WM patients, respectively, and impact disease presentation, treatment outcome, and/or overall survival. Familial predisposition is common in WM. Asymptomatic patients should be observed. Patients with disease related hemoglobin <10g/L, platelets <100x109/L, bulky adenopathy and/or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease or transformed disease should be considered for therapy. Plasmapheresis should be used for patients with symptomatic hyperviscosity, and pre-rituximab for those with high serum IgM levels to pre-empt a symptomatic IgM flare. Treatment choice should take into account specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, immunosuppression and secondary malignancies, and planning for future autologous stem cell transplantation. Frontline treatments include rituximab alone, or combined with alkylators (bendamustine, cyclophosphamide), proteasome-inhibitors (bortezomib, carfilzomib), nucleoside-analogues (fludarabine, cladribine) and ibrutinib. In the salvage setting, an alternative frontline regimen, ibrutinib, everolimus, or stem cell transplantation can be considered. Investigational therapies under development for WM include agents that target MYD88, CXCR4, BCL2, and CD27/CD70 signaling, novel proteasome inhibitors, and chimeric antigen receptor modified T-cell therapy.

How I treat Waldenström macroglobulinemia

AbstractWaldenström macroglobulinemia (WM) is a B-cell neoplasm manifested by the accumulation of clonal immunoglobulin (Ig)M-secreting lymphoplasmacytic cells. MYD88 and CXCR4 warts, hypogammaglobulinemia, infections, myelokathexis syndrome-like somatic mutations are present in >90% and 30% to 35% of WM patients, respectively, and impact disease presentation, treatment outcome, and overall survival. Familial predisposition is common in WM. Asymptomatic patients should be observed. Patients with disease-related hemoglobin <10 g/L, platelets <100 × 109/L, bulky adenopathy and/or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or transformed disease should be considered for therapy. Plasmapheresis should be used for patients with symptomatic hyperviscosity and before rituximab for those with high serum IgM levels to preempt a symptomatic IgM flare. Treatment choice should take into account specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, immunosuppression and secondary malignancies, and planning for future autologous stem cell transplantation. Frontline treatments include rituximab alone or rituximab combined with alkylators (bendamustine and cyclophosphamide), proteasome inhibitors (bortezomib and carfilzomib), nucleoside analogs (fludarabine and cladribine), and ibrutinib. In the salvage setting, an alternative frontline regimen, ibrutinib, everolimus, or stem cell transplantation can be considered. Investigational therapies under development for WM include agents that target MYD88, CXCR4, BCL2, and CD27/CD70 signaling, novel proteasome inhibitors, and chimeric antigen receptor-modified T-cell therapy.

Disseminated Gastric MALT Lymphoma with Monoclonal Gammopathy, t(11;18)(q21;q21), and Subsequent Development of T-Large Granular Lymphocytic Leukemia: A Case Report and Review of the Literature.

Background. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is a well-characterized entity that may share clinical and morphological findings with other low-grade non-Hodgkin's lymphomas. Dissemination of MALT-type lymphoma to bone marrow and peripheral blood simultaneously with the presence of T-large granular cell leukemia (T-LGL) has rarely been reported. Case Presentation. This is the case of a 42-year-old male who presented with a gastric MALT-type lymphoma, disseminated to the bone marrow and the peripheral blood with high serum IgM levels and t(11;18)(q21;q21). The morphological, immunophenotypical and, immunohistochemical studies of the successive bone marrow and peripheral blood samples had revealed the coexistence of two distinct lymphoma cell populations: a B-cell, marginal zone type population expressing CD19, CD20, CD22, CD79b, IgM, and kappa light chain, and a T-large granular cell population, developed after treatment with rituximab expressing CD3, CD8, CD5, CD7, and CD45. Conclusion. Based on the analysis of this unusual case we performed an extensive review of the literature to elucidate the relationship between T-LGL and B-cell lymphomas and to emphasize the importance of paraprotein analysis at diagnosis of gastric MALT lymphoma.

Clinical characteristics of angioedema with eosinophilia.

Angioedema with eosinophilia (AE) is a very rare allergy disease, case reports of which have been published sporadically since 1984. Here, we retrospectively analyzed the clinical features of 10 AE patients in Korea. Nine of the 10 subjects were young females, ranging from 23 to 38 years old. Twenty percent of the subjects had episodic-type AE with high serum IgM and eosinophil counts, while 80% were non-episodic type with normal serum IgM levels but high eosinophil counts. All patients had used systemic corticosteroids to control AE. One patient with refractory episodic-type AE was treated with anti-IgE antibody. This is the first study to evaluate the clinical characteristics of AE in a Korean population.