Lymphoplasmacytic Bone Marrow Infiltration Research Articles

Novel Approaches to Managing Patients with Relapsed and Refractory Waldenström Macroglobulinemia.

Waldenström macroglobulinemia is a rare non-Hodgkin lymphoma (NHL) characterized by lymphoplasmacytic bone marrow infiltration associated with an immunoglobulin M (IgM) monoclonal gammopathy. Over the past two decades, a number of important novel therapies have emerged for the treatment of relapsed and refractory (R/R) WM. The purpose of this review is to discuss these novel agents. Chemoimmunotherapy which formed the basis treatment for R/R WM is slowly being replaced by novel targeted agents. These therapies, including Bruton's tyrosine kinase inhibitors, proteasome inhibitors, and B-cell lymphoma 2 inhibitors, have widened the landscape of management. Emerging therapies currently under investigation, such as bispecific T-cell engagers, chimeric antigen T-cell receptor therapy, and novel small molecule inhibitors, have additionally shown the potential to improve response and survival. The treatment of R/R WM has greatly evolved, in large part due to a greater understanding of the biology of WM, and the evaluation of novel targeted agents in the basket trials of NHL, showing early activity in the small WM cohorts. Combination regimens with these established and emerging novel therapies have the potential to further improve disease control and induce higher rates of deep responses. Strategies aimed at altering the disease trajectory would require randomized controlled trials to provide relevant data on optimal integration and sequencing of more effective and tolerable regimens earlier in the disease course.

Long-term Survival in a Patient With Transformation of Waldenström's Macroglobulinemia into DLBCL.

Waldenström's macroglobulinemia (WM) is a rare slow-growing B-cell lymphoma that is characterized by lymphoplasmacytic bone marrow infiltration and the production of monoclonal immunoglobulin M (IgM) paraprotein. In 5-10% of patients, WM undergoes transformation into diffuse large B-cell lymphoma (DLBCL), which is more aggressive, with poor prognosis and a low survival rate. Α 69-year-old woman was diagnosed with WM in 2009. She received six cycles of chemoimmunotherapy and a remarkable remission was achieved. However, in 2013 the disease transformed into DLBCL. The patient received chemotherapy and after the completion of the first cycle of therapy, the disease was significantly minimized. At the end of the therapy, there was no evidence of disease, and the patient remains disease-free. The cytogenetic profile of the patient did not reveal expression of BCL2 apoptosis regulator, BCL6 transcription repressor, Epstein-Barr virus small RNA, syndecan 1 nor cyclin D1. According to a staging system based on the platelet count, lactate dehydrogenase and previous treatment for WM, the described patient was classified as being at intermediate risk with an expected 2-year survival probability of 47% after WM transformation into DLBCL. However, the patient unexpectedly exceeded these prognostic indications. The findings for this patient are of great interest compared with the existing literature which suggests that the survival and prognosis for patients with transformed DLBCL are not favorable.

Multicenter Prospective Phase II Study of Rituximab Combined, Bortezomib, Lenalidomide, Dexamethasone Followed By Lenalidomide Maintenance (R-VRD) in Patients with Waldenstrom's Macroglobulinemia (KMM1803)

Backgroud: Waldenström macroglobulinemia (WM) is an indolent B-cell malignancy characterized by the presence of immunoglobulin M (IgM) monoclonal gammopathy and lymphoplasmacytic bone marrow infiltration. Recently, the superior efficacy of BTK inhibitors and other novel agents has been established. However, BTK inhibitors has been shown limited efficacy in patients with CXCR4 mutation and MYD88 wild type. Therefore, the importance of chemotherapy which do not contain BTK inhibitors still remain. This study was conducted to estimate the efficacy and safety of the combination of rituximab, bortezomib, lenalidomide and dexamethasone in patients with WM in South Korea. Methods : Between Aug. 2018 and Aug. 2022, a total of 39 patients were included in this study at 12 academic institutes in South Korea. The primary end-point of the study was the median progression-free survival (PFS), and the secondary end-points were the overall survival (OS), overall response rate (ORR), minimal residual disease (MRD) achievement and toxicities. Eligible patients were confirmed clinicopathological diagnosis of WM who has Measurable and symptomatic disease meeting at least 1 of the recommendations from the Second International Workshop on Waldenström Macroglobulinemia (IMWWM) for requiring treatment. Pateints who received rituximab treatment within the last 12 months before the first dose of study drug were excluded. Patients received the 28-day cycle of Rituximab (375 mg/m 2 IV on day 1), Bortezomib (1.3 mg/m 2 SC on day 1, 8, 15), Lenalidomide (15 mg per oral day 1-21) and dexamethasone (20 mg iv or oral day 1-4). Enrolled patients were received induction therapy with rituximab and bortezomib, lenalidomide and dexamethasone every 4 weeks for 6 cycles and then lenalidomide (10 mg on day 1-21) maintenance for 2 years. All patients were checked MYD88 and CXCR4 mutation at the baseline work up of this study and MRD achievement was checked by MYD88 PCR every 6 months for 3 years. Results : The median (range) age was 65.2 years. Lymphadenopathy were noted around 50%. In this study, MYD88 mutation was noted 74.3% and CXCR4 mutation was noted 20%, respectively. The response rates were following: CR in 4 (13.3%), VGPR in 3 (10.0 %) PR in14 (46.7 %), MR in 3 (10.0%) and < MR in 6 (20.0 %). Overall response rates (≥PR (partial response)) rate was 70.0 % and more than MR were 80%. 2yrs PFS and OS were 56% and 93%, respectively. We are now checking MRD by MYD88 PCR for ongoing patients. The detailed response rates and survival outcomes will be reported soon according to MYD88 and CXCR4 mutation status. And comparison of survival difference according to MRD negativity will be also announced after finishing data collection of MRD. Conclusions: R-VRD regiment could be helpful for MYD88 mutation negative or CXCR4 mutation positive patients. BTK inhibitors show superior response and survival outcomes for patients with MYD88 mutation positive and CXCR4 mutation negative. So, we are supposed that R-VRD could be optional treatment for patients who are not suitable for BTK inhibitors.

IgM monoclonal gammopathies of clinical significance: diagnosis and management.

IgM monoclonal gammopathy of undetermined significance is a pre-malignant condition for Waldenström macroglobulinemia and other B-cell malignancies, defined by asymptomatic circulating IgM monoclonal protein below 30 g/L with a lymphoplasmacytic bone marrow infiltration of less than 10%. A significant proportion, however, develop unique immunological and biochemical manifestations related to the monoclonal protein itself in the absence of overt malignancy and are termed IgM-related disorders or, more recently, monoclonal gammopathy of clinical significance. The indication for treatment in affected patients is dictated by the pathological characteristics of the circulating IgM rather than the tumor itself. The clinical workup and treatment options vary widely and differ from those for Waldenström macroglobulinemia. The aim of this review is to alert clinicians to IgM monoclonal gammopathy of clinical significance and to provide practical guidance on when to screen for these phenotypes. We discuss clinical characteristics, the underlying clonal profile, diagnostic workup and treatment considerations for five important subtypes: cold agglutinin disease, type I and II cryoglobulinemia, IgM-associated peripheral neuropathy, Schnitzler syndrome and IgM-associated AL amyloidosis. The inhibition of the pathogenic effects of the IgM has led to great success in cold agglutinin disease and Schnitzler syndrome, whereas the other treatments are centered on eradicating the underlying clone. Treatment approaches in cryoglobulinemia and IgM-associated peripheral neuropathy are the least well developed. A multidisciplinary approach is required, particularly for IgM-related neuropathies and Schnitzler syndrome. Future work exploring novel, clone-directed agents and pathogenic IgM-directed therapies is welcomed.

Inflammatory Waldenström's macroglobulinaemia: A French monocentric retrospective study of 67 patients.

Waldenström's macroglobulinaemia (WM) is a B-cell neoplasm resulting from bone marrow lymphoplasmacytic infiltration and monoclonal IgM secretion. Some patients present concomitant inflammatory syndrome attributed to the disease activity; we named this syndrome inflammatory WM (IWM). We retrospectively analysed all WM patients seen in a single tertiary referral centre from January 2007 to May 2021, and after excluding aetiologies for the inflammatory syndrome using a pertinent blood workup, including C-reactive protein (CRP), and imaging, we identified 67 (28%) IWM, 166 (68%) non-IWM, and nine (4%) WM with inflammatory syndrome of unknown origin. At treatment initiation, IWM patients had more severe anaemia (median Hb 90 vs 99g/l; p<0.01), higher platelet count (median 245 vs 196×109/l; p<0.01) and comparable serum IgM level (median 24.9 vs 23.0g/l; p=0.28). A positive correlation was found between inflammatory and haematological responses (minimal response or better) (odds ratio 32.08; 95% confidence interval 8.80-98.03; p<0.001). Overall survivals (OS) were similar (median OS: 17 vs 20years; p=0.11) but time to next treatment (TNT) was significantly shorter for IWM (TNT1: 1.6 vs 4.8years, p<0.0001). IWM mostly shared the same presentation and outcome as WM without inflammatory syndrome.

Natural History and Outcomes of Asymptomatic IgM Monoclonal Gammopathy

Waldenström's macroglobulinemia (WM) is a distinct clinical entity defined by the presence of a serum monoclonal IgM and bone marrow (BM) infiltration of ≥10% lymphoplasmacytic cells. Asymptomatic (smoldering) WM (aWM) is defined by the presence of serum IgM ≥3 g/dL and/or ≥10% BM lymphoplasmacytic infiltration but no evidence of end-organ damage (symptomatic anemia/cytopenias, constitutional symptoms, lymphadenopathy, hepatosplenomegaly or IgM-related symptoms such as hyperviscosity, severe neuropathy etc) that can be attributed to the underlying clonal disorder (Kyle et al; Blood 2012). IgM monoclonal gammopathy of undetermined gammopathy (MGUS) is defined by the presence of a monoclonal IgM of <3 g/dL, <10% of clonal lymphoplasmacytic cells in the BM and the absence of symptoms related to the underlying clonal disorder or monoclonal IgM. Herein, we report the outcomes of IgM MGUS and aWM in a well-defined cohort of 103 consecutive subjects with asymptomatic IgM monoclonal gammopathy.All patients were diagnosed and followed in the Department of Clinical Therapeutics (Athens, Greece) since 1995 and had BM biopsies available. Patients who presented with IgM-related complications (neuropathy, Schnitzler syndrome, IgM related amyloidosis etc) were not included. At the time of diagnosis of the IgM gammopathy, median age of all subjects was 71 years (range 25-86), 76% had IgMκ and 24% IgMλ; only one had a biclonal gammopathy (IgM and IgG). Median IgM was 1024 mg/dL (range 104 - 5320) and the monoclonal spike in the SPEP was 0.84 g/dL (ranging <0.1-4.35) and only 3% had M-monoclonal protein ≥3 g/dl. Median hemoglobin was 12.8 gr/dl, median platelet counts was 271 x 109/L (range 104-499), median peripheral blood lymphocytes 1850/uL (range 220 - 5620) and median β2-microglobulin (β2M) was 2 mg/L (range 1.1-16.8). Among 71 patients with available free light chains at the time of initial diagnosis, 44 (63%) had abnormal FLC ratio. The median clonal cell BM infiltration was 20% (range 0-90%) and there was an association of serum IgM levels and extent of clonal cell infiltration (r=0.416, p<0.001). Immunoparesis (low levels of non-involved immunoglobulins) was present in 32% of the subjects; 22% hag low IgG, 28% low IgA and 18% had both IgG and IgA suppressed.According to the definition by Kyle et al, 62 (61%) subjects had aWM and 41 (39%) IgM MGUS. Patients with aWM had higher M-protein (median 1.24 vs 0.55 g/dL) and more often monoclonal protein ≥1 g/dl (58% vs 13%, p<0.001) so that 42% of patients with <1 g/dL of monoclonal IgM had ≥10% clonal lymphoplasmacytic cells. There were no differences in other characteristics such as gender, age, hemoglobin levels or β2M. Median follow up of the whole cohort is 5 years (range 1-21); 15 (14%) patients have progressed to develop symptomatic disease and 8 (7%) have died without developing symptomatic disease. For patients with aWM the respective rate of PD to symptomatic disease and of unrelated death was 20% and 3% at 2 years and 39% and 8% at 5 years respectively. For those with IgM MGUS the PD rate and unrelated death rates were 0% and 3% at 2 years and 3% and 7% at 5 years. Thus, aWM was associated with a 7-fold increase of risk of progression to symptomatic disease compared to IgM MGUS (95% CI 3-27, p=0.001). Symptoms defining progression included peripheral neuropathy in 4 patients, B-symptoms in 5, anemia (<10 g/dl) in 8 and organomegaly (splenomegaly and lymphadenopathy) in two. The overall survival for all patients is 91% at 5 years, similar for IgM MGUS and aWM. In patients with aWM, hemoglobin <12 g/dl (p=0.004) and BM clonal cells ≥50% (p=0.04) were associated with higher risk of progression but not IgM levels or abnormal FLCs ratio or the presence of immunoparesis. In multivariate analysis, hemoglobin <12 g/dl (p=0.016) and BM clonal cells ≥50% (p=0.051) were independently associated with shorter time to PD.In conclusion, patients with aWM should be followed without treatment unless symptoms develop. Bone marrow infiltration ≥50% and a hemoglobin <12 g/dL are the major risk factors for progression to symptomatic disease. For those with IgM MGUS the risk of progression is low but they should be evaluated periodically for the development of symptoms related to the underlying dyscrasia. Because 42% of patients with monoclonal IgM <1 g/dL had ≥10% lymphoplasmacytic cells, bone marrow biopsy is indicated in all patients. [Display omitted] DisclosuresKastritis:Amgen: Research Funding; Takeda: Honoraria; Genesis: Honoraria; Janssen: Honoraria, Research Funding. Terpos:Genesis/Celgene: Honoraria, Other: DMC member, Research Funding; BMS: Honoraria; GSK: Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Other: SC member; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Other: SC member, Research Funding. Dimopoulos:Novartis: Consultancy, Honoraria; Genesis Pharma: Research Funding; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology.

Defining an Ultra-Low Risk Group in Asymptomatic IgM Monoclonal Gammopathy.

Simple SummaryPatients with asymptomatic IgM monoclonal gammopathies include IgM monoclonal gammopathy of undetermined significance (IgM MGUS) and smoldering Waldenström macroglobulinemia (SWM), all with some risk of progression to symptomatic Waldenström macroglobulinemia, amyloidosis, or other lymphoproliferative disorder. Due to their low incidence, few studies have focused on the risk of progression, with SWM being the most studied. As both are recognized clinical-pathological entities that share similar clonal and phenotypical features, we focus on defining new biomarkers of progression in this population with long follow-up.We analyzed 171 patients with asymptomatic IgM monoclonal gammopathies (64 with IgM monoclonal gammopathy of undetermined significance—MGUS and 107 with smoldering Waldenström macroglobulinemia - SWM) who had a bone marrow (BM) evaluation performed at diagnosis. Abnormal free-light chain ratio (53% vs. 31%) and MYD88 mutation prevalence (66% vs. 30%) were higher in patients with SWM. No other differences were found among groups. With a median follow-up of 4.3 years, 14 patients progressed to Waldenström macroglobulinemia, 1 to amyloidosis, and 28 died without progression. The MYD88 mutation was found in 53% of patients (available in 160 patients). Multivariate analysis showed that immunoparesis (subhazard ratio—SHR 10.2, 95% confidence interval—CI: 4.2–24.8; p < 0.001) and BM lymphoplasmacytic infiltration ≥ 20% (SHR: 6, 95% CI: 1.6–22.1; p = 0.007) were associated with higher risk of progression. We developed a risk model based on these two risk factors. In the absence of both variables, an ultra-low risk group was identified (SHR 0.1, 95% CI 0.02–0.5; p = 0.004), with 3% and 6% of cumulative incidence of progression at 10 and 20 years, respectively. Bootstrap analysis confirmed the reproducibility of these results. This study finds immunoparesis and BM infiltration as biomarkers of progression as well as a low-risk group of progression in asymptomatic IgM monoclonal gammopathies.

A Systematic Review on Efficacy and Safety of Bortezomib Based Regimens for Treatment of Waldensterom Macroglobulinemia

Introduction: Waldenström macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by lymphoplasmacytic bone marrow infiltration and immunoglobulin M (IgM) monoclonal gammopathy. Various studies have shown that the proteasome inhibitor bortezomib (V) targets signaling pathways of relevance in WM. We reported published data on the efficacy profile of (V) for the patients of WM. Methods: We performed a comprehensive literature search on articles following PRISMA guidelines. Beginning with articles published after 2004, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library and Web of Science. Total 580 articles were identified initially and after detailed screening, we finalized 9 studies involving 375 patients with Waldenstrom Macroglobulinemia (WM) treated by combination of Bortezomib. Results: The total number of patients in the studies involving Bortezomib were 375 and dose of the drug used ranged between 1.3 mg/m2 to 1.6mg/m2. The Complete response (CR) ranged from 0-19% and the partial response (PR) ranged from 44-58%. Bortezomib(V): In the study Treonet et al., N=27, the highest major respose rate was 85% and minimal response rate was 37%. In the study Chen et al., N=27, the major response rate was 26% and the PR was 44%. Progression free survival (PFS) was 16.3 months for Chen et al. Bortezomib(V), Rituximab(R), and Dexamethasone(D): In the study Treon et al., N=23, the highest major response rate was 96%, CR was 13%, Very good partial response (VGPR) was 13%, and PR was 46%. Highest PR and was observed in Dimopolous et al., which was 58% and 42 months respectively. Bortezomib(V), and Rituximab(R): In the study Agathocleus et al., N=42, the highest CR was 14.2-19%. The highest PR was between 47.6-52.3%. In the study Ghobrial et al., N=37, the CR was 3% and PR was 46%. PFS was 15.6 months. Bortezomib(V), Rituximab(R) and Everolimus(E): In the study Ghobrial et al., N=46, the CR was 4%, PR was 46% and PFS was 18 months. Conclusion: Despite heterogenicity in WM patients and various regimens used in literature, Bortezomib containing regimens are a remarkably effective treatment. Combination regimens showed an overall response rate of 96%. The main side effects being anemia, leukopenia, thrombocytopenia, nausea and sensory neuropathies. Although we recommend future randomized prospective trials to better understand the efficacy and safety profile of Bortezomib for WM treatment. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

IBCL-019: Waldenström Macroglobulinemia (WM) in a Public Health Service in Sao Paulo, Brazil

Context: WM is a rare indolent non-Hodgkin lymphoma that mainly affects people over 60 years old. It is characterized by lymphoplasmacytic cells bone marrow infiltration and IgM gammopathy. Patients have asthenia, weight loss, mucosal bleeding, lymph node enlargement, splenomegaly and neurological changes resulting from hyperviscosity and/or cytopenias. Treatment goal is to relieve symptoms. Recently, targeted drugs have been used, which may increase its median overall survival in the next years. Notwithstanding these drugs are not equally available around the world. Objective: To recognize clinical, epidemiological profile and treatment evaluation of WM patients at Santa Casa de Sao Paulo, Brazil. Design: WM retrospective analysis cohort diagnosed between January 1, 2000 and December 31, 2016. Patients or other participants: We analyzed patients with WM diagnosis. HIV, HBV, and HCV positive serology patients were excluded. Results: There were 18 patients, 10 men/8 women, with 61 years old median age. Fifteen patients presented with splenomegaly; 14 had B symptoms at diagnosis. Median serum IgM was 3019 mg/dL; 8 patients were submitted to plasmapheresis because of symptomatic hyperviscosity syndrome. 70% were classified as High/Very-high risk and all patients were treated upfront. As 1st line treatment we used alkylant + prednisone in 12 patients; alkylant + prednisone + anthracycline in 3 patients; fludarabine in 2 patients and to 1 patient only prednisone. Less than 25% got CR/VGPR; 5.5% got PR and 72% were refractory. There were 2 deaths before 2nd line treatment for which we used fludarabine-based therapy in 9, alkylant + prednisone + anthracycline in 2 and alkylant + prednisone in 1 patient. Ten patients were dead before 3rd line therapy. Mean OS was 55 months. Hb under 9.5 g/dl and platelets under 120×103mm3 had statistically significant worse median OS. Conclusions: Our Waldenstrom macroglobulinemia cohort showed poor response to 1st line chemotherapy regimens. IPSS-WM showed that they arrive in severe clinical conditions making it a challenging treatment. The absence of new available target drugs might have resulted in bad 1st line response and a high relapse rate.

Natural History of Asymptomatic IgM Monoclonal Gammopathies: Impact of the Bone Marrow Aspiration into the Classification and Prognosis

Introduction: As in multiple myeloma, Waldenström macroglobulinemia (WM) is preceded by an asymptomatic phase, mainly as monoclonal gammopathy of undetermined significance (MGUS) or by a smoldering WM (SWM) phase. It has recently been reported that patients with IgM MGUS have a higher risk of progression in comparison to those with other MGUS isotypes. Moreover, it has been described that if the IgM MGUS is associated with adverse factors such as abnormal serum free light chains ratio and more than 15 g /L serum M-spike, the risk of progression at 20 years is as high as 55%. The aim of this study was to evaluate the risk of progression of asymptomatic IgM monoclonal gammopathies, using bone marrow aspiration as the main criteria for classification between SWM and IgM MGUS.Methods: We reviewed retrospectively the medical records of 206 patients with asymptomatic IgM monoclonal gammopathies, 143 (69.4%) with IgM MGUS and 63 (30.6%) with SWM diagnosed in our institution from May 1982 to December 2017. In the absence of clinical manifestations, IgM MGUS was defined as the presence of less than 30 g/L of serum IgM monoclonal protein and less than 10% lymphoplasmacytic bone marrow (BM) infiltration. The diagnosis of SWM required the presence of any size IgM M spike associated with ≥10% lymphoplasmacytic bone marrow infiltration with no target organ involvement, constitutional symptoms, hyperviscosity, lymphadenopathies or peripheral neuropathy. Progression to WM was defined according to the 2014 International Consensus.Results: The median age of the series was 70 years (range, 29 to 98) and the male/female distribution was 106/100. SWM group had a significantly higher median serum M spike than the MGUS group (9.2 vs. 4.6 g/L; p<0.001) as well as slightly higher serum IgM levels (median 12.6 g/L vs. 11 g/L, p< 0.001). We did not find differences either in the β2-microglobulin or albumin values between the two groups. IgG and IgA immunoparesis (low uninvolved immunoglobulin level) was similar between patients with IgM MGUS and SWM. MYD88 L265P presence was determined in 125 patients, being positive in 85% of the SWM cases compared to 34% in the IgM MGUS group (p < 0.001).Only 6 (2.9%) of the patients had more than 30 g/L of serum M protein. For this reason, diagnosis of SWM was mainly based on results of BM aspiration. Median BM infiltration by plasma cells and lymphocytes was significantly higher in patients with SWM when compared to patients with MGUS (4 vs. 3%, p=0.027; 24 vs. 9%, p < 0.001, respectively), being the lymphocyte infiltration the most relevant difference. Thus, serum M protein correlated significantly with BM lymphocyte percentage (p=0.011) but not reaching significance when plasma cell infiltration (p=0.071) was analyzed.Median time of follow up was of 3.3 years for living patients. The evolving pattern of the M-spike was identified in 21 patients (10.2%). This paraprotein behavior was associated with a shorter progression to symptomatic WM (p=0.026), but mainly due to its higher frequency in the SWM group than in the MGUS one (19% vs. 6.3%, p=0.005).Diagnosis of SWM impacted negatively the prognosis of the patients, with a higher rate of progression to symptomatic disease at 3 years (15% vs. 2%). Thus, the risk of progression of SWM was 11 times greater than those with IgM MGUS (HR 11.7, p < 0.001; 95% CI 3.3-41.3) (Figure 1). There was also a significant difference on survival between both groups of patients (median overall survival 20 vs. 13 years; p=0.027).Conclusions: In our series, the progression rate from IgM MGUS to symptomatic WM was clearly inferior to that reported in other historical series and quite similar to the progression rate of IgG MGUS (1% per year), being also significantly higher for patients with SWM. Evolving pattern is rare in IgM MGUS but it was identified in 19% of patients with SWM. These findings suggest that bone marrow evaluation is crucial in the prognosis of asymptomatic IgM monoclonal gammopathies. [Display omitted] DisclosuresRosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Bladé:Janssen: Honoraria.

Effect of sebelipase alfa on survival to 3 years of age and liver function in infants with rapidly progressive lysosomal acid lipase deficiency: Results from two studies

Waldenström macroglobulinemia (WM) is a distinct hematologic malignancy characterized by a lymphoplasmacytic bone marrow infiltration and the presence of immunoglobulin (Ig)M monoclonal protein. Patients typically present at an advanced age, and a substantial proportion are asymptomatic at diagnosis. A unifying diagnosis of WM may be missed by an unsuspecting hematologist, as symptomatic patients present with a multitude of non-specific manifestations. Although constitutional and neuropathy-related symptoms predominate, concomitant IgM-induced hyperviscosity-associated features can provide useful diagnostic clues. There are specific indications for initiation of therapy. This review focuses on the most up-to-date management strategies of WM, in addition to highlighting the recent discoveries of MYD88 and CXCR4 mutations that have shed unprecedented light on the complex signaling pathways, and opened avenues for novel therapeutic targeting. Although WM remains incurable, with the rapid emergence and integration of effective novel therapies, its clinical course appears poised to improve in the foreseeable future.

Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation.Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006).Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented.Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. DisclosuresThomas:Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

Waldenström's macroglobulinemia

Waldenström macroglobulinemia (WM) is a rare and incurable B-cell neoplasm characterized by lymphoplasmacytic bone marrow infiltration and the production of serum monoclonal immunoglobulin M. Therapeutic strategies for WM should be based on individual patient and disease characteristics, including age, suitability as a candidate for autologous stem cell transplantation, hyperviscosity, and comorbidities. Rituximab forms the backbone of most regimens owing to its high efficacy and tolerability. Improved response rates to bendamustine, bortezomib, or carfilzomib in combination with rituximab and dexamethasone have been reported. For older patients, a recent phase III trial showed that oral fludarabine was more effective than chlorambucil. A Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has also been reported as a promising agent. Through recent whole-genome sequencing in WM, MYD88L265P and CXCR4WHIM have been identified as somatic mutations. Approximately 90% of WM patients carry MYD88L265P, which activates IRAK and BTK, which in turn activate NFκB. MYD88L265P has been found to play a role in WM cell proliferation and survival. The other mutation, CXCR4WHIM, has been implicated in tumor progression and drug resistance to ibrutinib. This novel genomic landscape may alter the diagnosis, prognosis, and treatment of WM.

Waldenström macroglobulinemia: What a hematologist needs to know

Waldenström macroglobulinemia (WM) is a distinct hematologic malignancy characterized by a lymphoplasmacytic bone marrow infiltration and the presence of immunoglobulin (Ig)M monoclonal protein. Patients typically present at an advanced age, and a substantial proportion are asymptomatic at diagnosis. A unifying diagnosis of WM may be missed by an unsuspecting hematologist, as symptomatic patients present with a multitude of non-specific manifestations. Although constitutional and neuropathy-related symptoms predominate, concomitant IgM-induced hyperviscosity-associated features can provide useful diagnostic clues. There are specific indications for initiation of therapy. This review focuses on the most up-to-date management strategies of WM, in addition to highlighting the recent discoveries of MYD88 and CXCR4 mutations that have shed unprecedented light on the complex signaling pathways, and opened avenues for novel therapeutic targeting. Although WM remains incurable, with the rapid emergence and integration of effective novel therapies, its clinical course appears poised to improve in the foreseeable future.

The Role of CXC-Chemokine IL-8, IL-6 and CXCR2 Receptor in Lymphoplasmacytic Lymphoma: Correlations with Microvascular Characteristics and Clinical Features

Neovascularisation is a vital process underlying the development and progression of malignant neoplasms. Limited information on the subject is available regarding Waldenstrom’s macroglobulinemia/Lymphoplasmacytic lymphoma (WM/LPL), a rare and usually indolent B-cell lymphoma. We therefore studied by immunohistochemistry microvessel characteristics and IL-6, IL-8, CXCR2 and VEGF expression in the bone marrow of WM/LPL patients and investigated any possible correlation with disease characteristics and outcome. Sixty-three patients were studied (47 WM and 16 LPL) of whom 32, 25 and 6 were low, intermediate and high risk respectively, according to the IPSSWM staging system. Seventy-six percent of the patients required treatment while 24% were asymptomatic and were regularly followed- up. Microvascular characteristics, i.e microvessel density (MVD), total vascular area (TVA) and several other sizeand shape-related parameters, were evaluated in CD34-stained bone marrow slides using computerized image analysis. A Histo-score (H-score) was calculated for IL-6, IL-8, CXCR2 and VEGF expression. IL-6, IL-8, IL-8 receptor CXCR2 and VEGF expression was observed in 84%, 43%, 89% and 90% respectively. A positive correlation between IL-6 and CXCR2 H-scores was observed; IL-6 and VEGF H-scores correlated with hypoalbulinemia and increased serum β2- microglobulin respectively and both with bone marrow lymphoplasmacytic infiltration and MVD. The degree of angiogenesis, microvessel shape, VEGF expression and CXCR2 expression correlated with a shorter time to first treatment in multivariate analysis. In conclusion, in WM/LPL, increased expression of Th-2 cytokines, CXCR2 and VEGF is implicated in neovascularization. CXCR2 and VEGF expression along with the extent and the architecture of the microvessels are brought forward as contributors to biologic aggressiveness reflected by a need for earlier treatment.

Persistent monotypic plasma cells with absence of neoplastic B cell component in a treated case of waldenström macroglobulinemia: a sign of residual disease?

Waldenström macroglobulinemia (WM) is a rare indolent variant of non- Hodgkin's lymphoma characterised by lymphoplasmacytic infiltration of bone marrow (BM) associated with a serum IgM paraprotein. The WHO classification states that the neoplastic cells of WM usually are positive for monotypic surface immunoglobulin light chain, IgM, CD19, and CD20 and are negative for CD5, CD10, and CD23. Serum monoclonal protein detection by serum protein electrophoresis and bone marrow aspirate and biopsy are required for WM diagnosis, monitoring and response assessment. Pathologist must dissuade themselves from making a hasty decision on calling a complete response in WM when neoplastic B cell component is absent. Evaluation of clonality of any residual plasma cells must be done in all cases of WM to evaluate the presence and extent of residual or persistent disease. Role of additional therapy targeted at these residual plasma cells in WM can be evaluated as tools for achieving complete remission. Herein, we present a case of WM with residual monotypic plasmacytosis in BM, without B lymphocytes after therapy.

Genomic Studies Have Identified Multiple Mechanisms of Genetic Changes in Waldenström Macroglobulinemia

The pathophysiology of Waldenström macroglobulinemia (WM), a lymphoproliferative disorder characterized by lymphoplasmacytic bone marrow infiltration associated with serum IgM paraprotein, is rather unclear; however, progress has been made in recent years to better determine the genetic profile of WM tumor cells. Studies based on high-throughput genomic analyses-including single-nucleotide polymorphism array (SNPa), array-based comparative genomic hybridization, and, recently, whole-genome sequencing--have improved deciphering some of the key molecular pathways associated with WM. Beyond the discovery of the myeloid differentiation primary response gene 88 (MYD88) L265P mutation, which will help greatly in the differential characterization of WM from other B-cell low-grade lymphomas, several other mechanisms of gene deregulation were identified and mapped that recurrently pointed out nuclear factor-kappa B (NF-κB), breakpoint cluster region (BCR), and Toll-like receptor (TLR) signaling pathways as potential targets for a better understanding of the physiopathology of WM and for future drug development. Herein, we summarize the current knowledge of the genomic patterns of WM to highlight its complexity.

Cast Nephropathy and Light-Chain Deposition Disease in Waldenström Macroglobulinemia

Waldenström macroglobulinemia is a rare low-grade hematologic malignancy due to clonal proliferation of B lymphocytes responsible for immunoglobulin M (IgM) monoclonal gammopathy secreted in serum. This disease is characterized by lymphoplasmacytic tumoral infiltration of bone marrow and various organs, especially the liver and spleen. Kidney involvement in Waldenström macroglobulinemia has been described previously with reports of various forms of glomerular injury: large intracapillary IgM pseudothrombi, cryoglobulinemia-associated membranoproliferative glomerulonephritis, or amyloidosis. Interstitial infiltration by tumoral B lymphocytes is another classic pattern. Conversely, tubular involvement in the form of myeloma-like casts or basement membrane deposition of monoclonal light chain (light-chain deposition disease) is unusual. We report the occurrence of cast nephropathy associated with light-chain deposition disease in 2 patients with Waldenström macroglobulinemia, which resulted in severe and prolonged kidney failure.

Progression in smoldering Waldenström macroglobulinemia: long-term results

AbstractThe purpose of this study was to define the risk of progression and survival of patients with smoldering Waldenström macroglobulinemia (SWM). SWM is defined clinically as having a serum monoclonal IgM protein ≥ 3 g/dL and/or ≥ 10% bone marrow lymphoplasmacytic infiltration but no evidence of end-organ damage (anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly). We searched a computerized database and reviewed the medical records of all patients at Mayo Clinic who fulfilled the criteria of SWM between 1974 and 1995. During 285 cumulative person-years of follow-up of the 48 patients with SWM (median, 15.4 years), 34 (71%) progressed to symptomatic Waldenström macroglobulinemia (WM) requiring treatment, one to primary amyloidosis, and one to lymphoma (total, 75%). The cumulative probability of progression to symptomatic WM, amyloidosis, or lymphoma was 6% at 1 year, 39% at 3 years, 59% at 5 years, and 68% at 10 years. The major risk factors for progression were percentage of lymphoplasmacytic cells in the bone marrow, size of the serum M-spike, and the hemoglobin value. Patients with SWM should be followed and not treated until symptomatic WM develops. Treatment on a clinical trial for those at greatest risk of progression should be considered.

Risk stratification in Waldenström macroglobulinemia

Waldenström macroglobulinemia is characterized by the production of serum monoclonal IgM and lymphoplasmacytic bone marrow infiltration. At least 25% of patients are asymptomatic at diagnosis and treatment is only mandatory in cases of symptomatic disease. Beside reports on treatment results, reviewing risk assessment is another way to describe the clinical course of the disease. This information may be particularly useful when numerous treatment options are available. While the introduction of new treatment approaches reinforces the need for careful risk assessment, the identification of useful prognostic information requires prolonged follow-up in patients who have not been treated with current therapeutic options. This limitation should be taken into account when using and interpreting available prognostic information, especially survival estimates.