Waldenström Macroglobulinemia - A State-of-the-Art Review: Part 1: Epidemiology, Pathogenesis, Clinicopathologic Characteristics, Differential Diagnosis, Risk Stratification, and Clinical Problems

Michele Bibas1, Shayna Sarosiek2 and Jorge J. Castillo2.

1 Department of Clinical Research, Hematology. National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCSS Rome Italy.
2 Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Correspondence to: Michele Bibas. Department of Clinical Research, Hematology. National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCSS Via Portuense 292 00148 Rome Italy. E-mail: michele.bibas@inmi.it

Published: July 01, 2024
Received: May 31, 2024
Accepted: June 19, 2024
Mediterr J Hematol Infect Dis 2024, 16(1): e2024061 DOI 10.4084/MJHID.2024.061

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Waldenström macroglobulinemia (WM) is an infrequent variant of lymphoma, classified as a B-cell malignancy identified by the presence of IgM paraprotein, infiltration of clonal, small lymphoplasmacytic B cells in the bone marrow, and the MYD88 L265P mutation, which is observed in over 90% of cases. The direct invasion of the malignant cells into tissues like lymph nodes and spleen, along with the immune response related to IgM, can also lead to various health complications, such as cytopenias, hyperviscosity, peripheral neuropathy, amyloidosis, and Bing-Neel syndrome. Chemoimmunotherapy has historically been considered the preferred treatment for WM, wherein the combination of rituximab and nucleoside analogs, alkylating drugs, or proteasome inhibitors has exhibited notable efficacy in inhibiting tumor growth. Recent studies have provided evidence that Bruton Tyrosine Kinase inhibitors (BTKI), either used independently or in conjunction with other drugs, have been shown to be effective and safe in the treatment of WM. The disease is considered to be non-curable, with a median life expectancy of 10 to 12 years.

Key Points

•    An indolent, low-grade non-Hodgkin lymphoma known as Waldenström macroglobulinemia (WM) is characterized by lymphoplasmacytic cells infiltrating the bone marrow and a monoclonal IgM paraproteinemia.
•    The age-adjusted incidence of WM in the US population is 0.36 per 100,000 (or 0.63 per 100,000 for WM and LPL combined, shown as WM/LPL).
•    The initial evaluation of a patient with WM can be challenging, and the clinical features of patients can vary greatly.
•    IgM abnormalities are common within WM families and merit further evaluation because they may eventually provide a basis for screening and prevention.
•    A family history of WM/LPL has prognostic implications for WM patients.
•    Next-generation sequencing has revealed recurring somatic mutations in WM. Common mutations include MYD88 (95%–97%), CXCR4 (30%–40%), ARID1A (17%), and CD79B (8%–15%).
•    Patients diagnosed with WM or LPL should only begin treatment if they have lymphoma-related symptoms. If a patient exhibits no symptoms, we can monitor them for an extended period before initiating therapy.

Definition

According to WHO-HAEM4,[1] we can diagnose lymphoplasmacytic lymphoma (LPL) when trephine biopsies reveal an infiltration by clonal lymphoplasmacytic aggregates. These criteria are supported by WHO-HAEM5,[2] which lists two types of LPL: (1) IgM-LPL/WM (about 95%) and (2) non-IgM LPL (about 5%), which includes cases with IgG or IgA monoclonal proteins, monoclonal free light chains (FLCs), non-secretory LPL, and IgM-LPL that does not involve the bone marrow. The search for MYD88 (L265P), the driver mutation of LPL detectable in about 90% of cases in both groups, may help to distinguish LPL from nodal and extranodal MZL.[3] But the lack of a MYD88 mutation does not rule out LPL. Further, 40% of cases have CXCR4 mutations associated with hyperviscosity symptoms and resistance to BTK inhibitors.[3]
The International Consensus Classification of Mature Lymphoid Neoplasms (ICC)[4] recognizes two IgM MGUS entities: (1) IgM MGUS of plasma cell type and (2) IgM MGUS not otherwise defined (NOS), which is different from WHO-HAEM5.[4] The first is characterized by the absence of the MYD88 mutation and the growth of clonal plasma cells devoid of B cells, making it a precursor to IgM MM. The IGH:CCND1 rearrangement, t(11;14)(q13;q32), or other IGH rearrangements associated with MM may exist. IgM MGUS NOS, on the other hand, is distinguished by the growth of monoclonal B cells, which usually have the MYD88 mutation; however, these cells do not show the lymphoplasmacytic aggregates typical of LPL. WM may develop in IgM-MGUS NOS. The ICC[4] and WHO-HAEM5[2] now classify primary cold agglutinin disease (CAD) as a separate illness from LPL/WM or IgM MGUS.[5]
History. In 1943, Jan Gosta Waldenstrom (JW) observed three cases of elevated globulin levels and recurring purpura, primarily affecting the lower extremities.[6] These patients developed unique pigmentations, leading to the designation of Purpura hyperglobulinemia of Waldenstrom. In 1944, JW documented two patients with symptoms including oronasal hemorrhage, lymphadenopathy, normochromic anemia, elevated erythrocyte sedimentation rate, thrombocytopenia, hypoalbuminemia, low blood fibrinogen levels, and an increase in lymphoid cells in the bone marrow. The patients did not show skeletal bone lesions or bone pain, distinguishing this condition from multiple myeloma. The overabundance of lymphoid cells in their bone marrow differed from plasma cells in other patients diagnosed with multiple myeloma. JW collected blood samples and sent them to KO Pedersen, the ultracentrifuge supervisor at the Svedberg Institute. In 1944, JW published the results for the unusual 19S component, known as macroglobulinemia or Waldenström disease.[7]
Epidemiology. The prevalence of WM/LPL among newly diagnosed NHL cases in the United States is approximately 2%. Surveillance, Epidemiology, and End Results (SEER) data from 2000 to 2019 shows that the age-adjusted incidence of WM in the US population is 0.36 per 100,000 (or 0.63 per 100,000 for WM and LPL combined, shown as WM/LPL).[8] Individuals under the age of 30 are rarely diagnosed with WM. The occurrence of the condition starts increasing at the age of 40, and the rates continue to increase with each successive decade. The prevalence rate of WM/LPL among White Americans is 0.74 per 100,000, which is more than twice as high as the prevalence among any other racial or ethnic group.[8] Between 2000 and 2012, the combined incidence rates of WM and LPL in northern Sweden were 50% to 75% higher (1.48 and 1.75 per 100.000, respectively, for 2 counties) than the overall incidence rate in Sweden (1.05 per 100.000).[9] This is two to three times higher than the combined rate in the United States (0.61 per 100,000) during the same period. A few studies conducted on specific Asian communities provide support for the observed differences between white individuals and Asians and Pacific Islanders in the United States.[10,11] Gender impacts the incidence. In the United States, the prevalence of WM is approximately twice as high in males (0.51 per 100,000) compared to females (0.25 per 100,000). There was a 65% increase in the yearly age-adjusted incidence from 1990 (0.3 per 100,000) to 2019 (0.5 per 100,000). The rise is more significant in males (percent change (PC) = 60.4) compared to females (PC = 47.7) and in the elderly (PC = 69.5 vs. 47.7 for ages 60+ and 60 years, respectively).[8-11]
Family History in Waldenstrom Macroglobulinemia. The medical literature reported additional families with the condition after describing the first WM family in 1962.[12-16] According to population-based registries, family members of people with WM have an increased risk of developing WM and other B-cell cancers.[17,18]
In addition, family studies provided preliminary evidence for the role of environmental exposures in WM development.[19] A comprehensive case-control analysis found that persons with a first-degree relative diagnosed with a hematologic malignancy have a 64% higher risk of acquiring WM/LPL.[20] These observations were verified by two population-based registry investigations.[21,22]
Pathogenesis. It is hypothesized that LPL/WM cells originate from B-cells undergoing the last stages of B-cell maturation.[23] Clonal B cells may be found in the peripheral blood of WM patients, but lymphocytosis is infrequent.[23,24] WM cells express monoclonal IgM, but certain clonal cells also exhibit surface IgD. WM lymphoplasmacytic cells have pan-B-cell markers like CD19, CD20 (including FMC7), CD22, and CD79. Expression of CD5, CD10, and CD23 is detectable in around 10%–20% of cases.[24] The expression of these markers does not conclusively rule out the diagnosis of WM.[25-27] Somatic hypermutation contributes to evidence supporting the notion that the WM B-cell clone in most patients originates before the germinal center stage. The presence of isotype-switching transcripts and no diversity within clones increases the likelihood of finding the VH3/JH4 gene families.[28] The predominant etiology of WM cases is likely attributed to the presence of IgM and/or IgM IgD memory B-cells.[28]
WM patients have cells showing chromosomal abnormalities even when immunoglobulin heavy chain (IgH) translocations are absent.[29] Roughly 50% of people diagnosed with WM display deletions in the chromosomal region 6q21e23.[30,31] Additionally, approximately 40% of patients with 6q deletions also exhibit simultaneous increases in the 6p gene.[32] The chromosomal region under consideration encompasses two potential genes: TNFAIP3, which functions to inhibit nuclear factor kappa B (NF-kB) signaling, and PRDM1, a pivotal regulator of B-cell maturation.[33] Getting rid of an NF-kB suppressor is very important because WM cells need NF-kB to be phosphorylated and move into the nucleus to survive.[34]
Protease inhibitor therapy may help WM patients stop the breakdown of NF-kB inhibitors of kappa B (I-B) and other harmful NF-kB regulators.[35-37]

Somatic Events

The utilization of next-generation sequencing in the study of WM has revealed a high occurrence of mutations in several genes, including MYD88, CXCR4, TP53, and others.[38]
Cytogenetic Abnormalities in WM. WM is characterized by a median of two to three chromosomal abnormalities in each patient.[38,39] There is a strong correlation between a shift from asymptomatic to symptomatic WM and the deletion of 6q, the most common chromosomal aberration occurring in thirty percent to fifty percent of patients.[40-42] Other abnormalities that are frequently seen include trisomy(tri) 4, tri18, del13q, tri12, and del17p; however, none of these abnormalities are found in more than fifteen percent of patients.[43,44] There is a correlation between the deletion of 17p/TP53 and an unfavorable prognosis, which is present in seven percent of patients with WM.[45] In contrast to MM and other B-cell lymphoproliferative disorders, there has been no consistent description of translocations in WM.[46,47]
Role of MYD88 Mutations. MYD88 mutations were initially detected in diffuse large B-cell lymphoma (DLBCL) associated with the activated B-cell (ABC) subtype.[48,49] Allele-specific polymerase chain reaction (PCR) detects MYD88 L265P expression in 90% to 95% of WM patients, including both CD19-sorted WM cells and unsorted bone marrow cells.[50,51] When comparing WM to other B-cell cancers, it is seen that MYD88 mutations occur at a low prevalence. Patients with WM have also been shown to have non-L265P MYD88 mutations, such as S219C, M232T, and S243N, observed in other B-cell malignancies with MYD88 mutations.[53]
Patients diagnosed with IgM MGUS show approximately 50% to 90% prevalence for MYD88 mutations, whereas those with IgG or IgA MGUS show no such mutations.[54-56] Individuals diagnosed with IgM MGUS and possessing a mutated MYD88 gene have a higher propensity for developing WM.[57-59] IRAK1/IRAK4 and BTK, the targets of ibrutinib, facilitate the activation of NFkB.[60] Nevertheless, it is crucial to acknowledge that BTK can activate NFkB independently of IRAK4 and IRAK1.[61] Using peptides that stop MYD88 from homodimerizing or genetically silencing the MYD88 gene can stop IRAK1/IRAK4 and BTK from recruiting and activating, which causes apoptosis in WM cells with the MYD88 mutant.[62,63] Moreover, WM patients show hyperactivation of hematopoietic cell kinase (HCK)[64] HCK activation in the signaling pathways associated with mutant WM cell proliferation and survival. These pathways include BTK, PI3K/AKT, and MAPK/ERK1/2 signaling.[64]
The Role of CXCR4 Mutations. About 30% to 40% of WM patients have point mutations in the C-terminal region of CXCR4.[58,65] So far, only marginal zone B-cell lymphoma (MZL) and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) have also shown CXCR4 mutations. Interestingly, CXCR4 mutations are subclonal to MYD88 mutations.[65] Patients with a wild-type MYD88 gene may also have these changes in the C-terminal domain of CXCR4.[66] Germline mutations in the C-terminal region of CXCR4 characterize WHIM syndrome, a condition characterized by autosomal dominant warts, hypogammaglobulinemia, infections, and myelokathexis syndrome.[67,68] WM patients show a significant prevalence of nonsense and frameshift mutations within the C-terminal domain of CXCR4.[67-69] MYD88 suppression leads to the induction of apoptosis in both wild-type (WT) and mutant CXCR4-expressing WM cells, even though CXCR4 mutations often enhance cell survival. This observation illustrates the heightened importance of the survival signaling pathway, specifically mutant MYD88, in the context of WM.[67–70]
The clonality of CXCR4 mutants demonstrates significant variety, which stands in contrast to the MYD88 gene. A single patient can exhibit multiple mutations in the CXCR4 gene. The CXCR4 gene appears to be directly linked to the occurrence of clonal deletions in the 6q chromosomal region. Somatic mutations in the CXCR4 gene may influence the manifestation of WM, similar to the effects shown in MYD88 mutations.[71] People who have CXCR4 mutations are less likely to have adenopathy. On the other hand, people who have CXCR4 nonsense mutations are more likely to get bone marrow disease, high serum IgM levels, hyperviscosity, and coagulopathy.[71]

The Role of Other Somatic Events

As the aggressiveness of IgM monoclonal gammopathies grows, there is a corresponding increase in the number of detectable genetic defects. An investigation examined the 12 prevailing WM genes and revealed that 21% of individuals with IgM MGUS exhibited alterations, 35% were asymptomatic, and 50% displayed symptoms.[72] A range of somatic mutations in ARID1A, such as nonsense and frameshift variants, have been identified in approximately 3–17% of individuals diagnosed with WM.[56,73,74] When ARID1A mutations occur, individuals with WM exhibit increased bone marrow infiltration.[75] The absence of its homolog ARID1B, situated on 6q, may contribute to the unfavourable prognosis associated with 6q deletion. Around 10% of WM patients carry mutations in CD79A and CD79B.[76] The B-cell receptor (BCR) pathway comprises two components that can form heterodimers.[76,77] Consequently, activating mutations in these components may play a role in the chronic BCR signaling found in WM cells.[78,79] Changes in CD79A and CD79B were rarely found in CXCR4 mutations, suggesting that CD79A/B mutations may help WM to spread through pathways directed by mutant MYD88.[67]
Approximately 10% of newly diagnosed individuals with WM and 25% of those who have progressed to more advanced stages have TP53 abnormalities, such as mutations or deletions in the TP53 locus on chromosome 17 (17p13.1).[80,81] These abnormalities may potentially link to mutant MYD88 and CXCR4.[82] Similar to other types of lymphomas, TP53 abnormalities in WM indicate a higher likelihood of a more aggressive illness.[83] Although TP53 mutations suggest unfavorable results with immunochemotherapy in chronic lymphocytic leukemia, there is still a lack of conclusive data for WM.[84] The molecular investigation for WM now recommends TP53 mutation testing, which includes checking for 17p deletions. This is especially important for patients who experience a relapse and need treatment.[84,85]

Tumor Microenvironment

WM cells’ ability to migrate to the bone marrow is a critical characteristic. The expression of stromal-derived factor-1 (SDF-1), a chemokine, influences the in vitro migration of human cells.[86] This is prominently present in WM bone marrow. Recent findings have highlighted the important role of mast cells, T-cells, monocytes, and endothelial cells in the development of WM.[87] An excessive proliferation of mast cells distinguishes WM from MZL. The role of mast cells in the bone marrow of people with WM has been shown to play a role in the excessive growth of cancerous B cells through the interaction between CD40L and CD40 molecules.[87] Researchers have focused on examining the expression of PD-1, its ligands PD-L1 and PD-L2, and the presence of T cells in WM. Both WM cell lines and patient bone marrow cells showed increased expression of the PD-L1 and PD-L2 genes after exposure to IL-21, interferon-gamma, and IL-6.[88] Patients with Waldenstrom macroglobulinemia who had more PD-L1 and PD-L2 expression in their bone marrow tend to have more aggressive disease.[88] More evidence indicates that bone marrow-derived mesenchymal stem cells (BMSCs) can regulate the proliferation of tumor cells in WM and contribute to developing resistance to treatments. Ephrin receptor B2 (Eph-B2) overexpression in WM cells enhances the adhesion and proliferation of endothelial cells.[89] Patients with WM exhibit activation of Eph-B2 receptors. The suppression of Ephrin-B2 or Eph-B2 effectively prevented increased adhesion and proliferation resulting from the interaction between the endothelium and WM cells.[91]

Clonal Hematopoiesis (CH) in WM

The expansion of somatic mutations in hematopoietic progenitor cells, known as clonal hematopoiesis (CH), has been associated with various detrimental consequences.[92-94] Researchers have identified CH clones in patients diagnosed with WM.[95] Recently, 14% of WM patients were found to carry a clonal hematopoiesis of indeterminate potential (CHIP) clone.[96] This discovery coincided with a significant increase in the probability of progressing from an asymptomatic state to a symptomatic manifestation of WM. There is no correlation between the existence of CH and decreased survival rates.[96]

Diagnostic Criteria

WM is diagnosed when patients have an IgM monoclonal protein of any size and evidence of lymphoplasmacytic lymphoma infiltration in their bone marrow, even if <10% of cellularity.[1,2,4] The immunophenotypic profile of WM cells includes the detection of surface IgM, CD5, CD19, CD20, CD22, CD79a, CD23, CD25, CD27, FMC7, CD138, and CD103. While WM is the most frequently reported kind of lymphoplasmacytic lymphoma (LPL), a small proportion (5%) of LPL cases display IgG, IgA, or non-secretory features, which have been associated with an increased likelihood of extramedullary involvement.[1,2,4]

Initial Investigation

Medical History and Physical Examination. Clinically, WM is characterized by fatigue, discomfort, and difficulty breathing, often associated with anemia. Symptoms may also include thrombocytopenia or acquired von Willebrand disease (vWD), which can increase susceptibility to bleeding or bruising. Hyperviscosity can also be present. A funduscopic examination is recommended for evaluating hyperviscosity, especially in patients with serum IgM levels above 3,000 mg/dl. A comprehensive neurological examination is recommended to identify sensory and motor neuropathy. Physical examinations may also detect hepatosplenomegaly and lymphadenopathy. Cryoglobulinemia may be accompanied by symptoms like the Raynaud phenomenon or ulcers. Cold agglutinin anemia is rare, and familial history of WM or other lymphoproliferative diseases should be investigated.[97-100]
Laboratory Studies Typically, the initial diagnostic workup includes several important laboratory tests.[101] These include a complete blood count (CBC), a complete metabolic panel (CMP), quantitative immunoglobulins, free light chains, and serum and urine protein electrophoresis with immunofixation. Additionally, serum viscosity, serum LDH, and beta-2-microglobulin tests are also performed.[97-101] The amount of immunoglobulin M (IgM) in the blood might be an indirect biomarker for detecting LPL in the bone marrow. Still, the association between serum IgM levels and tumor burden may not correspond. Nearly 70% of people with WM have lower than normal IgA and/or IgG levels in their serum at the time of diagnosis.[97-101] Immunofixation using the SPEP method can detect the IgM monoclonal (M) protein. Since quantitative tests may not be able to identify small levels of IgM, combining immunofixation with qualitative tests is crucial to ensure the detection of all particles. Genuine bi- or tri-clonality, class switching, and the presence of IgG or IgA M-spikes are rare.[97-101] We recommend quantifying serum-free light chains in people with WM in some cases, particularly when there is a suspicion of light chain amyloidosis. Urine electrophoresis and immunofixation techniques can detect Bence Jones proteinuria, which is less common than in multiple myeloma.[97-101] Serum viscosity can be a valuable diagnostic tool for people with hyperviscosity symptoms. For those suspected of having hyperviscosity syndrome, measuring serum immunoglobulin M (IgM) levels provides a more accurate and precise diagnostic approach.[97-101] A high serum IgM level can sometimes be associated with artificially low hemoglobin levels produced by volume expansion. When clinically necessary, we perform screening for acquired von Willebrand disease (vWD) by assessing the VW antigen, ristocetin cofactor, and FVIII level. Acquired VWD is typically seen with >5,000 mg/dl serum IgM levels. Patients with WM with elevated levels of von Willebrand factor may have a more unfavorable prognosis.[97-101]
Table 1
Table 1. Significant and useful investigations in the context of WM.
Table 2
Table 2. Manifestations of Waldenstrom Macroglobulinemia in a clinical setting.

Bone Marrow Investigations

Bone marrow biopsies reveal increased lymphocytes restricted to either kappa or lambda light chains. The trephine biopsy sections show interstitial, nodular, or diffuse infiltration patterns. Paratrabecular infiltration is a rare phenomenon. In lymphocytes and lymphoplasmacytic cells, immunohistochemistry and flow cytometry tests demonstrate the detection of IgM, kappa, or lambda light chains, CD19, CD20, weak CD22, and homogeneous CD25. WM cells can express CD5, a protein typically found among individuals diagnosed with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).[97-101] Furthermore, WM cells may also express CD23, a protein commonly found in CLL. Approximately 10%–20% of WM cells may exhibit the presence of CD10, a protein typically linked to follicular lymphoma (FL).[102] Due to the difficult logistics of producing tumor metaphases in a laboratory setting, cytogenetic testing is typically not included in the diagnosis procedure for individuals with WM.[103] However, conventional cytogenetic or fluorescence in situ hybridization (FISH) tests can be advantageous in differential diagnosis.[104-107] We recommend testing the bone marrow aspirate for the presence of the MYD88 L265P mutation.[108-110] A large percentage (50–90%) of patients with IgM monoclonal gammopathy of unknown significance (MGUS) exhibit the MYD88 L265P mutation.[109,110] Therefore, this mutation alone cannot be considered a conclusive indicator of WM. A subset of patients, ranging from 3% to 5%, who satisfy both the immunophenotypic and clinical criteria for WM may not possess the MYD88 L265P mutation, commonly referred to as "wild-type MYD88". The absence of a MYD88 mutation has been linked to an adverse prognosis in terms of survival.[111] Approximately 30%–40% of individuals diagnosed with WM have CXCR4 mutations.[112]

Imaging

In most cases, WM is a disorder that affects bone marrow, but around 10%–15% may have extramedullary symptoms during the initial physical examination, such as lymphadenopathy, hepatosplenomegaly, or pleural effusions. CT scans of the chest, abdomen, and pelvis are necessary for the initial staging of patients with WM who are being considered for therapy initiation. In cases of aggressive transformation, PET/CT scanning is very helpful because DLBCL histology is often present.[97-101]

Differential Diagnosis

All IgM-secreting lymphomas show similarities to WM.
Table 3a
Table 3a. .Differential diagnosis of Waldenstrom Macroglobulinemia.
Table 3b
Table 3b. Outline the criteria differentiating those diseases from WM.

IgM MGUS-NOS

Patients have IgM MGUS-NOS if they show an IgM monoclonal gammopathy without any apparent evidence of bone marrow structural involvement with lymphoplasmacytic lymphoma. Additionally, these patients may exhibit a MYD88 mutation, and there is no indication of any other B-cell neoplasms.

IgM MGUS, Plasma Cell Type (IGM MGUS-PC)

Plasma cell type IgM MGUS (IGM MGUS-PC) is classified as a precursor to MM. It is characterized by the presence of clonal plasma cells (<10%) without a detectable B-cell component and with wild-type MYD88 and includes patients who have t(11;14) (q13;q32) or other cytogenetic abnormalities that are characteristic of multiple myeloma (MM).

IgM-Related Disorders/Monoclonal Gammopathy of Clinical Significance (MGCS)

Certain patients exhibit clinical characteristics linked to the monoclonal IgM paraprotein, but they fail to meet the diagnostic criteria for WM. These patients are classified as IgM-associated diseases, aligning with the monoclonal gammopathy of clinical significance (MGCS) category in the updated ICC classification.[4]

IgM Multiple Myeloma

IgM-MM is distinguished from WM by the presence of plasmacytic infiltration in the bone marrow. Compared to WM, IgM-MM is frequently associated with osteolytic lesions and renal insufficiency. Cytogenetic abnormalities such as 13q deletion, 11:14 translocation, or 4:14 translocation can distinguish MM and WM. Identifying mutations in MYD88, present in WM but absent in MM, significantly enhances the distinction between the two entities.

Marginal Zone Lymphoma (MZL)

Differentiating between WM and MZL, especially splenic marginal zone lymphoma (SMZL), may pose a challenge. Pan-B-cell markers for immunophenotyping, such as CD19, CD20, CD22, and surface Ig, are always present in WM and SMZL. Individuals with SMZL demonstrate higher CD22 and CD11c expression levels than individuals with WM. Conversely, CD25 positivity is more common in patients with WM (88% vs. 44%). Between SMZL and WM, the k/L ratio varies, with a ratio of 1.2:1 for SMZL and 4.5:1 for WM. In WM, the CD103 antigen always shows a negative result. However, in 40% of patients with SMZL, it demonstrates a positive result. Both diseases commonly show a positive presence of the monoclonal antibody FMC7, with a heterogeneous distribution in WM and a homogenous distribution in SMZL. By utilizing the combination of CD25 and CD22, it is possible to differentiate between WM and SMZL. Analysis of the MYD88 mutation may serve as a reliable indicator for differentiating WM from other comparable conditions.

Mantle Cell Lymphoma (MCL)

The invasion of the bone marrow by uniform, small to medium-sized lymphoid cells with irregular nuclei can differentiate MCL from WM. MCL primarily impacts the bone marrow, lymph nodes, and extranodal regions such as the gastrointestinal tract and spleen. Most cases of mantle cell lymphoma consistently exhibit the t(11;14)(q13;q32) chromosomal translocation.


Follicular Lymphoma

Follicular lymphoma is distinct from WM because it involves the invasion of tiny, cleaved cells into the paratrabecular region of the bone marrow. Furthermore, cytogenetic investigation demonstrates t(14;18) in 70–90% of cases.

Chronic Lymphocytic Leukemia (CLL)

CLL with an IgM monoclonal protein may be similar to WM. In CLL, lymphocytes are usually tiny and fully developed, lacking visible nucleoli and exhibiting the distinctive smudge cells on a blood smear with a positive expression of CD5 and CD23 while showing negative expression of cytoplasmic immunoglobulin (Ig). On the other hand, in WM, the lymphocytes are negative for CD5 and CD23 but significantly positive for cytoplasmic Ig.

Risk Stratification

Asymptomatic Disease. Patients can meet the diagnostic criteria for WM and have no symptoms of the illness, also called "asymptomatic WM" or "smoldering WM".[113] Patients who do not show symptoms should not be treated. An observation-based approach is suitable, as no evidence demonstrates that immediate therapy is more effective than an observation-based approach. The likelihood of disease progression in asymptomatic WM patients was 6% after 1 year, 39% after 3 years, 59% after 5 years, and 65% after 10 years.[114] Nevertheless, even if there are no evident symptoms present, it may be necessary to start therapy if the IgM serum concentrations are extremely high (e.g., above 60 g/l) or if there is severe anemia with levels below a certain threshold (e.g., 8 mg/dl).[114] The AWM risk score, which includes the percentage of involvement of the bone marrow by LPL and serum IgM, beta-2-microglobulin, and albumin levels, can be used to classify asymptomatic WM patients into low, intermediate, and high risk for treatment initiation.[115]
Symptomatic Disease. We classify patients with WM as symptomatic if they display signs or symptoms associated with tumor infiltration. Some of these signs are constitutional symptoms, cytopenias, infiltration of the central nervous system, organomegaly, and/or symptoms caused by the IgM or light chain monoclonal protein itself, such as hyperviscosity syndrome, cryoglobulinemia, cold agglutinin syndrome, light chain deposition disease, amyloidosis, IgM demyelinating peripheral neuropathy, and IgM deposition disease. Any of the above constitute criteria for treatment initiation based on the recommendations by the 2nd IWWM.[114-115] The International Prognostic Scoring System for WM (IPSSWM) can help categorize patients who will start frontline therapy into different risk groups.[116] The updated version of the prognosis scoring system (revised IPSSWM) includes factors such as age (65 vs. 66–75 vs. > 76 years), beta-2-microglobulin levels of 4 mg/L, serum albumin levels <3.5 g/dl, and LDH≥250 IU/L.[116] This classification enables the identification of both an extremely low-risk and extremely high-risk cohort. The 3-year mortality rate associated with WM was seen to be 0%, 10%, 14%, 38%, and 48% (p < 0.001) for these prognostic groups, whereas the 10-year survival rate was established to be 84%, 59%, 37%, 19%, and 9% (p < 0.001). The IPSSWM and its variants serve as prognostic tools and should not be used to determine the necessity of therapy.
Table 4
Table 4. Revised International prognostic score system for Waldenstrom macroglobulinemia. Adapted from reference 150.
Table 5
Table 5. Outline the Revised International prognostic score system for Waldenstrom macroglobulinemia.

Immunoglobulin M-Mediated Morbidity

Hyperviscosity Syndrome. WM patients can experience symptomatic hyperviscosity due to elevated serum IgM levels. Individuals with IgM levels below 3,000 mg/dL do not require viscosity testing, as clinical hyperviscosity is infrequent in such a group.[82] We often observe nosebleeds, bleeding gums, and changes in vision due to bleeding in the retina.[117] Individuals suspected of having hyperviscosity should evaluate and analyze the possible influence of cryoglobulins on the viscosity of their blood serum. The existence of cryoglobulins can result in falsely decreased levels of IgM in the serum. For this specific situation, we recommend placing the serum sample in a warm bath at a temperature of 37°C.[118-121] This could result in a more accurate measurement of the serum IgM concentration. It is advised that patients diagnosed with WM and having serum IgM levels above 3000 mg/dL receive a thorough examination of the fundus by a skilled ophthalmologist once a year.[122,123]
Cryoglobulinemia. Patients with WM may have monoclonal IgM that can display cryoglobulin-like properties. Type I is usually the predominant type of cryoglobulinemia, but the exact prevalence and incidence have not been determined.[124] The WMUK Rory Morrison national registry, which includes over 1300 cases, reported a prevalence rate of 7%.[125] Another study in Greece found that 5.5% of a group of 595 WM patients had cryoglobulins.[126] Recently, in a study of 102 patients with WM, a high percentage of them exhibited cryoglobulinemia and experienced cryoglobulin symptoms.[124] Of note, even a small concentration of detectable cryoglobulin could trigger symptoms.[124-126]
Immunoglobulin M-Associated Neuropathy. The estimated incidence rate of IgM-related peripheral neuropathy in patients with WM varies from 5% to 40%. Approximately 8% of idiopathic neuropathy cases are associated with monoclonal gammopathy.[127,128] Among these cases, IgM accounts for 60%, IgG for 30%, and IgA for 10%. Several mechanisms lead to nerve damage, including (a) the effects of IgM antibodies against nerve components, resulting in demyelinating polyneuropathies; (b) the presence of IgM deposits in the endoneurium without antibody activity, leading to axonal polyneuropathy; (c) the formation of sporadic tubular deposits in the endoneurium, associated with IgM cryoglobulin; and (d) in extremely uncommon cases, the existence of amyloid deposits or infiltration of neoplastic cells.[129-133] About half of the people diagnosed with IgM neuropathy have antibodies against the myelin-associated glycoprotein (MAG). Anti-MAG usually causes neuropathy that results in deficiencies in both motor and sensory functions. An extended phase of stability typically marks this syndrome, which typically displays a symmetrical and distal pattern of involvement.[134-137] People who have monoclonal IgM antibodies that target gangliosides with disialosyl moieties, specifically GD1b, GD3, GD2, GT1b, and GQ1b, tend to have sensory neuropathy that is mostly caused by loss of myelin.[138-140] Antibodies targeting GD1b and GQ1b have been associated with the onset of sensory ataxic neuropathy. Monoclonal IgMs targeting antigangliosides display significant clinical symptoms of chronic ataxic neuropathy, such as ophthalmoplegia and/or cold agglutination activity that impacts red blood cells.[138-141] Miller-Fisher syndrome, a variant of Guillain-Barré syndrome, has been associated with Campylobacter jejuni lipopolysaccharides (LPS).[142] Motor neuron disease is linked to people who have WM and monoclonal IgM with anti-GM1 and sulfoglucuronyl paragloboside activity.[143,144] Only a small number of individuals diagnosed with WM exhibit symptoms of the POEMS syndrome, characterized by polyneuropathy, organomegaly, endocrinopathy, an M protein, and skin issues.[145]
Cold Agglutinin Hemolytic Anemia. The ICC[4] and the WHO-HAEM5[5] have recently differentiated primary cold agglutinin disease (CAD) from cold agglutinin syndrome (CAS), which is secondary to other conditions. CAS is often linked to cold agglutinin titers above 1:1000 and affects less than 10% of patients with WM. Monoclonal IgM, which recognizes several red cell antigens at temperatures below 37°C, is responsible for hemolytic anemia.[146-150] Monoclonal components commonly contain the IgM kappa light chain.[151] Its interactions with red cell I/I antigens lead to the binding and activation of complement. Raynaud syndrome, acrocyanosis, and livedo reticularis are other medical conditions that result from an accumulation of red blood cells in the skin's blood vessels. Both cryoglobulins and cold agglutinins, particularly those that exhibit anti-Pr specificity, can exhibit characteristics that macroglobulins can display.[151,152]
Bleeding Propensity in WM. Although the current body of literature lacks strong evidence of platelet dysfunction, specific medical conditions, such as acquired von Willebrand factor syndrome, hyperviscosity, aberrant hematopoiesis, cryoglobulinemia, and amyloidosis, have been identified as potential factors that can interfere with coagulation pathways and result in bleeding. Furthermore, many people diagnosed with WM are typically elderly and experience one or several comorbidities. Understanding the processes that cause bleeding is critical since many commonly used treatments for WM, like chemoimmunotherapy and Bruton tyrosine kinase inhibitors, have been linked to an increased risk of bleeding episodes.[154,155] Approximately 17% of individuals had indicators of bleeding. Nevertheless, the severity of these symptoms was not adequately characterized.[156,158]
AL Amyloidosis. Individuals diagnosed with WM have a greater risk of developing amyloidosis, which includes both AL amyloidosis and the apparently but potentially coexisting transthyretin (ATTR) amyloidosis.[159-166] WM-associated AL amyloidosis occurs in approximately 7.5% of patients with WM.[159] We should prioritize the precise identification of amyloid deposits using mass spectrometry-based techniques, immunoelectron microscopy, and immunohistochemistry. Due to its rarity, extensive, high-quality trials to guide treatment decisions for WM-associated AL amyloidosis are lacking.[159-166] Measuring the 24-hour urinary albumin concentration or the urinary albumin/creatinine ratio annually, along with the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and alkaline phosphatase concentrations, may allow for the early detection of AL amyloidosis in patients with IgM MGUS or WM with early signs of renal, cardiac, and liver amyloid involvement. Patients who have incidentally discovered amyloid deposits, such as through bone marrow biopsy or other biopsies, but do not show any signs of organ damage should undergo regular monitoring. A level of NT-proBNP below 180 ng/L argues against the presence of cardiac amyloidosis.[159-167] If there is a documented increase in either biomarker over these criteria throughout the follow-up period, it may be appropriate to explore using cardiac magnetic resonance or echocardiography to confirm the presence of cardiac involvement.

Lymphoma Cell-Mediated Morbidity

Anemia. Anaemia is the most common reason for medical intervention and therapy in patients with WM. Many factors, such as the invasion of malignant cells in the bone marrow, iron deficiency, and hemolysis, can trigger anemia in people with WM. Increased levels of IgM can cause fluid accumulation in the body, leading to dilutional anemia. Patients diagnosed with absolute iron deficiency anemia as the only criteria for starting therapy in the setting of WM should have a physical exam to exclude gastrointestinal bleeding as an alternative explanation. Given the old age of many individuals with WM, it is plausible that a secondary malignancy, such as colon cancer, could be present simultaneously. Data also suggests that WM cells have increased hepcidin synthesis and secretion. Because hepcidin inhibits iron absorption, intravenous iron supplementation may be beneficial in some cases.[167] To evaluate warm or cold autoimmune hemolytic anemia, an in-depth investigation of hemolysis is required.[168] It's crucial to consider potential cobalamin and folate insufficiency, chronic renal, hepatic, or thyroid dysfunction, and inadequate nutrient intake.[168]
Extramedullary disease. Extramedullary WM is characterized by a clonal lymphoplasmacytic infiltrate in anatomical locations different from bone marrow. Case reports have documented lung manifestations such as masses, nodules, diffuse infiltrates, or pleural effusions resulting from WM.[169] Also, malabsorption, diarrhea, bleeding, or obstruction may suggest that the gastrointestinal system, specifically the stomach, duodenum, or small intestine, is affected. In some WM patients, cancer cells infiltrating the kidneys may cause renal failure.[170] Typically, cases arise after treatment rather than at the initial diagnosis, suggesting the possibility of clonal evolution or heterogeneity.[170] Recent case series revealed a median overall survival of 10 years, with a 79% survival rate (95% CI: 57-90%) for patients with WM with extramedullary diseases.[170,171] Individuals with WM that include all IPSS risk variables also have a similar survival rate.[171] These studies suggest that extramedullary WM, in contrast to multiple myeloma, remains treatable and may not result in a poor prognosis for these patients.[171]
Bing-Neel Syndrome (BNS). BNS is a disorder characterized by migrating and accumulating clonal lymphoplasmacytic cells (LPCs) in the central nervous system (CNS). In 1936, doctors Jens Bing and Axel Neel documented two individuals with neurological issues, hyperglobulinemia, and LPCs in their cerebrospinal fluid (CSF).[172] Only 1-2% of people with WM develop BNS.[173] Patients frequently exhibit a wide range of neurological abnormalities, including balance difficulties, ataxia, sensory and motor impairments, headaches, and cognitive impairments. Imaging studies, investigations of CSF fluid, and biopsies are all viable methods to definitively establish a clinical diagnosis of BNS. The first assessment should include gadolinium-enhanced magnetic resonance imaging (MRI) scans of the brain and the entire spine.[174-176] The leptomeningeal type, which results from the infiltration and migration of LPCs within the CNS, is the predominant form of CNS involvement in individuals with BNS, while the presence of brain masses is less frequent.[174-176] The detection of IgH locus rearrangements and MYD88 L256P gene mutations may serve as effective diagnostic methods for BNS.[177]
Young Patients with Waldenström Macroglobulinemia. WM is a cancer that primarily affects older patients. However, one in four people with WM are younger than 60, and one in ten are 50 or younger.[179-181] WM can potentially cause significant harm to this young patient population (50 years of age), which has a long-life expectancy and no significant comorbidities. Recent research examined the clinical traits and prognoses of a significant young WM (50-year-old) patient population encompassing more than five decades (1960–2013).[181] This study compared the long-term outcomes of a significant cohort of young WM patients to those of a paired older WM patient cohort (65 years). When compared to older patients (>65 years) at the time of diagnosis, younger patients with WM had an estimated 10-year OS rate of 74%, with a higher percentage of deaths being attributed to WM (91% vs. 58%, p<0.0001). Consequently, despite the disease's slow progression, nearly all young patients succumb to it, resulting in an estimated loss of 11.2 years of life after diagnosis. The prevalence of lymphadenopathy, splenomegaly, hyperviscosity symptoms, and serum IgM levels were all higher in younger patients with WM at the time of diagnosis.[178-181] Interestingly, WM caused almost all WM-related deaths in younger patients but only about half in the older WM group. The DSS of older patients has improved due to advances in non-WM-related care, such as supportive care and comorbidity management, as well as a rise in life expectancy due to improved WM-directed therapies. Younger patients with lower mortality and comorbidities may benefit less from these factors and die from WM-related causes.[181,182]

Conclusions

This first section of the state-of-the-art review presented a comprehensive description of the pathophysiology, clinicopathologic features, differential diagnosis, risk stratification, and clinical difficulties associated with WM. In the second section of this review, we will focus primarily on the treatment of MW. More specifically, we will investigate both the traditional, consolidated method and the novel therapeutic strategy, paying special emphasis to the utilization of genomics and novel targeted agents.

References   

  1. Swerdlow SH, Campo E, Harris NL. Et al. (Eds.): World Health Organization classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. Lyon: IARC; 2017.
  2. Alaggio R, Amador C, Anagnostopoulos I. et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022 Jul;36(7):1720-1748. https://doi.org/10.1038/s41375-022-01620-2 PMid:35732829 PMCid:PMC9214472
  3. Treon SP, Xu L, Yang G. et al. MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia. N Engl J Med. 2012;367: 826-33. https://doi.org/10.1056/NEJMoa1200710 PMid:22931316
  4. Campo E, Jaffe ES, Cook JR. et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood. 2022 Sep 15;140(11):1229-1253. https://doi.org/10.1182/blood.2022015851 PMid:35653592 PMCid:PMC9479027
  5. Randen U, Troen G, Tierens A, Steen C, Warsame A, Beiske K, et al. Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. Haematologica.2014;99:497-504. https://doi.org/10.3324/haematol.2013.091702 PMid:24143001 PMCid:PMC3943313
  6. Waldenström J. Purpura hyperglobulinemica. Nord med. 1943;20: 288.
  7. Waldenström J. Incipient myelomatosis or 'essential' hyperglobulinemia with fibrinogenopenia a new syndrome? Acta Medica Scandinavica. 1944. CXVII: 217-46. https://doi.org/10.1111/j.0954-6820.1944.tb03955.x
  8. McMaster ML. The epidemiology of Waldenström macroglobulinemia. Semin Hematol. 2023 Mar;60(2):65-72.  https://doi.org/10.1053/j.seminhematol.2023.03.008 PMid:37099032 PMCid:PMC10351685
  9. Brandefors L, Kimby E, Lundqvist K, Melin B, Lindh J. Familial Waldenstrom's macroglobulinemia and relation to immune defects, autoimmune diseases, and haematological malignancies--A population-based study from northern Sweden. Acta Oncol. 2016;55(1):91-8. https://doi.org/10.3109/0284186X.2015.1096019 PMid:26559865
  10. Iwanaga M, Chiang CJ, Soda M, Lai MS, Yang YW, Miyazaki Y, Matsuo K, Matsuda T, Sobue T. Incidence of lymphoplasmacytic lymphoma/Waldenström's macroglobulinaemia in Japan and Taiwan population-based cancer registries, 1996-2003. Int J Cancer. 2014 Jan 1;134(1):174-80. doi: 10.1002/ijc.28343. Epub 2013 Jul 16. PMID: 23784625. https://doi.org/10.1002/ijc.28343 PMid:23784625
  11. Jeong S, Kong SG, Kim DJ, Lee S, Lee HS. Incidence, prevalence, mortality, and causes of death in Waldenström macroglobulinemia: a nationwide, population-based cohort study. BMC Cancer. 2020 Jul 3;20(1):623. doi: 10.1186/s12885-020-07120-9. https://doi.org/10.1186/s12885-020-07120-9 PMid:32620091 PMCid:PMC7333304
  12. Massari R, Fine JM, Metais R. Waldenstrom's macroglobulinaemia observed in two brothers. Nature. 1962 Oct 13;196:176-8. doi: 10.1038/196176b0. https://doi.org/10.1038/196176b0 PMid:13933388
  13. Vannotti A. Etude clinique dun cas de macroglobulinemia de Waldenstrom a caractere familial, associe a des trouble endocriniens. Schweiz Med Wochenschr 1963;93:1744-6.
  14. Coste F, Massais P, Menkes C. Un cas de macroglobulinemia. Rev Rhum Mal Osteoartic 1964;31:37-9.
  15. Seligmann M. A genetic predisposition to Waldenstrom's macroglobulinemia. Acta Med Scand 1966;179(S445):140-6. https://doi.org/10.1111/j.0954-6820.1966.tb02353.x PMid:4160689
  16. Seligmann M, Danon F, Mihaesco C, et al. Immunoglobulin abnormalities in families of patients with Waldenstro¨m's macroglobulinemia. Am J Med 1967;43(1):66-83. https://doi.org/10.1016/0002-9343(67)90149-0 PMid:4143650
  17. McMaster ML, Csako G, Giambarresi TR, et al. Long-term evaluation of three multiple-case Waldenstro¨m macroglobulinemia families. Clin Cancer Res 2007; 13(17):5063-9 https://doi.org/10.1158/1078-0432.CCR-07-0299 PMid:17785558
  18. McMaster ML. Familial Waldenström Macroglobulinemia: Families Informing Populations. Hematol Oncol Clin North Am. 2018 Oct;32(5):787-809. https://doi.org/10.1016/j.hoc.2018.05.006 PMid:30190018
  19. Treon SP, Hunter ZR, Aggarwal A, Ewen EP, Masota S, Lee C, Santos DD, Hatjiharissi E, Xu L, Leleu X, Tournilhac O, Patterson CJ, Manning R, Branagan AR, Morton CC. Characterization of familial Waldenstrom's macroglobulinemia. Ann Oncol. 2006 Mar;17(3):488-94. doi: 10.1093/annonc/mdj111. Epub 2005 Dec 15. PMID: 16357024. https://doi.org/10.1093/annonc/mdj111 PMid:16357024
  20. Vajdic CM, Landgren O, McMaster ML, Slager SL, Brooks-Wilson A, Smith A, Staines A, Dogan A, Ansell SM, Sampson JN, Morton LM, Linet MS. Medical history, lifestyle, family history, and occupational risk factors for lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr. 2014 Aug;2014(48):87-97. https://doi.org/10.1093/jncimonographs/lgu002 PMid:25174029 PMCid:PMC4155457
  21. Altieri A, Bermejo JL, Hemminki K. Familial aggregation of lymphoplasmacytic lymphoma with non-Hodgkin lymphoma and other neoplasms. Leukemia. 2005 Dec;19(12):2342-3. https://doi.org/10.1038/sj.leu.2403991 PMid:16224483
  22. Kristinsson SY, Björkholm M, Goldin LR, McMaster ML, Turesson I, Landgren O. Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden. Blood. 2008 Oct 15;112(8):3052-6. https://doi.org/10.1182/blood-2008-06-162768 PMid:18703425 PMCid:PMC2569164
  23. Oishi N, Inoue T, Odate T, Mochizuki K, Ohashi K, Kirito K, Kondo T. Composite monoclonal B-cell lymphocytosis and MYD88 L265P-positive lymphoplasmacytic lymphoma in a patient with IgM light chain amyloidosis: Case report. Pathol Int. 2020 Jul;70(7):458-462. https://doi.org/10.1111/pin.12937 PMid:32323419
  24. Smith BR, Robert NJ, Ault KA. In Waldenström's macroglobulinemia, the quantity of detectable circulating monoclonal B lymphocytes correlates with clinical course. Blood. 1983;61:911. https://doi.org/10.1182/blood.V61.5.911.911 PMid:6403083
  25. Preud'homme JL, Seligmann M. Immunoglobulins on the surface of lymphoid cells in Waldenström's macroglobulinemia. J Clin Invest.1972;51:701. https://doi.org/10.1172/JCI106858 PMid:4622108 PMCid:PMC302175
  26. San Miguel JF, Vidriales MB, Ocio E, et al. Immunophenotypic analysis of Waldenström's macroglobulinemia. Semin Oncol. 2003;30:187. https://doi.org/10.1053/sonc.2003.50074 PMid:12720134
  27. Hunter ZR, Branagan AR, Manning R, et al. CD5, CD10, and CD23 expression in Waldenstrom's macroglobulinemia. Clin Lymphoma 2005;5:246. https://doi.org/10.3816/CLM.2005.n.008 PMid:15794857
  28. Paiva B, Montes MC, García-Sanz R, et al. Multiparameter flow cytometry for the identification of the Waldenström's clone in IgM MGUS and Waldenström's macroglobulinemia: new criteria for differential diagnosis and risk stratification. Leukemia. 2013;28:166. https://doi.org/10.1038/leu.2013.124 PMid:23604227
  29. Wagner SD, Martinelli V, Luzzatto L. Similar patterns of V kappa gene usage but different degrees of somatic mutation in hairy cell leukemia, prolymphocytic leukemia, Waldenström's macroglobulinemia, and myeloma. Blood. 1994;83:3647. https://doi.org/10.1182/blood.V83.12.3647.3647 PMid:8204889
  30. Aoki H, Takishita M, Kosaka M, Saito S. Frequent somatic mutations in D and/or JH segments of Ig gene in Waldenström's macroglobulinemia and chronic lymphocytic leukemia (CLL) with Richter's syndrome but not in common CLL. Blood. 1995;85:1913. https://doi.org/10.1182/blood.V85.7.1913.bloodjournal8571913 PMid:7703494
  31. Shiokawa S, Suehiro Y, Uike N, Muta K, Nishimura J. Sequence and expression analyses of mu and delta transcripts in patients with Waldenström's macroglobulinemia. Am J Hematol. 2001;68:139. https://doi.org/10.1002/ajh.1169  PMid:11754393
  32. Sahota SS, Forconi F, Ottensmeier CH, et al. Typical Waldenstrom macroglobulinemia is derived from a B-cell arrested after cessation of somatic mutation but prior to isotype switch events. Blood. 2002;100:1505. https://doi.org/10.1182/blood.V100.4.1505.h81602001505_1505_1507 PMid:12149241
  33. Schop RF, Kuehl WM, Van Wier SA, et al. Waldenström macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions. Blood. 2002;100:2996. https://doi.org/10.1182/blood.V100.8.2996 PMid:12351413
  34. Yan WW, Fan HS, Xu JY, Liu JH, Du CX, Deng SH, Sui WW, Xu Y, Qiu LG, An G. [Immunoglobulin M multiple myeloma: a six-case report and literature review]. Zhonghua Xue Ye Xue Za Zhi. 2021 Dec 14;42(12):1011-1014. Chinese. https://doi.org/10.3760/cma.j.issn.0253-2727.2021.12.008 PMID: 35045672; PMCID: PMC8770889.
  35. Braggio E, Keats JJ, Leleu X, et al. High-resolution genomic analysis in Waldenström's macroglobulinemia identifies disease-specific and common abnormalities with marginal zone lymphomas. Clin Lymphoma Myeloma. 2009;9:39. https://doi.org/10.3816/CLM.2009.n.009 PMid:19362969 PMCid:PMC3646570
  36. Nguyen-Khac F, Lambert J, Chapiro E, et al. Chromosomal aberrations and their prognostic value in a series of 174 untreated patients with Waldenström's macroglobulinemia. Haematologica. 2013;98:649. https://doi.org/10.3324/haematol.2012.070458 PMid:23065509 PMCid:PMC3659998
  37. Braggio E, Keats JJ, Leleu X, et al. Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenström's macroglobulinemia. Cancer Res. 2009;69:3579. https://doi.org/10.1158/0008-5472.CAN-08-3701 PMid:19351844 PMCid:PMC2782932
  38. Leleu X, Eeckhoute J, Jia X, et al. Targeting NF-kappaB in Waldenström macroglobulinemia. Blood. 2008;111:5068. https://doi.org/10.1182/blood-2007-09-115170 PMid:18334673 PMCid:PMC2384134
  39. Ocio EM, Schop RFJ, Gonzalez B, et al. 6q deletion in Waldenstrom macroglobulinemia is associated with features of adverse prognosis. Br J Haematol 2007;136(1):80-6. https://doi.org/10.1111/j.1365-2141.2006.06389.x PMid:17222197
  40. Mansoor A, Medeiros LJ, Weber DM, et al. Cytogenetic findings in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Chromosomal abnormalities are associated with the polymorphous subtype and an aggressive clinical course. Am J Clin Pathol 2001;116(4):543-9. https://doi.org/10.1309/6U88-357U-UKJ5-YPT3 PMid:11601139
  41. Ocio EM, Hernandez JM, Mateo G, et al. Immunophenotypic and cytogenetic comparison of Waldenstrom's macroglobulinemia with splenic marginal zone lymphoma. Clin Lymphoma 2005;5(4):241-5. https://doi.org/10.3816/CLM.2005.n.007 PMid:15794856
  42. Terré C, Nguyen-Khac F, Barin C, et al. Trisomy 4, a new chromosomal abnormality in Waldenström's macroglobulinemia: a study of 39 cases. Leukemia 2006;20(9):1634-6. https://doi.org/10.1038/sj.leu.2404314 PMid:16838026
  43. Braggio E, Dogan A, Keats JJ, Chng WJ, Huang G, Matthews JM, Maurer MJ, Law ME, Bosler DS, Barrett M, Lossos IS, Witzig TE, Fonseca R. Genomic analysis of marginal zone and lymphoplasmacytic lymphomas identified common and disease-specific abnormalities. Mod Pathol. 2012 May;25(5):651-60. https://doi.org/10.1038/modpathol.2011.213 PMid:22301699 PMCid:PMC3341516
  44. Poulain S, Braggio E, Roumier C, et al. High-throughput genomic analysis in Waldenström's macroglobulinemia. Clin Lymphoma Myeloma Leuk 2011;11(1):106-8. https://doi.org/10.3816/CLML.2011.n.021 PMid:21454205
  45. Poulain S, Roumier C, Galiègue-Zouitina S, et al. Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia. Am J Hematol 2013;88(11):948-54. https://doi.org/10.1002/ajh.23545 PMid:23861223
  46. Kutálková K, Sedlaříková L, Adam Z, Ševčíková S. Genetické změny u Waldenströmovy makroglobulinemie [Gene mutations connected to Waldenstöm macroglobulinemia]. Vnitr Lek. 2016 Jan;62(1):40-3. Czech PMID: 26967235.
  47. Krzisch D, Guedes N, Boccon-Gibod C, et al. Cytogenetic and molecular abnormalities in Waldenström's macroglobulinemia patients: Correlations and prognostic impact. Am J Hematol 2021;96(12):1569-79. https://doi.org/10.1002/ajh.26339 PMid:34462944
  48. Schop RF, Van Wier SA, Xu R, et al. 6q deletion discriminates Waldenström macroglobulinemia from IgM monoclonal gammopathy of undetermined significance. Cancer Genet Cytogenet 2006;169(2):150-3. https://doi.org/10.1016/j.cancergencyto.2006.04.009 PMid:16938573
  49. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470: 115-9, 2011. https://doi.org/10.1038/nature09671 PMid:21179087 PMCid:PMC5024568
  50. Alcoceba M, García-Álvarez M, Medina A, et al. C. MYD88 Mutations: Transforming the Landscape of IgM Monoclonal Gammopathies. Int J Mol Sci. 2022 May 16;23(10):5570. https://doi.org/10.3390/ijms23105570 PMid:35628381 PMCid:PMC9141891
  51. Xu L, Hunter Z, Yang G, et al. MYD88 L265P in Waldenstrommacroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. Blood 121:2051-8, 2013. https://doi.org/10.1182/blood-2013-05-502211 PMCid:PMC3713420
  52. Varettoni M, Arcaini L, Zibellini S, et al. Prevalence and clinical significance of the MYD88 L265P somatic mutation in Waldenstrommacroglobulinemia and related lymphoid neoplasms. Blood 121: 2522-8, 2013. https://doi.org/10.1182/blood-2012-09-457101 PMid:23355535
  53. Jiménez C, Sebastián E, Del Carmen Chillón M, et al. MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström'smacroglobulinemia. Leukemia 27:1722-8, 2013. https://doi.org/10.1038/leu.2013.62 PMid:23446312
  54. Poulain S, Roumier C, Decambron A, et al. MYD88 L265P mutation in Waldenstrom's macroglobulinemia. Blood 121: 4504-11, 2013. https://doi.org/10.1182/blood-2012-06-436329 PMid:23532735
  55. Ansell SM, Hodge LS, Secreto FJ, et al. Activation of TAK1 by MYD88 L265P drives malignant B-cell growth in Non-Hodgkin lymphoma. Blood Cancer J 4:e183, 2014. https://doi.org/10.1038/bcj.2014.4 PMid:24531446 PMCid:PMC3944662
  56. Treon SP, Xu L, Hunter ZR. MYD88 mutations and response to ibrutinib in Waldenström's Macroglobulinemia. N Engl J Med 2015; 373:584-6. https://doi.org/10.1056/NEJMc1506192 PMid:26244327
  57. Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Manning RJ, Tripsas C, Patterson CJ, Sheehy P, Treon SP. The genomic landscape of Waldenstom's Macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood123:1637-46, 2014. https://doi.org/10.1182/blood-2013-09-525808 PMid:24366360
  58. arettoni M., Zibellini S, Arcaini L, et al. MYD88(L265P) mutation is an independent risk factor for progression in patients with IgM monoclonal gammopathy of undetermined significance. Blood 122:2284-5, 2013. https://doi.org/10.1182/blood-2013-07-513366 PMid:24072850
  59. Treon SP, Tedeschi A, San-Miguel J, Garcia-Sanz R, Anderson KC, Kimby E, Minnema MC, Benevolo G, Qiu L, Yi S, Terpos E, Tam CS, Castillo JJ, Morel P, Dimopoulos M, Owen RG. Report of consensus Panel 4 from the 11th International Workshop on Waldenstrom's macroglobulinemia on diagnostic and response criteria. Semin Hematol. 2023 Mar;60(2):97-106. doi: 10.1053/j.seminhematol.2023.03.009. Epub 2023 Apr 20. https://doi.org/10.1053/j.seminhematol.2023.03.009 PMid:37173155
  60. Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR. Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom's macroglobulinemia. Blood 123:2791-6, 2014. https://doi.org/10.1182/blood-2014-01-550905 PMid:24553177
  61. Lin SC, Lo YC, Wu H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465: 885-90, 2010. https://doi.org/10.1038/nature09121 PMid:20485341 PMCid:PMC2888693
  62. Dubois S, Viailly PJ, Bohers E, Bertrand P, Ruminy P, Marchand V, Maingonnat C, Mareschal S, Picquenot JM, Penther D, Jais JP, Tesson B, Peyrouze P, Figeac M, Desmots F, Fest T, Haioun C, Lamy T, Copie-Bergman C, Fabiani B, Delarue R, Peyrade F, André M, Ketterer N, Leroy K, Salles G, Molina TJ, Tilly H, Jardin F. Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P-Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases. Clin Cancer Res. 2017 May 1;23(9):2232-2244. https://doi.org/10.1158/1078-0432.CCR-16-1922 PMid:27923841
  63. Yang G, Zhou Y, Liu X, Xu L, Cao Y, Manning RJ, Patterson CJ, Buhrlage SJ, Gray N, Tai Y, Anderson KC, Hunter ZR, Steven P, Treon SP. A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood 88:1222-32, 2013. https://doi.org/10.1182/blood-2012-12-475111 PMid:23836557
  64. Liu X, Hunter ZR, Xu L, et al. Targeting Myddosome Assembly in Waldenstrom Macroglobulinaemia. Br J Haematol. 2016 Apr 13. doi: 10.1111/bjh.14103. [Epub ahead of print] https://doi.org/10.1111/bjh.14103 PMid:27073043
  65. Yang G, Buhrlage S, Tan L, et al. HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib. Blood 127:3237-52, 2016. https://doi.org/10.1182/blood-2016-01-695098 PMid:27143257
  66. Schmidt J, Federmann B, Schindler J, et al. MYD88 L265P and CXCR4 mutations in lymphoplasmacytic lymphoma identify cases with high disease activity. Br J Haematol 2015;169:795-803. https://doi.org/10.1111/bjh.13361 PMid:25819228
  67. Xu L, Hunter ZR, Tsakmaklis N, et al. Clonal architecture of CXCR4 WHIM-like mutations in Waldenstro¨m macroglobulinaemia. Br J Haematol 2016;172:735-44. https://doi.org/10.1111/bjh.13897 PMid:26659815 PMCid:PMC5409813
  68. Poulain S, Roumier C, Venet-Caillault A, et al. Genomic landscape of CXCR4 mutations in Waldenstrom macroglobulinemia. Clin Cancer Res 2016;22:1480-8. https://doi.org/10.1158/1078-0432.CCR-15-0646 PMid:26490317
  69. Hernandez PA, Gorlin RJ, Lukens JN, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet 2003;34:70-4. https://doi.org/10.1038/ng1149 PMid:12692554
  70. Liu Q, Chen H, Ojode T, et al. WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4. Blood 2012;120:181-9. https://doi.org/10.1182/blood-2011-12-395608 PMid:22596258 PMCid:PMC3390956
  71. Cao Y, Hunter ZR, Liu X, et al. CXCR4 WHIM-like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88(L265P) -directed survival signalling in Waldenstro¨m macroglobulinaemia cells. Br J Haematol 2015;168:701-7. https://doi.org/10.1111/bjh.13200 PMid:25371371
  72. Guerrera ML, Tsakmaklis N, Xu L, Yang G, Demos M, Kofides A, Chan GG, Manning RJ, Liu X, Chen JG, Munshi M, Patterson CJ, Castillo JJ, Dubeau T, Gustine J, Carrasco RD, Arcaini L, Varettoni M, Cazzola M, Treon SP, Hunter ZR. MYD88 mutated and wild-type Waldenström's Macroglobulinemia: characterization of chromosome 6q gene losses and their mutual exclusivity with mutations in CXCR4. Haematologica. 2018 Sep;103(9):e408-e411. doi: 10.3324/haematol.2018.190181. Epub 2018 Mar 29. https://doi.org/10.3324/haematol.2018.190181 PMid:29599202 PMCid:PMC6119142
  73. Landgren O. Advances in MGUS diagnosis, risk stratification, and management: introducing myeloma-defining genomic events. Hematology Am Soc Hematol Educ Program. 2021 Dec 10;2021(1):662-672. doi: 10.1182/hematology.2021000303. https://doi.org/10.1182/hematology.2021000303 PMid:34889381 PMCid:PMC8791104
  74. Sacco A, Fenotti A, Affò L, Bazzana S, Russo D, Presta M, Malagola M, Anastasia A, Motta M, Patterson CJ, Rossi G, Imberti L, Treon SP, Ghobrial IM, Roccaro AM. The importance of the genomic landscape in Waldenström's Macroglobulinemia for targeted therapeutical interventions. Oncotarget. 2017 May 23;8(21):35435-35444. doi: 10.18632/oncotarget.16130. https://doi.org/10.18632/oncotarget.16130  PMid:28423722 PMCid:PMC5471067
  75. Treon SP, Xu L, Guerrera ML, et al. Genomic landscape of Waldenström macroglobulinemia and its impact on treatment strategies. J Clin Oncol. 2020;38(11):1198-1208. https://doi.org/10.1200/JCO.19.02314 PMid:32083995 PMCid:PMC7351339
  76. Hunter ZR, Xu L, Yang G, et al. Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia. Blood. 2016;128(6):827-838. https://doi.org/10.1182/blood-2016-03-708263 PMid:27301862 PMCid:PMC4982454
  77. Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling withibrutinibin diffuse large B cell lymphoma. Nat Med 21:922-6, 2015.
  78. Argyropoulos KV, Vogel R, Ziegler C, et al. Clonal B-cells in Waldenstro¨m's macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling. Leukemia 2016;30:1116-25. https://doi.org/10.1038/leu.2016.8 PMid:26867669 PMCid:PMC4858584
  79. Chan VWF, Lowell CA, DeFranco AL. Defective negative regulation of antigen receptor signaling in Lyn-deficient B lymphocytes. Curr Biol 1998;8:545-53. https://doi.org/10.1016/S0960-9822(98)70223-4 PMid:9601638
  80. Jiménez C, Prieto-Conde MI, García-Álvarez M, et al. Unraveling the heterogeneity of IgM monoclonal gammopathies: a gene mutational and gene expression study. Ann Hematol. 2018;97 (3):475-484. https://doi.org/10.1007/s00277-017-3207-3 PMid:29353304
  81. Jiménez C, Alonso-Álvarez S, Alcoceba M, et al. From Waldenström's macroglobulinemia to aggressive diffuse large B-cell lymphoma: a whole-exome analysis of abnormalities leading to transformation. Blood Cancer J. 2017;7(8):e591. https://doi.org/10.1038/bcj.2017.72 PMid:28841204 PMCid:PMC5596383
  82. García-Sanz R, Jiménez C. Time to move to the single-cell level: applications of single-cell multi-omics to hematological malignancies and Waldenström's macroglobulinemia-a particularly heterogeneous lymphoma. Cancers (Basel). 2021;13(7):1541. https://doi.org/10.3390/cancers13071541 PMid:33810569 PMCid:PMC8037673
  83. Gustine JN, Tsakmaklis N, Demos MG, et al. TP53 mutations are associated with mutated MYD88 and CXCR4, and confer an adverse outcome in Waldenström macroglobulinaemia. Br J Haematol. 2019;184(2):242-245. https://doi.org/10.1111/bjh.15560 PMid:30183082
  84. Poulain S, Roumier C, Bertrand E, et al. TP53 mutation and its prognostic significance in Waldenstrom's macroglobulinemia. Clin Cancer Res. 2017;23(20):6325-6335. https://doi.org/10.1158/1078-0432.CCR-17-0007 PMid:28754818
  85. Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(1):23-33. https://doi.org/10.1016/j.annonc.2020.09.019 PMid:33091559
  86. Garcia-Sanz R, Varettoni M, Jiménez C, Ferrero S, Poulain S, San-Miguel JF, Guerrera ML, Drandi D, Bagratuni T, McMaster M, Roccaro AM, Roos-Weil D, Leiba M, Li Y, Qiu L, Hou J, De Larrea CF, Castillo JJ, Dimopoulos M, Owen RG, Treon SP, Hunter ZR. Report of Consensus Panel 3 from the 11th International workshop on Waldenström's Macroglobulinemia: Recommendations for molecular diagnosis in Waldenström's Macroglobulinemia. Semin Hematol. 2023 Mar;60(2):90-96. https://doi.org/10.1053/j.seminhematol.2023.03.007 PMid:37099028
  87. Boutilier, A.; Elsawa, S. Macrophage Polarization States in the Tumor Microenvironment. Int. J. Mol. Sci. 2021, 22, 6995. https://doi.org/10.3390/ijms22136995 PMid:34209703 PMCid:PMC8268869
  88. Tournilhac, O.; Santos, D.D.; Xu, L.; Kutok, J.; Tai, Y.-T.; Le Gouill, S.; Catley, L.; Hunter, Z.; Branagan, A.R.; Boyce, J.A.; et al. Mast cells in Waldenstrom's macroglobulinemia support lymphoplasmacytic cell growth through CD154/CD40 signaling. Ann. Oncol. 2006, 17, 1275-1282. https://doi.org/10.1093/annonc/mdl109 PMid:16788002
  89. Jalali, S.; Price-Troska, T.; Paludo, J.; Villasboas, J.; Kim, H.-J.; Yang, Z.-Z.; Novak, A.J.; Ansell, S.M. Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia. Blood Adv. 2018, 2, 1985-1997. https://doi.org/10.1182/bloodadvances.2018021113 PMid:30104397 PMCid:PMC6093740
  90. Agarwal, A.; Ghobrial, I.M. The Bone Marrow Microenvironment in Waldenström Macroglobulinemia. Clin. Lymphoma Myeloma Leuk. 2013, 13, 218-221. https://doi.org/10.1016/j.clml.2013.02.006 PMid:23490994 PMCid:PMC3654400
  91. Leblebjian, H.; Agarwal, A.; Ghobrial, I. Novel Treatment Options for Waldenström Macroglobulinemia. Clin. Lymphoma Myeloma Leuk. 2013, 13, S310-S316. https://doi.org/10.1016/j.clml.2013.05.023 PMid:24290218 PMCid:PMC3870149
  92. Azab, F.; Azab, A.K.; Maiso, P.; Calimeri, T.; Flores, L.; Liu, Y.; Quang, P.; Roccaro, A.M.; Sacco, A.; Ngo, H.T.; et al. Eph-B2/EphrinB2 Interaction Plays a Major Role in the Adhesion and Proliferation of Waldenstrom's Macroglobulinemia. Clin. Cancer Res. 2012, 18, 91-104. https://doi.org/10.1158/1078-0432.CCR-11-0111 PMid:22010211
  93. Beerman I, Bhattacharya D, Zandi S, Sigvardsson M, Weissman IL, Bryder D, et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci USA. 2010;107:5465-70. https://doi.org/10.1073/pnas.1000834107 PMid:20304793 PMCid:PMC2851806
  94. Jan M, Ebert BL, Jaiswal S. Clonal hematopoiesis. Semin Hematol. 2017;54:43-50. https://doi.org/10.1053/j.seminhematol.2016.10.002 PMid:28088988 PMCid:PMC8045769
  95. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26): 2488-2498. https://doi.org/10.1056/NEJMoa1408617 PMid:25426837 PMCid:PMC4306669
  96. Xie M, Lu C, Wang J, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12): 1472-1478. https://doi.org/10.1038/nm.3733 PMid:25326804 PMCid:PMC4313872
  97. Tahri S, Mouhieddine TH, Redd R, Lampe L, Nilsson KI, El-Khoury H, et al. Clonal hematopoiesis is associated with increased risk of progression of asymptomatic Waldenstrom macroglobulinemia. Blood Adv. 2022;6:2230-5. https://doi.org/10.1182/bloodadvances.2021004926 PMid:34847227 PMCid:PMC9006277
  98. Grunenberg A, Buske C. How to manage waldenström's macroglobulinemia in 2024. Cancer Treat Rev. 2024 Apr;125:102715. doi: 10.1016/j.ctrv.2024.102715. Epub 2024 Mar 5. https://doi.org/10.1016/j.ctrv.2024.102715 PMid:38471356
  99. Gertz MA. Waldenström macroglobulinemia: 2023 update on diagnosis, risk stratification, and management. Am J Hematol. 2023 Feb;98(2):348-358.  https://doi.org/10.1002/ajh.26796 PMid:36588395 PMCid:PMC10249724
  100. Dogliotti I, Jiménez C, Varettoni M, Talaulikar D, Bagratuni T, Ferrante M, Pérez J, Drandi D, Puig N, Gilestro M, García-Álvarez M, Owen R, Jurczak W, Tedeschi A, Leblond V, Kastritis E, Kersten MJ, D'Sa S, Kaščák M, Willenbacher W, Roccaro AM, Poulain S, Morel P, Kyriakou C, Fend F, Vos JMI, Dimopoulos MA, Buske C, Ferrero S, García-Sanz R. Diagnostics in Waldenström's macroglobulinemia: a consensus statement of the European Consortium for Waldenström's Macroglobulinemia. Leukemia. 2023 Feb;37(2):388-395. doi: 10.1038/s41375-022-01762-3. Epub 2022 Nov 26. https://doi.org/10.1038/s41375-022-01762-3 PMid:36435884 PMCid:PMC9898035
  101. Kapoor P, Rajkumar SV. Current approach to Waldenström macroglobulinemia. Blood Rev. 2023 Nov;62:101129.  https://doi.org/10.1016/j.blre.2023.101129 PMid:37659912
  102. Kumar SK, Callander NS, Adekola K, Anderson LD Jr, Baljevic M, Baz R, Campagnaro E, Castillo JJ, Costello C, D'Angelo C, Derman B, Devarakonda S, Elsedawy N, Garfall A, Godby K, Hillengass J, Holmberg L, Htut M, Huff CA, Hultcrantz M, Kang Y, Larson S, Lee H, Liedtke M, Martin T, Omel J, Robinson T, Rosenberg A, Sborov D, Schroeder MA, Sherbenou D, Suvannasankha A, Valent J, Varshavsky-Yanovsky AN, Snedeker J, Kumar R. Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2024 Jan;22(1D):e240001.  https://doi.org/10.6004/jnccn.2024.0001 PMid:38244272
  103. Schop RF, Fonseca R. Genetics and cytogenetics of Waldenström's macroglobulinemia. Semin Oncol. 2003; 30:142-145. [PubMed: 12720124] https://doi.org/10.1053/sonc.2003.50075 PMid:12720124
  104. Ocio EM, Schop RF, Gonzalez B, et al. 6q deletion in Waldenström macroglobulinemia is associated with features of adverse prognosis. Br J Haematol. 2007; 136:80-86. [PubMed: 17222197] https://doi.org/10.1111/j.1365-2141.2006.06389.x PMid:17222197
  105. Chang H, Qi C, Trieu Y, Jiang A, Young KH, Chesney A, Jani P, Wang C, Reece D, Chen C. Prognostic relevance of 6q deletion in Waldenström's macroglobulinemia: a multicenter study. Clin Lymphoma Myeloma. 2009 Mar;9(1):36-8. https://doi.org/10.3816/CLM.2009.n.008 PMid:19362968
  106. Braggio E, Fonseca R. Genomic abnormalities of Waldenström macroglobulinemia and related low-grade B-cell lymphomas. Clin Lymphoma Myeloma Leuk. 2013; 13:198-201. [PubMed: 23477936] https://doi.org/10.1016/j.clml.2013.02.015 PMid:23477936
  107. Feyler S, O'Connor SJ, Rawstron AC, et al. IgM myeloma: a rare entity characterized by a CD20- CD56-CD117- immunophenotype and the t(11;14). Br J Haematol. 2008; 140:547-551. [PubMed: 18275432] https://doi.org/10.1111/j.1365-2141.2007.06969.x PMid:18275432
  108. Avet-Loiseau H, Garand R, Lode L, et al. Translocation t(11;14)(q13;q32) is the hallmark of IgM, IgE, and non-secretory multiple myeloma variants. Blood. 2003; 101:1570-1571. [PubMed: 12393502] https://doi.org/10.1182/blood-2002-08-2436 PMid:12393502
  109. Chen R, Zhou D, Wang L, Zhu L, Ye X. MYD88L265P and CD79B double mutations type (MCD type) of diffuse large B-cell lymphoma: mechanism, clinical characteristics, and targeted therapy. Ther Adv Hematol. 2022 Jan 31;13:20406207211072839. https://doi.org/10.1177/20406207211072839 PMid:35126963 PMCid:PMC8808040
  110. de Groen RAL, Schrader AMR, Kersten MJ, Pals ST, Vermaat JSP. MYD88 in the driver's seat of B-cell lymphomagenesis: from molecular mechanisms to clinical implications. Haematologica. 2019 Dec;104(12):2337-2348. https://doi.org/10.3324/haematol.2019.227272 PMid:31699794 PMCid:PMC6959184
  111. Yu X, Li W, Deng Q, Li L, Hsi ED, Young KH, Zhang M, Li Y. MYD88 L265P Mutation in Lymphoid Malignancies. Cancer Res. 2018 May 15;78(10):2457-2462. https://doi.org/10.1158/0008-5472.CAN-18-0215 PMid:29703722
  112. Xu L, Hunter ZR, Yang G, et al. Detection of MYD88 L265P in peripheral blood of patients with Waldenström's Macroglobulinemia and IgM monoclonal gammopathy of undetermined significance. Leukemia. 2014; 28:1698-1704. [PubMed: 24509637] https://doi.org/10.1038/leu.2014.65 PMid:24509637
  113. Bachelerie F. CXCL12/CXCR4-axis dysfunctions: Markers of the rare immunodeficiency disorder WHIM syndrome. Dis Markers. 2010;29(3-4):189-98. https://doi.org/10.1155/2010/475104 PMid:21178277 PMCid:PMC3835381
  114. Kyle RA, Therneau TM, Dispenzieri A, et al. Immunoglobulin m monoclonal gammopathy of undetermined significance and smoldering Waldenström macroglobulinemia. Clin Lymphoma Myeloma Leuk 2013;13(2):184-6. https://doi.org/10.1016/j.clml.2013.02.00 5 PMid:23490989 PMCid:PMC3654087
  115. Kyle RA, Treon SP, Alexanian R, et al. Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's macroglobulinemia. Semin Oncol 2003;30(2):110-15. https://doi.org/10.1053/sonc.2003.50038 PMid:12720119
  116. Bustoros M, Sklavenitis-Pistofidis R, Kapoor P, Liu CJ, Kastritis E, Zanwar S, Fell G, Abeykoon JP, Hornburg K, Neuse CJ, Marinac CR, Liu D, Soiffer J, Gavriatopoulou M, Boehner C, Cappuccio JM, Dumke H, Reyes K, Soiffer RJ, Kyle RA, Treon SP, Castillo JJ, Dimopoulos MA, Ansell SM, Trippa L, Ghobrial IM. Progression Risk Stratification of Asymptomatic Waldenström Macroglobulinemia. J Clin Oncol. 2019 Jun 1;37(16):1403-1411. https://doi.org/10.1200/JCO.19.00394 PMid:30990729 PMCid:PMC6544461
  117. P. Morel, A. Duhamel, P. Gobbi, MA Dimopoulos, M.V. Dhodapkar, J. McCoy, et al., International prognostic scoring system for Waldenstrom ¨ macroglobulinemia, Blood 113 (18) (2009) 4163-4170 https://doi.org/10.1182/blood-2008-08-174961 PMid:19196866
  118. Kastritis E, Morel P, Duhamel A, et al. A revised international prognostic score system for Waldenström's macroglobulinemia. Leukemia. 2019;33(11):2654-2661 https://doi.org/10.1038/s41375-019-0431-y  PMid:31118465
  119. Perez Rogers A, Estes M. Hyperviscosity Syndrome: StatPearls. StatPearls Publishing LLC; 2022
  120. Gertz MA. Acute hyperviscosity: syndromes and management. Blood. 2018 Sep 27;132(13):1379-1385.  https://doi.org/10.1182/blood-2018-06-846816 PMid:30104220 PMCid:PMC6161773
  121. Abeykoon JP, Zanwar S, Ansell SM, et al. Predictors of symptomatic hyperviscosity in Waldenstrom macroglobulinemia. Am J Hematol. 2018;93(11):1384-1393. https://doi.org/10.1002/ajh.25254 PMid:30121949
  122. Mackenzie MR, Babcock J. Studies of the hyperviscosity syndrome. II: macroglobulinemia. J Lab Clin Med. 1975;85:227.
  123. Gertz MA, Kyle RA. Hyperviscosity syndrome. J Intensive Care Med. 1995;10:128. https://doi.org/10.1177/088506669501000304 PMid:10155178
  124. Singh A, Eckardt KU, Zimmermann A, et al. Increased plasma viscosity as a reason for inappropriate erythropoietin formation. J Clin Invest. 1993;91:251. [PubMed: 8423222] https://doi.org/10.1172/JCI116178 PMid:8423222 PMCid:PMC330021
  125. Khwaja J, Vos JMI, Pluimers TE, Japzon N, Patel A, Salter S, Kwakernaak AJ, Gupta R, Rismani A, Kyriakou C, Wechalekar AD, D'Sa S. Clinical and clonal characteristics of monoclonal immunoglobulin M-associated type I cryoglobulinaemia. Br J Haematol. 2024 Jan;204(1):177-185. doi: 10.1111/bjh.19112. Epub 2023 Sep 19. PMID: 37726004. https://doi.org/10.1111/bjh.19112 PMid:37726004
  126. Uppal E, Khwaja J, Bomsztyk J, McCarthy H, Kothari J, Walton P, et al. The Rory Morrison WMUK Registry for Waldenström macroglobulinemia: the growth of a national registry for a rare disorder. BrJ Haematol. 2023;201:905-12. https://doi.org/10.1111/bjh.18680 PMid:36698318
  127. Dimopoulos MA, Kastritis E. How I treat Waldenström macroglobulinemia.Blood. 2019;134(23):2022-35. https://doi.org/10.1182/blood.2019000725 PMid:31527073
  128. Retamozo S, Quartuccio L, Ramos-Casals M. Cryoglobulinemia. Med Clin (Barc). 2022 May 27;158(10):478-487. English, Spanish. doi: 10.1016/j.medcli.2021.11.017. Epub 2022 Feb 22. https://doi.org/10.1016/j.medcli.2021.11.017 PMid:35216803
  129. Nobile-Orazio E, Marmiroli P, Baldini L, et al. Peripheral neuropathy in macroglobulinemia: Incidence and antigen-specificity of M proteins. Neurology. 1987;37:1506. https://doi.org/10.1212/WNL.37.9.1506 PMid:2442666
  130. Treon SP, Hanzis C, Ioakimidis L, et al. Clinical characteristics and treatment outcome of disease-related peripheral neuropathy in Waldenström's macroglobulinemia (WM). J Clin Oncol. 2010;28:15s:Abstract 8114. https://doi.org/10.1200/jco.2010.28.15_suppl.8114
  131. Nemni R, Gerosa E, Piccolo G, Merlini G. Neuropathies associated with monoclonal gammopathies. Haematologica. 1994;79:557.
  132. Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia. N Engl J Med. 1998;338:1601. https://doi.org/10.1056/NEJM199805283382207 PMid:9603799
  133. Vital A. Paraproteinemic neuropathies. Brain Pathol. 2001;11:399. https://doi.org/10.1111/j.1750-3639.2001.tb00407.x PMid:11556684 PMCid:PMC8098264
  134. Latov N, Braun PE, Gross RB, et al. Plasma cell dyscrasia and peripheral neuropathy: Identification of the myelin antigens that react with human paraproteins. Proc Natl Acad Sci U S A. 1981;78:7139. https://doi.org/10.1073/pnas.78.11.7139 PMid:6273914 PMCid:PMC349211
  135. Chassande B, Leger JM, Younes-Chennoufi AB, et al. Peripheral neuropathy associated with IgM monoclonal gammopathy: correlations between M-protein antibody activity and clinical/electrophysiological features in 40 cases. Muscle Nerve. 1998;21:55. https://doi.org/10.1002/(SICI)1097-4598(199801)21:1<55::AID-MUS8>3.0.CO;2-F
  136. Weiss MD, Dalakas MC, Lauter CJ, et al. Variability in the binding of anti-MAG and anti-SGPG antibodies to target antigens in demyelinating neuropathy and IgM paraproteinemia. J Neuroimmunol. 1999;95:174. https://doi.org/10.1016/S0165-5728(98)00247-1 PMid:10229128
  137. Latov N, Hays AP, Sherman WH. Peripheral neuropathy and anti-MAG antibodies. Crit Rev Neurobiol 1988;3:301.
  138. Dalakas MC, Quarles RH. Autoimmune ataxic neuropathies (sensory ganglionopathies): are glycolipids the responsible autoantigens? Ann Neurol. 1996;39:419. https://doi.org/10.1002/ana.410390402 PMid:8619518
  139. Eurelings M, Ang CW, Notermans NC, et al. Antiganglioside antibodies in polyneuropathy associated with monoclonal gammopathy. Neurology. 2001;57:1909. https://doi.org/10.1212/WNL.57.10.1909 PMid:11723289
  140. Ilyas AA, Quarles RH, Dalakas MC, et al. Monoclonal IgM in a patient with paraproteinemic polyneuropathy binds to gangliosides containing disialosyl groups. Ann Neurol. 1985;18:655. https://doi.org/10.1002/ana.410180605 PMid:2417543
  141. Willison HJ, O'Leary CP, Veitch J, et al. The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies. Brain. 2001;124:1968. https://doi.org/10.1093/brain/124.10.1968 PMid:11571215
  142. Lopate G, Choksi R, Pestronk A. Severe sensory ataxia and demyelinating polyneuropathy with IgM anti-GM2 and GalNAc-GD1A antibodies. Muscle Nerve. 2002;25:828. https://doi.org/10.1002/mus.10122 PMid:12115971
  143. Jacobs BC, O'Hanlon GM, Breedland EG, et al. Human IgM paraproteins demonstrate shared reactivity between Campylobacter jejuni lipopolysaccharides and human peripheral nerve disialylated gangliosides. J Neuroimmunol. 1997;80:23. https://doi.org/10.1016/S0165-5728(97)00130-6 PMid:9413256
  144. Nobile-Orazio E, Manfredini E, Carpo M, et al. Frequency and clinical correlates of antineural IgM antibodies in neuropathy associated with IgM monoclonal gammopathy. Ann Neurol. 1994;36:416. https://doi.org/10.1002/ana.410360313 PMid:8080249
  145. Gordon PH, Rowland LP, Younger DS, et al. Lymphoproliferative disorders and motor neuron disease: an update. Neurology. 1997;48:1671. https://doi.org/10.1212/WNL.48.6.1671 PMid:9191785
  146. Pavord SR, Murphy PT, Mitchell VE. POEMS syndrome and Waldenström's macroglobulinemia. J Clin Pathol. 1996;49:181. https://doi.org/10.1136/jcp.49.2.181 PMid:8655693 PMCid:PMC500360
  147. Crisp D, Pruzanski W. B-cell neoplasms with homogeneous cold-reacting antibodies (cold agglutinins). Am J Med. 1982;72:915. https://doi.org/10.1016/0002-9343(82)90852-X PMid:6807086
  148. Pruzanski W, Shumak KH. Biologic activity of cold-reacting autoantibodies (first of two parts). N Engl J Med. 1977;297:538. https://doi.org/10.1056/NEJM197709082971005 PMid:69990
  149. Whittaker SJ, Bhogal BS, Black MM. Acquired immunobullous disease: a cutaneous manifestation of IgM macroglobulinemia. Br J Dermatol. 1996;135:283. https://doi.org/10.1111/j.1365-2133.1996.tb01162.x PMid:8881675
  150. Daoud MS, Lust JA, Kyle RA, Pittelkow MR. Monoclonal gammopathies and associated skin disorders. J Am Acad Dermatol. 1999;40:507. https://doi.org/10.1016/S0190-9622(99)70434-2 PMid:10188670
  151. Berentsen, S. Cold agglutinin-mediated autoimmune hemolytic anemia in Waldenstrom's macroglobulinemia. Clin. Lymphoma Myeloma 2009, 9, 110-112. [Google Scholar] [CrossRef] https://doi.org/10.3816/CLM.2009.n.030 PMid:19362990
  152. Gertz, M.A. Updates on the Diagnosis and Management of Cold Autoimmune Hemolytic Anemia. Hematol. Oncol. Clin. N. Am. 2022, 36, 341-352. [Google Scholar] [CrossRef] https://doi.org/10.1016/j.hoc.2021.11.001 PMid:35282954 PMCid:PMC9088174
  153. Owen, R.G.; Rawstron, A.; de Tute, R.M. Waldenström Macroglobulinaemia: Pathological Features and Diagnostic Assessment. In Waldenström's Macroglobulinemia; Leblond, V., Treon, S., Dimopoulos, M., Eds.; Springer International Publishing: Cham, Switzerland, 2017; pp. 3-19. [Google Scholar] https://doi.org/10.1007/978-3-319-22584-5_1
  154. García-Sanz R, Montoto S, Torrequebrada A, et al; Spanish Group for the Study of Waldenström Macroglobulinaemia and PETHEMA (Programme for the Study and Treatment of Haematological Malignancies). Waldenström macroglobulinemia: presenting features and outcome in a series with 217 cases. Br J Haematol 2001;115(03):575-582 https://doi.org/10.1046/j.1365-2141.2001.03144.x PMid:11736938
  155. Merchionne F, Procaccio P, Dammacco F. Waldenström's macroglobulinemia. An overview of its clinical, biochemical, immunological and therapeutic features and our series of 121 patients collected in a single center. Crit Rev Oncol Hematol 2011;80(01): 87-99 https://doi.org/10.1016/j.critrevonc.2010.09.007 PMid:21036057
  156. Perkins HA, MacKenzie MR, Fudenberg HH. Hemostatic defects in dysproteinemias. Blood 1970;35(05):695-707 https://doi.org/10.1182/blood.V35.5.695.695 PMid:4986530
  157. Merlini G, Baldini L, Broglia C, et al. Prognostic factors in symptomatic Waldenstrom's macroglobulinemia. Semin Oncol 2003;30(02):211-215 https://doi.org/10.1053/sonc.2003.50064 PMid:12720138
  158. Brysland SA, Maqbool MG, Talaulikar D, Gardiner EE. Bleeding Propensity in Waldenström Macroglobulinemia: Potential Causes and Evaluation. Thromb Haemost. 2022 Nov;122(11):1843-1857. doi: 10.1055/a-1896-7092. https://doi.org/10.1055/a-1896-7092 PMid:35817084 PMCid:PMC9626029
  159. Zanwar S, Abeykoon JP, Ansell SM, et al. Primary systemic amyloidosis in patients with Waldenstrom macroglobulinemia. Leukemia 2019;33(3):790-4. https://doi.org/10.1038/s41375-018-0286-7 PMid:30315235
  160. Sipe JD, Benson MD, Buxbaum JN, et al. Nomenclature 2014: Amyloid fibril proteins and clinical classification of the amyloidosis. Amyloid. 2014; 21:221-224. https://doi.org/10.3109/13506129.2014.964858 PMid:25263598
  161. Terrier B, Jaccard A, Harousseau JL, et al. The clinical spectrum of IgM-related amyloidosis: a French nationwide retrospective study of 72 patients. Medicine (Baltimore). 2008; 87:99-109. https://doi.org/10.1097/MD.0b13e31816c43b 6 PMid:18344807
  162. Brambilla F, Lavatelli F, Valentini V, et al. Changes in tissue proteome associated with ATTR amyloidosis: insights into pathogenesis. Amyloid. 2012; 19(Suppl 1):11-13. https://doi.org/10.3109/13506129.2012.674989 PMid:22551153
  163. Vrana JA, Gamez JD, Madden BJ, et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood. 2009; 114:4957- 4959. https://doi.org/10.1182/blood-2009-07-230722 PMid:19797517
  164. Fernandez de Larrea C, erga L, Morbini P, et al. A practical approach to the diagnosis of systemic amyloidoses. Blood. 2015; 125:2239-2244. https://doi.org/10.1182/blood-2014-11-609883 PMid:25636337
  165. Schonland SO, Hegenbart U, Bochtler T, et al. Immunohistochemistry in the classification of systemic forms of amyloidosis.
  166. Merlini G, Dispenzieri A, Sanchorawala V, et al. Systemic immunoglobulin light chain amyloidosis. Nat Rev Dis Primers 2018;4(1):38. https://doi.org/10.1038/s41572-018-0034-3 PMid:30361521
  167. Vergaro G, Castiglione V, Aimo A, et al. N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T hold diagnostic value in cardiac amyloidosis.Eur J Heart Fail 2023;25(3):335-46. https://doi.org/10.1002/ejhf.2769 PMid:36597836
  168. Ciccarelli BT, Patterson CJ, Hunter ZR, et al. Hepcidin is produced by lymphoplasmacytic cells and is associated with anemia in Waldenström's macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2011; 11:160-163. https://doi.org/10.3816/CLML.2011.n.038 PMid:21454222
  169. Treon SP, Tripsas CK, Ciccarelli BT, Manning RJ, Patterson CJ, Sheehy P, Hunter ZR. Patients with Waldenström macroglobulinemia commonly present with iron deficiency and those with severely depressed transferrin saturation levels show response to parenteral iron administration. Clin Lymphoma Myeloma Leuk. 2013 Apr;13(2):241-3. doi: 10.1016/j.clml.2013.02.016. Epub 2013 Mar 22. https://doi.org/10.1016/j.clml.2013.02.016 PMid:23523274
  170. Ito K, Harada K, Uchino Y, Hirano K, Sekiguchi N. Extramedullary hematopoietic pleural effusion in Waldenström's macroglobulinemia. EJHaem. 2023 Jul 6;4(3):833-836. doi: 10.1002/jha2.754. https://doi.org/10.1002/jha2.754 PMid:37601852 PMCid:PMC10435710
  171. Roccaro AM, Sacco A, Jimenez C, Maiso P,Moschetta M, Mishima Y, Aljawai Y, Sahin I, Kuhne M, Cardarelli P, Cohen L, San Miguel JF, Garcia-Sanz R, Ghobrial IM. C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma. Blood 2014;123:4120 https://doi.org/10.1182/blood-2014-03-564583 PMid:24711662
  172. Banwait R, Aljawai Y, Cappuccio J, McDiarmid S, Morgan EA, Leblebjian H, Roccaro AM, Laubach J, Castillo JJ, Paba-Prada C, Treon S, Redd R, Weller E, Ghobrial IM. Extramedullary Waldenström macroglobulinemia. Am J Hematol. 2015 Feb;90(2):100-4. doi: 10.1002/ajh.23880. Epub 2014 Nov 19. https://doi.org/10.1002/ajh.23880 PMid:25349134
  173. Bing J, Neel AV. Two Cases of Hyperglobulinaemia With Affection of the Central Nervous System on a Toxi- Infectious Basis. Acta Med Scand (1936) 88(5-6):492-506. doi: 10.1111/j.09546820.1936.tb12571.x https://doi.org/10.1111/j.0954-6820.1936.tb12571.x
  174. Simon L, Fitsiori A, Lemal R, Dupuis J, Carpentier B, Boudin L, et al. BingNeel Syndrome, a Rare Complication of Waldenström Macroglobulinemia: Analysis of 44 Cases and Review of the Literature. A Study on Behalf of the French Innovative Leukemia Organization (FILO). Haematologica (2015) 100 (12):1587. https://doi.org/10.3324/haematol.2015.133744 PMid:26385211 PMCid:PMC4666335
  175. Castillo JJ, D'Sa S, Lunn MP, Minnema MC, Tedeschi A, Lansigan F, et al. Central Nervous System Involvement by Waldenström Macroglobulinaemia (Bing-Neel Syndrome): A Multi-Institutional Retrospective Study. Br J Haematol (2016) 172(5):709-15. doi: 10.1111/bjh.13883 https://doi.org/10.1111/bjh.13883 PMid:26686858 PMCid:PMC5480405
  176. Fitsiori A, Fornecker LM, Simon L, Karentzos A, Galanaud D, Outteryck O, et al. Imaging Spectrum of Bing-Neel Syndrome: How Can a Radiologist Recognise This Rare Neurological Complication of Waldenström's Macroglobulinemia? Eur Radiol (2019) 29(1):102-14. doi: 10.1007/s00330- 018-5543-7 https://doi.org/10.1007/s00330-018-5543-7 PMid:29922935
  177. Minnema MC, Kimby E, D'Sa S, Fornecker LM, Poulain S, Snijders TJ, et al. Guideline for the Diagnosis, Treatment and Response Criteria for Bing-Neel Syndrome. Haematologica (2017) 102(1):43-51. doi: 10.3324/haematol.2016.147728 https://doi.org/10.3324/haematol.2016.147728 PMid:27758817 PMCid:PMC5210231
  178. Poulain S, Boyle EM, Roumier C, Demarquette H, Wemeau M, Geffroy S, et al. MYD88 L265P Mutation Contributes to the Diagnosis of Bing Neel Syndrome. Br J Haematol (2014) 167(4):506-13. doi: 10.1111/bjh.13078 https://doi.org/10.1111/bjh.13078 PMid:25160558
  179. Nelson S, Boise LH, Kaufman JL, et al. Changing Epidemiology and Improved Survival in Patients with Waldenstrom Macroglobulinemia: Review of  Surveillance, Epidemiology, and End Results (SEER) Data. Blood. 2013;122(21):3135. https://doi.org/10.1182/blood.V122.21.3135.3135
  180. Castillo JJ, Olszewski AJ, Kanan S, Meid K, Hunter ZR, Treon SP. Overall survival and competing risks of death in patients with Waldenstrom macroglobulinemia: an analysis of the surveillance, epidemiology and end results database. Br J Haematol. 2015;169(1):81-89. https://doi.org/10.1111/bjh.13264 PMid:25521528
  181. Varettoni M, Ferrari A, Frustaci AM, Ferretti VV, Rizzi R, Motta M, Piazza F, Merli M, Benevolo G, Visco C, Laurenti L, Ferrero S, Gentile M, Del Fabro V, Abbadessa A, Klersy C, Musto P, Fabbri N, Deodato M, Dogliotti I, Greco C, Corbingi A, Luminari S, Arcaini L. Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies. Am J Hematol. 2020 Dec;95(12):1473-1478. https://doi.org/10.1002/ajh.25961 PMid:32780514
  182. Chohan KL, Paludo J, Vallumsetla N, Larson D, King RL, He R, Gonsalves W, Inwards D, Witzig TE, Swaika A, Jain T, Leung N, Ailawadhi S, Reeder CB, Lacy MQ, Rajkumar SV, Kumar S, Kyle RA, Gertz MA, Ansell SM, Kapoor P. Survival trends in young patients with Waldenström macroglobulinemia: Over five decades of experience. Am J Hematol. 2023 Jan 1. doi: 10.1002/ajh.26807. https://doi.org/10.1002/ajh.26807 PMid:36588384