Waldenström macroglobulinemia (WM) is an IgM-secreting lymphoplasmacytic lymphoma (LPL), with up to 1,500 new cases diagnosed annually in the United States.1 The median age at diagnosis is approximately 70 years, although a steady increase in incidence is notable with advancing age.2 A consistently higher prevalence in men and Caucasians compared with other races is also striking.3 Genome-wide association studies performed by McMaster and colleagues4 have identified independent high-risk susceptibility loci occurring in excess in familial WM cases. Nearly 20% of patients with WM have a first-degree relative with a B-cell disorder.4,5
Clinical Manifestations
The clinical presentation of WM can be variable (Table 1). Although some presenting features, arising from increasing lymphoplasmacytic cellular burden, can mirror those of other indolent lymphomas, certain IgM-related symptoms are unique to this malignancy. Fatigue, the most common presenting feature, is largely attributable to anemia, but in the setting of high levels of circulating cytokines, it can be disproportionately more pronounced than the degree of anemia.6 Cytopenias may result from increasing marrow LPL involvement, but are manifestations of autoimmune phenomena, rarely, or can result from splenomegaly, with hypersplenism.7 Peripheral neuropathy is noted in up to 20% of patients, most commonly due to IgM binding to myelin-associated glycoprotein (anti-MAG) and less commonly due to antisulfatide or antiganglioside antibodies or to deposition of amyloid in nerves.8 Concomitant immunoglobulin amyloid light and/or heavy chain (AL/ALH) amyloidosis, resulting from misfolding of the clonal IgM heavy and/or involved free light chains, may be encountered in up to 8% of patients. Symptoms in such cases are driven by amyloid deposition–related organ dysfunction.9 Clinicians should remain vigilant for co-occurrence of AL/ALH amyloidosis, and specifically focus on certain telltale signs/symptoms at each visit (Table 1).10 Histologic transformation to an aggressive lymphoma is encountered in up to 4%, and typically occurs late in the disease course.11 Patients may present acutely, with an infection or hyperviscosity syndrome (Table 1).10 Importantly, the serum viscosity level and the symptom complex, rather than the absolute serum IgM level, should be relied on for making a diagnosis of symptomatic hyperviscosity and consideration of urgent plasma exchange.12 Rapid hemolysis and anemia, with or without acrocyanosis from cold agglutinin disease, can rarely be a presenting feature in 1% to 2% of patients.13 Acquired hemophilia, characterized by spontaneous hemorrhages, or acquired von Willebrand disease may be seen, with several postulated mechanisms, including selective von Willebrand factor (vWF) adsorption on WM cells, increased vWF proteolysis, and the presence of both neutralizing or nonneutralizing anti-vWF antibodies, leading to an occasional presentation with bleeding emergencies.14,15 Type 1 or 2 cryoglobulinemia, may be seen in a small subset of patients.16 Physical and radiographic examination at diagnosis should specifically focus on lymphadenopathy and hepatosplenomegaly assessment, noted in 15% to 25% of patients.4,6 A fundoscopic examination of dilated eyes, to rule out hyperviscosity-related retinal changes, is also imperative in patients presenting with visual disturbance or other features of hyperviscosity, as well as those with high circulating IgM (≥3,500 mg/dL), irrespective of the symptoms.17 A high index of suspicion is needed for attributing the acute onset of symptoms to the underlying WM. Clues supporting the diagnosis may be seen on the peripheral blood smear performed to evaluate cytopenias, showing evidence of rouleaux formation, or may be found from the incidental detection of elevated total protein level on the comprehensive metabolic panel, with evidence of circulating monoclonal IgM on further assessment through subsequent monoclonal protein studies (Table S1 in the supplementary materials, available online with this article).
Clinical Manifestations of Newly Diagnosed Waldenström Macroglobulinemia
Diagnostic Criteria for WM
Virtually all cases of WM are preceded by IgM monoclonal gammopathy of undetermined significance (MGUS). Unlike IgA MGUS, the incidence of IgM MGUS increases with age, which explains why WM predominantly affects the elderly.18 Recently, 2 distinct subtypes of IgM MGUS have been proposed: IgM MGUS-not otherwise specified (IgM MGUS-NOS) and IgM MGUS-plasma cell (IgM MGUS-PC). The latter, representing the precursor cell to IgM multiple myeloma, is characterized by the presence of clonal IgM-positive plasma cells but lacks clonal B-cells, and is typically MYD88WT, whereas the IgM MGUS-NOS is considered the precursor stage for WM.19,20 Although these distinct IgM MGUS phenotypes provide an interesting insight into the biology of WM, they need additional validation.
The diagnosis of IgM MGUS versus WM hinges on the degree of bone marrow infiltration by LPL (Table 2). Per the Mayo Clinic criteria, WM is characterized by the presence of IgM monoclonal protein and >10% LPL infiltrate.21 Approximately 1 in 5 patients with WM have smoldering WM (SWM) at diagnosis, without the presence of symptoms or indications for initiating treatment per the consensus criteria from the Second International Workshop on WM (Figure 1).22 The distinction between SWM and active WM is important, because SWM does not require treatment and patients managed with active surveillance demonstrate comparable survival to the age- and sex-matched US population.21,23
Diagnostic Criteria for IgM Gammopathies and the Consensus Criteria for Initiating Treatment for Active WM
Clinical features and definitions for active WM and its related precursor states.
Abbreviations: ALH, amyloid light/heavy chain; LPL, lymphoplasmacytic lymphoma; MGUS, monoclonal gammopathy of undetermined significance; WM, Waldenström macroglobulinemia.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.7024
Per the consensus criteria, evidence of IgM monoclonal gammopathy with histologic evidence of any degree of marrow involvement by LPL is sufficient to diagnose WM (Table 2). Based on these criteria, a high proportion of patients otherwise classified as having IgM MGUS are classified as having WM, which would then make it a common malignancy. The rationale for using a higher cutoff of LPL infiltration (≥10%) to define WM by the Mayo Clinic criteria stems from the high prevalence of IgM MGUS and low rate of its progression to active WM (∼1.5%/year).24,25 Furthermore, sensitive tools for clonality assessment can identify clonal LPL cells in the marrow aspirates of even patients categorized as having IgM MGUS per the Consensus criteria.26 Moreover, demonstration of the MYD88L265P mutation in 50% to 80% of patients with IgM MGUS suggests that clonal cells are indeed present at the MGUS state.27,28 Similarly, the morphologic LPL infiltrate cutoff of 10% to distinguish between asymptomatic IgM monoclonal gammopathies of SWM and MGUS can be prone to observer variance, highlighting the difficulty in categorizing a disease that likely exists in a continuum into distinct diagnostic clinical entities. Until more robust prospective data emerge, the notable difference in the progression rates of IgM MGUS (LPL <10%) and SWM (LPL ≥10%) guide our nomenclature for these 2 asymptomatic entities.29 A lower threshold would make WM one of the commonest hematologic malignancies when it clearly isn’t.
Genomic Profile of WM
The MYD88L265P mutation, a recurrent point mutation in the MYD88 gene is the commonest somatic mutation, reported in 80% to 95% of patients.27,30–32 Normally, the MYD88 adaptor protein plays a critical role in the toll-like receptor (TLR)/IL-1R signaling and is recruited by TLR/IL-1R activation, which induces inflammatory and immune genes.33 The mutated MYD88 adaptor protein promotes spontaneous Myddosome assembly, which ultimately activates the transcription factor, NF-κB, through Bruton tyrosine kinase (BTK), phospholipase-Cγ, and IL-1R–associated kinase signaling.33 The mutated MYD88 also upregulates hematopoietic cellular kinase, which in turn activates BTK and the extracellular-regulated kinase pathway.34 In cases where the histopathologic diagnosis is uncertain but WM is suspected, the presence of the MYD88 mutation favors the diagnosis of WM. Although not pathognomonic for WM, the MYD88L265P mutation is more frequently encountered in WM than other B-cell malignancies.35
Other frequently identified mutations in WM involve the CXCR4 gene, and is detected in 25% to 40% of patients.36 The CXCR4 cell-surface chemokine receptor upon binding to ligand, CXCL2/SDF-1, promotes cell proliferation, lymphocyte trafficking, migration, and stemness. CXCR4 mutation prevents CXCR4 receptor internalization and leads to continued signaling through the MAPK/AKT pathway, supporting WM cell survival.37,38 More than 40 different types of subclonal frameshift or nonsense CXCR4 mutations have been described, with CXCR4S338× being the most common.36,38 This poses challenges with their identification, because allele-specific PCR or droplet digital PCR (ddPCR) cannot be used to detect all mutations, and the sensitivity of Sanger sequencing is low (Supplementary Table S1). CD19 sorting increases the test sensitivity.39 Currently, the CXCR4 mutational testing is neither routinely available nor mandatory from a diagnostic standpoint. However, these mutations have prognostic implications (see later discussion). Additionally, point mutations in TP53 and ARID1A have been detected in 5% to 25% (likely lower in newly diagnosed WM) and 17% of patients, respectively, but other mutations (CD79B, KMT2D, NOTCH2, TRAF3, TNFAIP3, TERT) are detected less frequently on whole-exome sequencing.30,36,40,41 The commonly identified structural variants include deletion 6q in 30% to 50% of patients, trisomy of chromosomes 4, 12, 18 in 10% to 12% of patients, and deletion 13q and 17p in up to 10% of patients.36,42,43
Prognostic Impact of Genotype in WM
A study of 176 patients with IgM MGUS showed that high serum IgM concentration (≥1 g/dL) and the presence of MYD88 mutation independently shortened the progression to active WM.44 A recent study used ddPCR, a technique more sensitive than allele specific-PCR for mutational analysis, for MYD88L265P and CXCR4S338× mutation (C1013G and C1013A) analysis in patients with IgM MGUS (n=101) and SWM (n=69) demonstrated that a high bone marrow mutation burden (≥8% MYD88 and ≥2% CXCR4) was associated with an increased risk of progression to active WM.45 Conversely, other studies have shown that patients with SWM who harbor the MYD88WT genotype have a shorter time to progression (TTP) to active WM compared with patients with the MYD88L265P genotype (median TTP, 1.8 vs 4.5 years [n=106; P<.001] and 1.7 vs 4.7 years [n=42; P=.11], respectively).23,46 Multiple studies have demonstrated that patients with the MYD88WT genotype also have an increased risk for histologic transformation,19,47 with a 5-year transformation rate of 16% versus 2.8% for the MYD88WT and MYD88L265P genotype, respectively.11 Interestingly, some overlap has been noted in the mutational profiles of MYD88WT WM and diffuse large B-cell lymphoma in a small study of 18 patients, although the differentially expressed genes for the MYD88WT genotype were largely overlapping with those expressed in the MYD88L265P genotype.48 Conflicting reports on the prognostic impact of MYD88L265P in patients with active WM exist. In a study of whole-genome sequencing involving 175 patients, those with the MYD88WT genotype (n=15) presented at an older age, demonstrated lower marrow LPL infiltrate, and had inferior survival, after adjusting for age and beta-2 microglobulin.49 However, a Mayo Clinic study demonstrated comparable 5-year overall survival (OS) for patients with the MYD88WT and MYD88L265P genotypes (85% vs 82%).31
There are emerging concerns regarding compromised treatment efficacy in patients with the CXCR4MUT genotype (Supplementary Table S2). In particular, nonsense mutations seem to be associated with worse outcomes compared with the frameshift mutations.50 Salvage therapy with ibrutinib demonstrated inferior progression-free survival (PFS) for the CXCR4-mutated subset, underscoring the resistance conferred by the presence of CXCR4 mutation (Supplementary Table S2).51 Similarly, in a multi-institutional study, a trend toward shorter PFS was noted among patients with the CXCR4MUT genotype compared with those with the CXCR4WT genotype (estimated median PFS, 3.9 years [95% CI, 0.8–not reached (NR)] vs 5.5 years [95% CI, 5.3–NR], respectively; P=.05) who were treated with frontline bendamustine/rituximab.52 Whether the inferior response rates and shorter PFS of patients with CXCR4MUT genotype ultimately translates to reduced OS remains to be established, and large datasets, with longer follow-up, would need to be queried.
Emerging data from a post hoc biomarker analyses of the Aspen trial, examining 2 BTK inhibitors, ibrutinib and zanubrutinib, demonstrate inferior outcomes with the presence of TP53 mutation.53,54 Among patients with CXCR4MUT, TP53MUT, and TERTMUT, the findings trended toward lower very good partial response (VGPR) rate or major response rate (MRR) and longer median time to response than for the patients with the respective wild-type alleles.40 Specifically, patients with TP53MUT experienced reduced VGPR, MRR, and PFS in the ibrutinib arm, but no significant differences were observed in the zanubrutinib arm.40 The VGPR rate for TP53MUT subset was significantly higher in the zanubrutinib arm (35% vs 13%; P<.05). Additionally, structural variants like deletion 6q, deletion 11q, trisomy 4, and deletion 17p likely lead to inferior outcomes, but their independent prognostic value needs to be further delineated.43
Risk Stratification of Patients With WM
Historically, the median OS for patients with WM has been reported to be approximately 10 years, with an improvement in the outcomes in recent years in the elderly population.55–58 Although a subset of patients continues to have poor outcome, the treatment landscape of WM is rapidly expanding and the incremental benefit of novel therapeutics in this indolent disease remains to be untangled. Age at presentation is by far the strongest risk factor for survival, with more advanced age being consistently associated with inferior outcome, even after adjusting for cause specific survival.57 Even in the very elderly (age ≥75 years) patients, the predominant cause of death is WM-related, and poorer outcomes are observed compared with the age and sex-matched US population.59 Hepatosplenomegaly at presentation has also been noted as an independent adverse prognostic feature.60 Various laboratory parameters, including albumin, beta-2 microglobulin, lactate dehydrogenase (LDH), serum IgM, and hemoglobin levels and platelet count may affect prognosis.22,61,62 The International Prognostic Scoring System for WM (IPSS-WM) resulted from a multi-institutional effort that assessed prognostic factors at the time of treatment initiation (Table 3),63 and since its introduction has remained the cornerstone of risk stratification in treatment-naïve patients. However, the patients in the original derivation cohort of IPSS-WM were treated prior to 2001, and the discovery of novel mutations and the use of novel agents have necessitated revisiting it. Because up to 20% to 40% of patients with WM succumb to unrelated causes, the true impact of WM on survival is confounded.62,64 The IPSS-WM derivation did not take the alternate causes of death into account and requires validation with a competing-risk analysis. A subsequent iteration of IPSS-WM, the revised-IPSSWM (rIPSSWM), attempted to overcome some of these limitations and identified stratified age and albumin, LDH, and beta-2 microglobulin levels as independent prognostic factors (Table 3).57 However, the rIPSSWM was not fully validated, did not address the prognostic impact of cytogenetics and mutations, and is yet to be routinely adopted in clinical practice. Low serum albumin level is indicative of poor overall health and nutritional status, and reflects reduced hepatic synthesis, mediated in part by high levels of circulating IL-6 and other cytokines in patients with WM.65 Additionally, low albumin level may result from AL/ALH amyloidosis, a complication of WM with distinctly poorer outcomes.9 Elevated LDH level, a marker of high cell turnover and aggressive disease biology, is also independently prognostic.60,62 Using these parameters, a new simplified model, the modified staging system for WM (MSS-WM), has been proposed (Table 3).66 In the development of MSS-WM, stratified age, elevated LDH level, and low serum albumin level, but not MYD88L265P mutation, were independently prognostic.66 Stratifying patients into 4 distinct risk groups, the MSS-WM has been externally validated. However, the modeling was limited by the lack of data on the TP53 and CXCR4 mutational signatures of the patients, and the independent prognostic impact of these alterations on OS continues to remain unknown. The incorporation of mutational status into the existing prognostic models will likely make these prognostic systems more biologically driven, but such data on the prognostic effect of mutational status, particularly on OS, are currently limited. The presence of CXCR4 mutations clearly leads to slower response as well as lower response rates with BTK inhibitors, but its differential impact on OS is yet to be observed in a large study in the Western population. In a small study, Varettoni et al67 demonstrated that CXCR4 mutations do not affect OS.
Risk Stratification Tools for Waldenström Macroglobulinemia
Symptomatic hyperviscosity, encountered in approximately 13% of patients, does not impact survival.12 Histologic transformation and AL/AHL amyloidosis, on the other hand, are complications known to adversely affect the disease trajectory. Through a multicenter, international collaborative effort, Durot et al68 developed and validated a prognostic index for patients with transformed WM, identifying 3 adverse features, elevated serum LDH, platelet count <100 × 109/L, and previous use of WM-directed therapy, leading to the creation of 3 risk groups with 2-year survival rates of 81%, 47%, and 21%, respectively. This model risk stratified patients more accurately than the International Prognostic Index (IPI) or the revised IPI.68
A large Mayo Clinic study, involving a cohort of 997 patients with WM, has demonstrated markedly poor survival after the development of AL/ALH amyloidosis in a small subset. Among 75 (7.5%) patients who developed AL/ALH, 40 (53%) had WM and AL/ALH diagnosed concurrently, whereas 35 (47%) developed this complication later during their disease course. The cohort of patients with synchronous WM and AL/ALH had a substantially shorter survival compared with those without coexisting AL/ALH (median, 2.5 vs 12 years, respectively; hazard ratio, 5.9; P<.0001).9
Prognostic Impact of Response to Therapy
Complete response is infrequently attained with chemoimmunotherapy and is rare with BTK inhibitor–based regimens, perhaps due to persistent CD20-negative plasma cells. Previous studies have shown that patients achieving minor response have comparable OS to those attaining major response, and that deeper responses are inconsistently associated with better outcomes.69 Although, the primary endpoint of the registrational Aspen trial was VGPR or deeper responses, data supporting the prognostic value of achieving a deep response are nonexistent or unconvincing. The prognostic effect of attaining measurable residual disease (MRD), independent of IgM response is also being explored. de Tute et al70 used a flow cytometry assay (limit of detection 0.004%) to assess the marrow B-cell depletion, based on CD22weak CD25-positive expression in the R2W trial involving treatment-naïve patients randomized to BCR (bortezomib/cyclophosphamide/rituximab) or FCR (fludarabine/cyclophosphamide/rituximab). The 3-year PFS rate was higher in patients with undetectable B cells, deemed “MRD-negative” (89% vs 58% in MRD-positive patients [24/53 patients at the end of treatment; hazard ratio, 0.14; P=.002]).
Summary
WM is a rare and typically indolent type of non-Hodgkin lymphoma, without any pathognomonic biomarkers. Early intervention at the SWM stage is not warranted, and clear indications for initiation of therapy exist. However, a wide variation in outcomes is observed among patients with active WM. Incorporation of genomic testing in clinical trials is of critical importance to accurately understand its predictive impact on various therapies, and harmonization of methodologies for mutational testing is crucial to gain additional insight into prognostication. We believe that greater refinement of the currently used prognostic scoring systems, with incorporation of genomics, will likely ensue as our understanding of how the disease biology affects the clinical course deepens over the foreseeable future.
References
- 1.↑
Sekhar J, Sanfilippo K, Zhang Q, et al. Waldenström macroglobulinemia: a Surveillance, Epidemiology, and End Results database review from 1988 to 2005. Leuk Lymphoma 2012;53:1625–1626.
- 2.↑
Kastritis E, Kyrtsonis MC, Morel P, et al. Competing risk survival analysis in patients with symptomatic Waldenström macroglobulinemia: the impact of disease unrelated mortality and of rituximab-based primary therapy. Haematologica 2015;100:e446–449.
- 3.↑
Wang H, Chen Y, Li F, et al. Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study. Cancer 2012;118:3793–3800.
- 5.↑
Treon SP, Hunter ZR, Aggarwal A, et al. Characterization of familial Waldenstrom’s macroglobulinemia. Ann Oncol 2006;17:488–494.
- 6.↑
Gertz MA. Waldenström macroglobulinemia: 2019 update on diagnosis, risk stratification, and management. Am J Hematol 2019;94:266–276.
- 7.↑
Kapoor P, Singh E, Radhakrishnan P, et al. Splenectomy in plasma cell dyscrasias: a review of the clinical practice. Am J Hematol 2006;81:946–954.
- 8.↑
Klein CJ, Moon JS, Mauermann ML, et al. The neuropathies of Waldenström’s macroglobulinemia (WM) and IgM-MGUS. Can J Neurol Sci 2011;38:289–295.
- 9.↑
Zanwar S, Abeykoon JP, Ansell SM, et al. Primary systemic amyloidosis in patients with Waldenström macroglobulinemia. Leukemia 2019;33:790–794.
- 10.↑
Kapoor P, Rajkumar SV. Current approach to Waldenström macroglobulinemia. Blood Rev 2023;62:101129.
- 11.↑
Zanwar S, Abeykoon JP, Durot E, et al. Impact of MYD88L265P mutation status on histological transformation of Waldenström macroglobulinemia. Am J Hematol 2020;95:274–281.
- 12.↑
Abeykoon JP, Zanwar S, Ansell SM, et al. Predictors of symptomatic hyperviscosity in Waldenström macroglobulinemia. Am J Hematol 2018;93:1384–1393.
- 13.↑
Berentsen S. Cold agglutinin-mediated autoimmune hemolytic anemia in Waldenström’s macroglobulinemia. Clin Lymphoma Myeloma 2009;9:110–112.
- 14.↑
Hivert B, Caron C, Petit S, et al. Clinical and prognostic implications of low or high level of von Willebrand factor in patients with Waldenstrom macroglobulinemia. Blood 2012;120:3214–3221.
- 15.↑
Napolitano M, Siragusa S, Mancuso S, et al. Acquired haemophilia in cancer: a systematic and critical literature review. Haemophilia 2018;24:43–56.
- 16.↑
Sidana S, Rajkumar SV, Dispenzieri A, et al. Clinical presentation and outcomes of patients with type 1 monoclonal cryoglobulinemia. Am J Hematol 2017;92:668–673.
- 17.↑
Menke MN, Feke GT, McMeel JW, et al. Ophthalmologic techniques to assess the severity of hyperviscosity syndrome and the effect of plasmapheresis in patients with Waldenström’s macroglobulinemia. Clin Lymphoma Myeloma 2009;9:100–103.
- 18.↑
Love TJ, Rögnvaldsson S, Thorsteinsdottir S, et al. Prevalence of MGUS is high in the Istopmm study but the prevalence of IgA MGUS does not increase with age in the way other immunoglobulin subtypes do. Blood 2022;140(Suppl 1):256–258.
- 19.↑
Treon SP, Gustine J, Xu L, et al. MYD88 wild-type Waldenstrom macroglobulinaemia: differential diagnosis, risk of histological transformation, and overall survival. Br J Haematol 2018;180:374–380.
- 20.↑
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;140:1229–1253.
- 21.↑
Kapoor P, Ansell SM, Fonseca R, et al. Diagnosis and management of Waldenström macroglobulinemia: Mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines 2016. JAMA Oncol 2017;3:1257–1265.
- 22.↑
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;30:116–120.
- 23.↑
Zanwar S, Abeykoon JP, Ansell SM, et al. Disease outcomes and biomarkers of progression in smouldering Waldenström macroglobulinaemia. Br J Haematol 2021;195:210–216.
- 24.↑
Gobbi PG, Baldini L, Broglia C, et al. Prognostic validation of the international classification of immunoglobulin M gammopathies: a survival advantage for patients with immunoglobulin M monoclonal gammopathy of undetermined significance? Clin Cancer Res 2005;11:1786–1790.
- 25.↑
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538–548.
- 26.↑
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 2014;28:166–173.
- 27.↑
Varettoni M, Arcaini L, Zibellini S, et al. Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom’s macroglobulinemia and related lymphoid neoplasms. Blood 2013;121:2522–2528.
- 28.↑
Xu L, Hunter ZR, Yang G, et al. MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. Blood 2013;121:2051–2058.
- 29.↑
Kyle RA, Benson JT, Larson DR, et al. Progression in smoldering Waldenstrom macroglobulinemia: long-term results. Blood 2012;119:4462–4466.
- 30.↑
Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med 2012;367:826–833.
- 31.↑
Zanwar S, Abeykoon JP, Ansell SM, et al. Characteristics and outcome of patients with MYD88 wild-type Waldenström macroglobulinemia. J Clin Oncol 2020;38(Suppl):Abstract 8550.
- 32.↑
Patkar N, Subramanian PG, Deshpande P, et al. MYD88 mutant lymphoplasmacytic lymphoma/Waldenström macroglobulinemia has distinct clinical and pathological features as compared to its mutation negative counterpart. Leuk Lymphoma 2015;56:420–425.
- 33.↑
Chen L, Zheng L, Chen P, et al. Myeloid differentiation primary response protein 88 (MyD88): the central hub of TLR/IL-1R signaling. J Med Chem 2020;63:13316–13329.
- 34.↑
Yang G, Buhrlage SJ, Tan L, et al. HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib. Blood 2016;127:3237–3252.
- 35.↑
Jiménez C, Sebastián E, Chillón MC, et al. MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström’s macroglobulinemia. Leukemia 2013;27:1722–1728.
- 36.↑
Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood 2014;123:1637–1646.
- 37.↑
Roccaro AM, Sacco A, Jimenez C, et al. C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma. Blood 2014;123:4120–4131.
- 38.↑
Cao Y, Hunter ZR, Liu X, et al. The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s macroglobulinemia. Leukemia 2015;29:169–176.
- 39.↑
Gustine JN, Xu L, Yang G, et al. Bone marrow involvement and subclonal diversity impairs detection of mutated CXCR4 by diagnostic next-generation sequencing in Waldenström macroglobulinaemia. Br J Haematol 2021;194:730–733.
- 40.↑
Dimopoulos M, Opat S, D’Sa S, et al. ASPEN biomarker analysis: response to BTK inhibitor treatment in patients with Waldenström macroglobulinemia harboring CXCR4, TP53, and TERT mutations. Presented at the 11th International Workshop on Waldenström’s Macroglobulinemia; October 27–30, 2022; Madrid, Spain.
- 41.↑
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;184:242–245.
- 42.↑
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;96:1569–1579.
- 43.↑
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;98:649–654.
- 44.↑
Varettoni 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 2013;122:2284–2285.
- 45.↑
Moreno DF, López-Guerra M, Paz S, et al. Prognostic impact of MYD88 and CXCR4 mutations assessed by droplet digital polymerase chain reaction in IgM monoclonal gammopathy of undetermined significance and smouldering Waldenström macroglobulinaemia. Br J Haematol 2023;200:187–196.
- 46.↑
Bustoros M, Sklavenitis-Pistofidis R, Kapoor P, et al. Progression risk stratification of asymptomatic Waldenström macroglobulinemia. J Clin Oncol 2019;37:1403–1411.
- 47.↑
Talaulikar D, Tomowiak C, Toussaint E, et al. Evaluation and management of disease transformation in Waldenström macroglobulinemia. Hematol Oncol Clin North Am 2023;37:787–799.
- 48.↑
Hunter ZR, Xu L, Tsakmaklis N, et al. Insights into the genomic landscape of MYD88 wild-type Waldenström macroglobulinemia. Blood Adv 2018;2:2937–2946.
- 49.↑
Treon SP, Cao Y, Xu L, et al. Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood 2014;123:2791–2796.
- 50.↑
Castillo JJ, Xu L, Gustine JN, et al. CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenström macroglobulinaemia treated with ibrutinib. Br J Haematol 2019;187:356–363.
- 51.↑
Treon SP, Meid K, Gustine J, et al. Long-term follow-up of ibrutinib monotherapy in symptomatic, previously treated patients with Waldenström macroglobulinemia. J Clin Oncol 2021;39:565–575.
- 52.↑
Zanwar S, Abeykoon JP, Castillo JJ, et al. A multicenter, international collaborative study evaluating frontline therapy with bendamustine rituximab for Waldenström macroglobulinemia. Hemasphere 2022;6:Abstract P1159.
- 53.↑
Poulain S, Roumier C, Bertrand E, et al. TP53 mutation and its prognostic significance in Waldenstrom’s macroglobulinemia. Clin Cancer Res 2017;23:6325–6335.
- 54.↑
D’Sa S, Matous JV, Advani R, et al. Report of consensus panel 2 from the 11th international workshop on Waldenström’s macroglobulinemia on the management of relapsed or refractory WM patients. Semin Hematol 2023;60:80–89.
- 55.↑
Castillo JJ, Olszewski AJ, Kanan S, et al. Overall survival and competing risks of death in patients with Waldenström macroglobulinaemia: an analysis of the Surveillance, Epidemiology and End Results database. Br J Haematol 2015;169:81–89.
- 56.↑
Dhodapkar MV, Hoering A, Gertz MA, et al. Long-term survival in Waldenstrom macroglobulinemia: 10-year follow-up of Southwest Oncology Group-directed Intergroup trial S9003. Blood 2009;113:793–796.
- 57.↑
Kastritis E, Morel P, Duhamel A, et al. A revised international prognostic score system for Waldenström’s macroglobulinemia. Leukemia 2019;33:2654–2661.
- 58.↑
Chohan KL, Paludo J, Vallumsetla N, et al. Survival trends in young patients with Waldenström macroglobulinemia: over five decades of experience. Am J Hematol 2023;98:432–439.
- 59.↑
Zanwar S, Abeykoon JP, Ansell SM, et al. Waldenström macroglobulinemia in the very elderly (≥75 years): clinical characteristics and outcomes. Blood 2020;136(Suppl 1):44–45.
- 60.↑
Ghobrial IM, Fonseca R, Gertz MA, et al. Prognostic model for disease-specific and overall mortality in newly diagnosed symptomatic patients with Waldenstrom macroglobulinaemia. Br J Haematol 2006;133:158–164.
- 61.↑
Anagnostopoulos A, Zervas K, Kyrtsonis MC, et al. Prognostic value of serum beta2-microglobulin in patients with Waldenstrom’s macroglobulinemia requiring treatment. Clin Lymphoma Myeloma 2006;7:205–209.
- 62.↑
Kastritis E, Kyrtsonis MC, Hadjiharissi E, et al. Validation of the International Prognostic Scoring System (IPSS) for Waldenstrom’s macroglobulinemia (WM) and the importance of serum lactate dehydrogenase (LDH). Leuk Res 2010;34:1340–1343.
- 63.↑
Morel P, Duhamel A, Gobbi P, et al. International prognostic scoring system for Waldenstrom macroglobulinemia. Blood 2009;113:4163–4170.
- 64.↑
Ruan G, Zanwar S, Abeykoon JP, et al. Predictors of short-term survival in Waldenström macroglobulinemia. Leuk Lymphoma 2020;61:2975–2979.
- 65.↑
Elsawa SF, Ansell SM. Cytokines in the microenvironment of Waldenström’s macroglobulinemia. Clin Lymphoma Myeloma 2009;9:43–45.
- 66.↑
Zanwar S, Le-Rademacher J, Durot E, et al. Simplified risk stratification model for patients with Waldenström macroglobulinemia. J Clin Oncol 2024;42:2527–2536.
- 67.↑
Varettoni M, Zibellini S, Defrancesco I, et al. Pattern of somatic mutations in patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance. Haematologica 2017;102:2077–2085.
- 68.↑
Durot E, Kanagaratnam L, Zanwar S, et al. A prognostic index predicting survival in transformed Waldenström macroglobulinemia. Haematologica 2021;106:2940–2946.
- 69.↑
Gertz MA, Abonour R, Heffner LT, et al. Clinical value of minor responses after 4 doses of rituximab in Waldenström macroglobulinaemia: a follow-up of the Eastern Cooperative Oncology Group E3A98 trial. Br J Haematol 2009;147:677–680.
- 70.↑
de Tute R, Counsell N, Rawstron A, et al. Minimal residual disease (MRD) in Waldenstrom macroglobulinaemia (WM): depletion of WM-phenotype B-cells is strongly associated with progression following rituximab-based therapy. Presented at the 11th International Workshop on Waldenström’s Macroglobulinemia; October 27–30, 2022; Madrid, Spain.
- 71.
Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin Oncol 2003;30:110–115.
