Definition and characteristics

Waldenström macroglobulinaemia is a rare chronic lymphoproliferative disorder that is usually indolent. Only 10-15% of patients show more rapid progression of the disease. The incidence is 3:1,000,000. Men develop the disease about twice as often as women, and older people (>65 years) are particularly affected.

Classification

According to the WHO classification of 2017, Waldenström macroglobulinaemia is assigned to the mature B-cell neoplasms and here to the lymphoplasmocytic lymphomas (LPL). Characteristic and also diagnosis-defining features of Waldenström macroglobulinaemia are lymphoplasmacytic infiltration of the bone marrow and monoclonal immunoglobulin M (IgM). The origin of the pathological cell population is probably B cells, which have not yet undergone an isotype change but have already undergone the germinal center reaction.

Waldenström macroglobulinaemia WHO classification 2017 (Swerdlow et al. 2017)

Mature B-cell neoplasia

Lymphoplasmocytic lymphoma (LPL)
- Waldenström macroglobulinaemia

Waldenström macroglobulinaemia can arise from IgM-MGUS

Laboratory diagnosis of IgM-MGUS (monoclonal gammopathy of uncertain significance) develops into Waldenström macroglobulinaemia at a progression rate of 1.5-2% per year (Kyle et al. 2003, Bustoros et al. 2019). IgM-MGUS is defined by a serum monoclonal IgM concentration of less than 30 g/L and less than 10% plasma cells in the bone marrow (Swerdlow et al. 2017). 6q deletions characteristic of Waldenström macroglobulinaemia (see also chromosomal analysis) are a risk factor for transformation of IgM-MGUS into Waldenström macroglobulinaemia (Paiva et al. 2015, Guerrera et al. 2018).

Facts

  • >90%
    >90%

    of all patients have a MYD88 mutation

    (Treon et al. 2012)

Diagnostics

Cytomorphology

In the diagnosis of the various lymphomentities, cytomorphology and histology are guiding factors for downstream diagnostics. On the one hand, the assessment of the blood and bone marrow smear provides an initial landmark statement as to whether lymphoma is present or possible. Cytomorphology and histology are also useful for assessing the degree of lymphoma maturity.

Immunophenotyping

Immunophenotyping allows a clear determination of lineage affiliation to the T- or B-lineage in lymphomas. Furthermore, multiparametric flow cytometry is often indispensable for differentiation between different lymphoid entities.

The neoplastic cells express pan-B cell markers (CD19, CD20, CD79, CD22) (Swerdlow et al. 2017, Dimopoulos & Kastritis 2019), with CD22 usually being weakly expressed (Dimopoulos & Kastritis 2019). The tumor cells are usually positive for the markers CD25, CD27, FMC7, CD52, CD38 and express IgM (Swerdlow et al. 2017, Dimopoulos & Kastritis 2019). Typically, the degenerated cells are negative for CD5, CD10, CD103, and CD23 (Swerdlow et al. 2017, Dimopoulos & Kastritis 2019). BCL2 is expressed in the vast majority of cases (98%) and represents a potential therapeutic target (Paiva et al. 2014, Dimopoulos & Kastritis 2019) (using venetoclax, see also Table 3 under Therapy).

Chromosome analysis

6q deletion characteristic of Waldenström macroglobulinaemia

The most common chromosomal alteration in Waldenström macroglobulinaemia is a deletion in the long arm of chromosome 6 (6q deletion). The minimally deleted region includes several genes important for pathogenesis and pathobiology, these are regulatory factors of NFкB signaling (TNFAIP3, HIVEP2), apoptosis (FOXO3), and plasma cell differentiation (PRDM1), as well as the BTK regulator IBTK, the BCL2 regulator BCLAF1, and the ARID1B gene (Guerrera et al. 2018, Treon et al. 2020). The 6q deletion occurs in approximately half of all patients (Braggio et al. 2012). However, this abnormality is not specific to Waldenström macroglobulinaemia, but is also commonly found in other mature B-cell neoplasms such as CLL or marginal zone lymphoma (MZL).

A gain of the short arm of chromosome 6 (6p gain) is found as the second most common chromosomal abnormalities, this can result for example from the formation of an isochromosome 6p (Braggio et al. 2009 (1)). However, 6p gain occurs exclusively in combination with 6q deletion (Braggio et al. 2009 (2) & 2012). Characteristic of Waldenström macroglobulinaemia appear to be whole or partial gains of chromosome 4 as well as a gain of the long arm of chromosome 8 (Braggio et al. 2009 (2) & 2012). In addition, interstitial deletions occur in the long arm of chromosome 13, affecting the same minimally deleted region as in CLL (Braggio et al. 2009 (2) & 2012). Patients with Waldenström macroglobulinaemia may have gains of chromosomes 3 and 18, which have also been described in patients with MZL and CLL (Braggio et al. 2009 (2) & 2012).

FISH

While rearrangements of the IGH locus are very rare in Waldenström macroglobulinaemia compared to other mature B-cell neoplasms (Braggio et al. 2012), ATM deletions (11q deletions) are detectable in 7% of patients and TP53 deletions (17p deletions) in 8% of patients (Nguyen-Khac et al. 2013). Deletion of the TP53 gene, as in other mature B-cell neoplasms, is associated with a rather unfavorable outcome (Nguyen-Khac et al. 2013).

Molecular genetics

Mutation in MYD88 gene characteristic in Waldenström macroglobulinaemia

Molecularly, the L265P mutation in the MYD88 gene is significant in Waldenström macroglobulinaemia. This mutation occurs in approximately 90% of all lymphoplasmacytic lymphomas (Treon et al. 2012). It is characteristic of Waldenström macroglobulinaemia but is not specific. The L265P mutation in the MYD88 gene has also been found in patients with IgM MGUS at a lower frequency than in Waldenström macroglobulinaemia (Treon et al. 2012, Varettoni et al. 2013 (1)). MYD88 mutations in IgM-MGUS represent an independent risk factor for disease progression (Varettoni et al. 2013 (2)).

The MYD88 L265P mutation in Waldenström macroglobulinaemia mediates aberrant activation of the NFкB signaling pathway in a manner dependent on Bruton tyrosine kinase (BTK) and interleukin-1 receptor associated kinase (IRAK), which promotes cell growth and survival (Treon et al. 2020 and others). BTK dependence is now used as a therapeutic target (reviewed in Therapy). Central regulators of this MYD88-dependent pathway, such as the inhibitor of BTK (IBTK) and the NFкB regulators HIVEP2 and TNFAIP3 are encoded on the long arm of chromosome 6 (et al. Treon et al. 2020) and are affected by the typical 6q loss (see also Chromosome analysis).

In patients with unmutated MYD88 gene, recurrent mutations in factors of the NFкB pathway have been described by a comprehensive genetic characterization by Hunter et al. However, all identified factors act downstream of BTK. This could possibly contribute to the potential clinical consequence of patients with wild-type MYD88 showing a reduced response to the BTK inhibitor ibrutinib (see also Table 3 under Therapy) (Hunter et al. 2018, Treon et al. 2020). Other recurrent mutations in patients with MYD88 wild-type involve epigenetic factors (KMT2D, KMT2C, KDM6A) and cellular response to DNA damage (TP53, ATM, TRRAP) (Hunter et al. 2018). This mutational landscape has some overlap with the mutational landscape of DLBCL (Treon et al. 2020).

Other recurrent mutations in Waldenström macroglobulinaemia

In addition to the characteristic MYD88 L265P mutation, the nonsense S338X mutation in the CXCR4 gene is present in approximately 30% of patients with Waldenström macroglobulinaemia (Roccaro et al. 2014, Efebera et al. 2014). Other nonsense and frameshift mutations are known (Poulain et al. 2016). Common to all CXCR4 mutations is the loss of regulatory amino acids in the C-terminal domain, resulting in aberrant activation of the AKT and ERK signaling pathways, which in turn promote tumor cell survival (Treon et al. 2020, among others). In other mature B-cell neoplasms, these mutations occur in less than 10% of patients. Thus, the CXCR4 mutation is relatively specific for Waldenström macroglobulinaemia (Treon et al. 2020). A CXCR4 mutation and a clonal 6q deletion are mutually exclusive; instead, focal subclonal deletions of pathogenetically relevant genes localized to chromosome 6q are found (Guerrera et al. 2018) (see also Figure 1).

CXCR4 mutations occur almost exclusively together with a MYD88 mutation (Hunter et al. 2017). Thus, three major genotypes can be distinguished that influence prognosis and therapy (see Figure 1 and cf. Prognosis and Therapy). The genotype MYD88 WT (wild type) and CXCR4 MUT (mutation) has been described but occurs very rarely (Hunter et al. 2018, Kaiser et al. 2021).

Figure 1: Similarities and differences between the MYD88 and CXCR4 genotypes of Waldenström macroglobulinaemia in terms of their frequency, pathomechanisms, and clinic (modeled with adaptations after Hunter et al. 2017, expanded after Hunter et al. 2018, Guerrera et al. 2018, and Kaiser et al. 2021). Due to its rarity, the MYD88 WT and CXCR4 MUT genotypes are grayed out. 

ARID1A mutations are found in approximately 17% of patients (Treon et al. 2012). As an indirect regulator of TP53, nonsense or frameshift ARID1A mutations can lead to dysregulation of apoptosis (Treon et al. 2020).

Mutations in CD79A and CD79B, which are central factors in the B-cell receptor signaling pathway, occur at a frequency of 8-12% (Treon et al. 2020). TP53 mutations are detectable in 2-3% of patients and are associated with an unfavorable prognosis (Poulain et al. 2017, Gustine et al. 2019, Treon et al. 2020).

Prognosis

The International scoring system for Waldenström macroglobulinaemia (ISSWM), introduced in 2009, classified Waldenström macroglobulinaemia into three risk groups taking into account the prognostic parameters of age, ß2-microglobulin level, cytopenias, and level of gammopathy (Morel et al. 2009).

In 2019, the score was revised to consider ß2-microglobulin level, LDH level, and serum albumin concentration in addition to age. Depending on the age of the patient, each parameter is weighted by up to 2 risk points. The classification according to the "revised international prognostic score system for Waldenström macroglobulinaemia" (rIPSSWM) is now done in 5 risk groups (Kastritis et al. 2019), see Table 1.

Table 1: Assignment of points for the formulatin of the staging system

Risk factor

Points

Age:  < 65

0

Age: 66-75

1

Age:  > 75

2

β2-microglobuin >4 mg/L

1

LDH  > 250 IU/L

1

Serum albumin <3,5  g/dL

1

Stage

Score

5-year OS

10-year OS

Very low

0

95%

84%

Low

1

86%

59%

Intermediate

2

78%

37%

High

3

47%

19%

Very high

4-5

36%

9%

In contrast to the ISSWM (Morel et al. 2009), the data on which the rIPSSWM is based were collected after the introduction of combined immunochemotherapy with rituximab (Kastritis et al. 2019). Prognostically relevant gene mutations or chromosomal abnormalities are also not considered in the rIPSSWM.

Mutations of MYD88 and CXCR4 and TP53 alterations are prognostically relevant

The presence of a mutation in the MYD88 gene is associated with better overall survival compared with MYD88 wild type (Treon et al. 2014 (1), Treon et al. 2018 (1)). Clinical presentation is also affected by the MYD88 L265P mutation, with patients with the mutation having higher bone marrow infiltration and higher serum IgM levels compared with MYD88 wild type (Treon et al. 2014 (1)).

CXCR4 mutations also influence the clinical presentation; in particular, cases with CXCR4 nonsense mutations show an association with increased bone marrow infiltration and elevated IgM levels; also, a greater proportion of patients with this genotype present with symptomatic hyperviscosity at diagnosis. While a CXCR4 mutation does not seem to influence overall survival (Treon et al. 2014 (1), Treon et al. 2020), a reduced response and progression-free survival is shown under therapy with BTK inhibitors (see also Therapy). Taking into account the negative impact of a MYD88 wild type on survival as well as therapy resistance to BTK inhibitors due to a CXRC4 mutation, the MYD88 mutant and CXCR4 wild type genotype represents the most favorable constellation in Waldenström macroglobulinaemia (see also Figure 1) (Hunter et al. 2017). This also has therapeutic implications (e.g., Treon et al. 2020).

Mutations and/or deletions of the TP53 gene are associated with an unfavorable prognosis (Poulain et al. 2017, Gustine et al. 2019, Treon et al. 2020), but have rarely been evaluated in routine clinical practice (Dimopoulos & Kastritis 2019).

Prognosis calculation for Waldenström macroglobulinaemia

Here you can access the prognosis calculation of the ISSWM score. The rIPSSWM score can be determined using Table 1.

Therapy

Close monitoring in asymptomatic Waldenström macroglobulinaemia

Based on the therapeutic indication, two subgroups can be distinguished in Waldenström macroglobulinaemia. Up to 30% of patients are asymptomatic at diagnosis, and this group is therefore classified as asymptomatic or smoldering Waldenström macroglobulinaemia (SMW) (Pophali et al. 2019). The rate of progression to symptomatic Waldenström macroglobulinaemia is 12% per year (Bustoros et al. 2019).

For these patients, there is a need for close monitoring. The risk for progression to symptomatic Waldenström macroglobulinaemia can be determined using an online tool. The model is based on a study of the risk of progression in 439 patients with asymptomatic Waldenström macroglobulinaemia, in which the authors included cases with both IgM MGUS and SWM. Independent risk factors identified were bone marrow infiltration ≥70%, IgM protein level ≥4,500 mg/dL, β2-microglobulin ≥4.0 mg/dL, and albumin ≤3.5 g/dL. Patients could be divided into three risk groups with significant differences in "Time To Progression" (TTP). For low-risk patients, the TTP was 9.3 years, for intermediate-risk patients it was 4.8 years, and for patients in the high-risk group it was 1.8 years. The patients at high risk of progression also had a worse prognosis in terms of disease-specific survival (Bustoros et al. 2019). MYD88 mutation status was also known for a total of 106 of the patients. MYD88 wild type was also a factor in increased risk of progression (Bustoros et al. 2019). Another study also identified CXCR4 mutations as a risk factor for progression of asymptomatic Waldenström macroglobulinaemia (Varettoni et al. 2017).

Therapy of symptomatic Waldenström macroglobulinaemia

In the therapy of Waldenström macroglobulinaemia, in addition to the reduction of tumor burden, the control of symptomatology is an essential goal (Dimopoulos & Kastritis 2019). This may result from IgM paraprotein on the one hand (e.g., neuropathy, cryoglobulinemia, hyperviscosity, amyloidosis) and from hematopoietic tissue involvement on the other (e.g., cytopenias, lymphadenopathy, hepatomegaly, splenomegaly) (Onkopedia Guideline Waldenström macroglobulinaemia 2018, Dimopoulos & Kastritis 2019). Since complete remissions (CR, complete remission) are rarely achieved in Waldenström macroglobulinaemia (Dimopoulos & Kastritis 2019), other metrics have been established to assess treatment response, these are listed in Table 2. A "major response" is considered to be at least a partial response (CR, VPGR and PR, see Table 2).

Table 2: Definition of the different response categories in Waldenström macroglobulinaemia according to the consensus of the 6th International Workshop on Waldenström macroglobulinaemia (IWWM-6) (selection according to Owen et al. 2013).

 

CR

(complete response)

VGPR

(very good partial response)

PR

(partial response)

MR

(minor response)

IgM detection

Absence of serum monoclonal IgM protein by immunofixation

Monoclonale IgM protein is detectable

Monoclonal IgM protein is detectable

Monoclonal IgM is detectable

Serum IgM level

Normal

≥90% reduction in serum IgM level from baseline

≥50% but <90% reduction in serum IgM level from baseline

≥25% but <50% reduction in serum IgM level from baseline

Extramedullary disease

Complete resolution of extramedullary disease, i.g., lymphadenopathy and splenomegaly if present at baseline

Complete resolution of extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at baseline

Reduction in extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at baseline

 

Signs or symptoms of disease

 

No signs or symptoms of active disease

No new signs or symptoms of active disease

No newsigns or symptoms of active disease

Bone marrow morphology

Morphologically normal bone marrow aspirate and trephine

 

 

 

 

For the therapy of Waldenström macroglobulinaemia, various targeted therapeutics or therapy regimens are available. The current gold standard for induction therapy for physically fit patients is rituximab-based therapies. The anti-CD20 antibody is combined with chemotherapeutic agents, usually bendamustine or dexamethasone/cyclophosphamide (Onkopedia guideline Waldenström disease 2018).

If there is no suitability for chemoimmunotherapy, monotherapy with the BTK inhibitor ibrutinib is a treatment option (Onkopedia guideline Waldenström macroglobulinaemia 2018). In both first-line (Treon et al. 2018 (2)) and pretreated refractory/relapsed patients (Treon et al. 2015 (1), Treon et al. 2021), ibrutinib is very active, showing overall response rates above 90% and a "major response" >70% (Treon et al. 2015 (1), Treon et al. 2018 (2), Treon et al. 2021, Owen 2021). The second-generation BTK inhibitor zanubrutinib has similar high overall response rates (Trotman et al. 2020, Tam et al. 2020, Kapoor & Treon 2020). Direct comparison between ibrutinib and zanubrutinib showed that, on trend, more patients achieved very good partial remission (VGPR) and the toxicity of zanubrutinib, with the exception of neutropenia, is significantly reduced (Tam et al. 2020, Kapoor & Treon 2020, Owen 2021).

Bortezomib belongs to the proteasome inhibitor class and also shows good activity in combination with rituximab with overall response rates >80%. The incidence of severe neurotoxicity can be reduced by weekly subcutaneous administration (Onkopedia guideline Waldenström macroglobulinaemia 2018).

Influence of symptomatology on the choice of therapy

When selecting the appropriate therapeutic regimen, disease-associated symptoms must be considered in addition to age, suitability for chemoimmunotherapy, and comorbidities (Onkopedia guideline Waldenström macroglobulinaemia 2018, Gertz 2018, Dimopoulos & Kastritis 2019).

If the focus is on reducing a high tumor burden, a rapid-acting therapeutic regimen can be considered. These include rituximab-based therapeutic regimens (Dimopoulos & Kastritis 2019).

If paraprotein-related symptoms are the primary concern, plasmapheresis can be performed prior to induction in patients with hyperviscosity syndrome (Onkopedia guideline Waldenström macroglobulinaemia 2018). This may also be considered in some circumstances to lower high plasma IgM levels (Onkopedia guideline Waldenström macroglobulinaemia 2018). With rituximab treatment, a transient IgM increase ("IgM flare") may be observed in 30-80% of patients, which may exacerbate any existing paraprotein-related symptomatology (Dimopoulos & Kastritis 2019). Because bortezomib does not cause a transient IgM rise and can lead to rapid reduction in IgM levels (Dimopoulos & Kastritis 2019), patients with high paraprotein benefit in particular (Onkopedia guideline Waldenström macroglobulinaemia 2018). For patients with cardiac amyloidosis, ibrutinib may be less preferable due to the risk of atrial fibrillation (Dimopoulos & Kastritis 2019).

Influence of genetic mutations on therapy choice

Genetic characterization plays an increasingly important role in therapy selection. In particular, the influence of different genotypes has been described for ibrutinib-based therapy. The MYD88 mutations, which can be detected in the vast majority of patients with Waldenström macroglobulinaemia, mediate BTK-dependent activation of the NFкB pathway, which is used as a therapeutic target. In contrast, the mutational landscape in cases with wild-type MYD88 suggests that NFкB signaling may be activated downstream of BTK (Hunter et al. 2018). Patients with unmutated MYD88 show poor response as well as reduced progression-free survival with ibrutinib treatment (Treon et al. 2015 (1), Treon et al. 2015 (2), Treon et al. 2021). CXCR4 mutations lead to activation of the AKT and ERK signaling pathways, which also promote tumor cell survival, and are associated with reduced and/or delayed response with ibrutinib (Cao et al. 2015, Treon et al. 2015 (1), Treon et al. 2015 (2), Treon et al. 2018 (2), Treon et al. 2021). Therefore, determination of MYD88 mutation status (Onkopedia guideline Waldenström macroglobulinaemia 2018) and CXCR4 mutation status (Kumar et al. 2020) is recommended for planned ibrutinib therapy (Treon et al. 2020).

Also for other substance classes or therapy algorithms, various studies provide evidence for a (possible) influence of MYD88 and CXCR4 genotypes, an overview is given in Table 3.

For example, two studies could show that under treatment with regimens based on the proteasome inhibitors bortezomib and carfilzomib, respectively, the mutation status of CXCR4 had no impact on response rates, progression-free survival and overall survival (Treon et al 2014 (2), Sklavenitis-Pistofidis et al 2018) (see also Table 3). In addition, there is preliminary evidence that a "major response" is also achievable in patients with MYD88 wild-type when treated with the second-generation BTK inhibitors acalabrutinib and zanubrutinib, with rates of 57% and 50%, respectively (Owen et al 2020, Dimopoulos et al 2020, Owen 2021).

Table 3: Impact of MYD88 and CXCR4 mutation status on therapy, overview after Treon et al. 2020. Abbreviations/definitions: PR, partial remission; VGPR, "very good partial remission"; "major response," partial or better than partial response; PFS, "progression free survival"; OS, "overall survival"; TTNT, "time to next treatment."

Therapy

MYD88-Mutation status

CXCR4-Mutation status

Chemoimmunotherapy

 

 

Bendamustine-

based therapy

Prospective study Bendamustin+Rituximab:

Shorter PFS in MYD88 wild-type

 

Retrospective study:

No impact of MYD88-status on overall response attainment, but PFS and TTNT were shorter inMYD88 wild-type

 

 

 

 

Retrospective Study Bendamustine+Rituximab:

No impact of CXCR4 mutation status on PFS 

Rituximab

+Dexamethason

+Cyclophosphamid

Retrospective Study:

No impact of MYD88-status on overall response attainment, but PFS and TTNT were shorter in MYD88-wild-type patients

 

BTK inhibitors

 

 

Ibrutinib monotherapy

Prospective Study:

no major response und fewer PFS in patients with MYD88 wild-type

Prospective Study:

Fewer major responses and VGPRs, inreased time to response, and shorter PFS in CXCR4-mutated patients

Ibrutinib

+ Rituximab

 

Prospective Study:

Fewer major responses and VGPRs and shorter PFS in CXCR4-mutated patients

Zanubrutinib

 

Prospective Study (preliminary):

Fewer major responses and VGPRs in CXCR4-mutated patients

Proteasome inhibitors

 

 

Bortezomib

based therapy

 

Retrospective Study:

No impact of CXCR4 mutation status on response rates, PFS, and OS

Carfilzomib

+ dexamethasone

+ rituximab

 

Prospective Study:

No impact of CXCR4 mutation status on response rates, PFS andOS

Ixazomib

+ dexamethasone

+ rituximab

 

Prospective Study:

Longer median time to response in CXCR4-mutated patients, response rates and PFS not affected

mTOR inhibitor (Everolimus)

Prospective Study:

No response in MYD88 wild-type patients

Prospective Study:

Lower overall and major response in CXCR4 mutated patients

BCL2-Inhibitor (Venetoclax)

 

 

Prospective Study (preliminary):

Lower major response and VGPR in CXCR4 mutated patients

 

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