108: Macroglobulinemia Flashcards
A lymphoid neoplasm resulting from the accumulation, in the marrow and other organs, of a clonal population of lymphocytes, lymphoplasmacytic cells, and plasma cells, which secrete a monoclonal immunoglobulin (Ig) M
Waldenström macroglobulinemia (WM)
WM corresponds to lymphoplasmacytic lymphoma (LPL)
Most cases of LPL are WM; less than 5% of cases can secrete IgA, IgG, κ or λ light chains, or be nonsecretory.
TRUE OR FALSE
Lymphocytosis in WM is uncommon.
TRUE
Lymphocytosis in WM is uncommon.
Immunophenotypic profile of WM lymphoplasmacytic cells
Positive:CD19, CD20 (including FMC7), CD22, and CD79
CD5, CD10, and CD23 :10% to 20%
CD25 and CD27*
CD22dim/CD25+/CD27+/IgM+ population may be present among clonal B lymphocytes in patients with essential monoclonal gammopathy (synonym: monoclonal gammopathy of unknown significance [MGUS]) of the IgM type who ultimately saw progression to WM.
TRUE OR FALSE
No recurrent translocations have been described in WM
TRUE
No recurrent translocations have been described in WM
In contrast to myeloma plasma cells, no recurrent translocations have been described in WM, which can help to distinguish WM from IgM myeloma cases, because IgM myeloma cases often exhibit t11;14 translocations.
The most recurrent cytogenetic finding in WM cases
Deletions in chromosome 6q21–23
Deletions in chromosome 6q21–23: half of WM patients, with concordant gains in 6p in about 40% of 6q-deleted patients.
In a series of 174 untreated WM patients, 6q deletions, followed by trisomy 18, 13q deletions, 17p deletions, trisomy 4, and 11q deletions, were observed.
Deletion of 6q and trisomy 4 were associated with adverse prognostic markers
The most recurrent somatic mutation in WM
MYD88L265P
By PCR assays, 50% to 80% of IgM MGUS patients also express MYD88L265P, and expression of this mutation was associated with increased risk for malignant progression.
The second most common somatic mutation after MYD88L265P
CXCR4
Present in 30% to 35% of WM patients and impact serine phosphorylation sites that regulate CXCR4 signaling by its only known ligand, CXCL12, otherwise called stromal cell–derived factor 1a.
The location of somatic mutations found in the C-terminus of CXCR4 in WM are similar to those observed in the germline of patients with_______ syndrome
WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome
A congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.
MYD88 and CXCR4 mutations
Characteristics of WM patients with MYD88L265PCXCR4NS mutations
Higher marrow disease involvement, serum IgM levels, symptomatic disease requiring therapy, hyperviscosity syndrome, and acquired von Willebrand disease
MYD88 and CXCR4 mutations
MYD88L265PCXCR4FS or MYD88L265PCXCR4WT
Intermediate marrow and serum IgM levels
MYD88 and CXCR4 mutations
MYD88WTCXCR4WT
Lowest marrow disease burden
MYD88 and CXCR4 mutation
More aggressive clinical presentation associated with what genotype
CXCR4NS genotype
Risk of death was not affected by CXCR4 mutation status.
MYD88 and CXCR4 mutations
Genotype associated with risk of death and aggressive disease transformation
MYD88WT
TRUE OR FALSE
In contrast to most indolent lymphomas, splenomegaly and lymphadenopathy are common
FALSE
In contrast to most indolent lymphomas, splenomegaly and lymphadenopathy are uncommon (≤15%).
Purpura is frequently associated with cryoglobulinemia and in rare circumstances with light-chain amyloidosis (AL)
The morbidity associated with WM is caused by the concurrence of two main components:
- Tissue infiltration by neoplastic cells
- Physicochemical and immunologic properties of the monoclonal IgM
Syndrome that cause marked increase in the resistance to blood flow and the resulting impaired transit through the microcirculatory system
Hyperviscosity Syndrome
Monoclonal IgM increases red cell aggregation and red cell internal viscosity while reducing red cell deformability.
The presence of cryoglobulins contributes to increasing blood viscosity, as well as to the tendency to induce erythrocyte aggregation.
Serum viscosity is proportional to IgM concentration up to _____ g/L, then increases sharply at higher levels.
Contribute to inappropriately low erythropoietin production, which is the major reason for anemia in these patients
Renal synthesis of erythropoietin is inversely correlated with plasma viscosity.
30 g/L
Hyperviscosity Syndrome
Clinical manifestations are related to circulatory disturbances that can be best appreciated by
Ophthalmoscopy
Shows distended and tortuous retinal veins, hemorrhages, and papilledema
Hyperviscosity Syndrome
Symptoms usually occur when the monoclonal IgM concentration exceeds ___ g/L or when serum viscosity is greater than ____ centipoises (cp)
Monoclonal IgM: > 50 g/L
Serum viscosity: > 4.0 centipoises (cp)
But there is individual variability, with some patients showing no evidence of hyperviscosity even at 10 cp
The most common symptoms of hyperviscosity syndrome
Oronasal mucosal bleeding, visual disturbances because of retinal bleeding, and dizziness that rarely may lead to stupor or coma
TRUE OR FALSE
The monoclonal IgM can behave as a cryoglobulin in up to 20% of patients and is usually type II and asymptomatic in most cases.
FALSE
The monoclonal IgM can behave as a cryoglobulin in up to 20% of patients and is usually type I and asymptomatic in most cases.
Mixed cryoglobulins (type II) consisting of IgM-IgG complexes may be associated with hepatitis C infections.
Treatment of cryoglobulinemia
Plasmapheresis or plasma exchange
Symptoms of cryoglobulinemia
Result from impaired blood flow in small vessels
- Raynaud phenomenon; acrocyanosis and necrosis of the regions most exposed to cold, such as the tip of the nose, ears, fingers, and toes;
- Malleolar ulcers
- Purpura
- Cold urticaria
Renal manifestations are infrequent.
Viral infection associated with mixed cryoglobulins (type II) consisting of IgM-IgG complexes
Hepatitis C
The nerve damage in Immunoglobulin M–Related Neuropathy is mediated by diverse pathogenetic mechanisms:
- IgM antibody activity toward nerve constituents causing demyelinating polyneuropathies;
- Endoneurial granulofibrillar deposits of IgM without antibody activity, associated with axonal polyneuropathy;
- Occasionally by tubular deposits in the endoneurium associated with IgM cryoglobulin; and, rarely,
- By amyloid deposits or by neoplastic cell infiltration of nerve structures
Half of the patients with IgM neuropathy have a distinctive clinical syndrome that is associated with antibodies against a minor 100-kDa glycoprotein component of nerve known as
Myelin-associated glycoprotein (MAG)
Anti-MAG antibodies are generally monoclonal IgMκ and usually also exhibit reactivity with other glycoproteins or glycolipids that share antigenic determinants with MAG.
The anti– MAG-related neuropathy is typically distal and symmetrical, affecting both motor and sensory functions; it is slowly progressive with a long period of stability.
Immunoglobulin M–Related Neuropathy
Antiganglioside monoclonal IgMs associated with sensory ataxic neuropathy
Chronic ataxic neuropathy, sometimes with ophthalmoplegia and/or red blood cell cold-agglutinating activity
Anti-GD1b and anti-GQ1b antibodies
Immunoglobulin M–Related Neuropathy
Associated with chronic demyelinating neuropathy and severe sensory ataxia, unresponsive to glucocorticoids
Monoclonal IgM proteins that bind to gangliosides with a terminal trisaccharide moiety including ganglioside M2 (GM2) and GalNac-GD1A
Antiganglioside IgM proteins may also cross-react with lipopolysaccharides of Campylobacter jejuni, whose infection is known to precipitate the _________________, a variant of the Guillain-Barré syndrome.
Miller-Fisher syndrome
Molecular mimicry may play a role in this condition
Monoclonal IgM may have cold agglutinin activity; that is, it can recognize specific red cell antigens at temperatures below ___ °C, producing chronic hemolytic anemia.
37 °C
temperatures below 37 °C, producing chronic hemolytic anemia.
This disorder occurs in less than 10% of WM patients
Cold Agglutinin Hemolytic Anemia is associated with cold agglutinin titers greater than
1:1000
The monoclonal component is usually an_________________ and reacts most commonly with red cell ________antigens, resulting in complement fixation and activation.
IgM kappa light chain (IgMκ)
I/i antigens
Amorphous IgM deposits in the dermis result in IgM storage papules on the extensor surface of the extremities, referred to as
Macroglobulinemia cutis
TRUE OR FALSE
The incidence of cardiac and pulmonary involvement is higher in patients with monoclonal IgM than with other immunoglobulin isotypes.
TRUE
The incidence of cardiac and pulmonary involvement is higher in patients with monoclonal IgM than with other immunoglobulin isotypes.
The most common pulmonary symptom, followed by dyspnea and chest pain
Cough
TRUE OR FALSE
In contrast to myeloma, infiltration of the kidney interstitium with lymphoplasmacytoid cells can occur in WM, and renal or perirenal masses are not uncommon.
TRUE
In contrast to myeloma, infiltration of the kidney interstitium with lymphoplasmacytoid cells can occur in WM, and renal or perirenal masses are NOT uncommon.
Kidney involvement is less common and less severe in WM than in myeloma
Two cardinal features of the Schnitzler syndrome
Chronic urticaria and IgM gammopathy
Usually not associated initially with clinical features of WM, although evolution to WM is not uncommon
Syndrome described as direct infiltration of the CNS by monoclonal lymphoplasmacytic cells as diffuse infiltrates or as tumors
Characterized clinically by confusion, memory loss, disorientation, seizures, and/or motor dysfunction.
Bing- Neel syndrome
Most common finding in patients with symptomatic WM
Anemia
Caused by a combination of factors: decrease in red cell survival, impaired erythropoiesis, moderate plasma volume expansion, hepcidin production leading to an iron reutilization defect, and blood loss from the gastrointestinal tract
Usually normocytic and normochromic, and rouleaux formation is often pronounced
Mean red cell volume may be elevated spuriously owing to erythrocyte aggregation.
Almost always present and may be the first clue to the presence of macroglobulinemia
Raised erythrocyte sedimentation rate
The clotting abnormality detected most frequently
Prolongation of thrombin time
Marrow finding in WM
Marrow infiltration by a lymphoplasmacytic cell population characterized by small lymphocytes with evidence of plasmacytoid and plasma cell maturation
The pattern of marrow infiltration may be diffuse, interstitial, or nodular, usually with an intertrabecular pattern of infiltration.
A solely paratrabecular pattern of infiltration is unusual and should raise the possibility of follicular lymphoma.
Marrow cell immunophenotype of WM should be confirmed by flow cytometry and/or immunohistochemistry
sIgM+ CD19+ CD20+ CD22+ CD79+
Up to 20% of cases may express CD5, CD10, or CD23
In these cases, chronic lymphocytic leukemia and mantle cell lymphoma should be excluded.
Characterized as “Intranuclear” periodic acid–Schiff–positive inclusions consisting of IgM deposits in the perinuclear space, and sometimes in intranuclear vacuoles
Dutcher-Fahey bodies
TRUE OR FALSE
An increased number of mast cells, usually in association with the lymphoid aggregates, is commonly found in WM
TRUE
An increased number of mast cells, usually in association with the lymphoid aggregates, is commonly found in WM
Their presence may help in differentiating WM from other B-cell lymphomas
Test recommended for identification and characterization of the IgM monoclonal protein
High-resolution electrophoresis combined with immunofixation of serum and urine
The light chain of the monoclonal IgM is κ in 75% to 80% of patients.
The concentration of the serum monoclonal protein is highly variable but, in most cases, lies within the range of 15–45 g/L.
Used to determine IgM levels for serial evaluations
Densitometry
TRUE OR FALSE
The presence of cold agglutinins or cryoglobulins may affect determination of IgM levels; therefore, testing for cold agglutinins and cryoglobulins should be performed at diagnosis.
TRUE
The presence of cold agglutinins or cryoglobulins may affect determination of IgM levels; therefore, testing for cold agglutinins and cryoglobulins should be performed at diagnosis.
If present, subsequent serum samples should be analyzed at 37 °C for determination of the serum monoclonal IgM level.
Patients typically become symptomatic at serum viscosity levels of ___ cp and above, which relates to serum IgM levels above ____ g/L.
4 cp
60 g/L
Patients may be symptomatic at lower serum viscosity and IgM levels, and in these patients cryoglobulins may be present.
Recurring nosebleeds, headaches, and visual disturbances are common symptoms in patients with symptomatic hyperviscosity.
Funduscopy might reveal hyperviscosity-associated findings, and among the first clinical signs of hyperviscosity:
Appearance of peripheral and midperipheral dot and blotlike hemorrhages in the retina
Indications for treating WM
- Patients with constitutional symptoms, such as recurrent fever, night sweats, fatigue caused by anemia, or weight loss
- Progressive symptomatic lymphadenopathy and/or splenomegaly
- Anemia with a hemoglobin value of 100 g/L or less or a platelet count of 100 × 109/L or less owing to marrow infiltration
- Complications, such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia
The panel recommended that initiation of therapy should not be based on the IgM level per se, because this may not correlate with the clinical manifestations of WM.
Therapeuic agents for initial therapy of WM
- Oral Alkylating Agents
- Nucleoside Analogue
- CD20-Directed Antibody
- Proteasome Inhibitors
- Combination Therapies
Factors to be taken into account in considering alkylating agent therapy for patients with WM
Necessity for more rapid disease control given the slow response, as well as consideration for preserving stem cells in patients who are candidates for autologous SCT therapy
Pretreatment factors associated with shorter survival in the entire population of patients receiving single-agent chlorambucil:
- Age older than 60 years
- Male sex
- Hemoglobin less than 100 g/L
- Leukocytes less than 4 × 109/L
- Platelets less than 150 × 109/L
A chimeric monoclonal antibody that targets CD20, a widely expressed antigen on lymphoplasmacytic cells in WM
Rituximab
4 weekly IV infusions of 375 mg/m2
TRUE OR FALSE
In many WM patients, a permanent increase or flare of the serum IgM may occur immediately after initiation of rituximab treatment.
FALSE
In many WM patients, a transient increase or flare of the serum IgM may occur immediately after initiation of rituximab treatment.
Does not herald treatment failure, and most patients will return to their baseline serum IgM level by 12 weeks
Treatment before rituximab therapy for patients with baseline serum IgM levels of greater than 50 g/L or serum viscosity of greater than 3.5 cp
Plasmapheresis
Because of the decreased likelihood of response in patients with higher IgM levels, as well as the possibility that serum IgM and blood viscosity levels may abruptly rise, Rituximab monotherapy should not be used as sole therapy for the treatment of patients at risk for hyperviscosity signs and symptoms.
Patients who were treated with single-agent rituximab found the objective response rate was significantly lower in patients who had:
Low serum albumin (<35 g/L) or a serum monoclonal protein greater than 40 g/L
WM patients who carried this amino acid at position 158 had a fourfold higher major response rate (ie, 50% decline in serum IgM levels) to rituximab
Valine
A correlation between polymorphisms at position 158 in the FcγRIIIa receptor (CD16), an activating Fc receptor on important effector cells that mediate antibody-dependent cell-mediated cytotoxicity, and rituximab response was observed in WM patients.
Individuals may encode either the amino acid valine or phenylalanine at position 158 in the FcγRIIIa receptor.
The fully human anti-CD20 monoclonal antibody that an be used in patients with rituximab-intolerant WM.
Ofatumumab
The most common grade 3 or higher adverse events with Ofatumumab
- Infusion reactions (11%)
- Chest pain (5%)
- Hemolysis (5%)
- Neutropenia (5%)
Novel Therapeutics Agents for WM
BTK inhibitor:
Ibrutinib
Acalabrutinib
Zanubrutinib
BCL2 inhibitor: Venetoclax
Major response rates were lower in patients with this BTKi particulkarly those with MYD88WT and CXCR4 mutations, and the National Comprehensive Cancer Network recommends genotyping before initiation
Ibrutinib
Response assessments in WM rely primarily on measuring:
serum IgM or IgM paraprotein levels
Although complete responses require disappearance of the IgM monoclonal protein and resolution of marrow and/or extramedullary WM disease.
The use of IgM as a surrogate marker of disease is that it can fluctuate, independent of tumor-cell killing with some agents:
Rituximab:
Bortezomib and ibrutinib:
A finding referred to as “IgM discordance”
Rituximab: induce a flare in serum IgM levels
Bortezomib and ibrutinib: suppress IgM levels
TRUE OR FALSE Prognostic factors
MYD88 WT status may be an inferior prognostic marker for survival.
TRUE
MYD88 WT status may be an inferior prognostic marker for survival.
TRUE OR FALSE Prognostic factors
Hemoglobin levels of less than 90–120 g/L associated with decreased survival in several series.
TRUE
Hemoglobin levels of less than 90–120 g/L associated with decreased survival in several series.
International Prognostic Scoring System for WM (IPSSWM)
- Advanced age (>65 years)
- Hemoglobin less than or equal to 115 g/L
- Platelet count less than or equal to 100 × 109/L
- β2-microglobulin greater than 3 mg/L, and
- Serum monoclonal protein concentration greater than 70 g/L
Importantly, the IPSSWM retained its prognostic significance in subgroups defined by age, treatment with alkylating agent, and nucleoside analogues.
