Page 39 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE - IgM monoclonal gammopathies of clinical significance J. Khwaja et al. Table 1. List of IgM monoclonal gammopathies of clinical significance.
IgM monoclonal gammopathies of clinical significance
Cold agglutinin disease*
Type 1 and 2 cryoglobulinemia*
IgM-related neuropathies (including anti-MAG peripheral neuropathy*, non-MAG peripheral neuropathy, antiganglioside neuropathies, chronic ataxic neuropathies with disialosyl antibodies)
IgM-associated AL amyloidosis*
Schnitzler syndrome*
Monoclonal gammopathy of renal significance (including immunoglobulin deposition disease, light chain proximal tubulopathy, proliferative glomerulonephritis with monoclonal immunoglobulin deposits)
Acquired von Willebrand syndrome and other coagulation factor deficiencies
Acquired C1 inhibitor deficiency
Pure red cell aplasia
IgM POEMS
*These entities are discussed in further detail in this review. MGUS: monoclonal gammopathies of clinical significance; MAG: myelin- associated glycoprotein; POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin abnormalities.
commonly arises from a CD20+ lymphoplasmacytic cell without class-switching.1 The risk of progression to lym- phoma, chronic lymphocytic leukemia, AL amyloidosis or multiple myeloma is 1.1 event per 100 person-years.5 In the largest series of 210 patients with IgM MGUS with a median follow-up of 29.3 months, no patients progressed to IgM myeloma.5 The incidence and prevalence of IgM MGCS are unknown. Clonal B cells in MGUS have the same genetic and molecular signature as the WM clone. How- ever, MGUS cases have a significantly lower number of mutations than in WM, indicating multiple genetic hits are required for progression. The somatic MYD88L265P mutation constitutively activates nuclear factor kB and triggers B- cell proliferation. It is considered an early acquired muta- tion and is present in the majority of patients with WM or IgM MGUS.6,7 The gene encoding the chemokine receptor CXCR4, involved in homing of B cells in the bone marrow, is mutated (CXCR4MUT) in a smaller proportion. This is usually a subclonal mutation and likely a late event. IgM myeloma has a distinct cell of origin, a pro-B cell, with frequent t(11;14), an absence of MYD88L265P mutation and high BCL2/BCL2L1 ratio.8 These clonal characteristics may have therapeutic implications. Table 2 summarizes the data on the underlying histology and clonal characteristics of IgM MGCS compared with those seen in WM and IgM MGUS in general.
Primary cold agglutinin disease
In primary CAD, autoimmune hemolytic anemia is caused by a cold agglutinin that is a monoclonal IgMk in more than 90% of cases and is produced by clonal lymphocytes in the bone marrow. The antibody binds erythrocyte
antigens (typically type I) optimally at 4˚C resulting in ag- glutination and classical complement pathway activation.9 The thermal amplitude describes the temperature range at which the antibodies are active, and only those with a thermal amplitude reaching higher than 28˚C are con- sidered pathogenic. In most cases, complement activation is incomplete and extravascular hemolysis of C3b-opson- ized erythrocytes occurs in the liver. Less frequently there is initiation of the terminal pathway, assembly of the membrane attack complex (C5b-C9) and intravascular hemolysis, which can lead to acute life-threatening ane- mia. Cold agglutinins in the context of infection, auto- immune disease and overt lymphoma9 (including chronic lymphocytic lymphoma, diffuse large B-cell lymphoma and WM) are referred to as cold agglutinin syndrome. The management of cold agglutinin syndrome is directed at treating the underlying cause and is not further discussed here.
Clinical characteristics
Patients with CAD present with chronic anemia and/or cold-induced circulatory symptoms. Of 232 patients in an international retrospective case series, the median IgM was 3.2 g/L and over 90% had hemolytic anemia and cir- culatory symptoms. Thirty-eight percent required trans- fusions at or before diagnosis and 47% during follow-up. Around half had acrocyanosis or Raynaud syndrome af- fecting daily living. Ulcers or gangrene were rare (<2%).10 In a third of cases, hemoglobin concentration is below 80g/L.11 Circulatory symptoms do not correlate with either the degree of anemia or the bone marrow histology.10,11 There is an increased risk of thrombosis in CAD, likely re- lated to intravascular hemolysis,12,13 which is not correlated with the severity of the anemia.10 CAD is a chronic disease
Haematologica | 107 September 2022
2038