Page 47 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE - IgM monoclonal gammopathies of clinical significance J. Khwaja et al.
Figure 4. Management of IgM-related neuropathies. *Nerve biopsy after consultation with an expert neurologist, in selected cases only. CNS: central nervous system; HIV: human immunodeficiency virus; CIDP: chronic inflammatory demyelinating polyneuropathy; MAG: myelin-associated glycoprotein; Ab: antibody; NCS/EMG: nerve conduction studies/electromyography; MRI: magnetic resonance imaging; CSF: cerebrospinal fluid; CANOMAD: chronic ataxic neuropathy, ophthalmoplegia, IgM M- protein, cold agglutinins and disialosyl ganglioside antibodies; POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin abnormalities; BR: bendamustine plus rituximab; DRC: dexamethasone, rituximab, cyclophosphamide.
Treatment
In general, in anti-MAG and non-anti-MAG neuropathy, treatment should be initiated only in those with significant or progressive disability.52 The aim of treatment is to halt progression and improve neurological function, although this may potentially take months to years, even after IgM responses. Although many neurological disability scales exist, they are not available outside of specialist neurology clinics and there is no standardized method of response assessment. The use of serial validated patient-reported outcome scores (e.g., the Inflammatory Rasch-Built Overall Disability Scale) is advocated, as this can be easily under- taken in non-specialist clinics.52 An observational trial is currently recruiting with an aim to develop an IgM-specific disability scale (NCT03918421). Patients should be managed in a multidisciplinary fashion with input from neurology, hematology, physiotherapy and occupational therapy. Rituximab is widely, but inconsistently used in the setting of IgM-related neuropathies. A meta-analysis of rituximab demonstrated improvement in disability scales at 8 to 12 months and long-term efficacy was demonstrated in a third of patients.54 A transient flare of symptoms following the administration of rituximab was observed in 12% in a large series of patients with anti-MAG antitbodies.55 Ste- roids, intravenous immunoglobulins and plasma exchange alone do not provide long-term clinical benefit in anti- MAG neuropathy56,57 and are resource-intense, respect- ively. In contrast, intravenous immunoglobulins and
rituximab-based regimens are effective in CANOMAD syn- drome (producing partial clinical responses or better in 53% and 52% of patients, respectively),58 while chronic in- flammatory demyelinating polyneuropathy is responsive to intravenous immunoglobulins,52 highlighting the rel- evance of correct diagnostic classification.
Although data are largely limited to retrospective series, targeting the underlying clone is feasible in IgM-related neuropathy; the optimum depth of response is unknown. Clinical improvement or stabilization is significantly more likely with rituximab-containing therapy (dexamethasone, rituximab, cyclophosphamide; bendamustine plus rituxi- mab; cyclophosphamide, prednisolone, rituximab, vincris- tine), non-amyloid-related neuropathy and attainment of at least partial haematologic response.49,50
There is an unmet need for reliable biomarkers for diag- nosis, appropriate selection of patients for treatment and criteria for monitoring response.59 There is a lack of pros- pective clinical trials to optimize treatment options. A phase II clinical trial, MAGNAZ, of the oral BTK inhibitor zanubrutinib in anti-MAG peripheral neuropathies is underway.60
Schnitzler syndrome
Schnitzler syndrome is a rare auto-inflammatory disorder characterized by an IgM monoclonal gammopathy and
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