Mutational Profile in 75 Patients With Anti–Myelin-Associated Glycoprotein Neuropathy

Abstract

Background and ObjectivesNeuropathy with antibodies to myelin-associated glycoprotein (MAG) is the most common paraproteinemic IgM neuropathy. Recently, the mutational profile of theMYD88andCXCR4genes has been included in the diagnostic workup of IgM monoclonal gammopathies. The objective of our study was to assess the prevalence ofMYD88L265PandCXCR4S338Xgene variants in patients with anti-MAG antibody neuropathy. Secondary aims were to evaluate possible correlations between the mutational profile and neuropathy severity, antibody titers, and treatment response.MethodsSeventy-five patients (47 men, mean age at molecular analysis 70.8 ± 10.2 years; mean disease duration 5.1 ± 4.9 years) with anti-MAG antibody neuropathy were recruited. Among them, 38 (50.7%) had IgM monoclonal gammopathy of undetermined significance, 29 (38.7%) Waldenstrom macroglobulinemia (WM), and 8 (10.6%) chronic lymphocytic leukemia/marginal zone lymphoma/hairy cell leukemia variant. Molecular analysis was performed on DNA from the bone marrow mononuclear cells in 55 of 75 patients and from peripheral mononuclear cells in 18 of 75 patients. Forty-five patients were treated with rituximab, 6 with ibrutinib, 2 with obinutuzumab-chlorambucil, and 3 with venetoclax-based therapy. All the patients were assessed with the Inflammatory Neuropathy Cause and Treatment (INCAT) Disability Scale, INCAT Sensory Sum Score, and MRC Sum Score at baseline and follow-up. We considered as responders, patients who improved by at least 1 point in 2 clinical scales.ResultsFifty patients (66.7%) carried theMYD88L265Pvariant, with a higher frequency in WM and naive patients (77.2% vs 33.3%,p= 0.0012). No patients harbored theCXCR4S338Xvariant. There were no significant differences in hematologic data (IgM levels, M protein, and anti-MAG antibody titers), neuropathy severity, or response to rituximab inMYD88-altered andMYD88wild-type patients. Nine of 11 (81.8%) patients treated with novel targeted drug, according to theMYD88status, responded to treatments.DiscussionMYD88L265Pvariant has a high prevalence (66.7%) in anti-MAG antibody neuropathy representing a potential effective mutational target for Bruton tyrosine kinase inhibitors. MYD88L265Pvariant, however, does not seem to be a prognostic factor of neuropathy severity or response to rituximab. In patients not responding or becoming refractory to rituximab, a tailored therapy with new effective target therapies should be considered.

Paraproteinemia‐associated neuropathy with or without anti‐myelin‐associated glycoprotein antibody

“…Furthermore, mutations in MYD88 enhanced BTK expression 40 . The MYD88 mutation was detected in 80%–100% of WM cases 41 and in >60% of anti‐MAG neuropathy cases, 42,43 indicating that BTK inhibitors might have a therapeutic effect. BTK inhibitors include first‐generation ibrutinib and second‐generation selective BTK inhibitors, such as acalabrutinib, zanubrutinib and tirabrutinib.…”

Anti-MAG neuropathy: historical aspects, clinical-pathological correlations, and considerations for future therapeutical trials

“…In the study by Svahn and colleagues, 11 approximately 68% had monoclonal gammopathy of unknown significance (MGUS), 29% had Waldenström's macroglobulinemia, and 3% had chronic lymphocytic leukemia or B-CLL. Castellani and colleagues reported that 66.7% of 75 patients tested had a mutation in MYD88, more often in macroglobulinemia 47 48 making them susceptible to treatment with Bruton tyrosine kinase inhibitors.…”