Long Term Follow-up of Rituximab for Anti-Myelin-Associated Glycoprotein Demyelinating Polyneuropathy in IgM Gammopathies: Clinical, Hematological and Neurophysiological Correlations
Authors: Amaducci Enrico , Dogliotti Irene , Vitale Claudio , Schiavetti Irene , Clerico Michele , Benevolo Giulia , Parisi Mattia , Bertuzzo Davide , Peri Veronica , Cavallo Federica , Ragaini Simone , Consoli Chiara , Pironti Mariapia , Bruno Benedetto , Lopiano Leonardo , Di Liberto Alessandra , Drandi Daniela , Ferrero Bruno , Ferrero Simone 
Published: December 2024

Background and purpose. Anti-myelin-associated glycoprotein (MAG) demyelinating polyneuropathy (PNP) is a rare and underdiagnosed condition, associated with monoclonal Immunoglobulin M (IgM) gammopathy of undeterminate significance (MGUS) or Waldenstroem macroglobulinemia (WM), that might deeply compromise patients' (pts) quality of life (QoL). Rituximab (RTX) has been largely used, with good efficacy if timely infused. We reported safety and efficacy of RTX in a small, retrospective, homogeneous series of anti-MAG PNP pts treated in a single Institution [Parisi, EJN 2022]. We here present updated, long-term clinical, hematological and neurophysiological results of that original series, along with a novel series of pts.

Methods. Anti-MAG PNP pts with relevant clinical impairment were evaluated by a multidisciplinary team prior to, during and after treatment with RTX. Neurological evaluation included electromyography (EMG), INCATds, mISS, PGIC scale, serum anti-MAG titer, and physical examination. Hematological assessment included bone marrow biopsy (BMB) and BM aspirate, complete blood count, paraprotein quantification, serum immunofixation and IgM level; multiparameter flow cytometry (MFC) and droplet digital PCR for MYD88L265P, CXCR4 gene mutations were performed in unsorted BM samples. IgM MGUS or WM diagnoses were defined according to IWWM criteria [Semin, Oncol 2003]. RTX (375 mg/m2 weekly) was administered in “cohort 1” for 4 courses and in “cohort 2” for 8 courses. Hematological and neurological evaluations were performed before (T0), 1 year (T1) and 2 years (T2) after RTX, including CD19+ cells count in peripheral blood (PB) and evaluation of hematological response. PNP relapse (REL) was defined as increase ≥1 point at INCATds score or ≥2 points at mISS.

Results. Between 2017 and 2023, 41 pts with confirmed anti-MAG PNP and IgM gammopathy were treated with RTX at the Hematology Division of Torino University Hospital; 7 pts had already received prior RTX while 35 were treatment naïve. Median age at the time of BMB was 71 years (range 50-82), 28 pts (68%) were male, 26 pts (63%) had WM vs 15 pts (37%) IgM MGUS. Median IgM baseline level was 507 mg/dL (range 121-1479 mg/dL), and median anti-MAG titer 1:60000 (range 1:5000-1:200000). Median BMB invasion by lymphoplasmacytic lymphoma (LPL) was 20% (range 5-60%) in those with confirmed WM; median clonal B lymphocyte and plasma cells (PCs) levels in BM aspirate by MFC were respectively 0.17% (range 0-35%) and 0% (range 0-2.34%). 35/38 evaluable pts (92%) carried MYD88L265P mutation in BM with a median level of 5x10-3 (range 4.7x10-4 - 1x10-1) while 6 out of the 19 evaluable pts (13 WM and 6 MGUS) were CXCR4MUT in BM with a median level of 1.75x10-3 (range 6x10-4-3.3x10-2). Interestingly, the median time between clinical PNP onset to RTX was 22 months (range 4-174). 22 pts were in cohort 1 (4 RTX), 19 in cohort 2 (8 RTX). Major response rate (MRR) was 47% at T1 and 58% at T2. Median baseline level of CD19+ B cells in PB in 7 evaluable pts was 67/µL (range 5-637/µL), while after RTX 7 out of 12 pts had no detectable CD19+ cells.

Neurological responses (EMG, clinical scales and QoL) were initially reported elsewhere [Parisi, EJN 2022] and will be updated after the follow-up (FU) completion.

Median FU was 79.5 months. 9 pts (22%, 7 WM and 2 MGUS) were retreated with RTX for clinical PNP relapse with a median time to next treatment of 27 months (range 11-65). Median CD19+ in PB was 41 c/µL (range 0-129 c/µL) prior to retreatment. 7 out of 9 REL pts came from cohort 1 (p=0.0535), but we should acknowledge that the median FU was longer in cohort 1 than in cohort 2 (89 vs 57 months, respectively, p=0.34). Finally, one REL patient required additional treatment achieving clinical response with zanubrutinib due to PNP progression, and another patient died for unrelated cardiovascular disease.

Conclusions. This study describes a homogeneous, consistent and well characterized series of pts affected by IgM gammopathies and anti-MAG PNP effectively treated with RTX in a single center; likelihood of PNP recurrence after RTX seems to be correlated to the number of cycles given, but additional FU is needed to confirm this hypothesis. This work highlights how the cooperation between hematologists and neurologists might improve diagnostics, monitoring and outcome in this rare condition.