Rate and characteristics of inflammatory neuropathies associated with brentuximab vedotin therapy.

BACKGROUND AND PURPOSE: Peripheral neuropathy is a frequent complication of brentuximab vedotin (BV), used in CD30+ lymphoma treatment. Classic BV-induced neuropathy (BV-CN) is a mild distal sensory axonal polyneuropathy. Severe BV-induced inflammatory neuropathies (BV-IN) have been described. BV-IN contribute to lymphoma-associated morbidity but might be immunotherapy-responsive. Our primary objective was to evaluate the rate of BV-IN. Our secondary objectives were to determine risk factors and warning signs. METHODS: We conducted a retrospective cohort study on all patients treated with BV at our center between April 2014 and September 2021. Clinical, biological, and electrophysiological data were collected. BV-induced neuropathy was defined as the occurrence of neuropathy up to 3 months after BV discontinuation. BV-IN was defined with criteria adapted from European Academy of Neurology/Peripheral Nerve Society 2021 electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. Other neuropathies were classified as BV-CN. RESULTS: Among 83 patients, 41 (49%) developed neuropathy: 35 BV-CN and 6 BV-IN. Thus, the rate of BV-IN was 7.2%. Compared to patients with BV-CN, no predisposing factor was identified. However, patients with BV-IN more frequently presented muscle weakness (67% vs. 5.7%, p < 0.05), gait disorders (83% vs. 20%, p < 0.05), or acute or subacute onset (67% vs. 14%, p < 0.05). BV-IN was frequently more severe (Common Terminology Criteria for Adverse Events grade ≥3; 50% vs. 0%, p < 0.05). Four patients were treated with immunotherapy. CONCLUSIONS: Brentuximab vedotin-induced neuropathy is an overlooked complication. Based on four easily identifiable "red flags", we provide an algorithm to help non-neurologist physicians that care for BV-treated patients to detect BV-IN. The aim of the algorithm is to decrease the diagnostic and management delay of this disabling neuropathy.

Revisiting the spectrum of IgM-related neuropathies in a large cohort of IgM monoclonal gammopathy.

INTRODUCTION: A significant number of patients with a peripheral neuropathy have IgM monoclonal gammopathy (IgM-MG). In this work, we encompassed the spectrum and outcome of IgM-related neuropathies (IgM-NP) in a large monocentric cohort of patients with IgM-MG. METHODS: We retrospectively reviewed the neurological and hematological findings and the course of neuropathy in all patients with IgM-MG over a five-year period in our center (Henri Mondor hospital, Assistance Publique Hôpitaux de Paris (APHP), France). RESULTS: Among 550 patients with IgM-MG, 83 patients (15%) had IgM-NP (55 males, mean age 67 y.o.). The median serum level of IgM-MG was 3.4 g/L, mostly kappa light chain component. The hematological diagnosis was Monoclonal Gammopathy of Undetermined Significance (MGUS) in 62 patients. Anti-MAG antibodies were detected in 38 patients with heterogeneous clinical and neurophysiological features. Four patients had neurolymphomatosis presenting as a non-length dependent predominantly motor neuropathy, which occurred long after the finding of IgM-MG and was responsive to hematological treatment. Five patients had an AL amyloid neuropathy revealed by a small fiber neuropathy. Finally, 30 patients were classified as "Neuropathy of Uncertain Relationship with the IgM" (NURIM) with characteristics close to those of an anti-MAG-NP at the time of diagnosis, except for the neurophysiological features with a predominant axonal pattern. CONCLUSION: This study emphasizes the wide spectrum of IgM-NP associated with a variety of hematological diagnoses. In particular, the course and prognosis vary considerably. In this setting, further studies are needed to unravel the group of patients classified as NURIM.

The value of electrochemical skin conductance measurement using Sudoscan® in the assessment of patients with familial amyloid polyneuropathy.

OBJECTIVE: To reappraise the value of electrochemical skin conductance (ESC) measurement by Sudoscan® to assess the distal involvement of small autonomic fibers in familial amyloid polyneuropathy (FAP) due to various transthyretin (TTR) mutations. METHODS: ESC was measured at both hands and feet in 126 patients with either Val30Met (n = 65) or non-Val30Met (n = 61) TTR mutation. This series included clinically asymptomatic (n = 21) and paucisymptomatic (n = 30) patients, as well as patients with moderate (n = 37) or advanced (n = 38) TTR-FAP. RESULTS: ESC measures did not differ between patients according to the type of TTR variant and were reduced in 24% of clinically asymptomatic patients, 40% of paucisymptomatic patients, 65% of patients with moderate TTR-FAP, and 92% of patients with advanced TTR-FAP. ESC measures were found to correlate with patients' clinical status, especially assessed by the Neuropathy Impairment Score and Karnofsky Performance Status. CONCLUSION: ESC measures well correlate with the severity of TTR-FAP and could provide early marker of the disease. SIGNIFICANCE: ESC measures appear to be relevant to evaluate distal autonomic involvement in the context of amyloidosis.

Long-term treatment of transthyretin familial amyloid polyneuropathy with tafamidis: a clinical and neurophysiological study.

Tafamidis is a transthyretin (TTR) stabilizer recently approved to slow the neurologic impairment in TTR familial amyloid polyneuropathy (TTR-FAP). The pivotal studies on Tafamidis reported encouraging results on the short term, in the early onset Val30Met-TTR-FAP patients at an early stage of the neuropathy. However, the effect of the drug in the non-Val30Met patients, at a more advanced stage of the disease and on the long term, is less known. In this study, we report the effect of Tafamidis in 43 TTR-FAP patients with a variety of pathogenic mutations, including 53% of non-Val30Met variants, at different stages of neuropathy followed on the long term. General and neurological assessment was performed in a standardized protocol every 6-12 months along with neurophysiological variables, including testing of small nerve fibres. The mean follow-up under treatment was 2 years with a subset of 26 patients treated for 3 years. Overall, Tafamidis was well tolerated. A significant clinical deterioration of the neuropathy and the patient's general condition was observed across the 3 years follow-up, although neurophysiological parameters remained stable for the first 2 years. In contrast, patients had a significant increase of BMI under treatment. Deterioration of the neuropathy correlated to an older age at disease onset or treatment initiation and to poor clinical status at baseline. A higher BMI at baseline was associated with a lower progression of the neuropathy. About one-third of the patients who received 3 years of tafamidis had still preserved walking capacity or good clinical condition, suggesting that tafamidis slowed the disease progression in some patients. Overall, our work shows that tafamidis is well tolerated in TTR-FAP but does not prevent the steady progression of the neuropathy on the long term. Age, neurologic status, and general condition at baseline appear to be best predictors of tafamidis efficacy on the neurological function.