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Reliable biomarkers are needed to inform clinical management and trials in Charcot-Marie-Tooth disease (CMT), the most common inherited neuropathy. Peripherin and periaxin, biomarkers of peripheral nerve axonal damage and demyelination, respectively, have recently been validated in the inflammatory neuropathies. Here, we evaluate their potential utility in CMT, alongside neurofilament light chain (NfL) and existing outcome measures.We measured serum peripherin, periaxin, and NfL in patients with CMT1A (n=12),CMT2A (n=8) and CMTX (n=8), and compared levels to healthy controls (HC, n=20).Peripherin was higher in CMT1A, CMT2A, and CMTX compared to HC (all p<0.05). NfL was higher in all neuropathy groups versus HC (all p<0.01). Periaxin was elevated in two out of eight CMT2A patients, two out of eight CMTX patients, and below detection limit in CMT1A. Strong correlations were observed between peripherin and clinical tests: stair climb test CMT1A (rho = -0.912, p=0.0006) and 6-minute walk test in CMTX (rho = -1, p=0.0167).Fluid biomarkers show promise in CMT. We aim to selectively measure periaxin in patients with clinical evidence of disease progression, where elevated levels may indicate active demyelination. Larger cohorts are being tested to assess the individual and combined contributions of all three biomarkers to clinical evaluation.roberto.bellanti@nhs.net

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Dr. Cummings will be a panelist.

Significance & Background: Drug hypersensitivity reactions (HSRs) impact patient cancer treatments and outcomes. These reactions can be defined by their clinical presentation (phenotypes), pathophysiology (endotype), and biomarkers. For patients undergoing rapid desensitization (RDD), biomarkers such as skin testing, serum tryptase, and serum lnterleukin (IL)-6 levels can be used to guide protocol selection (both initial and subsequent if continued reactions) and clinical outcomes. Purpose: To develop a RDD treatment algorithm based on the initial and breakthrough HSR phenotypes and associated biomarkers in patients referred to the Brigham and Women's Hospital Drug Desensitization Center. Methods: This study was a retrospective IRB-approved descriptive analysis of adult patients from January 2022 through August 2023. Data collected included symptom presentation, desensitization protocols/outcomes and the following associated biomarkers: skin test, tryptase, and IL-6 levels at the initial reaction and during breakthrough desensitization reactions (BTRs). Interventions: Patients were classified into 3 groups based on endophenotype (Type 1, Cytokine Release Reactions (CRR), and Mixed). Positive skin testing and/or elevated tryptase levels with only symptoms of Type 1 HSR were provided multiple bag desensitization protocols. Patients with an elevated IL-6 that only experienced CRR symptoms were provided a 1 bag protocol. Patients that experienced mixed reactions symptoms of both CRR and Type 1 and/or positive biomarkers received multiple bag protocols. Results: A total of 1,633 desensitization protocols were provided to 326 patients. Biomarkers obtained included skin testing (242 patients), initial reaction tryptase levels (185 patients), BTR tryptase levels (154 patients), initial reaction IL-6 levels (35 patients), and BTR IL-6 levels (142 patients). Based on biomarkers specific desensitization protocols were administered, 4 bag / 16 step (30), 3 bag / 12 step (835), 2 bag / 8 step (327), 1 bag /4-6 step (356) and 1 bag challenges (85). There were 87% protocols (1423) were completed without reactions and 13% with mild to moderate reactions, without deaths. Of the 228/1633 (14%) desensitization protocols completed in patients with an initial CRR phenotype, 208 (91.2%) were successfully completed without reactions. Discussion: Defining the pathogenic mechanism of HSRs helps select specific desensitization protocols (number of bags, steps, and premedication), which increases safety upon re-exposure. The application of biomarkers, although useful in understanding HSR phenotype and endotypes, may have an even greater impact when used to predict response or modify treatment in the setting of desensitization to targeted therpies.