Co-occurrence of myositis and neuropathy after anti-CD30 therapy in a late-adolescent Hodgkin lymphoma patient

Abstract

Objective: Immune-related adverse events (irAEs) are recognized in oncology, particularly with immune checkpoint inhibitors and other targeted therapies. Brentuximab Vedotin (BV), is an anti-CD30 antibody-drug conjugate- its association with immune-mediated myositis remains unexplored. We report a case of an adolescent with Hodgkin lymphoma (HL) who developed neuropathy and myositis following BV therapy.

Materials & methods: The diagnostic work-up included MRI as well as microscopic analyses (histology, electron microscopy, and immunostainings including CD30 and MxA) of a gastrocnemius muscle biopsy. Proteomic analysis was also performed on the same biopsy, and paradigmatic protein dysregulations were validated through immunostaining. Serum NCAM1 levels were measured using ELISA.

Results: The patient, diagnosed with HL at 15 years, developed neuropathy after Vincristine treatment and was switched to BV. During BV therapy, she experienced progressive muscle weakness and foot drop, leading to discontinuation. MRI confirmed myositis, and biopsy revealed neurogenic and inflammatory changes with complement deposition and mitochondrial dysfunction. Proteomics showed upregulation of inflammatory relevant proteins, with HPRT1 (749.43-fold) being the most increased one. Intravenous immunoglobulin (IVIG) therapy improved muscle strength.

Discussion: Myositis following BV therapy has not been reported. Findings suggest an immune-mediated mechanism with B-cell involvement. Given the response to IVIG, B-cell-directed therapies may be beneficial. This case identifies BV-induced myositis as a novel irAE.

Keywords: Anti-CD30; Brentuximab vedotin; Chemotherapy; Hodgkin lymphoma; Myositis.

Fig. 1

Clinical findings in the index patient: A Timeline of preceding events, in-hospital stay and follow-up. B MRI of the lower thigh demonstrating myositis of the gastrocnemius muscle on both sides under BV treatment (left) and 6 months after termination of therapy (right). C Results of ELISA-based NCAM1 quantification in sera derived from healthy donors (left), our patient (middle; measure in technical triplicates) and Charcot-Marie-Tooth type 1A (CMT1A; PMP22 duplication) cases (right) included as disease controls. D Histological stains on gastrocnemius biopsy revealing neurogenic changes including numerous atrophic, partially angular shaped and grouped fibres (H&E and ATPase 9.4 stains) and myogenic-inflammatory changes (black arrows in H&E and Oil red stains) occasionally accompanied by lipid droplet accumulation within the sarcoplasm (white arrows in Oil red stains) or vacuoles (arrowhead in Oil red stains) as well as ringed fibres (black arrow in NADH-TR stain). Scale bars for H&E, NADH-TR & Oil red = 80 µm and for ATPase 9.4 stain = 200 µm. E Ultra-structural studies on same biopsy showing sarcomeric disintegrations (black arrows), altered mitochondrial morphology, increase of lipid droplets and build-up of protein aggregates within vacuoles (white arrows). Scale bars = 2 µm. F Immunofluorescence studies on the same biopsy for inflammation and myofibrosis markers. Sparse CD4, CD8, CD20, CD45, and CD68 positive cells are seen in addition to increase of MHC-II and MxA in the vicinity of damaged muscle fibres. Small regenerating fibres also express CD56. Immunostaining for MHC-I and C5b-9 displaying complement deposition on scattered muscle fibres and capillaries. Scale bars = 100 µm. Immunostaining for biglycan (BGN) showing considerable increase within the extracellular matrix. Scale bar = 200 µm. Further routine stains showed irregular Myotilin (MYOT) distribution in degenerating fibres, punctuate TDP43-immunoreactivity in the perimysium and within few muscle fibres as well as irregular sarcoplasmic deposition of gamma-Sarcoglycan (SCGC) in some muscle fibres. Scale bars = 100 µm

Fig. 2

Results of proteomic profiling and validation studies on gastrocnemius muscle of the index patient: A Abundance plot showing the dynamic range of all proteins identified in proteins extracts of gastrocnemius muscle via liquid chromatography coupled to tandem mass spectrometry based on their relative quantification using always the 3 highest abundant peptides for each protein, allowing protein comparison within an experiment. All identified proteins of the controls (black) are sorted with decreasing abundance while the patient (red) was plotted in the same order to directly compare the different abundances. All identified proteins cover a dynamic range of eight orders of magnitude. B Volcano plot highlighting statistically significant increased proteins (purple dots) as well as decreased proteins (yellow dots). (C) Proteomaps-based in silico analyses of dysregulated proteins for upregulated (left panel) and downregulated (right panel) biological processes and related proteins separately. (D) Immunofluorescence studies of paradigmatic proteins (Periostin = POSTN, Cathepsin D = CTSD, Nicotinamide N-methyltransferase = NNMT, Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 = SERCA2, Transketolase = TKT & Dysferlin = DYSF, Calsequestrin = CASQ, Triadin = TRDN) to validate proteomic findings making use of another analytical approach. Scale bars = 80 µm