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Paraneoplastic myelopathies are rare, and their treatment response or prognosis are poorly defined. We report a patient with paraneoplastic longitudinally extensive transverse myelitis associated with Waldenström macroglobulinemia (WM) who responded to treatment with ibrutinib and venetoclax.

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A 68-year-old male with untreated WM (MYD88 L265P mutation) developed a two-month history of unsteadiness, tingling, and numbness in his extremities, which progressed to bilateral weakness in his limbs. Cerebrospinal Fluid (CSF) analysis documented lymphocytic pleocytosis and clonal B-cells, without oligoclonal bands or paraneoplastic antibodies. Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) serologies were negative. Magnetic resonance imaging (MRI) showed marked cord expansion (mid-C2-C7) and central cord T2 hyperintensity (C2-T1). Lateral column tract-specific involvement and a lack of meningeal or tumefactive focus led to paraneoplastic myelitis diagnosis. Initial treatment with methylprednisolone markedly improved his symptoms, but the patient progressively worsened with difficulty walking, requiring support. Intravenous immunoglobulin and rituximab were given for his relapse with no clinical improvement, and a repeat MRI showed persistent cord edema and enhancement extending now to the dorsal columns. Twelve months post-rituximab initiation, worsening anemia necessitated his enrollment in a Phase II ibrutinib-venetoclax study (NCT04273139) for treatment-naïve WM. Rituximab was discontinued, and the patient received three months of ibrutinib-venetoclax therapy, after which he reported neurological improvement. Clinical examination revealed full strength in the legs, with some residual signs of hyperreflexia and moderately decreased vibratory sense in the feet. MRI also showed marked improvement in cord edema and enhancement. The patient remained neurologically stable one year after ibrutinib-venetoclax treatment.

Our observations may support a role for concurrent BTK and BCL2 inhibition in paraneoplastic conditions associated with B-cell lymphoproliferative disorders. However, better control of WM may have also contributed to clinical improvement. Larger cohort studies are needed to validate these findings.