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eNeurologicalSci
eNeurologicalSci
eNeurologicalSci
2405-6502
Elsevier

S2405-6502(24)00034-0
10.1016/j.ensci.2024.100527
100527
Case Report
Paraneoplastic myelitis associated with Waldenström macroglobulinemia responsive to treatment with ibrutinib – venetoclax: A case report
Narasimhan Sathya sathyanarasimhan9@gmail.com
a⁎
Galetta Kristin M. b
Castillo Jorge J. c
Bhattacharyya Shamik d
a Department of Neurology, Brigham and Women's Hospital, 15 Francis Street, Boston, MA 02115, United States
b Department of Neurology, Stanford University School of Medicine, Palo Alto, CA 94305, United States
c Dana-Farber Cancer Institute, Boston, MA 02122, United States
d Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States
⁎ Corresponding author. sathyanarasimhan9@gmail.com
07 9 2024
12 2024
07 9 2024
37 10052726 4 2024
8 8 2024
5 9 2024
© 2024 The Authors. Published by Elsevier B.V.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Waldenström macroglobulinemia (WM) is a B-cell lymphoproliferative malignancy characterized by IgM paraproteinemia and presence of lymphoplasmacytic cells in the bone marrow. Isolated longitudinally extensive transverse myelitis (LETM) is a rare manifestation of WM. We report a rare case of paraneoplastic LETM in a 68-year-old male with treatment-naïve WM (MYD88 L265P mutation in bone marrow aspirate), who responded to ibrutinib and venetoclax therapy. Our patient presented with a two-month history of unsteadiness, tingling, and numbness in both hands and feet, that progressed to bilateral leg and arm weakness. Based on radiographic findings, a diagnosis of paraneoplastic LETM was made and he was treated acutely with IV methylprednisolone followed by a quick oral prednisone taper. However, he subsequently relapsed and symptomatically worsened while on rituximab therapy. Accounting for worsening anemia, our patient was enrolled in a Phase II trial evaluating the effects of ibrutinib-venetoclax therapy in treatment naïve WM. After three months of study therapy, he had a complete response of myelopathy symptoms and MRI lesions. Our observation of sustained disease response in this patient may support a role for concurrent BTK and BCL2 inhibition in paraneoplastic myelitis associated with B-cell lymphoproliferative disorders. However, this observation needs to be validated in larger cohort studies and potentially in clinical trials if further data are supportive.

Highlights

• Paraneoplastic myelopathies are rare, so the prognosis and response to treatment are poorly defined.

• Therapeutic inhibition of BTK is regarded as a next-generation approach to attenuate errant innate and adaptive immune functions by inhibiting the antigen-presenting capacity of B-cells and the generation of encephalitogenic T-cells.

• Brain-penetrant properties of BTK inhibitors may impact compartmentalized inflammation and neurodegeneration within the central nervous system by targeting CNS-resident B cells and microglia.

• Early studies have shown that in patients with MYD88 L265P mutation show improved responses to ibrutinib in WM patients compared to patients without these mutations.

• Our observation of sustained disease response in this patient may support a role for concurrent BTK and BCL2 inhibition in paraneoplastic disorders associated with B-cell lymphoproliferative disorders.

Keywords

Paraneoplastic myelitis
MYD88 L265P mutations
BTK inhibitors
Onconeural antibodies
Longitudinally extensive transverse myelitis
Ibrutinib-Venetoclax therapy
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pmc1 Introduction

Paraneoplastic neurological disorders (PNDs) are a rare group of diseases that occur when the immune system has a reaction to a tumor and anti-cancer antibodies or activated T cells mistakenly attack normal cells in the nervous system [1]. Longitudinally extensive transverse myelitis (LETM) is defined as a spinal cord lesion that extends over three or more vertebral levels. In patients with systemic malignancy, paraneoplastic LETM occurs rarely and has been most frequently reported with lung cancers and lymphoproliferative malignancies like Waldenström macroglobulinemia (WM) [2]. WM is a rare, indolent, B-cell lymphoproliferative disorder characterized by lymphoplasmacytic cells in the bone marrow and monoclonal immunoglobulin M (IgM) paraproteinemia [3]. The management of paraneoplastic disorders focuses on a combination of oncological therapy and immunomodulation. As response to therapy is poor, emerging targeted therapies that modulate specific immune pathways without broad immunosuppression may be considered. We describe a patient with paraneoplastic LETM associated with WM who responded to treatment with ibrutinib and venetoclax.

2 Case report

A 68-year-old male with Raynaud's disease, hyperlipidemia, diverticulosis, and treatment-naïve WM (MYD88 L265P mutation in bone marrow aspirate), presented with a two-month history of unsteadiness, tingling, and numbness in both hands and feet that progressed to bilateral leg and arm weakness. WM was diagnosed three years before his neurological presentation, following a clinicopathological evaluation for anemia with elevated serum IgM levels (1690 mg/dL) and presence of lymphoplasmacytic cells on bone marrow studies.

Cerebrospinal Fluid (CSF) analysis showed lymphocytic pleocytosis with 1 RBC/uL, 32 mononuclear cells per uL (67 % lymphocytes, 30 % monocytes), total protein of 186 mg/dL, glucose 60 mg/dL, no oligoclonal bands or paraneoplastic antibodies. Cytology and flow cytometry analysis of the CSF were positive for clonal B-cells. Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) serologies on cell-based fluorescence-activated cell sorting (FACS) assays were negative. Magnetic resonance imaging (MRI) showed cord expansion from mid-C2-C7 with central cord T2 hyperintensity extending from C2-T1 (Fig. 1, Panel A), consistent with paraneoplastic myelitis. Upon diagnosis, the patient was promptly started on IV methylprednisolone followed by a short oral prednisone taper that markedly improved his symptoms.Fig. 1 MRI of cervical spine before ibrutinib-venetoclax treatment.

(A.1) Sagittal T2-weighted image showing hyperintense signal in the central spinal cord from C2–7 levels, (A.2) T2-weighted axial image of spinal cord showing hyperintense signal in central cord and bilateral lateral columns, (A.3) Post‑gadolinium contrast axial image showing bilateral enhancement of lateral columns. (B.1) Sagittal T2-weighted image showing cord edema and T2 hyperintensity from C2–7 levels, (B.2) T2-weighted axial image of spinal cord showing T2 hyperintensity more prominent in dorsal columns, (B.3) Post-contrast axial image showing enhancement of lateral and dorsal columns.

Fig. 1

However, a month later, he felt worse and had difficulty walking, requiring support. A repeat MRI showed persistent cord expansion and increased gadolinium enhancement. For his relapse, the patient was started on oral prednisone followed by a long taper with only moderate improvement of his symptoms. Subsequently, he received intravenous immunoglobulin and rituximab 1000 mg. Two months after treatment with rituximab, cervical and thoracic spine MRIs showed persistent spinal cord edema with increased gadolinium enhancement now involving the dorsal columns (Fig. 1, Panel B), and he continued to have symptoms of weakness and unsteadiness.

Twelve months after starting rituximab, the patient met the criteria for initiating therapy for WM due to anemia requiring transfusions. Accordingly, he was enrolled in a Phase II study on the combination of ibrutinib and venetoclax in treatment naïve patients with WM (NCT04273139). He was treated with ibrutinib and venetoclax for three cycles, starting with ibrutinib 420 mg oral dose, once daily, for twenty-eight days. Venetoclax 400 mg oral dose was added from cycle 2 for twenty-eight days (successfully ramped up from 100 mg once daily). Eventually, due to trial discontinuation, his treatment was truncated, and he received only three of the twenty-four planned months of treatment with ibrutinib and venetoclax. Rituximab was withheld throughout this period. He did not receive any further doses of rituximab or other immunotherapy after the trial therapy was discontinued.

Since completing treatment, he has felt neurologically well, and his hemoglobin has stayed stable with remission of WM. Matching his perception, his clinical examination improved to full strength in his legs with some residual signs of hyperreflexia and moderately decreased vibratory sense in the feet. A retrospective Expanded Disability Status Scale (EDSS) assessment showed improvement from 6 (nadir of presentation with walking requiring support) to 2 (at last follow-up). Imaging was notable for marked improvement in spinal cord edema and gadolinium enhancement. (Fig. 2) At the last follow-up, one year after treatment with ibrutinib and venetoclax, he remained neurologically stable. Serum neurofilament light chain (NfL) level measured at one-year post-treatment was within the normal range for age and sex.Fig. 2 MRI cervical spine post ibrutinib-venetoclax treatment

(A) Sagittal T2-weighted image showing resolution of hyperintense signal in the central spinal cord, (B) T2-weighted axial image of spinal cord showing resolution of hyperintense signal in lateral and dorsal columns, (C) Post-contrast axial image showing no cord enhancement.

Fig. 2

3 Discussion

Paraneoplastic neurological disorders (PNDs) do not reflect direct tumor invasion of neuronal tissues but are triggered by an immune response against neural self-antigens that are aberrantly expressed or sensitized by tumors. Due to this shared antigenic expression, the immune system reacts to neural cells, affecting any part of the nervous system, including the central and peripheral nervous systems, neuromuscular junctions, and muscles. Antibodies, T-cells, or both may be mediators in this secondary immune response.

Paraneoplastic myelitis is a rare, immune-mediated inflammatory disorder of the spinal cord associated with an underlying malignancy. The prognosis and treatment response in patients with paraneoplastic myelitis are poorly defined in literature, and despite treatment, many patients eventually become wheelchair dependent. Treatment primarily focuses on managing the underlying malignancy and instituting immunotherapy. Currently, for PNDs of the central nervous system (CNS) that are likely antibody-mediated, acute therapies consist of combinations of corticosteroids, intravenous immunoglobulin, plasma exchange, and cytotoxic therapy such as rituximab and cyclophosphamide. PNDs of the CNS associated with T-cell-mediated neuronal destruction tend to be poorly responsive to treatment and cause severe morbidity [4].

To our best knowledge, myelopathy in WM has been reported only twice before, and the first case of successfully treating myelopathy in WM reported in literature describes a response to rituximab therapy [5]. In this study, the spinal cord changes likely represented direct infiltration by lymphoplasmacytic B-cells. However, in our patient, the lateral and dorsal column tract-specific gadolinium enhancement was more consistent with inflammatory myelitis rather than lymphoproliferative cord invasion (no mass like lesion in parenchyma or meninges [6]). Our patient also had a complete response of myelopathy symptoms and MRI lesions when initiated on ibrutinib and venetoclax.

Ibrutinib is a highly potent, small-molecule inhibitor of Bruton's Tyrosine Kinase (BTK), a cytosolic enzyme centrally involved in B-cell receptor signaling and B-cell and myeloid cell activation and functioning. Therapeutic inhibition of BTK is regarded as a next-generation approach to attenuate errant innate and adaptive immune functions by inhibiting the antigen-presenting capacity of B-cells and the generation of encephalitogenic T-cells [7]. Preclinical studies in animal models of multiple sclerosis corroborated the impact of BTK inhibition by evobrutinib on meningeal inflammation and cortical demyelination. The brain-penetrant properties of BTK inhibitors may impact compartmentalized inflammation and neurodegeneration within the central nervous system by targeting CNS-resident B cells and microglia. Our patient's improvement with ibrutinib, may indicate its superior brain-penetrant properties and effect on innate immune cells, which may be essential mediators in the pathogenesis of paraneoplastic myelitis. Additionally, early studies have shown that in patients with MYD88 L265P mutation, multiple proinflammatory pathways are upregulated. These studies also show improved responses to ibrutinib in WM patients with MYD88 mutations compared to patients without these mutations [8].

Venetoclax blocks the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to the programmed cell death of lymphoma cells. Ibrutinib and venetoclax have been approved for patients with chronic lymphocytic leukemia (CLL) [9], and preclinical models indicate that the combination of the two drugs may be synergistic.

4 Conclusion

Our observation of sustained disease response in this patient may support a role for concurrent BTK and BCL2 inhibition in paraneoplastic myelitis associated with B-cell lymphoproliferative disorders. However, the clinical improvement could also have been indirectly from better control of WM. This observation needs to be validated in larger cohort studies and potentially in clinical trials if further data are supportive.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Informed consent

A written informed consent was obtained from the concerned patient after approval of the above material, in compliance with the journal guidelines.

CRediT authorship contribution statement

Sathya Narasimhan: Writing – original draft, Conceptualization. Kristin M. Galetta: Writing – review & editing, Conceptualization. Jorge J. Castillo: Writing – review & editing, Conceptualization. Shamik Bhattacharyya: Writing – review & editing, Conceptualization.

Declaration of competing interest

Sathya Narasimhan: None.

Jorge J. Castillo: reports research funds and/or consulting fees from AbbVie, AstraZeneca, Beigene, Cellectar, Janssen, Kite, LOXO, Mustang Bio, and Pharmacyclics.

Kristin M. Galetta: None.

Shamik Bhattacharyya: received research support from National Institute of Health, Alexion Pharmaceuticals, UCB, and Roche. He has consulted for Alexion Pharmaceuticals, Teladoc Health. He has received publishing honorarium from American Academy of Neurology and UpToDate.
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