Upper Gastrointestinal Tract Lymphoma With Natalizumab

PRACTICAL IMPLICATIONS

In patients with multiple sclerosis who are treated with natalizumab, new, persistent, and/or upper gastrointestinal symptoms should prompt assessment for DLBCL (Tysabri, Biogen, RTP, NC).

The humanized recombinant monoclonal antibody natalizumab (Tysabri) is a selective antagonist of the α4 subunit of the leukocyte adhesion molecule integrin, VLA-3. Blockade of VLA-3 leads to inhibition of immune cell transmigration into target organs, notably the intestinal lining and CNS.^1,2 Natalizumab is approved to treat relapsing-remitting multiple sclerosis (RRMS) in the United States and Europe and Crohn disease in the United States. After approval in 2004, natalizumab was withdrawn in 2005 because of 3 reported cases of progressive multifocal leukoencephalopathy (PML). In 2006, it reentered the market with additional monitoring requirements.

Despite good tolerability and safety, natalizumab is associated with hepatotoxicity, PML, cutaneous zoster, and, rarely, melanomas and gliomas.^1–3 Individual case reports have suggested a link with hematological neoplasia's including primary CNS lymphoma (PCNSL), peripheral T-cell lymphoma (PTCL), and extranodal diffuse large B-cell lymphoma (DLBCL).^1,2

DLBCL constitutes approximately 30% of all lymphomas, with the upper gastrointestinal tract (GIT) being the most common site of extranodal presentation, with an incidence of 0.5 cases/100,000 person years.³ After a single report of natalizumab-associated gastric DLBCL in a 61-year-old male patient with MS, we report a further 2 cases of gastric DLBCL from a single center.

Case

Patient 1

A 25-year-old woman presented in 2012 with left-lower limb sensory deficit and fatigability and was diagnosed with RRMS 3 years later. She was treated with dimethyl fumarate for 9 months before ceasing because of side effects and continued disease activity and switched to natalizumab. She remained clinically and radiologically stable for 30 months. She was John Cunningham virus negative.

In 2018, she presented with 4 months of epigastric pain associated with a single episode of hematemesis. Gastroscopy revealed gastritis with a suspicious nonbleeding prepyloric ulcer confirmed on biopsy as DLBCL.

She was treated with 6 cycles of rituximab, cyclophosphamide, vincristine, doxorubicin, prednisolone (R-CHOP) with complete response, and no evidence of recurrent disease. Her MS has remained in remission over 18 months (Expanded Disability Status Scale [EDSS] 0) with no further treatment and ongoing 6-month surveillance MRIs.

Patient 2

A 53-year-old woman diagnosed with RRMS in 2007 was initially treated with interferon beta-1a (Rebif44). This was discontinued after 8 months after disease progression and poor tolerance. She subsequently started natalizumab, and over 7 years (88 doses) remained neurologically and radiologically stable with only mild fatigue and vertigo (EDSS 1.0).

She presented in December 2015 after 3 weeks of upper abdominal pain, anorexia, and vomiting. Imaging indicated small bowel obstruction, and at laparotomy, a jejunal mass was excised. Histology confirmed a gastric DLBCL with a Ki67 positive high proliferative index (figure). She underwent chemotherapy with R-CHOP and methotrexate for 6 cycles and has had no evidence of residual disease.

Figure. Gastric Histopathology of Patient 2.

Left aspect of the slide: diffuse proliferation of large lymphoid cells effacing normal gastric mucosa architecture (×10 magnification).

In 2018, she initiated rituximab for MS, in discussion with the hematology team. She remains neurologically stable (EDSS 1.0).

Discussion

To date, there has been one other reported case of natalizumab-associated gastric DLBCL, as previously mentioned.¹ Nine cases of PCNSL have been reported in patients receiving natalizumab, with exposure ranging between 2 and 21 doses; a case of PTCL of the CNS was also reported in a 39-year-old patient with MS after 17 doses of natalizumab (appendix e-2, links.lww.com/CPJ/A218).

Although an increased incidence of nonHodgkin lymphoma (NHL) has been reported in a number of autoimmune conditions, a large Swedish cohort study found that multiple sclerosis was an exception and not associated with an increased risk of developing NHL.⁴ All patients with MS reported thus far with natalizumab-related lymphoma, including these further 2 cases, have had no risk factors for lymphoma other than immunosuppressive therapy. Epstein–Barr virus and HIV have been negative in all cases, the exception being a Crohn disease patient with PCNSL.^1,4,5

Proposed mechanisms of natalizumab include reduced leukocytic extravasation in the CNS and GIT through antagonism of ligand interaction, thus decreasing inflammatory immune responses and potentially affecting immune surveillance with long-term exposure.⁶ The apparent predilection for lymphomas in the CNS and GIT—sites in which immune surveillance may be impaired by natalizumab—would support a causative association, as would the rarity of extra-nodal DLBCL. Furthermore, a recent study indicated natalizumab therapy led to increased peripheral B-cell differentiation, activation, and cytokine production, increasing a further potential mechanism of B-cell dysregulation.⁷

In addition to the previous reported case, this study adds a further 2 patients with this rare malignancy from a single center, suggesting an association between natalizumab and gastric DLBCL. Although monitoring for PML will remain the primary concern for physicians using natalizumab, we suggest vigilance and prompt investigation of patients developing upper gastrointestinal symptoms in the context of exposure to this agent.

Appendix. Authors

Study Funding

No targeted funding reported.

Disclosure

The authors report no disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.