Adult T-cell Leukemia Following Satralizumab Treatment for Neuromyelitis Optica Spectrum Disorder

Abstract

A 78-year-old woman with aquaporin 4 antibody-positive neuromyelitis optica spectrum disorder (NMOSD) developed acute-type adult T-cell leukemia (ATL) 1 month after initiating satralizumab, without prior human T-cell leukemia virus type 1 screening. She presented with respiratory symptoms and hematochezia after receiving three doses. Laboratory tests revealed abnormal lymphocytosis and HTLV-1 positivity, with monoclonal proliferation. Despite CHOP chemotherapy, the patient died within two weeks of treatment initiation. interleukin-6 inhibition may impair the host defense against HTLV-1 oncogenesis. This case highlights the potential risk of ATL following treatment with satralizumab, especially in HTLV-1 endemic areas, and the importance of HTLV-1 screening and clonality assessment before treatment in patients with NMOSD.

Introduction

The advent of molecular-targeted therapies has significantly reduced disease activity and improved functional outcomes in patients with neuromyelitis optica spectrum disorder (NMOSD) (1-5). Among these therapies, complement inhibitors, such as eculizumab and ravulizumab, are associated with an increased risk of meningococcal infection, whereas agents targeting the interleukin-6 (IL-6) receptor (e.g., satralizumab) or CD19/CD20-positive B cells (e.g. inebilizumab and rituximab) require close monitoring for infectious complications.

To mitigate the risks associated with complement inhibition, standard precautions include meningococcal vaccination before treatment initiation and the prompt administration of antibiotics during febrile episodes. In contrast, B cell-depleting therapies require comprehensive screening and preventive strategies to address the potential reactivation or exacerbation of infections such as hepatitis B and C, tuberculosis, fungal diseases, and varicella-zoster virus (VZV).

Despite these established precautions, routine screening for human T-cell leukemia virus type 1 (HTLV-1) infection is not commonly conducted before the initiation of molecular-targeted therapies in NMOSD.

We herein report a rare case of adult T-cell leukemia (ATL) that developed shortly after initiation of satralizumab therapy. This case underscores the urgent need for an HTLV-1 risk assessment, including serological testing and a clonality analysis, before administering immunosuppressive therapies, particularly in regions endemic for HTLV-1.

Case Report

A 78-year-old woman presented with blurred vision in her left eye accompanied by pain in the left occipital region. Her symptoms had persisted for 17 days before presentation. She had initially consulted a local ophthalmologist 15 days before admission, where optic disc edema had been observed in the left eye, raising the suspicion of optic neuritis. She was referred to our hospital's ophthalmology department seven days later.

An ophthalmic examination revealed a positive relative afferent pupillary defect in the left eye, partial temporal visual field defects, and mild hyperintensity of the left optic nerve sheath on coronal and axial short tau inversion recovery sequences on orbital magnetic resonance imaging (MRI; Fig. 1a, b). Based on these findings, the patient was diagnosed with left optic perineuritis. The patient was subsequently referred to the neurology department for a further evaluation and management on the day of hospital presentation (designated Day X).

Figure 1.

Orbital and systemic imaging findings. (a) Coronal view of orbital MRI showing mild hyperintensity of the left optic nerve sheath (arrow). (b) Axial view of orbital MRI highlighting partial hyperintensity of the left optic nerve sheath (arrow). (c) PET-CT scan demonstrating systemic lymphadenopathy, including cervical, axillary, and abdominal lymph nodes, as well as splenic involvement. (d) Upper endoscopy revealing circumferential ulcerative lesions extending from the superior duodenal angle to the descending portion of the duodenum.

Her medical history was notable only for bilateral cataract. She had no known allergies or history of blood transfusion. The family history included a brother with lung cancer, with no known cases of HTLV-1 infection or ATL. The patient was a lifelong resident of Okinawa Prefecture, a non-smoker, and not a habitual alcohol consumer.

A neurological examination revealed no abnormalities, except for a left temporal visual field defect. Initial laboratory investigations revealed a white blood cell count of 8,800 /μL (neutrophils, 60.0%; lymphocytes, 31.1%; monocytes, 7.4%; eosinophils, 0.5%; basophils, 1.0%; automated differential count), red blood cell count of 3.85×10⁶/μL, platelet count of 286×10³/μL, lactate dehydrogenase level of 287 U/L, and C-reactive protein level of 0.18 mg/dL. Serum anti-aquaporin-4 (AQP4) antibodies were positive (20.6 U/mL, enzyme-linked immunosorbent assay). A cerebrospinal fluid analysis showed ＜1 cells/μL, a protein level of 36 mg/dL, negative oligoclonal bands, and an immunoglobulin G index of 0.40. Orbital MRI showed resolution of the high signal in the left optic nerve sheath, and chronic ischemic changes were observed only on brain MRI.

Based on these findings, NMOSD was diagnosed on Day X+7. Based on the MRI findings, it was considered that the inflammation had reached its peak, acute-phase treatment, such as steroid pulse therapy, was not administered, and oral prednisolone therapy (10 mg/day) was initiated. Satralizumab was initiated on day 49. The patient remained asymptomatic and received subsequent doses of satralizumab on Days X+63 and X+77.

However, on Day X+88, she developed upper respiratory tract symptoms suggestive of a common cold. Laboratory results showed leukocytosis, with a white blood cell count of 14,300 /μL and 23% abnormal lymphocytes. By Day X+104, she presented with melena, and her leukocyte count had increased to 25,300 /μL with 30% abnormal lymphocytes. Hematology referral was initiated (Fig. 2). Peripheral blood smears revealed characteristic “flower cells,” and serological testing confirmed HTLV-1 infection (HTLV-I/II antibodies: 50.1 U/mL; confirmed by a line immunoassay).

Figure 2.

Clinical course and treatment timeline. Timeline summarizing key clinical events, including initiation of prednisolone (10 mg/day), administration of satralizumab on Days 49, 63, and 77, and the onset of common cold symptoms and melena. Sat: satralizumab, Lym: lymphocyte, Ab.Lym: abnormal lymphocyte

Bone marrow aspiration revealed the presence of abnormal lymphoid cells with nuclear irregularities. A Southern blot analysis confirmed the monoclonal integration of HTLV-1 proviral DNA, establishing a diagnosis of ATL. A further analysis using the Rapid Amplification of Integration Sites without Interference by Genomic DNA (RAISING) method showed a near-monoclonal proliferation pattern.

On Day X+133, the patient was admitted with worsening fatigue and extreme leukocytosis (white blood cell count: 176,400 /μL). Positron emission tomography-computed tomography revealed involvement of the cervical, axillary, and abdominal lymph nodes along with splenic infiltration, consistent with lymphoma-type ATL (Fig. 1c). A diffuse fluorodeoxyglucose uptake in the duodenum suggested gastrointestinal involvement. Upper endoscopy revealed circumferential ulcerative lesions extending from the superior duodenal angle to the descending portion (Fig. 1d). A histopathological analysis confirmed infiltration of ATL cells.

She was diagnosed with acute-type ATL, and CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) was initiated on Day X+137. Due to the high tumor burden, the patient developed tumor lysis syndrome, which led to rapid clinical deterioration. Despite intensive supportive care, she died on Day X+146 due to complications associated with the tumor lysis syndrome (Fig. 3).

Figure 3.

Disease progression and outcome. (a) A clonality analysis of HTLV-1-infected cells performed using the RAISING method combined with next-generation sequencing technology. The percentage indicates the proportion of monoclonal reads relative to total reads. (b) Clinical course following hospitalization: initiation of CHOP chemotherapy, development of tumor lysis syndrome, and death on Day 146 despite supportive care. Lym: lymphocyte, Ab.Lym: abnormal lymphocyte

Discussion

Satralizumab is a humanized monoclonal antibody that targets the IL-6 receptor and is designed to extend the half-life of tocilizumab (6). It exerts its therapeutic effect by suppressing various IL-6-mediated pathological processes, including immune cell differentiation, antibody production, and blood-brain barrier disruption, thereby reducing the disease activity in NMOSD. Owing to its subcutaneous administration and favorable efficacy and safety profile, satralizumab has become a widely used molecular-targeted therapy for NMOSD in Japan.

Although satralizumab was approved in 2020 for AQP4 antibody-positive NMOSD (3), its predecessor, tocilizumab, has been used since 2005 to treat conditions such as Castleman disease, rheumatoid arthritis, and adult-onset Still's disease (7,8). Based on clinical experience with IL-6 inhibitors, standard pretreatment screening protocols typically include an evaluation for latent infections, such as hepatitis B and C, tuberculosis, fungal infections, and VZV (9,10). However, in the present case, screening for HTLV-1 and manual peripheral blood smear examinations were not conducted. This oversight may have contributed to the subsequent development of ATL shortly after initiation of satralizumab.

HTLV-1 is a retrovirus primarily transmitted through vertical (mother-to-child) routes and sexual contact. It infects CD4-positive T lymphocytes and is associated with two major diseases: ATL and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (11,12). Although only approximately 5% of HTLV-1 carriers develop ATL (13), malignant transformation of infected T cells is a key pathogenic step. ATL is classified into four clinical subtypes: smoldering, chronic, lymphoma, and acute. The acute form, as seen in this case, is associated with a particularly poor prognosis and a median survival of approximately 6.2 months (14).

To our knowledge, this is the first reported case of ATL development following satralizumab administration. Although rare, ATL cases have been documented during tocilizumab therapy (15). Furthermore, there have been reports of worsening HAM/TSP during tocilizumab treatment (16). Notably, IL-6 suppresses the tumorigenic activity of HTLV-1-infected cells by inhibiting HTLV-1 bZIP factor, a viral protein that promotes cellular transformation. This inhibition suppresses the differentiation of regulatory T cells and reduces IL-10 production, ultimately preventing the tumorigenesis of infected cells (17). Thus, the inhibition of IL-6 signaling by satralizumab may attenuate this protective mechanism, potentially facilitating the onset of ATL in HTLV-1-infected individuals. Because there have been no reports of the rapid onset of B-cell lymphomas following the introduction of these agents, it is considered to be a T cell-specific response.

Despite the widespread use of IL-6 inhibitors in autoimmune diseases, reports on ATL development remain exceedingly rare (18,19). This suggests that only a small subset of HTLV-1 carriers are at an elevated risk. High HTLV-1 proviral load (defined as ＞4% of peripheral blood mononuclear cells) has been recognized as a significant risk factor for ATL (20,21). More recently, clonal expansion, rather than proviral load alone, has emerged as a more precise predictor of disease progression (22-25). The RAISING method enables the quantitative assessment of clonality. A clonality value ≥0.5 is considered indicative of a high risk. Approximately 4% of asymptomatic HTLV-1 carriers fall into this high-risk category, with a median time to ATL development of 380 days (23-25). In the case reported by Nakamura et al. (15), ATL developed approximately two years after the initiation of tocilizumab treatment for RA. Conversely, in our case, ATL developed shortly after drug introduction. These differences suggest distinct underlying mechanisms. Although no such reports currently exist, longitudinal monitoring with a clonality analysis may allow for the prediction of ATL development.

In the present case, a clonality analysis was not conducted before the initiation of satralizumab. However, post-diagnosis testing revealed nearly monoclonal proliferation (98.9%), suggesting that the patient had already been at a high risk for ATL before receiving IL-6 inhibitor therapy. Importantly, HTLV-1 infection with high clonality often remains undetectable in the absence of specialized testing, underscoring the need for targeted screening in high-prevalence regions.

Based on these findings, screening for HTLV-1 infection and assessing infected cell clonality should be considered before initiating satralizumab treatment, particularly in endemic areas. In patients with a clonality index ≥0.5, alternative therapeutic strategies that do not involve IL-6 inhibition are warranted to minimize the risk of ATL development. Given that similar cases have also been reported with rituximab (26), complement inhibitors such as ravulizumab or eculizumab, rather than B-cell depletion therapy, may represent the safest treatment options in terms of minimizing the risk of ATL development. Although clonality testing is not currently part of routine clinical practice in Japan, integrating accessible methods to assess the HTLV-1 proviral load and clonality would facilitate safer and more personalized treatment strategies, including the use of satralizumab, for patients with NMOSD.

Finally, further research is needed to elucidate the potential oncogenic risks associated with IL-6 receptor inhibition and develop evidence-based risk-stratification models for HTLV-1 carriers undergoing immunosuppressive therapy.

Conclusion

Before initiating satralizumab therapy for NMOSD, it is imperative to assess patients with HTLV-1 infection. In confirmed HTLV-1 carriers, additional evaluations using proviral load measurement and clonality analysis should be considered to assess the risk of developing ATL. Incorporating these precautionary measures may enhance treatment safety and prevent serious adverse outcomes associated with IL-6 receptor inhibition.

Written informed consent was obtained from the patient's family for publication of case details and accompanying images.

Author’s disclosure of potential Conflicts of Interest (COI).

K. Sakurai received honoraria from Alexion Pharmaceuticals, Chugai Pharmaceutical, Mitsubishi Tanabe Pharma, UCB, Argenx, Novartis, and Biogen. The other group members declare no competing interests.

Funding Statement

This work was supported by grants from the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development (AMED; Grants JP25ek0109735h and JP25fk0108733h and 25ek0109759e and 25ek0109617s), the Rare and Intractable Diseases Program of the Ministry of Health, Labour and Welfare of Japan (Grant JPMH25FC1012), and the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant JSPS25K02584).