Diffuse large B-cell lymphoma complicated by cytokine release syndrome and immune effector cell–associated neurotoxicity on day 355 of epcoritamab therapy: a case report

INTRODUCTION

Bispecific antibodies (BsAbs) redirect T cells to attacking tumors, thereby facilitating T-cell-mediated cell death. BsAbs are now widely used in clinical practice for the treatment of intractable recurrent hematological malignancies.^1,2 Consequently, the frequency of adverse effects of BsAbs, such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), has increased. Until now, these adverse effects have mostly been considered to occur during the early stages of BsAb therapy.³ We recently encountered an unusual case of a patient who developed CRS and ICANS approximately 1 year after the initiation of BsAb therapy. This appears to be a valuable case for discussing risk and predictive factors (predicting the time of onset) for CRS and ICANS development during BsAb therapy.

The patient was an 82-year-old woman. In February Year X-7, she presented with swelling of multiple superficial lymph nodes and was diagnosed with diffuse large B-cell lymphoma of the germinal center B type. Fluorescence in situ hybridization analysis did not reveal any c-myc and bcl-2 rearrangements. The serum lactate dehydrogenase (LDH) level was 300 (criterion range, 124–222) U/L, and the serum soluble interleukin (IL)-2 receptor level was 1179 (criterion range, 220–530) U/mL. Positron emission tomography/computed tomography revealed multiple areas of accumulation (Figure 1a). Bone marrow examination revealed no evidence of infiltration. The performance status, disease stage, and the international prognostic index were 0, III, and 3 (age, LDH, and stage), respectively. There were no B symptoms. From July Year X-7, the patient received six courses of R-CHOP therapy (rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m², and prednisone 100 mg/body), which resulted in complete remission (CR 1) (Figure 1b). However, the illness recurred in February Year X-4. The patient was subsequently treated with six courses of R-MECP therapy (rituximab 375 mg/m², carboplatin 300 mg/m², etoposide 70 mg/m², mitoxantrone 8 mg/m², and prednisone 40 mg/m²), which again resulted in CR (CR 2). The illness recurred once more in March Year X-2, and the patient received six courses of PBR therapy (polatuzumab vedotin 1.8 mg/kg, bendamustine 90 mg/m², and rituximab 375 mg/m²), which led to CR 3. The lymphocyte count was 3720/μL immediately before the start of PBR therapy and decreased to 90/μL by its completion. In November Year X-1, the illness recurred again (Figure 1c), and by December, epcoritamab was initiated (following a bendamustine washout period of 15.5 months). At this time, the lymphocyte count was 530/μL (Figure 2). Head magnetic resonance imaging (MRI) revealed no abnormalities (Figure 3a). For prophylaxis against CRS and ICANS development, acetaminophen and diphenhydramine were administered before each epcoritamab dose during the first course of the therapy. In addition, dexamethasone 16 mg was administered for four consecutive days from each epcoritamab dosing day. From the second course onward, dexamethasone 4 mg was administered only on each epcoritamab dosing day. During the second course, the patient developed grade (G) 1 CRS,⁴ which resolved in response to acetaminophen alone. At the end of the second course of this therapy, CT confirmed CR 4. Therefore, the patient continued on epcoritamab treatment. In November Year X (day 338 from the start of the first course of this therapy), at the beginning of the 13th course of this therapy (Table 1), the lymphocyte count was 2150/μL; platelet count, 293 000/μL (criterion range, 158 000–348 000/μL); serum LDH, 300 (criterion range, 124–222) U/L; serum C-reactive protein (CRP), 1.21 (criterion range, 0.00–0.14) mg/dL; and serum ferritin, 637.9 (criterion range, 4.3–199.1) ng/mL. Dexamethasone 4 mg was administered as prophylaxis against CRS and ICANS development. On day 355 of this therapy (day 18 of the 13th course of the therapy; bendamustine washout period, 27.5 months), the patient had a fever (38.1 °C) and clouding of consciousness and was diagnosed with G1 CRS and G3 ICANS with an immune effector cell–associated encephalopathy (ICE) score of 0.⁴ No electrolyte abnormalities were noted, and the drugs administered were kept unchanged. She was administered a single dose of tocilizumab 8 mg/kg and dexamethasone 10 mg every 6-h. She additionally received levetiracetam.³ On the day after treatment initiation, the ICE score improved to 9. The dexamethasone dose was gradually tapered to 0. Cerebrospinal fluid (CSF) examination revealed a cell count of 1/μL and protein level of 56.6 (criterion range, 15–45) mg/dL. Multiplex polymerase chain reaction analysis of the CSF revealed negative results for all herpes simplex virus-1,2, varicella zoster virus, Epstein–Barr virus, cytomegalovirus, human herpesvirus-6,7,8, adenovirus, hepatitis B virus, human parvovirus B19, John Cunningham virus, and BK virus. Bacterial culture and cytodiagnosis were also negative, and electroencephalogram revealed no abnormalities. MRI demonstrated a high signal intensity area in the pons on fluid-attenuated inversion recovery images (Figure 3b). A repeat MRI performed a week later revealed a reduction in the high signal intensity area (Figure 3c). MRI will be performed again to check the course of the lesion depicted as a high signal intensity area. CT confirmed CR. At present, the patient is still receiving epcoritamab.

Fig. 1.

Imaging findings

a. PET/CT image at the first visit showing multiple areas of accumulation.

b. PET/CT image after six courses of R-CHOP therapy confirming CR.

c. PET/CT performed upon recurrence after PBR therapy (before epcoritamab therapy initiation) showing multiple areas of accumulation. CR, complete remission; PET/CT, positron emission tomography/computed tomography

Fig. 2.

Clinical course after epcoritamab treatment initiation

Fig. 3.

Contrast-enhanced MRI of the head

a. No abnormalities were noted before epcoritamab treatment initiation.

b. A high signal intensity area noted in the pons on FLAIR images taken just upon ICANS onset.

c. A repeat MRI performed 1 week after ICANS onset showing a reduction in the high signal intensity area in the pons on FLAIR images. FLAIR, fluid-attenuated inversion recovery; ICANS, immune effector cell–associated neurotoxicity syndrome; MRI, magnetic resonance imaging

Table 1. Test findings after 13 courses of epcoritamab therapy.

Day	338 (1)	···	350 (13)	···	355 (18)	···	358 (21)	···	364 (27)
Epcoritamab	13 th cycle ↓
CRS ICANS					↓(G1) ↓(G3)
ICE Score	10				0	9	10	10	10
Inspection					Lumbar Puncture	EEG	MRI		MRI
Ferritin ng/mL (4.3–199.1)	637.9		482.3		805.3				887.7
LDH U/L (124–222)	300		262		348		222		238
Fib mg/dL (200–400)					398	283
CRP mg/dL (0.00–0.14)	1.21		0.45		1.56		0.23		0.04
IL-1β pg/mL (≤ 0.928)		0.620			< 0.125		< 0.125
IL-6 pg/mL (≤ 7.0)		6.92			56.7		16.4
IL-10 pg/mL (≤ 2.03)		1.00			2.25		< 0.78
TNF-α pg/mL (2.27–11.2)		16.0			12.3		5.44
INF-γ (≤ 0.1)		0.4			≤ 0.1		≤ 0.1

Abbreviations: (), number of days as counted from the first day of the 13th cycle; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; G, grade; ICE, immune effector cell-associated encephalopathy; EEG, electroencephalogram; MRI, magnetic resonance imaging; LDH, lactate dehydrogenase; Fib, fibrinogen; CRP, C-reactive protein; IL, interleukin; TNF, tumor necrosis factor; INF, interferon

In this case, the patient was diagnosed with ICANS (G3) and CRS (G1) on the basis of the high serum interleukin (IL)-6 and ferritin levels, clinical symptoms, and results of CSF examination and MRI (Table 1).^5–8

BsAbs have two binding sites, enabling them to bind to two epitopes on the same antigen or two different antigens and exert their effects. One arm of the BsAb binds to the target tumor-associated antigen, and the other simultaneously binds to CD3 on the surfaces of CD4+ helper T cells and CD8+ cytotoxic T cells. This interaction forms an immunological synapse that activates T cells without requiring T-cell recognition of the major histocompatibility complex/antigen complex on tumor cells. The activated T cells release perforin and granzyme, resulting in T-cell-dependent killing of tumor cells via apoptosis.⁷

BsAbs can cause CRS and ICANS as adverse effects.^3,7 CRS is a result of rapid cytokine release when the T cells are activated upon engagement with the tumor cells.

Although the pathophysiology of ICANS in patients receiving BsAb therapy remains to be fully elucidated, it has been speculated to involve inflammatory cytokine-mediated blood–brain barrier disruption and immune effector cell trafficking to the central nervous system (CNS).⁸ The cytokines involved in ICANS include IL-2, IL-6, interferon gamma, and tumor necrosis factor alpha.^5–8

The reported incidences of BsAb-induced CRS and ICANS ranges from 26.1% to 64% (≥G3: 0.7%–7%) and from 0.7% to 12% (≥G3: 0%–3%), respectively.^3,9,10 Regarding the timing of their onset, both events often develop upon the first target dose level of BsAb being reached.^3,9,11 Development after the second or subsequent cycles of therapy have been reported rarely.⁹

As regards risk factors for CRS development during various therapies, risk factors during chimeric antigen receptor T-cell (CAR-T) therapy have been reported. These risk factors include young age, high tumor burden, poor disease control, platelet count <150 000/μL, and high serum LDH and CRP levels.^5,6

Risk factors for ICANS during CAR-T therapy include high serum levels of CRP, fibrinogen, ferritin, LDH, and IL-1, IL-6, and IL-10.^5,6,11 However, no studies have reported on the risk factors for the development of these adverse events during BsAb therapy. Thus, whether the risk factors for CRS and ICANS development during CAR-T therapy could also be as risk factors for these adverse events during BsAb therapy remains unclarified.

In the literature, the latest reported onset of CRS was on day 56 of epcoritamab therapy and that of ICANS was on day 141.³ However, the details of these cases remain obscure.

Considering that this patient had received prior bendamustine treatment, the reduction in lymphocyte count was potentially prolonged (bendamustine washout period, 15.5 months).¹² Additionally, the cessation of bendamustine treatment may have stimulated gradual recovery of the lymphocyte count (bendamustine washout period, 27.5 months).¹² Epcoritamab activates T cells (Figure 2).¹³ Overlaps of these two effects probably resulted in CRS and ICANS in the present case. Furthermore, considering the high serum LDH and ferritin levels, this case may be viewed as highly susceptible for CRS and ICANS development (Table 1).^5,6,11 Monitoring CRS and ICANS development during each stage of BsAb therapy is recommended, particularly in patients showing increased lymphocyte count over time.

This report is limited because lymphocyte activation was not evaluated.

In conclusion, the presented case is the first reported case of CRS and ICANS developing approximately 1 year after the start of BsAb therapy. Identifying risk and predictive factors for CRS and ICANS development in patients receiving BsAb therapy is desirable.

ETHICS COMMITTEE APPROVAL

This study was approved as a retrospective study by the ethics committee in January 2026.

INFORMED CONSENT

Informed consent was obtained from all participants included in the study.

AUTHORSHIP CONTRIBUTIONS

Concept: K.A., Y.S., S.H., H.T., M.K., N.M., Y.I., M.K.; Design: K.K., Y.N., H.K., D.T., T.A., M.H., S.E., Y.K., and T.N.; Data collection and processing: Y.S.; Analysis and interpretation: Y.S. and H.K.; Manuscript writing: Y.S.

CONFLICT OF INTEREST

Y.S. reports having received lecture fees from Chugai Pharmaceutical Co., Ltd. and AbbVie GK.

FINANCIAL DISCLOSURE

The authors received no financial support for the publication of this report.