Successful use of Remcyte®-based continuous hemodiafiltration in a case of refractory CRS and ICANS complicated by tumor lysis syndrome–associated AKI

Abstract

Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are severe complications associated with T cell–redirected immunotherapies, including bispecific antibodies. These conditions are typically managed with corticosteroids and interleukin-6 receptor antagonists such as tocilizumab. However, some patients remain unresponsive to these standard treatments. We report the case of a 73-year-old woman with relapsed high-grade B-cell lymphoma treated with epcoritamab who developed persistent fever and neurological impairment following drug administration. Despite repeated use of tocilizumab and corticosteroids, her symptoms progressed, and she was admitted to the intensive care unit. Laboratory testing revealed markedly elevated interleukin-6 levels (23,000 pg/mL), and she subsequently developed acute kidney injury due to tumor lysis syndrome. Continuous blood purification therapy using Remcyte®, a novel hemodiafilter with high cytokine adsorption capacity and favorable platelet compatibility, was initiated. Within 48 h, her consciousness level improved, serum interleukin-6 decreased significantly, and blood purification was discontinued without complications. This case suggests that Remcyte® may be beneficial in cases of cytokine-mediated syndromes unresponsive to standard therapies, particularly in patients with concurrent kidney dysfunction. Further accumulation of cases is required to clarify its therapeutic indications, optimal timing of use, and clinical utility in patients without renal involvement.

Introduction

Cytokine release syndrome (CRS) is a serious systemic inflammatory syndrome with multiple organ dysfunction. Although CRS is known to occur more frequently in chimeric antigen receptor T-cell (CAR-T) therapy, it’s also associated with haploidentical allogeneic transplantation and monoclonal antibody-based therapy [1]. Immune effector cell-associated neurotoxity syndrome (ICANS) is a neuropsychiatric syndrome and also occur in patients with CAR-T therapy and bispecific antibody therapy. Mostly, ICANS can occur with CRS [2]. Although immediate steroid thepary, anti-cytokine therapy including tocilizumab, and supportive intensive care are crucial for patients with CRS and ICANS, no clear criteria have been established for the selection or timing of therapeutic interventions [3].

Remcyte® (TOYOBO CO., LTD., Osaka, Japan) is a novel hemodiafilter which is packed with a polymer alloy membrane composed of polyethersulfone (PES), sulfonated poly(arylene ether) copolymers (SPNs), and polyvinylpyrrolidone (PVP). It has superior ability to remove a wide range of cytokines and a higher platelet survival rate [4].

Herein, we report a case of CRS and ICANS that was refractory to corticosteroids and tocilizumab, and subsequently developed acute kidney injury (AKI) due to tumor lysis syndrome. The patient demonstrated rapid clinical improvement following the initiation of continuous hemodiafiltration (CHDF) using Remcyte® without any complication.

Case report

A 73-year-old woman with a history of oropharyngeal carcinoma treated with chemoradiotherapy and previously long-term remission after treatment for follicular lymphoma, experienced relapse three months earlier as high-grade transformation to diffuse large B-cell lymphoma. She received a total of three courses of R-DeVIC (Rituximab, Carboplatin, Etoposide, Ifosphamide, Dexamethasone) therapy. Due to multiple treatment-refractory lesions, epcoritamab was initiated 15 days prior (cycle 1, day 1). On day 8, epcoritamab was administered again, after which she developed fever 7 days earlier and was diagnosed with grade 1 CRS, for which tocilizumab was administered. On day 15, another dose of epcoritamab was given, and she subsequently developed fever overnight, again diagnosed as grade 1 CRS, and treated with tocilizumab. Despite additional dexamethasone administration, her fever persisted and disturbance of consciousness developed. She was diagnosed with ICANS and admitted to the intensive care unit (ICU) for advanced management.

Glasgow coma scale was E2V4M6 with drowsiness. A physical examination revealed body tempretature was 38.7 ℃, blood pressure was 114/60 mmHg with marked peripheral warmness, heart rate was 102 beats/min with sinus rhythm, and oxygen saturation was 100% at 3 L/min oxygen.

Blood tests revealed a leukocyte level of 3,700 /μL, a hemoglobin level of 11.0 g/dL, a platelet level of 3,700/μL, a lactate dehydrogenase level of 13,891 IU/L, a creatinine level of 1.0 mg/dL (base line creatinine level of 0.6 mg/dL), and a IL-6 level of 23,000 pg/mL.

Although the patient was already diagnosed CRS and ICANS, and tocilizumab and dexamethasone was administrated, disturbance of consciousness and fever associated with CRS persisted. Pulsed methylprednisolone therapy (1000 mg/day, three days) was initiated. Because the patient developed AKI due to tumor lysis syndrome and was in an oliguric state (the urine out put was 280 mL/24 h), and since serum creatinine levels had doubled within 24 h, further deterioration of renal function was anticipated. Therefore, CHDF was initiated. In addition to the indication for dialysis due to AKI, Remcyte®, a novel hemodiafilter with superior cytokine adsorption capacity and its higher platelet survival rate compared with the conventional AN69-ST membrane, was selected with the aim of ameliorating the underlying hypercytokinemia. CHDF settings were as follows: Remcyto® (membrane surface area 1.6 m²); blood flow rate, 120 mL/min; replacement fluid flow rate, 400 mL/h; dialysate flow rate, 400 mL/h; ultrafiltration flow rate, 800 mL/h; anticoagulation with heparin, 250 units/h. By the second day of ICU admission, the patient exhibited improvement in consciousness, permitting discontinuation of CHDF. Serum IL-6 levels decreased to 1,554 pg/mL, and the patient was subsequently transferred out of the ICU. The changes in the key laboratory parameters before and after CHDF are summarized in Table 1. Although additional IL-6 measurements could not be obtained due to insurance limitations, both the patient’s consciousness and overall clinical condition continued to improve, and retreatment with epcoritamab became feasible beginning on day 10 after ICU discharge.

Table 1.

CHDF; continuous hemodiafiltration, ICU; intensive care unit

Arterial blood gas		Blood chemistry
(A) The admission day of ICU (before CHDF)
pH	7.382	TP	5.3 g/dL
pO2	102.0 mmHg	Alb	3.4 g/dL
pCO2	35.9 mmHg	AST	327 IU/L
HCO3−	20.8 mmol/L	ALT	88IU/L
Lactate	1.4 mmol/L	ALP	190 IU/L
Blood count		γ-GTP	484 IU/L
WBC	0.3 × 103 /μL	LDH	13,891 IU/L
RBC	2.42 × 106 /μL	AMY	43 IU/L
Hb	7.3	CK	32 IU/L
Ht	21.2% g/dL	T-Bil	0.5 mg/dL
Plt	9.0 × 103 /μL	BUN	33 mg/dL
Coagulation		Cre	1.0 mg/dL
PT-INR	1.37	eGFR	42 mL/min/1.73 m2
PT activity	56%	UA	5.9 mg/dL
APTT	47.3 s	Na	134 mEq/L
Fbg	142 mg/dL	K	3.8 mEq/L
FDP	43.2 μg/mL	Cl	103 mEq/L
		Ca	7.1 mg/dL
		P	4.0 mg/dL
		Serology
		CRP	0.95 mg/dL
		IL-6	23,000 pg/mL
(B) The second day of ICU (after CHDF)
pH	7.483	TP	4.6 g/dL
pO2	99.3 mmHg	Alb	2.8 g/dL
pCO2	32.0 mmHg	AST	132 IU/L
HCO3−	23.7 mmol/L	ALT	76 IU/L
Lactate	1.2 mmol/L	ALP	202 IU/L
Blood count		γ-GTP	398 IU/L
WBC	1.0 × 103 /μL	LDH	9520 IU/L
RBC	3.36 × 106 /μL	AMY	29 IU/L
Hb	10.1	CK	105 IU/L
Ht	27.6% g/dL	T-Bil	0.6 mg/dL
Plt	7.0 × 103 /μL	BUN	22 mg/dL
Coagulation		Cre	0.42 mg/dL
PT-INR	1.01	eGFR	108 mL/min/1.73 m2
PT activity	98%	UA	2.5 mg/dL
APTT	44.9 s	Na	138 mEq/L
Fbg	192 mg/dL	K	3.6 mEq/L
FDP	28.1 μg/mL	Cl	106 mEq/L
		Ca	7.7 mg/dL
		P	2.1 mg/dL
		Serology
		CRP	14.57 mg/dL
		IL-6	1554.0 pg/mL

Discussion

Here, we present a case of CRS and ICANS successfully treated by combination therapy with tocilizumab, pulse steroid, and the novel hemodiafilter Remcyto®. Although tociluzumab and steroid therapy are recommened for thsese cases, in this case, conventional therapies proved ineffective, and the rapid adsorption of IL-6 by Remcyto® was suggested to have contributed to the improvement of the patient’s condition.

CRS is a severe complication of epcoritamab, and its incidence reported 49.7%. The incidence of ICANS with epcoritamab is also reported 6.4% [1]. In T cell–engaging immunotherapies including epcoritamab, interferon-gamma released by T cells and tumor cells activates macrophages, resulting in massive secretion of IL-6 and tumor necrosis factor, which in turn trigger CRS [5]. The efficacy of the IL-6 receptor antagonist tocilizumab in CRS underscores the central role of IL-6 in its pathogenesis. Elevated IL-6 levels have been suggested to correlate with CRS severity. A study of CRS following HLA-haploidentical allogeneic hematopoietic cell transplantation with post-transplantation cyclophosphamide reported a median IL-6 level of 42.2 pg/mL, with patients exhibiting higher IL-6 levels demonstrating poorer outcomes compared to those with lower levels [6]. On the other hand, the development of ICANS is considered to be multifactorial, involving three major pathophysiological components: excessive cytokine release, endothelial dysfunction, and neuroinflammation within the central nervous system. Among these, IL-6 and interleukin-1 play central roles in the excessive cytokine release [7], leading to disruption of the blood–brain barrier [8] and subsequent endothelial injury, which in turn triggers secondary neuroinflammation through activation of microglia and astrocytes [9]. Although tocilizumab ameliorates CRS, it does not prevent the onset of ICANS, suggesting that IL-6 plays a less dominant role in the pathogenesis of ICANS compared with CRS; nevertheless, it remains an important initiating factor in its development. In our case, the pre-treatment IL-6 concentration was markedly elevated at 23,000 pg/mL. Despite a potentially unfavorable prognosis, prompt therapeutic intervention led to survival. It should be noted, however, that IL-6 is not routinely measurable in all institutions, and in this case, the value was obtained only after ICU discharge.

Treatment for severe CRS induced typically consists of corticosteroids—including high-dose pulse therapy—and tocilizumab. Based on treatment protocols for CAR-T therapy–related CRS, tocilizumab is administered at a dose of 8 mg/kg, while corticosteroids such as dexamethasone are given at 10–20 mg every 6 h, with escalation to methylprednisolone 1000 mg pulse therapy if response is inadequate [10]. Although steroid therapy is usually prioritized initially and tocilizumab added if insufficient [11], the timing of administration and selection of pulse therapy remain unstandardized. In the treatment of ICANS, corticosteroid therapy remains the mainstay, and depending on the severity, interventions for cerebral edema and administration of anticonvulsants such as levetiracetam are recommended; in general, management in the ICU is required. As noted above, tocilizumab monotherapy is not effective and should be considered in combination with other therapies [12, 13]. However, no clear criteria have been established for the selection or timing of therapeutic interventions, and in some cases, clinical improvement cannot be achieved even with these measures. For such refractory cases, agents such as anakinra, an interleukin-1 receptor antagonist [14], and monoclonal antibodies targeting GM-CSF and interferon-γ, including lenzilumab and emapalumab [15], have shown potential benefit, although these remain under investigation and have not yet been established as standard treatments.

Remcyte® is a novel hemodiafilter developed in Japan. In vitro studies have demonstrated its superior ability to remove a wide range of cytokines, including IL-6, and a higher platelet survival rate compared with the conventional AN69-ST membrane. In vivo studies using endotoxin-induced sepsis model rats also showed marked improvement in survival and cytokine clearance compared with the control group, similar to AN69-ST [4]. In the present case, the patient developed AKI secondary to tumor lysis syndrome, fulfilling the renal indication for acute blood purification therapy. However, because both CRS and ICANS remained refractory to standard treatments, Remcyte® was introduced with the expectation of achieving therapeutic benefit through cytokine adsorption. Consequently, IL-6 levels decreased markedly, accompanied by improvement in clinical manifestations. Although there have been no prior reports demonstrating the efficacy of cytokine removal with Remcyte® in the treatment of CRS or ICANS, this case suggests that rapid cytokine clearance may have contributed to clinical improvement. Furthermore, because PVP suppresses platelet adsorption, Remcyte® may be a relatively safe option even in patients with hematologic disorders accompanied by cytopenia, such as in the present case.

Here in, we report a case of CRS and ICANS treated with novel hemodiafilter Remcyte®.Its ability to remove a wide range of cytokines, including IL-6 would be beneficial for patients with CRS and ICANS treated with conventional therapies. In addition, a high platelet survival rate would also be useful for patients with thrombocytopenia. Although Remcyte® is not currently established as a standard treatment, blood purification using Remcyte® may offer clinical benefit in cases of CRS and ICANS complicated by AKI, such as that caused by tumor lysis syndrome. Blood purification therapy using Remcyte® should be considered a therapeutic option for patients presenting with this type of clinical condition. Further investigation is warranted to determine appropriate indications, optimal timing of intervention, and whether similar benefits can be observed in cases without AKI. Accumulation of additional clinical cases will be essential to clarify these issues.