Hemoadsorption as a Supportive Strategy for Severe Toxicity Associated With Chimeric Antigen Receptor T-Cell Therapy: A Case Series.

Chimeric antigen receptor T-cell (CAR-T) therapy, a novel approach for the treatment of hematological malignancies, involves the use of genetically engineered T cells that target and destroy cancer cells. 1 The process includes collecting a patient’s cells, modifying them to express CARs that recognize cancer-specific antigens, and then reinfusing them into the patient. 2 Current indications for CAR-T treatment include relapsed or refractory B-cell leukemia, lymphoma, and multiple myeloma; this treatment modality can potentially lead to disease remission and increased overall and disease-free survival. 3 However, CAR-T therapy poses risks of side effects, such as immune effector cell-associated neurotoxicity syndrome (ICANS), hematological and cardiac toxicity, and acute kidney injury (AKI). 4 The most prevalent and significant complication is cytokine release syndrome (CRS), which can occur in a high proportion of patients undergoing CAR-T treatment (20%-90%). 5

CRS is a systemic inflammatory response triggered by the rapid release of a large amount of proinflammatory cytokines, such as interleukin-6 (IL-6), induced by CAR-T treatment. 6 Symptoms of CRS range from mild flu-like symptoms to life-threatening multiple-organ dysfunction, presenting with symptoms such as fever, severe hypotension, cardiomyopathy, acute respiratory distress syndrome, and capillary leak syndrome. 7

The management of CRS involves supportive care and administration of anti-inflammatory agents, such as tocilizumab, corticosteroids, and anakinra. 8 Extracorporeal blood purification techniques, including hemoadsorption, have primarily been used for septic shock to remove excess inflammatory molecules and cytokines. 9 In anecdotal cases, this technique has also been explored for severe or refractory CRS following CAR-T therapy, yielding promising results. 10

This case series reports our experience on the efficacy of hemoadsorption as a supportive strategy for patients with severe multiple-organ toxicity associated with CAR-T therapy.

Patients and Methods

We retrospectively analyzed data from patients who underwent CAR-T therapy for hematological indications at our center between 2020 and 2023. In this cohort, we identified patients treated with hemoadsorption for clinical indications. For these patients, we collected demographic data, comorbid condition and hematological history, details of CAR-T infusion, and subsequent follow-up data, including the onset of complications and related treatments.

The inflammatory pattern was evaluated by measuring serum IL-6, ferritin, and C-reactive protein levels using standard laboratory techniques. Additionally, we gathered data regarding hemoadsorption to assess changes in clinical and inflammatory parameters during extracorporeal treatment. Patient outcomes included CRS resolution, disease progression, and death.

The Ann Arbor staging system was used for the anatomic staging of disease. 11 CRS was graded according to the American Society for Transplantation and Cellular Therapy criteria based on the degree of fever, hypoxia, and hypotension. 12 ICANS was graded according to the severity of neurological symptoms, including cognitive dysfunction, level of consciousness, motor weakness, seizures, and cerebral edema, as per the American Society for Transplantation and Cellular Therapy guidelines. 12

AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, 13 considering the increases in serum creatinine levels compared with pre–CAR-T infusion values, and decreased urine output. AKI was subsequently classified into 3 stages: stage 1 (1.5-1.9 times baseline creatinine), stage 2 (2-2.9 times baseline creatinine), and stage 3 (≥3 times baseline creatinine). The Eastern Cooperative Oncology Group performance status was used to evaluate patients’ functional statuses. 14

Finally, the mantle cell lymphoma international prognostic index and international prognostic index were used to stratify patients based on the severity and prognosis of mantle cell lymphoma and diffuse large B-cell lymphoma, respectively. 15

The study protocol was approved by our institutional review board (registration number: 515/2020), and the requirement for informed consent was waived. This study adhered to the principles outlined in the Declaration of Helsinki.

Case Series

Of 48 patients (29 men and 19 women; mean age 61 ± 11 years) who received CAR-T therapy during the study period, 4 patients (8.3%) were treated with hemoadsorption ( Table 1 ): 3 with diffuse large B-cell lymphoma and 1 with mantle cell lymphoma. All patients had a history of refractory B-cell lymphoma treated with multiple therapeutic lines. At the time of CAR-T infusion, they presented with a high disease burden and extranodal involvement. Additionally, all patients had a low performance status and a high-risk profile. Before CAR-T infusion, all patients underwent lymphodepletion with fludarabine and cyclophosphamide for 3 days. The 3 patients with diffuse large B-cell lymphoma underwent infusion with the tisagenlecleucel CAR-T product, whereas the patient with mantle cell lymphoma received brexucabtagene autoleucel ( Table 2 ). Table 1 Main Clinical and Laboratory Characteristics at Baseline (Day of CAR-T Infusion) in Patients Treated With Hemoadsorption Patient 1 2 3 4 Clinical features Age, y 69 47 77 75 Sex F F M F Hypertension No No Yes Yes Diabetes No No Yes No Charlson Index 4 2 6 6 Hematological Diagnosis NOS-DLBCL NOS-DLBCL MCL NOS-DLBCL previous therapy lines 2 2 3 2 disease stage 4B 4A 3SB 4B IPI/MIPI High High High High ECOG 3 4 3 3 Laboratory LDH, U/L 992 3,059 470 647 CRP, mg/L 40 59.3 54.7 16.4 IL-6, ng/L 21 11 41 48 Ferritin, μg/L 322 3,131 1,599 450 Platelets, ×10 9 /L 56 51 19 168 sCr, mg/dL 0.6 1.5 0.7 0.7 Abbreviations: CAR-T, chimeric antigen receptor T-cell; CRP, C-reactive protein; ECOG, Eastern Cooperative Oncology Group; F, female; IL-6, interleukin-6; IPI, international prognostic index; LDH, lactate dehydrogenase; M, male; MCL, mantle cell lymphoma; MIPI, mantle cell lymphoma international prognostic index; NOS-DLBCL, diffuse large B-cell lymphoma, not otherwise specified; sCr, serum creatinine. Table 2 CAR-T Therapy Schedule, Postinfusion Complications, and Management in Patients Treated With Hemoadsorption Patient 1 2 3 4 CAR-T therapy Lymphodepletion regimen Fluda 25 mg Cy 250 mg Fluda 25 mg Cy 250 mg Fluda 30 mg Cy 500 mg Fluda 25 mg Cy 250 mg CAR-T product Tisagenlecleucel Tisagenlecleucel Brexucabtagene autoleucel Tisagenlecleucel Postinfusion complications CRS Yes Yes Yes Yes Onset from infusion 0 1 2 1 Max stage 4 4 4 4 ICANS Yes Yes Not valuable Yes Onset from infusion 5 2 — 1 Max stage 4 3 — 4 Other toxicities Coagulopathy Cardiomyopathy ICU admission from infusion, d 3 3 4 1 Vasoactive support Yes Yes Yes Yes IMV Yes Yes Yes Yes Peak IL-6, ng/L >5,000 a 4,842 4,575 2,974 Day from infusion 3 3 5 4 Peak CRP, mg/L 148 221 82 46.6 Day from infusion 3 3 2 2 Peak ferritin, μg/L 6,564 50,565 29,330 56,401 Day from infusion 10 5 8 5 Peak sCr, mg/dL 1.9 2.4 1.7 1.5 Day from infusion 7 3 5 5 AKI stage 3 3 (with oliguria) 2 3 Pharmacological treatment Tocilizumab Yes Yes Yes Yes First dose (day from CAR-T) 2 1 2 1 Cumulative dose, mg 1,920 1,920 1,500 1,600 Corticosteroids (dexamethasone) Yes Yes Yes Yes First dose (day from CAR-T) 4 2 4 2 Cumulative dose, mg 170 540 790 270 Anakinra Yes Yes Yes Yes First dose (day from CAR-T) 7 2 4 3 Cumulative dose, mg 700 1,300 700 1,400 Abbreviations: AKI, acute kidney injury; CAR-T, chimeric antigen receptor T-cell; CRP, C-reactive protein; Cy, cyclophosphamide; CRS, cytokine release syndrome; Fluda, fludarabine; ICANS, immune effector cell-associated neurotoxicity syndrome; ICU, intensive care unit; IL-6, interleukin-6; IMV, invasive mechanical ventilation; sCr, serum creatinine. a Above laboratory limit.

All patients developed early and severe grade 4 CRS, characterized by hyperpyrexia, rapid clinical deterioration, and markedly elevated levels of inflammatory markers. Severe ICANS occurred concomitantly in 3 patients. All patients required intensive care with vasoactive support for cardiovascular shock and mechanical ventilation for acute respiratory failure. Moreover, all patients developed AKI; urinary output was preserved in 3 patients, while oliguria was observed in 1 patient.

According to the current clinical practice and recommendations, patients underwent standard CRS management, including administration of tocilizumab, corticosteroids, and anakinra. However, because this multitarget pharmacological approach did not result in prompt improvement of the hyperinflammatory syndrome, the therapy was intensified by incorporating extracorporeal blood purification coupled with hemoadsorption.

The combined treatment was initiated after a mean of 5.2 ± 1.7 days after CAR-T infusion. All patients underwent continuous venovenous hemodiafiltration using the CytoSorb adsorbing cartridge (CytoSorbents Corporation), incorporated in series with an AN69ST membrane hemofilter on a continuous renal replacement therapy platform (Prismaflex; Baxter) with initial blood flow rates of 100 to 150 mL/min. Each adsorbent cartridge was used for 24 hours with repeated treatments based on the clinical indications.

After these treatments, standard continuous venovenous hemodiafiltration was continued for each patient as long as clinically indicated. Notably, no treatment-related complications were observed; thrombocytopenia, which was partially present before CAR-T therapy, was attributed to lymphodepletion chemotherapy and concurrent inflammation.

Hemoadsorption was associated with a significant reduction in IL-6 (from −18% to −95%) and ferritin levels (from −29% to −67%). Patient 4 ( Table 3 ), who exhibited a less pronounced reduction in IL-6 levels, developed concomitant severe cardiomyopathy. This patient died after only 1 cycle of hemoadsorption owing to severe multiple-organ dysfunction syndrome. Table 3 Operative Parameters and Laboratory and Clinical Characteristics of CAR-T Patients Treated With Hemoadsorption-Based Blood Purification Patient Days From CAR-T Infusion Blood Purification Modality Dialysis Membranes Anticoagulation No. HA cycles CVVHDF Duration (d) IL-6 at HA Start (ng/L) IL-6 at HA Stop (ng/L) Delta IL-6 (%) NE at HA Start (μg/kg/min) NE at HA Stop (μg/kg/min) CRS Resolution 1 7 CVVHDF modified AN69S + CytoSorb RCA 2 6 >5,000 a 255 −95% 0.03 Stop Yes 2 3 CVVHDF AN69ST + CytoSorb RCA 3 11 4,842 559 −88% 0.4 Stop Yes 3 6 CVVHDF modified AN69S + CytoSorb RCA 4 5 4,575 1,477 −67% 0.14 Stop Yes 4 5 CVVHDF AN69ST + CytoSorb No 1 1 2,452 1,997 −18% 0.5 0.7 No b Abbreviations: CAR-T, chimeric antigen receptor T-cell; CRS, cytokine release syndrome; CVVHDF, continuous venovenous hemodiafiltration; HA, hemoadsorption; IL-6, interleukin-6; NE, norepinephrine; RCA, regional citrate anticoagulation. a Above laboratory limit. b Patient with concomitant severe cardiomyopathy.

In contrast, the remaining 3 patients, in whom other causes of shock were excluded, achieved complete CRS resolution ( Table 3 ). Notably, these patients experienced improvements in their hemodynamic conditions, allowing gradual reduction and discontinuation of vasoactive support ( Tables S1-S4 and Figures S1-S4 ). Respiratory mechanics and gas exchange also improved, and 2 patients were weaned from mechanical ventilation. Moreover, all patients experienced full recovery of kidney function.

Of the 3 patients who survived CRS, 2 died of disease progression and infection. Only 1 patient survived, who ultimately died due to disease progression 2 months after hospital discharge.

Discussion

Herein, we report our experience of using hemoadsorption to treat CRS associated with CAR-T therapy. In patients with severe CRS and multisystemic involvement, combining hemoadsorption with conventional blood purification therapy led to significant reductions in inflammatory markers and clinical improvements, especially regarding hemodynamic stability.

CRS, a common and potentially life-threatening complication of CAR-T therapy, is primarily triggered by the release of inflammatory factors from activated immune and endothelial cells. 16 Risk factors for severe CRS include cancer-related aspects such as high tumor burden and poor performance status and treatment-related factors such as the type of costimulatory domain and the use of fludarabine. 7 , 16 Our patients were at a high risk due to advanced hematological neoplasms and comorbid conditions, such as diabetes and hypertension, contributing to a poor prognosis.

The course of CRS can be further complicated by multiple-organ toxicities, including ICANS, AKI, acute respiratory distress syndrome, cardiovascular and liver failure, and cytopenia. 17 , 18 The pharmacological treatment of CRS includes a multitarget approach. Tocilizumab, an IL-6 receptor antagonist, is the first-line treatment for IL-6-mediated hyperinflammation 19 ; if ineffective, corticosteroids can be initiated. For severe, unresponsive CRS, additional agents, such as anakinra and JAK 1-2 inhibitors may be used. 20 In our cases, these strategies were used sequentially without any evident benefits, prompting the use of hemoadsorption.

Hemoadsorption is based on the interaction between blood and an adsorbent material that can remove circulating toxins through mechanisms such as hydrophobic interactions and hydrogen bonding. 21 Some evidence suggests that hemoadsorption may be effective in reducing cytokine levels and improving outcomes in patients with CRS of different etiologies, including sepsis, as well as noninfectious causes such as CRS following immunotherapy or cardiac surgery. 22 , 23

In our cases, we used the CytoSorb cartridge, which consists of highly biocompatible porous polymer beads that are capable of extracting molecules up to a size of 65 kDa. 24 Originally developed for the management of septic shock, 25 CytoSorb has since been applied across a spectrum of conditions, including necrotizing fasciitis, meningococcal sepsis, pancreatitis, trauma, hyperbilirubinemia, rhabdomyolysis, poisoning, and, more recently, COVID-19-related CRS. 26 , 27

Nevertheless, the clinical benefits of hemoadsorption in these contexts remain largely limited to anecdotal reports, small case series, and a few small randomized trials, and its impact on mortality remains uncertain. 28 , 29 , 30 Similarly, only isolated reports have suggested the potential utility of hemoadsorption in mitigating CAR-T-related CRS and ICANS by reducing proinflammatory cytokine levels. 10 , 31 , 32

Our findings contribute to the growing body of evidence supporting the potential of hemoadsorption as an adjunctive treatment, together with pharmacological therapies, for severe and refractory CRS. However, despite the relevant role of hemoadsorption in resolving inflammation and improving organ dysfunction, our patients had poor outcomes, primarily because of underlying disease progression. This highlights the complexity of such clinical conditions and the multiple risk factors present in these patients before CAR-T infusion.

Our study has limitations owing to its descriptive and retrospective nature and the lack of a predefined protocol for hemoadsorption therapy in this specific clinical setting. In addition, distinguishing between the effects of pharmacological therapy and those of extracorporeal removal is challenging. Furthermore, the absence of a control group may make it difficult to determine the true efficacy of concurrent application of hemoadsorption with standard treatments. Additionally, access to hemoadsorption is not universal across intensive care units, and the high cost may limit its availability. This could pose a significant barrier to the widespread adoption and generalization of this approach.

Nevertheless, our results are important from several perspectives. First, they emphasized the need for initial risk stratification to guide the management of patients treated with CAR-T therapy. Thus, the potential efficacy of extracorporeal treatment in this context could expand the indications for hemoadsorption therapy as a supportive strategy for managing severe systemic complications of CAR-T therapy. This is relevant as CAR-T therapy is expected to evolve, with its indications expanding to various tumor types and non-tumor conditions, such as autoimmune diseases. 33

In conclusion, while awaiting results from ongoing randomized trials, 34 our data suggest that a strategy based on hemoadsorption may offer an additional therapeutic option for mitigating CAR-T-related CRS in selected patients with refractory diseases. Larger controlled studies are needed to validate these preliminary findings and define the patient selection criteria, timing, treatment schedule, and concomitant anti-inflammatory therapies.

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Supplementary Materials

Supplementary File (PDF) Figures S1-S4; Tables S1-S4.

Article Information

Authors’ Full Names and Academic Degrees

Pasquale Esposito, MD, PhD Massimiliano Gambella, MD, Elisa Russo, MD, Anna Maria Raiola, MD, Elena Beltrametti, MD, Novella Conti, MD, Elisa Porcile, MD, Stefania Bianzina, MD, Monica Centanaro, MD, Francesca Viazzi, MD, PhD, and Emanuele Angelucci, MD.

Authors’ Contributions

Concept and design: PE, MG, and NC. Acquisition, analysis, or interpretation of data: all authors. Each author contributed important intellectual content during article drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

Support

None.

Financial Disclosures

The authors declare that they have no relevant financial interests.

Data Sharing

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Peer Review

Received August 30, 2024. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and the Editor-in-Chief. Accepted in revised form December 20, 2024.

Complete author and article information provided before references.

Supplementary File (PDF).

Figure S1: Clinical course and management of CAR-T patient (Patient #1) treated with hemoadsorption.

Figure S2: Clinical course and management of CAR-T patient (Patient #2) treated with hemoadsorption.

Figure S3: Clinical course and management of CAR-T patient (Patient #3) treated with hemoadsorption.

Figure S4: Clinical course and management of CAR-T patient (Patient #4) treated with hemoadsorption.

Table S1: Clinical and laboratory course of CAR-T patient (Patient #1) treated with hemoadsorption.

Table S2: Clinical and laboratory course of CAR-T patient (Patient #2) treated with hemoadsorption.

Table S3: Clinical and laboratory course of CAR-T patient (Patient #3) treated with hemoadsorption.

Table S4: Clinical and laboratory course of CAR-T patient (Patient #4) treated with hemoadsorption.