1. Introduction
Cellular and immunotherapeutic modalities have transformed the landscape of treatment for hematologic malignancies, particularly for patients with refractory or relapsed disease. Among these therapies, CAR T-cell therapy and BsAbs have emerged as powerful tools, especially in B-cell malignancies. CAR T-cell therapy involves the genetic modification of T cells to recognize and eliminate malignant cells by targeting specific antigens, such as CD19, achieving durable remissions in some patients [ 1 , 2 ]. In recent years, BsAbs, including bispecific T-cell engager (BiTE) therapies, have further expanded the immunotherapy arsenal, providing a novel approach that bridges T cells and cancer cells. By binding to CD3 on T cells and a specific tumor antigen, such as CD20 or CD19, bispecific antibodies facilitate a targeted immune response against malignant cells [ 3 , 4 ].
Despite their efficacy, both CAR T-cell therapy and BsAbs introduce a complex array of early and delayed complications that can significantly influence patient outcomes. Early complications, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are driven by the acute immune activation inherent to CAR T-cell and bispecific antibody treatments. CRS, one of the most prevalent complications, results from a surge of cytokines released by activated T cells, leading to systemic inflammation that can be life-threatening if not managed effectively [ 5 , 6 ]. ICANS is another major complication that impacts the central nervous system, causing a spectrum of symptoms from mild confusion to severe cerebral edema. Prompt intervention, often with corticosteroids or IL-6 inhibitors like tocilizumab, is critical to mitigate these early toxicities and ensure patient safety [ 7 , 8 ]. Figure 1 illustrates the mechanism of activation of CRS.
In contrast, delayed complications arise from prolonged immune reconstitution and chronic immune dysregulation following CAR T-cell or bispecific therapies. A key delayed complication of allogeneic HSCT is graft-versus-host disease (GVHD), where donor T cells mount an immune response against the recipient’s tissues, leading to chronic, often debilitating symptoms [ 9 , 10 ]. Furthermore, CAR T-cell and bispecific antibody-treated patients face an elevated risk of cytopenias, chronic infections, and secondary malignancies due to long-term impacts on immune function. Such complications necessitate vigilant monitoring and long-term management strategies to optimize therapeutic outcomes and maintain quality of life [ 11 , 12 ].
The advent of these immunotherapies has introduced new complexities in the pathophysiology of treatment-related complications. Patient-specific factors, such as baseline immune function, underlying malignancy characteristics, and therapeutic approach, contribute to each individual’s risk profile. For instance, bispecific antibodies are known to induce CRS, yet they may exhibit distinct neurotoxicity profiles compared to CAR T-cell therapies [ 13 , 14 ]. Additionally, the risk of infections remains a significant concern, as prolonged immune suppression leaves patients vulnerable to opportunistic infections long after treatment completion. A thorough understanding of these mechanisms is critical to developing targeted interventions that minimize adverse effects while preserving the efficacy of these promising therapies [ 15 , 16 ].
This review aims to provide an in-depth overview of the clinical applications, complications, and management strategies associated with CAR T-cell and bispecific therapies in hematologic malignancies. By exploring current advances and challenges, we hope to inform the development of safer, more effective treatment approaches that improve patient outcomes in the long term.
2. Material and Methods
2.1. Study Design
This review synthesizes existing literature on CAR T-cell and bispecific therapies in hematologic malignancies, focusing on complications and management strategies. A narrative approach was employed to integrate findings from preclinical studies, clinical trials, and expert consensus documents. Emphasis was placed on key therapeutic agents, including CAR-T-cell therapies and bispecific T-cell engagers, their efficacy, and associated complications.
2.2. Data Sources
The primary databases used for literature search included PubMed, Google Scholar, and Web of Science, targeting peer-reviewed articles from 2010 to 2024. Keywords such as “CAR-T therapy complications”, “bispecific antibody toxicity”, “CRS”, and “ICANS” were used. Additionally, relevant clinical guidelines from organizations like American Society for Transplantation and Cellular Therapy (ASTCT) were included.
2.2.1. Inclusion and Exclusion Criteria
Inclusion Criteria: Peer-reviewed articles discussing the clinical use of CAR-T and bispecific therapies; Studies reporting complications, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS); Articles focusing on diagnostic biomarkers, imaging techniques, and management protocols.
Exclusion Criteria: Non-English language publications; Studies unrelated to hematologic malignancies or cellular therapies.
2.2.2. Data Extraction
Key data points, including patient demographics, treatment regimens, complications, and outcomes, were extracted from each article. Information was categorized into early and late complications, and specific focus was given to grading systems and therapeutic interventions.
2.2.3. Ethical Considerations
All included studies adhered to ethical standards approved by their respective institutional review boards. No new patient data were collected for this review.
2.2.4. Analysis and Presentation
Thematic analysis was employed to synthesize data, with key findings categorized into diagnostic approaches, treatment strategies, and emerging therapies. Table 1 was created to summarize evidence systematically. Furthermore Table 2 was added with a list of abbreviations used in the manuscript.
This structured methodology ensures a comprehensive and clinically relevant overview, serving as a resource for practitioners managing complications of cellular therapies.
3. Indications for CAR-T and Bispecific Therapies in Hematologic Malignancies
3.1. B-Cell Acute Lymphoblastic Leukemia (B-ALL)
CAR-T therapy has demonstrated significant efficacy in relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), particularly in patients under the age of 25. Tisagenlecleucel, a CD19-directed CAR-T-cell therapy, received FDA approval based on a pivotal trial where 81% of pediatric and young adult patients with relapsed or refractory B-ALL achieved a complete remission (CR) within three months of infusion, with 60% maintaining durable remissions at 12 months [ 17 ]. Additionally, bispecific antibodies such as blinatumomab, which targets both CD3 on T cells and CD19 on B cells, have shown promising outcomes in adult B-ALL patients. In the TOWER trial, blinatumomab demonstrated a CR rate of 44% in relapsed or refractory adult B-ALL patients, with a median overall survival (OS) of 7.7 months compared to 4.0 months in the standard chemotherapy group [ 18 , 19 ]. These therapies provide highly effective options for patients at high risk of relapse, with CAR-T offering durable responses and bispecific antibodies providing an off-the-shelf alternative for rapid disease control.
3.2. Multiple Myeloma (MM)
In the setting of relapsed or refractory multiple myeloma (MM), CAR-T therapies targeting B-cell maturation antigen (BCMA) have emerged as powerful treatment options. Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are two BCMA-directed CAR-T therapies that have shown remarkable efficacy in patients who have exhausted other treatments, with response rates exceeding 80% in clinical trials [ 20 ]. Bispecific antibodies, such as teclistamab, which binds to BCMA on myeloma cells and CD3 on T cells, provide an off-the-shelf treatment option, especially useful for patients who may not be candidates for CAR-T therapy due to manufacturing time or prior lymphodepletion requirements [ 21 , 22 ].
3.3. Chronic Lymphocytic Leukemia (CLL)
While CAR-T therapy is less commonly utilized in chronic lymphocytic leukemia (CLL) due to the disease’s generally indolent nature, it has demonstrated efficacy in cases of Richter’s transformation, where CLL progresses to an aggressive lymphoma. In a multicenter retrospective study evaluating anti-CD19 CAR-T therapy for Richter’s transformation, an overall response rate (ORR) of 63% was reported, with 46% achieving complete remission (CR). Additionally, the median overall survival (OS) for responding patients was 8.5 months, highlighting its potential as a therapeutic option for this aggressive condition [ 23 , 24 ]. For standard CLL, bispecific antibodies are being investigated as promising alternatives. In a phase I trial, glofitamab, a bispecific antibody targeting CD20 and CD3, achieved a CR rate of 39% and an ORR of 64% in relapsed/refractory B-cell lymphomas, suggesting its potential utility in CLL patients who have relapsed after CAR-T therapy or are unsuitable candidates for intensive treatments [ 25 ].
3.4. Mantle Cell Lymphoma (MCL)
Mantle cell lymphoma (MCL) has become a significant area of focus for CAR-T therapies. Brexucabtagene autoleucel, a CD19-directed CAR-T therapy, has demonstrated substantial response rates in patients with relapsed or refractory MCL, providing a durable treatment option for those who have failed other therapies [ 2 ]. Axicabtagene ciloleucel has also demonstrated continued durable responses in relapsed and refractory indolent non-Hodgkin lymphoma [ 26 ]. Given the aggressive nature of MCL and frequent relapses, CAR-T therapy is particularly beneficial. In addition, bispecific antibodies like glofitamab are currently under investigation as a complementary option to CAR-T for MCL [ 27 ].
3.5. Diffuse Large B-Cell Lymphoma (DLBCL)
Diffuse large B-cell lymphoma (DLBCL) is among the most common hematologic malignancies treated with CAR-T therapy. FDA-approved CAR-T products such as axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel have demonstrated effectiveness in patients with relapsed or refractory disease, achieving response rates of 50–80% depending on the specific product [ 28 ]. In addition, bispecific antibodies like epcoritamab, targeting CD20 and CD3, are under investigation in DLBCL and may provide a viable option for patients who cannot tolerate the toxicities associated with CAR-T therapy [ 29 ].
3.6. Follicular Lymphoma (FL)
Follicular lymphoma (FL), although typically indolent, can progress to a more aggressive form requiring novel therapies. CAR-T therapy has shown efficacy in relapsed or refractory FL, with CD19-directed products such as axicabtagene ciloleucel achieving an overall response rate (ORR) of 94% and a complete response (CR) rate of 79% in clinical trials. Durable remissions have been reported, with a median progression-free survival (PFS) of 39.6 months in responders [ 26 ]. For patients seeking alternatives to CAR-T therapy, bispecific antibodies such as mosunetuzumab, which targets CD20 on B cells and CD3 on T cells, demonstrated an ORR of 80% and a CR rate of 60% in heavily pretreated FL patients in early-phase trials. These therapies offer a less intensive treatment option with manageable side effects, including low-grade cytokine release syndrome (CRS) in approximately 44% of patients, most of which were Grade 1 or 2 [ 30 ].
4. Early Complications of CAR-T Therapy: Diagnostic Workup and Management
4.1. Introduction to Early Complications
CAR-T-cell therapy has emerged as a powerful treatment for various hematologic malignancies, yet it is often accompanied by significant early complications. These adverse effects, predominantly CRS and ICANS, arise from the intense immune activation associated with CAR-T cells targeting tumor antigens. Understanding the diagnostic workup for these complications is essential for ensuring timely and effective management, ultimately improving patient outcomes [ 31 , 32 , 33 ].
4.2. Cytokine Release Syndrome (CRS) Overview
CRS is the most frequent and well-documented early complication of CAR-T therapy, occurring in a majority of patients within days of infusion. It occurs in 50–90% of patients depending on the CAR construct and target antigen, such as CD19 or BCMA. Severe CRS (Grade ≥ 3) has been reported in approximately 10–20% of cases, often requiring interventions such as vasopressors or mechanical ventilation. For instance, in the pivotal ZUMA-1 trial evaluating axicabtagene ciloleucel, CRS was observed in 93% of patients, with Grade ≥ 3 CRS in 13%. CRS results from a robust release of inflammatory cytokines—most notably interleukin-6 (IL-6)—due to CAR-T-cell proliferation and activation [ 7 , 11 ].
CRS symptoms vary widely, ranging from mild flu-like symptoms to severe systemic inflammation, which can lead to hypotension, high fever, and multi-organ failure. The severity of CRS is categorized into four grades, each guiding specific treatment strategies [ 7 , 34 ].
4.3. Diagnostic Workup for CRS in CAR-T Therapy
The diagnostic process for CRS involves grading the severity based on clinical presentation and laboratory markers. For patients showing signs of CRS, regular monitoring of vital signs and inflammatory markers, such as C-reactive protein (CRP) and ferritin, is critical. Elevated CRP and ferritin levels correlate with increased inflammation and can indicate the intensity of CRS. For higher-grade CRS (Grades 3 and 4), additional diagnostic measures, including echocardiography and blood gas analysis, may be warranted to assess organ function and guide therapy [ 5 , 35 , 36 ]. Imaging and more invasive testing may be required in severe cases to rule out other causes of systemic inflammation.
4.4. Management of CRS Based on Diagnostic Findings
Management strategies for CRS are tailored according to the CRS grade. Mild cases (Grade 1) typically require supportive care, including antipyretics and intravenous fluids. However, for moderate to severe cases (Grades 2–4), treatment with tocilizumab—a monoclonal antibody targeting IL-6 receptors—is recommended and can be administered every 8 h if symptoms persist. In cases where tocilizumab alone is insufficient, corticosteroids, such as dexamethasone, may be added to control the inflammatory response. Severe cases (Grade 4) often necessitate transfer to the intensive care unit for close monitoring and advanced supportive measures, such as vasopressors or mechanical ventilation if necessary [ 23 , 37 , 38 ].
4.5. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Overview
ICANS (immune effector cell-associated neurotoxicity syndrome) is a significant and potentially severe early complication of CAR-T-cell therapy, often occurring following or concurrently with cytokine release syndrome (CRS). Epidemiological studies have shown that the incidence of ICANS ranges from 20% to 64% in patients undergoing CAR-T-cell therapy, with higher-grade neurotoxicity (Grade ≥ 3) reported in 10–28% of cases, depending on the CAR-T construct and underlying malignancy. For example, ICANS was observed in 64% of patients treated with axicabtagene ciloleucel for large B-cell lymphoma, with severe cases in 28% [ 39 , 40 , 41 ].
This neurotoxic complication is characterized by a spectrum of symptoms, including confusion, aphasia, tremors, and, in severe cases, seizures, status epilepticus, and cerebral edema. These symptoms can escalate rapidly, underscoring the need for immediate diagnosis and intervention. The pathophysiology of ICANS is complex and remains incompletely understood. Current evidence suggests it is mediated by both direct effects of CAR-T cells trafficking to the central nervous system (CNS) and secondary inflammatory responses, including elevated cytokines such as IL-6, IFN-γ, and TNF-α, which disrupt the blood–brain barrier [ 39 , 40 , 41 ].
ICANS typically manifests within a few days of CRS onset, often mirroring its severity. Prompt diagnosis relies on standardized grading tools such as the Immune Effector Cell-Associated Encephalopathy (ICE) score, which evaluates the patient’s orientation, handwriting ability, and command-following, among other parameters. Early recognition and grading are critical to implementing timely interventions, which may include corticosteroids and supportive neurocritical care [ 39 , 40 , 41 ].
5. Late Complications of CAR-T Therapy: Diagnostic Workup and Management
5.1. Introduction to Late Complications in CART-Therapy
While CAR-T therapy has demonstrated significant efficacy in treating hematologic malignancies, it is associated with various late complications, often emerging weeks to months post-treatment. These complications can include prolonged cytopenias, infections, B-cell aplasia, and, in some cases, secondary malignancies. Understanding these risks and implementing effective diagnostic workup and management strategies are essential for optimizing long-term patient outcomes [ 42 , 43 , 44 ].
5.2. Prolonged Cytopenias in CART-Therapy
Prolonged cytopenias are among the most common late complications of CAR-T therapy, often resulting from the lymphodepletion regimen combined with CAR-T-cell activity. These cytopenias—manifesting as persistent neutropenia, thrombocytopenia, and anemia—are reported in approximately 30–40% of patients, with rates varying based on the CAR construct, disease type, and patient characteristics. Persistent neutropenia significantly elevates the risk of opportunistic infections, while thrombocytopenia increases bleeding risks, and anemia contributes to fatigue and reduced quality of life. Studies have shown that Grade ≥ 3 neutropenia persists beyond 30 days in 15–20% of patients, with thrombocytopenia observed in a similar proportion. In a large cohort study, 37% of patients required prolonged transfusion support for anemia and thrombocytopenia more than one month post-infusion. Persistent cytopenias extending beyond 90 days occur in approximately 10–15% of patients, necessitating further investigation to rule out bone marrow failure or underlying myelodysplasia [ 45 , 46 , 47 ].
The diagnostic approach includes regular complete blood counts to monitor for cytopenias and bone marrow biopsies if cytopenias persist beyond three months to rule out bone marrow failure or underlying myelodysplasia. Management typically involves growth factor support (such as G-CSF for neutropenia), transfusions, and, in some cases, immunosuppressive therapies if an autoimmune etiology is suspected [ 45 , 46 , 47 ].
5.3. Infections and Opportunistic Pathogens in CART-Therapy
Due to the immunosuppressive effects of CAR-T therapy and prolonged cytopenias, patients are at increased risk of infections, particularly from opportunistic pathogens. Early in the course of therapy, bacterial and viral respiratory infections are most common, occurring in approximately 40–50% of patients. As time progresses, viral reactivations, including herpes simplex virus (HSV) and cytomegalovirus (CMV), occur in 20–30% of patients, while fungal infections, such as invasive aspergillosis, are observed in 10–15% of cases [ 30 , 48 , 49 ].
Diagnostic workup includes routine blood cultures, viral PCR testing, and radiological imaging to identify infection sources. Preventive measures such as prophylactic antivirals, antifungals, and antibiotics, along with immunoglobulin replacement therapy, are recommended to protect against recurrent infections [ 30 , 48 , 49 ].
5.4. B-Cell Aplasia and Hypogammaglobulinemia in CART-Therapy
CAR-T therapy, especially when targeting CD19, can lead to prolonged B-cell aplasia due to the depletion of both malignant and normal B cells. This condition results in hypogammaglobulinemia, which increases susceptibility to recurrent sinopulmonary infections. Diagnostic workup involves monitoring serum immunoglobulin levels and B-cell counts. Management typically includes regular immunoglobulin replacement therapy to maintain adequate IgG levels and prevent infections until B-cell recovery, which can take months to years in some patients [ 50 , 51 , 52 ].
5.5. Secondary Malignancies in CART-Therapy
Secondary malignancies following CAR-T therapy, though rare, are a significant consideration in long-term patient management. These malignancies may result from prior chemotherapy, radiation, or insertional mutagenesis associated with the genetic modification of T cells. Additionally, pre-existing clonal hematopoiesis or extensive prior treatment history can increase this risk. Routine surveillance and early detection are essential to mitigate morbidity and improve outcomes [ 53 , 54 , 55 ]. Authors recommended surveillance modalities include the following: Imaging: Imaging should be considered, such as CT or PET-CT scans, to monitor for solid tumors or hematologic malignancies based on patients’ complaints and on a case-to-case basis. MRI can be considered for patients requiring reduced radiation exposure; Hematologic Assessments: Routine complete blood counts (CBC) with differential and peripheral smear evaluations to identify early signs of hematologic malignancies. Molecular testing and bone marrow biopsy may be warranted for unexplained cytopenias or other abnormal findings; Monitoring for Clonal Hematopoiesis: Regular assessment for clonal hematopoiesis of indeterminate potential (CHIP) using next-generation sequencing (NGS), particularly in patients with significant genotoxic exposure history; Standard Cancer Screening: Adherence to age- and gender-appropriate cancer screening protocols, such as mammography, colonoscopy, or low-dose CT scans for lung cancer in high-risk individuals.
5.6. Graft-Versus-Host Disease (GVHD)
In patients who have undergone prior allogeneic stem cell transplants, CAR-T therapy may trigger or exacerbate graft-versus-host disease (GVHD). GVHD can affect multiple organs, presenting with symptoms like skin rash, liver dysfunction, and gastrointestinal disturbances. Diagnostic workup includes biopsy of affected tissues, liver function tests, and endoscopy if gastrointestinal involvement is suspected. Management typically involves corticosteroids and additional immunosuppressive agents, with more severe cases requiring specialized treatment, such as ruxolitinib for steroid-refractory GVHD [ 56 , 57 , 58 , 59 ].
5.7. Neurological Complications
While acute neurotoxicity, ICANS, is well recognized, delayed neurological complications can also occur after CAR-T therapy. These can include cognitive impairments, mood changes, and, in rare cases, chronic seizures. Neurological assessment through regular monitoring, magnetic resonance imaging (MRI), and electroencephalogram (EEG) can help in diagnosing late-onset neurotoxicity. Management may involve symptomatic treatments, anti-epileptic medications, and supportive neuropsychiatric care for persistent cognitive symptoms [ 60 , 61 , 62 ].
5.8. Management of Late Complications
Management of late CAR-T complications is multifaceted and requires a long-term, multidisciplinary approach. Patients benefit from routine follow-ups with hematologists, infectious disease specialists, and neurologists to monitor and manage ongoing issues. For infections, prophylactic antimicrobials and immunoglobulin replacement are crucial. For cytopenias, growth factors and transfusions may be necessary. Additionally, patients should undergo routine surveillance for secondary malignancies and ongoing neuropsychological evaluations. Advances in CAR-T technology aim to reduce these late toxicities, with research focused on refining CAR designs and identifying biomarkers to predict long-term outcomes [ 43 , 48 , 63 , 64 , 65 ].
6. Early Complications of Bispecific Antibodies: Diagnostic Workup and Management
6.1. Introduction to Bispecific Antibodies and Early Complications
BsAbs, including BiTEs, have emerged as effective immunotherapy agents in hematologic malignancies. These agents function by simultaneously binding a tumor antigen, such as CD19 or BCMA, and a T-cell marker, like CD3, facilitating T-cell-mediated lysis of cancer cells. BsAbs have demonstrated significant clinical efficacy, with agents such as blinatumomab achieving an overall response rate (ORR) of 44% and a complete remission (CR) rate of 33% in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Similarly, teclistamab, a BCMA-targeting BsAb for relapsed/refractory multiple myeloma, demonstrated an ORR of 63% and a CR rate of 39% in heavily pretreated patients [ 66 , 67 ].
Despite their efficacy, BsAbs are associated with early complications, predominantly cytokine release syndrome (CRS) and neurotoxicity. CRS has been reported in up to 70% of patients receiving BsAbs, with severe (Grade ≥ 3) cases occurring in approximately 5–10%. Neurotoxicity, while less common, affects 10–15% of patients and can range from mild confusion to seizures or cerebral edema [ 68 ]. These complications, similar to those observed with CAR-T-cell therapies, necessitate precise diagnostic and management protocols to ensure safety and optimize therapeutic outcomes.
6.2. Cytokine Release Syndrome (CRS) in BsAbs
CRS is a prevalent and clinically significant complication of BsAb therapy, occurring as a result of rapid cytokine release when T cells are activated upon engagement with tumor cells. Recent studies have reported the incidence of CRS in BsAb therapy to range between 60% and 80%, with severe cases (Grade ≥ 3) occurring in approximately 5–10% of patients, depending on the specific BsAb and patient population studied. For example, teclistamab, a BCMA-targeting BsAb for relapsed/refractory multiple myeloma, demonstrated an overall CRS rate of 72%, with Grade 3 CRS in <1% of cases [ 36 , 39 , 67 ].
CRS in BsAb therapy is typically milder compared to that seen with CAR-T-cell therapies, yet it still necessitates vigilant monitoring. Mild symptoms often include fever, fatigue, and myalgias, while severe manifestations can progress to hypotension requiring vasopressors, hypoxia necessitating oxygen supplementation, and multi-organ dysfunction [ 36 , 39 , 67 ].
To facilitate early detection and grading of CRS, routine monitoring of inflammatory biomarkers is essential. Elevations in C-reactive protein (CRP) and ferritin are commonly observed and serve as surrogate markers for cytokine-mediated inflammation. Additionally, interleukin-6 (IL-6) levels have been identified as a key biomarker, with studies correlating IL-6 elevations with CRS severity. For patients presenting with respiratory symptoms, imaging such as chest X-rays or computed tomography (CT) scans may aid in identifying complications such as pulmonary edema or fluid overload, ensuring timely intervention [ 36 , 39 , 67 , 69 , 70 , 71 , 72 , 73 ].
6.3. Diagnostic Workup for CRS in BsAb Therapy
The diagnostic approach to CRS in BsAb therapy emphasizes regular clinical assessment and laboratory evaluations. For patients undergoing BsAb treatment, baseline levels of CRP and ferritin are established, and these markers are subsequently monitored to track inflammation. In cases where symptoms indicate severe CRS, additional tests like liver function tests, lactate dehydrogenase, and renal function panels help assess the impact on organ systems. Imaging, such as chest X-rays, may be necessary for patients presenting with respiratory symptoms, allowing for the identification of any fluid overload or pulmonary edema [ 72 , 73 , 74 ].
6.4. Management of CRS in BsAb Therapy
Management of CRS associated with BsAbs is tiered based on severity. For low-grade CRS, symptomatic treatment such as antipyretics and hydration is typically sufficient. In moderate to severe cases, tocilizumab, an IL-6 receptor antagonist, is administered, with corticosteroids added if symptoms persist or worsen. Patients with severe CRS may require intensive care monitoring, where vasopressors and respiratory support can be provided as necessary [ 75 , 76 ].
6.5. Neurotoxicity and ICANS in Bispecific Antibodies
Neurotoxicity is a less common but potentially severe early complication of bispecific antibody (BsAb) therapy, with an incidence ranging between 10 and 15% depending on the BsAb agent and patient population. This complication presents with a spectrum of symptoms, including mild confusion, tremors, aphasia, and, in severe cases, seizures, status epilepticus, and cerebral edema. Although neurotoxicity in BsAb therapy is less frequent and often milder compared to ICANS (immune effector cell-associated neurotoxicity syndrome) observed with CAR-T-cell therapy, its occurrence necessitates prompt diagnosis and management to prevent irreversible neurological damage [ 67 , 75 , 76 , 77 ].
Unlike CRS, neurotoxicity with BsAb therapy typically emerges later, often following or coinciding with CRS resolution. This temporal distinction requires vigilant monitoring of patients even after CRS symptoms subside. The pathophysiology of neurotoxicity in BsAb therapy is not fully elucidated but may involve inflammatory cytokine-mediated blood–brain barrier disruption and immune effector cell trafficking to the central nervous system (CNS). Elevated levels of cytokines such as IL-6 and TNF-α are commonly observed during episodes of neurotoxicity [ 67 , 75 , 76 , 77 ].
The Immune Effector Cell-Associated Encephalopathy (ICE) score is widely employed for assessing neurological function in patients receiving BsAb therapy. This tool evaluates cognitive and motor functions, including orientation, handwriting, and ability to follow commands, allowing for standardized grading of neurotoxicity severity. Early and accurate grading is critical for implementing timely interventions, such as corticosteroids or supportive neurocritical care, to mitigate long-term sequelae [ 67 , 75 , 76 , 77 ].
6.6. Diagnostic Workup for Neurotoxicity
Early diagnosis of neurotoxicity involves frequent neurological assessments using tools like the ICE score, as well as EEG monitoring in cases with severe or persistent symptoms. Imaging studies such as MRI are recommended for patients showing acute neurotoxic symptoms to rule out alternative causes like infections or brain edema. Serum biomarker analysis, focusing on inflammatory markers, supports clinical findings and can indicate the severity of the immune response involved in neurotoxicity [ 75 , 76 , 77 ].
6.7. Management of Neurotoxicity in BsAb Therapy
Management of neurotoxicity primarily involves corticosteroids, such as dexamethasone, which are administered based on the severity of symptoms. In patients exhibiting cerebral edema, osmotic therapy may be used to control intracranial pressure, and anti-epileptic drugs are introduced for seizure management. Supportive care with neuropsychiatric evaluation is critical for persistent symptoms. Severe neurotoxicity cases may require intensive care unit (ICU)-level care with continuous monitoring and neuroprotective strategies to mitigate long-term sequelae [ 75 , 76 , 77 , 78 , 79 ].
6.8. Future Directions in the Management of Early Complications in BsAbs
Ongoing research aims to refine diagnostic criteria and develop predictive biomarkers to anticipate early complications from BsAb therapy, allowing for preemptive intervention. Innovations include developing next-generation BsAbs that selectively modulate immune activation, potentially reducing the incidence and severity of CRS and neurotoxicity. Clinical trials continue to assess various BsAbs, with an emphasis on optimizing safety profiles through tailored dosing regimens and combination therapies that mitigate immune-related side effects while preserving therapeutic efficacy [ 75 , 80 , 81 ].
7. Late Complications of Bispecific Antibody Therapy: Diagnostic Workup and Management
7.1. Introduction to Late Complications in BsAb Therapy
BsAbs have become increasingly prominent in treating hematologic malignancies due to their ability to engage immune cells directly with tumor cells. However, late complications associated with BsAb therapies have emerged, which include prolonged cytopenias, B-cell aplasia, infections, and, occasionally, the development of secondary malignancies. Recognizing and managing these late-onset adverse effects is essential for optimizing patient outcomes and extending the benefits of BsAb therapy [ 82 , 83 ].
7.2. Prolonged Cytopenias in BsAb Therapy
Prolonged cytopenias are a recognized late complication of BsAb therapy, occurring in a significant proportion of patients due to sustained T-cell activation and immune system stress. Recent studies report the incidence of prolonged cytopenias, including neutropenia, thrombocytopenia, and anemia, in approximately 30–50% of patients receiving BsAbs, depending on the agent and treatment setting. These cytopenias can persist for weeks to months following treatment, increasing the risk of infections and bleeding complications, particularly in patients with pre-existing bone marrow compromise [ 67 , 75 , 82 , 83 , 84 ].
The diagnostic approach to prolonged cytopenias includes regular monitoring of complete blood counts (CBCs) to detect trends over time and identify the need for intervention. For cytopenias persisting beyond three months, bone marrow biopsies are recommended to evaluate for underlying marrow suppression, hypocellularity, or secondary myelodysplastic syndrome (MDS). These investigations are critical for ruling out disease progression or treatment-related marrow toxicity [ 82 , 83 , 84 ].
Management of prolonged cytopenias involves a combination of supportive care measures. Granulocyte colony-stimulating factor (G-CSF) is often employed to stimulate neutrophil recovery in cases of prolonged neutropenia, reducing infection risk. For thrombocytopenia and anemia, transfusions of platelets and packed red blood cells are used to manage symptoms and prevent complications. Recent clinical data suggest that individualized care plans, including dose adjustments or treatment delays, may further mitigate the impact of cytopenias while preserving therapeutic efficacy [ 82 , 83 , 84 ].
7.3. Infections and Opportunistic Pathogens in BsAb Therapy
Due to the immunosuppressive nature of BsAb therapies, patients are at increased risk for infections, particularly with opportunistic pathogens. Late-onset infections often involve viral reactivations, such as cytomegalovirus and herpes simplex, as well as fungal infections. A systematic review of MM patients reported that 56% of patients receiving BsAbs experienced infections of any grade, with 24% encountering grade ≥ 3 infections. Notably, patients treated with BCMA-targeted BsAbs had higher rates of severe infections compared to those receiving non-BCMA BsAbs [ 85 ].
Diagnostic workup for infections includes routine viral PCR testing, cultures, and imaging such as chest radiographs or computed tomography (CT) scans to detect respiratory or systemic infections. Management strategies involve antimicrobial prophylaxis, immunoglobulin replacement for hypogammaglobulinemia, and close monitoring for signs of infection during and after therapy [ 84 , 85 , 86 ].
7.4. B-Cell Aplasia and Hypogammaglobulinemia in BsAb Therapy
BsAbs targeting CD19 or CD20 can result in prolonged B-cell depletion, leading to hypogammaglobulinemia and susceptibility to bacterial infections. The diagnostic workup for B-cell aplasia includes monitoring B-cell counts and serum immunoglobulin levels. Patients with persistent B-cell aplasia may require immunoglobulin replacement therapy to maintain protective IgG levels and reduce infection risk. Management involves regular assessments and periodic intravenous immunoglobulin (IVIG) infusions, especially if patients exhibit recurrent infections [ 82 , 83 , 84 , 85 , 86 , 87 ].
7.5. Secondary Malignancies in BsAb Therapy
There is no direct evidence linking BsAb therapies to an increased risk of secondary malignancies. Rare cases of secondary cancers reported in patients undergoing BsAb therapy are likely attributable to factors such as prior treatments, genetic predispositions, or the natural progression of the underlying disease [ 13 , 82 ].
Given the lack of direct causative evidence, the need for routine surveillance for secondary malignancies in patients receiving BsAbs should be individualized. When surveillance is deemed appropriate, modalities may include the following: Routine Imaging: Consider periodic CT or PET scans in patients with high-risk features or a history of prior malignancies; Hematologic Assessments: Regular complete blood counts (CBC) and peripheral blood smears to monitor for unexpected hematologic abnormalities; Biopsies: For cases of suspected transformation or unexplained lesions detected on imaging.
Management of secondary malignancies, if identified, depends on the specific diagnosis and may include chemotherapy, radiation, or surgical interventions as necessary. While no clear link exists between BsAbs and malignancies, a personalized approach to monitoring remains essential to ensure patient safety and optimal outcomes [ 13 , 82 ].
7.6. Chronic Inflammatory and Autoimmune Reactions
Late-stage BsAb therapy can sometimes trigger chronic inflammatory or autoimmune reactions due to sustained T-cell activation. These reactions may present as autoimmune cytopenias, such as hemolytic anemia or thrombocytopenia, and may persist long after the completion of therapy. Diagnostic workup includes antibody testing, direct antiglobulin testing, and assessments for other autoimmune markers. Management of these reactions typically involves immunosuppressive therapies such as corticosteroids or, in severe cases, additional immunomodulatory agents [ 88 , 89 , 90 ].
7.7. Neurotoxicity
Although neurotoxicity is more common as an early complication, late-onset neurological symptoms can also occur with BsAb therapy. Patients may experience cognitive impairments, mood disorders, or chronic headaches. For these patients, regular neurological exams, imaging with MRI, and electroencephalograms (EEGs) may be necessary to assess for ongoing neurotoxicity. Symptomatic management includes the use of anti-epileptics for seizures and neuropsychiatric support for cognitive or mood-related symptoms [ 13 , 91 , 92 , 93 ]. Despite the comorbidity associated with neurotoxicity, non-relapse mortality is higher due to infections [ 94 ].
7.8. Management and Future Directions
Management of late complications from BsAbs necessitates a multidisciplinary approach involving hematologists, infectious disease specialists, and neurologists. Late complications such as prolonged cytopenias occur in approximately 20–30% of patients, while hypogammaglobulinemia is observed in up to 60% of those treated with BsAbs targeting CD19 or BCMA. To mitigate these risks, routine laboratory testing (e.g., complete blood counts, serum immunoglobulin levels), imaging, and supportive therapies such as intravenous immunoglobulin (IVIG) infusions are critical.
Future developments in BsAb design aim to reduce immune-related toxicities, such as cytokine release syndrome (CRS), which occurs in 30–70% of cases, with severe CRS (Grade ≥ 3) reported in approximately 5–10%. Innovations include modifying target specificity to minimize off-tumor effects and incorporating safety switches to regulate immune activation. Biomarker research is ongoing, focusing on identifying predictive markers for long-term toxicities and patient-specific risk stratification. These advancements hold promise for enhancing the safety and efficacy profiles of BsAb therapies, ultimately improving long-term outcomes for patients with hematologic malignancies [ 65 , 95 , 96 , 97 , 98 , 99 ].
8. Conclusions
CAR-T-cell therapy and bispecific antibodies have reshaped the therapeutic landscape for hematologic malignancies, providing new hope for patients with otherwise refractory or relapsed disease. However, these therapies come with a range of early and late complications that require meticulous diagnostic workup and individualized management strategies to optimize patient outcomes. Early complications such as cytokine release syndrome (CRS) and neurotoxicity demand timely intervention with protocols adapted to the severity of symptoms, utilizing tools like the ICE score for neurotoxicity and biomarkers for inflammatory response to enable prompt diagnosis and treatment. Similarly, for bispecific antibodies, early complications mirror those seen with CAR-T therapy, necessitating similar diagnostic vigilance and therapeutic strategies tailored to manage these unique toxicities effectively.
Late complications associated with both CAR-T therapy and bispecific antibodies, including prolonged cytopenias, infections, and B-cell aplasia, highlight the need for long-term monitoring and multidisciplinary care. The immunosuppressive nature of these treatments predisposes patients to opportunistic infections and, in some cases, secondary malignancies, underscoring the importance of routine follow-up with laboratory testing, imaging, and immunoglobulin replacement therapy when appropriate. For bispecific antibodies, late complications are managed through continued surveillance and supportive care, with an emphasis on mitigating autoimmune reactions and neurotoxicity that may emerge as the treatment progresses. As we refine the understanding of these late effects, personalized approaches that predict and prevent complications based on individual patient risk profiles will be essential.
Looking forward, advancements in CAR-T and bispecific antibody technologies aim to minimize these complications by enhancing the precision and safety of immune activation. Research focused on identifying predictive biomarkers, optimizing dosing regimens, and developing next-generation constructs with reduced toxicity is paving the way for safer, more effective therapies. Through an ongoing commitment to understanding and addressing the full spectrum of complications, clinicians can continue to improve the quality of life and survival outcomes for patients undergoing these transformative treatments in hematologic oncology.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Author Contributions
Conceptualization, A.B. and B.A.; methodology, A.B. and B.A.; formal analysis, A.B., C.M. and B.A.; investigation, A.B., B.A. and C.M.; resources, A.B., B.A. and C.M.; data curation, A.B. and B.A.; writing—original draft preparation, A.B., B.A., C.M., L.Z., S.G., A.I. and C.C.; writing—review and editing, all authors.; visualization, A.B., C.M. and B.A.; supervision, C.C. and A.I. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
This study was conducted in accordance with the Declaration of Helsinki, and the need for approval by the Institutional Review Board (or Ethics Committee) of Hackensack Meridian Health was waived, given no patients’ identifying data were used in the study.
Informed Consent Statement
Patient consent was waived as this project represented a non-interventional study utilizing routinely collected data for secondary research purposes.
Data Availability Statement
The complete datasets used and/or analyzed during this study are available from the corresponding author upon request. Requests can be made through the corresponding author (Ayrton Bangolo; Email: ayrton.bangolo@hmhn.org ).
Conflicts of Interest
A.B., B.A., C.M., L.Z., and C.C. declare no conflicts of interest. A.I.: Consultancy, Honoraria, and/or Speaker Bureau: TG Therapeutics and AstraZeneca; Advisory Board: Secura Bio.
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