Critical Care Management of Toxicities Associated with Targeted Agents and Immunotherapies for Cancer

Abstract

Objective:

To describe the most common serious adverse effects and organ toxicities associated with emerging therapies for cancer that may necessitate admission to the ICU.

Data Sources and Study Selection:

PubMed and Medline search of relevant articles in English on the management of adverse effects of immunotherapy for cancer.

Data extraction and Data Synthesis:

Targeted immunotherapies including tyrosine kinase inhibitors, monoclonal antibodies, checkpoint inhibitors, and immune effector cell therapy have improved the outcome and quality of life of patients with cancer. However, severe and life-threatening side effects can occur. These toxicities include infusion or hypersensitivity reactions, cytokine release syndrome, pulmonary, cardiac, renal, hepatic, and neurologic toxicities, hemophagocytic lymphohistiocytosis, opportunistic infections, and endocrinopathies. Cytokine release syndrome is the most common serious toxicity after administration of monoclonal antibodies and immune effector cell therapies. Most of the adverse events from immunotherapy results from an exaggerated T-cell response directed against normal tissue, resulting in the generation of high levels of proinflammatory cytokines. Toxicities from targeted therapies are usually secondary to “on target toxicities”. Management is largely supportive and may include discontinuation of the specific agent corticosteroids and other immune-suppressing agents for severe (grade 3 or 4) immune-related adverse events like neurotoxicity and pneumonitis.

Conclusions:

The complexity of toxicities associated with modern targeted and immunotherapeutic agents for cancer require a multidisciplinary approach among ICU staff, oncologists, and organ specialists and adoption of standardized treatment protocols to ensure the best possible patient outcomes.

Introduction

The treatment of cancer has evolved significantly in the last two decades with the development of tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs), immune checkpoint inhibitors (ICIs), and immune effector cell (IEC) therapy. These approaches have improved the outcome and quality of life of patients with cancer. However, severe and life-threatening side effects can occur necessitating admission to the intensive care unit (ICU) (Table 1). As oncologic patients get increasingly exposed to these novel therapies, it is paramount for clinicians to recognize their toxicities and institute rapid and effective treatments. In this first of a two-part review of oncologic critical care, we will focus on the most common organ toxicities associated with new and emerging therapies for cancer and their management.

Table 1.

Targeted Agents and Immunotherapies and their Associated Toxicities

Type of Therapy	Toxicities
Tyrosine Kinase Inhibitors	Renal toxicity (interstitial nephritis, thrombotic microangiopathy, tumor lysis syndrome) Neurotoxicity (PRES, ischemic or hemorrhagic stroke, seizures, Guillain-Barre syndrome, myasthenia gravis, cerebral edema, subdural hematoma) Pulmonary (pneumonitis, pulmonary hypertension, thromboembolism) Cardiac (dysrhythmias, acute coronary syndrome, QT prolongation)
Monoclonal Antibodies	Infusion reactions Cytokine Release Syndrome Pulmonary (pneumonitis, thromboembolic events) Neurotoxicity (PRES, ischemic stroke, intracranial hemorrhage, aseptic meningitis, encephalopathy) Renal (interstitial nephritis, thrombotic microangiopathy, tumor lysis syndrome) Cardiac toxicity (Kounis syndrome, cardiomyopathy, dysrhythmias, acute coronary syndrome)
Immune Checkpoint Inhibitors	Pneumonitis Cardiac (myocarditis, pericarditis, dysrhythmias) Neurotoxicity (Guillain-Barre syndrome, myasthenia gravis, meningoencephalitis, cerebral edema, seizures, PRES) Nephrotoxicity (interstitial nephritis, glomerulonephritis, tumor lysis syndrome, nephrotic syndrome) Hepatotoxicity Endocrine (hypophysitis, adrenal insufficiency, thyroid dysfunction)
Chimeric Antigen Receptor (CAR) Cell Therapy	Cytokine Release Syndrome ICANS

PRES = posterior reversible encephalopathy syndrome; ICANS = immune effector cell-associated neurotoxicity syndrome

Novel Agents and Toxicity Profiles

Tyrosine kinase inhibitors block the action of tyrosine kinases, vital for tumor cell signaling, proliferation, and metabolism (1). Severe adverse events with TKIs include cardiomyopathy, pneumonitis, pulmonary hypertension and thromboembolism, neurotoxicity, and hemorrhagic complications (Table 2) (1–3).

Table 2.

Targets and Toxicities Associated with Tyrosine Kinase Inhibitors

Drug	Target	Indication	Neurotoxicity	Pulmonary Toxicity	Other Toxicities
Sunitinib	VEGFR, PDGFR, c-Kit, RET	Renal cell carcinoma, GIST. Pancreatic neuroendocrine tumor	PRES, ischemic stroke, GBS and MG	Pneumonitis, Alveolar hemorrhage	Renal: Interstitial nephritis, Thrombotic microangiopathy
Vandetanib	VEGFR, EGFR, RET	Medullary thyroid carcinoma	PRES, Ischemic stroke	Pneumonitis
Ibrutinib	BTK	CLL, mantle cell lymphoma	ICH	Pneumonitis	Renal: Tumor lysis syndrome Cardiac: arrhythmias
Lenvatinib	VEGFR 1, 2, 3, FGFR, RET, KIT, PDGFR-α	Metastatic differentiated thyroid cancer	Ischemic stroke, TIA, ICH, seizures, PRES		Renal toxicity
Sorafenib	VEGFR 2, 3, PDGFR KIT, FLT 3	Renal cell, hepatocellular and thyroid carcinomas	Ischemic stroke	Pneumonitis, Bronchospasm	Renal: interstitial nephritis and thrombotic microangiopathy
Pazopanib	VEGFR, PDGFR, KIT, FGFR	Renal cell carcinoma	Ischemic stroke, TIA, ICH (including SAH), PRES	Pneumonitis	Hepatotoxicity
Axitinib	VEGFR 1, 2, 3	Renal cell carcinoma	Ischemic stroke and PRES	Thromboembolic events, Pneumonitis, Hemoptysis
Ceritinib	ALK	NSCLC	Seizures	Pneumonitis
Imatinib	BCR-ABL	ALL, gastrointestinal stromal tumors, MDS	Subdural hematomas and ICH	Pneumonitis	Renal: Interstitial nephritis
Vemurafenib, Dabrafenib	BRAF inhibitor	Metastatic melanoma	Cerebral edema
Dasatinib	BCR-ABL	ALL, CML	Subdural hematomas and ICH	Thromboembolic events, Pulmonary hypertension, Pneumonitis	Renal: Tumor lysis syndrome Cardiac: bradycardia
Ponatinib	BCR-ABL	CML, Philadelphia (+) ALL		Thromboembolic events	Cardiac: Acute coronary syndrome
Nilotinib	BCR-ABL	CML			Cardiac: Acute coronary syndrome, QT prolongation Renal: Tumor lysis syndrome
Bortezomib Carfilzomib	26S proteasome inhibitor	Multiple myeloma			Renal: Thrombotic microangiopathy

NSCLC = non-small cell lung carcinoma; SCC = squamous cell carcinoma; GIST = gastrointestinal stromal tumor; ICH = intracerebral hemorrhage; TIA (transient ischemic attack); SAH = subarachnoid hemorrhage; PRES = posterior reversible encephalopathy syndrome; GBS = Guillain-Barre Syndrome; MG = myasthenia gravis; ALL = acute lymphoblastic leukemia; MDS = myelodysplastic syndrome; CML = chronic myelogenous leukemia; CLL = chronic lymphocytic leukemia

Monoclonal antibodies (mAbs) are designed to bind to specific tumoral antigens, inflammatory cytokines and their receptors, or to endothelial and epithelial growth factors (3–6). Adverse events are diverse ranging from severe infusion reactions to pulmonary toxicities (Table 3). The toxicity spectrum varies depending on the mechanism of action of the mAb.

Table 3.

Specific Targets and Toxicities Associated with Monoclonal Antibodies

Drug	Target	Indication	Neuro-Toxicity	Pulmonary Toxicity	Other Toxicities
Alemtuzumab	Anti-CD52				Infusion reaction Cardiac: Kounis syndrome
Bevacizumab	VEGF-α	Colorectal, NSCLC, ovarian cancer, cervical cancer, glioblastoma, renal cell carcinoma	ICH, stroke or TIA, PRES	Thromboembolic events, Bronchospasm	Infusion reaction Cardiac: dysrhythmias, cardiomyopathy, acute coronary syndrome Renal: interstitial nephritis and thrombotic microangiopathy
Blinatumomab	CD19/CD3	B-cell ALL	Neurotoxicity similar to ICANS		Hemophagocytic lymphohistiocytosis
Cetuximab	EGFR	Colorectal, SCC head and neck	Aseptic meningitis, PRES	Pneumonitis, Bronchospasm	Infusion reaction, toxic epidermal necrolysis Cardiac: Kounis syndrome
Ramucirumab	VEGFR2	NSCLC	Ischemic stroke
Trastuzumab	HER 2	Breast, gastric and esophageal cancer	PRES	Pneumonitis, Bronchospasm	Infusion reaction Cardiac: acute coronary syndrome
Brentuximab	Anti-CD30				Infusion reaction
Rituximab	Anti-CD20	Non-Hodgkin lymphoma, DLBCL		Interstitial pneumonitis and interstitial lung disease	Infusion reaction, Stevens- Johnson syndrome Cardiac: dysrhythmias, cardiomyopathy, Kounis syndrome

NSCLC = non-small cell lung carcinoma; SCC = squamous cell carcinoma; GIST = gastrointestinal stromal tumor; ICH = intracerebral hemorrhage; TIA (transient ischemic attack); PRES = posterior reversible encephalopathy syndrome; GBS = Guillain-Barre Syndrome; MG = myasthenia gravis; ALL = acute lymphoblastic leukemia; MDS = myelodysplastic syndrome; CML = chronic myelogenous leukemia; CLL = chronic lymphocytic leukemia; ICANS = Immune Effector Cell-associated Neurotoxicity Syndrome; DLBCL = diffuse large B cell lymphoma

Immune checkpoint inhibitors, are mAbs that bind to programmed cell death (PD)-1/programmed death ligand (PDL)-1 and cytotoxic T-lymphocyte antigen 4 (CTLA4) to block T-cell inhibition, thereby upregulating T-cells and enhancing their anti-tumor immunity (7). Most toxicities from ICIs arise from immune-mediated inflammatory responses that lead to organ toxicity (4, 8, 9). Severe toxicities may affect different organ systems and manifest with pneumonitis, neurotoxicity, cardiomyopathy, renal failure or hepatitis (Table 4).

Table 4.

Targets and Toxicities Associated with Immune Checkpoint Inhibitors

Drug	Target	Indication	Neuro-Toxicity	Pulmonary Toxicity	Other Toxicities
Ipilimumab	CTLA4	Metastatic melanoma	Aseptic meningitis, GBS, MG, myelitis, PRES and MS relapse,	Pneumonitis	Cardiac: pericarditis, myocarditis Endocrine: Hypophysitis, thyroid dysfunction Hepatotoxicity Renal: Interstitial nephritis, glomerulonephritis
Pembrolizumab	PD-1	NSCLC, melanoma, Hodgkin’s lymphoma	GBS, MG, seizures, encephalitis	Pneumonitis, alveolar hemorrhage,	Hemophagocytic lymphohistiocytosis Renal: Interstitial nephritis Cardiac: Pericardial effusion, myocarditis, dysrhythmias Hepatotoxicity Renal: Interstitial nephritis, glomerulonephritis Endocrine: Hypophysitis
Nivolumab	PD-1	NSCLC, melanoma, renal cell carcinoma, Hodgkin’s lymphoma	GBS, encephalitis, MG, cerebral edema	Pneumonitis	Cardiac: Myocarditis Endocrine: thyroid dysfunction, hypophysitis Hepatotoxicity Renal: Interstitial nephritis, glomerulonephritis, nephrotic syndrome
Atezolizumab	PDL-1	NSCLC, urothelial cancer	Encephalitis, seizures		Endocrine: thyroid dysfunction, hypophysitis Renal: Interstitial nephritis

NSCLC = non-small cell lung carcinoma; PRES = posterior reversible encephalopathy syndrome; GBS = Guillain-Barre Syndrome; MG = myasthenia gravis; MS = multiple sclerosis

Immune effector cell (IEC) therapies include chimeric antigen receptors (CARs) and T-cell receptors (TCRs). CARs are autologous cells modified to express a single chain antibody that recognizes a tumoral antigen (e.g., CD19 CAR T-cells recognize CD19 in B-cell malignancies)(10, 11). TCRs are autologous T-cells with a modified T-cell receptor that recognize the major histocompatibility complex of a specific tumoral antigen (12). Toxicities of CARs are secondary to the exaggerated inflammatory response caused by their activation leading to shock, hypoxic respiratory failure, and/or neurotoxicity (10, 13). In the case of TCRs, adverse events due to their proliferation are minimal, but “off-target” toxicities exist. CARs are a promising treatment for chemotherapy-refractory B-cell malignancies, but more than 30–40% of patients who receive this therapy require ICU admission (14, 15).

Toxicity Profiles

Infusion reactions

Infusion reactions due to mAbs, are divided into immediate and delayed (4). Immediate infusion reactions may reflect hypersensitivity reactions (anaphylaxis), reactions due to immunogenicity to non-specific proteins of the mAbs (anaphylactoid) and cytokine release syndrome (CRS). Anaphylaxis is IgE mediated and occurs within minutes to 1 hour of infusion following repeat exposure to the mAb (4, 9, 16, 17). Anaphylactoid reactions are non-IgE mediated and usually have a milder clinical presentation (16, 18). Cytokine release syndrome, which is T-cell mediated, has a myriad of clinical symptoms and will be discussed in detail in the next section. Monoclonal antibodies associated with severe infusion reactions include rituximab (anti-CD20), brentuximab (anti-CD30), alemtuzumab (anti-CD52), trastuzumab and pertuzumab (anti-HER2), bevacizumab (anti-vascular endothelial growth factor [VEGF]), and cetuximab (anti-epithelial growth factor receptor [EGFR])(4, 9, 16, 17, 19). Infusion reactions are extremely rare for checkpoint inhibitors (<1%), except for avelumab (20%) (7, 19).

Signs and symptoms of anaphylaxis include angioedema, bronchospasm, hypotension, or anaphylactic shock (16, 19). Initial non-specific protein-related reactions may also present with hypotension and fever but are usually milder, self-limited and are unlikely to require an ICU admission (16, 18). Treatment of infusion reactions includes immediate interruption of the infusion and supportive care with epinephrine (in anaphylaxis), antihistamines, and corticosteroids (4). Vasopressor support and mechanical ventilation may be required. In the case of a severe infusion reaction, desensitization, premedication with antihistamines and corticosteroids, and re-challenging with a lower rate and dose of the infusion may minimize the risk of subsequent reactions (4, 16, 19).

Infusion reactions from mAbs can be similar in presentation to CRS. However, the following are differentiating features: 1) CRS typically occurs with the first dose administered and more than 2 hours post-infusion, while hypersensitivity infusion reactions occur immediately and after at least one uneventful dose has been administered; and 2) CRS is T-cell and cytokine-mediated while hypersensitivity reactions are IgE mediated and lead to mast cell activation, release of histamines, leukotrienes and prostaglandins (16, 19). It is important to note that exceptions can occur; anaphylaxis due to cetuximab is observed with the first dose due to preformed IgE antibodies (4, 17).

Delayed serious infusion reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, are rare and limited to case reports with rituximab and cetuximab (4, 21, 22), and with ICIs (23).

Cytokine Release Syndrome due to Immune Effector Cell Therapy

Cytokine release syndrome (CRS) is the most common toxicity with CARs (60–94% of patients), with 13–20% requiring high doses vasopressors (24–27). The incidence and severity of CRS increases with large tumor burden and higher cell dosing (14, 24). A recent consensus group defined CRS related to IECs as “a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T-cells and/or other immune effector cells”(28). The inflammatory response during CRS is associated with marked elevations of inflammatory cytokines (e.g.; IL-6, IL-8, IL-10, INF-γ) and endothelial activation markers such as von-Willebrand factor and angiopoietin-2 (29–31).

CRS symptoms usually occur within the first 7–14 days of CAR T-cell infusion depending on the construct (25, 27, 32). The hallmark symptoms are fever, hypotension, and hypoxemia. A consensus was recently reached for CRS grading (Figure 1) (28). As the syndrome evolves, various organ systems may be affected leading to multisystem organ failure. Cardiac toxicity manifests as tachycardia, arrhythmias, heart blocks, hypotension and shock. Decreased left ventricular ejection is also observed. Hypoxemic respiratory failure can rapidly progress from capillary leak syndrome and non-cardiogenic pulmonary edema to acute respiratory distress syndrome (ARDS). Renal failure, hepatoxicity, disseminated intravascular coagulopathy and skin lesions can also occur.

Figure 1. CRS Grading and Management Considerations Associated with Immune Effector Cell Therapy.

The major clinical manifestations of CRS are fever, hypotension, and hypoxia. The CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. The mainstays of treatment of grade ≥2 CRS are anti–IL-6 monoclonal antibodies (tocilizumab) and corticosteroids. Recommended dose of corticosteroids can vary among institutions and within protocols. Suicide and elimination genes are still experimental (119–122).

Treatment of ≥ grade 2 CRS includes anti-IL-6 therapy with tocilizumab and siltuximab, and corticosteroids to suppress inflammation and CAR proliferation (14, 33) (Figure 1). Recent data suggest anti-IL-1 receptor anakinra, anti-granulocyte macrophage colony stimulating factor, and JAK1 and 2 inhibition with ruxolitinib are successful in suppressing CRS in animal models (34–36). Since the clinical presentation of CRS may mimic sepsis, alternative causes of fever, hypotension and hypoxemia, need to be simultaneously investigated.

The clinical presentation of CRS caused by mAbs is similar to that observed with IECs. High tumor burden, rapid infusion, and high doses of the mAbs can increase the risk and severity of CRS (17, 20). Treatment for mAb-induced CRS includes acetaminophen, antihistamines, tocilizumab, and corticosteroids (4, 17). Supportive care of specific organ failure should be similar to that of IECs.

Pulmonary toxicities

The incidence of ICI-related pneumonitis ranges between 1–10% and is more common with anti-PD-1/PD-L1 agents and with combination therapy (37–42). Acute pneumonitis typically presents 3 months (2–24 months) following treatment initiation but may occur earlier with dual agent therapy (40, 41). Non-specific clinical symptoms and radiographic patterns have been described (40). Due to their low specificity, a meticulous approach to rule out infection is necessary during the work-up of respiratory failure in this population. Computed tomography of the chest and early fiberoptic bronchoscopy and bronchoalveolar lavage to rule out infectious etiologies, while empirically treating, is recommended.

Treatment strategies for severe pneumonitis include permanent discontinuation of the ICI and initiation of IV methylprednisolone 1–2 mg/kg/day (39, 43). Corticosteroid taper should be performed over 4–6 weeks (43, 44). Most adverse events from ICIs resolve within weeks to months of initiation of corticosteroid therapy(44), although mortality related to ICI pneumonitis is seen in 14% of patients (45). Additional treatments to consider in refractory patients include infliximab, mycophenolate mofetil (MMF), cyclophosphamide and intravenous immunoglobulin (IVIg) (39).

Cytokine release syndrome can cause acute respiratory distress syndrome (ARDS) as a direct consequence of capillary leak leading to non-hydrostatic pulmonary edema. Hydrostatic pulmonary edema may result from CRS-associated acute dilated cardiomyopathy. Excessive fluid administration could further exacerbate respiratory failure. Besides close monitoring for signs of respiratory failure and utilizing lung protective ventilation, infectious causes should be ruled out(46, 47). Treatment with anti-IL-6 therapy and corticosteroids is recommended (Figure 1) (14, 33).

Drugs targeting angiogenesis inhibition such as bevacizumab and aflibercept and TKIs (dasatinib, ponatinib and axitinib) are associated with pulmonary thromboembolic complications (6). Interstitial pneumonitis and interstitial lung disease has been reported with rituximab (8–20%) (48, 49) and time to onset varies from 2 weeks to 3 months after initiation of treatment (48, 49). Treatment consists of cessation of the antibody and glucocorticoids. TKIs have also been associated with other pulmonarycomplications such as pneumonitis, pleural effussions, and pulmonary hypertension (6, 50, 51). Pulmonary hypertension (pHTN) is usually observed with dasatinib in less than 1% of patients, and has also been reported with the use of imatinib(50, 51). While it is recommended to screen patients for cardiopulmonary disease prior to their use, pHTN usually resolves after discontinuation of the medication (50, 51). Pneumonitis has been observed in <10% of patients treated with dasatinib and <1% with imatinib, and discontinuation of the medication usually leads to resolution of the symptoms(50, 51). Its incidence increases when combining therapy with TKIs (afatinib, erlotinib, gefitinib,osimertnib) and ICIs (nivolumab)(53).

Neurotoxicity

Neurological complications vary significantly in presentation, and treatment can be challenging. CAR-associated neurotoxicity, now referred to as Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) presents in 70–80% of patients receiving CARs and 30–40% of cases are severe (13–15, 33). ICANS may occur either within 7 days of CAR-T cell infusion with or without CRS, or after resolution of CRS (1–2 weeks after infusion). The syndrome is usually reversible, but can be severe and lead to death if left unrecognized(54). Mild presentations include tremors, headache, mild aphasia, confusion and dysgraphia (14, 28, 33, 55) (Figure 2A). As symptoms evolve, global aphasia, seizures, status epilepticus, coma, paresis and cerebral edema can occur (14, 28, 33, 55). Similar to CRS, a consensus was recently reached for ICANS grading that includes the use of the Immune Effector Cell-Associated Encephalopathy (ICE) assessment tool (Figure 2A and 2B) (28). The pathophysiology of ICANS includes local central nervous system (CNS) inflammation, endothelial dysfunction of the blood-brain barrier (BBB) and cell trafficking of CARs into the CNS(13, 55). Management of seizures, status epilepticus and cerebral edema is vital (14). Corticosteroids reverse symptoms in many cases and are recommended in patients with severe (grade 3 and 4) neurotoxicity associated with the axicabtagene-ciloleucel CAR construct (Figure 2A) (14, 55). Use of corticosteroids for other CARs, such as tisagenlecleucel, is not routinely recommended and can be considered for severe persistent symptoms. Thus, due to the variability between cell products, the use of corticosteroids should be carefully discussed with the oncologist balancing the patient’s clinical condition versus the risk of affecting CAR replication.

Figure 2A. ICANS Grading and Treatment Considerations.

The grading of ICANS is determined by the most severe events (ICE score, level of consciousness, motor symptoms, seizures, and signs of elevated ICP/cerebral edema) not attributable to any other cause. Patients with grade 3 and 4 neurotoxicity should be monitored and managed in the ICU. Frequent neurologic examination and treatment of seizures and cerebral edema require close collaboration with neurology and neurosurgical consult services. Corticosteroids are indicated in patients with grade 3 and 4 neurotoxicity. Suicide and elimination genes are still experimental (119–122).

Figure 2B.

Immune Effector Cell-Associated Encephalopathy (ICE) Score

With ICIs, neurologic toxicities can present within 1 week of infusion and have significant morbidity and mortality (45, 56). Neurologic toxicities are more common with anti-PD-1/PDL-1 antibodies and combination therapy (43). Both Guillain-Barre syndrome and myasthenia gravis have been described with ICIs and sunitinib (2, 3, 44, 56, 57) (Table 4). While the presentation can be typical, a significant number of patients present with variants associated to severe myositis and polyradiculoneuropathies (56, 57). Diagnosis includes a comprehensive clinical exam, cerebrospinal fluid (CSF) studies demonstrating pleocytosis and elevated protein, electromyography and nerve conduction studies(23, 43). Creatine kinase levels should be monitored (8, 45, 57). Acetylcholine antibodies, while helpful, are not always positive and should not guide treatment (56, 57). Treatment for both Guillain-Barre syndrome and myasthenia gravis include corticosteroids, plasmapheresis and IVIg (3, 23, 43, 56, 57). Since many cases present with concurrent severe myositis, corticosteroid- sparing treatments such as rituximab and infliximab can be considered.(44, 56, 58).

Posterior reversible encephalopathy syndrome (PRES) is common with mAbs, ICIs, and TKIs (Tables 2, 3, 4)(2, 3, 9). In the case of anti-angiogenic therapies, PRES is triggered by acute endothelial injury with breakdown of the blood-brain barrier and subsequent cerebral edema (2). However, with ICIs and other mAbs the pathophysiology is unclear (56). The main features are altered mental status, headache, visual disturbances, and seizures. Typical findings on magnetic resonance imaging (MRI) are symmetric T2 or fluid-attenuated inversion recovery imaging (FLAIR) hyperintensities located in the occipital and parietal regions (2). (9, 56). Lowering of high blood pressure and discontinuation of the agent are the mainstays of treatment (2, 56).

Aseptic meningitis, encephalitis and encephalopathy may present in patients treated with mAbs and ICIs (2, 44, 57, 59) (Tables 3 and 4). Infectious causes should be ruled out and treated concomitantly until a definite diagnosis is made. MRI findings and CSF studies vary significantly; however, a CSF with lymphocytic pleocytosis may suggest an immune-related process (23, 43, 60). Treatment includes corticosteroids, IVIg and rituximab(23, 56, 60) Responses to treatment vary significantly and relapses can be observed, therefore a corticosteroid taper over 4–8 weeks is recommended (43, 56). Encephalopathy caused by blinatumomab, a bispecific mAb, is very similar to ICANS and can be severe in 13% of patients(2, 6). Treatment includes discontinuation of the medication, corticosteroids and supportive care(2, 6).

Seizures present with TKIs and ICIs (2, 3). Treatment include antiepileptic drugs, corticosteroids, IVIg and apheresis in refractory cases (2, 3, 56, 57). Transverse myelitis is described with ipilimumab and reversed after high dose corticosteroids (2, 56). Cerebral edema can occur with nivolumab and the BRAF inhibitors vemurafenib and dabrafenib (3). Anti-angiogenic agents, either mAbs (bevacizumab, ramucirumab) or TKIs (imatinib, dasatinib, lenvatinib mesylate, sunitinib, sorafenib, ibrutinib) are associated with intracranial hemorrhage (0.3%−3.3%) and ischemic cerebral events (1.3–1.9%) (2, 3, 6, 17). Hemorrhagic presentations include intraparenchymal hemorrhages independent of CNS lesions, subarachnoid hemorrhage and subdural hematomas (2, 3). In the case of ibrutinib, dasatinib, and imatinib, bleeding has been attributed to inhibition of platelet aggregation via inhibition of cyclooxygenase, kinases vital to platelet aggregation or collagen dependent aggregation (3, 61). In these patients, the utility of platelet transfusions should be discussed with the hematology and oncology teams. Relapse of autoimmune disorders such as multiple sclerosis has been described with the use of ipilimumab(3).

Cardiac toxicities

The cardiovascular symptoms of CRS associated to both CARs and mAbs can range from tachycardia to life threatening complications such as dysrhythmias, impaired left ventricular ejection fraction and vasodilatory shock requiring high dose vasopressors(14, 17, 31, 33, 62, 63). Treatment is largely supportive and include corticosteroids and IL-6 antagonists (14, 33). Initial investigations should include electrocardiography, continuous telemetry and echocardiography to identify the potential dysrhythmias and ejection fraction, respectively.

Cardiovascular toxicities from mAbs vary significantly (Table 3). Infusion of mAbs, such as rituximab and bevacizumab can cause significant dysrhythmias and cardiomyopathy independent of cardiovascular risk factors(64, 65). Classic acute coronary syndromes such as vasospastic angina and stent thrombosis are reported with bevacizumab, trastuzumab and ranibizumab(66). A more specific coronary syndrome associated with mAbs (rituximab, infliximab, cetuximab and alemtuzumab) is Kounis Syndrome(66–68). Kounis syndrome is defined by the presence of mast cell degranulation, cross bridging of platelets and secondary allergic thrombosis (67). Any allergic reaction can cause Kounis syndrome, but in this case antibodies directed against the mAbs lead to mast cell activation(68). Opiates such as morphine should be administered with extreme caution in patients with Kounis syndrome, since this can induce massive mast cell degranulation and aggravate the allergic reaction(67). Management is limited to case reports that suggest treatment of both an anaphylactic reaction and acute coronary syndrome simultaneously. The use of epinephrine can be considered both helpful and harmful(69).

The incidence ICI-associated myocarditis is low (<1%) but comprises 22% of the fatalities associated with ICIs (7, 45, 70). Symptoms usually start 30 days after starting therapy(70). As soon as myocarditis is recognized, stopping the agent and starting high dose corticosteroids is recommended (71). In refractory cases, infliximab, anti-thymocyte globulin and mycophenolate mesylate (MMF) can be considered(43).

QTc prolongation and increased cardiovascular ischemic events are reported with nilotinib (72, 73). In patients with pre-existing cardiovascular risk factors, ponatinib increases the risk of cardiac ischemic events(72, 73). Screening for underlying coronary artery disease is recommended for patients who will receive TKIs known to cause cardiovascular toxicity.

Renal failure

Acute kidney injury (AKI) can occur in 10–20% of patients treated with ICIs (74, 75). Patients develop pyuria, proteinuria and typical pathological features of an acute lymphocytic tubulointerstitial nephritis (76–80). Nephrotic syndrome can also occur (79). AKI occurs at a median of 3 months after initiation of ICIs and more than 2 months after the last dose (76, 80). Treatment and prognostic data are limited, but in addition to discontinuation of the ICI, the use of corticosteroids can be considered (75, 76, 80). Other treatments such as rituximab, infliximab, MMF and plasmapheresis are described (80). Experimental models suggest that patients receiving ICIs are more susceptible to AKI due to sepsis and shock (81).

Anti-vascular endothelial growth factors (VEGF) antibodies (e.g., bevacizumab) and anti-VEGF TKIs such as sunitinib and sorafenib can cause a variety of kidney injuries as high levels of VEGF are expressed in the normal kidney (79, 82, 83). The most serious of these are interstitial nephritis and thrombotic microangiopathy (79, 82, 83). Other TKIs (bortezomib and carfilzomib) can also cause thrombotic microangiopathy (79, 84–86).

Tumor lysis syndrome can cause AKI after treatment with mAbs (e.g. rituximab, obinutuzumab), TKIs (e.g. alvocidib, ibrutinib, nilotinib, dasatinib) and CARs (87–89). Management of TLS should not differ from that described for cytotoxic agents(88, 89). AKI due to CRS occurs after treatment with CARs and mAbs (29, 90–92). The mechanism of AKI is multifactorial: hypoperfusion from hemodynamic instability and fluid shifts, and direct injury from cytokines (91, 92). Management should be supportive and treating the underlying CRS with corticosteroids and anti-IL-6 therapy. The AKI associated with TLS after CARs can be difficult to differentiate from CRS, especially since it can present concomitantly with CRS. Therefore, supportive treatment for TLS should be considered in patients with high tumor burden before and after infusion of CARs.

Other Considerations

Secondary hemophagocytic lymphohistiocytosis (HLH) was described in patients receiving CAR T-cells, ICIs (pembrolizumab) and blinatumomab (93–95). Its presentation can mimic other conditions such as CRS and sepsis, making its diagnosis challenging. Signs and symptoms include fever with multi-organ dysfunction (e.g., altered mental status/seizure, respiratory distress syndrome, hypotension/shock, severe liver dysfunction), hepato/splenomegaly, anemia, thrombocytopenia, and hypertriglyceridemia. LDH, ferritin and IL-2R levels are markedly elevated and bone marrow aspirates show hemophagocytosis (93, 95). Diagnostic criteria and recommendations have been made in the CAR-T population, but further data are required to evaluate their sensitivity and specificity(96–98). The treatment of HLH in patients with concurrent CRS includes corticosteroids and anti-IL-6 therapy, with consideration of etoposide if there is no clinical improvement(33, 99).

Hepatotoxicity has been described with ICIs. This is usually manifested with transient elevation in transaminases although fulminant liver failure has been reported (58, 74, 100). Hepatitis occurs in 5%−10% of patients treated with ipilimumab, nivolumab, and pembrolizumab (58, 101–106). Corticosteroids are the treatment of choice for grade 3 or 4 liver toxicity (43). Elevation in transaminases can also occur during CRS following treatment with CAR-T cells and blinatumomab (90, 92, 107).

A recent international consensus document concluded that targeted therapies do not intrinsically increase the incidence of serious infections (109). Nevertheless, opportunistic infections including Aspergillus fumigatus pneumonia, cytomegalovirus hepatitis, and Pneumocystis jirovecii pneumonia in patients receiving ipilimumab and pembrolizumab and CARs have been reported (110–113). The use of corticosteroids and other immune suppressing agents for the treatment of AEs due to immunotherapy likely renders these patients at higher risk of opportunistic infections (114). Thus, for cancer patients receiving immunotherapy who require 20 mg of prednisone daily or the equivalent for at least 4 weeks, Pneumocystis jirovecii prophylaxis is recommended (115). Viral hepatitis reactivation can occur with targeted cancer therapies, particularly rituximab, sometimes with fulminant results (116–118).

Endocrinopathies are described with ICIs (Table 1). Both hyperthyroidism and hypothyroidism can develop in 1–10% of cases and increase to 20% with combination therapy (7, 43, 44). Hypophysitis can also occur, and while rare with anti-PD-1/PDL-1, rates of 16% are observed with anti-CTLA-4 or combination of anti-CTLA-4 and anti-PD-1 therapy (43, 44). Patients may be asymptomatic or can present with headache, visual disturbances or other endocrine-related syndromes. Magnetic resonance imaging of the brain is important to exclude secondary meningeal or parenchymal lesions. Levels of thyroid stimulating hormone, adrenocorticotropin hormone and cortisol should be monitored regularly in patients receiving ICIs (23, 43). In patients recently treated with ICIs, suspicion of adrenal insufficiency and hypo/hyperthyroidism should lead to immediate workup and use of corticosteroids and hormone replacement, if indicated. For all moderate-to-severe endocrinopathies, anti-PD-1/PD-L1 agents should be held until the patient is stable on hormone-replacement therapy or the endocrinopathy resolves.

Summary

Novel immunotherapeutic agents for cancer have led to a decreased overall death rate but can be associated with severe and life-threatening complications requiring ICU admission. The complexity of toxicities associated with these therapies require a multidisciplinary approach among ICU staff, oncologists, and organ specialists and adoption of standardized treatment protocols to ensure the best possible patient outcomes.