Radiol Oncol 2024; 58(2): 170-178. doi: 10.2478/raon-2024-0027 170 review Potentially fatal complications of new systemic anticancer therapies: pearls and pitfalls in their initial management Milena Blaz Kovac1,2, Bostjan Seruga2,3 1 Ljubljana Community Health Centre, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Division of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia Radiol Oncol 2024; 58(2): 170-178. Received 22 February 2024 Accepted 10 March 2024 Correspondence to: Assoc. Prof. Boštjan Šeruga, M.D., Ph.D., Division of Medical Oncology, Institute of Oncology Ljubljana, Zaloška cesta 2, SI-1000 Ljubljana, Slovenia. E-mail: bseruga@onko-i.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Various types of immunotherapy (i.e. immune checkpoint inhibitors [ICIs], chimeric antigen receptor [CAR] T-cells and bispecific T-cell engagers [BiTEs]) and antibody drug conjugates (ADCs) have been used increas- ingly to treat solid cancers, lymphomas and leukaemias. Patients with serious complications of these therapies can be presented to physicians of different specialties. In this narrative review we discuss potentially fatal complications of new systemic anticancer therapies and some practical considerations for their diagnosis and initial treatment. Results. Clinical presentation of toxicities of new anticancer therapies may be unpredictable and nonspecific. They can mimic other more common medical conditions such as infection or stroke. If not recognized and properly treated these toxicities can progress rapidly into life-threatening conditions. ICIs can cause immune-related inflammatory disorders of various organ systems (e.g. pneumonitis or colitis), and a cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) may develop after treatment with CAR T-cells or BiTEs. The cornerstones of management of these hyper-inflammatory disorders are supportive care and systemic immunosup- pressive therapy. The latter should start as soon as symptoms are mild-moderate. Similarly, some severe toxicities of ADCs also require immunosuppressive therapy. A multidisciplinary team including an oncologist/haematologist and a corresponding organ-site specialist (e.g. gastroenterologist in the case of colitis) should be involved in the diagnosis and treatment of these toxicities. Conclusions. Health professionals should be aware of potential serious complications of new systemic anticancer therapies. Early diagnosis and treatment with adequate supportive care and immunosuppressive therapy are crucial for the optimal outcome of patients with these complications. Key words: potentially fatal toxicity; immune checkpoint inhibitor; chimeric antigen receptor T-cells; Bispecific T-cell engager; antibody dug conjugate; immunosuppressive therapy treatment who develop acute illnesses often seek medical attention with general practitioners (GPs) and in emergency departments.1,2 Prompt identifi- cation of oncologic emergencies, timely interven- tion and coordinated follow-up with oncology care teams are crucial for optimal outcome.3 However, there may be a lack of knowledge about manage- ment of toxic complications of new anticancer Introduction The outcome of patients with cancer has improved substantially over the last few decades. Most mod- ern cancer care is delivered in the outpatient set- ting. Patients with cancer can develop various oncologic emergencies which can be cancer or treatment related. Patients undergoing anticancer Radiol Oncol 2024; 58(2): 170-178. Blaz Kovac M and Seruga B / Potentially fatal complications of systemic anticancer therapies 171 therapies such as immunotherapy among non- oncologist health providers, including emergency physicians (EPs).4 The most common and well-known classic on- cologic emergencies are: (i) metabolic (e.g. tumour lysis syndrome [TLS], hypercalcemia, syndrome of inappropriate antidiuretic hormone), (ii) hema- tologic (e.g. febrile neutropenia, hyperviscosity syndrome), (iii) structural (e.g. superior vena cava syndrome, malignant epidural spinal cord com- pression, malignant pericardial effusion, or (iv) treatment related (e.g. chemotherapy-induced oral mucositis, radiation pneumonitis).5 New systemic anticancer therapies can cause life-threatening complications which may be generally less-known than classical oncologic emergencies. In this narrative review we discuss potentially fatal complications of new systemic anticancer therapies that differ from classic oncologic emer- gencies and provide some practical considera- tions for their diagnosis and initial management. For this purpose, a comprehensive search of the literature was performed through PubMed using the following key words: “immune checkpoint in- hibitor”, “CAR T-cells”, “bispecific T-cell engager”, “antibody drug conjugate”, “toxicity” and “adverse event”. Articles describing diagnosis and manage- ment of treatment-related toxicities, including rec- ommendations of oncologic societies and working groups were included. Immune checkpoint inhibitors The immune checkpoint inhibitors (ICIs) are pre- scribed as monotherapy or in combination with chemotherapy and/or targeted anticancer agents in patients with both early and advanced solid cancers and Hodgkin’s lymphoma (Table 1). These agents are monoclonal antibodies which enhance the immune response to cancer cells. They block negative regulators of T-cell activation, such as cytotoxic T lymphocyte associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and programmed cell death 1 ligand (PD-1L), and rein- vigorate pre-existing T-cells (Figure 1). They target neoantigens presented by the major histocompat- ibility complex (MHC) molecules on the surface of cancer cells. Efficacy of ICIs may be restricted due to the lack of neoantigens presented on cancer cells, defects in expression of the MHC or in other components of the antigen-presenting machinery in cancer cells, development of resistant tumour subclones and lack of T-cells in the immunosup- pressive microenvironment of the tumour.6 ICIs are usually administered repeatedly every few weeks in the outpatient setting. The ICIs have a unique toxicity profile distinct from that of chemotherapy and other targeted agents. As these agents enhance immune response they can cause immune-related adverse events (irAEs) (i.e. immune-related inflammatory disor- TABLE 1. Approved immune checkpoint inhibitors in the European Union Immune checkpoint inhibitor Target Approved indications Early cancer Advanced cancer Atezolizumab (Tecentriq) PD-L1 NSCLC Urothelial carcinoma, NSCLC, SCLC, TNBC, HCC Avelumab (Bavencio) PD-L1 _ Urothelial carcinoma, RCC, Merkel cell carcinoma Cemiplimab (Libtayo) PD-1 _ Cutaneous SCC, Basal cell carcinoma, NSCLC, Cervical carcinoma Durvalumab (Imfinzi) PD-L1 _ NSCLC, SCLC, HCC, Biliary tract cancer Ipilimumab (Yervoy) CTLA-4 _ Melanoma, RCC, NSCLC, MPM, CRC, Oesophageal carcinoma Nivolumab (Opdivo) PD-1 Urothelial carcinoma, melanoma, NSCLC, oesophageal and GEJ cancer Melanoma, NSCLC, RCC, cHL, Head and neck SCC, MPM, Urothelial carcinoma, CRC, Oesophageal SCC, Gastric, GEJ or Oesophageal adenocarcinoma Pembrolizumab (Keytruda) PD-1 RCC, melanoma, NSCLC, TNBC RCC, Melanoma, NSCLC, HL, Urothelial carcinoma, Head and neck SCC, Cancers with MSI-H or MMRd, Oesophageal carcinoma, Endometrial carcinoma, Cervical carcinoma, Gastric and GEJ adenocarcinoma CRC = colorectal cancer; cHL = classical Hodgkin lymphoma; CTLA-4 = cytotoxic T-lymphocyte antigen; GEJ = gastro-oesophageal junction; HCC = hepatocellular carcinoma; HL = Hodgkin lymphoma; MMRd = mismatch repair deficiency; MPM = malignant pleural mesothelioma; NSCLC = non-small cell lung cancer; MSI-H: microsatellite instability – high; OSCC = oesophageal squamous cell carcinoma; PD-1 = program death 1; PD-L1 = program death ligand; RCC = renal cell carcinoma, SCC = squamous cell carcinoma; SCLS = small cell lung cancer; TNBC = triple-negative breast cancer Radiol Oncol 2024; 58(2): 170-178. Blaz Kovac M and Seruga B / Potentially fatal complications of systemic anticancer therapies172 ders), which can be life-threatening. In contrast to chemotherapy and some other targeted drugs development of irAEs is more unpredictable. They can affect any organ system and can occur at any time during a patient’s treatment or sometimes long after therapy with an ICI has been discon- tinued.7 A majority of irAEs occur during the first four months of treatment with an ICI and they most commonly affect the skin, endocrine, gas- trointestinal and pulmonary systems. Some other irAEs such as ICI-related myocarditis, hypophysi- tis, encephalitis and myositis are very rare but im- portant cause of morbidity and mortality.8,9 Early identification and treatment of irAEs is crucial to limiting their severity and duration. However, the presentation of irAEs is often non-specific and can mimic other common medical conditions such as infections, stroke, intracranial bleeding and myo- cardical infarction. Before treatment with an irAE is started it is very important to rule out these con- ditions. Importantly, mild irAEs can rapidly pro- gress to be life-threatening conditions. Therefore, when an irAE is suspected the patient’s symp- toms and vital signs should be closely monitored. Detailed recommendations outlining the diagno- sis, treatment and follow-up of patients with irAEs have been published by oncologic societies.10 In general, in patients with mild or moderate sympto- matic irAEs (i.e. grade ≤ 2) symptomatic treatment in the outpatient setting is recommended and ear- ly follow-up with a treating oncologist should be arranged. Exceptions are patients with symptoms suggestive of immune-related myocarditis, neuro- logical irAEs involving the central nervous system (i.e. hypophysitis, meningitis, encephalitis and my- elitis), dyspnoea or myasthenic syndromes, who should be hospitalised immediately and treated by a multidisciplinary team involving the oncolo- gist and the corresponding organ-site specialist (Figure 2). In patients with moderate symptoms (i.e. grade 2) systemic corticosteroids (e.g. methyl- prednisolone 0.5−1 mg/kg/day) are recommended. All patients with severe and life-threatening irAEs (i.e. grade ≥ 3) should be immediately hospital- ized and presented to the multidisciplinary team (Figure 2).10 The cornerstones of management of severe irAEs are supportive care and immunosup- pressive therapy with systemic corticosteroids (e.g. methylprednisolone 1−2 mg/kg/day), including initial high-dose pulse corticosteroids (e.g. meth- ylprednisolone 500−1000 mg/day for three days) in some conditions. In some severe cases refractory to corticosteroids blocking of tumour necrosis factor (TNF)-α with infliximab, blocking of the interleu- kin-6 receptor (IL-6R) with tocilizumab, intrave- nous immunoglobulins (IVIGs) and mycopheno- late mofetil may be beneficial.9,10 When symptoms of the irAR are severe initiation of corticosteroids cannot be postponed and empirical antimicrobial therapy can be started concurrently with corticos- teroids and discontinued when infection is exclud- ed.10 Chimeric antigen receptor T-cells and bispecific T-cell engagers CAR T-cells and BiTEs are both T-cell engag- ing therapies and have a similar toxicity profile. Chimeric antigen receptor (CAR) T-cells are a cell-based therapy in which patient’s T-cells are extracted by leukapheresis and then genetically FIGURE 1. Mechanisms of action of new anticancer therapies. (A) Immune checkpoint inhibitor; (B) CAR T-cell; (C) Bispecific T-cell engager and (D) Antibody drug conjugate. A B C D Radiol Oncol 2024; 58(2): 170-178. Blaz Kovac M and Seruga B / Potentially fatal complications of systemic anticancer therapies 173 modified through the insertion of DNA encoding recombinant protein CAR on their surface, ex- panded and then administered back to the patient. Whereas the extracellular domain of the CAR rec- ognizes a cancer-specific antigen, its intracellular domain activates the T-cell immunogenic antineo- plastic response (Figure 1).11,12 For example, tisa- genlecleucel binds to the Cluster of Differentiation (CD)19 on B-cell leukaemia and lymphoma cells and activates the immune system to destroy ma- lignant cells. CAR T-cells are now an established treatment for patients with relapsed and/or refrac- tory B-cell lymphomas, B-cell acute lymphoblastic leukaemia and multiple myeloma (MM) (Table 2). CAR T-cells can engraft long-term and provide long-term ongoing responses against cancer cells. For most patients, CAR T-cell therapy is a one-time treatment. Before infusion of CAR T-cells patients receive lymphodepleting chemotherapy. Research into CAR T-cells is also extending to other diseas- es, including solid tumors, infections and autoim- mune disorders. On average, patients are hospital- ized for 12 days after infusion of the CAR T-cells.13 While natural antibodies have two targeting arms that bind to the same target antigen, bispecific an- tibodies are engineered hybrid molecules with two distinct binding domains that target two distinct antigens. Bispecific T-cell engagers (BiTEs) bind si- multaneously to a selected antigen on cancer cells and to the invariant component of the T-cell recep- tor complex, a CD3 chain with signalling capacity (Figure 1).14 For example, one arm of glofitamab binds to the CD3 on T-cells and another arm to the CD20 on B-cell lymphoma cells (Table 2). BiTEs are approved for use in patients with relapsed and/or refractory B-cell lymphomas, MM and uveal mela- noma (Table 2). Similar to CAR T-cells, targeting of cancer cells with BiTEs is independent of the MHC. T-cell engagement is dependent on repeated administration of the BiTEs. Premedication with systemic corticosteroids and step-up dosing reduc- es the risk of severe immune-related toxicities with BiTEs that are described below. It is recommended that within a step-up phase of treatment patients are hospitalized or at least remain within the prox- imity of a healthcare facility for a short time after the administration of a BiTE.14,15 The cytokine release syndrome (CRS) or cy- tokine storm is a result of activated T-cells, other immune cells and vascular endothelial cells, TABLE 2. Approved CAR T cell therapies and bispecific T cell engagers in the European Union Agent Type of therapy Target Indications Tisagenlecleucel (Kymriah) CAR T CD19 B-cell acute lymphoblastic leukaemia, Diffuse large B-cell lymphoma, Follicular lymphoma Axicabtagene ciloleucel (Yescarta) CAR T CD19 Primary mediastinal large B-cell lymphoma, Diffuse large B-cell lymphoma, High grade B-cell lymphoma, Follicular lymphoma Brexucabtagene autoleucel (Tecartus) CAR T CD19 Mantle-cell lymphoma, B-cell acute lymphoblastic leukaemia Lisocabtagene maraleucel (Breyanzi) CAR T CD19 Follicular lymphoma grade 3B, Primary mediastinal large B-cell lymphoma, Diffuse large B-cell lymphoma Idecabtagene vicleucel (Abecma) CAR T BCMA Multiple myeloma Ciltacabtagene autoleucel (Carvykti) CAR T BCMA Multiple myeloma Talquetamab (Talvey) BiTE GPRC5D/CD3 Multiple myeloma Teclistamab (Tecvayli) BiTE BCMA/CD3 Multiple myeloma Glofitamab (Columvi) BiTE CD20/CD3 Diffuse large B-cell lymphoma Mosunetuzumab (Lunsumio) BiTE CD20/CD3 Follicular lymphoma Tebentafusp (Kimmtrak) BiTE Gp100/CD3 Uveal melanoma Teclistamab (Tecvayli) BiTE BCMA/CD3 Multiple myeloma BCMA = B-cell maturation antigen; BiTE = bispecific T cell engager; CAR T = chimeric antigen receptor T-cells; CD3 = cluster of differentiation 3; CD19 = cluster of differentiation 19; CD20 = cluster of differentiation 20; GP100 = G protein 100; GPRC5D = G protein-coupled receptor, class C, group 5, member D Radiol Oncol 2024; 58(2): 170-178. Blaz Kovac M and Seruga B / Potentially fatal complications of systemic anticancer therapies174 which results in the overproduction of inflamma- tory cytokines. It typically manifests in the first week after therapy, rarely later.16 While some pa- tients experience mild, flu-like symptoms others may experience more severe and potentially life- threating complications similar to septic shock and multi-organ failure. CRS usually presents with a fever which may not respond to antipyretics, and hypotension, headache, hypoxia, rash and organ dysfunction.17 In contrast to CRS, immune cell- associated neurologic syndrome (ICANS) is less frequent than CRS. It usually manifests around seven days after administration of therapy, rarely several weeks later, and it is often associated with preceding CRS. Patients with ICANS may present with an altered level of consciousness, aphasia, im- pairment of cognitive skills, motor weakness, sei- zures, and cerebral oedema.17,18 The pathophysiol- ogy of ICANS is associated with the accumulation of pro-inflammatory cytokines and CAR T-cells in the central nervous system, together with the ac- tivation of resident glial cells.19 The T-cell engag- ing therapies are not only associated with CRS and ICANS, but can also cause various hematologic toxicities, including haemophagocytic lymphohis- tiocytosis (HLH), prolonged myelosuppression, coagulopathies and tumor lysis syndrome (TLS).20 Presentation of HLH may be similar to CRS and is characterized by a fever, cytopenia, spleno- megaly, jaundice, and the pathologic finding of haemophagocytosis in bone marrow and other tis- sues. CRS usually precedes HLH by a few days but in rare cases HLH can develop weeks after resolu- tion of the CRS.21 When toxicity of T-cell engagers is suspected a treating haematologist/oncologist should be consulted and the patient should be admitted to the hospital, preferably to the cancer centre. Mild CRS and ICANS are often self-limited with proper supportive care but can rapidly pro- gress into life-threatening conditions, which may require management in the intensive care unit (ICU). Patients with these complications require close vigilance and prompt pharmacological treat- ment when there is no adequate response to sup- portive care and/or in the case of moderate or se- vere symptoms (grade ≥ 2) (Table 4).18-21 Supportive care includes antipyretics, intravenous hydration and symptomatic management of organ toxicities and constitutional symptoms in patients with CRS and intravenous hydration and aspiration precau- tions in patients with ICANS. When there is a com- bination of fever and hypotension, which does not require vasopressors (i.e. grade 2) CRS should be managed with the IL-6R antagonist tocilizumab (Figure 2). Although there is limited experience with additional therapies, alternate IL-6R antago- nists such siltuximab and clazakizumab or the IL-1 receptor antagonist anakinra may be used for CRS refractory to tocilizumab.22-23 Systemic corti- costeroids should be added only in refractory, pro- longed, or higher-grade CRS. Patients with moder- ate symptoms of ICANS and/or mild somnolence awakening to voice (i.e. grade 2) should be treated with systemic corticosteroids (e.g. dexametha- sone 10 mg bid). In severe cases initial high-dose pulse corticosteroids (e.g. methylprednisolone/day 500−1000 mg of for three days) are recommended. When ICANS and CRS occur concurrently tocili- zumab should be used with caution as it can lead to deterioration of ICANS (Figure 2).22 The corner- stones of treatment of HLH are corticosteroids and an IL-6R antagonist. Both of these are contraindi- cated in patients with severe infection and under- line the importance of arriving at a clear diagnosis prior to the initiation of treatment. In severe cases of HLH additional therapy with etoposide should FIGURE 2. Management of toxicities of immunotherapy. BiTE = bispecific T-cell engager; CAR = chimeric antigen receptor; CRS = cytokine release syndrome; HLH = haemophagocytic lymphohistiocytosis; ICANS = immune effector-cell associated neurotoxicity syndrome; ICI = immune checkpoint inhibitor; irAE = immune-related adverse events Radiol Oncol 2024; 58(2): 170-178. Blaz Kovac M and Seruga B / Potentially fatal complications of systemic anticancer therapies 175 be considered.24 Prolonged cytopenias can be treat- ed with growth factor support and corticosteroids, and infections due to prolonged B-cell aplasia with infusion of IVIGs. Management of disseminated intravascular coagulation (DIC) is supportive, in the case of severe DIC corticosteroids and an IL-6R antagonist can be used.22 Antibody-drug conjugates Antibody-drug conjugates (ADCs) have been de- scribed as ‘magic bullets’ of cancer treatment. The rationale behind the design of ADCs is to achieve targeted delivery of cytotoxic molecules by link- ing them to antibodies targeting tumour-specific antigens with the expectation of less toxicity than conventional chemotherapy (Figure 1). For exam- ple, enfortumab vedotin is a nectin-4-directed antibody and microtubule inhibitor monomethyl auristatin E conjugate. The use of antibody-drug conjugates (ADCs) is expanding rapidly, with development moving progressively from lym- phomas and leukaemias to various solid cancers, and from monotherapy to combination strategies (Table 5).25,26 Despite their very promising design most of the currently-approved ADCs can cause severe and potentially life-threatening toxicities. Each com- ponent of the ADC, including the antibody, linker, and cytotoxic payload, may affect the extent of the ADC-induced toxicities (Table 5).27 Apart from myelosuppression, infections and TLS other im- portant toxicities of these agents are interstitial lung disease (ILD)/ pneumonitis, liver failure and skin toxicity (Table 5). Clinical symptoms of ILD/ pneumonitis are generally nonspecific, including dyspnoea, cough and fever and can mimic infec- tious pneumonia. As pneumonitis can rapidly progress to a life-threatening condition, early con- sultation with the oncologist and the pulmonolo- gist is recommended. The aim of management of ADC-related pneumonitis is to suppress inflam- mation and prevent the build-up of irreversible lung fibrosis. Therefore, the cornerstone of treat- ment of symptomatic (i.e. grade ≥ 2) ILD/pneumo- nitis is treatment with systemic corticosteroids (e.g. methylprednisolone 1−2 mg/kg/day) (Table 3). In very severe cases initial high-dose pulse corti- costeroids (e.g. methylprednisolone 500−1000 mg/ day for three days) is recommended. To prevent deterioration of ILD/ pneumonitis systemic corti- costeroids may be considered even in patients with asymptomatic (i.e. grade 1) ILD/pneumonitis who have only radiologic changes in their lung. Other immunosuppressive agents are recommended in refractory cases.28 The Steven-Johnson syndrome and toxic epidermal necrolysis are two forms of the same life-threatening skin disorder which cause rash, skin peeling, and sores of the mucous membranes. Treatment includes fluid replacement and nutrition, wound care, eye care, pain medi- TABLE 3. Grades 2 and 3 of the selected immune-related adverse events (irAEs) irAE Grade 2 Grade 3 Maculo-papular rash Papules and/or pustules covering 10−30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL; papules and/ or pustules covering > 30% BSA with or without mild symptoms Papules and/or pustules covering > 30% BSA with moderate or severe symptoms; limiting self-care ADL; associated with local superinfection with oral antibiotics indicated Diarrhoea/enterocolitis Increase of 4−6 stools/day over baseline Increase of ≥ 7 stools/day over baseline ILD/Pneumonitis Symptomatic (presence of new or worsening symptoms: dyspnoea, cough), medical intervention indicated, limiting instrumental ADL Severe symptoms, oxygen indicated, limiting self-care ADL Rheumatologic toxicity Moderate pain, stiffness and/or weakness limiting instrumental ADL Severe pain, stiffness and/or weakness limiting self- care ADL Neuro-muscular toxicity Moderate pain associated with weakness, limiting instrumental ADL Pain associated with severe weakness, limiting self- care ADL Hepatotoxicity ALT or AST 3−5 x ULN ALT > 5 x or AST < 20 x ULN Renal toxicity Serum creatinine >1.5−3 x above the baseline or the UNL, KDIGO stage 2: increase in serum creatinine 2−2.9 x above the baseline Serum creatinine > 3 x above the baseline or > 3−6 x ULN, KDIGO stage 3: increase in serum creatinine > 3 x or to > 4.0 mg/dl or initiation of dialysis ALT = alanine transaminase; ADL = activities of daily living; AST = aspartate aminotransferase; BSA = body surface area; ILD = interstitial lung disease; KDIGO = kidney disease improving global outcomes; ULN = upper limit normal Radiol Oncol 2024; 58(2): 170-178. Blaz Kovac M and Seruga B / Potentially fatal complications of systemic anticancer therapies176 cation, medication to reduce inflammation of the eyes and mucous membranes, antibiotics to con- trol infection systemic high-dose corticosteroids and IVIGs. Patients with these disorders usually require admission to the ICU.29 Conclusions The armamentarium of new systemic anticancer therapies is expanding rapidly. Clinical presenta- tion of potentially fatal complications of these new TABLE 4. Grades of the cytokine release syndrome (CRS) and the immune cell-associated neurologic syndrome ICANS Toxicity Grade 1 Grade 2 Grade 3 Grade 4 CRS Fever: ≥ 38°C Hypotension: none Hypoxia: none Fever: ≥ 38°C AND Hypotension: not requiring vasopressor AND/OR Hypoxia Fever: ≥ 38°C AND Hypotension: requiring vasopressor AND/OR Hypoxia Fever: ≥ 38°C AND Hypotension requiring multiple vasopressors AND/ OR Hypoxia requiring positive pressure ICANS ICE score: 7−9 No depressed level of consciousness ICE score: 3−6 AND/OR Mild somnolence awaking to voice ICE score: 0−2 AND/ OR Depressed level of consciousness awakening only to tactile stimulus AND/ OR clinical seizure focal or generalized that resolve with intervention AND/OR Focal or local oedema on neuroimaging ICE sore: 0 AND/OR Stupor or coma AND/OR Life- threatening prolonged seizure AND/OR Diffuse cerebral oedema on neuroimaging, decerebrate or decorticate posturing or papilledema, cranial nerve VI palsy, or Cushing’s triad Immune effector cell-associated encephalopathy (ICE) assessment tool: (A) Orientation: orientation to year, month, city, and hospital: 4 points. (B) Naming: ability to name three objects: 3 points. (C) Following commands: ability to follow simple commands: 1 point. (D) Writing: ability to write a standard sentence: 1 point. (E) Attention: ability to count backward from 100 by 10: 1 point TABLE 5. Approved antibody drug conjugates in the European union and their potentially fatal toxicities Antibody drug conjugate Target/ cytotoxic agent Indication Potentially fatal complications Belantamab mafodotin (Blenrep) BCMA/ mcMMAF Multiple myeloma Pneumonitis Thrombocytopenic bleeding Brentuximab vedotin (Adcetris) CD30/ MMAE Hodgkin and non-Hodgkin lymphoma Progressive multifocal encephalopathy (reactivation of JCV) Pancreatitis ILD/Pneumonitis/ ARDS Serious infections/Opportunistic infections Severe skin reactions (SJS, TEN) Liver failure Tumor lysis syndrome Gemtuzumab ozogamicin (Mylotarg) CD33/ ozogamicin AML Liver failure (VOD/SOS) Myelosuppression Tumour lysis syndrome Inotuzumab ozogamicin (Besponsa) CD22/ ozogamicin B-cell ALL Liver failure (VOD/SOS) Myelosuppression Tumor lysis syndrome Loncastuximab tesirine (Zynlonta) CD19/ PBD DLCBCL Opportunistic infections Oedema and effusions Polatuzumab vedotin (Polivy) CD79b/ MMAE DLCBCL Neutropenic infection Opportunistic infection Progressive multifocal encephalopathy Tumor lysis syndrome Enfortumab vedotin (Padcev) Nectin-4/ MMAE Advanced urothelial carcinoma Severe skin reactions (SJS, TEN) ILD/Pneumonitis Hyperglycaemia/Diabetic ketoacidosis Trastuzumab deruxtecan (Enhertu) HER-2/ Dxd Advanced breast, non-small cell lung and gastric cancer Pneumonitis/ILD Neutropenic infection Trastuzumab emtansine (Kadcyla) HER-2/ Emtansine Early and advanced breast cancer Liver failure Haemorrhagic events ILD/Pneumonitis Sacituzumab govitecan (Trodelvy) Trop-2/ SN-38 Advanced breast cancer Neutropenic infection Severe diarrhoea ALL = acute lymphoblastic leukaemia; AML = acute myeloid leukaemia; ARDS = adult respiratory distress syndrome; BCMA = B-cell maturation antigen; CD = cluster of differentiation; DLCBCL = diffuse large cell B-cell lymphoma; Dxd = an exatecan derivative and a topoisomerase I inhibitor; HER-2 = human epidermal growth factor receptor 2; ILD = interstitial lung disease; JCV = John Cunningham virus; mcMMAF = maleimidocaproyl monomethyl auristatin F; MMAE = monomethyl auristatin E; PBD = pyrrolobenzodiazepine; SN-38 = 7-ethyl-10 hydroxycamptothecin; SJS = Steven-Johnson syndrome; TEN = toxic epidermal necrolysis; Trop-2 = trophoblast cell surface antigen 2; VOD/SOS = hepatic veno-occlusive disease/sinusoidal obstruction syndrome Radiol Oncol 2024; 58(2): 170-178. Blaz Kovac M and Seruga B / Potentially fatal complications of systemic anticancer therapies 177 therapies may be unpredictable and nonspecific and can mimic common medical conditions such as infections. Moreover, if not recognized and properly treated they can progress rapidly to life- threatening conditions. Patents with cancer who during their treatment develop acute illnesses may also present to GPs and EPs for initial workup. Therefore, it is very important that they are edu- cated about side effects of new systemic anticancer therapies. Beside supportive care the mainstay of treatment of potentially severe toxicities of ICIs, CAR T-cells, BiTEs and sometimes of ADCs is sys- temic glucocorticoids and other immunosuppres- sive agents. In general, immunosuppressive ther- apy should start as soon as symptoms are mild- moderate. In patients with severe symptoms who require prompt immunosuppressive treatment concurrent empirical antimicrobial therapy may be started and continued until infectious cause of the acute illness is excluded. A multidisciplinary team involving a treating oncologist/haematolo- gist and the corresponding organ-site specialist should be involved in the diagnosis and treatment of these treatment-related toxicities. In the chang- ing landscape of oncology an establishment of cancer-specific urgent care centres might have an important role in the management of acutely ill pa- tients with cancer.30 Acknowledgments This work was supported by the Slovenian Research and Innovation Agency (ARIS), grant P3- 0321. References 1. Bischof JJ, Presley CJ, Caterino JM. Addressing new diagnostic and treat- ment challenges associated with a new age of cancer treatment. Ann Emerg Med 2019; 73: 88-90. doi: 10.1016/j.annemergmed.2018.08.421 2. Mayer DK, Travers D, Wyss A, Leak A, Waller A. Why do patients with cancer visit emergency departments? Results of a 2008 population study in North Carolina. J Clin Oncol 2011; 29: 2683-8. doi: 10.1200/JCO.2010.34.2816 3. Lewis MA, Hendrickson WA, Moynihan TJ. Oncologic emergencies: patho- physiology, presentation, diagnosis, and treatment. CA Cancer J Clin 2011; 61: 287-314. doi: 10.3322/caac.20124 4. Alahmadi A, Altamimi H, Algarni M. Evaluation of knowledge of immuno- therapy toxicities among emergency physicians in Riyadh, Saudi Arabia. Cureus 2022; 14: e30325. doi: 10.7759/cureus.30325 5. Higdon ML, Higdon JA. Treatment of oncologic emergencies. Am Fam Physician 2006; 74: 1873-80. PMID: 17168344 6. Pardoll DM. The blockade of immune checkpoints in cancer immunothera- py. Nat Rev Cancer 2012; 12: 252-64. doi: 10.1038/nrc3239 7. Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol 2016; 27: 559-74. doi: 10.1093/ annonc/mdv623 8. Palaskas N, Lopez-Mattei J, Durand JB, et al. Immune checkpoint inhibitor myocarditis: pathophysiological characteristics, diagnosis, and treatment. J Am Heart Assoc 2020; 9: e013757. doi: 10.1161/JAHA.119.013757 9. Müller-Jensen L, Zierold S, Versluis JM, Boehmerle W, Huehnchen P, Matthias Endres M, et al. Characteristics of immune checkpoint inhibitor- induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis: a retrospective multicentre cohort study. Eur J Cancer 2022; 175: 224-35. doi: 10.1016/j.ejca.2022.08.009 10. Haanen J, Obeid N, Spain L, Carbonnel F, Wang Y, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2022; 33: 1217-38. doi: 10.1016/j.annonc.2022.10.001 11. Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells express- ing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol 2013; 10: 267-76. doi: 10.1038/nrclinonc.2013.46 12. Mikkilineni L, Kochenderfer JN. CAR T cell therapies for patients with multiple myeloma. Nat Rev Clin Oncol 2021; 18: 71-84. doi: 10.1038/ s41571-020-0427-6 13. Kish J, Liu R, Pfeffer D, Vennam S, Lussier C, Nayak P. Real-world duration of hospitalization for CAR-T treatment: U.S. patient experience in multiple hematologic malignancies. [abstract]. Annual Meeting of the American- Society-of-Clinical-Oncology (ASCO). J Clin Oncol 2023; 41(Suppl S): e18896. doi: Goebeler ME, Bargou RC. T cell-engaging therapies - BiTEs and beyond. Nat Rev Clin Oncol 2020; 17: 418-34. doi: 10.1038/s41571-020-0347-5 14. Ball K, Dovedi SJ, Vajjah P, Phipps A. Strategies for clinical dose optimization of T cell-engaging therapies in oncology. mAbs 2023; 15: 2181016. doi: 10.1080/19420862.2023.2181016 15. Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020; 383: 2255-73. doi: 10.1056/NEJMra2026131 16. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic tox- icity associated with immune effector cells. Biol Blood Marrow Transplant 2019; 25: 625-38. doi: 10.1016/j.bbmt.2018.12.758 17. Hernani R, Benzaquén A, SolanC. Toxicities following CAR-T therapy for hematological malignancies. Cancer Treat Rev 2022: 111: 102479. doi: 10.1016/j.ctrv.2022.102479 18. Morris EM, Neelapu SS, Giavridis T, Sadelain M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol 2022; 22: 85-96. doi: 10.1038/s41577-021-00547-6 19. Rejeski K, Subklewe M, Locke FL. Recognizing, defining, and managing CAR-T hematologic toxicities. Hematology Am Soc Hematol Educ Program 2023; 2023: 198-208. doi: 10.1182/hematology.2023000472 20. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy - assessment and manage- ment of toxicities. Nat Rev Clin Oncol 2018; 15: 47-62. doi: 10.1038/ nrclinonc.2017.148. 21. Santomasso BD, Nastoupil LJ, Adkins S, Lacchetti C, Schneider BJ, Anadkat M, et al. Management of immune-related adverse events in patients treated with chimeric antigen receptor T-cell therapy: ASCO Guideline. J Clin Oncol 2021; 39: 3978-92. doi: 10.1200/JCO.21.01992 22. Strati P, Ahmed S, Kebriaei P, Nastoupil LJ, Claussen CM, Watson G, et al. Clinical efficacy of anakinra to mitigate CAR T-cell therapy-associated toxic- ity in large B-cell lymphoma. Blood Adv 2020; 4: 3123-7. doi: 10.1182/ bloodadvances.2020002328 23. Rosée PL, Horne AC, Hines M, von Bahr Greenwood T, Machowicz R, Berliner N, et al. Recommendations for the management of hemophago- cytic lymphohistiocytosis in adults. Blood 2019; 133: 2465-77. doi: 10.1182/ blood.2018894618 24. Drago JZ, Modi S, Chandarlapaty S. Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat Rev Clin Oncol 2021; 18: 327-44. doi: 10.1038/s41571-021-00470-8 25. Tsuchikama K, Anami Y, Ha SYY, Yamazaki CM. Exploring the next genera- tion of antibody-drug conjugates. Nat Rev Clin Oncol 2024; 21: 203-23. doi: 10.1038/s41571-023-00850-2 Radiol Oncol 2024; 58(2): 170-178. Blaz Kovac M and Seruga B / Potentially fatal complications of systemic anticancer therapies178 26. Tarantino P, Ricciuti B, Pradhan SM. Optimizing the safety of antibody-drug conjugates for patients with solid tumours. Nat Rev Clin Oncol 2023; 20: 558-76. doi: 10.1038/s41571-023-00783-w 27. Rugo HS, Crossno CL, Gesthalter YB, Kelley K, Moore HB, Rimawi MF, et al. Real-world perspectives and practices for pneumonitis/interstitial lung disease associated with trastuzumab deruxtecan use in human epidermal growth factor receptor 2-expressing metastatic breast cancer. JCO Oncol Pract 2023; 19: 539-46. doi: 10.1200/OP.22.00480 28. Lacouture ME, Patel AB, Rosenberg JE, Peter H O’Donnell. Management of dermatologic events associated with the nectin-4-directed antibody-drug conjugate enfortumab vedotin. Oncologist 2022; 27: e223-32. doi: 10.1093/ oncolo/oyac001 29. Cooksley T, Rice T. Emergency oncology: development, current position and future direction in the USA and UK. Support Care Cancer 2017; 25: 3-7. doi: 10.1007/s00520-016-3470-1