Neurologic complications of cancer treatment with molecularly targeted and biologic agents

INTRODUCTION — Neurologic complications of anticancer therapy may result from direct toxic effects on the nervous system, or indirectly from drug-induced metabolic derangements or cerebrovascular disorders, or, in the case of ipilimumab, autoimmune disorders. Their recognition is important because of potential confusion with metastatic disease, paraneoplastic syndromes or comorbid neurologic disorders that do not require dose reduction or discontinuation. If the neurologic disorder is caused by the chemotherapy, discontinuation of the offending agent may prevent irreversible injury.

Here we discuss the neurologic complications associated with molecularly targeted and biologic agents, including both biologic response modifiers and therapeutic monoclonal antibodies. The neurologic complications associated with conventional cytotoxic chemotherapy agents and chimeric antigen receptor (CAR) T-cell therapies are discussed elsewhere. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Overview of neurologic complications of platinum-based chemotherapy".)

BIOLOGIC RESPONSE MODIFIERS — Until recently, biologic response modifiers were often used in combination with conventional chemotherapeutic agents (biochemotherapy) for a number of cancers. However, these regimens have largely been replaced with newer targeted agents and immunotherapies in most cancers.

Interferon — Interferon alfa (IFNa) is occasionally used to treat hairy cell leukemia, Kaposi sarcoma, melanoma, and chronic myeloid leukemia (CML). IFNa is associated with a variety of substantial toxicities, which may limit the ability to deliver a full course of therapy [1]. Frequent systemic toxicities include flu-like symptoms (myalgias, nausea, vomiting, arthralgias, fever, chills, and headache) and depression. The flu-like symptoms tend to be worse at the onset of therapy and usually improve with time.

Neurotoxicity tends to be dose-related. It is generally mild when low doses of IFNa are used, as in the adjuvant setting for patients with malignant melanoma. In a detailed evaluation of 37 such patients treated with IFNa, the most frequent neurotoxicity was tremor, observed in eight cases (22 percent) [2]. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Adjuvant therapies not commonly used'.)

At higher doses, such as those used for patients with advanced melanoma, IFNa can cause confusion, lethargy, hallucinations, and seizures [3,4]. Although these effects are usually reversible, a permanent dementia or persistent vegetative state may result [4].

More commonly, patients develop a depressive syndrome over weeks to months. Neuropsychiatric symptoms are usually mild to moderate and typically resolve within two to three weeks of IFN discontinuation [5]. Cognitive impairments involving memory, processing speed, and executive functioning have also been reported in some studies of cancer patients receiving IFNa [6,7] but not in others [2,8].

Rarely, IFNa has been associated with oculomotor palsy, sensorimotor neuropathy [9], myasthenia gravis [10], brachial plexopathy, an action tremor [11], and polyradiculopathy [12].

There were two available preparations of IFNa (2a and 2b), but interferon alfa-2b has been discontinued worldwide.

The side effect profile of pegylated preparations of IFNa 2a, which have a longer half-life, are similar to those observed with standard IFNa-2a except that in some studies, neutropenia and thrombocytopenia are slightly more severe [13]. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection", section on 'Adverse reactions'.)

Interleukin 2 — Interleukin 2 (IL-2) has been used both alone and in several biochemotherapy combinations, both with and without IFN, for a number of cancers, particularly renal cell carcinoma and melanoma. (See "Systemic therapy of advanced clear cell renal carcinoma" and "Interleukin 2 and experimental immunotherapy approaches for advanced melanoma" and "Interleukin 2 and experimental immunotherapy approaches for advanced melanoma", section on 'Toxicity'.)

Toxicity is dose-dependent. Neuropsychiatric complications, which occur in up to 30 to 50 percent of patients, include cognitive changes, delusions, hallucinations, and depression [14]. Confusion may be a dose-limiting effect of high-dose IL-2 regimens, but it is rarely seen with combination biochemotherapy regimens [15]. Symptoms typically resolve upon termination of treatment [16].

Less commonly, transient focal neurologic deficits [17], acute leukoencephalopathy, carpal tunnel syndrome, myositis [18], myasthenia gravis [19], and brachial neuritis [20] have been reported with IL-2. Administration of IL-2 directly into the tumor bed (with lymphokine-activated killer [LAK] cells) for the treatment of gliomas can cause significant cerebral edema, and neurotoxicity appears to be dose-limiting [21,22].

One case of grade 5 neurotoxicity has been reported in a patient treated with IL-2 and granulocyte macrophage colony-stimulating factor (GM-CSF). This patient experienced a fatal cerebral hemorrhage associated with thrombocytopenia, leading the authors to recommend extreme caution in using these agents together [23]. Others have not reported excessive neurotoxic effects in patients treated with both agents [24,25].

Tumor necrosis factor — Systemic administration of tumor necrosis factor-alpha (TNF-a) is limited by toxicity; neurologically, these effects include encephalopathy, transient aphasia, or other focal deficits [26]. As a result, the use of TNF-a in patients with cancer is limited to isolated limb perfusion for patients with advanced sarcoma or melanoma. Isolated limb perfusion with TNF-a is associated with a mild sensory neuropathy that typically begins two to three weeks after perfusion and generally abates after eight weeks [27]. (See "Cutaneous melanoma: In-transit metastases" and "Cutaneous melanoma: Management of local recurrence" and "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities".)

MONOCLONAL ANTIBODIES AND ANTIBODY-DRUG CONJUGATES

Alemtuzumab — Alemtuzumab is a humanized monoclonal antibody that targets CD52 and is approved for the treatment of B-cell chronic lymphocytic leukemia. Similar to rituximab, progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with this agent [28].

Bevacizumab — Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) used in the treatment of a variety of cancers. Several clinical trials of bevacizumab or one of its biosimilars combined with chemotherapy suggest a significant increase in the risk of serious arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, and myocardial infarction). (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Bevacizumab and aflibercept'.)

Reversible posterior leukoencephalopathy syndrome (RPLS) occurs in less than 0.1 percent of patients treated with bevacizumab or one of its biosimilars. Symptoms can include headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. RPLS may be associated with mild to severe hypertension. The onset may occur from 16 hours to one year after initiation of therapy. Symptoms usually resolve with discontinuation of bevacizumab and control of any associated hypertension. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Reversible posterior leukoencephalopathy and brain capillary leak syndrome' and "Reversible posterior leukoencephalopathy syndrome".)

Bevacizumab increases the risk for bleeding, and concerns have been raised about a potential increase in the risk of intracerebral hemorrhage in patients treated with bevacizumab who have brain metastases or primary brain tumors. However, the available data suggest that rates of serious hemorrhage are low. Patients with a history of treated nonhemorrhagic brain metastases probably should not be excluded from systemic therapy with bevacizumab or other angiogenic therapies as long as they are not on concurrent anticoagulation. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Intracranial bleeding'.)

The decision to use bevacizumab in an anticoagulated patient with a recurrent primary brain tumor is more complex and must be based upon a careful assessment of the risk to benefit ratio. This subject is discussed in detail elsewhere. (See "Management of recurrent high-grade gliomas", section on 'Side effects'.)

Rarely, severe optic neuropathy has been reported in brain tumor patients after bevacizumab treatment [29]. In a case series of six patients, all had previously received standard chemoradiation, with radiation doses to the optic apparatus that were limited to those generally considered within tolerance levels.

Cetuximab — Cetuximab is a chimeric mouse-human antibody against epidermal growth factor that is used in the treatment of head and neck cancer as well as colorectal cancer. In a study of 420 patients with advanced colorectal cancer who received cetuximab monotherapy, 26 percent developed headaches [30]. Patients on cetuximab may develop symptomatic hypomagnesemia, which may lead to severe fatigue, cramps, and somnolence. (See "Nephrotoxicity of molecularly targeted agents and immunotherapy", section on 'EGFR inhibitors'.)

Cases of aseptic meningitis have also been reported in association with cetuximab [31-33].

Brentuximab — Brentuximab vedotin is a CD30-directed antibody-drug conjugate that is used for treatment of certain CD30-positive lymphomas. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma" and "Treatment of relapsed or refractory peripheral T cell lymphoma", section on 'Brentuximab'.)

In clinical trials, 36 to 69 percent of patients treated with brentuximab developed a peripheral neuropathy of any grade; approximately 4 to 14 percent had severe (grade 3 or 4 (table 1)) neuropathy [34-39]. The peripheral neuropathy was mainly sensory and cumulative, but motor neuropathy was also reported.

Neuropathy is reversible in approximately two-thirds of patients with long-term follow-up. In the ESCHELON-1 trial of 1334 patients with Hodgkin lymphoma, 72 percent of patients who developed neuropathy of any grade had complete resolution with median follow-up of 61 months [40]. Fourteen percent had partial resolution, and 14 percent had ongoing neuropathy without improvement. The median times to partial and complete resolution were 2.9 and 6.6 months, respectively.

The US Food and Drug Administration (FDA)-approved manufacturer's labeling recommends that dosing of brentuximab be held for new or worsening grade 2 or 3 (table 1) neuropathy, held until improvement to grade 1, then restarted at a lower dose; the drug should be discontinued for grade 4 neuropathy.

Rare reports of PML prompted the FDA to add a boxed warning regarding this complication in January 2012. In addition, there is a single report documenting 11 cases of inflammatory demyelinating polyradiculoneuropathy consistent with Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy in patients treated with brentuximab [41]. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis" and "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis".)

Bispecific T cell engagers

●Blinatumomab – Blinatumomab is a bispecific T cell engager monoclonal antibody directed at both CD19 on precursor B-cell acute lymphoblastic leukemia (ALL) tumor cells and CD3 on cytotoxic T cells that has activity in the treatment of Philadelphia chromosome (Ph)-negative relapsed or refractory B-cell precursor ALL. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Blinatumomab'.)

Blinatumomab is administered by continuous intravenous infusion over four weeks followed by a two-week treatment-free interval. Patients are hospitalized around the time of infusion initiation to monitor for signs and symptoms of cytokine release syndrome and neuropsychiatric toxicities, including seizures. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Blinatumomab'.)

Neurotoxicity is commonly observed after blinatumomab. A wide range of symptoms have been described, ranging from headache and tremor to more severe encephalopathy, referred to as immune effector cell-associated neurotoxicity syndrome (ICANS). Prescribing information for blinatumomab contains recommendations for dose reduction and/or discontinuation based upon the neurotoxicity severity. Recognition and treatment of ICANS are discussed separately. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

●Teclistamab – Teclistamab is a bispecific T cell engager monoclonal antibody directed at both B cell maturation antigen (BCMA) on multiple myeloma tumor cells and CD3 on the patient’s T-cells. It is approved in the United States for treatment of refractory multiple myeloma. (See "Multiple myeloma: Treatment of third or later relapse", section on 'Bispecific antibodies'.)

Prescribing information carries warnings for ICANS, which is seen in over 50 percent of patients. Recognition and treatment of ICANS are discussed separately. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

Enfortumab vedotin — Enfortumab vedotin is a nectin-4-directed monoclonal antibody microtubule inhibitor drug conjugate that is approved for metastatic refractory urothelial cancer. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

In the initial clinical trial of 125 patients treated with enfortumab vedotin, peripheral sensory neuropathy developed in 50 (40 percent), but it was severe (grade 3 or 4) in only two (2 percent) [42]. A similar frequency was reported in an expanded set of 310 patients treated with the drug (50 percent any grade, 2 percent grade 3) [43]. The median time to onset of grade 2 or worse neuropathy was 3.8 months. Of the patients who developed neuropathy, at the time of the last evaluation, 19 percent had resolved completely, and 26 percent had partial improvement. The prescribing information for enfortumab suggests withholding the drug for grade 2 or worse symptoms.

Polatuzumab — Polatuzumab vedotin is an antibody-drug conjugate containing the antimicrotubule agent monomethyl auristatin E that is approved in combination with bendamustine and rituximab for treatment of relapsed or refractory diffuse large B-cell lymphoma. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Polatuzumab/bendamustine/rituximab'.)

Polatuzumab can cause a predominantly sensory peripheral neuropathy, which is usually mild, but can be severe [44]. It can occur as early as the first cycle of therapy, and is cumulative. In one study of 173 patients treated with polatuzumab plus bendamustine and rituximab, 40 percent reported new or worsening neuropathy, which was grade 1 in 26 percent, grade 2 in 12 percent, and grade 3 in 2.3 percent [45].

Rituximab — Rituximab is a humanized monoclonal antibody directed against the CD20 antigen that is found on the surface of normal and malignant B lymphocytes. It is used for the treatment of low-grade or follicular B-cell lymphoma, as well as other disorders where B lymphocytes are involved in disease pathogenesis. Neurologic complications are uncommon, but some patients complain of headaches, myalgias, dizziness [46,47], or paresthesias [48]. (See "Initial treatment of stage I follicular lymphoma".)

Rare cases of PML have been reported in patients being treated with rituximab [49]. In a review of 57 patients who developed PML after rituximab, all patients had received prior therapies with alkylating agents, corticosteroids, purine analogs, or drugs to prevent allogeneic stem cell or solid organ graft rejection. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

In addition, rituximab has been associated with RPLS [50]. (See "Reversible posterior leukoencephalopathy syndrome".)

Intrathecal (IT) rituximab is also reasonably well-tolerated. In a phase I study, none of the five patients treated at the maximum tolerated IT dose of 25 mg exhibited toxicity. The dose-limiting toxicity at 50 mg was grade 3 hypertension, with one patient experiencing transient diplopia, nausea, and vomiting in the setting of hypertension [51]. However, acute-onset, painful lumbosacral paresthesias have been reported in patients treated with IT rituximab 25 mg via lumbar puncture, occurring immediately after administration of the drug and resolving completely within a few hours [51,52]. There were no neurologic deficits associated with the events or on follow-up.

Tisotumab vedotin — Tisotumab vedotin is a tissue factor-directed antibody and microtubule inhibitor drug-conjugate approved for use for those with recurrent or metastatic cervical cancer with disease progression on, or after, chemotherapy. (See "Management of recurrent or metastatic cervical cancer", section on 'Second-line therapy'.)

Across clinical trials, neurologic toxicity has occurred in 42 percent of patients with cervical cancer treated with tisotumab vedotin; 8 percent experienced grade 3 peripheral neuropathy [53]. Adverse reactions have included peripheral neuropathy (20 percent), which can be both sensory and motor, muscular weakness (3 percent), and demyelinating peripheral polyneuropathy (1 percent). The median time to onset was 2.4 months (range 0 to 11.3 months). Symptoms improved in many patients with discontinuation of therapy. Dose reduction guidelines for neuropathy are included in the companion drug information for tisotumab vedotin.

Tositumomab radioconjugate — Tositumomab radioconjugate (Iodine-131 tositumomab) is one of several anti-CD-20 radioimmunoconjugates used in the treatment of indolent non-Hodgkin lymphoma. These agents deliver targeted radiotherapy to tumor-bearing areas. A minority of treated patients experience headache or myalgias during treatment [54,55]. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Radioimmunotherapy'.)

Trastuzumab — Trastuzumab is a humanized anti-HER2 monoclonal antibody that is used either alone or in combination with cytotoxic agents for the treatment of HER2-overexpressing breast cancer in the metastatic and adjuvant settings. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer" and "Systemic treatment for HER2-positive metastatic breast cancer".)

A few patients experience headaches, dizziness, and insomnia after infusion of the antibody [56]. Paresthesias and peripheral neuropathy are even less common.

Ado-trastuzumab emtansine — Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that incorporates trastuzumab with the cytotoxic microtubule inhibitor DM1. It is approved for advanced breast cancer in patients previously exposed to trastuzumab and taxanes. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Treatment-free interval of less than six months'.)

Peripheral neuropathy, mainly grade 1 and predominantly sensory, has been reported in 21 to 22 percent of treated patients in clinical trials; it was grade 3 or worse in 1.5 to 2.2 percent [57]. The drug should be temporarily discontinued for grade 3 or 4 toxicity until resolution to ≤grade 2.

T-DM1 may be associated with an increase in the risk of central nervous system radiation necrosis and/or cerebral edema from brain metastases treated with stereotactic radiosurgery (SRS). In one retrospective review of 12 patients, the incidence of radiation necrosis was 50 percent for patients who received T-DM1 during SRS and 28.6 percent for patients who discontinued T-DM1 before SRS [58]. In another series of four patients, T-DM1 was associated with significantly increased cerebral edema at sites of prior SRS as evidenced by brain magnetic resonance imaging (MRI) as well as neurologic findings [59]. The time between SRS and T-DM1 infusion ranged from 3 to 449 days.

IMMUNE CHECKPOINT INHIBITORS — Immune checkpoint inhibitors are used in the treatment of multiple cancers; these agents work by blocking the interaction between immune checkpoint proteins on the surface of cytotoxic T cells such as cytotoxic T-lymphocyte-associated-4 (CTLA-4) and programmed cell death protein 1 (PD-1) and their ligands, CD80/CD86 and programmed death-ligand 1 (PD-L1), respectively. Pembrolizumab, nivolumab, and cemiplimab are monoclonal antibodies against PD-1, whereas atezolizumab, avelumab, and durvalumab are monoclonal antibodies against PD-L1. Ipilimumab is a monoclonal antibody directed against CTLA-4 and is used alone or in combination with nivolumab.

Checkpoint inhibitors break down tolerance to the tumor-associated antigens, and this may result in decreased tolerance to self-antigens, leading to immune-related adverse effects (irAEs). The overall incidence of neurologic irAEs in patients treated with ICIs is low overall, with the most common being headache and peripheral sensory neuropathy. More serious neurologic irAEs occur infrequently including motor neuropathy, Guillain-Barré syndrome, myasthenia gravis, encephalitis, aseptic meningitis, transverse myelitis, and lymphocytic hypophysitis causing hypopituitarism. These toxicities are discussed in more detail elsewhere. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Neurologic' and "Toxicities associated with immune checkpoint inhibitors", section on 'Hypophysitis'.)

CAR-T CELL THERAPY — In CAR-T cell therapy, the patient's T cells are collected from blood and modified to express a chimeric antigen receptor (CAR) specific for a tumor antigen, followed by ex vivo expansion and then re-infusion back to the patient. Multiple CAR-T cell immunotherapies are approved by the US Food and Drug Administration to treat certain types of relapsed or refractory B-cell hematologic malignancies. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'CAR-T' and "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Chimeric antigen receptor T cell therapy' and "Multiple myeloma: Treatment of third or later relapse", section on 'Chimeric antigen receptor T cells'.)

Neurotoxicity is a common toxicity observed after CAR-T cell therapy. A wide range of symptoms have been described, ranging from headaches to encephalopathy, also known as immune effector cell-associated neurotoxicity syndrome (ICANS). In addition to ICANS, other neurologic toxicities have also been observed with certain products, including transverse myelitis, Guillain-Barre syndrome, cranial neuropathies, and delayed-onset parkinsonism. ICANS and other neurologic toxicities are discussed in more detail elsewhere. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

NTRK INHIBITORS

Larotrectinib — Larotrectinib, an orally active, highly selective inhibitor of the neurotrophic tyrosine receptor kinase (NTRK) gene, is approved for a variety of solid tumors that have NTRK gene fusions. (See "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease", section on 'Secretory (NTRK gene fusion positive)' and "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'NTRK gene fusion-positive tumors'.)

Neurologic events are common in patients treated with larotrectinib, but most are mild. Among 176 patients who received the drug, neurologic adverse events of any grade occurred in 53 percent, including grade 3 and 4 events in 6 and 0.6 percent, respectively [60]. The majority occurred within the first three months of treatment. Reactions included dizziness, gait disturbance, delirium, memory impairment, and tremor; the grade 3 and 4 events included delirium, dysarthria, dizziness, gait disturbance, paresthesias, and encephalopathy.

Prescribing information for larotrectinib suggests withholding or permanently discontinuing the drug based on severity; if the drug is withheld, the dose should be reduced when treatment is resumed.

Entrectinib — Entrectinib is an oral NTRK/ROS inhibitor approved for solid tumors with NTRK gene fusions as well as ROS1-positive metastatic non-small cell lung cancer. A variety of neurologic events have also been described with entrectinib, including cognitive impairment, mood disorders, dizziness, and sleep disturbances. In 355 patients treated with entrectinib across clinical trials, 27 percent experienced cognitive impairment, although grade 3 events occurred in only 4.5 percent [61]. Prescribing information for entrectinib similarly suggests withholding or permanently discontinuing the drug based on severity; if the drug is withheld, the dose should be reduced when treatment is resumed.

LORLATINIB — Lorlatinib is a third-generation inhibitor of anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinases that is approved for ALK mutation-positive non-small cell lung cancer that is refractory to other ALK inhibitors. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Lorlatinib'.)

An unusual pattern of neurotoxicity has been reported with this agent that appears to be unique compared with other ALK inhibitors. In a phase II trial of 276 patients who received lorlatinib, treatment-related adverse effects included cognitive dysfunction (more forgetful, difficulty with multitasking) in 49 (18 percent), mood effects (typically lability and/or irritability) in 41 (15 percent), speech disturbance (typically difficulty with word finding or slowing of speech) in 20 (7 percent), auditory hallucinations in five, and peripheral neuropathy in 83 (30 percent) [62]. Central nervous system effects of any cause were reported in 107 of the 276 patients overall (39 percent), and they were generally mild (grade 1 or 2) in severity, transient, dose dependent, intermittent, and reversible after dose reduction. The prescribing information for lorlatinib recommends withholding the drug for grade 2 or 3 central nervous system effects, resuming after resolution to grade ≤1 toxicity with a reduced dose, and permanent discontinuation for any grade 4 event.

ORAL SMALL MOLECULE TYROSINE KINASE INHIBITORS

Dasatinib, imatinib, and avapritinib — Some of the orally available small molecule tyrosine kinase inhibitors targeting Bcr-Abl and other tyrosine kinases, such as platelet-derived growth factor receptor (PDGFR; eg, dasatinib, imatinib, avapritinib), have been associated with central nervous system toxicities, including dizziness, insomnia, mood disorders (especially depression), and dysgeusia, most of which are low grade. One of these drugs, avapritinib, an inhibitor of exon 18 mutations in platelet-derived growth factor receptor alfa (PDGFRA), has also been associated with a high frequency of cognitive impairment (48 percent, with 5 percent grade 3 or 4) and with intracranial hemorrhage in 1 to 3 percent of treated patients, either of which might necessitate withholding or discontinuing the drug [63].

Rare causes of neurotoxicity

Ibrutinib — Ibrutinib is a small molecule inhibitor of Bruton tyrosine kinase that is approved for treatment of mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, and chronic graft versus host disease. Rarely, fatal bleeding events including intracranial hemorrhages have occurred. Rare cases of opportunistic infections such as progressive multifocal leukoencephalopathy and central nervous system aspergillosis have also been reported [64-66].

Ivosidenib — Ivosidenib is a small molecule inhibitor of isocitrate dehydrogenase 1 (IDH1) that is approved for treatment of relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation. Rare cases of Guillain-Barré syndrome are reported (2 of 258 patients [<1 percent] in one study [67]). However, this could represent a chance association. (See "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Remission re-induction' and "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)

Selinexor — Selinexor is a selective inhibitor of the nuclear export protein exportin 1 (XPO1) that is approved in combination with dexamethasone for the treatment of multiply relapsed or refractory multiple myeloma. (See "Multiple myeloma: Treatment of third or later relapse", section on 'Selinexor'.)

Neurologic adverse reactions, including dizziness, syncope, depressed level of consciousness, and mental status changes (including delirium), have occurred in approximately 30 percent of patients treated with the drug; events were severe (grade 3 or worse) in 9 percent [68]. The median time to develop neurologic symptoms was 15 days. Fatigue is also a common side effect.

Axitinib, cabozantinib, lenvatinib, pazopanib, selpercatinib, sorafenib, sunitinib, and tivozanib — Axitinib, cabozantinib, lenvatinib, pazopanib, selpercatinib, sorafenib, sunitinib, and tivozanib are molecularly targeted agents that inhibit multiple tyrosine kinases including the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase. An increased risk of hemorrhage, including rare central nervous system hemorrhages, arterial thromboembolic events, and reversible posterior leukoencephalopathy syndrome (RPLS) have been reported with agents that target VEGFR. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Intracranial bleeding'.)

A few cases of drug-induced toxic metabolic encephalopathy have been reported in patients receiving sorafenib for advanced hepatocellular cancer in the setting of cirrhosis [69,70].

A variety of types of neurotoxicity have been rarely reported with sunitinib:

●A single case report described a transient coma in a patient treated with sunitinib for sarcoma, which resolved when treatment was discontinued and recurred with rechallenge [71].

●Sunitinib can also cause hypothyroidism and may induce a hypothyroid coma [72,73]. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Thyroid dysfunction'.)

●A reversible cognitive disorder characterized by confusion, hallucinations, or extrapyramidal symptoms has also been described in older adult patients with preexisting arteriosclerotic leukoencephalopathy [74].

●RPLS is characterized by headaches, altered consciousness, visual disturbances, and seizures; hypertension is frequent but not invariable. Multiple case reports describe this complication in patients treated with sunitinib [75-79] and other agents targeting angiogenesis. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Reversible posterior leukoencephalopathy and brain capillary leak syndrome'.)

Vemurafenib — Vemurafenib is a potent inhibitor of the mutated BRAF gene, which is present in 40 to 60 percent of melanomas. There are isolated case reports of peripheral facial nerve palsy, which was bilateral in two patients [80].

SUMMARY — Neurologic complications associated with anticancer treatments, including molecularly targeted and biologic agents, adversely impact quality of life and may limit further therapy. Some of the most common are summarized below:

●Biologic response modifiers and neuropsychiatric complications – Interferons (IFN) and high-dose interleukin 2 (IL-2) are associated with neuropsychiatric complications. (See 'Biologic response modifiers' above.)

●PML – Rare cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving a variety of agents, including rituximab, bevacizumab, alemtuzumab, brentuximab, sorafenib, and sunitinib. (See 'Monoclonal antibodies and antibody-drug conjugates' above and 'Axitinib, cabozantinib, lenvatinib, pazopanib, selpercatinib, sorafenib, sunitinib, and tivozanib' above.)

●Antiangiogenic therapies and thromboembolic events – Patients receiving bevacizumab alone or in combination with chemotherapy are at higher risk for thromboembolic events, including cerebrovascular accidents. Early recognition may help avoid permanent neurologic damage. (See 'Bevacizumab' above.)

●Checkpoint inhibitors and immune-mediated adverse events – Although uncommon, a wide range of immune-mediated adverse events have been observed that affect the nervous system in patients treated with checkpoint inhibitors, including sensory and motor neuropathy, Guillain-Barré syndrome, myasthenia gravis, encephalitis, and aseptic meningitis. (See 'Immune checkpoint inhibitors' above.)

●CAR-T cells – CAR-T cell therapy carries a black box warning for cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. This syndrome is discussed in more detail elsewhere. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

●Bispecific T cell engagers – Approximately 50 percent of patients receiving blinatumomab or teclistamab develop neurologic or neuropsychiatric toxicities, and they may be severe. (See 'Bispecific T cell engagers' above.)

●TKIs and neurotoxicity – Some of the orally active small molecule tyrosine kinase inhibitors (TKIs) targeting Bcr-Abl and other tyrosine kinases, such as platelet-derived growth factor receptor (PDGFR), especially the exon 18 mutation platelet-derived growth factor receptor alfa (PDGFRA) inhibitor avapritinib, are associated with central nervous system toxicities, such as cognitive impairment or intracranial hemorrhage, which may necessitate withholding or discontinuing the drug. (See 'Dasatinib, imatinib, and avapritinib' above.)

●TRK inhibitors – A variety of neurologic events have been described with the tropomyosin receptor kinase (TRK) inhibitors larotrectinib and entrectinib, including cognitive impairment, mood disorders, dizziness, and sleep disturbances. (See 'NTRK inhibitors' above.)

●ALK inhibitors – Lorlatinib is an anaplastic lymphoma kinase (ALK) inhibitor with a unique pattern of neurotoxicity that includes cognitive dysfunction, mood effects, speech disturbance, auditory hallucinations, and peripheral neuropathy. (See 'Lorlatinib' above.)