Immunotherapy toxicity: checkpoint inhibitors, CAR-T and bispecific antibodies

Mechanism and timing. The same mechanism that produces the antitumour effect of immune checkpoint inhibitors (ICIs), namely the escape of autoreactive T cells from immune tolerance, causes much of the irAE burden. These events can occur at any time during treatment and even 6 to 12 months or more after it stops, and some (such as type 1 diabetes and thyroid destruction) are lifelong ^[2]. The 2021 ASCO and 2021 SITC guidelines organise management by the organ involved and the CTCAE grade, and because randomised trials are lacking, the recommendations rest mostly on expert consensus ^{[1, 2]}; the 2022 ESMO guideline also gives recommendations for the diagnosis, treatment and follow-up of immunotherapy toxicities ^[9].

Incidence and mortality. In the CheckMate 067 trial (melanoma), grade 3 or 4 treatment-related adverse events occurred in 16.3% with nivolumab, 27.3% with ipilimumab and 55.0% with nivolumab + ipilimumab ^[10]. In a meta-analysis of 112 trials (19,217 patients), toxic deaths were 0.36% with anti-PD-1, 0.38% with anti-PD-L1, 1.08% with anti-CTLA-4 and 1.23% with the combination; deaths occurred early (median 14.5 days with combination treatment and 40 days with monotherapy), and myocarditis had the highest fatality (39.7%), whereas colitis was the most common cause of death with anti-CTLA-4 and pneumonitis the most common with anti-PD-1/PD-L1 ^[3].

Before starting treatment. Baseline and periodic CBC, metabolic panel, TSH and free T4; urinalysis if kidney disease is suspected; in patients at high risk of myocarditis (heart disease, diabetes, anti-PD-‎(L)1 combined with anti-CTLA-4), consider a baseline ECG and troponin. Patient education about symptoms is essential; pre-existing autoimmune disease is not an absolute contraindication, but flares are common (about 50%) ^[2].

Treatment principles. Unlike chemotherapy, ICI dose reduction has no role in managing irAEs. Systemic corticosteroids are first-line treatment, and patients should be taught about their side effects (hyperglycaemia, mood disturbance, insomnia, gastritis and opportunistic infections such as pneumocystis); cases not responding to corticosteroids need a second-line immunosuppressant and specialist advice ^[2]. Before treatment, exclude other causes (for example Clostridioides difficile infection in diarrhoea), but do not delay starting treatment ^[2].

Rechallenge. After a grade 2 irAE, continuing the ICI is possible if symptoms have resolved or are controlled with prednisone 10 mg a day or less; after grade 3 or 4 the decision is based on the balance of benefit and risk. In two retrospective reviews, the previous irAE recurred after rechallenge in 43% and 26%, and a new irAE occurred in 13% and 26% ^[2].

Endocrinopathies: an important exception

In endocrinopathies, hormone replacement is the main treatment, and the ICI usually continues once the patient is stable, often without interruption; thyroiditis and type 1 diabetes usually do not need corticosteroids. In a patient with symptoms of hypothyroidism or a raised TSH and low free T4, check morning cortisol to exclude concurrent adrenal insufficiency ^[2]. The relative risk differs by regimen: in a meta-analysis of 38 trials (7551 patients), combination treatment compared with ipilimumab increased the risk of hypothyroidism (OR 3.81), hyperthyroidism (OR 4.27) and hypophysitis (OR 2.2), whereas PD-1 inhibitors compared with ipilimumab caused less hypophysitis (OR 0.29) but more hypothyroidism (OR 1.89) ^[11].

Myocarditis and the myositis–myocarditis–myasthenia triad

In a multicentre registry, the prevalence of myocarditis was 1.14% and the median time to onset 34 days after starting the ICI; 46% of patients had a major adverse cardiac event (cardiac death, cardiogenic shock, cardiac arrest or complete heart block), 38% of them with a normal ejection fraction. Combination ICI treatment (34% vs 2%) and diabetes were more common in affected patients, troponin T ≥1.5 ng/mL increased the risk fourfold, and lower corticosteroid doses were associated with higher residual troponin and more events ^[12]. Myositis, myocarditis and myasthenia often occur together (reported fatality 20% for myasthenia and 17% for myocarditis); so suspicion of any one should prompt assessment of all three (CK, troponin, ECG, myasthenia antibodies and respiratory assessment) ^[2].

Incidence and timing. In the axicabtagene ciloleucel label, CRS occurred in 93% of patients with large B-cell lymphoma (grade ≥3 in 9%, by the Lee criteria), with a median onset 2 to 3 days after infusion ^[13]. With the bispecific antibody teclistamab, CRS occurred in 64% (grade 1 in 46%, grade 2 in 18% and grade 3 in 0.2%), mostly during step-up doses, with a median onset 2 days after the last dose ^[14].

Consensus recommendations. SITC: in adults with grade 2 CRS, tocilizumab can be given, and earlier in older patients or those with comorbidities; if there is no improvement after one dose, add corticosteroids with the second tocilizumab dose, and if no improvement after two doses, consider third-line drugs (anakinra, siltuximab or high-dose methylprednisolone) and reassess for infection ^[5]. ASCO also treats prolonged or severe CRS with tocilizumab with or without corticosteroids ^[15]. Do not give CAR-T with active infection or an inflammatory disorder; monitor the patient at least daily for 7 days, keep them near the treatment centre for at least 2 weeks, and advise no driving for 2 weeks ^[13].

Presentation and timing. The first signs of ICANS are usually tremor, impaired handwriting, mild expressive difficulty (especially naming objects), impaired attention, apraxia and drowsiness ^[4]. In the axicabtagene label, neurotoxicity occurred in 74 to 87% of patients with large B-cell lymphoma (grade ≥3 in 25 to 31%) with a median onset of 4 to 5 days; 87% of affected patients developed it in the first 7 days and 98% of all cases in the first 8 weeks, but late encephalopathy and fatal cerebral oedema have also been reported ^[13]. With teclistamab, ICANS occurred in 6% ^[14].

Treatment principles. Tocilizumab did not resolve ICANS in several trials and may worsen it by raising IL-6 in the cerebrospinal fluid; so in ICANS, managing neurotoxicity takes priority over treating mild CRS, and corticosteroids are the mainstay. Levetiracetam is the drug of choice for seizures, and its prophylaxis can be considered in high-risk patients ^[5]. ASCO also manages moderate to severe ICANS with corticosteroids and supportive care ^[15].

Late neurotoxicity with anti-BCMA CAR-T. With ciltacabtagene autoleucel, parkinsonism in 3% (median onset 56 days, often persistent), cranial nerve palsies in 7% (especially cranial nerve VII; median onset 21 days) and Guillain-Barré syndrome (including a fatal case despite IVIG) have been reported; continue neurological monitoring after the acute period ^[8].

IEC-HS. The ASTCT panel defines this syndrome as an inflammatory syndrome with features of macrophage activation/HLH that is attributable to immune effector cell therapy and is associated with progression or new onset of cytopenias, hyperferritinaemia, coagulopathy with hypofibrinogenaemia and/or raised transaminases; it often appears later, as CRS is resolving. A ferritin above 2 × the upper limit of normal (or the baseline at infusion) or a rapid rise is a prerequisite for diagnosis ^[6]. Initial treatment is corticosteroids with or without anakinra, and assessing the response for about 48 hours before adding the next drug is recommended; ruxolitinib is second line and etoposide is for life-threatening and refractory cases. Tocilizumab or siltuximab without features of CRS is not recommended for IEC-HS ^[6]. With ciltacabtagene autoleucel, HLH/MAS occurred in 1% of patients, all in the setting of ongoing or worsening CRS ^[8].

ICAHT. Haematological toxicity is the most common adverse event after CAR-T and may be profound, prolonged and biphasic ^[7]. The EHA/EBMT consensus considers G-CSF from day 2 after infusion in high-risk patients (without an increase in severe CRS or ICANS in retrospective studies); more than 80% of patients eventually respond to G-CSF, and in refractory cytopenia after day 14, an infusion of stored autologous stem cells (boost) or a thrombopoietin agonist are options. The CAR-HEMATOTOX score before infusion identifies high-risk patients ^[7].

Infection prevention. Antiviral and anti-pneumocystis prophylaxis and IVIG replacement in hypogammaglobulinaemia per EHA/EBMT guidelines; fluoroquinolone prophylaxis is not recommended in low-risk patients and can be considered in high-risk patients when neutrophils fall below 500; anti-mould prophylaxis (for example micafungin or posaconazole) at high risk of grade ≥3 ICAHT when neutrophils are below 500, especially with a history of allogeneic transplant, previous aspergillosis or prolonged or high-dose corticosteroids (more than 10 mg dexamethasone); a neutropenic diet is not recommended ^[7]. Bispecific antibodies can also cause severe and fatal infections ^[14].

Secondary malignancy. T-cell lymphomas (sometimes CAR-positive) have occurred after anti-CD19 and anti-BCMA CAR-T and may appear a few weeks after infusion; lifelong monitoring is needed ^[13].