Severe toxicity from checkpoint protein inhibitors: What intensive care physicians need to know?

Checkpoint protein inhibitor antibodies (CPI), including cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors (ipilimumab, tremelimumab) and the programmed cell death protein 1 pathway/programmed cell death protein 1 ligand (PD-1/PDL-1) inhibitors (pembrolizumab, nivolumab, durvalumab, atezolizumab), have entered routine practice for the treatment of many cancers. In contrast to classical chemotherapy, CPIs do not target tumor cells; rather they enhance activation of immune cells, particularly T cells (Fig. 1) [1]. They have been associated with better outcomes in a number of solid and hematological malignancies [2]. Moreover, compared with chemotherapy, their tolerance seems to be higher with fewer side effects.

These new molecules are mostly prescribed for melanoma and non-small cell lung cancer (NSCLC), but also for other malignancies such as renal cell carcinoma, bladder carcinoma, squamous cell carcinoma of the head and neck, lymphoma [2]. The list of treatment indications will likely extend as the years go by, even as a first-line therapy. The number of patients treated will increase because of expanded indications and better survival [2‐5]. Moreover, the optimal duration of treatment remains unknown.

CPIs are associated with immune-related adverse events (IrAE) that need to be carefully monitored and managed during and after treatment. These drugs can promote infiltration of immune cells into normal tissues, which may lead to immune-mediated disorders. Almost every organ may be affected: skin, bowels, liver, lungs, kidneys, eyes, endocrine tissues, central nervous system [6]. In up to 20% of cases, severe and even life-threatening AE can occur and lead to intensive care unit (ICU) admission [7, 8].

This review focuses on the most severe IrAE that intensivists may encounter. Maintaining a high level of suspicion is a major challenge, as some of the toxicities might be uncovered later, in patients treated for a longer period of time with prolonged survival and new indications for those CPI.

We searched Medline and PubMed for reviews and original articles on CPI for treatment of solid tumors in adults published in English between 1 January 2009 and 30 January 2018, using the terms ‘antibody, monoclonal/adverse event’ [Mesh] AND ‘ipilimumab’ [Mesh], ‘tremelimumab’ [Mesh], ‘pembrolizumab’ [Mesh], ‘nivolumab’ [Mesh], ‘durvalumab’ [Mesh], ‘atezolizumab’, [Mesh], and ‘immunotherapy’ [Mesh]. We also searched using individual terms such as ‘CTLA4 inhibitors’, ‘programmed cell death protein 1 pathways’, ‘hepatitis’, ‘pneumonitis’, ‘skin’, ‘hypophysitis’, ‘colitis’, and ‘acute kidney failure’, ‘myocarditis, ‘neurological complication’, ‘encephalopathy’, ‘anemia’. Only severe adverse events eventually associated with ICU admission were considered for this review. Most of the articles were descriptive reports or randomized studies with safety outcomes, over the last 10 years of the search period. We used only original reports when available.

The severity of AE is defined for each organ by the National Cancer Institute (CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf) (Tables 1, 2).

In a meta-analysis of 21 randomized phase II/III immunotherapy trials (including 11,454 patients of whom 6528 received a CPI) conducted between 1996 and 2016, the incidence of fatal IrAE was 0.64%, mostly due to ipilimumab-induced colitis [7].

In patients receiving CPI, grade III–IV (Table 1) colitis occurred in 1.5%, grade III–IV aspartate aminotransferase (AST) elevation in 1.5%, grade III–IV rash in 1.1%, grade III–IV pneumonitis in 1.1%, hypothyroidism was observed in 0.3% of cases. Ipilimumab was associated with a higher risk of grade III–IV colitis than PD-1/PDL-1i [7]. In a recent meta-analysis, PD-1 and PDL-1i seem to be associated with grade III–IV IrAE with similar frequencies [10]. However, the incidence of these IrAE was far lower than the rate of complications from chemotherapy, particularly infections. Grade III–V toxicities were more common with CTLA-4i than with PD-1i (31% vs. 10%) [11]. IrAE leading to death were exceedingly rare for PD-1i (PDL-1i 0.1%, PD-1i 0.3%) and most often secondary to pneumonitis, whereas fatal gastrointestinal (GI) IrAE (diarrhea, colitis, colonic perforation) mostly occurred with CTLA-4i (severe events 31%) [11]. Furthermore, the safety profile of CPI varies among tumor types: melanoma has a higher risk of GI and skin IrAE and lower frequencies of pneumonitis [12, 13]. Moreover, combining two CPIs leads to more frequent severe complications in up to 55% of patients [14‐16]. Also, the incidence of rAE and severe IrAE will probably increase in the future, with the increasing number of patients currently treated and the use of combination regimens already tested in several trials [17‐19].

The kinetics of IrAE onset remains difficult to describe, but IrAE seem uncommon before 1 months of treatment [6, 13]. Although, in a recent report, severe IrAE can appear early during the treatment course [20] (within 40 days with Ipilimumab and anti-PD1–/PDL1 and 14.5 days with combination treatment), late complications of CPI may occur, sometimes up to 1 year after the start of the PDL1, and clinicians must remain aware of possible complications during follow-up [21]. Moreover, IrAE can occur after the CPI has been discontinued [22].

Toxicities associated with PD-1/PDL-1i agents may be slower to resolve than with ipilimumab, and long-term follow-up is therefore advised [23].

This section describes the most severe IrAE according to the frequency and severity of organ involvement (Figs. 2, 3, 4, Additional file 1: Fig. S1). In some recent studies, high-grade toxicity seems to be associated with high tumoral response rates [24, 25].

Due to the potential reversibility with treatment, CPI-related severe toxicity should lead to ICU admission at least for a time-limited trial, in case of organ failure or for patients at risk of organ failure. Such a trial may include mechanical ventilation, vasopressors, renal replacement therapy, and even extracorporeal membrane oxygenation in selected patients.

The recommendations for managing IrAE arise from general clinical consensus, because no prospective trials have been conducted to specifically test whether one management strategy is superior to another. Early recognition and treatment of IrAE are believed to be important in mitigating their severity. For severe grade III–IV, IrAE drug should be discontinued immediately [84].

From a practical standpoint, the management of such patients requires a close collaboration between specialists (e.g. nephrologist, hepatologist, infectious diseases specialist), oncologists, and intensivists (Fig. 6).

Although steroid treatment should be initiated as soon as possible, some other etiologies like infections or cancer progression must be ruled out. Table 2 summarizes the diagnostic work up before treatment. Most of the differential diagnoses can be ruled out quickly and work up should not delay the initiation of steroid treatment in case of severe IrAE. Systemic corticosteroids (oral or IV methylprednisolone) must be initiated at a dose of 1–2 mg/kg/day for 3 days and then reduced to 1 mg/kg/day. Corticosteroids regimen should then follow a gradual tapering over a period of at least 1 month [85]. Whenever IrAEs worsen or do not improve sufficiently after 3–5 days despite the use of adequate steroids dosage, additional immunosuppressive drugs should be considered. Although none of these treatments has been evaluated, they may include:

Hypothyroidism should be managed with thyroid hormone replacement and hyperthyroidism with standard anti-thyroid pharmacotherapy and beta-blockers in symptomatic cases [8].

Long-term treatment with corticosteroids and sometimes anti-TNF drugs may be complicated by severe opportunistic infections such as fungal infection, tuberculosis, or CMV. Therefore, it is recommended to give antibiotic prophylaxis with oral trimethoprim/sulfamethoxazole (400 mg/125 mg 3 times a week) together with steroids and to test patients for tuberculosis before adding any additional immunosuppressive drug (e.g. TNF alpha inhibitors) to corticosteroids [85.].

As the pathophysiological mechanism of IrAE involves excessive activation of the immune system, leading to toxic effects potentially targeting any organ and mimicking autoimmune diseases in their clinical presentation, it may also be difficult to differentiate between the side effects of CPI and the development of autoimmune paraneoplastic syndromes. This was emphasized in a recent report of patients without previous autoimmune manifestations who developed autoimmune encephalitis during immunotherapy [55, 87].

Interestingly, the same CPI may be reintroduced after IrAEIrAE resolution in most cases of grade III IrAEIrAE (Table 2). For grade IV IrAEIrAE, resumption of CPI may be more questionable. However, restarting CPI must be considered after a close collaboration between oncologist, specialist and intensivist, while weighing the individual risk/benefit ratio, and should be shared with the patient (Table 2).

Interestingly, some studies described higher cancer response rate for patients who also experienced high-grade IrAEIrAE [13]. These results need to be confirmed.

Severe immune-related complications of checkpoint protein inhibitor antibodies complications remain rare, but the number of patients treated will continue to rise. Although adverse events may occur less frequently after immunotherapy than after chemotherapy, intensivists should be aware of the side effects of this new type of medication that may require ICU admission. Moreover, some immune-related complications remain unknown and will reveal themselves with the increasing use of those new therapeutic agents.