Introduction

Cure rates in pediatric cancers have dramatically improved over the last 50 years. In the current era, children aged 1–18 years of age at diagnosis with acute lymphoblastic leukemia can experience up to 80% event-free survival and 90% cure of primary disease [1,2,3,4]. Similar improvements in survival can be seen in neuroblastoma [5, 6], osteosarcoma [7], and in children treated with hematopoietic stem cell transplant [8,9,10,11,12]. Improvements in diagnostics, drug development, and supportive care have all been important in improving these outcomes.

Supportive treatments in the pediatric intensive care unit (PICU) has addressed common circumstances such as tumor lysis syndrome, blast crises, acute kidney injury, and immunosuppression. In this review, less common, but increasingly prevalent, treatments will be discussed, as well as the side effects that are critical for the care givers in PICU to be aware.

The increased use of immunotherapy and cellular targets places new challenges in front of the pediatric intensive care team, and being prepared for these challenges will aid in continuing to improve outcomes and mitigate treatment-related morbidities.

Cancer Immunotherapy

The human immune system has intricate mechanisms to identify and destroy aberrant cancerous cells. Most of the time, these mechanisms work well, and we are free from clinically significant disease. However, when these mechanisms fail and aberrant cells are allowed to divide unchecked, people develop cancer. Traditional cancer chemotherapy is aimed at killing rapidly dividing cells of any kind. It is not eloquent enough to distinguish healthy cells dividing appropriately from aberrant cancer cells causing illness. Therefore, patients suffer frequent complications such as pancytopenia, mucositis, and hair loss. More recently, cancer therapy has been developed to harness and augment the patient’s own immune system and more specifically target cancer cells. A myriad of immunotherapies have been extensively studied in preclinical and early clinical trials, demonstrating promising clinical efficacy. Current therapies include T cell-mediated therapies for refractory and relapsed acute lymphocytic leukemia as well as monoclonal antibody and checkpoint inhibitor therapies for solid tumors, leukemia, and lymphomas [13, 14].

A recent search of the www.clinicaltrials.gov website found 38 studies listed involving immunotherapy for pediatric cancer patients. These new agents have a different set of side effects than traditional chemotherapy due to their different mechanism of action. Patients can develop autoimmune-like diseases or systemic inflammatory response syndromes necessitating PICU level care. Therefore, it is important for intensivists to be familiar with this rapidly developing class of medications.

Chimeric Antigen Receptor T Cells

Pediatric B cell acute lymphoblastic leukemia (B ALL), the most common childhood cancer, has a survival rate of approximately 90% for newly diagnosed patients [15]. Unfortunately, patients who are refractory or relapse have a poor prognosis [16, 17]. Recent advancements in immunotherapy have improved survival for patients with relapsed and refractory leukemia; using T cell therapies first successfully used in adults with chronic lymphocytic leukemia and B cell lymphoma [13, 18]. Recent clinical trials in pediatrics continue to demonstrate clinical benefit for patients with refractory or relapsed B ALL, including recurrence after hematopoietic stem cell transplant [19, 20]. T cell therapies include chimeric antigen receptor T cells (CAR–T cells) and bispecific T cell monoclonal antibodies. CAR–T cells are cytotoxic T cells collected from the patient and subsequently genetically engineered via gene transfer to express a receptor to specific antigens on the leukemia cell, most commonly CD19. The CAR–T cells are infused back into the patient, binding to the leukemia cells, resulting in T cell activation and antigen-mediated cell death. Further T cell proliferation results in continued targeting and destruction of cancer cells [20]. Bispecific T cell monoclonal antibodies (i.e., blinatumomab) bridge target cells (i.e., CD19 leukemia cells) to T effector memory cells, resulting in target cell lysis. These therapies have demonstrated efficacy in lymphoid malignancies, including B cell leukemia and non-Hodgkin lymphoma, in both adult and pediatric populations [21].

New Toxicities: Cytokine Release Syndrome

These novel therapies present new toxicities and challenges for the critical care physician. Cardiopulmonary compromise and neurological deficits necessitating PICU transfer and targeted supportive therapy may arise. CAR therapy capitalizes on T cell-mediated cell destruction, activation, and expansion causing dramatic elevation in cytokine levels and a systemic inflammatory state. This complication is known as cytokine release syndrome. The clinical syndrome may range from mild flu-like illness with fevers and malaise to life-threatening distributive shock, pulmonary edema, respiratory failure, coagulopathy and multisystem organ dysfunction requiring vasoactive infusions, mechanical ventilation, and blood product support. Additionally, neurological toxicities including encephalopathy, seizures, altered mental status, and motor deficits have been reported [13, 20].

Measurements of circulating cytokines reveal unique elevation patterns, with a small subset rising early, offering potential predictive models of severe CRS. In a study of 51 patients who received CAR–T cell therapy (39 pediatric subjects), 24 cytokines were consistently elevated in patients with CRS. Notably, interferon γ (IFN-γ) and spg − 130 rose prior to onset of CRS symptoms. Interleukin-6 (IL-6), IL-8, IL-10, sIL-2rα, and tumor necrosis factor α (TNF-α) along with others peaked during CRS symptoms [22]. Additionally, C reactive protein and ferritin are often elevated though less specific for CRS [20, 22]. Currently, there are limitations to clinical implementation of cytokine evaluations as a predictive, diagnostic tool. Clinical laboratory improvement amendments (CLIA)-certified cytokine assays are not universally available in a timely manner; however, testing opportunities may evolve with future advancements. Severe cases of CRS may mimic hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), suggesting that CRS falls on a continuum with these two clinical conditions. In a retrospective review of 39 pediatric patients who received CAR therapy, 12 patients met criteria for MAS/HLH with ≥ 5 of eight diagnostic criteria. An additional of three patients met four criteria and three patients had three criteria [23••]. The unifying origin may be unopposed macrophage activation, most strongly driven by IFN-γ [20, 24, 22]. Interestingly, one patient who developed severe CRS with HLH/MAS-like symptoms was found to carry a known genetic mutation for familial HLH, suggesting that some patients may be genetically predisposed to severe CRS after treatment with T cell-engaging therapies [13]. Studies to evaluate additional predictors, allowing for early identification of patients who are at risk for CRS, are warranted.

Grading of Cytokine Release Syndrome, Incidence, and Treatment

CRS is a spectrum of symptoms ranging from mild to severe. Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE 4.0) for immunotherapies was modified specifically for CRS to grade toxicities and guide monitoring and treatment [25] (Table 1). As CRS clinically mimics septic shock and MAS/HLH, upfront management focuses on supportive therapies for the common symptoms including fever, distributive shock, and respiratory failure treated with volume resuscitation and vasopressor support for hypotension secondary to vascular leak as well as non-invasive oxygenation–ventilation modalities and mechanical ventilation. Additionally, reports reveal potential for life-threatening coagulopathies including DIC that may require appropriate blood product support to achieve hemostasis [23••, 25, 20].

Table 1 Definition of toxicity grade in CAR–T therapy
Full size table

In the largest study of CRS in pediatric patients after CAR therapy, 18 of 39 patients (46%) developed grade 3–4 CRS; with 14 (36%) manifesting with cardiovascular impairment treated with vasoactive infusions, 10 of whom required ≥ 2 agents. Acute respiratory failure requiring mechanical ventilation occurred in six (15%) subjects. The median time of organ dysfunction was 15 days; however, longer recovery occurred in patients with elevated ferritin levels > 11,200 pmol/L. Only a single patient with grade 3–4 developed identifiable infection. All subjects survived to discharge [23••].

For patients with more severe CRS, including grade 3 to 4 symptoms, a targeted therapy has repeatedly demonstrated clinical benefit and ultimate resolution of symptoms. As mentioned above, analysis of patients receiving CAR therapy reveals a specific cytokine profile, notably elevations in IL-6 and IFN-γ. These findings led to the use of an IL-6 inhibitor, tocilizumab, as treatment for patients with severe manifestations of CRS. Tocilizumab has been extensively studied in the pediatric population, primarily for juvenile idiopathic arthritis (sJIA) and the safety profile and efficacy for this disease is well known [26, 27]. Multiple studies have reported improvement in CRS symptoms after a single dose of tocilizumab with resolution of fever within day as well as weaning of vasoactive infusions within the first 24 h and ultimate discontinuation within 5 days [23••, 20]. This unique therapeutic intervention should be considered in all patients who require ICU level of care as well as those with cardiovascular dysfunction and grade 4 symptomatology [23••, 25]. The dosing for tocilizumab ranges from 4 to 12 mg/kg and due to the long half-life of 11–14 days, often only a single dose is required. For refractory cases of CRS with continued need of vasopressors and/or mechanical ventilation, a second dose of tocilizumab, in an effort to improve IL-6 receptor saturation, may be considered with or without the addition of systemic corticosteroids [28, 23••, 29]. Corticosteroids are strong anti-inflammatory agents; however, due to the broad nature of immune suppression, the theoretical risk for CAR–T cell attenuation exists as it may blunt T cell activation and proliferation. This therapy should be reserved for more severe, refractory cases of CRS or neurological toxicities (discussed below) in collaboration with the pediatric oncology team. Initial evaluations and follow-up of patients who received corticosteroids for treatment of life-threatening CRS did not reveal loss of circulating CAR–T cells, nor increased rate of leukemia relapse [13, 20]. Further studies are necessary and ongoing to ultimately describe long-term effects of corticosteroids.

Neurological Symptoms

Neurological complications are reported with CAR therapy and though less frequent than CRS, they require attention as they can be life-threatening and may require PICU management. Although less well studied at this point, cohorts and cases have been reported which identify symptoms ranging from hypertension, encephalopathy, seizures, both focal and generalized, visual deficits, paresis, papilledema, and cerebral edema. Routine neurological investigations, including computed tomography scans, and magnetic resonance imaging along with cerebral spinal fluid assessments have not revealed a clear etiology; in one patient, contrast-enhanced MRI demonstrated signs of intracranial edema while many other imaging studies have been normal [30]. Recent evaluation of cerebral spinal fluid in patients with neurological toxicity have confirmed presence of CAR–T cells as well as dramatic elevations in cytokines relative to serum values in both patients with and without CNS disease [30, 31]. This suggests blood–brain barrier penetration by CAR–T cells potentially causing a focused neurological CRS independent of systemic CRS. As tocilizumab does not cross the blood–brain barrier, patients with severe neurological compromise have been successfully treated with corticosteroids and anti-epileptic drugs with resolution of symptoms [30, 31]. Although often self-limited, more severe neurological consequences form cerebral edema, including death, have been reported. Neurotoxicity often occurs after onset of CRS during the defervescence phase or may develop with lower grade CRS [30, 20].

Timing of Cytokine Release Syndrome

CRS presents with peak T cell proliferation, occurring days after CAR therapy infusion. Symptoms may begin as early as 1 day after infusion. Fever precedes more severe symptoms. In the recent retrospective review, all patients with grade 3–4 CRS developed fever prior to cardiopulmonary symptoms, and as all patients with fever were admitted, no subjects developed more severe symptoms in the outpatient setting. For patients with grade 3–4 CRS, the median time to ICU admission was 5.6 days after T cell infusion [23••]. Profound shock followed fever, peaking near day 6 and followed by respiratory symptoms, coagulopathy, and renal dysfunction. Hepatic insults and encephalopathy demonstrated delayed onset, approximately 10 days after infusion [23••].

Immune Check Point Inhibitors

While the human immune system has evolved to recognize invading microorganisms as well as aberrant cancer cells, it also has developed mechanisms to keep it in check to avoid attacking self-antigens and developing autoimmune disease. These are termed checkpoints. Their function is to downregulate activated T cells. Cancer cells are able to utilize these check points to evade destruction from the immune system. Drugs termed checkpoint inhibitors are monoclonal antibodies which reverse the inhibition of activated T cells, thus allowing activated T cells to recognize and attack cancer cells [32].

Ipilimumab is the most widely studied of the checkpoint inhibitors. It targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Ipilimumab was the first of this type of monoclonal antibody to show a survival advantage in advanced melanoma patients [33]. Monoclonal antibodies target programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1); both check points have also been developed and are undergoing investigation in a number of cancers [32, 34]. These medications are now being trialed in combination with each other as well as with traditional chemotherapy in patients with melanoma as well as other solid tumors and hematologic malignancies. There is evidence for improved efficacy with combination therapy but with that comes the risk of increased toxicity [35]. Toxicities may be severe enough to require PICU care. Therefore, it is important for the intensivist to have some knowledge of this relatively new class of medications [32, 36••].

Toxicities are predictably related to immune reactivation resembling autoimmune disease. Most of the toxicity data comes from adult studies, though there is limited pediatric data available. In one pediatric study involving 33 patients given CTLA-4 inhibitors, 27% developed grade 3–4 toxicity. Similar to adult data, these toxicities included pneumonitis, pancreatitis, colitis, colonic perforation, Stevens–Johnson syndrome, and endocrinopathies [32, 36••]. Other potentially critical toxicities requiring ICU care described in adult trials include fatal myocarditis [37], neurologic complications such as Guillain–Barre [38] and posterior reversible encephalopathy (PRES) [39], hepatitis [32], and renal insufficiency [40].

Holding further doses of the offending agent may be all that is needed with mild toxicity. However, with more severe toxicity, immunosuppressive therapy with corticosteroids or other agents such as infliximab or mycophenolate mofetil may be necessary [32]. Nishino et al. describe a case series of adults treated with the PD-1 inhibitor nivolumab for a variety of cancers who went on to develop pneumonitis [41]. The most common radiographic finding described was that of cryptogenic organizing pneumonitis in 65% followed by nonspecific interstitial pneumonitis in 15% and hypersensitivity pneumonitis in 10% and acute interstitial pneumonia/acute respiratory distress syndrome in 10%. Seventeen of 20 patients (85%) were treated with corticosteroids while three patients received both steroids and infliximab [41]. Decisions to provide immunosuppressive therapy should be made in conjunction with the oncology team as theoretically, these agents may dampen the antitumor effect.

Immunotherapy for High-Risk Neuroblastoma

At a time when long-term survival of neuroblastoma hovered in the 15% range [42], the Children’s Oncology Group (COG) published a multicenter trial on the use of autologous bone marrow transplant (BMT) in the treatment of high-risk neuroblastoma [43]. In children who received BMT in the treatment of high-risk neuroblastoma, when compared to children who received chemotherapy alone, 3-year event-free survival improved from 27 to 43% [43]. Furthermore, subsequent therapy with 13-cis-retinoic acid improved event-free survival to greater than 50% whether children received BMT or chemotherapy alone [43].

Also being developed and studied at the same time was a therapeutic approach towards treating high-risk or chemotherapy-resistant neuroblastoma with immunotherapy [44,45,46,47,48]. Immunotherapy directed towards the antigen GD2 has gained important traction as a mainstay of treatment for chemotherapy refractory and high-risk neuroblastoma [49,50,51]. The side effects of treatment have a significant impact related to logistics of treatment, including location of administration and availability of rapid resuscitation of children who experience acute life-threatening complications—which are frequently limited to the duration of the infusion [52,53,54, 51].

Antibody-Dependent Cell-Mediated Cytotoxicity and Neuroblastoma

The ganglioside GD2 is a carbohydrate antigen found in high density in neuroblastoma cells [55] and is highly preserved after therapy [56]. Anti-GD2 treatment strategies provide an effective treatment in chemotherapy refractory disease [51]. Two different anti-GD2 IgG antibodies have been studied clinically in the treatment of chemotherapy refractory neuroblastoma, ch14.18 [51] and murine 3F8 [49]. In a multicenter trial, subjects were assigned to receive up-front therapy (induction, autologous stem cell transplantation, and radiotherapy), followed by standard therapy (isotretinoin) or immunotherapy (isotretinoin, ch14.18, and IL-2) [51]. Results demonstrated a 2-year event-free survival in the immunotherapy arm of 66 and 46% in the standard therapy arm [51]. This study provided important background for the National Cancer Institute (NCI)/COG sponsored study ANBL1221, which was to examine the clinical outcomes for patients receiving irinotecan, temozolomide, and temsirolimus (regimen A) compared to patients receiving irinotecan, temozolomide, and ch14.18 with GM-CSF. On interim review, findings were such that too few patients responded to regimen A, and as of August 2016, all patients (as of 9/1/2017) were being enrolled on regimen B (https://childrensoncologygroup.org/index.php/anbl1221).

Side Effects of Anti-GD2 Therapy

Many of the clinical studies involving anti-GD2 antibodies clearly document the most relevant side effects that impact the use of the treatment [52, 44,45,46, 50, 51]. The side effects and the treatments, while limited largely to the duration of the infusion (for both the ch14.18 and murine 3F8), the severity is such that critical care services and rapid resuscitation protocols are necessary for the safe administration of the antibody.

The most common side effect documented in the administration of anti-GD2 antibodies in the treatment of neuroblastoma is pain [51]. Documented pain of NCI scale grade 3 or 4 was as much as 50% of patients receiving the ch14.18 antibody [51] and 100% receiving 3F8 [44]. The sites of pain varied, most commonly in the abdomen, but also involving the lower back, extremities, and head [44, 46, 50, 51].

Strategies to combat the severe pain range from premedication with acetaminophen and opioid narcotics such as morphine or hydromorphone [52, 44, 46, 50] to the use of systemic analgesia by infusion throughout the duration of the treatment [53, 57]. In an small case series from the University of British Columbia, children receiving a 10-h infusion of ch14.18 for four consecutive days in each of five 28-day cycles received escalating doses of dexmedetomidine infusion (0.1–0.6 mcg/kg/h) and hydromorphone (0.002–0.008 mg/kg/h) beginning 1 h prior to the infusion [53]. With adequate pain control, there were analgesia-related side effect of hypotension (30% of treatment days) and hypoxemia (8% of treatment days) which were treatable and resolved at the end of each of the infusions [53]. From a monitoring standpoint, these patients require continuous cardiopulmonary monitoring, which in many institutions would require admission to a monitored oncology floor, or PICU. Another small case series involved the use of intravenous lidocaine for the duration of each of four daily infusions of ch14.18 over 5 h [57]. The use of lidocaine infusion significantly reduced the amount of opioid pain medication needed to adequately manage treatment related pain, as well as allow for more time for patients to be up and out of bed [57]. Again, patients receiving systemic lidocaine infusions require continuous cardiopulmonary monitoring and may require admission to a PICU in some institutions. Though there is no pediatric data supporting the use of ketamine for patients receiving immunotherapy against GD2, there has been anecdotal discussion of this practice among some of the higher volume centers performing this therapy and likely warrants further study.

Other common side effects that may impact the pediatric critical care service are capillary leak syndrome and hypersensitivity, which may be related in some cases [51]. Peripheral capillary leak symptoms have been documented in as many as 10–18% of patients receiving anti-GD2 therapy [46, 51]. While the symptomology generally lasts only the duration of the infusion of the antibody, rapid assessment and management with intravenous fluids is ideal. While pretreatment with diphenhydramine is directed towards the urticaria that has been associated with antibody infusion [44, 51], rapid availability of subcutaneous epinephrine and inhaled bronchodilators ought to be part of the rescue milieu for the treatment of life-threatening hypersensitivity and/or anaphylactoid reaction.

Other rare, but important to remember, side effects for the critical care team to be aware of are posterior reversible encephalopathy syndrome seen in patients receiving 3F8 [54], electrolyte abnormalities [46, 50], and encephalitis [58]. Lastly, 16–22% patients have been documented to develop treatment-related hypotension that may require fluid resuscitation or vasoactive infusion support [44, 46, 50, 51]. Conversely, hypertension has also been documented in patients receiving anti-GD2 treatment [44, 46]. In addition to hypertension associated with the antibody treatment, some patients may development chemotherapy or disease-related chronic hypertension that requires chronic treatment with antihypertensive agents. Navigating the use of chronic vasodilator therapy (such as calcium channel blocker or ACE-inhibitor treatment) in the face of a risk for antibody related hypotension requires a thoughtful approach, for which an individualized approach is appropriate.

Conclusion

Treatment for childhood cancer has advanced significantly in recent years with survival rates for pediatric patients continuing to improve [7]. However, toxicities from cancer therapy continue to be a concern. Pediatric oncology patients continue to require complex care in PICUs due to toxicity from their cancer therapy. Newer therapies utilize the immune system to more elegantly and specifically attack cancer cells than traditional chemotherapy. CAR–T cells create a systemic inflammatory response syndrome (SIRS) response that may require ICU support similar to patients with sepsis. Other patients may develop cerebral edema or other neurologic side effects [5, 12]. It is important for intensivists to understand the grading of these toxicities and when to employ treatments such as tocilizumab or steroids. Toxicity from immune checkpoint inhibitors resembles autoimmune diseases. Patients may require critical care due to severe colitis, pneumonitis, or myocarditis [24, 28]. Intensivists should be knowledgeable regarding when use of anti-inflammatory agents such as infliximab, mycophenolate mofetil, or steroids is appropriate. Antibody therapies such as those used in neuroblastoma therapy also stimulate the immune system and can cause a SIRS response requiring PICU care. Other toxicities such as severe neuropathic pain are predictable based on whether or not other cells express the target antigen [43].