1126 SECTION IX Pediatric Critical Care Hematology and Oncology GVHD prevention regimens differ between institutions and are chosen based on the donor and recipient pairing, underlying disease, stem c[.]
1126 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology GVHD prevention regimens differ between institutions and are chosen based on the donor and recipient pairing, underlying disease, stem cell source, recipient comorbidities, conditioning regimen and potential stem cell manipulation Agents commonly used for prevention include cyclosporine, tacrolimus, methotrexate, rapamycin, mycophenolate mofetil, and corticosteroids Depletion of the T-cell component of the stem cell graft effectively reduces the risk of GVHD Corticosteroids are the mainstay of treatment for GVHD Due to prolonged treatment with corticosteroids, some patients with chronic GVHD develop adrenal insufficiency When a patient with chronic GVHD needs intensive care, one should consider the use of stress-dose hydrocortisone Neurologic Complications Neurologic complications contribute significantly to morbidity and mortality following HCT and are more common following HCT than in nontransplant oncology patients.55,254–256 Seizures appear to be the most common clinical manifestation following HCT, occurring in approximately half of the reported cases of neurologic complications.254,255 Other symptoms include encephalopathy, motor function deficits, cranial nerve palsies, visual disturbances, and impaired coordination.55,254–256 Leukoencephalopathy primarily occurs in HCT patients who receive cranial radiation and/or intrathecal chemotherapy before and after transplantation Clinically, this condition manifests days to months after transplantation and may present with dysarthria, ataxia, dysphasia, confusion, and/or decreased sensorium in severe cases The white matter changes can be detected with either CT or MRI Peripheral nervous system neurotoxicity also occurs posttransplantation as an immune-mediated complication Inflammatory degenerating polyneuropathy, myasthenia gravis, and polymyositis have all been described posttransplantation.257–259 These conditions present with muscle flaccidity, hypoactive deep tendon reflexes, and absence of extensor plantar reflexes In an analysis of 165 pediatric HCT recipients, 40 (24%) patients were found to experience neurologic complications.254 In that study, neurologic complications were categorized as either (1) transient and nonrepetitive symptoms lasting less than 24 hours and without abnormalities on MRI or on cerebrospinal fluid (CSF) analysis, or (2) persistent (lasting 24 hours) or repetitive symptoms associated with radiographic cerebral imaging and/or CSF analysis abnormalities Of the 165 patients, 19 (12%) satisfied the criteria of the second group In that report, neurologic complications occurred most commonly in children who had undergone unrelated allogeneic transplantation (39%), more than in related allogeneic transplants (21%) or autologous transplants (11%) The finding of neurologic complications occurring more commonly in allogeneic rather than autologous HCT recipients has been previously noted.260–260 These data support the finding that neurologic complications following HCT are related to the presence of GVHD and immunosuppression.254,260,263–266 Common etiologies of neurologic complications in these children include central nervous system (CNS) infections, intracranial hemorrhage and stroke, metabolic disturbances, medication toxicity, and CNS involvement of the underlying disease.254–256 CNS infections are a consequence of neutropenia and immunosuppression Depending on the time period after transplantation, patients may develop bacterial meningitis, aspergillus invasion of the brain parenchyma and vessels, cerebral toxoplasmosis, or viral encephalitis These CNS infections contribute significantly to the morbidity and mortality following HCT.267 In addition to the association of GVHD with CNS infections, medications used to treat GVHD are a common cause of neurologic complications Neurotoxicity from CSA or tacrolimus can include tremor, seizures, headaches, cortical blindness, neuropathy, or mental status changes These effects can be observed with drug levels in the therapeutic range and usually are reversible with elimination of the drug From 5% to 6% of HCT patients taking CSA may experience seizures.268,269 Phenytoin, phenobarbital, or carbamazepine, used to treat seizures, can alter cytochrome P-450 activity and interfere with CSA or tacrolimus levels Valproic acid or levetiracetam may be a better alternative.270–272 Several chemotherapy agents that may be used in the HCT conditioning regimen have neurotoxicity High-dose carmustine, used in autologous transplants for Hodgkin disease and other lymphomas, has been associated with seizures Busulfan, frequently used in allogeneic transplants, can also cause seizures Antiepileptic medications are often given prophylactically during busulfan administration Levetiracetam is a good option in this situation due to its lack of effect on cytochrome P-450 activity Phenytoin induces cytochrome P-450, alters busulfan metabolism, and lowers the patient’s exposure to busulfan, potentially increasing the risk of relapse.271,272 CSA and tacrolimus are associated with posterior reversible encephalopathy syndrome (PRES) observed in HCT patients.254 PRES is a clinical entity that presents with headache, mental status changes, visual disturbance, and seizures Neurologic imaging shows subcortical vasogenic edema preferentially involving the posterior regions of the brain This syndrome is not unique to HCT patients and has been reported in patients with acute hypertension, preeclampsia, and renal disease Treatment includes control of blood pressure, management of seizures, and replacement of calcineurin inhibitors such as tacrolimus or CSA with a different class of immunosuppressive agent.273 If appropriately recognized and promptly treated, the neurologic changes in PRES are reversible However, this entity can present with life-threatening complications, such as cerebral hemorrhages, cerebellar herniation, hydrocephalus, and status epilepticus.274 CSA, tacrolimus, and chemotherapeutics may cause renal wasting of magnesium, resulting in hypomagnesemia and lowering of the seizure threshold A pediatric analysis suggests that metabolic derangements remain a significant cause of encephalopathy after HCT, seen in 14% of pediatric HCT patients.256 Hypoxia, ischemia, hepatic failure, electrolyte imbalance, and renal failure have all been implicated as a cause for metabolic derangements resulting in encephalopathy Idiopathic hyperammonemia can occur in patients after high-dose chemotherapy Altered mental status and respiratory alkalosis with an elevated plasma ammonia occur Left untreated, irreversible cerebral edema may result Neurovascular complications are a potential cause of neurologic toxicities during HCT Thromboembolic episodes, subdural hemorrhages, and intracerebral hemorrhages are described TTP is reported as a cause of encephalopathy following pediatric HCT.256 In a report of 21 children with a definitive diagnosis of encephalopathy following HCT, (10%) were found to have TTP and (5%) had evidence of a stroke.256 In that same report, (5%) of the 22 children with intracranial imaging was found to have a subdural hematoma and (10%) were noted to have infarctions In a different report, (11%) of the 19 children with persistent neurologic symptoms (.24 hours) after HCT were diagnosed with intracranial hemorrhage.254 In a study of pediatric patients receiving HCT or conventional chemotherapy, (12%) CHAPTER 93 Critical Illness in Children Undergoing Hematopoietic Progenitor Cell Transplantation of the 76 patients with a neurologic complication were found to have a vascular event.255 In terms of prognosis, neurologic complications portend a poor prognosis Nearly 60% of the children with persistent/repetitive symptoms and either radiographic or CSF abnormalities following HCT died More than one-third died as a result of their neurologic complication.254 In another study of 113 pediatric allogeneic HCT patients, children with a neurologic complication following HCT were significantly more likely to die than those who did not have them.263 Thirty-three (32%) of 102 patients without a neurologic complication had died at years of follow-up as compared with 10 (91%) of the 11 patients with a neurologic complication (P , 001) Similarly, in the Associazione Italiana Ematologia Oncologia Pediatrica prospective study of 636 pediatric patients transplanted for acute leukemia, CNS toxicity was associated with early treatment-related death.55 In that report, severe CNS toxicity was related to a threefold increase in the risk of treatment-related death as compared with absent or mild toxicity (P 02) However, in a logistic regression model of all organ toxicities, the relationship between CNS toxicity and early treatment-related death was not statistically significant (RR, 2.2; 95% CI, 0.8–5.5; P 11) Finally, in a study of encephalopathy after pediatric HCT, 17 (65%) of 26 patients died; 12 never recovered from their encephalopathy.256 In that report, only (15%) of the 26 patients experienced a full recovery of their encephalopathy Chimeric Antigen Receptor T Cells Chimeric antigen receptor T-cell (CART) therapy may represent an adjunctive treatment for patients with HCT CART is discussed in more detail in Chapter 92 CART therapy is a form of cancer treatment that is referred to as immunotherapy or immune effector cell therapy CAR T cells consist of autologous T cells that are genetically modified to identify specific cell surface markers on tumor cells (i.e., CD19 and/ or CD22 in the case of B-cell ALL) After the T cell binds to the target on the surface of the cell, T-cell activation is triggered and results in tumor cell killing CART therapy has been most frequently used in pediatrics for the treatment of relapsed or refractory B-cell ALL.275 Historically, patients with relapsed/refractory B-cell ALL have done poorly, with an overall survival ranging from 30% to 40% with chemotherapy alone.276–281 In early trials, CART therapy resulted in an almost 90% complete remission rate and a 1-year event-free survival rate of 50%.282,283 The first CART product to be approved by the US Food and Drug Administration for use in pediatric and young adult patients was Novartis’s Tisagenlecleucel (Kymriah) in 2017, with the treating indication of relapsed/refractory B-cell ALL.284 While this new form of cancer therapy holds much promise in the treatment of a number of different malignancies, there is an associated risk of substantial acute complications, namely, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) CRS is thought to be the result of CAR T-cell activation leading to the release of a milieu of proinflammatory cytokines Most patients (76%–100%) will experience some degree of CRS after CART therapy, most commonly in the first to weeks following the infusion of cells, but with a time frame ranging from hours to weeks.285–287 The systemic inflammatory response that characterizes CRS clinically resembles that of sepsis in the patient, with fevers, hypotension, cytopenias, coagulopathy, and the potential for multiorgan dysfunction Due to the similarity in presentation, active infection must be ruled out and appropriately 1127 treated CRS is graded in severity based on clinical characteristics and the need for interventions (eTable 93.3).288 Notably, imaging and laboratory studies are not included in the grading criteria since measurement of specific cytokines is often not available, can be unreliable, and may lag behind the clinical presentation The development of biomarkers to help predict the development of CRS and to trend its resolution is an area under investigation.289 ICU management was required in 27% to 44% of patients enrolled in past clinical trials due to CRS.282,283,285,290 The development of severe CRS has been linked to a number of factors: higher malignant disease burden prior to treatment, greater cell dose of CAR T cells, and the degree of elevation of proinflammatory cytokines such as interferon-g and IL-6 following infusion.288 Treatment of CRS consists of supportive care (acetaminophen for fever, vasopressors, mechanical ventilation, renal replacement therapy, and other therapies as needed) as well as the drug tocilizumab, which is a monoclonal antibody to the IL-6 receptor, reducing the proinflammatory effects of IL-6 Siltuximab is also a monoclonal antibody, which works by directly binding IL-6 and has been used to treat CRS refractory to tocilizumab.286–288,291 Efforts had previously been made to avoid steroids or early use of anticytokine therapy due to the fear of CAR T-cell loss from lymphotoxicity or due to the potential for decreased treatment efficacy if the inflammatory response was hindered However, retrospective studies have not appeared to be consistent with these findings and more formal studies are needed As a result, the overall trend in management has been the use of early anticytokine therapy with tocilizumab upon the initial appearance of findings consistent with CRS.286–288 If the patient is deteriorating despite alternative measures, the use of steroids should be considered Overall, the treatment algorithms for CRS are variable in terms of when certain medications, such as tocilizumab, should be given Treatment is often dictated by the specific CART product used, treating center experience, and/or whether the patient is enrolled in a specific clinical trial ICANS is the second most common complication attributed to CART therapy It consists of neurotoxicity presenting as one or more of the following: headache, tremor, confusion, dysgraphia, expressive aphasia, delirium, seizures, encephalopathy, and, rarely, cerebral edema.285,288 It has been reported to occur in 25% to 50% of patients receiving CART therapy.285,292 Its mechanism has not been fully elucidated, making identification and treatment less clear than that of CRS.293 Imaging and laboratory markers have not demonstrated consistent findings in patients who have developed ICANS but are frequently performed to rule out other causes of neurologic deterioration Brain MRI may be normal, but it may also reveal cerebral edema, microhemorrhages, or leptomeningeal enhancement MRI may be performed serially in patients in whom there is concern for clinical deterioration.285,287,288,294 Electroencephalography may demonstrate slowing or seizure activity, depending on the severity Neurology consultation is recommended and fundoscopic exam is also frequently performed to assess for papilledema as a marker of increased intracranial pressure (ICP).288 ICANS most typically occurs either during or following CRS However, it may also occur alone, without a history of prior CRS Occasionally, patients will have a delayed onset a few weeks following the CAR T-cell infusion Because symptoms of ICANS can be vague and were historically difficult to quickly ascertain, a scoring tool has been proposed along with an associated grading scale.288 Separate grading and scoring criteria have also been developed for adults (eTable 93.4) and children (eTable 93.5) due to the differences in 1127.e1 eTABLE Consensus Criteria for Clinical Staging and 93.2 Grading of Acute Graft-Versus-Host Disease (GVHD) Acute GVHD Skin Liver Gut Rasha ,25% or persistent nauseab Bilirubin 2–3 mg/dLc Diarrhea 500 mL/dayd Rash 25%–50% Bilirubin 3–6 mg/dL Diarrhea 1000 mL/day Rash 50% Bilirubin 6–15 mg/dL Diarrhea 1500 mL/day Generalized erythroderma with bullae Bilirubin 15 mg/dL Severe abdominal pain with or without ileus I Stages 1–2 None None II Stage or Stage or Stage III — Stages 2–3 or Stages 2–4 IV Stage or Stage or Stage 4f Stage Gradee a Use “rule of nines” or burn chart to determine extent of rash Persistent nausea with histologic evidence of GVHD in the stomach or duodenum c Range given as total bilirubin Downgrade one stage if an additional cause of elevated bilirubin can be documented d Volume of diarrhea applies to adults For pediatric patients, the volume of diarrhea should be based on body surface area Downgrade one stage if an additional cause of diarrhea has been documented e Criteria for grading given as degree of organ involvement required to confer that grade f Grade IV may include lesser organ involvement with Karnofsky performance status ,50%; thus patients with stage gut GVHD usually are grade IV Data from Przepiorka D, Weisdorf D, Martin P, et al 1994 consensus conference on acute GVHD grading Bone Marrow Transplant 1995;15:825-828 b eTABLE Cytokine Release Syndrome (CRS) Grading 93.3 Parameter a Fever Grade Grade Grade Grade Temperature 38°C Temperature 38°C Temperature 38°C Temperature 38°C None Not requiring vasopressors Requiring a vasopressor with or without vasopressin Requiring multiple vasopressors (excluding vasopressin) None Requiring low-flow nasal cannulac or blow-by Requiring high-flow nasal cannula,c facemask, nonrebreather mask, or Venturi mask Requiring positive pressure (e.g., CPAP, BiPAP, intubation, and mechanical ventilation) With Hypotension And/orb Hypoxia a Fever is defined as temperature 38°C not attributable to any other cause In patients who have CRS and then receive antipyretic or anticytokine therapy, such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity In this case, CRS grading is driven by hypotension and/or hypoxia b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause For example, a patient with a temperature of 39.5°C, hypotension requiring vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade CRS c Low-flow nasal cannula is defined as oxygen delivered at #6 L/min Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics High-flow nasal cannula is defined as oxygen delivered at L/min BiPAP, Bilevel positive airway pressure; CPAP, continuous positive airway pressure Data from Lee DW, Santomasso BD, Locke FL, et al ASBMT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells Biol Blood Marrow Transplant 2018;1–14 1127.e2 eTABLE ASBMT ICANS Assessment for Adults: Immune Effector Cell-Associated Encephalopathy (ICE) 93.4 Score and Consensus Grading Orientation Orientation to year, month, city, hospital: points Naming Ability to name three objects: points Following commands Ability to follow simple commands (e.g., “show me two fingers”): point Writing Ability to write a standard sentence: point Attention Ability to count backwards from 100 by 10: point Scoring 10 no impairment; 7–9: grade ICANS; 3–6: grade ICANS; 0–2: grade ICANS; (inability to perform assessment): grade ICANS Neurotoxicity Domain Grade Grade Grade Grade ICE score 7–9 3–6 0–2 Depressed level of consciousnessb Awakens spontaneously Awakens to voice Awakens only to tactile stimulus Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse Stupor or coma Seizure N/A N/A Any clinical seizure, focal or generalized, that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention Life-threatening prolonged seizure (.5 min) or repetitive clinical or electrical seizures without return to baseline in between Motor findingsc N/A N/A N/A Deep focal motor weakness, such as hemiparesis or paraparesis Elevated ICP/cerebral edema N/A N/A Focal/local edema on neuroimagingd Diffuse cerebral edema on neuroimaging; decerebrate or decorticate posturing; or cranial nerve VI palsy; or papilledema; or Cushing triad a ICANS grade is determined by most severe event above Patient with an ICE score of may be classified as grade ICANS if awake with global aphasia, but a patient with an ICE score of may be classified as grade ICANS if unarousable b Depressed level of consciousness may be attributable to no other cause (i.e., no sedating medications) c Tremors and myoclonus associated with immune effector cell therapies may be graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0, but not influence ICANS grading d Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading It may be graded according to CTCAE v5.0 ASBMT, American Society for Blood and Marrow Transplantation; EEG, electroencephalography; ICANS, immune effector cell-associated neurotoxicity syndrome; ICP, intracranial pressure Data from Lee DW, Santomasso BD, Locke FL, et al ASBMT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells Biol Blood Marrow Transplant 2018;1-14 a 1127.e3 eTABLE ASBMT ICANS Assessment and Consensus Grading for Children 93.5 Never Rarely Sometimes Often Always Answer the following based on interactions with the child over the course of the shift: Does the child make eye contact with the caregiver? Are the child’s actions purposeful? Is the child aware of his/ her surroundings? Does the child communicate needs and wants? Never Rarely Sometimes Often Always Neurotoxicity Domain Grade Grade Grade Grade ICE score for children 12 yearsa 7–9 3–6 0–2 CAPD score for children ,12 years 1–8 1–8 9 Unable to perform Depressed level of consciousness Awakens spontaneously Awakens to voice Awakens only to tactile stimulus Unarousable or requires vigorous or repetitive tactile stimuli to arouse; stupor or coma Seizure N/A N/A Any clinical seizure, focal or generalized, that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention Life-threatening prolonged seizure (.5 minutes); or repetitive clinical or electrical seizures without return to baseline in between Motor weaknessc N/A N/A N/A Deep focal motor weakness, such as hemiparesis or paraparesis Elevated ICP/cerebral edema N/A N/A Focal/local edema on neuroimagingd Decerebrate or decorticate posturing; or cranial nerve VI palsy; or papilledema; or Cushing triad, or signs of diffuse cerebral edema on neuroimaging Is the child restless? Is the child inconsolable? Is the child underactive; very little movement while awake? Does it take the child a long time to respond to interactions? b ICANS grade is determined by the most severe event (ICE or CAPD score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema) not attributable to other cause Baseline CAPD score should be considered before attributing to ICANS a A patient with an ICE score of may be classified as grade ICANS if awake with global aphasia, but a patient with an ICE score of may be classified as grade ICANS if unarousable b Depressed level of consciousness may be attributable to no other cause (i.e., no sedating medications) c Tremors and myoclonus associated with immune effector cell therapies may be graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 but not influence ICANS grading d Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading It may be graded according to CTCAE v5.0 ASBMT, American Society for Blood and Marrow Transplantation; CAPD, Cornell Assessment of Pediatric Delirium; EEG, electroencephalography; ICANS, immune effector cell-associated neurotoxicity syndrome; ICE, immune effector cell-associated encephalopathy; ICP, intracranial pressure Data from Lee DW, Santomasso BD, Locke FL, et al ASBMT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells Biol Blood Marrow Transplant 2018;1-14.; and Traube C, Silver G, Kearney J, et al Cornell Assessment of Pediatric Delirium: a valid, rapid, observational tool for screening delirium in the PICU Crit Care Med 2014;42:656-663 ... persistent/repetitive symptoms and either radiographic or CSF abnormalities following HCT died More than one-third died as a result of their neurologic complication.254 In another study of 113 pediatric allogeneic... complication following HCT were significantly more likely to die than those who did not have them.263 Thirty-three (32%) of 102 patients without a neurologic complication had died at years of follow-up... Tisagenlecleucel (Kymriah) in 2017, with the treating indication of relapsed/refractory B-cell ALL.284 While this new form of cancer therapy holds much promise in the treatment of a number of different malignancies,