CONTENTS
- Initial approach to CAR-T recipient in ICU
- CRS (cytokine release syndrome)
- HLH (hemophagocytic lymphohistiocytosis)
- DIC (disseminated intravascular coagulation)
- ICANS (immune effector cell-associated neurotoxicity syndrome)
- Podcast
- Questions & discussion
- Pitfalls
laboratory tests
- CAR-T lab panel (obtained daily for patients with CRS and/or ICANS):
- 🚗 Electrolytes, including Ca/Mg/Phos and uric acid.
- 🚗 Complete blood count with differential.
- 🚗 INR, PTT, fibrinogen.
- 🚗 CRP and ferritin.
- Infection evaluation:
- Blood cultures x2.
- Urinalysis and urine culture (if clinically appropriate).
- Nasal swab PCR for COVID +/- influenza, respiratory viruses.
- Procalcitonin (only for non-neutropenic patients who are being treated empirically with antibiotics for suspected sepsis).
imaging
- Chest X-ray (if febrile, hypoxic, or pulmonary symptoms).
- Additional scans as clinically warranted (e.g., CT head if neurologic abnormalities).
basics of CRS (cytokine release syndrome)
- CRS is a systemic inflammatory syndrome caused by immunotherapy, characterized by fever and multiple organ dysfunction.
epidemiology of CRS
- CRS is extremely common, with most patients experiencing at least some degree of CRS. Overall, about half of patients may require immunomodulatory therapy (e.g., tocilizumab, steroid).
- Risk factors for CRS include:(34613616)
- Higher tumor burden.
- Tumor type (e.g., higher rates with B-cell acute lymphoblastic leukemia).(32705293)
- Greater baseline inflammation.
- Risk factors for severe CRS include:
- Higher tumor burden.
- Concurrent infection.
- Development of CRS within <3 days after CAR-T infusion.
- Onset:
- Usually 2-3 days after infusion (range of ~1-14 days).(34461398)
- Duration:
- Median of about one week (with a range of ~2-58 days).
- Earlier initiation of therapy may reduce the duration.
clinical manifestations of CRS
Overall, CRS ranges from a flu-like illness to a sepsis-like illness with multiorgan failure. Manifestations may include:
- Fever and flu-like symptoms are the first features (e.g., chills, rigors, headache, myalgia, nausea, vomiting, diarrhea).(34613616, 32705293)
- Fever >38C is a requisite initial feature of CRS.
- Cardiac:
- Arrhythmias, including atrial fibrillation and ventricular tachycardia.
- Vasodilatory shock due to systemic inflammation.
- Systolic heart failure (new-onset cardiomyopathy).(34461398)
- Respiratory failure, which may require intubation.
- Acute kidney injury.
- Skin rash may be seen.
- Neurologic findings may occur among patients with simultaneous CRS and ICANS. These are described further below 📖.
laboratory findings of CRS
- Electrolytes:
- Hypophosphatemia is very common.
- Hypokalemia is common.
- Tumor lysis syndrome 📖 may occur simultaneously with CRS.
- CRP is generally elevated, with some limitations:
- CRP may lag behind clinical changes.
- Tocilizumab will suppress IL-6 and reduce the CRP level directly. Following tocilizumab therapy, CRP won't track with the severity of CRS.
- Procalcitonin has limited value in the context of CRS, especially among patients who are neutropenic. However, if a non-neutropenic patient has a procalcitonin which is well below 0.4 ng/mL, that suggests the absence of a bacterial infection.(36752185)
differential diagnosis of CRS
- Infection (including septic shock).
- Bacterial infection.
- Viral infection (especially COVID).
- Opportunistic infections.
- Heart failure.
- Pulmonary embolism.
- Hemophagocytic lymphohistiocytosis. 📖
- Tumor lysis syndrome.
staging of CRS
- Grade 1:
- Fever >38C not attributable to another etiology.*
- No hypotension or hypoxemia.
- Grade 2:
- Fever >38C not attributable to another etiology.*
- Either hypotension (not on pressors) and/or hypoxemia (≦6 liters/min).
- Grade 3:
- Fever >38C not attributable to another etiology.*
- Either hypotension (on single pressor, not counting vasopressin) and/or hypoxemia (requiring high flow nasal cannula or Venturi mask).
- Grade 4:
- Fever >38C not attributable to another etiology.*
- Hypotension (on multiple pressors, not counting vasopressin) and/or positive pressure ventilation (CPAP, BiPAP, or intubation).
*Fever may dissipate after treatment with tocilizumab and steroid. Subsequently, fever is not a required component of CRS.
management of CRS
general supportive care
- Empiric antibiotic therapy is reasonable initially if there is concern for septic shock (especially among patients with neutropenia).
- Acetaminophen may be beneficial.
- ⚠️ Avoid the use of GM-CSF (granulocyte-macrophage colony-stimulating factor) for patients with neutropenia, since this could exacerbate CRS. Indeed, neutralization of GM-CSF is being investigated as a treatment for CRS.
patients with simultaneous CRS and ICANS****
- Many patients will develop both CRS and ICANS together. Management may involve a combination of the therapies in this section, plus treatments in the section below on ICANS. 📖
- Tocilizumab is useful for CRS, but it may exacerbate ICANS:
- Dexamethasone is beneficial for both CRS and ICANS.
- When CRS and ICANS occur together, overall treatment should lean more heavily on dexamethasone (which treats both processes). For example:
tocilizumab
- Indications for tocilizumab:
- Grade 1 CRS: Consider 1 dose of tocilizumab if:
- (i) Prolonged CRS >72 hours.
- (ii) Prolonged CRS >24 hours following axicabtagene ciloleucel or brexucabtagene autoleucel.
- (iii) Significant symptoms, comorbidities, and/or age >65 years old.
- Grade 2 or higher CRS: dose as described below.
- Grade 1 CRS: Consider 1 dose of tocilizumab if:
- Dosing:
- Start with administration of 8 mg/kg (max dose 800 mg) over one hour. If there is no improvement, repeat this dose q8hr as needed. Limit to a maximum of 3 doses in a 24-hour period, as well as a maximum of 4 doses total.
- Note that tocilizumab should be titrated against symptoms of CRS (not symptoms of ICANS).
- ⚠️ Tocilizumab suppresses fever and CRP, so subsequent infection may be difficult to diagnose.(34613616)
steroid dosing for CRS
- Grade 1:
- Steroid is only selectively indicated:
- (a) For persistence >72 hours, consider management as per grade 2.
- (b) For idecabtagene and lisocabtagene, consider IV dexamethasone 10 mg q24 hours for early-onset CRS (<72 hours after infusion).(35390769)
- Grade 2:
- In patients with hypotension that persists after fluid resuscitation and after 1-2 doses of tocilizumab, consider dexamethasone 10 mg IV q12-q24 hours depending on the product for one or two doses, then reassess.
- Axicabtagene ciloleucel: Consider dexamethasone 10 mg IV q24 hours after the initial tocilizumab dosing, regardless of clinical response to tocilizumab.
- If no improvement within >24 hours of starting tocilizumab, manage as per grade 3.
- In patients with hypotension that persists after fluid resuscitation and after 1-2 doses of tocilizumab, consider dexamethasone 10 mg IV q12-q24 hours depending on the product for one or two doses, then reassess.
- Grade 3:
- Dexamethasone 10 mg IV q6-12hr, depending on the product (e.g., perhaps q6hr for axicabtagene or brexucabtagene). Rapidly taper once symptoms improve.
- If refractory, manage as per grade 4.
- Grade 4:
- Dexamethasone 10 mg IV q6hrs.
- If refractory to dexamethasone, consider 1,000 mg methylprednisolone daily for three days.
refractory CRS
- If the above therapies are unsuccessful, additional options may include anakinra or ruxolitinib. (34613616)
- Consider whether the patient may have HLH (section below). Treatment-refractory CRS and HLH exhibit significant overlap – with very similar management.
treatment guidelines:
- Footnotes:
- (h) For axicabtagene ciloleucel or brexucabtagene autoleucel, can consider tocilizumab if CRS symptoms persist for >24 hours.
- (i) For lisocabtagene maraleucel, consider tocilizumab for grade 1 CRS that develops <72 hours after infusion and consider adding dexamethasone 10 mg x 1. For CRS developing ≥72 hours after infusion, treat symptomatically.
- (j) After each dose, assess need for subsequent dosing.
- (k) Antifungal prophylaxis should be strongly considered in patients receiving steroids for the treatment of CRS and/or neurotoxicity.
- (l) Per the prescribing information for axicabtagene ciloleucel, consider the use of prophylactic steroids in patients after weighing the potential benefits and risks. Steroid prophylaxis for axicabtagene ciloleucel is dexamethasone 10 mg orally once daily for 3 days with the first dose starting pre-CAR T-cell infusion.
- (m) Alternative steroids at an equivalent dose may be considered.
- (n) For axicabtagene ciloleucel, consider IV dexamethasone 10 mg every 24 hours after initial tocilizumab dosing, regardless of clinical response to tocilizumab. For
lisocabtagene maraleucel, consider IV dexamethasone 10 mg every 12–24 hours if early-onset CRS. For idecabtagene vicleucel, consider IV dexamethasone 10 mg every 12–24 hours. - (o) For example, IV methylprednisolone 1000 mg/day for 3 days, followed by rapid taper at 250 mg every 12 h for 2 days, 125 mg every 12 h for 2 days, and 60 mg every 12 h for 2 days.
- (p) Other agents such as anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG, ATG, intrathecal chemotherapy, or extracorporeal cytokine adsorption with continuous renal replacement therapy (CRRT) might be considered. Reported experience with these agents is limited. Use of these therapies should be balanced against potential safety concerns, such as infection risk.
- (q) GM-CSF is not recommended in the setting of CAR T-cell therapy. An FDA-approved biosimilar is an appropriate substitute for filgrastim.
- ✝ Under conditions of limited tocilizumab availability, consider one of the following conservation strategies:
- Limit tocilizumab use to a maximum of 2 doses during a CRS episode.
- Consider using steroids more aggressively during a CRS episode.
- If necessary, consider replacing the second dose of tocilizumab with siltuximab or anakinra, although there is very limited evidence to support this approach.
basics
- CRS has many similarities to HLH, but they're not the same. CRS and HLH may exist on a spectrum of systemic hyperinflammation, with HLH representing more profound inflammation.(33559517)
- CAR-T cell therapy may rarely precipitate full-blown HLH. This will look a lot like CRS, but it may be refractory to usual treatments for CRS. HLH might occur at a rate of ~2-4% (but numbers are difficult to pin down, in the absence of clear diagnostic criteria).(33559517, 34724386, 35390769)
- CAR-T induced HLH tends to occur in the context of an additional HLH trigger:
- HLH often occurs in association with an underlying diffuse large B-cell lymphoma (DLBCL) or B-cell acute lymphoblastic leukemia (B-ALL). This process might be best regarded as HLH due to an underlying malignancy (exacerbated by CAR-T therapy).
- HLH may occur due to reactivation of systemic viral infection (e.g., EBV or CMV).
- (Further discussion of causes of HLH: 📖)
diagnosis of HLH due to CAR-T
The diagnosis of HLH is murky, since HLH and CRS have numerous similar features. Some criteria exist for HLH due to CAR-T therapy, but they are not properly validated. Features that may suggest a diagnosis of HLH include the following:
- Underlying diffuse large B-cell lymphoma (DBCL) or B-cell acute lymphoblastic leukemia (B-ALL).
- Profoundly elevated ferritin (e.g., >5,000-10,000 ng/mL).(34724386, 35390769)
- Hepatomegaly and/or splenomegaly.
- Unexplained cytopenias.
- Persistent fevers.
- Unusually prominent hyperfibrinolysis (with reduced fibrinogen and markedly elevated D-dimer).
- Hypertriglyceridemia.
- Failure to respond to standard therapies for CRS.
- Hemophagocytosis on tissue biopsy (e.g., bone marrow).
management of HLH
- Tocilizumab and steroid should be utilized, similar to the therapy for CRS (as outlined above). In milder cases of HLH, these therapies may be successful. Higher doses of steroid than usual may be considered.(35390769)
- Additional therapies may include high-dose anakinra 📖, ruxolitinib 📖, or etoposide.
- Anakinra seems to be a preferred therapy for patients not responding to steroid and tocilizumab.(35390769) If anakinra is utilized, rheumatologic doses may fail (e.g., 100 mg/day). Higher doses of anakinra are probably needed (e.g., ~5-8 mg/kg/day).(33559517) For example, 8 mg/kg/day was more effective in one study.(Gazeau 2021)
- Ruxolitinib inhibits signaling via multiple cytokine pathways. It has been shown to be effective for HLH with a favorable safety profile.
- Etoposide is a treatment of last resort. Etoposide is toxic to T-lymphocytes, so it may ablate the CAR-T cells – thereby undoing the benefit of CAR-T therapy altogether.(33559517)
- Fibrinogen replacement may be needed. ASCO guidelines suggest targeting a fibrinogen level >150 mg/dL.(34724386)
- Any additional trigger(s) of HLH should be treated (e.g., CMV, EBV).
basics
- DIC often occurs within the context of CRS or HLH. However, DIC may also occur as an isolated complication of CAR-T therapy.
- The diagnosis of DIC is based upon standard criteria (the International Society of Thrombosis and Hemostasis DIC score 📖). Alternative causes of DIC should be evaluated and excluded (e.g., sepsis).
management
- Supportive care should be provided, including blood product replacement for patients with active hemorrhage. Additionally, consider maintenance of a fibrinogen level >150 mg/dL.(34724386)
- Severe DIC is itself an indication for tocilizumab and steroid. For further details, see the ASCO guidelines 📄.(34724386)
basics
- ICANS is an encephalopathy due to systemic inflammation (which may cause increased endothelial permeability). ICANS usually occurs in the context of CRS, but not always.
- ICANS might be most similar to acute necrotizing encephalopathy 📖, another disorder which seems to be triggered by excessive systemic inflammation. ICANS also has some parallels to sepsis-induced encephalopathy. However, it's likely that different patients with ICANS may have different underlying pathophysiology (e.g., in some cases macrophages infiltrate the parenchyma of the brain, whereas other cases may involve prominent edema without cellular infiltration).(33140239)
epidemiology of ICANS
incidence
- ICANS is extremely common, occurring in perhaps ~75% of patients treated with axicabtagene ciloleucel or brexucabtagene autoleucel. Lower rates occur with other CAR-T constructs.
risk factors for ICANS include:
- Fludarabine use for pre-treatment lymphodepletion.(33140239)
- Different CAR-T constructs:(35570737)
- anti-CD19 products (axicabtagene ciloleucel, brexucabtagene autoleucel) have highest risk.
- Tisagenlecleucel and idecabtagene vicleucel have intermediate risk.
- Lisocabtagene ciloleucel has the lowest risk.
- Cancer type (ALL > lymphoma >>> multiple myeloma).(33040871)
- Higher burden of underlying malignancy (e.g., percent of bone marrow occupancy by ALL).(33040871)
- Pre-existing neurological comorbidities (including abnormal baseline neuroimaging). CAR-T therapy may trigger worsening of chronic neurologic disorders.(36877916)
- CRS that is severe and/or early-onset.
- Elevated inflammatory markers.
- Consumptive coagulopathy (thrombocytopenia <50 b/L, low fibrinogen, elevated D-dimer).
- Factors predisposing to capillary leak (low albumin, obesity).(32503897)
- (Sources disagree about the effect of age.)(36122055)
timing
- Onset:
- ICANS usually begins within the first week after CAR-T therapy, with a median onset of ~4-6 days. However, the range of onset is broad (extending out to months after CAR-T therapy). Onset may vary depending on the underlying malignancy and specific CAR-T treatment.
- ICANS often begins 2-4 days after CRS.
- Up to 10% of ICANS cases may begin >3 weeks post-infusion (e.g., following discharge from the hospital).(32503897)
- Duration:
- The median duration of symptoms is about 2-3 weeks.
- Prolonged encephalopathy lasting months can occur.
clinical manifestations of ICANS
common initial features:
- Language abnormalities:
- Early findings may include dysgraphia and/or expressive dysphasia (e.g., word-finding difficulties, verbal perseveration, hesitant speech, or paraphasic errors).(32503897)
- Expressive aphasia evolving into global aphasia is highly suggestive of ICANS).(34613477) This is unlike a stroke, which typically would cause rapid onset of aphasia.
- Tremor (described as heightened physiologic tremor), fine motor impairment, asterixis, myoclonus.(34724386, 33040871)
- Alteration in consciousness. A typical presentation is often described as encephalopathy with preserved alertness.(32503897)
- Deficits often fluctuate, with resolution and reappearance over time.(34724386)
other features include:
- Focal or generalized weakness can occur.
- Autonomic instability.(36525238)
- Headache, meningeal irritation.(36525238)
- Seizures (including status epilepticus).
- 🚨 Clinical features of cerebral edema may rarely occur: 📖
- Somnolence, obtundation.
- Headache.
- Nausea, vomiting.
- Visual alterations (vision loss, flashing lights, diplopia).
- Hypertension, bradycardia (Cushing response).
radiology of ICANS
overview
- Neuroimaging is recommended for patients with Grade 2 or higher ICANS.(NCCN guidelines 35390769) MRI with and without contrast is preferable if possible.
- Most patients with ICANS have normal neuroimaging (especially on CT scan).(34191544) However, patients with ICANS may also display a broad range of imaging abnormalities. Below are some more common findings, but other patterns are certainly possible.(35570737) Patterns below may occur in isolation, or multiple patterns may be seen simultaneously.
bilateral thalami and deep gray structures
- The most common imaging pattern might be symmetric T2/FLAIR hyperintensities that involve the thalami (especially the dorsal medial thalami), as well as the dorsal pons and tectal plate.(36525238, 33040871)
- Usually there is not contrast enhancement or diffusion restriction.
- Microhemorrhages may occur in affected areas.
- Wernicke encephalopathy can cause similar abnormalities, so empiric thiamine administration may be considered.
- This process might have some parallels with acute necrotizing encephalopathy (ANE). 📖
white matter FLAIR hyperintensities
- Patchy, reversible T2 hyperintensities may occur in the white matter. These may enhance with contrast.
- Distribution:
- Supratentorial or cerebellar white matter can be involved.
- Areas that tend to be involved may include the periventricular white matter, external capsule, extreme capsule, and claustrum.
- This can occur in areas with prior injury due to other causes.
diffuse cerebral edema
- Diffuse cerebral edema can be difficult to detect on neuroimaging, because diffuse edema may not cause any dramatic tissue shifts. Potential findings may include:
- Sulcal effacement.
- Reduced ventricular size.
- Cerebral edema is the most worrisome finding on neuroimaging. This may progress to malignant edema, causing herniation and death.
- Diffuse cytotoxic cortical edema may occur with diffusion restriction, which may be especially concerning. (34191544)
leptomeningeal enhancement
- Diffuse leptomeningeal enhancement may occur.(33391257) Unfortunately this pattern may be caused by infection, so lumbar puncture is needed to evaluate further.
involvement of the splenium of the corpus callosum
- T2 hyperintensity with diffusion restriction may involve the splenium of the corpus callosum.(33140239) Resolution occurs on follow-up imaging.
- This syndrome may resemble mild encephalopathy with reversible splenial lesion (MERS). 📖
other findings on neuroimaging may include:
- PRES-like findings.(35570737)
- Ischemic and hemorrhagic stroke.(33040871)
- Nonaneurysmal convexity subarachnoid hemorrhages.(33040871)
- Myelitis.(36877916)
laboratory findings of ICANS
- Laboratory abnormalities in ICANS are nonspecific:
- Systemic inflammation is often present (e.g., elevated CRP). However, CRP can normalize prior to the onset of ICANS.(35390769) Overall, inflammatory markers correlate well with CRS, but not with ICANS.(34055373)
- Consumptive coagulopathy may be present (e.g., thrombocytopenia, hypofibrinogenemia, elevated D-dimer).
- Laboratory evaluation is mostly useful to exclude alternative causes of delirium. 📖
- More on the evaluation of neuro-oncologic emergencies: 📖
lumbar puncture in ICANS
indication?
- The main rationale for lumbar puncture is to exclude CNS infection.
- Not all patients with ICANS necessarily require a lumbar puncture. Higher grade ICANS may be a stronger indication (e.g., Grade 3-4 ICANS).(35390769)
- Some experts have suggested that CSF removal may have a therapeutic role.(36877916)
safety barriers to lumbar puncture
- (1) Coagulopathy is common among this patient population (which may include thrombocytopenia and/or hypofibrinogenemia).
- ⚠️ Don't forget to check a fibrinogen level.
- (2) Diffuse cerebral edema on neuroimaging is a contraindication to lumbar puncture (since this may precipitate herniation).
- (3) Agitation, with subsequent inability to cooperate with the procedure, may be problematic.
CSF tests to obtain
- Opening pressure should be measured (as an index of intracranial pressure 📖).
- ICP in mm = 0.7(opening pressure in cm).
- 🔑 Significantly elevated opening pressure implies the presence of Grade 4 ICANS, which may have significant treatment implications.
- Cytology should be obtained (to evaluate for malignancy or hemophagocytosis).(36122055)
- PCR for JC virus may be considered, if progressive multifocal leukoencephalopathy is a consideration. 📖
- More on CSF tests to order here: 📖
CSF findings in ICANS
- CSF may be normal.
- Protein may be mildly or severely elevated (this correlates with the severity of ICANS, as a reflection of blood-brain barrier disruption).(32503897) Protein has a median level of 80-110 mg/dL, but may occasionally be >1,000 mg/dL.(33391257)
- Mild lymphocytic leukocytosis often occurs, but the cell count is rarely above 100 cells/uL.(32503897; 33140239)
EEG findings in ICANS
role of EEG in ICANS
- (1) Evaluation for seizures or ictal-interictal findings: Consider EEG for any patient with otherwise unexplained mental status alteration in the context of CAR-T therapy.
- (2) EEG findings usually track with the severity of ICANS, potentially providing an early warning sign of deterioration.
various findings may occur in ICANS:
- Relatively benign:
- Ictal-interictal continuum patterns:
diagnosis & differential diagnosis of ICANS
diagnosis of ICANS
- ICANS is usually a diagnosis of exclusion.
- The general approach to evaluation will depend on any individual patient's presenting findings. For patients presenting with encephalopathy, the approach is similar to the diagnostic strategy for a patient with delirium. 📖
differential diagnosis
- More common:
- Sepsis-related encephalopathy.
- Meningitis or encephalitis (including opportunistic infections, such as HHV6, CMV).
- Stroke (including hemorrhagic, due to coagulopathy).
- Medication-induced delirium.
- Metabolic abnormalities.
- PRES:
- Tumor inflammation associated neurotoxicity (TIAN) – if tumor is present in the CNS, it may become inflamed following CAR-T treatment.(36877916)
- Less common:
staging of ICANS
ICE score (0-10)
- 🧊 Orientation (4 points) – Year, month, city, hospital.
- 🧊 Naming (3 points) – Ability to name three objects.
- 🧊 Follow a simple command (1 point).
- 🧊 Able to write a sentence (1 point).
- 🧊 Attention – ability to count backwards from 100 in 10s (1 point).
grade ICANS based on the most severe finding:
- Grade 1:
- ICE score: 7-9.
- Consciousness: Normal level of consciousness.
- Grade 2:
- ICE score: 3-6.
- Consciousness: Mild somnolence (awakening to voice).
- Grade 3:
- ICE score: 0-2.
- Consciousness: Awakening only to tactile stimulus.
- Seizure:
- Clinical seizure that resolves rapidly.
- Nonconvulsive seizures on EEG that resolve with intervention.
- Neuroimaging: shows focal edema.
- Grade 4:
- ICE score: Cannot be performed due to impaired consciousness. (Note that a patient with global aphasia who is awake would be classified as Grade 3).(36122055)
- Consciousness: Unarousable or requires vigorous or repetitive tactile stimuli to arouse (stupor/coma).
- Seizure: Life-threatening, prolonged seizure (>5 minutes) or repetitive clinical or electrical seizures without return to baseline (status epilepticus).
- Neuroimaging shows diffuse cerebral edema.
- Clinical evidence of ICP elevation:
- Decerebrate or decorticate posturing.
- Cranial nerve VI palsy.
- Cushing's triad (bradycardia, hypertension, irregular respirations).
- Papilledema.
management of ICANS
supportive management
- Fever should be aggressively managed (e.g., with scheduled acetaminophen).
- Review medication list:
- Discontinue medications that may suppress mental status (if possible).
- Discontinue medications that may lower seizure threshold (if possible). This includes antibiotics such as cefepime and meropenem.(36877916)
- Thiamine supplementation should be considered, since thiamine deficiency is common in this patient population and may decrease blood-brain barrier function. Some experts recommend high-dose IV thiamine therapy for any patients with severe ICANS or CRS.(36877916)
combined CRS plus ICANS
- ~90% of patients with ICANS also have CRS.(34461398) Reported fatal cases of ICANS almost always occur simultaneously with CRS.(34191544)
- Treatment involves components of therapy for both conditions.
- Some nuances regarding management of this combination are discussed above, in the section on CRS. 📖
steroid dosing for ICANS
- Steroid is the cornerstone of treatment for ICANS. Dexamethasone might be preferred over methylprednisolone, given its greater penetration of the CNS.
- Grade 1:
- Isolated ICANS: Steroid generally isn't indicated. However, for lisocabtagene maraleucel or idecabtagene vicleucel, if ICANS develops <72 hours after infusion then consider dexamethasone 10 mg every 12-24 hours x2 doses and reassess.
- ICANS plus CRS: Consider adding steroid for patients who are receiving tocilizumab (as discussed above, isolated tocilizumab may worsen ICANS). 📖
- Grade 2:
- One dose of IV dexamethasone 10 mg and reassess.
- Can repeat every 6-12 hours, if no improvement.
- Grade 3:
- All patients should receive dexamethasone 10 mg q6hr, until there is improvement.
- Grade 4:
- High-dose methylprednisolone (e.g., 1,000 mg daily for three days, then 250 mg q12hr for 2 days, then 125 mg q12hr for 2 days, then 60 mg q12 hours for 2 days).
steroid-refractory ICANS
- Steroid usually causes improvement within hours to days. Failure to improve should lead to re-evaluation of alternative diagnostic possibilities.
- Additional therapies:
- Anakinra is generally a front-line consideration. High doses may be needed; for example, 8 mg/kg/day was effective in one study.(Gazeau 2021)
- Ruxolitinib.
seizure prophylaxis
- Seizure prophylaxis should be considered for:
- Axicabtagene ciloleucel with any grade of neurological toxicity.
- Brexucabtagene autoleucel with Grade 2 or higher neurologic toxicity.
- Patients at increased risk for seizures:
- Seizure history.
- Known cortical lesion.
- Concerning EEG results.
- Levetiracetam 💉 is generally the preferred agent, due to its favorable toxicity and pharmacokinetic profiles. 500-750 mg IV/PO BID may be utilized (depending on weight and renal function).(36122055, 32503897)
seizure management
- Additional antiepileptic therapy may be needed for seizures or ictal-interictal abnormalities detected on EEG.
- Treatment may include augmentation of levetiracetam dose, and possibly the addition of other antiepileptics (e.g., valproic acid or lacosamide).
- EEG abnormalities in ICANS may be more responsive to dexamethasone than antiseizure medication.(32503897) Thus, failure to control EEG rhythms could be an indication for more aggressive systemic immunomodulatory therapy.
- Management of status epilepticus is discussed further here. 📖
management of intracranial pressure (ICP) elevation
- Malignant elevation of intracranial pressure may occur, which is the cause of most deaths due to ICANS.
- Osmotherapy 📖 may be utilized temporarily, as a bridge to the efficacy of immunomodulatory treatments (e.g., steroid).
- Moderate or deep sedation may decrease brain metabolic rate and reduce intracranial pressure (e.g., higher than usual doses of propofol). 📖
- Aggressive fever control (e.g., scheduled acetaminophen, therapeutic temperature management with a goal of 36C). 📖
- Acetazolamide may be utilized (although there is relatively little evidence supporting this). 💉 (36122055, 32503897)
- Further discussion of the treatment of ICP elevation is here: 📖
monitoring
- Neuroimaging should be considered for persistent/worsening neurotoxicity after 24 hours of treatment, and then every 2-3 days subsequently if the patient isn't improving.(36525238)
- The role for serial neuroimaging is greatest among patients with severe obtundation or coma, in whom a reliable neurological examination is unobtainable.
- video EEG should be considered.
treatment guidelines
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- Avoid early diagnostic closure (based on the assumption that patients have CRS and/or ICANS).
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- 📄 = Link to open-access journal article.
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Going further:
- ASCO 2021 guidelines: 📄
- NCCN guidelines: 📄 (latest NCCN version is free, but you need to login to see it).
References
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