17.3 Oncologic, Immunotherapy & Hematologic Emergencies: Febrile Neutropenia, TLS, Hypercalcemia, irAEs, CAR-T, Hemophilia & TTP
Key Takeaways
Febrile neutropenia (ANC below 500 cells/mm3 with a temperature of 38.3 °C, or 38.0 °C sustained for 1 hour) needs an antipseudomonal beta-lactam such as cefepime 2 g IV within 60 minutes.
Rasburicase rapidly lowers uric acid in tumor lysis syndrome, but it is contraindicated in G6PD deficiency because it causes hemolysis and methemoglobinemia.
The 2023 Endocrine Society guideline suggests denosumab over IV bisphosphonates for hypercalcemia of malignancy, adding calcitonin for 48 to 72 hours when calcium exceeds 14 mg/dL.
Tocilizumab 8 mg/kg (maximum 800 mg) treats cytokine release syndrome after CAR-T therapy, while isolated neurotoxicity (ICANS) is treated with dexamethasone.
In hemophilia A, each unit/kg of factor VIII raises activity about 2%, so a 70-kg patient needs about 3,500 units to reach 100%; give factor before imaging for head trauma.
17.3 Oncologic, Immunotherapy & Hematologic Emergencies: Febrile Neutropenia, TLS, Hypercalcemia, irAEs, CAR-T, Hemophilia & TTP
Note
Exam scope: 2025 outline subtopic 2B4 (Immunology, Oncology and Hematology). Anticoagulant reversal (Section 10.1), heparin-induced thrombocytopenia (Section 10.2) and sickle cell disease (Section 10.3) are covered elsewhere. Chemotherapy extravasation is covered in Section 16.2.
Febrile Neutropenia
Definitions (IDSA):
- Fever: a single oral temperature of 38.3 °C or higher, or 38.0 °C or higher sustained for 1 hour.
- Neutropenia: an ANC below 500 cells/mm3, or expected to fall below 500 within 48 hours.
Neutropenic patients may show few signs of infection, so treat fever as an emergency. Draw blood cultures (from each catheter lumen and a peripheral site), then give an antipseudomonal beta-lactam within 60 minutes:
| Agent | Typical adult dose |
|---|---|
| Cefepime | 2 g IV every 8 hours |
| Piperacillin-tazobactam | 4.5 g IV every 6 hours |
| Meropenem | 1 g IV every 8 hours (preferred with ESBL risk) |
Add vancomycin only for specific indications: hemodynamic instability, suspected catheter infection, skin or soft tissue infection, pneumonia, known MRSA colonization, or Gram-positive cocci in blood cultures before identification. Routine empiric vancomycin does not improve outcomes.
Low-risk outpatients (MASCC score of 21 or higher, or a low CISNE score, with reliable follow-up) can receive oral ciprofloxacin plus amoxicillin-clavulanate after an observation period (ASCO/IDSA 2018). Clindamycin can replace amoxicillin-clavulanate for penicillin allergy.
Tumor Lysis Syndrome (TLS)
TLS follows rapid cell death, usually within days of starting therapy for bulky, fast-growing cancers such as Burkitt lymphoma, acute leukemias and high-grade lymphomas. It can also occur on its own.
Cairo-Bishop laboratory criteria (two or more within 3 days before to 7 days after therapy):
- Uric acid of 8 mg/dL or more
- Potassium of 6 mEq/L or more
- Phosphate of 4.5 mg/dL or more (adults)
- Calcium of 7 mg/dL or less
Clinical TLS means laboratory TLS plus AKI, dysrhythmia, seizure or sudden death.
| Intervention | Details |
|---|---|
| Hydration | About 2 to 3 L/m2 a day, aiming for urine output of at least 80 to 100 mL/m2/h; avoid potassium in fluids |
| Allopurinol | Blocks new uric acid formation but does not remove existing uric acid; adjust for kidney function; interacts with azathioprine and mercaptopurine |
| Rasburicase | Converts uric acid to allantoin within hours. Labeled dose is 0.2 mg/kg daily for up to 5 days; a single fixed dose (3 to 6 mg) is common practice with repeat doses as needed |
| Urine alkalinization | Not recommended: it promotes calcium phosphate and xanthine precipitation |
| Hyperkalemia, hyperphosphatemia | Standard potassium treatment (Section 11.2) and phosphate binders; early nephrology involvement for dialysis |
| Hypocalcemia | Treat only symptomatic hypocalcemia; giving calcium when phosphate is high causes calcium phosphate deposition |
Warning
Rasburicase boxed warnings: anaphylaxis, hemolysis and methemoglobinemia in G6PD deficiency (screen high-risk patients first), and falsely low uric acid levels. Rasburicase keeps working in the blood tube, so samples must be collected in prechilled heparin tubes, kept on ice and assayed within 4 hours.
Hypercalcemia of Malignancy
The 2023 Endocrine Society guideline:
- Recommends an IV bisphosphonate or denosumab for all patients with hypercalcemia of malignancy.
- Suggests denosumab over an IV bisphosphonate.
- For severe hypercalcemia (calcium above 14 mg/dL), suggests adding calcitonin, limited to 48 to 72 hours because of tachyphylaxis.
- For refractory or recurrent hypercalcemia despite bisphosphonates, suggests adding denosumab.
- For tumors that produce calcitriol (lymphomas), suggests glucocorticoids.
| Agent | Dose | Onset | Notes |
|---|---|---|---|
| Normal saline | Bolus, then about 200 to 300 mL/h to restore volume | Hours | Give a loop diuretic only after volume repletion, or for fluid overload |
| Calcitonin | 4 units/kg SC or IM every 12 hours | 4 to 6 hours | Short-lived because of tachyphylaxis |
| Zoledronic acid | 4 mg IV over at least 15 minutes | 2 to 4 days | Nephrotoxic; check kidney function |
| Denosumab | 120 mg SC | Days | Not cleared by the kidneys; high risk of hypocalcemia in advanced CKD |
Other Structural Oncologic Emergencies
- Malignant spinal cord compression: back pain with neurologic deficits in a patient with cancer. Give dexamethasone (commonly 10 mg IV, then 4 mg every 6 hours) and obtain an MRI of the whole spine urgently, followed by radiation or surgery. Very high doses (around 96 mg) add toxicity without clear benefit.
- Superior vena cava syndrome: facial and arm swelling with distended neck veins. Give steroids only for steroid-responsive tumors such as lymphoma or thymoma, ideally after tissue diagnosis. Stenting gives rapid relief, and anticoagulation is added if there is thrombus.
- Hyperleukocytosis with leukostasis: avoid red cell transfusion where possible because it raises blood viscosity. Treatment includes cytoreduction (hydroxyurea or induction chemotherapy), TLS prophylaxis and leukapheresis in selected patients.
Immune Checkpoint Inhibitor Toxicities
PD-1, PD-L1 and CTLA-4 inhibitors can cause immune-related adverse events (irAEs) in any organ, sometimes months after the last dose. Ask every patient with cancer about immunotherapy.
General approach (ASCO 2021):
| Grade | Action |
|---|---|
| Grade 1 | Usually continue the checkpoint inhibitor with close monitoring |
| Grade 2 | Hold the inhibitor; give prednisone 0.5 to 1 mg/kg/day |
| Grade 3 | Hold; give methylprednisolone or prednisone 1 to 2 mg/kg/day |
| Grade 4 | Permanently discontinue (for most organs); give high-dose steroids |
Steroids are tapered over at least 4 to 6 weeks.
Organ-specific points:
- Colitis not improving within 48 to 72 hours of steroids: add infliximab or vedolizumab.
- Hepatitis that does not respond to steroids: use mycophenolate. Avoid infliximab because of its own liver toxicity.
- Myocarditis: high mortality; give methylprednisolone 500 to 1,000 mg daily and admit to a monitored bed.
- Endocrinopathies (hypophysitis, adrenal insufficiency, thyroiditis, type 1 diabetes presenting as DKA): replace hormones. Adrenal crisis needs stress-dose hydrocortisone (Section 11.3). These conditions are usually permanent.
CAR-T Cell Therapy: CRS and ICANS
Autologous CD19- and BCMA-directed CAR-T therapies cause cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In June 2025, FDA removed the REMS programs for these products and shortened the recommended period for staying near the treatment center and avoiding driving to 2 weeks. Toxicity can still present to any ED.
| Syndrome | Features | Treatment |
|---|---|---|
| CRS | Fever, then hypotension and hypoxia; graded by the need for vasopressors and oxygen (ASTCT) | Tocilizumab 8 mg/kg IV over 1 hour (maximum 800 mg), repeated at least 8 hours apart if needed (up to 3 doses in 24 hours, 4 in total); add dexamethasone for higher grades or no response |
| ICANS | Word-finding difficulty, impaired handwriting, confusion, seizures, cerebral edema; graded with the ICE score | Dexamethasone 10 mg IV every 6 hours for grade 2 or higher. Tocilizumab does not treat isolated ICANS and may worsen it. Levetiracetam is commonly used to prevent seizures |
Treat fever in these patients as neutropenic fever as well, because infection and CRS often overlap.
Bleeding Disorders and Immune Platelet Disorders
Hemophilia
Give factor replacement first, then image. A patient with hemophilia and a head injury or suspected serious bleed should receive factor before the CT scan (World Federation of Hemophilia). Patients often carry their own factor and a letter describing their treatment plan.
| Deficiency | Expected rise | Dose for a target level |
|---|---|---|
| Factor VIII (hemophilia A) | About 2% per unit/kg | Weight (kg) × desired rise (%) × 0.5 |
| Factor IX (hemophilia B) | About 1% per unit/kg (standard products) | Weight (kg) × desired rise (%) × 1 |
Worked example: a 70-kg man with severe hemophilia A (under 1%) and an intracranial hemorrhage needs a target of about 100%. 70 × 100 × 0.5 = 3,500 units of factor VIII.
Patients with inhibitors need bypassing agents: recombinant factor VIIa or activated prothrombin complex concentrate (aPCC). Many patients now receive emicizumab prophylaxis, which distorts aPTT-based tests. aPCC given with emicizumab (more than 100 units/kg/day for more than 24 hours) has caused thrombotic microangiopathy and thrombosis, a boxed warning. Recombinant factor VIIa is preferred for breakthrough bleeding in these patients.
Thrombotic Thrombocytopenic Purpura (TTP)
The classic picture is microangiopathic hemolytic anemia with schistocytes, severe thrombocytopenia and organ injury from severe ADAMTS13 deficiency. It is a medical emergency:
- Therapeutic plasma exchange, with plasma infusion as a bridge
- Corticosteroids and rituximab
- Caplacizumab 11 mg IV before the first exchange, then 11 mg SC daily
- Avoid platelet transfusion unless bleeding is life-threatening, because it can worsen thrombosis
Immune Thrombocytopenia (ITP)
ASH (2019) recommends treatment when platelets are below 30,000/mm3 or there is bleeding:
- Prednisone 1 mg/kg (for no more than 6 weeks), or dexamethasone 40 mg daily for 4 days
- IVIG 1 g/kg when a rapid rise is needed
- Life-threatening bleeding: platelet transfusion with IVIG and high-dose IV methylprednisolone, with a thrombopoietin receptor agonist considered
A 52-year-old woman 10 days after chemotherapy for breast cancer has a temperature of 38.6 °C, BP 118/72 mmHg and HR 104 bpm. ANC is 200 cells/mm3. She has no central line, skin lesions or respiratory findings and no history of MRSA. Blood cultures are drawn. What is the most appropriate empiric therapy within the first hour?
Cefepime 2 g IV every 8 hours
Vancomycin plus cefepime 2 g IV every 8 hours
Ciprofloxacin plus amoxicillin-clavulanate at discharge
Ceftriaxone 2 g IV every 24 hours
A 24-year-old man of Mediterranean descent with newly diagnosed Burkitt lymphoma has uric acid 13.8 mg/dL, potassium 5.9 mEq/L, phosphate 6.8 mg/dL and creatinine 2.1 mg/dL. Quantitative G6PD testing shows deficiency. Which plan is most appropriate?
Rasburicase 0.2 mg/kg IV plus aggressive hydration
Aggressive hydration, allopurinol and early nephrology input for dialysis
Sodium bicarbonate infusion to raise urine pH above 7
Calcium gluconate infusion to correct calcium before phosphate falls
Six days after CD19-directed CAR-T cell infusion, a patient's CRS has resolved, but she now has new word-finding difficulty and her handwriting has deteriorated. Her ICE score indicates grade 2 ICANS. She is afebrile and hemodynamically stable. What is the most appropriate treatment?
Dexamethasone 10 mg IV every 6 hours
Tocilizumab 8 mg/kg IV as the only therapy
Observation alone until a seizure occurs
Haloperidol 5 mg IV for delirium
A 70-kg man with severe hemophilia A (baseline factor VIII below 1%) and no inhibitor falls and hits his head. He has a headache but a normal exam. CT is pending. What is the most appropriate first action?
Give factor VIII 1,750 units to reach about 50% activity
Give factor VIII about 3,500 units now to target about 100%
Give 4-factor prothrombin complex concentrate 50 units/kg
Wait for the CT result before giving any factor concentrate
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