---

Oncology & Hematology Pharmacotherapy: The Intensivist's Reference

---

PART 1 - CHEMOTHERAPY

1. Anthracyclines

• Acute cardiomyopathy - may present within days of a high dose (>250 mg/m² doxorubicin cumulative); manifests as fulminant HF, pulmonary edema, cardiogenic shock
• Arrhythmias - sinus tachycardia, non-specific ST-T changes, QTc prolongation acutely
• Extravasation - causes severe tissue necrosis; treat with dexrazoxane within 6 hours, cold packs (NOT warm), surgical debridement if needed

• Dilated cardiomyopathy / HFrEF - cumulative dose-dependent; risk rises sharply above doxorubicin 400 mg/m²; detected at median 3.5 months post-chemo but can appear years later (ACC/AHA Stage A HF begins at first exposure)
• LVEF drop >10% from baseline to <50% defines CTRCD (Cancer Therapeutics-Related Cardiac Dysfunction); 9% overall incidence in large cohort series
• Genetic risk: CBR and TTN truncating variants increase susceptibility
• Prevention: Dexrazoxane (only FDA-approved cardioprotectant for anthracyclines); ARBs (valsartan, PRADA trial data); LVEF monitoring by echo before and serially after

ICU tip: If LVEF <40% or HF does not resolve, hold anthracycline. Initiate HF therapy (ACEI/ARB + beta-blocker). Consult cardio-oncology.

---

2. Alkylating Agents

• Hemorrhagic cystitis (cyclophosphamide, ifosfamide) - acrolein metabolite; presents as gross hematuria, can cause clot retention and AKI; prevent with mesna + aggressive hydration; treat with bladder irrigation, cystoscopy, hyperbaric oxygen in refractory cases
• Ifosfamide encephalopathy - confusion, somnolence, seizures, coma; usually within 12-48h of infusion; treat with methylene blue 50 mg IV q4-6h; stop ifosfamide
• Cisplatin-induced AKI - tubular necrosis, Fanconi syndrome; prevent with pre-hydration (1-2L NS), mannitol, and avoiding concurrent nephrotoxins
• Acute vasculotoxicity (cisplatin) - myocardial infarction, stroke within hours of infusion; risk highest in testicular cancer patients
• Severe hyponatremia - SIADH from cyclophosphamide; can cause cerebral edema; correct sodium cautiously (≤8-10 mEq/L/day)
• Peripheral neuropathy crisis - cisplatin/oxaliplatin; oxaliplatin causes acute cold-triggered dysesthesias that can mimic angina
• Hemorrhagic myocarditis (cyclophosphamide at very high transplant doses >100 mg/kg) - tachyarrhythmias, HF, pericardial effusion

• Cisplatin: long-term nephrotoxicity (irreversible in severe cases), peripheral neuropathy (stockings-and-gloves), ototoxicity (high-frequency hearing loss), thromboembolic disease (elevated risk years after treatment)
• Cyclophosphamide: secondary leukemias (AML) and bladder cancer
• Gonadal failure in both sexes

---

3. Antimetabolites

• Methotrexate toxicity - severe mucositis, pancytopenia, AKI (MTX precipitates in tubules); monitor levels; rescue with leucovorin (folinic acid); glucarpidase (carboxypeptidase G2) for delayed clearance in renal failure; alkalinize urine (pH >7.0) and aggressive hydration
• 5-FU/Capecitabine cardiotoxicity - coronary vasospasm (most common mechanism), ACS, QTc prolongation, cardiogenic shock, Takotsubo cardiomyopathy; occurs in 3-8% of patients; higher risk with continuous infusion; stop immediately + IV nitroglycerin/calcium channel blockers; do NOT rechallenge
• High-dose Cytarabine (HiDAC) toxicities - cerebellar ataxia, confusion (monitor neurological exam; stop if nystagmus or ataxia); non-cardiogenic pulmonary edema; severe conjunctivitis (requires prophylactic steroid eye drops)
• Capecitabine DPD deficiency - 5-FU degradation enzyme deficiency (1-3% population) causes life-threatening mucositis, diarrhea, neutropenia from standard doses; test before initiation; treat supportively

• MTX: hepatotoxicity, pulmonary fibrosis (MTX pneumonitis can be fatal), neurotoxicity (leukoencephalopathy with IT or high IV doses)
• 5-FU/Capecitabine: hand-foot syndrome (palmar-plantar erythrodysesthesia)
• Fludarabine: profound, prolonged immunosuppression - risk of PCP, CMV reactivation, viral encephalitis; must use irradiated blood products to prevent transfusion-associated GVHD

---

4. Taxanes

• Severe hypersensitivity reaction (paclitaxel, Cremophor EL vehicle) - anaphylaxis within minutes of infusion; have epinephrine ready; premedicate with dexamethasone + H1/H2 blockers; switch to nab-paclitaxel in recurrent reactions
• Cardiac conduction - predominantly asymptomatic bradycardia, AV block (paclitaxel); rarely requires pacing

• Peripheral neuropathy (dose-limiting, often persistent; worse with cumulative doses)
• Docetaxel: fluid retention syndrome (pleural effusion, ascites, edema) - manage with diuretics; worse with multiple cycles
• Alopecia (reversible)

---

5. Vinca Alkaloids

• Inadvertent intrathecal vincristine - universally fatal ascending paralysis; absolute contraindication; must NEVER be given intrathecally; requires immediate neurosurgical lavage (rarely saves the patient)
• SIADH / hyponatremia - vincristine causes clinically significant hyponatremia; monitor sodium closely

• Peripheral neuropathy (prominent; can be dose-limiting)
• Autonomic neuropathy: constipation, ileus, urinary retention, orthostatic hypotension

---

6. Topoisomerase Inhibitors

• Irinotecan cholinergic syndrome - acute-onset (within 24h of dose): diarrhea, salivation, lacrimation, abdominal cramps; treat with atropine 0.25-1 mg IV/SC; must pre-treat in subsequent cycles
• Delayed severe diarrhea (irinotecan) - 24-96h post-dose; can cause dehydration, AKI, electrolyte emergencies; aggressive IV hydration + high-dose loperamide; UGT1A1*28 polymorphism (Gilbert's phenotype) predicts severe toxicity - dose reduce in homozygotes
• Severe mucositis + neutropenic sepsis - etoposide frequently causes myelosuppression

• Etoposide: secondary AML (t-AML) with chromosome 11q23 abnormalities

---

PART 2 - IMMUNOTHERAPY

7. Immune Checkpoint Inhibitors (ICIs)

• Anti-PD-1: Pembrolizumab, Nivolumab, Cemiplimab
• Anti-PD-L1: Atezolizumab, Durvalumab, Avelumab
• Anti-CTLA-4: Ipilimumab (most irAE-prone, especially colitis)
• Combination: Nivolumab + Ipilimumab (highest irAE rate)

• irAEs can occur months AFTER the last ICI dose - always take drug history
• Exclude infection before immunosuppression (especially for pulmonary and GI irAEs)
• ICI rechallenge after severe irAE: only consider after full recovery, for grade 3 cardiac/neurologic events generally permanently contraindicated
• Steroids themselves suppress anti-tumor immunity minimally if given for irAE control

• Permanent endocrine insufficiency (hypothyroidism is most common; diabetes insipidus, primary hypothyroidism, type 1 DM - NEED lifelong hormone replacement)
• Persistent autoimmune disorders (arthritis, sicca syndrome)
• ICI myocarditis - cardiac function may not fully recover

---

8. CAR-T Cell Therapy

• Pathophysiology: massive cytokine storm (IL-6, IFN-γ, IL-1) from T-cell and bystander activation
• Grading: Grade 1 (fever only) → Grade 4 (life-threatening: vasoplegic shock, respiratory failure, multi-organ failure)
• Timing: typically 2-7 days post-infusion (range 1-14 days)
• Management:
  • Grade 1-2: Antipyretics, supportive care
  • Grade 3+: Tocilizumab (IL-6R antagonist) 8 mg/kg IV - first-line; repeat in 8h if no response (max 4 doses); DO NOT give corticosteroids first (may blunt CAR-T efficacy)
  • Grade 4 / tocilizumab-refractory: Dexamethasone 10 mg q6h or methylprednisolone; siltuximab (anti-IL-6)
  • ICU-level: vasopressors for shock; mechanical ventilation; CRRT for AKI

• Pathophysiology: blood-brain barrier disruption, CNS cytokine infiltration
• Presentation: word-finding difficulties, confusion, tremor, seizures, cerebral edema; may follow CRS or occur independently
• Grading (ICANS grade 1-4 using ICE score); grade 3-4 = ICU indication
• Management:
  • All grades: Dexamethasone 10 mg IV q6-12h (corticosteroids preferred here, unlike CRS)
  • Seizures: levetiracetam (prophylaxis in high-risk patients)
  • Cerebral edema: dexamethasone + mannitol/hypertonic saline; neurology/neurosurgery consult
  • Do NOT give tocilizumab for ICANS alone (does not cross BBB)

• Prolonged cytopenias - can last months; require G-CSF, transfusions
• B-cell aplasia (CD19 CAR-T) - lifelong hypogammaglobulinemia; risk of encapsulated organisms; IVIG replacement every 3-4 weeks
• Late-onset HLH (hemophagocytic lymphohistiocytosis)
• Secondary infections (fungal, viral) due to profound immunosuppression

---

9. Bispecific T-Cell Engagers (BiTEs) and Related

• CRS (similar to CAR-T; usually grade 1-2 but can escalate with blinatumomab)
• Neurological toxicity (blinatumomab) - seizures, encephalopathy; administer prophylactic dexamethasone before infusion steps; grade 3+ → interrupt infusion
• Blinatumomab is a continuous IV infusion over 28 days - pump failure can cause abrupt withdrawal effects; must be continuously monitored

---

10. Cytokines

• Vascular leak syndrome - massive capillary leak: pulmonary edema (non-cardiogenic), hypotension, anasarca, oliguria
• Management: meticulous fluid balance (avoid aggressive resuscitation - worsens pulmonary edema), vasopressors (dopamine/phenylephrine preferred), renal support
• Cardiac: reversible cardiomyopathy, arrhythmias, MI mimics
• Neuropsychiatric: acute psychosis, coma

---

PART 3 - TARGETED THERAPY

11. Tyrosine Kinase Inhibitors (TKIs)

11a. BCR-ABL Inhibitors

• Ponatinib arterial occlusive events - MI, stroke, PAD; occurs in up to 30% at 24 months; major dose-reduction imperative
• Pleural effusion (dasatinib) - can be large and symptomatic; occurs in 20-35%; thoracentesis + drug holiday + steroids
• QTc prolongation (nilotinib) - risk of torsades; avoid in patients with baseline QTc >480ms; electrolyte correction mandatory
• Imatinib fluid retention - periorbital/peripheral edema, ascites, pleural effusion; dose-dependent; manage with diuretics
• Cardiac toxicity (ponatinib) - HTN, HF; aggressive BP management required

• Imatinib: bone marrow suppression, muscle cramps, growth retardation in children
• Nilotinib: accelerated atherosclerosis; risk of sudden cardiac death (QT)
• All TKIs: need lifelong treatment in CML (until deep molecular response achieved)

11b. VEGFR/Multi-Kinase Inhibitors

• Hypertensive crisis - very common (30-80%); can precipitate hypertensive encephalopathy, PRES, stroke; aggressive BP management needed; use amlodipine or carvedilol (avoid diltiazem - CYP3A4 interaction); hold drug for uncontrolled HTN
• GI perforation/fistula - sorafenib/sunitinib; presents with peritonitis; surgical emergency; stop drug permanently
• QTc prolongation/torsades - vandetanib, sunitinib; avoid concurrent QT-prolonging drugs
• Hepatotoxicity - pazopanib, sunitinib; severe ALT elevation; hold if >8× ULN

• Hypothyroidism (sunitinib especially - thyroiditis)
• Hand-foot syndrome
• Cardiovascular: cumulative risk of CV events 10% at 12 months, 17% at 24 months (VEGFR TKIs)
• Adrenal insufficiency (rare but recognized)

11c. EGFR Inhibitors

• Interstitial lung disease (ILD)/pneumonitis - 3-5% (higher with osimertinib); can be life-threatening; presents with acute dyspnea; CT shows GGO; stop EGFR-TKI; high-dose steroids
• QTc prolongation (osimertinib)
• Paronychia + secondary infection - septic paronychia; requires wound care + antibiotics

• Acneiform rash (all EGFR inhibitors) - correlates with efficacy; treat with tetracyclines
• Diarrhea (afatinib - can be severe)
• Pneumonitis (osimertinib - higher rate than prior generation)

11d. ALK/ROS1 Inhibitors

• Bradycardia (crizotinib - very common, usually asymptomatic; if symptomatic hold drug)
• ILD/pneumonitis (brigatinib especially within first week; early-onset pneumonitis)
• Hyperlipidemia crisis (lorlatinib) - severe hypertriglyceridemia, lipemia retinalis; risk of pancreatitis; monitor lipids
• CNS edema (lorlatinib) - mood changes, cognitive effects, rarely hallucinations

11e. BTK Inhibitors

• Atrial fibrillation - ibrutinib causes AF in 6-9% of patients (ROR 23.1 in pharmacovigilance); highest risk in first months; manage with rhythm/rate control; avoid warfarin (use DOAC or withhold anticoagulation if high bleed risk)
• Major bleeding - ibrutinib inhibits platelet collagen-receptor signaling; CNS hemorrhage reported (ROR 3.7); hold 3-7 days before surgery
• Ventricular arrhythmias - ibrutinib (ROR 4.7)
• HF / hypertension
• Invasive fungal infection - ibrutinib impairs innate immunity; Aspergillus, Pneumocystis; consider prophylaxis

• Ibrutinib: accumulating CV risk (AF, HTN, HF, stroke); next-gen inhibitors (acalabrutinib, zanubrutinib) have lower AF rates
• Atrial fibrillation is the dominant long-term morbidity of ibrutinib

11f. CDK4/6 Inhibitors

• Severe neutropenia - very common with palbociclib; neutropenic fever; dose-hold typically required
• QTc prolongation (ribociclib) - risk of torsades; avoid in patients with baseline QTc >450ms

• Cytopenias, fatigue
• Diarrhea (abemaciclib)
• Venous thromboembolism (class effect)

11g. mTOR Inhibitors

• Non-infectious pneumonitis - up to 13% with everolimus; bilateral infiltrates; steroid-responsive
• Metabolic emergency - hyperglycemia (diabetic ketoacidosis in pre-diabetic patients), hypertriglyceridemia, hypercholesterolemia
• Severe stomatitis - impairs nutritional intake

---

12. HER2-Directed Agents

• Trastuzumab-induced cardiomyopathy - reversible (unlike anthracycline cardiomyopathy); Type II CTRCD; does not relate to cumulative dose; LVEF drop common when combined with anthracyclines; hold if LVEF <40% or symptomatic HF; resume only after LVEF recovery and with full multidisciplinary risk assessment
• ILD/pneumonitis (T-DXd) - higher rate than T-DM1; can be fatal (grade 5 events reported in trials); strict monitoring required
• Infusion reactions (trastuzumab first infusion) - mild to moderate; premedicate; grade 3-4 are rare

• Trastuzumab cardiomyopathy: largely reversible with HF therapy (82% LVEF recovery in large series); continue HF therapy (ACEI + beta-blocker) during and after
• Lapatinib: hepatotoxicity, diarrhea

---

13. VEGF/Angiogenesis Inhibitors (Monoclonal Antibodies)

• Arterial thromboembolic events - MI, stroke; higher risk in older patients with prior CVD; stop bevacizumab permanently
• GI perforation - 1-3%; can occur without prior symptoms; surgical emergency; stop permanently
• Fistula formation (tracheoesophageal, GI-vaginal); stop permanently
• Hypertensive crisis - very common; PRES can occur
• Severe hemorrhage - hemoptysis in squamous NSCLC (contraindicated); GI hemorrhage; intracranial hemorrhage

• Wound healing impairment (hold ≥4-6 weeks before and after surgery)
• Proteinuria/nephrotic syndrome
• Thrombotic microangiopathy

---

14. PARP Inhibitors

• Myelodysplastic syndrome (MDS) / secondary AML - rare but serious; present months-years after treatment; pancytopenia + dysplastic changes
• Severe anemia - niraparib especially; may require transfusions; dose reduction

• Cytopenias, GI toxicity, fatigue

---

15. Proteasome Inhibitors

• Carfilzomib cardiac toxicity - acute cardiomyopathy, HF, pulmonary hypertension; higher CV risk than bortezomib; check for pre-existing HF before initiation
• Carfilzomib pulmonary toxicity - dyspnea, pulmonary HTN; may require drug discontinuation
• TLS - especially in high tumor burden myeloma on first cycles with bortezomib
• Pulmonary artery hypertension (carfilzomib)

• Bortezomib: peripheral neuropathy (dose-limiting); can be severe and irreversible at high cumulative doses; subcutaneous injection reduces rate vs IV
• Herpes zoster reactivation (mandatory antiviral prophylaxis - acyclovir/valacyclovir)
• Carfilzomib: cumulative CV risk

---

16. BCL-2 Inhibitor

• Tumor Lysis Syndrome (TLS) - the primary dose-limiting toxicity; risk stratification is mandatory before initiation; ramp-up dosing protocol exists specifically because of TLS risk (20 mg → 50 → 100 → 200 → 400 mg over 5 weeks)
• Monitoring: uric acid, K, PO4, Cr, Ca at baseline, 6-8h, and 24h after each ramp-up dose; in high-risk patients (high lymphocyte count, large nodes) - hospitalize for monitoring
• Treatment: rasburicase (hyperuricemia), aggressive IV hydration, dialysis if severe

---

17. Differentiation Agents (APL-specific)

• Differentiation Syndrome (DS) - formerly Retinoic Acid Syndrome; life-threatening; occurs in 10-25% of APL patients on ATRA ± ATO
  • Mechanism: differentiation of APL blasts releases massive inflammatory cytokines
  • Features: fever, dyspnea, pulmonary infiltrates, pleural/pericardial effusions, hypotension, weight gain, renal failure
  • Management: Dexamethasone 10 mg IV q12h immediately; do NOT stop ATRA (unless severe respiratory failure); hydroxyurea for leukocytosis; ICU-level monitoring; diuretics for fluid overload
• QTc prolongation (ATO) - risk of torsades; monitor ECG; correct K+ and Mg2+; avoid concurrent QT-prolonging drugs
• ATRA complications: pseudotumor cerebri (headache, papilledema, visual changes) - treat with acetazolamide ± steroids; teratogenic

---

PART 4 - MAJOR ONCOLOGIC EMERGENCIES (Consolidated ICU Reference)

A. Tumor Lysis Syndrome (TLS)

• Hyperuricemia (>8 mg/dL or 25% rise)
• Hyperkalemia (>6 mEq/L or 25% rise)
• Hyperphosphatemia (>4.5 mg/dL or 25% rise)
• Hypocalcemia (secondary) - tetany, arrhythmias, seizures

1. Aggressive IV hydration (target urine output >100 mL/h)
2. Rasburicase 0.2 mg/kg IV daily (converts uric acid to allantoin) - CONTRAINDICATED in G6PD deficiency (causes hemolysis); do NOT alkalinize urine if using rasburicase
3. Allopurinol (preventive; less effective once hyperuricemia established)
4. Treat hyperkalemia (calcium gluconate, insulin-glucose, sodium bicarbonate, kayexalate, dialysis)
5. Dialysis early in progressive AKI with electrolyte crisis; CRRT preferred in hemodynamically unstable

---

B. Febrile Neutropenia / Neutropenic Sepsis

• ANC <500 (or expected to drop to <500 in 48h) + fever ≥38.3°C (or ≥38.0°C sustained 1h)
• Empirical antibiotics within 1 hour: anti-pseudomonal beta-lactam (piperacillin-tazobactam, cefepime, or carbapenem)
• High-risk features → hospitalization + IV antibiotics
• Add vancomycin for: hemodynamic instability, catheter-related infection, skin/soft tissue infection, MRSA colonization, severe mucositis
• Anti-fungal cover (fluconazole/echinocandin/voriconazole) if persistent fever after 4-7 days of antibiotics or high-risk (prolonged neutropenia, HSCT)
• G-CSF (filgrastim/pegfilgrastim) for prophylaxis; consider in established febrile neutropenia with high-risk features

---

C. Hypercalcemia of Malignancy

• Most common paraneoplastic metabolic emergency; PTHrP-mediated (solid tumors) or osteolytic (myeloma, breast)
• Severity: >14 mg/dL = severe; >16 = life-threatening (cardiac arrhythmias, obtundation, renal failure)
• Management: IV saline resuscitation (2-4L), loop diuretics (after adequate hydration), zoledronic acid 4 mg IV (most potent bisphosphonate; onset 24-48h), denosumab for bisphosphonate-refractory; calcitonin for rapid acute lowering (effective within hours, tachyphylaxis in 48h); dialysis for severe/refractory with AKI

---

D. Spinal Cord Compression (Malignant)

• Back pain + neurological deficits = emergency
• MRI whole spine urgently
• Dexamethasone 10-16 mg IV immediately, then 4 mg q6h
• Radiation therapy (definitive in most); surgical decompression if radioresistant tumor, spinal instability, or progressing despite RT

---

E. Superior Vena Cava (SVC) Syndrome

• Facial plethora, arm/neck swelling, dyspnea, headache (worse lying flat), proptosis
• CT chest + venography
• Endovascular stenting (fastest symptomatic relief); radiation for radiosensitive tumors (SCLC, lymphoma); systemic chemotherapy for chemosensitive tumors; dexamethasone for edema; elevate head of bed; supplemental O2
• Thrombotic SVC syndrome: anticoagulation

---

F. Disseminated Intravascular Coagulation (DIC)

• Classic association: APL (t[15;17]) - often presents as catastrophic bleeding/clotting at diagnosis
• Treat underlying malignancy (ATRA + ATO for APL - this IS the treatment for APL-DIC)
• Platelet transfusion target >30-50k (or >50k if active bleeding)
• FFP for prolonged PT/aPTT with bleeding
• Cryoprecipitate for fibrinogen <100-150 mg/dL
• Heparin only in thrombosis-dominant DIC (controversial)

---

PART 5 - LONG-TERM COMPLICATIONS SUMMARY TABLE

---

QUICK ICU RECALL: DRUG-TO-EMERGENCY PAIRINGS

---

• Harrison's Principles of Internal Medicine, 22nd Ed. (2025) - Chapter 78, Cancer Molecular Targeted Therapy
• Braunwald's Heart Disease, 11th Ed. - Chapters 56-57, Cardio-Oncology
• Goldman-Cecil Medicine, 2-Volume Set - Chemotherapy Reference Tables
• Comprehensive Clinical Nephrology, 7th Ed. - Chapter on Metabolic Complications: Tumor Lysis Syndrome
• Fuster and Hurst's The Heart, 15th Ed. - Cardiotoxicities
• Pichon S, et al. "Life-threatening immune-related adverse events in the intensive care unit: a narrative review." Intensive Care Med. 2025. [PMID: 41123622]