SEVERE INFUSION REACTION TO RITUXIMAB
CASE REPORTHanna Yudchyts, Pharm D.
PGY-1 Pharmacy Resident
NSLIJ Lenox Hill Hospital
Objectives
Introduce patient case Discuss metabolic abnormalities
Hyperkalemia Lactic acidosis
Learn about Rituximab Review infusion reaction Discuss possible Tumor Lysis Syndrome
(TLS)
History of Present Illness
Chief complaint: Anaphylaxis HPI: JL is a 73 y/o F who presented to LHH
Emergency Department from oncology infusion center on 08/14/13 with anaphylaxis to Rituximab. During first infusion, she experienced nausea and vomiting. The infusion was stopped. Patient noted to have some shortness of breath and tongue swelling. EMS was called at 14:35. EMS arrived on the scene at 14:38.
Past Medical History
Non-Hodgkin’s Lymphoma• Mantle cell lymphoma, blastoid variant• No previous treatment received
Diabetes Mellitus type 2 Hypertension Hypercholesterolemia Home Medications
Losartan Metformin Glipizide Fenofibrate Ezetimibe/Simvastatin
EMS Finding and Actions Vital signs
Medications administered Epinephrine 0.3 mg IM Diphenhydramine 50 mg IV Methylprednisolone 125 mg IV Normal Saline 1 L IV
No improvement mental status decreased to unresponsive. Patient was intubated and brought to LHH emergency department at 15:30.
BP Pulse RR SpO2 BS
81/59 130 36 78 211
Upon Arrival at Emergency Department
Stat medications given at 16:22 Sodium Chloride 0.9% IV 1 L bolus Epinephrine 0.3 mg IM Famotidine 20 mg IV Propofol 5 mcg/kg/min, titrate to
acceptable sedation Vasopressin 40 units IV
Initial Findings
89.8 617.524.8
214
Lactic Acid
pH CO2 HCO3
15.2 6.79 58 9
130 99 38 8.2 8 4.05
•Urinalysis and blood cultures are negative•ECG: wide complex tachycardia
Lab values received between 16:42-17:11
Metabolic Abnormalities
Hyperkalemia
Severe hyperkalemia can lead to: Muscle weakness or paralysis Cardiac conduction abnormalities Cardiac arrhythmias
Treatment approaches: Antagonizing the membrane effects of K+
with Ca2+
Driving extracellular K+ into the cells Removing excess K+ from the body
Stabilize Cardiac Membranes with Calcium
Significant ECG findings or severe arrhythmias
Calcium Chloride 500-1000 mg
Calcium Gluconate 1000 mg
• IV infusion over 2-3 min Effect of Ca2+ is transient treatments to
shift K+ into cells and to remove K+ are required
Shift Potassium into Cells
Insulin+ Glucose Regular Insulin 10 units IV bolus + 50 ml of D50W
Beta 2 agonist Albuterol 10-20 mg in 4 ml saline via nebulizer
Sodium Bicarbonate Minimal effect on shifting K+ intracellularly 150 mEq in 1 L of D5W in water at 250 ml/h
The effect of shifting K+ into the cells is transient, treatments to remove K+ are also required
Strategies for Eliminating Potassium
Sodium Polystyrene Sulfonate (Kayexalate®) Cation exchange resin 15-30 g PO
Diuretic Limited short-term effect Furosemide 20-40 mg IV
Hemodialysis If above measures failed Hyperkalemia is severe Patient with renal failure Marked tissue breakdown large amount of K+ released
form injured cells
Lactic Acidosis
Common cause of metabolic acidosis Elevated plasma lactate concentration
(> 4meq/L) Elevated anion gap
Impaired tissue
oxygenation
Increased anaerobic metabolis
m
Rise in lactate
production
Decrease in serum
bicarbonate
concentration
Decrease in pH
Metabolic acidosis
Acidosis Treatment
Who should be treated pH < 7.10
Goal of therapy Reversal of underlying cause Goal for arterial pH > 7.10
Approach 1-2 mEq/kg Sodium Bicarbonate IV bolus Repeat after 30-60 min if pH < 7.10
Treatment Progression
• K: 8.2• pH: 6.79• LA: 15.2
17:00
• Insulin Regular 10 units + D50W x 4
• Calcium Gluconate 1 amp x 4• Sodium Bicarbonate 8.4% 1
amp x 4• Normal Saline 1L x 4 • Sodium Bicarbonate drip (3
amp in 0.45%NS)• Vancomycin 1 g + Zosyn
3.375 g IV
In between…
• K:8.6• pH: 6.94• LA: 16
18:30
Treatment Progression
No improvement in metabolic abnormalities despite medications administration
ICU team consulted Emergency hemodialysis awaiting at ICU
floor During transportation patient developed
Ventricular Tachycardia and rushed back to ED for CPR at 18:28
During the CPR…
Patient was shocked 3 times Received Epinephrine 1 mg x 3 Amiodarone 300 mg IV push 100 mEq (2 ampules) of Na+ bicarbonate No pulse Patient was declared deceased at 18:47
DiscussionProbable cause of death?
Rituximab
Murine/human monoclonal anitbody
FDA approved indications:
•Chronic lymphoid leukemia (CLL)
•Microscopic polyarteritis nodosa
•Non-Hodgkin’s lymphoma (NHL)
•Rheumatoid arthritis (RA)
•Wegener’s granulomatosis
Binds to the antigen CD20, located on pre-B and mature B lymphocytes
CD20 is expressed on > 90% of B-cell NHL, but not expressed on normal plasma cells or normal tissue
Black Box Warning
Basis of Infusion Reaction
Possible Tumor Lysis Syndrome?
Lab values indicating TLS K+: 8.2 mMol/L SCr: 4.05 mg/dL Ca2+: 7.3 mg/dL
No Uric Acid and Phosphate levels Super acute onset within hours
Similar case reports
Case Reports of Acute TLS
Tumor
type
Age (sex)
WBC (x109)
Immunotherapy Onset TLS
(hours)
Outcome
CLL 26 (F) 112 Rituximab 375 mg/m2
24 Improved
NHL 41 (M)
Rituximab 375 mg/m2
6 Improved
CLL 76 (M)
907 Rituximab 375 mg/m2
12 Expired
HL 36 (M)
ABVD 2 Improved
Conclusion
Infusion reaction to Rituximab Cardiac arrest Hyperkalemia Acute
kidney failure Possible tumor lysis syndrome
More information needed to confirm TLS Importance and timing of emergency
hemodialysis
References
1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2012. Available at www.rituxan.com
2. Bicarbonate therapy in lactic aciosis. In UpToDate, Wiederkehr M., Emmett M. Oct 3, 2012.
3. Advanced cardiac life support (ACLS) in adults. In UpToDate, Pozner C. Feb 4, 2013.
4. Yang H., Rosove M., Figlin R. Tumor Lysis Syndrome Occurring After the Administration of Rituximab in Lymphoproliferative Disorders: High-Grade Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia. Am J Hem. 1999; 62:247-250.
5. Davidson M, Thakkar S, Hix J et al. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med. 2004; 116:546-554.
6. McBride A, Westervelt P. Recognizing and managing the expanded risk of tumor lysis syndrome in hematologic and solid malignancies. J Hemtol and Oncol. 2012; 5: 75.
7. Suzuki T., Takeuchi M., Saeki H., et al. Super-acute onset of tumor lysis syndrome accompanied by hypercytokinemia during treatment of Hodgkin’s Lymphoma with ABVD chemotherapy. Clin Ther. 2010 Mar;32(3): 527-31.