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.