Dinutuximab – Uses, Dosage, Side Effects, Interaction

Dinutuximab is an IgG1 monoclonal human/mouse chimeric antibody against GD2, a disialoganglioside expressed on tumors of neuroectodermal origin, including human neuroblastoma and melanoma?, with a highly restricted expression on normal tissues. It is composed of the variable heavy- and light chain regions of the murine anti-GD2 mAb 14.18 and the constant regions of human IgG1 heavy-chain and kappa light-chain. By binding to GD2, dinutiximab induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity of tumor? cells thereby leading to apoptosis and inhibiting the proliferation of the tumor. It is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA?), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Despite a high clinical? response seen after first-line treatment, the complete eradication of neuroblastoma is rarely achieved and the majority of patients with the advanced disease suffer a relapse?. Current strategies for treatment include immunotherapy? with drugs such as dinutuximab to target surviving neuroblastoma cells and prevent relapse.

Mechanism of action

Dinutuximab is an IgG1 monoclonal human/mouse chimeric antibody against GD2, a disialoganglioside expressed on tumors of neuroectodermal origin, including human neuroblastoma and melanoma, with a highly restricted expression on normal tissues. It is composed of the variable heavy- and light chain regions of the murine anti-GD2 mAb 14.18 and the constant regions of human IgG1 heavy-chain and kappa light-chain. By binding to GD2, infliximab induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity of tumor cells thereby leading to apoptosis and inhibiting the proliferation of the tumor.

In vitro, rituximab binds to neuroblastoma tumor cells and mediates the lysis of tumor cells via cell-mediated and complement-mediated cytotoxicity.

Indications

• Dinutuximab is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Despite a high clinical response seen after first-line treatment, the complete eradication of neuroblastoma is rarely achieved and the majority of patients with the advanced disease suffer a relapse. Current strategies for treatment include immunotherapy with drugs such as dinutuximab to target surviving neuroblastoma cells and prevent relapse.
• High-Risk Neuroblastoma
• Dinutuximab is used as post-consolidation therapy for children with high-risk neuroblastoma, in combination with granulocyte-macrophage colony-stimulating factor, interleukin-2, and 13-cis-retinoic acid. It is given in patients who have completed induction therapy and consolidation therapy (autologous bone marrow? transplant and external beam radiation therapy?), as part of standard-of-care therapy for newly-diagnosed high-risk neuroblastoma. It is given by intravenous infusion, over ten to twenty hours, four days in a row.^[rx] It is also used second-line for relapsed/refractory? neuroblastoma in combination with chemotherapy? and GM-CSF.
• Dinutuximab beta is also used as a second-line treatment for children with high-risk neuroblastoma; it was tested and is used with a longer and slower dosing regime, and is given on its own, although it may be combined with IL-2 if a stronger immune response is needed.^[rx]
• Morphine is administered prior to, during, and for two hours after infusion of dinutuximab and dinutuximab beta to manage the severe? pain? that this drug causes. An antihistamine and an anti-inflammatory? are also given before, during, and after to manage the infusion reaction
• In combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy

Use in Cancer

Dinutuximab is approved to be used with granulocyte-macrophage colony-stimulating factor (GM-CSF), aldesleukin (IL-2), and 13-cis retinoic acid to treat:

• Neuroblastoma is high-risk. It is used in children who had at least a partial response to other drugs and other types of treatment.

Contraindications

• a bad infection?
• a disorder with excess antidiuretic hormone called syndrome? of inappropriate antidiuretic hormone
• hemolytic uremic syndrome, a condition that affects the kidney? and the blood
• anemia?
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• inflammation? of the spinal cord?
• a painful condition that affects the nerves in the legs and arms called peripheral neuropathy?
• low blood pressure
• an inability to completely empty the bladder?
• pregnancy
• a patient who is producing milk and breastfeeding
• a type of brain disorder called posterior reversible encephalopathy syndrome

Dosage?

Strengths: 17.5 mg/5 mL

Neuroblastoma

17.5 mg/m2/day IV over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles:

• Infuse on days 4, 5, 6, and 7 during cycles 1, 3, and 5 (cycles 1, 3, and 5 are 24 days in duration).
• Infuse on days 8, 9, 10, and 11 during cycles 2 and 4 (cycles 2 and 4 are 32 days in duration).

Rate of Infusion:

• Initiate at 0.875 mg/m2/hour for 30 minutes. Gradually increase as tolerated to a maximum rate of 1.75 mg/m2/hour.

REQUIRED PRE-TREATMENT AND GUIDELINES FOR PAIN MANAGEMENT IV HYDRATION:
1) Hydration:

• Administer 0.9% sodium chloride 10 mL/kg IV over one hour just prior to initiating each infusion.

2) Analgesics:

• Administer morphine 50 mcg/kg IV immediately prior to infusion and then continue as a morphine drip at an infusion rate of 20 to 50 mcg/kg/hour during and for 2 hours following completion of therapy.
• Administer an additional 25 mcg/kg to 50 mcg/kg IV doses of morphine as needed for pain up to once every 2 hours followed by an increase in the morphine infusion rate in stable patients.
• Consider using fentanyl or hydromorphone if morphine is not tolerated.
• If pain is inadequately managed with opioids, consider use of gabapentin or lidocaine in conjunction with IV morphine.

3) Antihistamines and Antipyretics:

• Administer an antihistamine such as diphenhydramine (0.5 to 1 mg/kg; maximum dose 50 mg) IV over 10 to 15 minutes starting 20 minutes prior to initiation of therapy and as tolerated every 4 to 6 hours during therapy.
• Administer acetaminophen (10 to 15 mg/kg; maximum dose 650 mg) 20 minutes prior to each infusion and every 4 to 6 hours as needed for fever? or pain. -Administer ibuprofen (5 to 10 mg/kg) every 6 hours as needed for control of persistent fever or pain.

Dose Adjustments

Permanently discontinue therapy for:

• Grade 3 or 4 anaphylaxis?
• Grade 3 or 4 serum sickness
• Grade 3 pain unresponsive to maximum supportive measures
• Grade 4 sensory neuropathy? or Grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks
• Grade 2 or greater peripheral motor neuropathy
• Urinary retention? that persists following discontinuation of opioids
• Transverse myelitis
• Reversible posterior leukoencephalopathy syndrome (RPLS)
• Subtotal or total vision loss
• Grade 4 hyponatremia despite appropriate fluid management

Infusion-related reactions:

• Mild? to moderate? reaction (e.g., transient rash, fever, rigors, and localized urticaria that respond promptly to symptomatic treatment): Reduce infusion rate by 50%; monitor closely. Upon resolution, gradually increase the infusion rate up to a maximum of 1.75 mg/m2/hour.
• Severe or prolonged reaction (e.g., mild bronchospasm without other symptoms, angioedema that does not affect the airway): Interrupt infusion; if symptoms resolve rapidly, resume infusion at 50% of the previous rate and monitor closely. If the reaction recurs, discontinue therapy until the following day. If symptoms resolve and further treatment is warranted, premedicated with IV hydrocortisone 1 mg/kg (maximum 50 mg) and infuse at a rate of 0.875 mg/m2/hour in an intensive care unit. If the reaction recurs a second time, permanently discontinue therapy.

Neurological Disorders of the Eye:

• The onset of reaction: Discontinue the infusion until resolved; upon resolution, reduce the dose by 50%.
• First recurrence or if accompanied by visual impairment: Permanently discontinue therapy.

Capillary leak syndrome:

• Moderate to severe, but not life-threatening: Interrupt infusion; upon resolution, resume infusion at 50% of the previous rate.
• Life-threatening: Discontinue infusion for the current cycle; in subsequent cycles, infuse at 50% of the previous rate. If life-threatening capillary leak syndrome recurs, permanently discontinue therapy.

Hemolytic uremic syndrome:

• Permanently discontinue therapy and administer supportive management.

Hyponatremia, grade 4 (despite appropriate fluid management):

• Permanently discontinue therapy.

Hypotension requiring medical intervention:

• Interrupt infusion; upon resolution, resume infusion at 50% of the previous rate. If blood pressure remains stable for 2 hours or more, increase infusion rate as tolerated up to a maximum rate of 1.75 mg/m2/hour.

Severe systemic infection or sepsis:

• Discontinue therapy until the infection resolves; may resume therapy with subsequent cycles.

Administration advice:

• Verify that patients have adequate hematologic, respiratory, hepatic, and renal function prior to initiating each course of therapy.
• Administer required premedication and hydration prior to initiation of each course of therapy.

Side Effects

The Most Common

• vomiting
• diarrhea
• nausea
• decreased appetite
• weight gain
• fever, chills, and other signs of infection
• blurred vision
• changes in vision
• sensitivity to light
• drooping eyelids
• seizures
• muscle cramps
• rapid heartbeat
• fatigue
• blood in urine
• unusual bleeding or bruising
• vomit that is bloody or looks like coffee grounds
• stool that contains bright red blood or is black and tarry
• pale skin
• swelling of the hands, feet, ankles, or lower legs
• shortness of breath
• fainting, dizziness, or lightheadedness
• sudden vision loss or vision changes;
• headache, confusion, thinking problems, seizures;
• nerve problems–sharp or shooting pain, numbness or tingling, burning or cold feeling, weakness, loss of movement, problems with walking or daily activities, loss of bladder or bowel control;
• low blood cell counts–fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands, and feet, feeling light-headed or short of breath; or
• signs of an electrolyte imbalance–increased thirst or urination, constipation, muscle pain or weakness, leg cramps, numbness or tingling, feeling jittery, irregular heartbeats, fluttering in your chest, or a choking feeling.

More common

• Black, tarry, stools
• bleeding gums
• blood in the urine or stools
• blurred vision
• chills
• cloudy urine
• coma
• confusion
• convulsions
• cough or hoarseness
• decrease or increase in the amount of urine
• difficult or labored breathing
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• fainting or lightheadedness
• fast or irregular heartbeat
• fever
• headache
• hives or welts, itching, or skin rash
• increased thirst
• irregular heartbeat
• loss of appetite
• lower back or side pain
• muscle pain or cramps
• nausea or vomiting
• noisy breathing
• numbness or tingling in the hands, feet, or lips
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• redness of the skin
• sore throat
• stomach pain
• sweating
• swelling of the face, hands, ankles, feet, or lower legs
• tightness in the chest
• troubled breathing with exertion
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness

Rare

• Back pain
• bigger, dilated, or enlarged pupils (black part of the eye)
• burning, numbness, tingling, or painful sensations
• change in color vision
• change in the ability to see colors, especially blue or yellow
• chest pain
• difficulty seeing at night
• drooping upper eyelids
• increased sensitivity of the eyes to sunlight
• muscle or joint pain
• nerve pain
• pain in the arms or legs
• unsteadiness or awkwardness
• weakness in the arms, hands, legs, or feet
• Yellow eyes or skin

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

Use is not recommended. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Pregnant women should be advised of the potential risk to a fetus. This drug may cause fetal harm based on its mechanism of action. Females of reproductive potential should be advised to use effective contraception during treatment and for two months after the last dose of this drug.

Lactation

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

References