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Moxetumomab pasudotox is a CD22-specific antibody conjugated to a truncated exotoxin used to treat relapsed or refractory hairy cell leukemia in patients who have already been treated with a purine nucleoside analog and one other treatment.
CD22 is a lineage-restricted B-cell antigen that is expressed solely in on B-chronic lymphocytic leukemia, hairy cell leukemia, acute lymphocytic leukemia the, and Burkitt’s lymphoma. The predecessor of Moxetumab pasudotox (MxP), named BL22, was first created based on the antibody RFB4 which specifically binds to CD22. This antibody was used to generate a recombinant immunotoxin in which a stabilized Fv segment by a disulfide bond is fused to the Pseudomonas exotoxin A (PE38) which does not have the cell-binding portion.[rx]
Moxetumomab pasudotox is a mouse monoclonal antibody to CD22 conjugated with a toxic fragment of Pseudomonas exotoxin A which is used in the therapy of resistant forms of hairy cell leukemia. Moxetumomab pasudotox has been linked to transient serum enzyme elevations during therapy but has not been linked to instances of clinically apparent liver injury with jaundice.
MxP appears as an improved form of BL22 by the mutation of the Fv region and the antibody phage-displayed. As well the residues SSY in the heavy chain are mutated to THW.[rx] It was developed by Astra Zeneca and FDA approved on September 13, 2018, after being granted the status of Fast Track, Priority Review, and Orphan Drug designations
Mechanism of action
MxP is a CD22-directed cytotoxin. It is stated as an immunotoxin which is defined as the class of agents that combine the selectivity of antibodies towards the target and the potency of toxins to perform the pharmacological anticancer function. CD22 is a B-lymphocyte-restricted transmembrane protein with a high density in HCL cells when compared with normal B cells. After binding to CD22, MxP is internalized and processed, which allows the release of the modified toxin. This toxin inhibits protein translation which induces an apoptotic state of the high CD22-expressed cancer cell.[rx]
The toxin included in MxP is the Pseudomonas exotoxin A which, after internalization, undergoes conformational changes and in the cytosol, the ribosylation activity of the domain III of the toxin inactivates the eukaryotic translation elongation factor (eEF-2) by transferring ADP (adenosine di-phosphate-ribose) from NAD to a modified histidine at position 715 in eEF-2. This action produces the inactivation of eEF-2 which leads to protein synthesis inhibition and programmed cell death.[rx]
Compared with its predecessor, MxP is even 50-fold more active on lymphoma cell lines and leukemic cells. In the phase I clinical trial, MxP showed no dose-limiting toxicity and the overall response rate was 79%. From pediatric patients with acute lymphoblastic leukemia, the complete response was observed in 12 individuals which is a result that has never been seen before.[rx]
In an open-label clinical trial, MxP showed a complete response, defined as the maintenance of hematologic remission, of more than 180 days in 30% of the patients, and 75% of the patients achieved at least partial response.[rx] Hence, the phase III clinical trial met the primary endpoint of a durable complete response.[rx]
Indications
- MxP is indicated for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least two prior systemic therapies including treatment with a purine nucleoside analog. The use of this drug is not recommended in patients with severe renal impairment (CrCl < 29 ml/min).[rx]
- HCL is an uncommon type of lymphocytic leukemia that starts in B cells or B lymphocytes. It is characterized by an accumulation of abnormal B lymphocytes. HCL is called “hairy” as it produces hair-like projections in the surface of the cancer cells. A usual symptom in people having HCL is the presence of splenomegaly and less often hepatomegaly.[rx]
- Moxetumomab pasudotox as monotherapy is indicated for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) after receiving at least two prior systemic therapies, including treatment with a purine nucleoside analogue (PNA)
- Relapsed/Refractory Hairy Cell Leukemia
Use in Cancer
Moxetumomab pasudotox-tdfk is approved to treat:
- Hairy cell leukemia that has relapsed or is refractory (does not respond to treatment). It is used in adults who have been treated with at least two systemic therapies, including a purine nucleoside analog.
Contraindications
- low amount of calcium in the blood
- hemolytic uremic syndrome, a condition that affects the kidney and the blood
- decreased kidney function
- pregnancy
Dosage
Strengths: tdfk 1 mg
Hairy Cell Leukemia
- 0.04 mg/kg IV over 30 minutes on Days 1, 3, and 5 of each 28-day cycle for a maximum of 6 cycles, disease progression, or unacceptable toxicity.
- Hydrate with 1 L of isotonic solution (e.g., 5% dextrose injection, and 0.45% or 0.9% sodium chloride injection) over 2 to 4 hours before and after each infusion. -Administer 0.5 L to patients under 50 kg.
- Advise patients to hydrate with up to 3 L of oral fluids (e.g., water, milk, or juice) per 24 hours on Days 1 through 8 of each 28-day cycle. In patients under 50 kg, up to 2 L per 24 hours is recommended.
- Premedicate 30 to 90 minutes prior to each infusion with and antihistamine (e.g., hydroxyzine or diphenhydramine), acetaminophen, and a histamine-2 receptor antagonist (e.g., ranitidine, famotidine, or cimetidine).
- Consider oral antihistamines and antipyretics for up to 24 hours following the infusion and an oral corticosteroid (e.g., 4 mg dexamethasone) to decrease nausea and vomiting. Maintain adequate oral fluid intake.
- Monitor fluid balance and serum electrolytes.
- Consider low-dose aspirin on Days 1 through 8 of each 28-day cycle.
- Monitor for thrombosis.
- For the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least 2 prior systemic therapies, including treatment with a purine nucleoside analog (PNA)
Instructions for Reconstitution, Dilution, and Administration
LUMOXITI must be reconstituted and diluted by a healthcare provider using an aseptic technique. Refer to the Healthcare Provider Instructions for Use for LUMOXITI for full reconstitution, dilution, and administration information.
Step 1: Calculate the Dose
Calculate the dose (mg) and the number of LUMOXITI vials (1 mg/vial) to be reconstituted. The final concentration of the reconstituted LUMOXITI solution is 1 mg/mL.
- DO NOT round down for partial vials.
- Individualize dosing based on the patient’s actual body weight prior to the first dose of the first treatment cycle.
- A change in dose should only be made between cycles when a change in weight of greater than 10% is observed from the weight used to calculate the first dose of the first treatment cycle. No change in dose should be made during a particular cycle.
Step 2: Reconstitution
Reconstitute LUMOXITI vials with Sterile Water for Injection, USP only.
- Reconstitute each LUMOXITI (1 mg/vial) with 1.1 mL Sterile Water for Injection, USP. The resulting 1 mg/mL solution allows a withdrawal volume of 1 mL.
- Direct the Sterile Water for Injection, USP along the walls of the vial and not directly at the lyophilized cake or powder.
- DO NOT reconstitute LUMOXITI vials with the IV Solution Stabilizer.
- Gently swirl the vial until completely dissolved. Invert the vial to ensure all cake or powder in the vial is dissolved. Do not shake.
- Visually inspect that the reconstituted solution is clear to slightly opalescent, colorless to slightly yellow, and free from visible particles.
- Do not use if solution is cloudy, discolored, or contains any particles.
- Use reconstituted solution immediately. Do not store reconstituted LUMOXITI vials. See Table 3 for storage times and conditions for the reconstituted solution.
Step 3: Dilution
Add the IV Solution Stabilizer to the infusion bag prior to adding LUMOXITI solution to the infusion bag. Vial of IV Solution Stabilizer is packaged separately.
- Obtain a 50 mL 0.9% Sodium Chloride Injection, USP infusion bag.
- Add 1 mL IV Solution Stabilizer to the infusion bag containing 50 mL 0.9% Sodium Chloride Injection, USP.
- Only one vial of IV Solution Stabilizer should be used per administration of LUMOXITI
- Gently invert the bag to mix the solution. Do not shake.
- Withdraw the required volume (calculated from Step 1) of LUMOXITI solution from the reconstituted vial(s)
- Inject LUMOXITI into the infusion bag containing 50 mL 0.9% Sodium Chloride Injection, USP and 1 mL IV Solution Stabilizer.
- Gently invert the bag to mix the solution. Do not shake.
- Discard any partially used or empty vials of LUMOXITI and IV Solution Stabilizer.
Step 4: Administration Instructions
For intravenous infusion only.
- Administer the diluted solution intravenously over 30 minutes.
- Do not mix LUMOXITI, or administer as an infusion with other medicinal products
- After the infusion, flush the intravenous administration line with of 0.9% Sodium Chloride Injection, USP at the same rate as the infusion. This ensures that the full LUMOXITI dose is delivered.
Dose Adjustments
If a severe infusion-related reaction (IRR) occurs, interrupt the infusion and manage it medically. Administer an oral or IV corticosteroid 30 minutes before resuming, and before each infusion thereafter.
MONITORING FOR CAPILLARY LEAK SYNDROME (CLS):
- Before every infusion checks weight and blood pressure.
- If weight has increased by 5.5 pounds (2.5 kg) or 5% or greater from Day 1 of the cycle and the patient is hypotensive, check for peripheral edema, hypoalbuminemia, and respiratory symptoms, including shortness of breath and cough.
- CLS is suspected, check for a decrease in oxygen saturation and pulmonary edema and/or serosal effusions.
DOSE ADJUSTMENTS FOR CLS:
- Grade 2 CLS: Delay dosing until recovery.
- Grade 3 CLS: Discontinue therapy.
- Grade 4 CLS: Discontinue therapy.
MONITORING FOR HEMOLYTIC UREMIC SYNDROME (HUS):
- Before every infusion check hemoglobin levels, platelet counts, and serum creatinine.
- If HUS is suspected, check blood LDH, indirect jaundice. সহজ বাংলা: জন্ডিসে বাড়তে পারে এমন হলুদ রঞ্জক।" data-rx-term="bilirubin" data-rx-definition="Bilirubin is a yellow pigment that can build up in jaundice. সহজ বাংলা: জন্ডিসে বাড়তে পারে এমন হলুদ রঞ্জক।">bilirubin, and blood smear schistocytes for hemolysis.
- Discontinue therapy in patients with HUS. Treat with supportive measures and fluid replacement, and monitor blood chemistry, complete blood counts, and renal function until resolution.
INCREASED CREATININE:
- For patients with baseline serum creatinine within normal limits, delay dosing for Grade 2 or higher creatinine increases (greater than 1.5-times baseline or the upper limit of normal); resume therapy upon recovery to Grade 1 (1- to 1.5-times baseline, or between the upper limit of normal and 1.5-times the upper limit of normal).
- For patients with a baseline serum creatinine of Grades 1 or 2, delay dosing for creatinine increases to Grade 3 or higher (greater than 3-times baseline or the upper limit of normal); resume therapy upon recovery to baseline grade or lower
Patient advice:
- Read patient labeling.
- Maintain a high fluid intake.
- Contact your healthcare provider immediately for infusion-related reactions or electrolyte abnormalities (e.g., muscle cramping, paresthesias, irregular or fast heartbeat, nausea, seizures).
Side Effects
The Most Common
- constipation
- pale skin
- tiredness
- dry eye or eye pain
- eye swelling or infection
- vision changes
- muscle cramps; numbness or tingling; irregular or fast heartbeat; nausea; or seizures
More common
- pain: Back pain means pain in the spine, muscles, discs, joints, or nerves of the back. সহজ বাংলা: পিঠ/কোমরের ব্যথা।" data-rx-term="back pain" data-rx-definition="Back pain means pain in the spine, muscles, discs, joints, or nerves of the back. সহজ বাংলা: পিঠ/কোমরের ব্যথা।">Back pain
- black, tarry stools
- blood in the urine
- blurred vision
- bone pain
- chest pain or tightness
- chills
- confusion
- cough
- dizziness
- drowsiness
- dry mouth
- fast or irregular heartbeat
- feeling of warmth
- fever
- headache
- increased or decreased urination
- increased thirst
- joint pain, stiffness, or swelling
- loss of appetite
- loss of consciousness
- lower back, side, or stomach pain
- mood or mental changes
- muscle cramps in the hands, arms, feet, legs, or face
- muscle pain
- muscle spasms (tetany) or twitching seizures
- nausea
- nervousness
- numbness and tingling around the mouth, fingertips, or feet
- painful or difficult urination
- pale skin
- pinpoint red spots on the skin
- pounding in the ears
- redness of the face, neck, arms, and occasionally, upper chest
- seizures
- slow or fast heartbeat
- sore throat
- stomach cramps or pain
- swelling of the face, fingers, feet, lower legs, or ankles
- trembling
- tremor
- troubled breathing
- troubled breathing with exertion
- ulcers, sores, or white spots in the mouth
- unusual bleeding or bruising
- unusual tiredness or weakness
- vomiting
- yellow eyes or skin
Rare
- Chest discomfort
- stomach bloating
- Constipation
- diarrhea
- dry eye
- Blindness
- bloody eye
- burning, dry, or itching eyes
- decreased vision
- discharge, excessive tearing
- discomfort, pain, or swelling of the eye or around the eye
- redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
Drug Interaction
| DRUG | INTERACTION |
|---|---|
| Articaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Articaine. |
| Benzocaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Benzocaine. |
| Benzyl alcohol | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Benzyl alcohol. |
| Bupivacaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Bupivacaine. |
| Butacaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Butacaine. |
| Butamben | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Butamben. |
| Capsaicin | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Capsaicin. |
| Chloroprocaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Chloroprocaine. |
| Cinchocaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Cinchocaine. |
| Cocaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Cocaine. |
| Darbepoetin alfa | The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Moxetumomab pasudotox. |
| Diphenhydramine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Diphenhydramine. |
| Dyclonine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Dyclonine. |
| Erythropoietin | The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Moxetumomab pasudotox. |
| Ethyl chloride | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Ethyl chloride. |
| Etidocaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Etidocaine. |
| Levobupivacaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Levobupivacaine. |
| Lidocaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Lidocaine. |
| Meloxicam | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Meloxicam. |
| Mepivacaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Mepivacaine. |
| Methoxy pol | The risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Moxetumomab pasudotox. |
| Oxetacaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Oxetacaine. |
| Oxybuprocaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Oxybuprocaine. |
| Peginesatide | The risk or severity of Thrombosis can be increased when Peginesatide is combined with Moxetumomab pasudotox. |
| Phenol | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Phenol. |
| Pramocaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Pramocaine. |
| Prilocaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Prilocaine. |
| Procaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Procaine. |
| Proparacaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Proparacaine. |
| Propoxycaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Propoxycaine. |
| Ropivacaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Ropivacaine. |
| Tetracaine | The risk or severity of methemoglobinemia can be increased when Moxetumomab pasudotox is combined with Tetracaine. |
Pregnancy and Lactation
US FDA pregnancy category: Not assigned.
Pregnancy
Based on its mechanism of action and findings in non-pregnant female animals, LUMOXITI is expected to cause maternal and embryo-fetal toxicity when administered to a pregnant woman. There are no available data on LUMOXITI use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction or developmental toxicity studies have not been conducted with LUMOXITI. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Lactation
No data are available regarding the presence of moxetumomab pasudotox-tdfk in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LUMOXITI and any potential adverse effects on the breastfed child from LUMOXITI or from the underlying maternal condition.
Why is this medication prescribed?
Moxetumomab pasudotox-tdfk injection is used to treat hairy cell leukemia (cancer of a certain type of white blood cell) that has returned or has not responded after at least two other cancer treatments. Moxetumomab pasudotox-tdfk injection is in a class of medications called monoclonal antibodies. It works by helping your immune system to slow or stop the growth of cancer cells.
How should this medicine be used?
Moxetumomab pasudotox-tdfk injection comes as a powder to be mixed with liquid and injected into a vein by a doctor or nurse in a medical office or hospital. It is usually injected slowly over a period of 30 minutes on days 1, 3, and 5 of a 28-day treatment cycle. This cycle may be repeated for up to 6 cycles. The length of treatment depends on how well your body responds to the medication and any side effects you experience.
During your treatment, your doctor will ask you to drink up to twelve 8-oz glasses of liquids such as water, milk or juice every 24 hours on days 1 through 8 of each 28-day treatment cycle.
Moxetumomab may cause serious reactions during or after you receive your infusion. You will be given medications 30 to 90 minutes before your infusion and after your infusion to help prevent reactions to moxetumomab. Your doctor may need to stop your treatment if you experience certain side effects. Tell your doctor if you experience any of the following symptoms: dizziness, fainting, wheezing or difficulty breathing, shortness of breath, fast heartbeat, muscle pain, nausea, vomiting, headache, fever, chills, cough, fainting, hot flashes, or flushing. It is important for you to tell your doctor how you are feeling during your treatment with moxetumomab pasudotox-tdfk injection. Call your doctor right away or get immediate emergency medical attention if you experience any of these symptoms after you leave your doctor’s office or medical facility.
Your doctor may reduce your dose, delay or stop your treatment with moxetumomab pasudotox-tdfk injection, or treat you with additional medications depending on your response to the medication and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment.
What special precautions should I follow?
Before receiving moxetumomab pasudotox-tdfk injection,
- tell your doctor and pharmacist if you are allergic to moxetumomab, any other medications, or any of the ingredients in moxetumomab pasudotox-tdfk injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
- tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- tell your doctor if you have or have ever had medical problems.
- tell your doctor if you are pregnant or plan to become pregnant. You will need to have a pregnancy test before you start moxetumomab. You should not become pregnant while you are receiving moxetumomab pasudotox-tdfk injection and for at least 30 days after your final dose. Talk to your doctor about birth control methods that will work for you. If you become pregnant while receiving moxetumomab pasudotox-tdfk injection, call your doctor immediately. Moxetumomab pasudotox-tdfk injection may harm the fetus.
- tell your doctor if you are breastfeeding or plan to breastfeed.
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761104s000lbl.pdf
- https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-moxetumomab-pasudotox-tdfk-hairy-cell-leukemia
- https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761104Orig1s000Approv.pdf
- https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761104Orig1s000MultidisciplineR.pdf
- https://pubchem.ncbi.nlm.nih.gov/substance/135626666
- https://www.cancer.gov/about-cancer/treatment/drugs/moxetumomabpasudotoxtdfk
- https://go.drugbank.com/drugs/DB12688
- https://www.ncbi.nlm.nih.gov/books/NBK548901/
- https://www.drugs.com/mtm/moxetumomab-pasudotox.html
- https://en.wikipedia.org/wiki/Moxetumomab_pasudotox
- https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d6510282-1a57-4614-9859-299a227a089c
- https://medlineplus.gov/druginfo/meds/a618052.html
- https://www.mayoclinic.org/drugs-supplements/moxetumomab-pasudotox-tdfk-intravenous-route/side-effects/drg-20444022
- https://www.webmd.com/drugs/2/drug-176309/moxetumomab-pasudotox-tdfk-intravenous/details/list-contraindications
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