Inotuzumab – Uses, Dosage, Side Effects, Interaction

Mechanism of action

Inotuzumab ozogamicin is comprised of cytotoxic antibiotic? N-acetyl-gamma-calicheamicin dimethyl hydrazide attached to a humanized monoclonal IgG4 antibody via 4-(4 acetylphenoxy) butanoic acid (acetyl butyrate) linker. The drug exerts a potent cytotoxic effect against CD22+ B-cell lymphoma? when the antibody binds to the CD22 receptor on the surface of B cells. The drug-CD22 complex is rapidly internalized into the cell, forming an endosome that subsequently fuses with lysosomes. N-acetyl-gamma-calicheamicin dimethyl hydrazide is then intracellularly released into the acidic environment. N-acetyl-gamma-calicheamicin dimethyl hydrazide is a calicheamicin derivative, which is naturally produced by the bacterium Micromonospora Tinospora, and is toxic to the body when not bound to the antibody. It mediates apoptosis of the cell by binding to the minor groove of DNA in a sequence-specific manner and undergoing a structural change to generate diradicals ^[rx]. These changes abstract hydrogen ions from the phosphodiester bonds of double-stranded DNA, resulting in breaks and cell apoptosis ^[rx].

Indications

• Indicated as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B cell precursor acute lymphoblastic leukemia (ALL).
• Refractory B-cell precursor acute lymphoblastic leukemia
• Relapsed B cell precursor Acute lymphoblastic leukemia
• Inotuzumab ozogamicin is used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia.

Use in Cancer

Inotuzumab ozogamicin is approved to treat:

• B-cell acute lymphoblastic leukemia (ALL). It is used in adults whose cancer has relapsed or is refractory (does not respond to treatment).

Inotuzumab ozogamicin is also being studied in the treatment of other types of cancer.

Contraindications

• a bad infection?
• acute leukemia
• low amount of magnesium in the blood
• low amount of calcium in the blood
• low amount of sodium in the blood
• low amount of potassium in the blood
• hemolytic uremic syndrome?, a condition that affects the kidney? and the blood
• anemia?
• decreased blood platelets
• low levels of white blood cells
• a painful condition that affects the nerves in the legs and arms called peripheral neuropathy?
• sudden blindness and pain? upon moving the eye
• ototoxicity, damage to the inner ear that affects hearing or balance
• hearing loss
• a heart attack?
• a clot in the lung
• a stroke?
• inflammation? of blood vessels in the brain or spinal cord?
• Raynaud’s phenomenon, a condition where blood vessels constrict too much with coldness or stress
• blood clot in a deep vein? of the extremities
• thrombotic thrombocytopenic purpura, a type of blood disorder
• decreased kidney function
• vomiting?
• amount of uric acid in the blood
•  pregnancy
• a patient who is producing milk and breastfeeding
• TPMT poor metabolizer
• a type of brain disorder called posterior reversible encephalopathy syndrome
• a clot in the aorta?
• kidney disease with likely reduction in kidney function

Dosage?

Strengths: 0.9 mg

Acute Lymphoblastic Leukemia

Cycle 1 (total dose is 1.8 mg/m2/cycle):

• Day 1: 0.8 mg/m2 IV
• Day 8: 0.5 mg/m2 IV
• Day 15: 0.5 mg/m2 IV

Duration of therapy: Cycle 1 is 21 days in duration, but may be extended to 28 days (7-day therapy-free interval starting on Day 21) if the patient achieves a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow for recovery from toxicity
Subsequent Cycles:
For patients who achieve a CR or CRi (total dose is 1.5 mg/m2/cycle):

• Day 1: 0.5 mg/m2 IV
• Day 8: 0.5 mg/m2 IV
• Day 15: 0.5 mg/m2 IV

Duration of therapy: 28 days (7-day therapy free interval starting on Day 21)
OR
For patients who do not achieve a CR or CRi (total dose is 1.8 mg/m2/cycle):

• Day 1: 0.8 mg/m2 IV
• Day 8: 0.5 mg/m2 IV
• Day 15: 0.5 mg/m2 IV

Duration of therapy: 28 days (7-day therapy free interval starting on Day 21); patients who do not achieve a CR or CRi within 3 cycles should discontinue therapy
For patients proceeding to hematopoietic stem cell transplant (HSCT):

• Duration of therapy: 2 cycles; a third cycle may be considered for those patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after 2 cycles

For patients not proceeding to HSCT:

• Duration of therapy: Additional cycles of treatment, up to a maximum of 6 cycles, may be administered.
• Premedicate patients with a corticosteroid, an antipyretic, and an antihistamine prior to dosing.
• Infuse for 1 hour at a rate of 50 mL/hr.
• Doses on days 8 and 15 may be varied by plus or minus 2 days (maintain a minimum of 6 days between doses).
• Complete remission (CR) is defined as less than 5% blasts in bone marrow and the absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts [platelets 100 x 10(9)/L or greater and absolute neutrophil? count (ANC) 1 x 10(9)/L or greater] and resolution of any extramedullary disease.
• Complete remission with incomplete hematologic recovery (CRi) is defined as less than 5% blasts in bone marrow and the absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts [platelets less than 100 x 10(9)/L and ANC less than 1 x 10(9)/L] and resolution of any extramedullary disease.
• For patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, steroids, and/or vincristine to a peripheral blast count of 10,000/mm3 or less is recommended prior to the first dose.
• Observe patients for infusion reactions during and for at least 1 hour after the end of the infusion.

Renal? Dose Adjustments

• Mild? (CrCl 60 to 89 mL/min), moderate? (CrCl 30 to 59 mL/min), or severe? (CrCl 15 to 29 mL/min) renal impairment: No adjustment recommended.
  End-stage renal disease (CrCl less than 15 mL/min): Data not available

Dose Adjustments

Dose Adjustments for Hematologic Toxicities:

• If ANC is 1 x 10(9)/L or greater prior to starting of therapy:
• If ANC decreases, interrupt the next cycle of therapy until recovery of ANC to 1 x 10(9)/L or greater.
• Discontinue therapy if low ANC persists for greater than 28 days and is probably related to this drug.

If the platelet count is 50 x 10(9)/L or greater prior to starting therapy

• If the platelet count decreases, interrupt the next cycle of therapy until the platelet count recovers to 50 x 10(9)/L or greater.
• Discontinue therapy if low platelet count persists for greater than 28 days and is probably related to this drug.

If ANC is less than 1 x 10(9)/L and/or platelet count is less than 50 x 10(9)/L prior to start of therapy:

• If ANC or platelet count decreases interrupt the next cycle of therapy until at least one of the following occurs:

1) ANC and platelet counts recover to at least baseline levels for the prior cycle
OR
2) ANC recovers to 1 x 10(9)/L or greater and platelet count recovers to 50 x 10(9)/L or greater
OR
3) Stable or improved disease (based on most recent bone marrow assessment) and the ANC and platelet count decrease is due to the underlying disease (not considered to have been caused by this drug).

Dose Adjustments for Nonhematologic Toxicities:

• Veno-occlusive disease (VOD) or other severe liver toxicity: Permanently discontinue therapy.
• Total bilirubin greater than 1.5 x upper limit of normal (ULN) and AST/ALT greater than 2.5 x ULN: Interrupt therapy until recovery of total bilirubin to 1.5 x ULN or less and AST/ALT to 2.5 x ULN or less prior to each dose unless due to Gilbert’s syndrome or hemolysis; permanently discontinue therapy if total bilirubin does not recover to 1.5 x ULN or less or AST/ALT does not recover to 2.5 x ULN or less.
• Infusion-related reaction: Interrupt the infusion and manage medically; depending on the severity of the reaction, consider discontinuation of therapy and administration of steroids and antihistamines; for severe or life-threatening infusion reactions, permanently discontinue therapy.
• Nonhematologic toxicity Grade 2 or greater: Interrupt therapy until recovery to Grade 1 or pretreatment Grade levels prior to each dose.

Dose Adjustments Depending on Duration of Dosing Interruption Due to Nonhematologic Toxicity:

• Interruption of less than 7 days (within a cycle): Interrupt the next dose (maintain a minimum of 6 days between doses).
• Interruption of 7 days or more: Omit the next dose in the cycle.
• Interruption of 14 days or more: After recovery, decrease the dose by 25% for the next cycle; if further dose modification is required, reduce the number of doses to 2 per cycle for subsequent cycles; if a 25% decrease in the total dose followed by a decrease to 2 doses per cycle is not tolerated, then permanently discontinue therapy.
• Interruption of more than 28 days: Consider permanent discontinuation of therapy.

Side Effects

The Most Common

• dizziness
• lightheadedness
• fever, chills, cough, or other signs of infection
• unusual bleeding or bruising
• black and tarry stools
• red blood in stools
• pale skin
• fatigue

More common

• fever, weakness, cold, or flu symptoms;
• cough, trouble breathing;
• swollen gums, mouth sores;
• pale skin, easy bruising, skin sores;
• a headache with chest pain and severe dizziness, fainting, fast or pounding heartbeats;
• signs of liver problems–upper stomach pain, jaundice (yellowing of the skin or eyes), or rapid weight gain, swelling in your arms or legs, painful swelling in your midsection; or
• unusual bleeding gums, abnormal vaginal bleeding, blood in your urine or stools, coughing up blood or vomit that looks like coffee grounds.

Rare

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• chest pain
• chills
• cough or hoarseness
• coughing up blood
• difficulty in breathing or swallowing
• dizziness
• fever
• headache
• increased menstrual flow or vaginal bleeding
• lower back or side pain
• nosebleeds
• painful or difficult urination
• pale skin
• paralysis
• pinpoint red spots on the skin
• prolonged bleeding from cuts
• red or dark brown urine
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• swollen glands
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• yellow eyes or skin

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category Not Assigned:

Pregnancy

Drugs that have caused, are suspected to have caused, or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Lactation

The effects in the nursing infant are unknown. Women should not breastfeed during therapy and for at least 2 months after the last dose.

References