Usual Adult Dose for 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.

Comments:

• 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.

Use: For the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)

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

Liver Dose Adjustments

See DOSE ADJUSTMENTS for nonhematologic toxicity.

Dose Adjustments

Dose Adjustments for Hematologic Toxicities:

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

• If platelet count decreases, interrupt the next cycle of therapy until 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:

• Venoocclusive 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.

Precautions

US BOXED WARNINGS:
HEPATOTOXICITY, INCLUDING HEPATIC VENO-OCCLUSIVE DISEASE (VOD) (ALSO KNOWN AS SINUSOIDAL OBSTRUCTION SYNDROME AND INCREASED RISK OF POST-HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) NON-RELAPSE MORTALITY HEPATOTOXICITY, INCLUDING VOD:

• Hepatotoxicity (including fatal VOD) has occurred in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) who received this drug.
• The risk of VOD was greater in patients who underwent HSCT after taking this drug; use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin level at the upper limit of normal (ULN) or greater before HSCT were significantly associated with an increased risk of VOD.
• Other risk factors for VOD in patients treated with this drug included ongoing or prior liver disease, prior HSCT, advanced age, later salvage lines, and a greater number of therapy cycles.
• Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of therapy.
• Permanently discontinue therapy if VOD occurs and treat severe VOD per standard medical practice.

INCREASED RISK OF POST-HSCT NON-RELAPSE MORTALITY:

• There was higher post-HSCT non-relapse mortality rate in patients receiving this drug, resulting in a higher Day 100 post-HSCT mortality rate.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Filtration of the diluted solution is not required; however, if the diluted solution is filtered, polyethersulfone (PES)-, polyvinylidene fluoride (PVDF)-, or hydrophilic polysulfone (HPS)-based filters are recommended. Do not use filters made of nylon or mixed cellulose ester (MCE).
• Infuse the diluted solution for 1 hour at a rate of 50 mL/hr at room temperature (20C to 25C; 68F to 77F).
• Infusion lines made of PVC (DEHP-or non-DEHP-containing), polyolefin (polypropylene and/or polyethylene), or polybutadiene are recommended.

Storage requirements:

• The manufacturer product information should be consulted.

Reconstitution/preparation techniques:

• Reconstitute each vial with 4 mL of Sterile Water for Injection.
• Gently swirl the vial to aid dissolution. DO NOT SHAKE.
• Inspect the reconstituted solution for particulates and discoloration. The reconstituted solution should be clear to opalescent, colorless to slightly yellow, and free of visible foreign matter.

General:

• This drug is cytotoxic. Follow applicable special handling and disposal procedures.
• Protect the reconstituted and diluted solution from light. Do not freeze the reconstituted or diluted solution.
• The maximum time from reconstitution through the end of administration should be 8 hours or less, with 4 hours or less between reconstitution and dilution.