Acute myeloid leukaemia (AML) in first remission concomitantly treated with interleukin-2 (IL-2)

Interleukin-2 (IL-2)

IL-2 is administered twice daily as a subcutaneous injection 1 to 3 minutes prior to the administration of histamine; each dose of IL-2 is 16 400 IU/kg (1 µg/kg).

Interleukin-2 (IL-2) is commercially available as a recombinant IL-2; aldesleukin. The dispensing and storage directions below are specific to aldesleukin.

Dispensing instructions for IL-2 (aldesleukin)

IL-2 (aldesleukin) should be aseptically reconstituted, diluted and dispensed in capped polypropylene tuberculin syringes by the pharmacy based on the individual patient’s weight (see administration chart for aldesleukin below) at the recommended dose of 16 400 IU/kg (1 µg/kg). Up to two weeks supply of pre-filled capped tuberculin syringes may be provided to patients for home administration, with instructions that the syringes be stored under refrigeration at 2°C–8°C prior to administration.

Studies have shown chemical stability and sterility of diluted aldesleukin (dispensed in capped polypropylene tuberculin syringes) for up to three weeks when prepared in a controlled aseptic environment and stored under refrigeration at 2°C–8°C.

NOTE: Dispensing of aldesleukin must be carried out under controlled aseptic conditions.

Dispensing of dilute IL-2 (Aldesleukin) for each patient

The diluted IL-2 (aldesleukin) is aseptically drawn up into sterile polypropylene tuberculin syringes and capped for each patient at 1 µg/kg dose, with a minimum standard dosage volume of 0.25 mL (50 µg) and a maximum dose of 0.5 mL (100 µg). Dosing volumes based on patient weight are provided in Table 1 below. This table also provides the volume required if a 20% dose reduction is prescribed.

Table 1. Administration chart for IL-2 (aldesleukin):

^* Injection volume rounded up to the nearest 0.05 mL
^** Injection volumes based on 20% reductions are rounded thus actual dose reductions vary from 15%-25%

Histamine

0.5 mL solution is sufficient for a single dose. Histamine is administered 1 to 3 minutes after each injection of IL-2. Each 0.5 mL histamine dose is injected slowly, over 5-15 minutes.

Treatment cycles

Histamine and IL-2 are administered for 10 treatment cycles: each cycle consists of a treatment period of 21 days (3 weeks) followed by a three-week or six-week treatment-free period.

For cycles 1-3, each cycle consists of 3 weeks of treatment, followed by a 3-week treatment free period. For cycles 4-10, each cycle consists of 3 weeks of treatment, followed by a 6-week treatment free period.

The recommended dosing regimen is presented in Tables 2 and 3.

Table 2. For treatment cycles 1-3 with histamine and IL-2:

^* see dose modification for provisions for the modification to dose and dosage schedule

Table 3. For treatment cycles 4-10 with histamine and IL-2, same as for Table 1 above, with the exception of number of cycles and duration of rest periods:

^* see dose modification for provisions for the modification to dose and dosage schedule

Dose modification

Patients should be monitored for the expected symptomatic adverse reactions and laboratory changes associated with this treatment. Doses of histamine and IL-2 should be modified as necessary based on individual patient tolerance to treatment. It is recommended that dose modifications be addressed early in treatment. The dose reductions can be temporary or permanent. Should histamine related toxicities occur (such as hypotension, headache), the injection time can be increased from 5 minutes to a maximum duration of 15 minutes.

For patients experiencing grade 1 toxicity events:

No altered dose recommendations with the exception of grade 1 neurologic toxicity and grade 1 generalised toxic dermatitis. For the dose recommendations for these grade 1 toxicity events refer to the relevant sections below:

For patients experiencing grade 1-4 neurologic toxicity:

• for grade 1 to 3 toxicity, treatment should be discontinued until grade 0 toxicity event has been achieved. Treatment should then be resumed at a 20% dose reduction for both histamine and IL-2.
• for grade 4 toxicity, discontinuation of treatment should be considered.

For patients experiencing grade 1-4 generalised toxic dermatitis:

• for grade 1 toxicity, the treatment should be delayed for 48 hours or until all symptoms have been resolved. Treatment should then be resumed using the full dose of histamine, but reducing the IL-2 dose by 20%.
• for grade 2 toxicity, the IL-2 dose should be reduced 50% and only increased to full dose if the symptoms do not reappear. Histamine and IL-2 doses should be separated by 60 minutes, which should be maintained throughout treatment.
• for grade 3 and 4 toxicity, treatment should be discontinued and not resumed until events have been resolved. Treatment should only be resumed after consideration of risk – benefit to the patient.

For patients experiencing grade 2 (including cardiac function, renal, hepatic) toxicity:

• treatment should be discontinued until the event has returned to grade 1
• the time of injection of the dose of histamine should be extended to a maximum of 15 minutes.
• for cardiac, hepatic or renal toxicities the dose should be reduced by 20% for both histamine and IL-2.

For patients experiencing grade 3 and 4 (including hypotension, arrhythmia) toxicities:

• treatment should be discontinued until the event is resolved. A maximum delay of one treatment cycle can be considered for the resolution of grade 3 and 4 events.

For persistent hypotension, headache, arrhythmia, cardiac, hepatic and renal toxicities:

• the time of injection of the dose of histamine should be extended to a maximum of 15 minutes.
• the dose amount of both histamine and IL-2 should be reduced by 20%.

Fever:

• IL-2 can be discontinued for 24 hours and then restarted at a 20% dose reduction level.

Abnormal WBC counts:

• the dose of IL-2 can be reduced by 20% for the remaining duration of the treatment course and if abnormal WBC counts re-occur during the following cycle a permanent IL-2 reduction is recommended.

Localised toxic dermatitis:

• treatment should be discontinued until symptoms resolved. Treatment can be resumed by administering histamine at the full dose and IL-2 at 50%.

One to 3 minutes after the subcutaneous administration of IL-2 has been completed, histamine should be administered by slow subcutaneous injection at a rate not to exceed 0.1 mL (0.1 mg histamine dihydrochloride) per minute. The usual time for administering a 0.5 mL histamine dose is 5 minutes. To reduce potential adverse reactions, the administration time may be lengthened to a maximum of 15 minutes. Histamine can be administered via an ambulatory infusion syringe pump or by controlled manual subcutaneous injection by syringe with a timer.

The preferred injection areas are the thighs and the abdomen. Histamine should not be injected into the same anatomic region as IL-2.

The twice daily dosing of IL-2 and histamine should be separated by a minimum of 6 hours. Patients should remain at rest for 20 minutes after injection of histamine.