Dose adjustment for adverse reactions

Non-haematological adverse reactions

If a severe non-haematological adverse reaction develops with Glivec use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.

If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, Glivec should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with Glivec may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from 800 mg to 600 mg, and in children from 340 to 260 mg/m2/day.
Haematological adverse reactions
Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the table below.
Dose adjustments for neutropenia and thrombocytopenia:
HES/CEL (starting dose 100 mg)
 ANC < 1.0 x 109/l

and/or

platelets < 50 x 109/l
 1. Stop Glivec until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l.

2. Resume treatment with Glivec at previous dose (i.e. before severe adverse reaction).
 
Chronic phase CML, MDS/MPD and GIST (starting dose 400 mg) HES/CEL (at dose 400 mg)
 ANC < 1.0 x 109/l

and/or
platelets < 50 x 109/l
 1. Stop Glivec until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l.

2. Resume treatment with Glivec at previous dose (i.e. before severe adverse reaction).

3. In the event of recurrence of ANC < 1.0 x 109/l and/or platelets < 50 x 109/l, repeat step 1 and resume Glivec at reduced dose of 300 mg.
 
Paediatric chronic phase CML

(at dose 340 mg/m2)
 ANC < 1.0 x 109/l

and/or

platelets < 50 x 109/l
1. Stop Glivec until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l.

2. Resume treatment with Glivec at previous dose (i.e. before severe adverse reaction).

3. In the event of recurrence of ANC < 1.0 x 109/l and/or platelets < 50 x 109/l, repeat step 1 and resume Glivec at reduced dose of 260 mg/m2.
 
Accelerated phase CML and blast crisis and Ph+ ALL (starting dose 600 mg)
aANC < 0.5 x 109/l

and/or

platelets < 10 x 109/l
 1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy).

2. If cytopenia is unrelated to leukaemia, reduce dose of Glivec to 400 mg.

3. If cytopenia persists for 2 weeks, reduce further to 300 mg.

4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop Glivec until ANC ≥ 1 x 109/l and platelets ≥ 20 x 109/l, then resume treatment at 300 mg.
 
Paediatric accelerated phase CML and blast crisis (starting dose 340 mg/m2)
 aANC < 0.5 x 109/l

and/or

platelets < 10 x 109/l
 1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy).

2. If cytopenia is unrelated to leukaemia, reduce dose of Glivec to 260 mg/m2.

3. If cytopenia persists for 2 weeks, reduce further to 200 mg/m2.

4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop Glivec until ANC ≥ 1 x 109/l and platelets ≥ 20 x 109/l, then resume treatment at 200 mg/m2.
 
DFSP

(at dose 800 mg)
 ANC < 1.0 x 109/l

and/or

platelets < 50 x 109/l
1. Stop Glivec