FLAG-Ida + Gemtuzumab Ozogamicin Regimen (Also known as FLAG-Ida + GO3x2) (AML19 Trial Course 1)

Transcription

1 FLAG-Ida + Gemtuzumab Ozogamicin Regimen (Also known as FLAG-Ida + GO3x2) (AML19 Trial Course 1) AML19 Adults with Acute Myeloid Leukaemia or High-Risk Myelodysplastic Syndrome ***Refer to trial protocol for further details*** Available for Routine Use in Burton in-patient Derby in-patient Burton day-case Derby day-case Burton community Derby community Burton out-patient Derby out-patient Indication Acute myeloid leukaemia Treatment Intent Radical. Induction therapy (course 1) Anti-Emetics Pre-chemotherapy 3- omit dexamethasone Post-chemotherapy B (omit dexamethasone) + ondansetron 8mg BD for 5 days Blood products Irradiated blood products required lifelong Day 1 G-CSF (Biosimilar) 300 micrograms Subcutaneous injection ONCE daily for 7 days (7 doses) Day 2 Chlorphenamine 10 mg Intravenous bolus 1 hour prior to Gemtuzumab Paracetamol 1000mg Oral or intravenous 1 hour prior to Gemtuzumab Ondansetron 8 mg Oral or intravenous BD D1-5 (first dose prior to chemotherapy) then BD prn Gemtuzumab Ozogamicin (Mylotarg ) 3 mg/m 2 (max 5 mg/day) Intravenous infusion in 100ml sodium chloride 0.9% (protected from light) over 2 hours via a 0.2-micron end-line filter. Fludarabine 30 mg/m 2 Intravenous infusion in 100ml sodium chloride Cytarabine <60 years Prednisolone 1 drop Eye drops 4 times daily in each eye for 12 days (Predsol 0.5% or equivalent) Metoclopramide 10 mg Oral or intravenous four times a day for 7 days Cotrimoxazole 480 mg Oral once daily until lymphocytes >1.0 x 10 9 /L PAGE 1 of 7

2 Aciclovir Allopurinol 400 mg 300 mg Oral twice daily until lymphocytes >1.0 x 10 9 /L Oral once daily (Reduce dose in renal impairment. See supportive care section for dosing in renal impairment and for advice for high risk patients) Day 3 Fludarabine 30 mg/m 2 Intravenous infusion in 100ml sodium chloride Day 4 Fludarabine 30 mg/m 2 Intravenous infusion in 100ml sodium chloride Idarubicin 8 mg/m 2 Intravenous infusion in 100ml sodium chloride. Start the infusion after the cytarabine Day 5 Chlorphenamine 10 mg Intravenous bolus 1 hour prior to Gemtuzumab Paracetamol 1000mg Oral or intravenous 1 hour prior to Gemtuzumab Ondansetron 8 mg Oral or intravenous BD D1-5 (first dose prior to chemotherapy) then BD prn Hydrocortisone 100mg Intravenous bolus 30 minutes prior to Gemtuzumab if patient had a reaction to 1 st dose of Gemtuzumab Gemtuzumab Ozogamicin (Mylotarg ) 3 mg/m 2 (max 5 mg/day) Intravenous infusion in 100ml sodium chloride 0.9% (protected from light) over 2 hours via a 0.2-micron end-line filter. Fludarabine 30 mg/m 2 Intravenous infusion in 100ml sodium chloride Idarubicin 8 mg/m 2 Intravenous infusion in 100ml sodium chloride. Start the infusion after the cytarabine PAGE 2 of 7

3 Day 6 Fludarabine 30 mg/m 2 Intravenous infusion in 100ml sodium chloride Idarubicin 8 mg/m 2 Intravenous infusion in 100ml sodium chloride. Start the infusion after the cytarabine Day 10 Posaconazole 300 mg Oral TWICE daily for 1 DAY, ONCE daily thereafter until 7 days after neutrophils recover to >0.5x10 9 /L (see supportive care section). This must not be started within 5 days of Mylotarg. Frequency & duration: See trial protocol for further details Notes: All patients who receive fludarabine should receive irradiated blood products throughout their chemotherapy and for life. The dose of Cytarabine in FLAG-Ida should be reduced to 1gm/m 2 on days 2-6 for patients 60years of age in both course 1 and 2. Patients receiving FLAG-Ida course 1 who have a WCC 30 x 10 9 /L - advised to omit G-CSF until the WCC has fallen to <30. Patients with Serum Alanine Aminotransferase (AST) or Aspartate Aminotransferase (ALT) more than 2.5 times the local upper limit of normal (ULN) or bilirubin more than twice the ULN are not eligible for Gemtuzumab randomisations. Patients allocated to receive Gemtuzumab must not have WBC count greater than 30 x 10 9 /L at the time of Gemtuzumab administration because of the risk of tumour lysis. Such patients should either have the WBC reduced with Hydroxycarbamide before commencing trial chemotherapy or have the administration of gemtuzumab delayed until day 4 of the chemotherapy. If there is a reaction to the first dose of Gemtuzumab, patients scheduled to receive a second dose should receive prophylactic hydrocortisone in addition to the measures detailed in Appendix B of the Protocol. PAGE 3 of 7

4 Patients should receive AmBisome 100mg intravenous infusion 3 times a week for antifungal cover, (Clinical decision, Dr Amott 2016). o A test dose of 1mg intravenous infusion in dextrose 5% should be given over 10 minutes then stopped (infusion must be protected from light). o If no reaction occurs after 30 minutes the infusion can be restarted and given over 30 minutes. o AmBisome is not compatible with sodium chloride 0.9% - the line should be flushed with dextrose 5% after administration. If AmBisome is given on the same day as Gemtuzumab Ozogamicin, administer the AmBisome first. If this is not possible or other IV infusions in sodium chloride 0.9% have already been given, flush the line with dextrose 5% before AmBisome administration. National dose banding tables have been approved for use by the Trial for nimp s. Baseline investigations 1. All patients should have their creatinine clearance measured using a 24 hour urine collection prior to each cycle (see below for dose modifications in case of renal impairment). The EGFR must not be used to assess renal function. If the creatinine is significantly increased in subsequent cycles renal function should be reassessed. 2. Consider reassessing cardiac function prior to cycle 2. modifications and toxicities 1. Renal impairment Patients with creatinine clearance <30 ml/min should be considered for alternative chemotherapy. Fludarabine Creatinine clearance ml/min >70 100% normal dose % normal dose <30 Use alternative regimen Cytarabine No reductions are necessary for renal impairment. PAGE 4 of 7

5 Idarubicin The manufacturer advises dose reductions based on serum creatinine, however there is no advice according to creatinine clearance. An elevated serum creatinine may not correspond to renal impairment, particularly in younger patients. The creatinine clearance should be calculated and if this is reduced, then it would be reasonable to use the serum creatinine to guide the dose reduction. Creatinine micromol/l <99 100% normal dose % normal dose >175 Clinical decision - consider alternative regime Gemtuzumab Ozogamicin (Mylotarg ) This is contraindicated if the renal function is abnormal. The Serum creatinine should be 1.5 upper limit of normal (ULN). 2. Hepatic impairment Fludarabine - no reductions are necessary for hepatic impairment. Cytarabine Bilirubin micromol/l <34 100% normal dose >34 50% normal dose Idarubicin Bilirubin micromol/l <40 100% normal dose % normal dose >85 Omit Gemtuzumab ozogamicin (Mylotarg ) This is contraindicated if liver function tests are abnormal. Patients must have Serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) 2.5 ULN and bilirubin 2.0 ULN. PAGE 5 of 7

6 3. Other toxicities A Cytosar syndrome has been described with use of Cytarabine. It is characterised by fever, myalgia, bone pain, occasional chest pains, maculopapular rash, conjunctivitis and malaise. This usually occurs 6-12 hours following infusion, and is more common with higher doses. Systemic steroids have been beneficial in treating this condition if severe. Gemtuzumab Ozogamicin (Mylotarg ) Premedication, consisting of an antihistamine (such as chlorphenamine) and paracetamol, should be given before each infusion to reduce the incidence of a post-infusion symptom complex. A steroid is not required unless a reaction occurs, in which case dexamethasone 8mg may be used prior to gemtuzumab on the next course. Vital signs should be monitored during infusion and for four hours following infusion. Maximum dose of 5mg per day for twice weekly gemtuzumab. 0.2micron end-line filter used within the Trust is the Baxter Millipore IV Express which is provided by the chemotherapy satellite along with the Mylotarg. Supportive care 1. Allopurinol 300mg once daily (Reduce dose to 100mg if GFR < 10ml/min) if there is risk of tumour lysis syndrome. Consider rasburicase if there is high risk of tumour lysis. The dose may need to be repeated for several days. 2. Ambisome 100mg three times a week given prophylactically prior to starting posaconazole. Ensure test dose is given on day 1 as anaphylaxis and anaphylactoid reactions have been reported in association with AmBisome infusion. Allergic type reactions, including severe infusion-related reactions can also occur. Although infusion-related reactions are not usually serious, consideration of precautionary measures for the prevention or treatment of these reactions should be given to patients who receive AmBisome therapy. Slower infusion rates (over 2 hours) or routine doses of chlorphenamine, paracetamol, pethidine and/or hydrocortisone have been reported as successful in their prevention or treatment. 3. When neutrophils <1.0x10 9 /l, commence Posaconazole 300mg orally TWICE daily for 1 day, then 300mg ONCE daily thereafter until 7 days after neutrophils recover to >0.5x10 9 /l (refer to Fungal Infection guideline). If a patient is already on posaconazole when Mylotarg commences, stop the posaconazole & monitor liver function tests. Ideally posaconazole should not be given until at least day 5 after the administration of gemtuzumab ozogamicin (Mylotarg ). PAGE 6 of 7

7 4. Prednisolone (0.5% Predsol) eye drops (or equivalent) should be used four times a day during the courses of high dose cytarabine and be continued for 5 days after each course finishes. 5. Aciclovir 400mg twice daily, (reduce to 200mg twice daily if CrCl<10ml/min). 6. Cotrimoxazole 480mg once daily, (consider Dapsone 100mg daily if allergic). References 1. AML19 Trial Protocol, version 7, February Ambisome Summary of Product Characteristics 29 th March 2017 (accessed ), Gilead Sciences Ltd on 3. Standard Care QACS FLAG-Ida Regimen, version 3, 12/12/14 by C. Ward. 4. Prescribing of AmBisome Clinical Decision, Dr Amott Standard Care QACS AIDA Induction Course, version 5, by C.Ward & K.Graham. 6. Fungal Infection, Full Clinical Guideline Ref:CG-T/2015/216, approved PAGE 7 of 7