Burkitt s Lymphoma or DLBCL with adverse features PATIENTS WITH GOOD PERFORMANCE STATUS

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1 Regimen R-CODOX M Indication Burkitt s Lymphoma or DLBCL with adverse features Therapeutic Intent Radical/Curative PATIENTS WITH GOOD PERFORMANCE STATUS Day Medication Dose Route Administration Details 1 Cyclophosphamide 800mg/m 2 IV 2 and 4 Cytarabine 70mg Intrathecal Refer to local intrathecal policy for further guidance. 1 Doxorubicin 40mg/m 2 IV Slow IV Bolus injection 1 and 11 Rituximab 375mg/m 2 IV Add to sodium chloride 0.9%, see local protocol or product SPC for information on rate of infusion. 1 and 8 Vincristine 1.5mg/m 2 IV Max dose 2mg. 50ml sodium chloride 0.9% minibag over 5-10 minutes. 2 to 5 Cyclophosphamide 200mg/m 2 IV 10 Methotrexate 300mg/ m 2 IV Infuse over 60 minutes in 100ml or 250ml sodium chloride 0.9% 10 Methotrexate 2700mg/ m 2 IV Infuse over 23 hours in 1000ml sodium chloride 0.9% 13 G-CSF daily SC 7 day course. 15 Methotrexate 12.5mg Intrathecal Bolus injection. Refer to local intrathecal policy for further guidance. An intensified intrathecal treatment is required for patients with CNS disease at diagnosis. This is given for the first cycle of RCODOX M as follows; Cycle Day Medication Dose Route Administration Details R-CODOX-M 6 Cytarabine 70mg Intrathecal Refer to local intrathecal R-CODOX-M 17 Methotrexate 12.5mg Intrathecal policy for further guidance. Page 1 of 6

2 PATIENTS WITH POORER PERFORMANCE STATUS Day Medication Dose Route Administration Details 1 Cyclophosphamide 800mg/m 2 IV 2 and 4 Cytarabine 70mg Intrathecal Refer to local intrathecal policy for further guidance. 1 Doxorubicin 40mg/m 2 IV Slow IV Bolus injection 1 and 11 Rituximab 375mg/m 2 IV Add to sodium chloride 0.9%, see local protocol or product SPC for information on rate of infusion. 1 and 8 Vincristine 1.5mg/m 2 IV Max dose 2mg. 50ml sodium chloride 0.9% minibag over 5-10 minutes. 2 to 5 Cyclophosphamide 200mg/m 2 IV 10 Methotrexate 100mg/ m 2 IV Infuse over 60 minutes in 100ml or 250ml sodium chloride 0.9% 10 Methotrexate 900mg/ m 2 IV Infuse over 23 hours in 1000ml sodium chloride 0.9% 13 G-CSF daily SC 7 day course. 15 Methotrexate 12.5mg Intrathecal Refer to local intrathecal policy for further guidance. An intensified intrathecal treatment is required for patients with CNS disease at diagnosis. This is given for the first cycle of RCODOX M as follows; Cycle Day Medication Dose Route Administration Details R-CODOX-M 6 Cytarabine 70mg Intrathecal Refer to local intrathecal R-CODOX-M 17 Methotrexate 12.5mg Intrathecal policy for further guidance. Page 2 of 6

3 Low risk patients Give three cycles of RCODOX M only, each cycle starting as soon as possible after neutrophils have regenerated >1 x10 9 /L and unsupported platelets >75 >1 x10 9 /L. Cycle Frequency Tests required prior to initiation of course Tests required prior to individual cycle Concurrent Medication Hydration High risk patients Give 2 cycles alternating with 2 cycles of R-IVAC (i.e. RCODOX M - R-IVAC - R-CODOX M - R-IVAC), each cycle starting as soon as possible after neutrophils have regenerated >1 x10 9 /L and unsupported platelets >75 >1 x10 9 /L. Two further doses of Rituximab will be administered on Day 21 and 42 after day one of the final course of R-IVAC to bring the total of Rituximab infusions to 8. The neutrophil count should be > 1.0 x 10 9 /l on the day of administration. See treatment algorithm for further information on risk stratification. FBC, U&E, LFT, Bone profile, glucose, LDH, serum Igs, electrophoresis. GFR calculated using the wright equation or EDTA testing. Undertake relevant staging. Consider cardiac function tests. WHO performance status. Tumour Lysis screen. FBC, U&E, LFT. GFR calculated using the Wright equation or EDTA testing. Antihistamine and paracetamol pre-medication prior to rituximab as per local policy. High risk of tumour lysis syndrome strongly consider rasburicase. Allopurinol for first two cycles. Anti-emetics as per local policy. PPI, although there have been case reports of reduced methotrexate clearance in patients taking concomitant PPI. If patient is considered low risk of GI disturbance ranitidine may be sufficient. Consider antifungal, antiviral, PCP prophylaxis and mouthwashes as per local policy (note interaction between co-trimoxazole and methotrexate and between itraconazole and vincristine). Stop methotrexate infusion at hour 24 regardless of dose given. Adequate hydration is essential during high dose methotrexate. Pre-hydration For at least 6 hours prior to commencement of the methotrexate. Hydration fluid given pre, during and after MTX infusion; 1 litre Sodium Chloride 0.9% with 20mmol Potassium Chloride add 50mmol Sodium Bicarbonate (= 50ml of 8.4% solution) ALTERNATE WITH 1 litre Dextrose 5% with 20mmol Potassium Chloride add 50mmol Sodium Bicarbonate (= 50ml of 8.4% solution) Infusion rate 125ml/m2/hr (max. 250ml/hr). Fluid balance Check fluid balance at regular intervals (4-hourly) throughout each day, taking early action if fluid overload occurs by giving furosemide if the urine Page 3 of 6

4 Folinic acid rescue & Methotrexate levels output falls below 400ml/m2 in any given 4-hour period. Check urine ph Adjust the sodium bicarbonate concentration to maintain the urinary ph between 7 and 8 (i.e. alkaline). A urinary ph greater than 7 must be achieved before starting the methotrexate infusion. Serum methotrexate levels should be obtained as follows; Initially 48 hours after commencement of methotrexate Then daily until methotrexate level is below 5 x 10-8 M (or 0.05µmol/L) when rescue is stopped Commence folinic acid rescue at hour 36 from start of methotrexate infusion. Administer intravenously at a dose of 15mg/m2 every 3 hours from hours 36 to 48 and then continue folinic acid every 6 hours until serum methotrexate level < 5 x 10-8 M (or 0.05µmol/L). Folinic acid can be given orally after the first 24 hours if patients are compliant, not vomiting and otherwise without complication. Page 4 of 6

5 Dose Modifications Hepatic Serum Bilirubin (micromol/l) AST/ ALT (units) Modification If AST 2-3 x ULN 75% of doxorubicin dose Or If AST >3x ULN 50% of doxorubicin dose % of doxorubicin dose >85 Omit doxorubicin Or % of vincristine dose >51 And Normal 50% of vincristine dose >51 And >180 Omit Renal Creatinine clearance (ml/min) Modification >20 100% of cyclophosphamide % of cyclophosphamide <10 50% of cyclophosphamide >80 100% of methotrexate % of methotrexate <50 A creatinine clearance of at least 50ml/min is required to proceed with this regimen, consider alternative treatment if poor renal function Haematological There are no dose modifications for haematological toxicity. Treatment should be delayed until neutrophil count >1 x10 9 /L and unsupported platelets >75 x10 9 /L Neurotoxicity Grade 2 motor weakness or Grade 3 sensory toxicity Higher grades of neurological toxicity Give 50% vincristine OMIT vincristine Additional Information None. Page 5 of 6

6 References Author Mead GM et al. A prospective clinicopathological study of dose modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial). Blood (2008)112: Dose Adjustments for Cytotoxics in Hepatic Impairment January 2009, available at Dose Adjustments for Cytotoxics in Renal Impairment January 2009, available at Pharmacy CNG Approved & Checked by Haematology CNG (Review Date = Jan 2017) Page 6 of 6