1.28 Protocol Name: CODOX-M/IVAC

Transcription

1 1.28 Protocol Name: CODOX-M/IVAC Indication Burkitt's or Burkitt's-like lymphoma - especially those with 1 of the following poor risk criteria: Lymphoblastic lymphoma - especially B subtype Acute Myeloid Leukaemia B-ALL (slg positive- usually L3 morphology Burkitt s or Burkitt-like) and Relapsed Acute Lymphoblastic Leukaemia This regimen is very intensive and was introduced by Magrath and colleagues at the National Cancer Institute, USA to treat Burkitt's lymphoma or Burkitts-like. Early results in this rare condition for both children and adults were very promising and the regimen has been adopted by many centres for the treatment of the most aggressive, poor risk high grade non-hodgkin's lymphomas. The current LY10 Trial uses lower doses of methotrexate than the previous LY06 Trial. Consult the LY10 Trial Protocol for full details. Pre-treatment evaluation and treatment Evaluate problems requiring urgent attention including impending airway obstruction, CNS disease, uric acid nephropathy, renal flow obstruction, metabolic problems or fever. Arrange for a Hickman or similar tunnelled central venous catheter to be inserted if possible. Document disease stage following clinical assessment, CXR and CT scan of chest, abdomen and pelvis (consider MRI scan for cranio-spinal involvement). Include the presence or absence of B symptoms together with WHO and ECOG performance status. Other investigations should include blood tests for FBC, ESR/PVisc, clotting screen (PT, aptt and fibrinogen), U&E, LFTs, calcium, magnesium, uric acid, LDH, immunoglobulin levels and serum protein electrophoresis. Baseline FSH, LH, oestradiol and testosterone levels should be considered CODOX-M,IVAC v 2.1 Page 1 of 11

2 An HIV test should be considered as Burkitt's lymphoma is one of the commonest histological subtypes seen in HIV-positive patients. A bone marrow aspirate (including cytogenetic analysis) and trephine biopsy must be performed as marrow involvement is common. A lumbar puncture (LP), in order to assess CSF cytology, glucose and protein, is mandatory as CNS involvement is common. It is suggested that cytarabine 70mg is given intrathecally at the time of the LP if Burkitt's or lymphoblastic lymphoma is a serious diagnostic possibility. Aspiration of pleural or ascitic fluid (including cytogenetic analysis) can sometimes be very useful for establishing a rapid diagnosis especially where the disease is, for example, intraabdominal and therefore inconvenient to biopsy. Creatinine clearance (measured by 24-hour urine collection or radio-isotopic methods) must be performed before any high dose methotrexate is given. Check & document height, weight and surface area. Consider pulmonary function tests to assess spirometry, TL CO and K CO in patients with pre-existing lung disease. Give adequate verbal/written information for patients and relatives concerning patient s disease, treatment strategy and side effects. Discuss potential risk of infertility with patient and relatives and consider sperm cryopreservation. Document WHO performance status of patient. Give adequate verbal and written information for patients and relatives concerning patient s disease, treatment strategy and side effects. Obtain written consent from patient or guardian. Serological tests for: Hepatitis B & C, CMV. ECG. CXR. ECHO if cardiac history, elderly or previous history suggestive of potential cardiac disease (Inc diabetes and hypertension) CODOX-M,IVAC v 2.1 Page 2 of 11

3 Drug Regimen - CODOX-M (OPCS code: X70.2) (methotrexate dose is reduced in patients of and over 65yrs old) Day Drug Dose Route Comments Vincristine 1.5mg/m 2 (max 2mg) IV bolus in 20mls 0.9% Saline 1 * Doxorubicin 40mg/m 2 IV bolus via fast running drip Cyclophosphamide 800mg/m 2 IV infusion in 250mls 0.9% Saline over 30mins Cytarabine 70mg IT bolus injection 2-5 Cyclophosphamide 200mg/m 2 IV infusion in up to 250mls 0.9% inc Saline over 15mins 3 Cytarabine 70mg IT bolus injection 8 Vincristine 1.5mg/m 2 IV bolus via fast running drip (max 2mg) <65yrs 300mg/m 2 IV infusion in 250mls 0.9% Saline >65yrs 100mg/m 2 over 60mins 10 Methotrexate <65yrs 2700mg/m 2 IV infusion in 1000mls 0.9% Saline >65yrs 900mg/m 2 over 23 hours 11 Calcium Folinate 15mg/m 2 13 GCSF (1amp) IV infusion in 100mls 5% dextrose over 30mins at 36 hours after the START of the methotrexate infusion then IV infusion in 100mls 5% dextrose repeated every 3hours Then every 6 hours until serum methotrexate level <5 x 10-8 M, (IV/PO as appropriate) SC daily until neutrophils >1.0x10 9 /l 15 Methotrexate 12.5mg IT bolus injection starting at T0 then starting at T1, T36 T39,T42,T45,T48 & T51 T54 onwards * Discontinue bicarbonate additives to IV infusions before starting chemotherapy. Adhere to the local Trust policy for intrathecal chemotherapy prescribing and administration. Methotrexate should only be given in the presence of a normal serum creatinine and a measured creatinine clearance of >50ml/min/m 2. Alkalinisation of urine using 3.0l/m 2 IV fluids with bicarbonate to ensure urine ph 7.0 should be commenced hours prior to the start of the methotrexate infusion and continued until Calcium Folinate rescue is no longer required. Commence methotrexate regardless of blood counts. Stop infusion at 24hours regardless of dose given. Serum methotrexate levels should be sent 48 hours after the start of the methotrexate infusion. If the 48 hour level is >2 x 10-6 M (2.0µmoles/l) the dose of Calcium Folinate should be doubled. IT IS OF PARAMOUNT IMPORTANCE that serum methotrexate levels are performed every 24 hours, Calcium Folinate rescue continued every 6 hours and urine ph maintained 7.0 until the methotrexate level is <5 x 10-8 M (0.05µmoles/l) CODOX-M,IVAC v 2.1 Page 3 of 11

4 commence the next cycle as soon as possible and on the day that the unsupported neutrophil count is >1.0 x 10 9 /l and platelets count is >75 x 10 9 /l. Drug Regimen - IVAC for patients <65 years (OPCS code: X70.5) Day Drug Dose Route 1-5 Etoposide 60mg/m 2 IV infusion in mls 0.9% Saline over 60mins Ifosfamide mixed with Mesna 1500mg/m mg/m 2 IV infusion in 500mls 0.9% Saline over 60mins 1-5 Mesna 600mg/m 2 IV infusion in 1L 0.9% Saline over 8hours inc 1&2 Cytarabine 2g/m 2 IV infusion in 1000mls 0.9% Saline over 3hours, every 12 hours i.e. total of 4 doses 5 Methotrexate 12.5mg IT bolus injection 7 GCSF (1 amp.) SC continued daily until neuts >1.0 x 10 9 /l commence the next cycle (CODOX-M) as soon as possible and on the day that the unsupported neutrophil count is >1.0 x 10 9 /l and platelets count is >75 x 10 9 /l. Drug Regimen - IVAC for patients >65 years (Ifosfamide and Cytarabine doses are reduced) (OPCS code: X70.5) Day Drug Dose Route 1-5 Etoposide 60mg/m 2 IV infusion in mls 0.9% Saline over 60mins Ifosfamide mixed with Mesna 1000mg/m 2 + IV infusion in 500mls 0.9% Saline over 60mins 200mg/m inc Mesna 400mg/m 2 IV infusion in 1L 0.9% Saline over 8hours - for 2 doses 1&2 Cytarabine 1g/m 2 IV infusion in 1000mls 0.9% Saline over 3hours, every 12 hours i.e. total of 4 doses 5 Methotrexate 12.5mg IT bolus injection 6 Calcium Folinate 15mg PO 24 hours after IT methotrexate 7 GCSF (1 amp.) SC continued daily until neuts >1.0 x 10 9 /l commence the next cycle (CODOX-M) as soon as possible and on the day that the unsupported neutrophil count is >1.0 x 10 9 /l and platelets count is >75 x 10 9 /l CODOX-M,IVAC v 2.1 Page 4 of 11

5 Cycle Frequency / Treatment Duration LOW RISK ie at least 3 of the factors below Normal LDH level WHO performance status 0-1 Ann Arbor stage I-II Number of extra-nodal sites (egg bone marrow, GI tract, CNS) 1 HIGH RISK ie all remaining patients are high risk. They should have 2 or more of the following features Raised LDH level WHO performance status 2-4 Ann Arbor stage III-IV Number of extra-nodal sites >1 3 cycles of CODOX-M are given 2 alternating cycles of each regimen is given, i.e. CODOX-M IVAC CODOX-M IVAC Note: Each cycle is started as soon as possible after neutrophils have regenerated to >1.0 x 10 9 /l and platelets (unsupported) to >75 x 10 9 /l. CNS involvement at diagnosis Intensified CNS chemotherapy treatment is as indicated below, regardless of age, and is given for THE FIRST TWO CYCLES ONLY. Day Drug Intrathecal Dose Intraventricular Dose (Ommaya Reservoir) CODOX-M 1,3,5 Cytarabine 70mg 15mg 15,1 7 16,1 8 Methotrexate 12.5mg 2mg Calcium Folinate 15mg oral dose, 24 hours after lumbar puncture/cytotoxic dose IVAC 5 Methotrexate 12.5mg 2mg 6 Calcium Folinate 15mg oral dose, 24 hours after lumbar puncture/cytotoxic dose 7,9 Cytarabine 70mg 15mg Intrathecal/intraventricular therapy for cycles 3 and 4 will be given according to the schedule for high risk patients without CNS disease 1.28 CODOX-M,IVAC v 2.1 Page 5 of 11

6 Insertion of an Ommaya reservoir should rarely be needed. If it is considered appropriate, it should be sited in week 3 of CODOX-M during the period of neutrophil recovery. A neutrophil count >0.5 x 10 9 /l is recommended. Radiotherapy Radiotherapy has not been demonstrated to be beneficial in the treatment of meningeal disease and adds significantly to myelotoxicity. Radiotherapy is only considered in the presence of the following circumstances: o intracerebral mass o meningeal disease where chemotherapy cannot commence immediately because of metabolic abnormalities o testicular involvement should be discussed with the principal investigator Concurrent Medication Adequate hydration, these patients are at high risk of developing tumour lysis syndrome. Start IV hydration at a rate of at least 3.0l/m 2 /day (sodium content 75mmol/l) or as close to this figure as is tolerated. Give frusemide as required to maintain urine output. DO NOT include potassium supplements with the IV fluids unless serum potassium falls below 3.0mmol/l. Add sodium bicarbonate to the IV solutions (start with 50mmol of sodium bicarbonate per litre of solution) if the patient has a raised serum uric acid level. Keep urine ph 7.0 (by increasing the amount of sodium bicarbonate in the infusion fluids to 100mmols/l, if necessary). Stop adding bicarbonate to infusions when uric acid is back within the normal range, or serum bicarbonate >30mmol/l and/or immediately prior to commencement of chemotherapy. Since most of these patients have very high tumour cell burdens and/or significant hyperuricaemia, rasburicase at a dose of 0.2mg/kg (rounded to nearest vial size) for 5-7 days is highly recommended. Where rasburicase is not used start allopurinol at a dose of 10mg/kg/day in 2-3 divided doses. Anti-ulcer drug as per local policy Antimicrobial prophylaxis as per local protocol including Itraconazole (liquid 200mg BD) for aspergillus prevention Check fluid balance at 4hour intervals through each day, taking early action if fluid overload occurs by giving frusemide if the urine output falls below 400 ml/m 2 in any given 4-hour period. FOR CODOX-M cycles: Drugs that compromise renal function e.g. aminoglycosides and cisplatin can decrease clearance of methotrexate and lead to systemic toxicity. Avoid concurrent use of NSAIDs including salicylates and sulphonamides. Large doses of penicillin may interfere with the active renal tubular secretion of methotrexate CODOX-M,IVAC v 2.1 Page 6 of 11

7 FOR CODOX-M cycles: If the serum creatinine increases by more than above baseline at 24 hours and/or the methotrexate level is greater than 5 x 10-6 M then the folinic acid rescue is increased. FOR IVAC cycles: Prednisolone 0.5% eye drops tds to avoid chemical conjunctivitis from high-dose cytarabine Investigations to be performed during chemotherapy During induction: at least daily FBC, U&E, creatinine, LFTs, uric acid, calcium, phosphate and magnesium so as to allow early recognition of tumour lysis syndrome. Thereafter: daily FBC, U&E, creatinine; thrice weekly LFTs, calcium and magnesium. Methotrexate: serum levels should be checked after high dose methotrexate as detailed above. Assessment of Response Assuming clinical response, the following is performed within 4 weeks of completion of the chemotherapy: FBC, ESR/PVisc, U&E, creatinine, LFTs and LDH CXR CT scan of areas abnormal at the time of presentation Bone marrow aspirate and trephine biopsy (if abnormal at the time of presentation) CSF cytology (if abnormal at the time of presentation) Anti-emetics Highly emetogenic as per local protocol Potential toxicities Severe myelosuppression (neutrophils <0.1 x 10 9 /l and platelets <20 x 10 9 /l) is expected Nausea & vomiting Vinca alkaloids: peripheral and autonomic neuropathy - watch for peripheral paraesthesia, constipation and paralytic ileus Mucositis Conjunctivitis (cytarabine) 1.28 CODOX-M,IVAC v 2.1 Page 7 of 11

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9 Dose Modifications Renal dysfunction: renal outflow obstruction and/or uric acid nephropathy are not uncommon. In these circumstances, more conventional chemotherapy ± haemodialysis or the insertion of nephrostomy tubes are recommended to obtain initial control of the lymphoma and allow improved renal function before commencing CODOX-M. Vincristine: dose reduction of only in the case of severe motor dysfunction. Creatinine Clearance 45-60ml/min Allopurinol Dose Doxorubicin Dose Methotrexate Dose Etoposide Dose 30-45ml/min 80% mg daily 75% 15-30ml/min 75% 10-15ml/min <10ml/min 100 daily or alternate days avoid Ifosfamide dose Cytarabine Dose 85% 70% 60% clinical decision CI Serum Doxorubicin Dose Vincristine Dose Etoposide Bilirubin ** Dose 20-34µmol/l 34-50µmol/l if transaminases 50-85µmol/l 25% or transaminases IU/L > 2-3 normal 75% dose & & normal >85µmol/l omit transaminases transaminases >180IU/L omit or AST or AST >180 clinical decision Ifosfamide dose Not recommended in patients with a bilirubin >17mol/L or serum transaminases or ALP more than 2.5 x upper normal limit. clinical decision Cytarabine Dose.100% Escalate doses in subsequent cycles in the absence of toxicity Review dose for second and third dose according to actual methotrexate clearance on previous doses. ** Note if raised bilirubin is not caused by hepatic dysfunction, DO NOT alter the dose 1.28 CODOX-M,IVAC v 2.1 Page 9 of 11

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11 West London Cancer Network References Magrath et al, JCO 1996 (14) 925 UK Lymphoma Group LY10 Protocol, Version 2.0, December 2002 Patient information Leukaemia Research Fund - Adult Acute Lymphoblastic Leukaemia booklet- Cancerbackup- Acute Lymphoblastic leukaemia booklet Revised by: Pauline McCalla, Nicki Panoskaltsis Authorised by: WLCN Haematology TWG Date for review by Haematology TWG: November CODOX-M-IVAC Version 2.1 Feb09.doc Page 11 of 11