1 Acute Lymphoblastic Leukaemia

Transcription

1 1 Acute Lymphoblastic Leukaemia 1.05 Intensification - Philadelphia Negative Patients Indication ALL Philadelphia negative patients Pre-treatment Evaluation The intensification module begins two weeks after completion of Phase 2 of induction, i.e. at the beginning of week 11, and ends in week 14. However, it should be postponed until the white cell count is greater than 3.0 x 10 9 /L and platelets greater than 100 x 10 9 /L in those with delayed haematological recovery. The intensification module consists of three separate pairs of injections of high dose methotrexate and L- asparaginase. Clotting screen, anti-thrombin III (ATIII) and/or fibrinogen and/or partial thromboplastin time (PTT) should be monitored daily while the patient is receiving the 3 days of L- asparaginase. FBC and blood film. Renal/liver/bone panel, LDH, CRP, uric acid, glucose. GFR (measured or calculated according to local practice) before the 1st and 3rd methotrexate infusions in the week before admission. Meticulous attention should be paid at all times to the GFR. The initial GFR before starting methotrexate should be well over 100 ml/min. The GFR before the third course of high-dose methotrexate should be above 50 ml/min. In the event of any query about this, delay the third methotrexate by up to a week and recalculate the GFR. If there was delayed methotrexate excretion after the first course, then repeat GFR before the 2nd infusion. Consult the Coordinators if in any doubt. Co-trimoxazole must be discontinued in the week prior to the first methotrexate infusion or in subsequent weeks until maintenance therapy starts. Document height, weight and body surface area. Strict fluid balance throughout treatment. A number of patients have had to have either one or all of these methotrexate doses delayed. If there is a delay, the following is recommended: Delay for one week, and if the blood count has still not reached the required level of white cell count 3 x 10 9 /L and platelets >100 x 10 9 /L then perform a bone marrow aspirate to confirm continuing remission. If remission is confirmed, give G-CSF (Lenograstim) until the counts reach the required level, and then proceed. If this strategy still leads to a delay of more than 2 weeks in the course, it is recommended that a trial coordinator be consulted for patients on UKALL XII; they will usually recommend that 50% of the methotrexate dose is given provided there is at least some degree of bone marrow function at the time. Other investigations during folinic acid rescue Daily Creatinine, sodium and potassium. Alternate days Bilirubin, AST, ALT, albumin, full blood count. Strict fluid balance throughout treatment methotrexate - high dose Version 2.2.doc2 Page 1 of 5

2 Drug Regimen (OPCS code: X70.5) Days Drug Dose Administration Comments IV infusion in 100ml D1, 8, & mg/m 2 note: T0 is the start of this Sodium Chloride 0.9% methotrexate infusion over 1hour (T0-1) D1, 8, & 22 D2, 9, & 23 D2, 9, & 23 (3 x 5doses) T36, 39, 42, 45, & 48 Methotrexate Asparaginase (Medac) 2700mg/m 2 IV infusion in 1000ml Sodium Chloride 0.9% over 23 hours(t1-24) 10,000u Intramuscularly 15mg/m 2 every 3 hours IV bolus in 50ml Glucose 5% for first two doses then oral if patient is not vomiting discontinue treatment at T24 even if infusion is not complete A test dose of 1000IU intradermally should be administered before treatment commences.(see adverse reactions) Continue FA rescue for at least 72 hours (T108) and until the methotrexate level is <1x10-7 M. D3-, 10-, & 24 - (3 x10doses) T54, 60, 66, 72, 78, 84, 90, 96, 102, 108 then every 6hours as dictated by plasma levels Folinic Acid (FA) 15mg/m 2 every 6hours. See comments oral if patient is not vomiting, otherwise IV bolus Monitor plasma levels at T48 & then every 24 hours until the level is <1x10-7 M. If level is: 2 x 10-5 M at 48 hours or 2 x 10-6 M at 72 hours or 1 x 10-7 M. at 96 hours then recalculate dose of folinic acid for the next 24 hours Considerations Prevention of L-asparaginase induced thrombophilia: There have been instances of serious thrombotic problems, particularly within the central nervous system. The following advice regarding management of asparaginase-induced thrombophilia is recommended: Levels of anti-thrombin III (ATIII) and/or fibrinogen and/or partial thromboplastin time (PTT) should be monitored daily while the patient is receiving the 3 days of L-asparaginase. It is suggested that if the level of fibrinogen below 0.8 g/ litre and/or the level of ATIII is below 70% and/or the PTT is >70 seconds at any time after day 8 of L-asparaginase, then replacement therapy should be given with either fresh frozen plasma and/or cryoprecipitate. See hydration protocol (concurrent medication) 1.05 methotrexate - high dose Version 2.2.doc2 Page 2 of 5

3 Dose Modifications Creatinine Clearance Allopurinol Dose Methotrexate Dose * >50ml/min mg daily 100% 10-50ml/min 50% 100 daily or alternate days <10ml/min avoid If the serum creatinine increases by more than 50% above baseline at 24 hours and/or the methotrexate level is greater than 5 x 10-6 M then the leucovorin rescue is increased. Folinic Acid Dose (after 48 hours, according to MTX level): Table for the calculation of folinic acid rescue based on MTX plasma levels. Time after MTX plasma concentration starting MTX <0.1µmol/I 0.1-2µmol/I 2-20µmol/I µmol/I >100µmol/I 48h None 15mg/m 2 q6h 15mg/m 2 q6h 10mg/m 2 q3h 100mg/m 2 q3h 72h None 15mg/m 2 q6h 10mg/m 2 q3h 100mg/m 2 q3h 1 g/m 2 q3h 96h None 15mg/m 2 q6h 10mg/m 2 q3h 100mg/m 2 q3h 1g/m 2 q3h 120h None 15mg/m 2 q6h 10mg/m 2 q3h 100mg/m 2 q3h 1 g/m 2 q3h Note: Dose folinic acid (next 24 hrs) = (Usual total daily dose) x (MTX level for that day) Denominator MTX level for that day Where: molar (M) µg/ml ** ng/ml µmol/i ** 1 x x x x x x x x x x x * Review dose for second and third dose according to actual methotrexate clearance on previous doses. At time points after 120h folinic acid administration should be continued as recommended for 120h. expressed in molar (M) units denominator for that day (expressed in molar (M) units). At 48 hours (from start of methotrexate infusion) = 2 x 10-5 M At 72 hours (from start of methotrexate infusion) = 2 x 10-6 M At 96 hours (from start of methotrexate infusion) = 1 x 10-7 M ** To convert methotrexate level expressed in µmol to µg multiply by methotrexate - high dose Version 2.2.doc2 Page 3 of 5

4 Serum Bilirubin Transaminases Methotrexate Dose <52µmol/litre And <180 IU/L 100% 53-84µmol/litre >85µmol/litre Or >180 IU/L 75% contraindicated Dose reduce, in patients with concomitantly impaired renal function. Concurrent Medication NOTE: patients must not receive Co-Trimoxazole in the week prior to the first methotrexate infusion or in subsequent weeks until maintenance therapy starts (due to increased risk of antifolate toxicity). Hydration using 50mmol sodium bicarbonate in 1litre dextrose saline with 20mmol potassium chloride (adjust the sodium bicarbonate concentration) to maintain the urinary ph between 7 and 8 (i.e. alkaline) before, during and after methotrexate dose. Pre-hydration must commence at least 24 hours prior to the commencement of methotrexate. Concurrent hydration at a rate of 1 litre over 8 hours (3 litres in 24 hours) must be maintained. Continue to hydrate at 125 ml/m 2 /hr for a minimum of 48hours after methotrexate infusion is complete. After 48 hours from the start of the intravenous methotrexate, ENSURE a combined oral and/or intravenous intake greater than 3 litres/m 2 /DAY until plasma methotrexate levels <1x10-7 M. Allopurinol 300mg daily. Anti-ulcer drug as per local policy. Antimicrobial prophylaxis as per local protocol including Itraconazole (liquid 200mg BD) for aspergillus prevention. 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. If the serum creatinine increases by more than 50% 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. Anti-emetics This regimen has high emetic potential - refer to local protocol. Note if raised bilirubin is not caused by hepatic dysfunction, DO NOT alter the dose It is expected that patients receiving high dose methotrexate will develop hypertransaminasemia and occasionally hyperbilirubinemia. These elevations can last up to 2 weeks following the methotrexate infusion and are not considered toxicity requiring discontinuation of repeated administration of methotrexate. Persistant hyperbilirubinemia and/or grade 3-4 hypertransaminasemia for longer than 3 weeks should result in discontinuation of the drug. Check fluid balance at 4hour intervals through each day, taking early action if fluid overload occurs by giving furosemide if the urine output falls below 400 ml/m 2 in any given 4-hour period methotrexate - high dose Version 2.2.doc2 Page 4 of 5

5 Adverse effects See above Neurotoxicity, mucositis, liver dysfunction, bone marrow depression. References UKALL XII- emc.medicines.org.uk WLCN. Treatment of Chemotherapy induced nausea and vomiting prescribing guidelines. May NLCN Dosage Adjustment for Cytotoxics in Hepatic Impairment, November 2003 Patient information Leukaemia Research Fund - Adult Acute Lymphoblastic Leukaemia booklet- Cancer BACUP - Acute Lymphoblastic leukaemia booklet Cancer BACUP fact file patient drug information leaflets Written by: Ish Patel, Nicki Panoskaltsis, Eduardo Olavarria Revised by: Nicki Panoskaltsis, Pauline McCalla Authorised by: WLCN Haematology TWG Date for review by Haematology TWG: 1.05 methotrexate - high dose Version 2.2.doc2 Page 5 of 5