Department of Clinical Haematology Oxford BMT Programme Cyclophosphamide/Fludarabine/TBI Reduced Intensity Conditioning for HLA-Haploidentical Related Transplant INDICATIONS Acute myeloid leukaemia Acute lymphoblastic leukaemia Myelodysplastic syndrome Myeloma Hodgkin’s disease Non-Hodgkin’s lymphoma Chronic lymphatic leukaemia Graft failure of previous transplant PRE-ASSESSMENT • • • • • • • • • • Ensure pre-transplant investigations are carried out as per ‘work-up’ investigations form (B3.10b). Ensure patient has triple lumen Hickman line in-situ and working (unless a working double lumen line already in situ). Ensure the results of pre-transplant investigations are checked by a Haematology SpR and recorded in the patient’s records. Ensure patient’s consent has been obtained. Haematology SpR to complete electronic BMT front sheet and email to secretary to distribute and file in patient records. Prescribe chemotherapy and supportive treatment 10 days before admission Send NHSBT Request form 2J to NHSBT for processing of bone marrow/stem cells at least 7 working days before the planned collection date and ensure a copy is placed in the medical notes. Ensure donor clearance is obtained, reviewed and documented in recipient’s notes prior to admission Ensure that patient receives irradiated blood products from the start of conditioning and indefinitely thereafter (see protocol on irradiated blood products). Ensure pregnancy test is carried out on day -7 on all women of child-bearing potential unless they have been sterilized or have undergone a hysterectomy. B.24 V.1.0 Authorised by: Dr Andy Peniket Page 1 of 7 This is a controlled document and therefore must not be changed May 2013 RIC CyFluTBI Haplo sib Department of Clinical Haematology Oxford BMT Programme SUMMARY DAY DRUG Admission Cyclophosphamide Mesna Fludarabine TBI Bone marrow/PBSCs Pentamidine -7 -6 -5 * * * * * * -4 -3 -2 * * * -1 0 +1 +2 +3 +4 * * * * * * * * Cyclophosphamide Mesna Mycophenolate mofetil (MMF) Tacrolimus *** Continue ** Continue * Continue Filgrastim (GCSF) Guide to first line antiemetics 5HT=5HT3 antagonist D=Dexamethasone M=Metoclopramide B.24 V.1.0 Authorised by: Dr Andy Peniket +5 5HT 5HT D D M M 5HT 5HT D M M Page 2 of 7 This is a controlled document and therefore must not be changed 5HT 5HT D D M M May 2013 RIC CyFluTBI Haplo sib Department of Clinical Haematology Oxford BMT Programme CHEMOTHERAPY AND FLUIDS Encourage 3L oral fluids daily, give iv if oral intake insufficient Day -6 and -5 00.00 1000mls sodium chloride 0.9% over 8 hours 08:00 500mls glucose 5% over 2 hours 10:00 (T=0) Furosemide 20mg IV, then PRN to maintain urine output >100mls/hr T = 0, 3, 6 & 9 hours Cyclophosphamide 14.5mg/kg IV od(AIBW if ABW > 125%IBW) In 500mls sodium chloride 0.9% over 1 hour Mesna 5.8mg/kg (400mg vials round dose up to nearest vial) In 100mls sodium chloride 0.9% over 15 mins 11:00 (T=1) 1000mls sodium chloride 0.9% over 6 hours 17:00 (T=7) Days -6 to -2 11:00 Fludarabine 1000mls sodium chloride 0.9% over 6 hours 30mg/m2 IV od In 100ml sodium chloride 0.9% over 30 mins Day -1 TBI 2GY 1 fraction Day 0 06.00 1000mls sodium chloride 0.9% over 6 hours Marrow/stem cell infusion (minimum 48 hours post Day -5 Cyclophosphamide) • • • Give hydrocortisone 100mg iv and chlorphenamine 10mg iv 15 minutes before cell infusion Actual body weight (ABW) Ideal body weight (IBW) Adjusted ideal body weight (AIBW) = IBW + [(0.25) x (actual body weight – IBW)] B.24 V.1.0 Authorised by: Dr Andy Peniket Page 3 of 7 This is a controlled document and therefore must not be changed May 2013 RIC CyFluTBI Haplo sib Department of Clinical Haematology Oxford BMT Programme Day +1 Pentamidine 4mg/kg/day iv (Maximum 300mg) in 100ml sodium chloride 0.9% over 1 hour (unless Pentamidine given within last 28 days) Day+3 and +4 00.00 1000mls sodium chloride 0.9% over 8 hours 08:00 500mls glucose 5% over 2 hours 10:00 (T=0) (day +3 dose to be given between 60 and 72 hours Cyclophosphamide after marrow / stem cell infusion) Furosemide 20mg IV, then PRN to maintain urine output >100mls/hr T = 0, 3, 6 & 9 hours 20mg/kg (400mg vials round dose up to nearest vial) In 100mls sodium chloride 0.9% over 15 mins Mesna 50mg/kg IV od (IBW) IV In 500mls sodium chloride 0.9% over 1 hour 11:00 (T=1) 1000mls sodium chloride 0.9% over 6 hours 17:00 (T=7) 1000mls sodium chloride 0.9% over 6 hours Day +5 • • • Filgrastim (biosimilar) 5 microgram/kg/day sc od Until absolute neutrophil count ≥1.0x109/l for three consecutive days Actual body weight (ABW) Ideal body weight (IBW) Adjusted ideal body weight (AIBW) = IBW + [(0.25) x (actual body weight – IBW)] DOSE MODIFICATIONS Discuss dose reduction for fludarabine with consultant if renal function impaired. Day -6 and -5 Cyclophosphamide: Dose is calculated using AIBW if actual body weight is > 125% IBW. Day +3 and +4 Cyclophosphamide: Dose is calculated using IBW B.24 V.1.0 Authorised by: Dr Andy Peniket Page 4 of 7 This is a controlled document and therefore must not be changed May 2013 RIC CyFluTBI Haplo sib Department of Clinical Haematology Oxford BMT Programme NURSING CARE PLANS Administration of Chemotherapy: Refer to nursing care plan N.91 Stem cell/Bone marrow infusion: Refer to nursing care plan N51 or N18 ANTI-EMETICS Day -6 , -5, -1, +3, +4 5HT3 antagonist PO/IV od Dexamethasone 8mg PO/IV od Metoclopramide 20mg PO/IV qd Day 0 5HT3 antagonist PO/IV od Metoclopramide 20mg IV pre-cell infusion CONCURRENT MEDICATION Allopurinol 300mg od po for 7 days – only in patients with acute leukaemia who are not in remission Norethisterone 5-10mg po TDS from day 0 until platelets >50x109/l (menstruating women only) Fluconazole 50mg OD po from day 0 until neutrophils >1.0x109/l (or longer if on steroids) Pentamidine 4mg/kg/day (max 300mg) iv on day+1 and day +30 (unless started on to co-trimoxazole) Aciclovir For CMV Prophylaxis If either donor or recipient or both are CMV + then: 2 500mg /m TDS iv or 800mg po QDS day -7 to day +30 then 800mg po QDS for 3 months, then 200mg TDS for further 3 months if VZV positive If both donor and recipient are CMV negative then consider HSV/VZV Prophylaxis Aciclovir dose is 250mg iv TDS or 200mg po TDS Duration of treatment depends on HSV and VZV status of recipient: HSV neg and VZV neg - no aciclovir needed HSV pos and VZV neg treat for 3 months HSV pos and VZV pos treat for 6 months HSV neg and VZV pos treat for 6 months B.24 V.1.0 Authorised by: Dr Andy Peniket Page 5 of 7 This is a controlled document and therefore must not be changed May 2013 RIC CyFluTBI Haplo sib Department of Clinical Haematology Oxford BMT Programme Mycophenolate Mofetil (MMF) Begin day +5. 15mg/kg po 8 hourly by suspension or adjusted to tablet size; IV route can be used if PO not tolerated (same dosing as PO, given over 2 hours in 5% dextrose at a concentration of 6mg/ml). Maximum total daily dose not to exceed 3g. If renal failure do not exceed dose of 1gm bd. No dose adjustment for liver disease. MMF dosing should be monitored and altered as clinically appropriate. Stop MMF at day +35 unless active GvHD present (discuss with consultant). Tacrolimus (Prograf) Begin day +5. 0.05 – 0.1mg/kg bd PO and adjust according to levels aiming for trough level of 5-10ng/ml. IV route can be used if PO not tolerated (Intravenous dose: third of oral dose). Aim to discontinue day +180 after transplantation Levels to be taken as per protocol B.5.0 Omeprazole 20mg OD from start of conditioning until platelet count >50x109/l Filgrastim (biosimilar) Begin day +5. 5microgram/kg/day sc od continued until absolute neutrophil count ≥1.0x109/l for three consecutive days. INVESTIGATIONS Daily Alternate days Mon/Thurs Mon/Fri Weekly Monday Other FBC, creatinine, urea & electrolytes, weight, urinalysis Liver function tests Clotting, calcium, magnesium, phosphate Group and save Zinc, urate Tacrolimus levels - trough level. See protocol B5.0 CMV PCR from Day+14 if either patient or donor is CMV positive Other specimens for virology as clinically indicated. Chest X-ray on admission then weekly and as clinically indicated MEDICATION ON DISCHARGE (TTO’s) Norethisterone Fluconazole Co-trimoxazole Aciclovir B.24 V.1.0 Authorised by: Dr Andy Peniket 9 Stop when platelets >50 x 10 /l 9 Stop when neutrophils >1x 10 /l (may be longer if patient on steroids) 960mg daily Mon, Wed, Fri: start when neutrophils >1x109/l and continue until one month after immunosuppressive therapy stopped. If allergic to cotrimoxazole, pentamidine 4mg/kg (max 300mg) iv monthly Depends on CMV/ HSV/ VZV status. Refer to page 5 of this protocol Page 6 of 7 This is a controlled document and therefore must not be changed May 2013 RIC CyFluTBI Haplo sib Department of Clinical Haematology Oxford BMT Programme Omeprazole Mycophenolate Mofetil (MMF) Tacrolimus Penicillin V Stop unless clinically indicated 15mg/kg po tds. Maximum total daily dose not to exceed 3g. If renal failure do not exceed dose of 1gm bd. Stop on day +35. On discharge the patient should be prescribed an oral dose to maintain trough levels between 5-10ng/ml. Check dose with registrar or consultant. Aim to discontinue by day +180 after transplantation in the absence of GvHD 250mg BD for life REFERENCES Brunstein C, Fuchs E, Carter S, Karanes C, Costa L, Wu J, Devine S, Wingard J, Aljitawi O, Cutler C, Jagasia M, Ballen K, Eapen M, O'Donnell P; Blood and Marrow Transplant Clinical Trials Network. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. (2011) 118(2):282-8. Summary of Product Characteristcs via www.medicines.org.uk for: Filgrastim (Zarzio®) Last updated: 18/02/2013 Tacrolimus (Prograf®) Last updated: 18/09/2012 www.medicinescomplete.com Mesna Uses and Administration Author(s) Dr Robert Danby, Bone Marrow Transplant Fellow Prof. Vanderson Rocha, Consultant Haematologist Julia Wong, Pharmacist. Circulation TSSG website, patient notes. Review Name B.24 V.1.0 Authorised by: Dr Andy Peniket Revision New document Date Version May 2013 1.0 Page 7 of 7 This is a controlled document and therefore must not be changed Review date May 2015 May 2013 RIC CyFluTBI Haplo sib