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Department of Clinical Haematology Oxford BMT Programme

Intravenous Busulfan/ for Sibling Allograft

Summary of Schedule Date: Day DRUG -9 -8 -7 -6 -5 -4 -3 -2 -1 0 +1 +3 +6 +11 Clonazepam * * * * * * To prevent reaction to Busulfan Admission *

Busulfan * * * * Cyclophosphamide * * Chemotherapy Mesna **** **** To protect your bladder from Cyclophosphamide Marrow/Stem cell infusion *

Pentamidine * Prevents a specific pneumonia called PCP Ciclosporin ** ** ** ** ** ** ** ** Continues to suppress immune system Metoclopramide (M) M M M M M M M Ondansetron (O) O O O O O O O O O Different types of anti-sickness D D D * * * * Day +1,+3,+6, (+11) Not always Continues to suppress immune system given

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Department of Clinical Haematology Oxford BMT Programme

Intravenous Busulfan/Cyclophosphamide for Sibling Allograft

INDICATIONS Acute myeloid leukaemia Acute lymphoblastic leukaemia Chronic myeloid leukaemia

Pre-assessment • Ensure pre-transplant investigations are carried out as per Checklist/Record B3.10b • Ensure patient has a suitable central line in situ. • Ensure results of pre-transplant investigations are checked by a Haematology SpR and recorded on Checklist/Record B.3.10b and filed in patient medical records • Ensure patient consent has been obtained • Haematology SpR to complete electronic BMT front sheet and email to BMT Administrator to distribute and file in patient record • Prescribe chemotherapy and supportive treatment at least 5 days before admission • Send NHSBT referral form at least one working day before the start of patient conditioning 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. • Day - 9 ensure pregnancy test is carried out on all women of child-bearing potential unless they have been sterilized or have undergone a hysterectomy.

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Department of Clinical Haematology Oxford BMT Programme

CHEMOTHERAPY AND FLUIDS Encourage 3L oral fluids daily, give iv if oral intake insufficient. Day -8 to - 5 Busulfan 3.2mg/kg/od in sodium chloride 0.9%, (final concentration 0.5mg/ml) iv infusion over 3 hours. Day –3 to -2 02.00 Pre-hydration 1000ml sodium chloride 0.9% iv infusion over 6hrs

08.00 Pre-hydration 500ml glucose 5% iv infusion over 2hrs

09.45 Furosemide 20mg iv, then prn to maintain urine output > 100ml/hr

10.00 Cyclophosphamide 60mg/kg/od in 500ml sodium chloride 0.9% iv (T=0) infusion over 1 hour

T= 0,3,6 & 9 Mesna 24mg/kg (round dose up to nearest 400mg vial) Hours: in 100ml sodium chloride 0.9% iv infusion over 15 minutes

11.00 (T+1) Post-hydration 1000ml sodium chloride 0.9% iv infusion over 6hrs

17.00 (T + 7) Post-hydration 1000ml sodium chloride 0.9% iv infusion over 8hrs Day 0 06.00 Pre-hydration 1000ml sodium chloride 0.9% iv infusion over 6hrs prior to cell infusion

Stem cell/marrow Give hydrocortisone 100mg iv, chlorphenamine Infusion 10mg iv 15 minutes before cell infusion. (Minimum of 48 hours after end of cyclophosphamide infusion) Day +1 Pentamidine 4mg/kg (Maximum 300mg) in 100ml sodium chloride 0.9% iv infusion over 1 hour Methotrexate 15mg/m2 iv bolus (at least 24hr post /stem cell infusion) Day +3,+6, (+11) Methotrexate 10mg/m2 iv bolus At the same time (Day 11 dose omitted for severe mucositis, check as Day +1 with consultant).

Nursing care plans: Administration of Chemotherapy: Refer to nursing care plan N.63a Stem cell/Bone marrow infusion: Refer to nursing care plan N. 51 or N.18 Administration of Pentamidine: Refer to nursing care plan N.73

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Department of Clinical Haematology Oxford BMT Programme

Dose Modification: Discuss dose reductions with consultant if renal function impaired.

Antiemetics Day – 8 to -2 Metoclopramide 10 – 20mg po/iv/qds Ondansetron 8mg po/iv/bd Day – 3 to -1 Dexamethasone 8mg po/iv/od Ondansetron 8mg po/iv/bd Day 0 Ondansetron 8mg po/iv/bd PRN Ensure prn are prescribed from admission and regular antiemetics are continued after day 0, with daily review.

Extravasation risk Cyclophosphamide- neutral Busulfan- Vesicant

Concurrent medication Clonazepam 2mg po nocte from day -9 to day -4

Ciclosporin Start orally on Day -3. Refer to protocol B.2.19 http://nssg.oxford-haematology.org.uk/bmt/clin-man/B-2-19-ciclosporin-for- patients-allogenic-bmt.pdf Antifungal Refer to Antifungal protocol H.94. prophylaxis Start from day 0 until neutrophils >1.0x109/l (or longer if on steroids ) (Note: Significant drug interaction between azole antifungals and busulfan. DO NOT START UNTIL Day 0. http://nssg.oxford-haematology.org.uk/general-clinical-management/H-94- antifungal-therapy-guidelines.pdf CMV, HSV and Recipient CMV Donor CMV Antiviral Prophylaxis VZV prophylaxis status status Seropositive (+) Seropositive (+) Letermovir 480mg OD (240mg OD in patients taking ciclosporin) PO/IV from day 0 to day +100 PLUS aciclovir 200mg PO TDS from start of Note: Letermovir conditioning until 12 months post-transplant. requires BLUTEQ Seropositive (+) Seronegative (-) Letermovir 480mg OD (240mg OD in patients taking form ciclosporin) PO/IV from day 0 to day +100 PLUS aciclovir 200mg PO TDS from start of conditioning until 12 months post-transplant. Seronegative (-) Seropositive (+) Aciclovir 500mg/m2 IV TDS or 800mg PO QDS from start of conditioning till day +30 then 800mg PO QDS for 3 months, then 200mg TDS until 12 months post- transplant Seronegative (-) Seronegative (-) Aciclovir 250mg/m2 IV TDS or 200mg PO TDS form start of conditioning until 12 months post-transplant Pentamidine 4mg/kg ( max dose 300m)g iv on day +1 and day +30. (Unless started on to co-trimoxazole) Omeprazole 20mg OD from start of conditioning until count >50x109/l

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Department of Clinical Haematology Oxford BMT Programme

Norethisterone 5-10mg po TDS from day 0 until >50x109/l (menstruating women only) Ursodeoxycolic See VOD protocol B.2.12 acid http://nssg.oxford-haematology.org.uk/bmt/clin-man/B-2-12-vod- management.pdf Allopurinol 300mg od for 7 days from Day -8 Only in patients with acute leukaemia who are not in remission

Investigations Daily FBC, creatinine, urea & electrolytes, weight, urinalysis Alternate days function tests Mon/Thurs clotting, calcium, magnesium, phosphate Mon/Fri group and save Monday Ciclosporin levels - trough level. See protocol. CMV PCR from Day+1 EBV PCR weekly from Day +1 Other Other specimens for virology as clinically indicated. Chest X-ray weekly and as clinically indicated

Medication on discharge (TTO’s) Ciclosporin See protocol.B.2.19. Check with consultant or registrar Antifungal Refer to Antifungal protocol H.94 prophylaxis Stop when neutrophils >1x 109/l (may be longer if patient on steroids)

Aciclovir Refer to concurrent medications in this protocol Letermovir Refer to concurrent medications in this protocol Co-trimoxazole 480mg daily Mon, Wed, Fri: start when neutrophils >1x109/l and continue until one month after immunosuppressive therapy stopped. The increase to 960mg when counts stable. If allergic to co-trimoxazole, pentamidine 4mg/kg iv (max dose 300mg) monthly Penicillin V 250mg BD for life. Erythromycin for penicillin allergic Omeprazole Stop when platelet count >50x109/l unless clinically indicated Norethisterone Stop when platelets >50 x 109/l

References 1. Kashyap A et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and 100-day mortality. Biology of Blood and Marrow Tranplantation 2002; 8: 493-500 2. Slattery J T et al. Marrow transplantation for chronic myeloid leukaemia: the influence of plasma busulfan levels on the outcome of transplantation. Blood 1997 Apr 15; 89 (8) 3055-60.

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Department of Clinical Haematology Oxford BMT Programme

Audit These processes are subject to the OxBMT audit programme.

Author(s) Dr Andy Peniket, BMT Programme Director - Version 1, 2011 Denise Wareham, BMT Coordinator – Version 1, 2011

Circulation NSSG Website

Review Name Revision Date Version Review date Dr Andy Peniket, Programme Director Busulphan from QDS Aug 2014 2.0 Aug 2016 Denise Wareham, BMT Coordinator to Lara Rowley BMT CNS OD. Generic changes Julia Wong, Haematology Pharmacist common to Oxford BMT protocols Cheuk-Kie Cheung, Specialist Cancer Heparin, CSA, Urso Feb 2017 3.0 Feb 2019 Pharmacist antifungals Denise Wareham, BMT Nurse Patient-friendly Coordinator Summary of Schedule, generic changes Cheuk-Kie Cheung Formatting May 2017 3.1 Feb 2019 Specialist Cancer Pharmacist

Dr Andy Peniket, BMT consultant Protocol review day. July 2019 3.3 July 2021 Nadjoua Maouche, Lead Anti-viral Haematology Pharmacist prophylaxis. Extravasation risk. Formatting

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