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Allogeneic myeloablative conditioning (haploidentical) busulfan and fludarabine

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Drug Dose Route Day
Fludarabine 40 mg/m2 IV infusion -5 to -2
Busulfan 3.2 mg/kg IV infusion -5 to -2
Infusion of stem cells 0
  • Pharmacokinetically guided IV busulfan, over fixed-dose delivery, in pretransplant conditioning may be recommended.r Refer to local institutional practices.
  • Hyperhydration alone can be given in place of mesna with hyperhydration as per local guidelines.rr Please see the haemorrhagic cystitis document for more information. 
  • Administration of corticosteroids should be avoided between infusion of cells and administration of cyclophosphamide due to risk of kinetic changes in alloreactive T-cells.
  • Tocilizumab 4-8 mg/kg may be used if severe symptoms of cytokine release syndrome (CRS) occur.r

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Day -6
CLONazepam 0.5 mg (PO) ONCE a day at night
Day -5 to -2
CLONazepam 0.5 mg (PO) TWICE a day (morning and night)
Fludarabine 40 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 60 minutes immediately followed by IV busulfan
Busulfan 3.2 mg/kg (IV infusion) in 250 mL to 500 mL sodium chloride 0.9% over 3 hours
Day -1
CLONazepam 0.5 mg (PO) ONCE a day in the morning then cease
Day 0
Infusion of stem cells
Day 3 and 4
Mesna 50 mg/kg (IV infusion) in 1000 mL sodium chloride 0.9% ONCE a day

by continuous infusion. Start 1 hour before the start of cyclophosphamide and continue until 24 hours after the completion of cyclophosphamide.
CYCLOPHOSPHamide 50 mg/kg (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 60 minutes ONCE a day
Day 5
Mycophenolate mofetil 15 mg/kg (PO) THREE times a day until day +35
TACrolimus 2 mg (PO) TWICE a day (12 hours apart), until day +60 and then taper through to day +120 or as per institutional guidelines.

  • Hyperhydration alone can be given in place of mesna with hyperhydration as per local guidelines.rr Please see the haemorrhagic cystitis document for more information. 
  • Administration of corticosteroids should be avoided between infusion of cells and administration of cyclophosphamide due to risk of kinetic changes in alloreactive T-cells.
  • As per the ANZHIT-1 study, tacrolimus can be tapered from day +60 to day +120 if there is no evidence of grade 2-4 aGVDH, relapse or low chimerism.r

Drug Dose Route Day
Fludarabine 40 mg/m2 IV infusion -5 to -2
Busulfan 3.2 mg/kg IV infusion -5 to -2
Infusion of stem cells 0
  • Pharmacokinetically guided IV busulfan, over fixed-dose delivery, in pretransplant conditioning may be recommended.r Refer to local institutional practices.
  • Hyperhydration alone can be given in place of mesna with hyperhydration as per local guidelines.rr Please see the haemorrhagic cystitis document for more information. 
  • Administration of corticosteroids should be avoided between infusion of cells and administration of cyclophosphamide due to risk of kinetic changes in alloreactive T-cells.
  • Tocilizumab 4-8 mg/kg may be used if severe symptoms of cytokine release syndrome (CRS) occur.r

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Day -6
CLONazepam 0.5 mg (PO) ONCE a day at night
Day -5 to -2
CLONazepam 0.5 mg (PO) TWICE a day (morning and night)
Fludarabine 40 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 60 minutes immediately followed by IV busulfan
Busulfan 3.2 mg/kg (IV infusion) in 250 mL to 500 mL sodium chloride 0.9% over 3 hours
Day -1
CLONazepam 0.5 mg (PO) ONCE a day in the morning then cease
Day 0
Infusion of stem cells
Day 3 and 4
Mesna 50 mg/kg (IV infusion) in 1000 mL sodium chloride 0.9% ONCE a day

by continuous infusion. Start 1 hour before the start of cyclophosphamide and continue until 24 hours after the completion of cyclophosphamide.
CYCLOPHOSPHamide 50 mg/kg (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 60 minutes ONCE a day
Day 5
Mycophenolate mofetil 15 mg/kg (PO) THREE times a day until day +35
TACrolimus 2 mg (PO) TWICE a day (12 hours apart), until day +60 and then taper through to day +120 or as per institutional guidelines.

  • Hyperhydration alone can be given in place of mesna with hyperhydration as per local guidelines.rr Please see the haemorrhagic cystitis document for more information. 
  • Administration of corticosteroids should be avoided between infusion of cells and administration of cyclophosphamide due to risk of kinetic changes in alloreactive T-cells.
  • As per the ANZHIT-1 study, tacrolimus can be tapered from day +60 to day +120 if there is no evidence of grade 2-4 aGVDH, relapse or low chimerism.r

  • Acute lymphoblastic leukaemia
  • Acute myeloid leukaemia
  • Chronic myeloid leukaemia
  • Multiple myeloma
  • Myelodysplastic syndrome
  • Myelofibrosis
  • Non-Hodgkin lymphoma
Venous access

Central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
Antiemetics for multi-day protocols

Patients being treated with multi-day anticancer protocols should receive antiemetics tailored to the emetogenic risk of the drugs administered each day during treatment and for two days after completion of the anticancer protocol.

No standard antiemetic regimen exists for multi-day anticancer protocols. A combination of an NK1 receptor antagonist, 5HT3, and a steroid is available on the PBS for the prevention of nausea and vomiting associated with all moderate to highly emetogenic anti-cancer therapies. 

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO every 6 hours when necessary.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Proton pump inhibitor

Consider commencing a PPI on admission (or at the start of conditioning regimen) and continue throughout transplant.

Due to profound and long lasting inhibition of gastric acid, avoid concomitant administration with drugs such as mycophenolate mofetil, posaconazole syrup or itraconazole capsules (Of note, PPI is allowed with posaconazole tablet formulation).

In cases where PPI may be considered inappropriate, substitution with a H2 antagonist may be a suitable alternative at the discretion of the transplant physician.
Drug dosing in obese patients undergoing conditioning chemotherapy in BMT

There is limited evidence on dosing in this patient group due to a lack of randomised clinical trials and under reporting of data. Consider individual patient clinical factors (including organ dysfunction), pharmacokinetic and pharmacodynamic properties of anticancer drugs in the chosen regimen, recent published evidence and the availability of therapeutic drug monitoring when determining dose selection.

See ASBMT opens in a new tab or window for more information about dose adjustment of specific drugs in conditioning regimens in overweight and obese patients.
Haemorrhagic cystitis associated with high dose chemotherapy

Hydration regimen pre high dose cyclophosphamide or ifosfamide (as per local guidelines).
There is limited evidence and no consensus regarding hydration regimens and mesna dose, route or timing of administration.

Read more about haemorrhagic cystitis
Mesna dosing and administration

There is evidence supporting variations in mesna doses and administration timings, with no clear evidence that one particular regimen is superior to another. The eviQ mesna recommendations may be based upon the individual trial/study or reference committee consensus and provide guidance on one safe way to administer the protocol. Individual institutional policy may vary and should be evidence-based.

Read more about haemorrhagic cystitis 
Busulfan monitoring

Therapeutic drug monitoring recommended. 

Read more about busulfan administration and monitoring
Anti-convulsant prophylaxis

Clonazepam 0.5 mg twice daily.

Commence clonazepam the night prior to the first dose of busulfan and continue until the morning after the last dose of busulfan
Cytokine release syndrome/Infusion-related reactions

Potentially life-threatening cytokine release syndrome (CRS) has been reported in patients receiving haploidentical related-donor (HRD) haematopoietic stem cell transplantation (SCT). 

Infusion reactions have also occurred and may be clinically indistinguishable from manifestations of CRS.

Clinical signs and symptoms of CRS may include, but are not limited to, fever, chills, hypotension, tachycardia, hypoxia, headache, and elevated liver enzymes. Patients should be closely monitored for signs or symptoms of these events.

Read more about cytokine release syndrome and hypersensitivity reaction.
GVHD prophylaxis

High dose cyclophosphamide (day +3 and +4), tacrolimus and mycophenolate mofetil (MMF).

Commence PO tacrolimus TWICE daily on day +5. Adjust dose according to trough levels (target level = 5 to 15 ng/mL). In the absence of GVHD and FULL donor chimerism, tapering to start at day +60 through to day +120 or as per institutional guidelines.

Note: the IV dose is approximately one-third to one-quarter of the oral dose, if converting.

Commence PO mycophenolate mofetil (MMF) THREE times daily on day +5. In the absence of GHVD cease without tapering at day +35.

If tacrolimus is stopped, the dose of MMF may need adjustment (reduced). The value of MMF blood levels are the subject of ongoing study.

Read more about acute graft versus host disease
CMV pre-transplant prophylaxis

In patients at high risk of CMV reactivation consider CMV prophylaxis. Practice may differ between institutions.
EBV monitoring

Reactivation of Epstein-Barr virus (EBV) infection and post-transplant lymphoproliferative disorder (PTLD) is a significant risk after allogeneic blood and marrow transplant (BMT). Regular EBV monitoring is highly recommended with this regimen. Consider regular monitoring for EBV reactivation by qPCR for 3 to 6 months post transplant and then as clinically indicated. Preemptive treatment is recommended.
SOS prophylaxis

Stratify according to risk profile.

Read more about sinusoidal obstruction syndrome (SOS/VOD).
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

Read more about the prevention and management of tumour lysis syndrome.
Pneumocystis jirovecii pneumonia (PJP) prophylaxis

PJP prophylaxis is recommended.

Read about prophylaxis of pneumocystis jiroveci (carinii) in cancer patients
Antiviral prophylaxis (HSV)

Antiviral prophylaxis is recommended.

Read about antiviral prophylaxis drugs and doses
Antifungal prophylaxis

Antifungal prophylaxis is recommended.

Read more about antifungal prophylaxis drugs and doses.
Growth factor support

G-CSF (short or long-acting) is available on the PBS for chemotherapy induced neutropenia depending on clinical indication and/or febrile neutropenia risk.  

Access the PBS website opens in a new tab or window
Blood product support

All transplant recipients are to receive irradiated blood products. Additionally, those patients who are CMV serologically negative are to receive CMV-negative or leukodepleted blood products (i.e. CMV safe), as dictated by local clinical policies.

Read more about the indications for the use of irradiated blood components opens in a new tab or window and cytomegalovirus (CMV) seronegative components opens in a new tab or window
Blood tests

FBC, EUC, eGFR and LFTs as required each day.
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy.

Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations

Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease. Possible suboptimal response to inactivated vaccines.

For more information about vaccinations in people with cancer refer to the Australian Immunisation Handbook opens in a new tab or window.
Fertility, pregnancy and lactation

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. There is a risk of fetal harm in pregnant women. A pregnancy test should be considered prior to initiating treatment in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and adequate contraception timeframe should be discussed with all patients of reproductive potential. Possibility of infant risk should be discussed with breastfeeding patients.

Read more about the impact of cancer treatment on fertility opens in a new tab or window
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) opens in a new tab or window unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Note: All dose reductions are calculated as a percentage of the starting dose

Renal impairment
Creatinine clearance (mL/min)
30 to 50 Consider reducing fludarabine by 50%
less than 30 Fludarabine contraindicated; consider alternative protocol
Hepatic impairment

Busulfan has not been administered in clinical studies in patients with hepatic impairment. Busulfan has extensive hepatic metabolism and risk of hepatic veno-occlusive disease with high doses; dosage adjustment may be needed.
GVHD Prophylaxis
Mycophenolate mofetil (MMF) In patients with severe chronic renal impairment (GFR < 25 mL/min/1.73 m2), avoid doses greater than 1 g twice daily or monitor mycophenolate concentration closely.
Tacrolimus Because of reduced clearance and prolonged half-life of tacrolimus in patients with severe hepatic impairment (Child-Pugh score of 10 or higher), lower dosages of tacrolimus and close monitoring of blood concentrations may be required in these patients to avoid toxicity (target level = 5 to 15 ng/mL).

Mesna dosing schedule should be repeated each day high-dose cyclophosphamide (50 mg/kg or 2 g/m2) is received. If the cyclophosphamide dose is adjusted (decreased or increased), the intravenous mesna dose should also be modified to maintain the mesna-to-cyclophosphamide ratio (1.0 - 1.5 x the daily dose of cyclophosphamide).r

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources:  

For more information see References & Disclaimer.

Busulfan
  Interaction Clinical management
Iron chelating agents (e.g. deferasirox) Increased toxicity of busulfan possible due to reduced clearance Discontinue iron chelating agent in advance prior to administering busulfan, if possible, and avoid combination. 
For patients who have recently been treated with an iron chelating agent or require concomitant administration, regularly monitor busulfan plasma concentrations (dosage adjustment may be indicated).
Itraconazole, voriconazole (theoretical) Increased toxicity of busulfan possible due to reduced clearance Avoid combination or monitor for increased busulfan toxicity (dosage adjustment may be indicated).
Note: No interaction has been observed between busulfan and fluconazole
Metronidazole Increased toxicity of oral busulfan possible due to reduced clearance Do not use 72 hours before or 72 hours after busulfan administration
Paracetamol Increased toxicity of busulfan possible due to reduced clearance (theoretical based on metabolism of agents) Use combination with caution or monitor for increased busulfan toxicity for patients who use paracetamol up to 72 hours before or concurrently with busulfan
Phenytoin Reduced efficacy of busulfan possible due to increased clearance Avoid combination; select alternative anti-convulsant (e.g. clonazepam, diazepam, lorazepam). If using phenytoin, monitor AUC of busulfan to guide levels
Cyclophosphamide
  Interaction Clinical management
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Increased toxicity of cyclophosphamide possible due to increased conversion to active (and inactive) metabolites Avoid combination or monitor for cyclophosphamide toxicity
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Reduced efficacy of cyclophosphamide possible due to decreased conversion to active (and inactive) metabolites Avoid combination or monitor for decreased clinical response to cyclophosphamide
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Amiodarone Possible additive pulmonary toxicity with high-dose cyclophosphamide (i.e. doses used prior to stem cell transplant; 60 mg/kg daily or 120 to 270 mg/kg over a few days) Avoid combination or monitor closely for pulmonary toxicity
Allopurinol, hydrochlorothiazide, indapamide Delayed effect. Increased risk of bone marrow depression; probably due to reduced clearance of active metabolites of cyclophosphamide Avoid combination, consider alternative antihypertensive therapy or monitor for myelosuppression
Ciclosporin Reduced efficacy of ciclosporin due to reduced serum concentration Monitor ciclosporin levels; adjust dosage as appropriate; monitor response to ciclosporin
Suxamethonium Prolonged apnoea due to marked and persistent inhibition of cholinesterase by cyclophosphamide Alert the anaesthetist if a patient has been treated with cyclophosphamide within ten days of planned general anaesthesia
Fludarabine
  Interaction Clinical management
Dipyridamole Reduced efficacy of fludarabine possible due to inhibition of adenosine uptake Avoid combination or monitor for decreased clinical response to fludarabine
Azole antifungals
For a table of selected drug-drug interactions with azole antifungals link to the full text article by Chau et al 2014 opens in a new tab or window (refer to table 2)
Mesna 
No specific or clinically significant drug interactions 
Mycophenolate mofetil
  Interaction Clinical management
Antacids Aluminium hydroxide and magnesium hydroxide reduce absorption of mycophenolate (mofetil or sodium); loss of efficacy may occur Avoid concurrent use or administer at least 2 hours apart
Cholestyramine Cholestyramine reduces absorption of mycophenolate (mofetil or sodium); loss of efficacy may occur Administer mycophenolate 1 hour or 4-6 hours after cholestyramine to minimise this effect. Monitor mycophenolate concentration and for clinical effect
Ciclosporin Ciclosporin reduces mycophenolate concentration, possibly by reducing its enterohepatic circulation Consider reducing mycophenolate dose if ciclosporin is stopped (e.g. if tacrolimus or sirolimus is substituted) and increasing it if ciclosporin is started
Metronidazole, norfloxacin Metronidazole may reduce mycophenolate's concentration, resulting in loss of efficacy Monitor mycophenolate concentration and for clinical effect and increase dose as required
Proton pump inhibitors PPIs may decrease absorption of mycophenolate mofetil (due to increased gastric pH) with possible loss of efficacy Monitor mycophenolate concentration and for clinical effect and increase dose as required
Tacrolimus
  Interaction Clinical management
Azole antifungals Metabolism of tacrolimus inhibited by azole antifungals (increased plasma concentration) Monitor tacrolimus levels and adjust accordingly to levels. Tacrolimus may require a dose reduction
Calcium channel blockers Plasma concentration of tacrolimus Monitor tacrolimus levels and adjust accordingly to levels
Caspofungin Caspofungin reduces tacrolimus concentration; may reduce its efficacy Monitor tacrolimus concentration and increase its dose if needed
Drugs that may prolong the QTc interval (e.g. azole antifungals, tricyclic antidepressants)  Risk factors should be corrected, where possible prior to commencement of tacrolimus. Concurrent use may increase the risk of QTc prolongation Monitor ECG and for signs of cardiac arrhythmia
Proton pump inhibitors Lansoprazole and omeprazole may inhibit tacrolimus metabolism, increasing its concentration and the risk of adverse effects Use pantoprazole or rabeprazole instead (appear less likely to interact) or monitor tacrolimus concentration and decrease tacrolimus dose if required
Infliximab Reduced tacrolimus concentrations possible due to increased clearance Monitor tacrolimus blood concentrations; adjust dosage as appropriate
General
  Interaction Clinical management
Warfarin Anti-cancer drugs may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inhibitors. If treating VTE, avoid use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window  inhibitors.

Dabigatran: avoid combination with strong P‑gp opens in a new tab or window inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Anti-cancer drugs can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and anti-cancer drug levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the anti-cancer therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update opens in a new tab or window

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter or address chemical compatibilities related to IV drug preparation and administration. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Day -6

This is an oral treatment

Pre treatment assessment

Anti-cancer drug patient assessment tool prior to each day of treatment.

Clonazepam

Administer clonazepam:
  • orally, first dose in the evening the day prior to busulfan administration.
Potential adverse events:
  • may cause dizziness and postural hypotension.

Note: missed doses can be taken unless it is almost time for the next scheduled dose, in which case the missed dose should be omitted and normal dosing should be resumed at the next scheduled dose.

Day -5 to -2

Pre treatment assessment

Anti-cancer drug patient assessment tool prior to each day of treatment.

Weigh patient twice a day.

Strict fluid balance.

Note: a large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

Daily abdominal girth measurement. Read more about Sinusoidal Obstruction Syndrome.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Clonazepam 

Administer clonazepam:
  • orally TWICE a day.
Potential adverse events:
  • may cause dizziness and postural hypotension.

Note: missed doses can be taken unless it is almost time for the next scheduled dose, in which case the missed dose should be omitted and normal dosing should be resumed at the next scheduled dose.

Prior to administration

Prime IV line(s).

Access CVAD.

Fludarabine

Administer fludarabine:
  • via IV infusion over 60 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.

Busulfan (irritant):

Ensure anticonvulsant medication has been administered prior to infusion.

Administer busulfan:
  • via IV infusion over 3 hours
  • flush with ~100 mL sodium chloride 0.9%.
Potential adverse events:
  • seizures have been reported with high doses of busulfan, monitor patients neurological status. 

See clinical information for more information on busulfan monitoring.

Post administration

Deaccess CVAD.

Continue safe handling precautions until 7 days after completion of drug(s).

Day -1

This is an oral treatment

Pre treatment assessment

Anti-cancer drug patient assessment tool prior to each day of treatment.

Clonazepam 

Administer clonazepam:
  • orally and cease after morning dose.
Potential adverse events:
  • may cause dizziness and postural hypotension.

Day 0

Pre treatment assessment

Anti-cancer drug patient assessment tool prior to each day of treatment.

Weigh patient twice a day.

Strict fluid balance.

Note: a large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

Daily abdominal girth measurement. Read more about Sinusoidal Obstruction Syndrome.

Pre treatment medication

Administer antiemetics if required.

Prior to administration

Prime IV line(s).

Access CVAD.

Commence antiviral and antifungal prophylaxis as prescribed. 

Stem cells infusion

Administer stem cells:
  • as per institutional guidelines.

Post administration

Deaccess CVAD.

Continue safe handling precautions until 7 days after completion of drug(s).

Day +3 and +4

Pre treatment assessment

Anti-cancer drug patient assessment tool prior to each day of treatment.

Weigh patient twice a day.

Strict fluid balance.

Note: a large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

Dipstick urinalysis to check for haematuria.

The administration of mesna will cause a false positive for ketonuria.

Daily abdominal girth measurement. Read more about Sinusoidal Obstruction Syndrome.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prior to administration

Prime IV line(s).

Access CVAD.

Mesna 

Mesna is to commence 60 minutes before the first dose of cyclophosphamide.

Hyperhydration alone can be given in place of mesna with hyperhydration as per local guidelines.rr Please see the haemorrhagic cystitis document for more information. 

Administer mesna:
  • via IV infusion over 24 hours
  • continue until 24 hours after the last dose of cyclophosphamide.

Cyclophosphamide

Administer cyclophosphamide: 
  • via IV infusion over 60 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.
Potential adverse events:
  • rapid infusion can cause dizziness, rhinitis, nausea and perioral numbness, if symptoms develop slow infusion rate.

Post administration

Deaccess CVAD.

Continue safe handling precautions until 7 days after completion of drug(s).

Day +5

Pre treatment assessment

Anti-cancer drug patient assessment tool prior to each day of treatment.

Weigh patient twice a day.

Strict fluid balance.

Note: a large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

Daily abdominal girth measurement. Read more about Sinusoidal Obstruction Syndrome.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

GVHD prophylaxis

Mycophenolate mofetil

Administer mycophenolate mofetil:
  • orally THREE times a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • to be taken on an empty stomach, one hour before or 2 hours after food
  • avoid antacids within two hours as they may interfere with its absorption.

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Tacrolimus

Administer tacrolimus:
  • orally TWICE a day (approximately 12 hours apart)
  • take capsules at the same time each day and in the same way (always with food or always on an empty stomach). Avoid concurrent use of grapefruit juice.

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Continue GVHD prophylaxis as per the transplant team.

Post administration

Continue antiviral and antifungal prophylaxis as prescribed.

Continue safe handling precautions until 7 days after completion of drug(s).

Discharge information

Discharge medications

Tacrolimus capsules and mycophenolate mofetil tablets - with written instructions on how to take them.

Growth factor support - as/if prescribed, and arrangements for administration.

Antiemetics - as/if prescribed.

Prophylaxis medications - as/if prescribed, i.e. antifungals, antivirals, PJP prophylaxis, tumour lysis prophylaxis.

Patient information

Ensure patient receives protocol patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Extravasation, tissue or vein injury

The unintentional instillation or leakage of a drug or substance out of a blood vessel into surrounding tissue. This has the potential to cause damage to affected tissue.

Read more about extravasation management
Haemorrhagic cystitis

An inflammatory process, characterised by diffuse bladder mucosal inflammation resulting in haemorrhage. Patients are at risk following blood and marrow transplant (BMT) or treatment with cyclophosphamide, ifosfamide and/or radiation therapy.

Read more about haemorrhagic cystitis
Headache

Mild headache is common with this treatment.
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Seizures

Tonic-clonic type seizures have been associated with high dose busulfan.
Taste and smell alteration

Read more about taste and smell changes
Tachycardia

An increase in heart rate (above 100 beats per minute) can occur with this treatment.

Early (onset days to weeks)
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about immediate management of neutropenic fever
Thrombocytopenia

A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.  

Read more about thrombocytopenia
Arthralgia and myalgia

Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation. 

Read more about arthralgia and myalgia
Cytokine release syndrome (CRS)

CRS is the most common side effect with cellular therapy and may be life threatening. Symptoms may include high fevers, rigors, myalgia, arthralgia, nausea and vomiting, diarrhoea, diaphoresis, rash, anorexia, fatigue, headache, hypotension, dyspnoea, tachypnoea and hypoxia. Close monitoring is recommended.
Diarrhoea

Read more about treatment induced diarrhoea
Dizziness

Feeling faint or lightheaded, weak or unsteady. Advise patients to stand up slowly from sitting down or lying down positions and increase fluid intake if dehydrated.
Fatigue

Read more about fatigue
Fluid retention and oedema

An excess amount of fluid around the cells, tissues or serous cavities of the body, leading to swelling.
Hypertension

High blood pressure is commonly associated with many anti-cancer drugs. Pre-existing hypertension should be controlled prior to initiation of drugs capable of causing hypertension.
Oesophagitis

Inflammation of the mucosal lining of the oesophagus.  It can progress to ulceration, haemorrhage, secondary infection and pain.
Oral mucositis and stomatitis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following anti-cancer treatment, radiation therapy to the head, neck or oesophagus, and high-dose chemotherapy followed by a blood and marrow transplant (BMT).

Read more about oral mucositis and stomatitis
Sinusoidal obstruction syndrome (SOS)

A serious and potentially fatal complication, presenting with hepatomegaly and/or right upper quadrant pain, jaundice and ascites. SOS typically occurs in the first 30 days following blood and marrow transplantation (BMT) although it can occur later.

Read more about sinusoidal obstruction syndrome (SOS/VOD)
Skin rash

Anti-cancer drugs can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. 

Read more about skin rash
Visual disturbance

Photopsia, blurred vision, vitreous floaters and visual impairment have been reported with this drug and generally occur after transitioning from a light to dark environment. 

Late (onset weeks to months)
Alopecia

Hair loss may occur from all parts of the body. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out.

Read more about alopecia and scalp cooling
Cognitive changes (chemo fog)

Changes in cognition characterised by memory loss, forgetfulness and feeling vague. This is also referred to as 'chemo brain' or 'chemo fog'.

Read more about cognitive changes (chemo fog) 
Drug induced gingival hyperplasia

Enlargement of the gingiva (gums).  In some cases, the gums may start to cover the teeth. Some patients may also experience bleeding and tenderness in the gums as a result of the enlargement.
Neurotoxicity

Neurotoxicity related to fludarabine is a rare but potentially serious adverse event characterised by visual disturbances, altered mental state and CNS toxicity. Seizures leading to paralysis or coma have been reported in the literature. Periodic neurologic assessments are recommended.

Delayed (onset months to years)
Pulmonary toxicity

Pulmonary toxicity may include damage to the lungs, airways, pleura and pulmonary circulation. 

Read more about pulmonary toxicity associated with anti-cancer drugs

eviQ is currently updating the way information is presented in the evidence section to improve usability, consistency and facilitate easier update and maintenance. An updated evidence template is being implemented in a staged approach, first across new protocols, then existing protocols as they are reviewed. Find out more

Haploidentical stem cells are the most commonly used alternate donor source for patients lacking a fully human leukocyte antigen (HLA) matched donor, and numbers performed have been steadily increasing. This is largely due to the introduction of post-transplant cyclophosphamide (PT-Cy), which has reduced the substantial graft versus host disease (GVHD) which otherwise would occur.

Few data are available on the outcomes of myeloablative conditioned haploidentical transplants subsequent to the routine introduction of PT-Cy. Current evidence supporting this and similar protocols is drawn from three small retrospective studies and three prospective trials, one conducted locally in Australia. The local study conditioning regimen mirrors the matched donor fludarabine/busulfan myeloablative conditioning protocol, facilitating adoption by Australian transplant centres.

Evidence level
(NHMRC)		 Study Study Design Disease

Is the conditioning regimen consistent with the protocol?
III-3 Moore et al.rr Prospective, multicentre

AML 14
ALL 9
CML 1
NHL 3
MDS 3
MPD/MM/Other 2

 Yes
III-3 Raiola et al.r Retrospective AML 25
ALL 12
Lymphoma 5
PMF 4
CML 3
MPD 1		 No
III-3 Solomon et al.r Prospective 

AML 12
ALL 2
NHL 2
HL 1
CML 3

 No
III-3 El-Cheikh et al.r Retrospective outcome comparison between centres using adjunct ATG in addition to PT-Cy Acute Leukaemia 186
Lymphoma 27
Other 73		 No
 III-3 Symons et al.r Prospective, single-institution AML 41
ALL 20
MDS 11
Lymphoma 11
CML 4
Other 9		 No
III-3 Sugita et al.r Prospective, multicentre AML 23
ALL 11
MDS/MPD 6
Lymphoma 6
Other 4		 No

AML = acute myeloid leukaemia; ALL = acute lymphoblastic leukaemia; NHL = non-Hodgkin lymphoma; HL = Hodgkin lymphoma; MDS = myelodysplastic syndrome; PMF = primary myelofibrosis; CML = chronic myeloid leukaemia; MPD = myeloproliferative disorders

Efficacy

Study No. of patients Donor/stem cell source Engraftment ANC/Plts TRM/NRM Relapse rate OS DFS Comments
Moore et al.r

32

PB

18 days (12-92)/28 days (13-262)

1yr 17.9%

2yr 10.2%

2yr 72.2%

2yr 67.5%

< 50yo, HCT-CI 0-1
4 high DRI, 24 int DRI, 4 low DRI
Raiola et al.r

50

BM

 18 days (13-30)/23 days (14-58)

6 months 18%

Day 300 22%

18 months 62%

18 months 51%

Similar conditioning – 27 patients TBF, 15 patients F-TBI
Solomon et al.r

20

PB

16 days (14-21)/27 days (16-56)

1yr 10%

1yr 40%

1yr 69%

1yr 50%

Similar conditioning, added cyclophosphamide 29 mg/kg
El-Cheikh et al.r 53 (+ATG) PB 88%
BM 12%

17 days (12-34)/28 days (9-200)

 1yr 8% NR 1yr 79% 1 yr 67% On MVA, DRI was the only significant factor in DFS and OS
199 (no ATG) PB 83%
BM 17%		 1yr 23% NR 1yr 69% 1yr 60%
Symons et al.r 96 BM

24 days (12-34)/29 days (9-200)

 1yr 11% 1yr 35% 1yr 73% EFS 57%  
Sugita et al.r 50 PB

 17 days (12-39)/31 days (11-284)

 2yr 10% 2yr 36% 2yr 68% 2yr 54%  

PB = peripheral blood; BM = bone marrow; NRM = non-relapse mortality; TRM = transplant-related mortality; OS = overall survival; DFS = disease-free survival; PFS = progression-free survival; EFS = event-free survival; NR = not reported; MVA = multivariate analyses; DRI = disease risk index

Figure 1. Survival outcomes. (A) Probability of DFS and (B) OS in MAC (red) and RIC (blue) recipients.r

© Blood Advances 2023

Figure 2. Relapse and transplant mortality outcomes. Cumulative incidence of (A) TRM and (B) relapse in MAC (red) and RIC (blue) recipients.r

© Blood Advances 2023

Toxicity

A summary of the toxicities associated with this protocol are included in the table below:

Study Mucositis

aGVHD
- G2-4
- G3/4

cGVHD
- total
- extensive
- limited

 Graft failure Haemorrhagic cystitis (HC) VOD/SOS Lung/IPS Infection
Moore et al.r

NR

1% G2-4 on day 100

3.2% G3/4 at 6 months

Total 48%
Moderate - severe 12%

0%

33.2% at day 120, median onset 61 days

9.5% at day 180

NR

CMV viraemia 78.9% at 12 months

CI CMV disease 8.1% at 12 months

EBV reactivation 15.6% at 12 months
Raiola et al.r

6% G3

12% G2-4
6% G3/4

Total 26%
Moderate 10%

4%

Total HC 40%
BK 26%

2% (total no grade)

Fatal interstitial pneumonia 1%

CMV at-risk 94%
CMV viraemia74%
EBV 10%
Bacterial infection <d100 25%
Fungal infection <d100 11%
Solomon et al.r

NR

30% G2-4
10% G3/4

35% at median 20 months
5% extensive

0%

Total HC NR
BK 75%

NR

≥ grade 3
bacterial (5%), or
viral (10%) pneumonia

CMV viraemia in 81% of at risk patients
≥ grade 3 bacteraemia 25%
No IFI
El-Cheikh et al.r (+ATG) NR 12% G2-4
NR G3/4		 Total 23% NR NR NR

NR

 NR
El-Cheikh et al. (no ATG) NR 22% G2-4
​NR G3/4		 Total 21% NR NR NR NR NR
Symons et al.r NR 11% G2-4
​4% G3/4

Total 15% @ 1yr
Moderate-severe 6%

 NR

Total HC 20%
BK 18%

 2%

Fungal 2%

CMV viraemia in 51% of at risk patients
Viral 27%
Fungal 18% (proven or probable)
Bacterial 59%
Sugita et al.r NR 18% G2-4
8% ​G3/4

Total 36% @ 2yrs
Moderate-severe 20%

 NR NR 2% IPS 0.5% NR

aGVHD = acute graft versus host disease; cGVHD = chronic graft versus host disease; VOD = veno-occlusive disease; SOS = sinusoidal obstruction syndrome; IPS = idiopathic pneumonia syndrome; NR = not reported; BK = BK Virus; CMV = cytomegalovirus; EBV = Epstein-Barr virus; IFI = invasive fungal infections

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Version 2

Date Summary of changes
23/10/2024

Protocol reviewed by the BMT reference committee with the following changes made:

  • evidence updated to align with the published ANZHIT-1 study and interim removed from the title
  • MMF and tacrolimus tapering amended to align with the ANZHIT-1 study.

Protocol increased to V2. Review in 2 years.

Version 1

Date Summary of changes
30/07/2021

New protocol taken to BMT Reference Committee meeting.
02/09/2022

Protocol approved for publication.
For review in 1 year.
25/07/2023 Neurotoxicity added to "Late" category of Side effects section.
02/04/2024 Extravasation, tissue or vein injury added to side effects per updates to extravasation document.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/3981

15 Jun 2025