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Allogeneic myeloablative conditioning protocol etoposide and total body irradiation (TBI)

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Drug Dose Route Day
Total Body Irradiation 1.2 Gy per fraction THREE times a day TBI -7 to -5
Total Body Irradiation 1.2 Gy per fraction TWICE a day TBI -4
Etoposide * 60 mg/kg IV infusion -3

The TBI total dose to be administered in this protocol is 13.2 Gy as eleven fractions over 4 days; this TBI schedule differs from other TBI regimens on eviQ, in that 3 fractions are to be administered each day for three days and then 2 fractions for one day. As it is recommended that each fraction of TBI is separated by 6 hours, some institutions may not be able to deliver this TBI dosing schedule.

* Doses in this protocol are expressed as etoposide; however Etopophos (etoposide phosphate) is the preferred formulation.
Note: 1 mg of etoposide = 1.136 mg Etopophos (etoposide phosphate). Use actual body weight.

Notes:
  • This protocol is not a standard approach for ALL patients; it may be a treatment option for younger patients in CR2 who generally have poorer outcomes.
  • This total body irradiation (TBI) dose is technically difficult to administer; it is crucial that there is close collaboration with the Radiation Oncology Department, prior to the delivery of this conditioning regimen.
  • Additionally, in the original publicationr an electron boost of 4 Gy was given to the testes on day -7 and 3 Gy twice daily to the chest on days -5 and -4.

The supportive therapies (e.g. antiemetics, premedications, 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 -7 to -5
Total Body Irradiation 1.2 Gy (TBI) per fraction THREE times a day at least 6 hours apart (10.8 Gy total dose delivered in NINE fractions over THREE days)
Day -4
Total Body Irradiation 1.2 Gy (TBI) per fraction TWICE a day at least 6 hours apart (2.4 Gy total dose delivered in TWO fractions)
Day -3
Etoposide 60 mg/kg (IV infusion) over 4 hours (etoposide phosphate is the preferred formulation and all administration details in this protocol refer to etopophos).
Day -1
ciclosPORIN 1.5 mg/kg (IV infusion) over 2 to 6 hours TWICE a day and continue until oral therapy can be tolerated. Adjust dose according to trough level to avoid toxicity.
Day 0
Infusion of stem cells
Day 1
Methotrexate 15 mg/m2 (IV bolus) over 3 to 5 minutes (at least 24 hrs after stem cell/marrow infusion)
Day 3, 6, 11
Methotrexate 10 mg/m2 (IV bolus) over 3 to 5 minutes

Note: folinic acid rescue could be considered 24 hours post each methotrexate dose as it is associated with reduced toxicity and does not increase the risks of GvHD or graft rejection.r 

Drug Dose Route Day
Total Body Irradiation 1.2 Gy per fraction THREE times a day TBI -7 to -5
Total Body Irradiation 1.2 Gy per fraction TWICE a day TBI -4
Etoposide * 60 mg/kg IV infusion -3

The TBI total dose to be administered in this protocol is 13.2 Gy as eleven fractions over 4 days; this TBI schedule differs from other TBI regimens on eviQ, in that 3 fractions are to be administered each day for three days and then 2 fractions for one day. As it is recommended that each fraction of TBI is separated by 6 hours, some institutions may not be able to deliver this TBI dosing schedule.

* Doses in this protocol are expressed as etoposide; however Etopophos (etoposide phosphate) is the preferred formulation.
Note: 1 mg of etoposide = 1.136 mg Etopophos (etoposide phosphate). Use actual body weight.

Notes:
  • This protocol is not a standard approach for ALL patients; it may be a treatment option for younger patients in CR2 who generally have poorer outcomes.
  • This total body irradiation (TBI) dose is technically difficult to administer; it is crucial that there is close collaboration with the Radiation Oncology Department, prior to the delivery of this conditioning regimen.
  • Additionally, in the original publicationr an electron boost of 4 Gy was given to the testes on day -7 and 3 Gy twice daily to the chest on days -5 and -4.

The supportive therapies (e.g. antiemetics, premedications, 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 -7 to -5
Total Body Irradiation 1.2 Gy (TBI) per fraction THREE times a day at least 6 hours apart (10.8 Gy total dose delivered in NINE fractions over THREE days)
Day -4
Total Body Irradiation 1.2 Gy (TBI) per fraction TWICE a day at least 6 hours apart (2.4 Gy total dose delivered in TWO fractions)
Day -3
Etoposide 60 mg/kg (IV infusion) over 4 hours (etoposide phosphate is the preferred formulation and all administration details in this protocol refer to etopophos).
Day -1
ciclosPORIN 1.5 mg/kg (IV infusion) over 2 to 6 hours TWICE a day and continue until oral therapy can be tolerated. Adjust dose according to trough level to avoid toxicity.
Day 0
Infusion of stem cells
Day 1
Methotrexate 15 mg/m2 (IV bolus) over 3 to 5 minutes (at least 24 hrs after stem cell/marrow infusion)
Day 3, 6, 11
Methotrexate 10 mg/m2 (IV bolus) over 3 to 5 minutes

Note: folinic acid rescue could be considered 24 hours post each methotrexate dose as it is associated with reduced toxicity and does not increase the risks of GvHD or graft rejection.r 

  • High risk acute lymphoblastic leukaemia (ALL); patients beyond CR1

Assess patient pre-transplant: link to co-morbidity index

Venous access

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

Read more about central venous access device line selection
Hypersensitivity/infusion related reaction

High risk with etoposide.
Antiemetics for multi-day protocols

Antiemetic therapy should be administered throughout the duration of the chemotherapy protocol and to cover delayed nausea. The acute and delayed emetic risk of multi-day chemotherapy protocols will overlap depending on the individual drugs and their sequence of administration. More or less antiemetic cover may be required. 

Prior to each dose of total body irradiation, prophylaxis with a 5-HT3 receptor antagonist and dexamethasone 4 mg daily is recommended. 

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 or 12.5 mg IV every 6 hours when necessary.

Read more about preventing chemotherapy induced nausea and vomiting
Proton pump inhibitor

Commence on admission or at start of conditioning regimen and continue throughout transplant. Due to profound and long lasting inhibition of gastric acid do not administer concurrently with posaconazole syrup or itraconazole capsules.

Of note, protocol pump inhibitor is allowed with posaconazole tablet formulation.
GVHD prophylaxis

Ciclosporin (CSA) and methotrexate (MTX).

Commence IV CSA on day -1 and change to PO formulation once tolerated.

Cyclosporin to be continued for a 9 months and then wean over 3 months to cease by 12 months post-BMT. Adjust dose according to trough levels (target level = 250 to 350 ng/mL). 

Methotrexate to be given by IV bolus on day + 1, 3, 6 and 11

Note: if PO CSA therapy is changed to the IV formulation, the IV CSA dose is one-third to one-half of the previous total daily oral dose (Neoral® brand).
CMV pre-transplant prophylaxis

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

Stratify according to risk profile.

Read more about sinusoidal obstruction syndrome (SOS/VOD) associated with blood and marrow transplantation (BMT).
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

Read more about the prevention and management of tumour lysis syndrome.
Pneumocystis jiroveci 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

Consider the use of filgrastim or lenograstim from day +5 until recovery

Access the PBS website
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 leucodepleted blood products (i.e. CMV safe), as dictated by local clinical policies. 

Read more about the indications for the use of irradiated blood components
Blood tests

FBC, EUC 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, including BCG, MMR, zoster and varicella vaccines, are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease.

Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook 10th edition (updated 2016).
Effects of cancer treatment on fertility

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment.

Read more about the effect of cancer treatment on fertility
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 antineoplastic 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 and reference committee consensus. 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 Reduce etoposide by 25%
less than 30 Reduce etoposide by 50%

Ciclosporin elimination is primarily biliary and renal failure does not alter ciclosporin clearance significantly. Monitor trough ciclosporin levels and adjust dose accordingly to avoid toxicity (target level = 250 to 300 ng/mL).

Methotrexate dose reduction should be considered in significant renal impairment (50% dose reduction in methotrexate dose if eGFR between 25 to 50% of normal), significant pleural effusion, significant liver dysfunction such as hyperbilirubinaemia (>150 micromol/L) and/or severe mucositis.

References & Disclaimer

Etoposide and Etoposide Phosphate
  Interaction Clinical management
CYP3A4 and P-gp inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin etc.) Increased toxicity of etoposide possible due to reduced clearance Avoid combination or monitor for etoposide toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of etoposide possible due to increased clearance Avoid combination or monitor for decreased clinical response to etoposide
Glucosamine Reduced efficacy of etoposide (due to induction of glucose-regulated stress proteins resulting in decreased expression of topoisomerase II) Avoid combination or monitor for decreased clinical response to etoposide
Grapefruit juice Reduced efficacy of etoposide possible due to possible alteration of P-gp mediated intestinal transport of etoposide Avoid combination or monitor for decreased clinical response to etoposide
Methotrexate
  Interaction Clinical management
Ciprofloxacin

NSAIDS

Probenecid

Proton pump inhibitors (e.g. esomeprazole, omeprazole, pantoprazole)		 Increased toxicity of methotrexate possible due to reduced clearance Avoid combination or monitor for methotrexate toxicity

Important note: with high-dose methotrexate therapy (1000 mg/m2 or greater), many of these drug combinations are contraindicated
Sulphonamides and penicillins (e.g. sulfamethoxazole (in Bactrim®, Septrin®), piperacillin (in Tazocin®) etc.) Increased toxicity of methotrexate possible due to displacement from serum protein binding Avoid combination or monitor for methotrexate toxicity
Trimethoprim Increased toxicity of methotrexate possible due to additive antifolate activity Avoid combination or monitor for methotrexate toxicity
Mercaptopurine Increased toxicity of mercaptopurine possible due to reduced clearance Avoid combination or monitor for mercaptopurine toxicity
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal function closely
Hepatotoxic drugs (e.g. azathioprine, leflunomide, retinoids, sulfasalazine) Additive hepatotoxicity Avoid combination or monitor liver function closely
Folic acid (e.g. as in multivitamins)

Asparaginase (administered immediately prior or concurrently)		 Reduced efficacy of methotrexate possible due antagonism of its action Avoid combination or monitor for decreased clinical response to methotrexate
Note: asparaginase administered shortly after methotrexate can enhance its efficacy and reduce its toxicity
Azole antifungals
For a table of selected drug-drug interactions with azole antifungals link to the full text article by Chau et al 2014 (refer to table 2)
Ciclosporin
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal function closely
Potassium sparing drugs (e.g. amiloride, eplerenone, spironolactone, ACE inhibitors, angiotensin II receptor antagonists etc.) Additive risk of hyperkalaemia Monitor potassium level closely if combination is used
Corticosteroids Corticosteroids are CYP3A4 substrates. Case reports of inhibition of CYP3A4 by corticosteroids, including high dose methylprednisolone and prednisolone, leading to increased levels of both agents If used in combination monitor ciclosporin level and assess for signs of steroid excess
Digoxin Digitalis toxicity due to decreased digoxin clearance Avoid combination or monitor for digitalis toxicity; dose reduction or withdrawal may be required
Etoposide Increased toxicity of etoposide possible due to reduced clearance Monitor for etoposide toxicity; adjust dose as needed
Colchicine, HMG-CoA reductase inhibitors (statins) Reduced clearance of colchicine and statins and etoposide, thereby enhancing the potential of these drugs to induce muscular toxicity, including muscle pain and weakness, myositis and occasionally rhabdomyolysis. If used concurrently, monitor closely for myotoxicity. Consider lower initial and maintenance dose of statin and cease immediately if signs and symptoms of myopathy occur
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of ciclosporin possible due to reduced clearance Avoid combination or monitor for ciclosporin toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John's wort etc.) Reduced efficacy of ciclosporin possible due to increased clearance Avoid combination or monitor for decreased clinical response to ciclosporin
Drugs metabolised by CYP3A4 (e.g. atorvastatin, benzodiazepines, calcineurin inhibitors, clarithromycin, dihydroergotamine, simvastatin, etc.) Increased effect/toxicity of these drugs possible due to inhibition of CYP3A4 by ciclosporin resulting in reduced clearance Avoid combination or monitor for increased effect/toxicity Note: simvastatin and ivabradine contraindicated
Drugs undergoing P-gp-mediated elimination (e.g. dabigatran, loperamide, phenytoin etc.) Increased effects/toxicity of these drugs possible due to inhibition of P-gp by ciclosporin resulting in reduced clearance Avoid combination or monitor for increased effect/toxicity
General
  Interaction Clinical management
Warfarin Antineoplastic agents may alter the anticoagulant effect of warfarin Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant (e.g. LMWH or unfractionated heparin)
Digoxin Antineoplastic agents 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 antineoplastic 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 antineoplastic 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
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook 10th Edition (updated 2016)

Day -7 to -4

General patient assessment prior to each day of treatment.

Prime IV line(s).

Access CVC.

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).

Hydration as prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Total body irradiation (TBI)

Ensure the patient has had their pre medication and is ready to go for TBI at the allocated time agreed upon by the nursing staff and the Radiotherapy Department.

Read more about the management of radiation induced nausea and vomiting

Administer dexamethasone, 5HT3 antagonist 30 to 60 minutes prior to each dose of TBI

All CVC lumens MUST be capped off prior to radiotherapy

TBI is given three times a day on days -7 to -5, 6 hours apart. On day -4 TBI is given twice. 

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

Day -3

General patient assessment prior to each day of treatment.

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).

Hydration as prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Etoposide phosphate

Administer etoposide phosphate (irritant):
  • via IV infusion over 4 hours
  • rapid infusion may cause hypotension
  • observe for hypersensitivity
  • flush with ~ 100 mL sodium chloride 0.9%.

Stop infusion at first sign of reaction:

  • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate.
  • for severe reactions seek medical assistance immediately and do not restart infusion.

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

Day -1

General patient assessment prior to each day of treatment.

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).

Hydration as prescribed.

Verify antiemetics taken or administer as prescribed.

Ciclosporin 

  • administer via IV infusion over 2 to 6 hours (or as per institution; can be administered as divided doses or as a continuous 24 hour infusion)
  • use non PVC containers and tubing
  • flush with 100 mL sodium chloride 0.9%
  • facial flushing and headache may occur with too rapid infusion of ciclosporin: reduce infusion rate 
  • patients should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter
  • administer second dose of ciclosporin 12 hours after first dose.

Continue ciclosporin twice a day ongoing or as per haematologist advice

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

Day 0

General patient assessment prior to each day of treatment.

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).

Hydration as prescribed.

Treatment - Time out  

Continue GVHD prophylaxis as prescribed.

Commence antiviral and antifungal prophylaxis as prescribed.

Administer stem cells as per institutional guidelines.

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

Day +1, 3, 6 and 11

General patient assessment prior to each day of treatment.

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).

Hydration as prescribed.

Continue ciclosporin as prescribed.

Continue antiviral and antifungal prophylaxis as prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Methotrexate

  • over 3 to 5 minutes 
    • by IV bolus via a side port of a freely flowing IV infusion OR
  • over 5 to 15 minutes
    • via a minibag
  • flush with ~50 mL of sodium chloride 0.9%

Deaccess CVC.

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

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Growth factor support
  • Arrangements for administration if prescribed.
Ciclosporin capsules
  • with written instructions on how to take them
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.
Patient information

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)
Nausea and vomiting

Read more about prevention of chemotherapy induced nausea and vomiting
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Taste and smell alteration

Read more about taste and smell changes
Paraesthesia

'Pins and needles' and/or burning sensations in the hands and feet. It is associated with ciclosporin and usually occurs during the first week of treatment with a tendency to lessen over time. 

Early (onset days to weeks)
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 neutropenia
Thrombocytopenia

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

Read more about thrombocytopenia
Anaemia

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

Read more about anaemia
Oesophagitis

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

Read more about oesophagitis
Oral mucositis

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

Read more about oral mucositis
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 antineoplastic agents. Pre-existing hypertension should be controlled prior to initiation of drugs capable of causing hypertension.
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) associated with blood and marrow transplantation (BMT)
Skin rash

Mild diffuse erythema can occur with total body irradiation (TBI). 

Read more about management of radiation-induced skin reactions
Xerostomia

Xerostomia is defined as the subjective sensation of dryness of the mouth.

Read more about xerostomia

Late (onset weeks to months)
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.
Hirsutism

Excessive male-pattern hair growth in women is associated with ciclosporin; coarse dark hair can grow on the face, chest and back, under the arms and in the pubic area.
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

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 antineoplastic drugs

Stanford and City of Hope (COH) groups first evaluated a conditioning regimen consisting of fractionated TBI to a total dose 1320 cGy in 11 fractions on day -7 through day -4 administered erect and with lung shielding together with IV etoposide at 60 mg/kg administered over 4 hours on day -3. This group subsequently demonstrated considerable activity of this regimen in patients with advanced acute leukaemia in a randomised prospective SWOG trial versus Bu/Cy conditioning.r A German study using the same regimen reported 64% DFS at 18 months in 17 high-risk patients (10 were not in remission at transplantation).r In less advanced disease, these groups reported cumulative probabilities of disease-free survival and relapse at 3 years of 61% and 12%, respectively, for 61 patients with AML and 64% and 12%, respectively, for 34 patients with ALL.r Given these initial results the Medical Research Council UKALL12/Eastern Cooperative Oncology Group study adopted this conditioning regimen as standard in 1993. This study reported a 5-year DFS of 54% in 170 patients with Philadelphia-negative ALL conditioned with etoposide-TBI. However, the 100-day transplant-related mortality (TRM) in the multicenter, multinational setting was 21%.r The Stanford and COH groups found that the etoposide-TBI regimen caused considerable mucosal and dermatologic toxicity but with NRM reported as 28%.r

Marks et al, reported a registry based comparison of the outcome of 500 adult and paediatric patients with ALL in CR1 or CR2 who received either Cy-TBI or etoposide-TBI prior to a HLA matched sibling transplantation.r Cy doses ranged from 100 to 130 mg/kg, and etoposide doses ranged from 40 to 60 mg/kg. 217 patients received Cy-TBI less than 13 Gy, 81 patients received Cy-TBI greater than or equal to 13 Gy, 53 patients received etoposide-TBI less than 13 Gy, and 151 received etoposide-TBI greater than or equal to 13 Gy. COH provided data as a single institution for 75 patients who received etoposide-TBI greater than or equal to 13 Gy as their conditioning regimen. The median follow-up of survivors was 67 months (range, 8-156 months).

Transplant-related mortality did not differ by conditioning regimen but was significantly associated with age greater than or equal to 20, and receiving PBSC vs. BM. In CR1, there were also no significant differences in relapse, LFS, or survival by conditioning regimen. In CR2, these outcomes differed among conditioning groups. In comparison with Cy-TBI less than 13 Gy, the risks of relapse, treatment failure and mortality tended to be lower with etoposide (regardless of TBI dose) or with TBI doses greater than13 Gy (p=0.0016). Relapse risk was also significantly correlated with age greater than or equal to 20, and presence of cytogenetic abnormalities. For both CR1 and CR2 transplantations, causes of death were similar among the groups; disease recurrence accounted for 47% of deaths.

Efficacy

Relapse:

Cumulative incidence of relapse after HLA-identical sibling transplantations for ALL in first (A) or second (B) complete remission, according to the pre transplantation conditioning regimen (pointwise P value at 5 years for CR1 patients: etoposide-TBI versus Cy-TBI less than 13 Gy, P = .23; etoposide-TBI versus Cy-TBI greater than or equal to 13 Gy, P = .78; Cy-TBI less than 13 Gy versus Cy-TBI greater than or equal to 13 Gy, P = .60; pointwise P value at 5 years for CR2 patients: etoposide-TBI versus Cy-TBI less than13 Gy, P = .22; etoposide-TBI versus Cy-TBI greater than or equal to 13 Gy, P = .033; Cy-TBI less than 13 Gy versus Cy-TBI greater than or equal to 13 Gy, P = .001). Vp16 indicates etoposide.

© American Society for Blood and Marrow Transplantation 2006

© American Society for Blood and Marrow Transplantation 2006

Overall Survival:r

Adjusted probability (derived from multivariate regression models) of LFS after HLA-identical sibling transplantations for ALL in first (A) or second (B) complete remission, according to the pre transplantation conditioning regimen (pointwise P value at 5 years for CR1 patients: etoposide-TBI versus Cy-TBI less than 13 Gy, P = .21; etoposide-TBI versus Cy-TBI greater than or equal to 13 Gy, P = .17; Cy-TBI less than 13 Gy versus Cy-TBI greater than or equal to 13 Gy, P = .59; pointwise P value at 5 years for CR2 patients: etoposide-TBI versus Cy-TBI less than 13 Gy, P = .002; etoposide-TBI versus Cy-TBI greater than or equal to 13 Gy, P = .23; Cy-TBI less than 13 Gy versus Cy-TBI greater than or equal to 13 Gy, P < .001). Vp16 indicates etoposide.

© American Society for Blood and Marrow Transplantation 2006

© American Society for Blood and Marrow Transplantation 2006

Toxicity

Toxicity data by pre-transplantation conditioning regimen is presented below.r The major single cause of death was recurrence of disease. Overall, the causes of death were similar in the 4 groups. GVHD, infection, interstitial pneumonia, and organ failure were the other major causes of treatment failure.

© American Society for Blood and Marrow Transplantation 2006

Philadelphia-positive ALL

Laport et al, reviewed the 20 year Stanford and COH experience of VP16+TBI regimen in Ph+ ALL.r 67 pts received VP16+TBI, 11 pts received VP16+Cy+TBI and 1 pt received VP16+Bu+TBI. All pts received an HLA matched sibling allograft. 62% CR1, 38% greater than CR1. 10 yr OS for CR1 54% and greater than CR1, 29% (p=0.01) with no increase in relapse between the groups (28% vs. 41%, p=0.28) but a substantial increase in TRM for the greater than CR1 group (31% vs 54%, p=0.03). Multivariate analysis of outcomes for OS and EFS are presented below.

© Blood 2008

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Bibliography

Bruserud, O., H. Reikvam, A. O. Kittang, et al. 2012. "High-dose etoposide in allogeneic stem cell transplantation." Cancer Chemother Pharmacol 70(6):765-782.

The anti-leukemic effect of etoposide is well documented. High-dose etoposide 60 mg/kg in combination with fractionated total body irradiation (TBI), usually single fractions of 1.2 Gy up to a total of 13.2 Gy, is used as conditioning therapy for allogeneic stem cell transplantation. Most studies of this conditioning regimen have included patients with acute leukemia receiving bone marrow or mobilized stem cell grafts derived from family or matched unrelated donors, and the treatment is then effective even in patients with high-risk disease. The most common adverse effects are fever with hypotension and rash, nausea and vomiting, sialoadenitis, neuropathy and metabolic acidosis. A small minority of patients develop severe allergic reactions. Etoposide has also been tested in a wide range of combination regimens, but for many of these combinations, relatively few patients are included, and some combinations have only been tested in patients who have undergone autologous transplants. However, the general conclusion is that many of these combinations are effective in patients with high-risk malignancies and the toxicity often seems acceptable. Thus, etoposide-based conditioning therapy should be further evaluated in patients having allogeneic transplants, but randomized trials are needed and the design of future trials should be based on the well-characterized TBI + high-dose etoposide regimen.

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17 Oct 2018