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NK T-Cell lymphoma SMILE (dexamethasone methotrexate iFOSFamide asparaginase etoposide)

Patients with lymphoma should be considered for inclusion into clinical trials. Link to ALLG website, ANZCTR website and Lymphoma Australia website.

This protocol is based on limited evidence; refer to the evidence section of this protocol for more information.

The anticancer drug(s) in this protocol may have been included in the ADDIKD guideline. Dose recommendations in kidney dysfunction have yet to be updated to align with the ADDIKD guideline. Recommendations will be updated once the individual protocol has been evaluated by the reference committee. For further information refer to the ADDIKD guideline. To assist with calculations, use the eviQ Estimated Glomerular Filtration Rate (eGFR) calculator.

Note: Native E-coli asparaginase (colaspase) ceased being manufactured in 2019. It is the view of the Haematology Reference Committee that protocols with evidence for pegaspargase use in the trials supporting them be recommended rather than substituting pegaspargase into native E-coli asparaginase containing protocols. 
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Cycle 1 and 2

Drug Dose Route Day
Methotrexate 2,000 mg/m2 IV infusion 1
Calcium folinate (Leucovorin) * 15 mg/m2 every 6 hours IV infusion 2
Dexamethasone 40 mg ONCE a day PO 2 to 4
Etoposide ** 100 mg/m2 IV infusion 2 to 4
iFOSFamide 1,500 mg/m2 IV infusion 2 to 4
Mesna 300 mg/m2 IV infusion 2 to 4
Mesna 300 mg/m2 at 4 and 8 hours post ifosfamide dose IV infusion 2 to 4
Filgrastim 5 micrograms/kg Subcut 6 and continue daily until neutrophil recovery
Asparaginase (colaspase) *** 6,000 International Units/m2 IV infusion 8, 10, 12, 14, 16, 18, 20

* Commence 36 hours after the start of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L

** Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Use actual body weight. Doses in this protocol are expressed as etoposide; however Etopophos (etoposide phosphate) is the preferred formulation.

*** The manufacturers of Leunase® brand of  asparaginase (colaspase) have confirmed that one Kyowa Unit (KU) is equivalent to one International Unit. Alternative formulations and routes of administration may be used depending on local institution policies. 

It is important to note that there are various formulations of asparaginase available and dosing for each formulations is different. Clinicians should therefore ensure that the dose prescribed is appropriate for the asparaginase product being administered.

Link to asparaginase document.

Frequency:
28 days 
Cycles:
2 to 3, patients in complete remission (CR) or partial remission (PR) can continue to receive SMILE up to 6 cycles or undergo a BMT.
Notes:

Patients in interim CR with original disease sites judged to be amenable to irradiation received sandwiched IFRT (Involved-Field Radiation Therapy) before the next treatment when treated on SMILE.r

Drug status:

Methotrexate, ifosfamide, calcium folinate, dexamethasone, mesna and etoposide are on the PBS general schedule

Asparaginase (colaspase): TGA approved but not PBS reimbursed

Filgrastim: (PBS authority)

Dexamethasone is available as 0.5 mg and 4 mg tablets

Cost:
~ $2,610 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

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.

Cycle 1 and 2

Day 1
Methotrexate 2,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 6 hours
Day 2
Calcium folinate (Leucovorin) 15 mg/m2 (IV infusion) Commence 36 hours after the start of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L
Dexamethasone 40 mg (PO) ONCE a day on days 2 to 4. Take in the morning with food.
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
iFOSFamide 1,500 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 6 hours (loaded with mesna)
Mesna 300 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 6 hours (loaded with ifosfamide)
Mesna 300 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% at 4 and 8 hours after completion of EACH ifosfamide dose
Day 3 and 4
Dexamethasone 40 mg (PO) ONCE a day on days 2 to 4. Take in the morning with food.
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
iFOSFamide 1,500 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 6 hours (loaded with mesna)
Mesna 300 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 6 hours (loaded with ifosfamide)
Mesna 300 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% at 4 and 8 hours after completion of EACH ifosfamide dose
Day 6
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously on day 6 and continue daily until neutrophil recovery.
Day 8, 10, 12, 14, 16, 18, 20
Asparaginase (colaspase) 6,000 International Units/m2 (IV infusion) in 250 mL to 500 mL sodium chloride 0.9% over 2 to 4 hours

Note: Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Use actual body weight. Doses in this protocol are expressed as etoposide; however Etopophos (etoposide phosphate) is the preferred formulation.

Frequency:
28 days 
Cycles:
2 to 3, patients in complete remission (CR) or partial remission (PR) can continue to receive SMILE up to 6 cycles or undergo a BMT.

Cycle 1 and 2

Drug Dose Route Day
Methotrexate 2,000 mg/m2 IV infusion 1
Calcium folinate (Leucovorin) * 15 mg/m2 every 6 hours IV infusion 2
Dexamethasone 40 mg ONCE a day PO 2 to 4
Etoposide ** 100 mg/m2 IV infusion 2 to 4
iFOSFamide 1,500 mg/m2 IV infusion 2 to 4
Mesna 300 mg/m2 IV infusion 2 to 4
Mesna 300 mg/m2 at 4 and 8 hours post ifosfamide dose IV infusion 2 to 4
Filgrastim 5 micrograms/kg Subcut 6 and continue daily until neutrophil recovery
Asparaginase (colaspase) *** 6,000 International Units/m2 IV infusion 8, 10, 12, 14, 16, 18, 20

* Commence 36 hours after the start of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L

** Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Use actual body weight. Doses in this protocol are expressed as etoposide; however Etopophos (etoposide phosphate) is the preferred formulation.

*** The manufacturers of Leunase® brand of  asparaginase (colaspase) have confirmed that one Kyowa Unit (KU) is equivalent to one International Unit. Alternative formulations and routes of administration may be used depending on local institution policies. 

It is important to note that there are various formulations of asparaginase available and dosing for each formulations is different. Clinicians should therefore ensure that the dose prescribed is appropriate for the asparaginase product being administered.

Link to asparaginase document.

Frequency:
28 days 
Cycles:
2 to 3, patients in complete remission (CR) or partial remission (PR) can continue to receive SMILE up to 6 cycles or undergo a BMT.
Notes:

Patients in interim CR with original disease sites judged to be amenable to irradiation received sandwiched IFRT (Involved-Field Radiation Therapy) before the next treatment when treated on SMILE.r

Drug status:

Methotrexate, ifosfamide, calcium folinate, dexamethasone, mesna and etoposide are on the PBS general schedule

Asparaginase (colaspase): TGA approved but not PBS reimbursed

Filgrastim: (PBS authority)

Dexamethasone is available as 0.5 mg and 4 mg tablets

Cost:
~ $2,610 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

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.

Cycle 1 and 2

Day 1
Methotrexate 2,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 6 hours
Day 2
Calcium folinate (Leucovorin) 15 mg/m2 (IV infusion) Commence 36 hours after the start of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L
Dexamethasone 40 mg (PO) ONCE a day on days 2 to 4. Take in the morning with food.
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
iFOSFamide 1,500 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 6 hours (loaded with mesna)
Mesna 300 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 6 hours (loaded with ifosfamide)
Mesna 300 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% at 4 and 8 hours after completion of EACH ifosfamide dose
Day 3 and 4
Dexamethasone 40 mg (PO) ONCE a day on days 2 to 4. Take in the morning with food.
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
iFOSFamide 1,500 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 6 hours (loaded with mesna)
Mesna 300 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 6 hours (loaded with ifosfamide)
Mesna 300 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% at 4 and 8 hours after completion of EACH ifosfamide dose
Day 6
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously on day 6 and continue daily until neutrophil recovery.
Day 8, 10, 12, 14, 16, 18, 20
Asparaginase (colaspase) 6,000 International Units/m2 (IV infusion) in 250 mL to 500 mL sodium chloride 0.9% over 2 to 4 hours

Note: Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Use actual body weight. Doses in this protocol are expressed as etoposide; however Etopophos (etoposide phosphate) is the preferred formulation.

Frequency:
28 days 
Cycles:
2 to 3, patients in complete remission (CR) or partial remission (PR) can continue to receive SMILE up to 6 cycles or undergo a BMT.
  • Newly diagnosed stage IV or relapsed/refractory extranodal natural killer/T-cell lymphoma
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.

High risk with asparaginase.

Acute anaphylactoid reactions are the most common dose-limiting toxicity, particularly with IV administration. Patients that develop hypersensitivity to the E. coli derived formulation may be able to switch to Erwinia asparaginase.

The Leunase brand of asparaginase (colaspase) is the only formulation for which the manufacturer advises an intradermal test dose prior to the initial dose or when a week or more has elapsed between doses. A negative skin reaction does not preclude the development of an allergic reaction and therefore the practice of a test dose is controversial.

Read more about Management of asparaginase therapy 
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. 

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
Pre-hydration

Pre-hydration with sodium bicarbonate 8.4% infusion. Urinary pH must be greater than 7 prior to commencing methotrexate infusion.
(Consider prescribing sodium bicarbonate oral capsules for administration prior to methotrexate infusion). Sodium bicarbonate 8.4% should continue until the methotrexate level is equal to or less than 0.05 micromol/L.
Methotrexate interactions

Avoid administering the following drugs in combination with high dose methotrexate: ciprofloxacin, NSAIDs, probenecid, proton pump inhibitors (PPIs) (e.g. esomeprazole, omeprazole, pantoprazole), sulphonamides (e.g. sulfamethoxazole (in Bactrim®, Septrin®)), penicillins (e.g. piperacillin (in Tazocin®)) and trimethoprim. Severe mucositis may occur if administered together.
High dose methotrexate

Monitoring of methotrexate levels is essential as delayed methotrexate excretion is potentially an emergency situation. Methotrexate levels to be monitored every 24 hours until level is less than 0.05 micromol/L.

Methotrexate is renally eliminated. Renal function must be evaluated prior to treatment.

Methotrexate exits slowly from third space compartments (e.g. pleural effusions or ascites), resulting in a prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels.

Glucarpidase is recommended in patients with high dose methotrexate (HDMTX)-induced acute kidney injury and delayed methotrexate clearance. It can rapidly lower methotrexate levels and early administration within 48 to 60 hours from the start of the HDMTX infusion is critical, as life-threatening toxicities may not be preventable beyond this time point.r

Read more about high dose methotrexate-induced toxicity.
Asparaginase

Asparaginase is associated with numerous toxicities including hypersensitivity, hepatotoxicity, coagulation abnormalities, pancreatitis, hyperlipidaemia, hyperglycaemia and CNS effects. Therefore routine monitoring and assessment of several parameters are required throughout treatment.

There are several different formulations of asparaginase available, each with different dosing and administration recommendations.

For comprehensive information on formulations, dosing, interactions, adverse reactions and specific monitoring parameters for asparaginase, see Management of asparaginase therapy document.
Pancreatitis

Pancreatitis can occur despite normal serum amylase, and can be fatal. In cases of clinical pancreatitis (unequivocal diagnosis based on lipase/amylase elevation, ultrasound and clinical findings) asparaginase treatment should be ceased and must not be resumed. Mild asymptomatic biochemical pancreatitis does not warrant discontinuing asparaginase therapy.
Ifosfamide induced encephalopathy

May occur in patients treated with high dose ifosfamide (~ 5 to 8 g/m2). Assess neurological function prior to each ifosfamide dose.

Read more about ifosfamide induced encephalopathy

Link to ifosfamide encephalopathy assessment chart
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
Etoposide conversion factor

Doses in this protocol are expressed as etoposide. Note: Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg.

Etoposide phosphate is the preferred formulation for this protocol, as solutions of conventional etoposide would exceed the maximum concentration of 0.4 mg/mL and may precipitate. All administration details in this protocol refer to etopophos.
Corticosteroids

Diabetic patients should monitor their blood glucose levels closely. To minimise gastric irritation, advise patient to take immediately after food. Consider the use of a H2 antagonist or proton pump inhibitor if appropriate.

Read more about acute short term effects from corticosteroids
Central nervous system (CNS) prophylaxis

Consider CNS relapse assessment in patients with high grade lymphoma. 

Read more about CNS prophylaxis in diffuse large cell lymphoma
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

Read more about the prevention and management of tumour lysis syndrome.
Mesna dosing and administration

There is evidence for several mesna doses as well as differing administration timings (e.g. 2, 4, 6, or 8 hours post initiation or completion of the ifosfamide/cyclophosphamide dose) with no clear evidence that one particular regimen is superior over 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.
Pneumocystis jirovecii pneumonia (PJP) prophylaxis

PJP prophylaxis is recommended.

Myelosuppression may be exacerbated if trimethoprim/sulfamethoxazole is used in combination with methotrexate.

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

­

Read more about antiviral prophylaxis drugs and doses
Antifungal prophylaxis ­

Read more about antifungal prophylaxis drugs and doses.
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative page
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
Blood product support

The use of FFP and cryoprecipitate may be required to maintain fibrinogen levels to a normal range.

Read more about Management of asparaginase therapy
Blood tests

FBC at baseline and repeat prior to each treatment. EUC, LFTs, LDH, BSL, serum uric acid, serum amylase and lipase at baseline and regularly throughout treatment as clinically indicated. 

Asparaginase may cause a marked increase in plasma triglycerides and total cholesterol levels. Monitoring recommended. 

During asparaginase therapy perform coagulation studies at baseline then at least once or twice weekly. Monitor fibrinogen levels at least twice weekly and consider monitoring antithrombin levels or APTT, PT, fibrinogen levels, pancreatic lipase prior to each dose of asparaginase (colaspase).

Monitor methotrexate levels every 24 hours until the level is less than 0.05 micromol/L.
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.

Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.

Read more about COVID-19 vaccines and cancer.
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 foetal 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 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 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) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.
The dose recommendations in kidney dysfunction (i.e.renal impairment) displayed may not reflect those in the ADDIKD guideline and have been included for historical reference only. Recommendations will be updated once the individual protocol has been evaluated by the reference committee, with this version of the protocol then being archived. Clinicians are expected to refer to the ADDIKD guideline prior to prescribing in kidney dysfunction.
International Consensus Guideline for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).

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

Haematological toxicity
Platelets x 109/L (nadir)
less than 25 Consider reducing the dose of methotrexate, ifosfamide and etoposide by 33% in the second cycle. Cease asparaginase (colaspase) and administer in second cycle if platelets recover
Renal impairment
Creatinine clearance (mL/min)
15 to less than 50 Reduce etoposide by 25%
less than 30 Reduce ifosfamide by 25%

Creatinine clearance must be greater than 80 mL/min prior to administration of full dose high dose methotrexate.

It is advised to reduce the methotrexate dose in proportion to the calculated creatinine clearance when this is less than 80 mL/min e.g. if creatinine clearance is 75 mL/min, then 75% of the calculated methotrexate dose is given.r

Methotrexate is contraindicated if CrCL is less than 30 mL/min
Hepatic impairment
Hepatic dysfunction
Mild or moderate Use etoposide with caution
Severe Consider continuing etoposide without dose reduction for patients with NK T-Cell lymphoma associated haemaophagocytic syndromer
Mucositis, stomatitis and diarrhoea
Grade 3 or Grade 4 Diarrhoea and ulcerative stomatitis require interruption of therapy otherwise haemorrhagic enteritis and death from intestinal perforation may occur: reduce methotrexate by 25%
Methotrexate
Concentration greater than 1 x 10-7 mmol/L (72 hours after administration in the first course) Reduce methotrexate dose by 33%
Cease or dose reduce asparaginase (colaspase) if any one of the following develops:
  • Consider reducing the dose by 50% if Grade 1 or 2 allergic reaction/hypersensitivity occurs; the use of prednisone at a dose of 1 mg/kg/d was permitted in the studyr
  • Discontinue if Grade 3 or 4 allergic reaction/hypersensitivity, pancreatitis, or hypotension occurs; if discontinued due to allergy/hypersensitivity, consider changing to a different formulation of asparaginase (erwinia asparaginase or pegasparaginase)
  • Discontinue if Grade 3 non-haematologic toxicity occurs; if the patient recovers in Cycle 2, asparaginase (colaspase) may be readministered.

Drug interactions in eviQ protocols are under review and being updated to align with current literature. Further site-wide updates and changes will occur in due course. References & Disclaimer

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:  

Asparaginase
  Interaction Clinical management
Methotrexate Reduced efficacy of methotrexate if asparaginase is given immediately prior to or with methotrexate. Enhanced efficacy and reduced toxicity of methotrexate if asparaginase is given shortly after methotrexate Administer asparaginase 9 to 10 days before or, preferably, shortly after methotrexate to enhance its efficacy and reduce its toxicity (unless otherwise scheduled per protocol)
Vincristine Increased vincristine neurotoxicity if given after or concurrently with asparaginase Administer vincristine 12 to 24 hours before asparaginase
Prednisolone Increased risk of asparaginase toxicity (including decreased production of clotting factors and hyperglycaemia) if given after or concurrently with asparaginase Administer prednisolone before asparaginase to avoid increased toxicity; monitor fibrinogen, ATIII and blood glucose levels
Dexamethasone
  Interaction Clinical management
CYP3A4 interactions Dexamethasone is a substrate of CYP3A4 and a weak to moderate inducer of CYP3A4. The clinical relevance of CYP3A4 induction by dexamethasone is unknown as the mechanism has yet to be established The effects of the concomitant use of dexamethasone with other CYP3A4 inducers, inhibitors or substrates is variable. If used concomitantly, monitor patients closely for adverse drug reactions
Warfarin Concurrent use may result in increased risk of bleeding or diminished effects of warfarin Monitor prothrombin time / INR (especially during initiation or discontinuation) and for signs of drug toxicity during concomitant use; adjust warfarin dose as required
Oral hypoglycaemics Corticosteroids may cause hyperglycaemia and worsen diabetes control Monitor blood glucose levels and adjust oral hypoglycaemic dose as required
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 oral etoposide possible due to possible alteration of P-gp mediated intestinal transport of etoposide Avoid combination or monitor for decreased clinical response to etoposide
Ifosfamide
  Interaction Clinical management
Aprepitant Increased risk of ifosfamide-induced neurotoxicity due to increased levels of active metabolites Avoid combination or monitor closely for neurotoxicity; consider alternate antiemetic regimens
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Increased toxicity of ifosfamide possible due to increased conversion to active and toxic metabolites Avoid combination or monitor for ifosfamide toxicity
CYP3A4 inhibitors (e.g. azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Reduced efficacy of ifosfamide possible due to decreased conversion to active metabolites Avoid combination or monitor for decreased clinical response to ifosfamide
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal function closely
Suxamethonium Potentiation of muscle relaxant effect possible Alert the anaesthetist if a patient has been treated with ifosfamide within ten days of planned general anaesthesia
CNS depressants (including opiates, opioids, phenothiazines) Increased risk of ifosfamide-induced neurotoxicity due to additive CNS effects Avoid combination or monitor for excessive CNS depression/encephalopathy
Mesna 
No specific or clinically significant drug interactions 
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, 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
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 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp  inhibitors.

Dabigatran: avoid combination with strong P‑gp 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
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines. Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

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. 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 website for further information.

Day 1

General patient assessment prior to each day of treatment.

Any toxicity grade 2 or greater may require delay of treatment and review by medical officer before commencing treatment.

Prime IV line(s).

Access CVAD.

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 weight
  • monitor pH on all urine output
  • strict fluid balance input and output

Hydration if prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Methotrexate 

Prehydration:
  • administer 100 mL sodium bicarbonate 8.4% in 1000 mL glucose 5% OR sodium chloride 0.9% over 4 hours
  • continue hydration with sodium bicarbonate 8.4% as prescribed
  • when urine pH is greater than 7 commence methotrexate
If the urine pH drops below 7 during the methotrexate infusion:
  • administer stat dose of 100 mL sodium bicarbonate 8.4% over 15 minutes
  • continue to test all urine for pH, if the pH continues to drop below 7 seek medical review as further doses of sodium bicarbonate may be required.
  • the starting time of the methotrexate infusion must be documented as the calcium folinate (leucovorin) rescue is to commence exactly 36 hours after the start of the methotrexate and continue until the methotrexate level is less than 0.05  micromol/L.
Methotrexate
  • Administer via IV infusion over 6 hours
  • flush with ~50 mL of sodium chloride 0.9%
Post methotrexate:
  • continue hydration with sodium bicarbonate 8.4% until methotrexate level is less than 0.05 micromol/L
  • continue to monitor all urine pH and fluid input and output
  • monitor methotrexate concentration every 24 hours until the level is less than 0.05 micromol/L

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

Days 2 to 4

General patient assessment prior to each day of treatment.

Any toxicity grade 2 or greater may require delay of treatment and review by medical officer before commencing 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).

  • continue daily weight
  • monitor pH on all urine output
  • dip stick all urine for haematuria 
  • strict fluid balance input and output 

Hydration if prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Calcium Folinate (Leucovorin)

  • administer by IV bolus via a side port of the IV line over 1 to 2 minutes
  • flush with ~ 50mL of sodium chloride 0.9%.

Note: Start calcium folinate (leucovorin) rescue 36 hours after commencement of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L.

Dexamethasone

  • administer orally ONCE a day in the morning
  • to be taken with or immediately after food.

Note: if a dose is forgotten or vomited, contact treating team.

Etoposide

Administer etoposide (irritant):
  • via IV infusion over 30 to 60 minutes
  • rapid infusion may cause hypotension
  • observe for hypersensitivity
  • flush with ~ 100 mL sodium chloride 0.9%
  • if using etoposide phosphate administer in ~ 50 mL sodium chloride 0.9% or glucose 5% over ~15 minutes.
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.

Ifosfamide infusion

Prior to administration:
  • assess neurological function at baseline and prior to each ifosfamide dose
    • inpatients: 4 hourly assessments until 24 hours after ifosfamide infusion is completed
    • outpatients: advise patient/carer of the potential for neurotoxicity
  • perform baseline urinalysis and monitor for haematuria prior to each ifosfamide dose
    • note the administration of mesna will cause a false positive for ketonuria
  • ensure patient receives at least 3 L of IV or oral fluids per day
Administer ifosfamide (irritant) with mesna:
  • via IV infusion over 6 hours
  • flush with ~100 mL of sodium chloride 0.9%

IV mesna

  • administer mesna via IV bolus at 4 and 8 hours post completion ifosfamide/mesna infusion
  • flush with ~100 mL of sodium chloride 0.9%

Deaccess CVAD.

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

Day 6

Filgrastim

  • inject subcutaneously ONCE daily, and until neutrophil recovery

Days 8, 10, 12, 14, 16, 18 and 20

General patient assessment prior to each day of treatment.

Any toxicity grade 2 or greater may require delay of treatment and review by medical officer before commencing treatment.

Prime IV line(s).

Access CVAD.

Hydration if prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Asparaginase (colaspase)

Prior to administration:

Test dose

  • Administer asparaginase (colaspase) 1 to 10 KU (= 1 international unit) in 0.1 mL of water for injection by intradermal injection:
  • observe the injection site for at least 60 minutes for any evidence of hypersensitivity.

Note: Leunase® product information advises an intradermal test dose to be administered prior to initial dose or when a week or more has elapsed between doses. A negative skin reaction does not preclude the development of an allergic reaction and thus the practice of an intradermal test dose is controversial.

Read more on detailed dosing information regarding asparaginase (colaspase) and the formulations available.

Administer asparaginase (colaspase)
  • via IV infusion over 2 to 4 hours
  • monitor for hypersensitivity reaction
  • flush with 100 mL sodium chloride 0.9%.

Deaccess CVAD.

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.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.
Patient information
  • Ensure patient receives 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 
Bone pain

Bone pain, usually in the lower back or pelvis, associated with G-CSF.
Encephalopathy

Ifosfamide induced encephalopathy has been reported in 10 to 30% of patients receiving high dose ifosfamide. Common symptoms include confusion, ataxia, weakness, seizures, somnolence and hallucinations. Onset may be 2 to 48 hours after commencing treatment. When reversible, symptoms usually resolve within 1 to 3 days.

Read more about ifosfamide-induced encephalopathy
Headache
Haemorrhagic cystitis

An inflammatory process, characterised by diffuse mucosal inflammation with haemorrhage involving the entire bladder. Patients are at risk following treatment with cyclophosphamide, ifosfamide and radiation therapy. 

Read more about haemorrhagic cystitis
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Taste and smell alteration

Read more about taste and smell changes

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
Abdominal pain

Dull ache, cramping or sharp pains are common with some anti-cancer drugs. These are caused by either increased or decreased gastrointestinal motility and can be associated with diarrhoea or constipation.
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Diarrhoea

Read more about treatment induced diarrhoea
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.
Hepatotoxicity

Anti-cancer drugs administered either alone or in combination with other drugs and/or radiation may cause direct or indirect hepatotoxicity. Hepatic dysfunction can alter the metabolism of some drugs resulting in systemic toxicity.
Hyperbilirubinaemia

An abnormal increase in the amount of bilirubin circulating in the blood which may result in jaundice.
Hyperglycaemia

High blood sugar, an excess of glucose in the blood stream.
Hyperlipidaemia and hypercholesterolaemia

Abnormally elevated levels of lipids and cholesterol in the blood.
Hypoalbuminaemia

Abnormally low levels of albumin in the blood.
Hypokalaemia

Abnormally low levels of potassium in the blood.
Nephrotoxicity

Renal dysfunction resulting from damage to the glomeruli, tubules or renal vasculature.
Oral mucositis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, 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
Pancreatitis

Inflammation of the pancreas with impairment of function is associated with asparaginase formulations. 
Photosensitivity

Increased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.
Side effects of corticosteroids

Insomnia, oedema, increased risk of infection e.g. oral thrush, gastric irritation, worsening of peptic ulcer disease, increased blood sugar levels, loss of diabetic control, mood and behavioural changes - including anxiety, euphoria, depression, mood swings, increased appetite and weight gain, osteoporosis and fractures (long term use), bruising and skin fragility are associated with corticosteroid use.
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

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
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) 
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

A search of the literature found limited evidence to support the use of SMILE for the treatment of extranodal natural killer (NK) cell lymphoma. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the 2012 phase II study by Kwong et al.r

Treatment results of extranodal natural killer T-cell (NK/T) lymphoma were historically poor. NK cells express high levels of multi-drug resistant (MDR) p-glycoprotein, so anthracycline-containing regimens are ineffective. L-asparaginase has activity in relapsed and refractory lymphoma. The French GELA and GOELAMS group developed an L-asparaginase containing regimen, AspMetDex (asparaginase (colaspase), methotrexate and dexamethasone). This phase 2 study recruited 19 patients with relapsed or refractory extranodal NK/T lymphoma. The overall response rate (ORR) was 74% after 3 cycles with a 1 year overall survival (OS) of 47%.r

The SMILE regimen incorporates asparaginase (colaspase), etoposide and 3 non– p-glycoprotein dependent drugs (dexamethasone, methotrexate and ifosfamide). SMILE has been studied in a multicentre phase 2 study of 38 patients with stage IV, relapsed or refractory extranodal NK/T patients.r After 2 courses the complete remission (CR) rate was 45%, with an ORR of 79% and 2 year OS of 51%. Longer term follow-up published noted a 3 year OS of 50%. These patients were stringently selected.

The Asia Lymphoma Study group performed a phase 2 multicentre study in a non-trial setting to examine its safety and generalisability in an unselected cohort.r Patients were recruited between March 2005 and February 2012 from 3 centres. 43 patients were newly diagnosed, and 44 were relapsed or refractory. A median of 3 courses of SMILE were administered. After 2 to 3 cycles the ORR was 78%, with a CR of 56%. On treatment completion, the ORR became 81% (CR 66% and partial remission rate (PR) 15%). At a median follow up of 31 months, the 5 year OS was 50% and the 4 year disease-free survival (DFS) was 64%. In this setting, the regimen had significant toxicity with grade III/IV neutropenia in 72.7% and a treatment-related mortality of 7%.

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials
Case series		 Yamaguchi et al. 2011r  Yes Yes Leucovorin 15 mg x 4 on days 2 to 4
Kwong at al. 2012r Yes Yes Leucovorin 45 mg/day on days 2 to 4, mesna 900 mg/m2 days 2 to 4
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN V.1.2021 Yes N/A -
BCCA N/A N/A N/A -
CCO 2019 Yes Yes -

Efficacy

Table 1. Outcome of 87 patients with NK/T-cell lymphoma treated with SMILEr

Treatment and Outcome Nasal Nonnasal Disseminated Overall
Newly diagnosed patients        
No. of patients 29 11 3 43
Median total courses of SMILE (range) 4(0-6) 3(2-6) 2(1-3) 4(0-6)
Regimen-related toxic death (%) 2(7) 1(9) 0 3(7)
Outcome on completion of treatment (%)        
CR 20(69) 4(36) 2(67) 26(60)
PR 5(17) 3(27) 1(33) 9(21)
Nonremission 2(7) 3(27) 0 5(11)
Relapsed/Refractory        
No. of patients 31 10 3 44
Median total courses of SMILE (range) 3(1-6) 3(1-6) 4(3-6) 3(1-60)
Regimen-related toxic death(%) 2(6) 1(10) 0 3(7)
Outcome on completion of treatment (%)        
CR 20(65) 7(70) 2(67) 29(66)
PR 3910) 1(10) 1(33) 5(11)
Nonremission 6(19) 1(10) 0 7(16)

Adapted from © Blood 2012

Table 2. Multivariate analysis of prognostic factors for complete remission and survivals after SMILE therapyr

© Blood 2012

Figure 1. Overall survival and disease-free survival of patients with NK/T-cell lymphoma treated with the SMILE regimenr

© Blood 2012

Toxicityr

Grade III/IV neutropenia occurred in 57 (67%) patients despite G-CSF. Serious infection occurred in 27 (31%), resulting in 5 deaths (6%), though 4 were in the context of refractory lymphoma.

Grade III/IV thrombocytopenia was common in 36 (42%) patients with no deaths. One patient developed acute renal failure after methotrexate administration and required haemodialysis, dying from complications. 6 cases (7%) developed grade III/IV reversible hepatotoxicity.

Minor allergic reactions to asparaginase (colaspase) occurred in 50%. 1 patient developed anaphylaxis requiring resuscitation.

Major adverse effects of SMILE in 87 patients with NK/T-cell lymphomar

© Blood 2012

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Bibliography

Tse, E. and Y. L. Kwong. 2013. "How I treat NK/T-cell lymphomas." Blood 121(25):4997-5005.

Natural killer (NK)/T-cell lymphomas and NK-cell leukemias are aggressive malignancies. Occurring worldwide, they show a predilection for Asian and South American populations. Neoplastic cells are surface CD3-, cytoplasmic CD3epsilon+, CD56+, cytotoxic-molecule positive, Epstein-Barr virus (EBV) positive, with germline T-cell receptor gene. Lymphomas occur commonly in the nasal and upper aerodigestive region. Occasional cases present in the skin, salivary gland, testis, and gastrointestinal tract. Rare cases are disseminated with lymphadenopathy, hepatosplenomegaly, and a leukemic phase. Positron emission tomography computed tomography is useful in staging, as lymphomas are 18-fluorodeoxyglucose avid. Quantification of circulating EBV DNA is an accurate biomarker of tumor load. Nasal NK/T-cell lymphomas present mostly with stage I/II disease. Concomitant/sequential chemotherapy and radiotherapy is standard treatment. Radiotherapy alone is inadequate because of high systemic failure rate. For stage III/IV nasal, nonnasal, and disseminated lymphomas, systemic chemotherapy is indicated. Regimens containing l-asparaginase and drugs unaffected by P-glycoprotein are most effective. Hematopoietic stem cell transplantation (HSCT) is not indicated for early-stage nasal lymphomas. HSCT for lymphomas not in remission has poor results. In advanced-stage nasal, nonnasal, disseminated, or relapsed lymphomas, HSCT may be considered when remission is achieved. Prognostic modeling and EBV DNA monitoring may be useful in risk stratification for HSCT.

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Version 5

Date Summary of changes
22/09/2020 Biosimilar drug added to clinical information. Version number changed to v.5
08/02/2022 PJP prophylaxis clinical information block updated.
30/03/2022 Protocol electronically reviewed by Haematology reference committee for lymphoma RCM 2021. Link to ID 4041 modified SMILE added. Side effects updated. Review period aligned with modified SMILE, for review in 1 year.

Version 4

Date Summary of changes
16/04/2020 'Mesna dosing and administration' block added to clinical information. Version number changed to v.4

Version 3

Date Summary of changes
07/03/2014 New protocol taken to haematology Reference Committee meeting
27/05/2014 Approved and published on eviQ
18/08/2014 Added link to ALLG, ANZCTR and Lymphoma Australia website with statement 'Patients with lymphoma should be considered for inclusion into clinical trials'.
11/09/2015 Reviewed at RCM, no changes, review in 2 years, updated drug costs.

31/05/2017

Transferred to new eviQ website. Version number change to v.3.
25/05/2018 Reviewed by Haematology Reference Committee with no significant changes, review in 2 years.
Treatment schedule changed from 'Cycle 1 to 3' to 'Cycle 1 to 2' to align with eviQ standard of stating the minimum number of cycles which may be given.
25/10/2018 Link added to high dose methotrexate-induced toxicity document in clinical information.
13/09/2019 Reviewed by Haematology Reference Committee, no changes made. Review in 2 years.
10/10/2019 Clinical information updated with PBS expanded indications for G-CSF. 

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/1552

31 Mar 2023