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Non-Hodgkin lymphoma hyper CVAD Part B

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

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.

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Drug Dose Route Day
Methotrexate 200 mg/m2 IV infusion 1
Methotrexate 800 mg/m2 IV infusion 1
Calcium folinate (Leucovorin) 15 mg/m2 every 6 hours * IV infusion 2
Cytarabine (Ara-C) 3,000 mg/m2 TWICE a day ** IV infusion 2 and 3
Pegfilgrastim 6 mg Subcut 4

* Every 6 hours until methotrexate level less than 0.05 micromol/L. Start 36 hours after commencement of methotrexate infusion

** Cytarabine to be reduced to 1000 mg/m2 in patients older than 60 years. 

Cycles:
3 to 4 depending on response.
For mantle cell lymphoma: If CR achieved after 2 cycles (i.e. 1 cycle of Part A and 1 cycle of Part B), then continue for a total of 6 cycles i.e. 3 cycles of Part B (Cycles 2, 4, 6) alternating with 3 cycles of Part A (Cycles 1, 3, 5); if PR achieved after 2 cycles then continue for a total of 8 cycles i.e. 4 cycles of Part B (Cycles 2, 4, 6, 8) alternating with 4 cycles of Part A (Cycles 1, 3, 5, 7).

Commence next cycle on day 21 or when WCC is greater than or equal to 2.0 x 10^9/L and platelets are greater than 60 x 10^9/L, which ever is earlier.
Notes:
  • The eviQ reference committee suggests that when treating patients with lymphoblastic lymphoma refer to the acute lymphoblastic leukaemia Ph- hyper CVAD part A and B/POMP treatment protocol.
  • Calcium folinate (Leucovorin®) must be administered at the precise timings as prescribed; the first dose must be given 36 hours after the commencement of the methotrexate infusion.
  • Methotrexate levels should be monitored at 24 hours after the completion of the methotrexate infusion and daily until the level is less than 0.05 micromol/L.
  • Cease PJP prophylaxis with sulfamethoxazole/trimethoprim at least one day prior to methotrexate infusion and recommence once neutrophils have recovered to greater than 1.0 x 109 /L.
  • Rituximab 
    Addition of rituximab to chemotherapy has been shown to be beneficial in the treatment of mantle cell lymphoma; consideration should be given to including rituximab with each cycle of Hyper CVAD for the treatment of MCL.
Drug status:

Pegfilgrastim: (PBS authority)

All other drugs in this protocol are on the PBS general schedule

Cost:
~ $2,880 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.

Day 1
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Methotrexate 200 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 2 hours
Methotrexate 800 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 22 hours
Day 2
Calcium folinate (Leucovorin) 15 mg/m2 (IV infusion) every 6 hours until methotrexate level less than 0.05 micromol/L. Start 36 hours after commencement of methotrexate infusion.
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 3 hours TWICE a day (every 12 hours) *
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food
Day 3
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 3 hours TWICE a day (every 12 hours) *
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food
Day 4
Pegfilgrastim 6 mg (Subcut) inject subcutaneously at least 24 hours after chemotherapy
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 4 and 5 may not be required and may be reduced or omitted at the clinician's discretion. **
Day 5
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 4 and 5 may not be required and may be reduced or omitted at the clinician's discretion. **

* Cytarabine to be reduced to 1000 mg/m2 in patients older than 60 years. 

** Link to ID 7 Prevention of chemotherapy induced nausea and vomiting

Cycles:
3 to 4 depending on response.
For mantle cell lymphoma: If CR achieved after 2 cycles (i.e. 1 cycle of Part A and 1 cycle of Part B), then continue for a total of 6 cycles i.e. 3 cycles of Part B (Cycles 2, 4, 6) alternating with 3 cycles of Part A (Cycles 1, 3, 5); if PR achieved after 2 cycles then continue for a total of 8 cycles i.e. 4 cycles of Part B (Cycles 2, 4, 6, 8) alternating with 4 cycles of Part A (Cycles 1, 3, 5, 7).

Commence next cycle on day 21 or when WCC is greater than or equal to 2.0 x 10^9/L and platelets are greater than 60 x 10^9/L, which ever is earlier.
Drug Dose Route Day
Methotrexate 200 mg/m2 IV infusion 1
Methotrexate 800 mg/m2 IV infusion 1
Calcium folinate (Leucovorin) 15 mg/m2 every 6 hours * IV infusion 2
Cytarabine (Ara-C) 3,000 mg/m2 TWICE a day ** IV infusion 2 and 3
Pegfilgrastim 6 mg Subcut 4

* Every 6 hours until methotrexate level less than 0.05 micromol/L. Start 36 hours after commencement of methotrexate infusion

** Cytarabine to be reduced to 1000 mg/m2 in patients older than 60 years. 

Cycles:
3 to 4 depending on response.
For mantle cell lymphoma: If CR achieved after 2 cycles (i.e. 1 cycle of Part A and 1 cycle of Part B), then continue for a total of 6 cycles i.e. 3 cycles of Part B (Cycles 2, 4, 6) alternating with 3 cycles of Part A (Cycles 1, 3, 5); if PR achieved after 2 cycles then continue for a total of 8 cycles i.e. 4 cycles of Part B (Cycles 2, 4, 6, 8) alternating with 4 cycles of Part A (Cycles 1, 3, 5, 7).

Commence next cycle on day 21 or when WCC is greater than or equal to 2.0 x 10^9/L and platelets are greater than 60 x 10^9/L, which ever is earlier.
Notes:
  • The eviQ reference committee suggests that when treating patients with lymphoblastic lymphoma refer to the acute lymphoblastic leukaemia Ph- hyper CVAD part A and B/POMP treatment protocol.
  • Calcium folinate (Leucovorin®) must be administered at the precise timings as prescribed; the first dose must be given 36 hours after the commencement of the methotrexate infusion.
  • Methotrexate levels should be monitored at 24 hours after the completion of the methotrexate infusion and daily until the level is less than 0.05 micromol/L.
  • Cease PJP prophylaxis with sulfamethoxazole/trimethoprim at least one day prior to methotrexate infusion and recommence once neutrophils have recovered to greater than 1.0 x 109 /L.
  • Rituximab 
    Addition of rituximab to chemotherapy has been shown to be beneficial in the treatment of mantle cell lymphoma; consideration should be given to including rituximab with each cycle of Hyper CVAD for the treatment of MCL.
Drug status:

Pegfilgrastim: (PBS authority)

All other drugs in this protocol are on the PBS general schedule

Cost:
~ $2,880 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.

Day 1
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Methotrexate 200 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 2 hours
Methotrexate 800 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 22 hours
Day 2
Calcium folinate (Leucovorin) 15 mg/m2 (IV infusion) every 6 hours until methotrexate level less than 0.05 micromol/L. Start 36 hours after commencement of methotrexate infusion.
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 3 hours TWICE a day (every 12 hours) *
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food
Day 3
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 3 hours TWICE a day (every 12 hours) *
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food
Day 4
Pegfilgrastim 6 mg (Subcut) inject subcutaneously at least 24 hours after chemotherapy
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 4 and 5 may not be required and may be reduced or omitted at the clinician's discretion. **
Day 5
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 4 and 5 may not be required and may be reduced or omitted at the clinician's discretion. **

* Cytarabine to be reduced to 1000 mg/m2 in patients older than 60 years. 

** Link to ID 7 Prevention of chemotherapy induced nausea and vomiting

Cycles:
3 to 4 depending on response.
For mantle cell lymphoma: If CR achieved after 2 cycles (i.e. 1 cycle of Part A and 1 cycle of Part B), then continue for a total of 6 cycles i.e. 3 cycles of Part B (Cycles 2, 4, 6) alternating with 3 cycles of Part A (Cycles 1, 3, 5); if PR achieved after 2 cycles then continue for a total of 8 cycles i.e. 4 cycles of Part B (Cycles 2, 4, 6, 8) alternating with 4 cycles of Part A (Cycles 1, 3, 5, 7).

Commence next cycle on day 21 or when WCC is greater than or equal to 2.0 x 10^9/L and platelets are greater than 60 x 10^9/L, which ever is earlier.

Indications:

  • Mantle cell lymphoma (MCL)
  • Aggressive non-Hodgkin lymphoma (NHL)

Caution:

  • This is an aggressive regimen; caution is advised in patients older than 60 years of age.
Venous access

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

Read more about central venous access device line selection
Emetogenicity MODERATE

Suggested default antiemetics have been added to the treatment schedule, and may be substituted to reflect institutional policy.

For patients with a prior episode of chemotherapy induced nausea or vomiting, a NK1 receptor antagonist is available on the PBS in combination with a 5HT3 antagonist and steroid.

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.
Cytarabine induced neurotoxicity

This may occur in patients treated with high dose cytarabine. Assess cerebellar function prior to each cytarabine dose.

Read more about neurotoxicity associated with high dose cytarabine and access the cytarabine cerebellar neurotoxicity assessment chart  
Ocular toxicities

Administer corticosteroid eye drops to minimise corneal toxicity from high dose cytarabine. Commence on the day of first dose of cytarabine and continue for at least 72 hours after completion of final cytarabine dose.

Read more about ocular toxicities associated with high dose cytarabine
Cytarabine syndrome

Treatment with cytarabine may cause a "cytarabine syndrome" characterised by flu-like symptoms, skin rash and occasionally chest pain.
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

Patients are at high risk of developing tumour lysis syndrome, prophylaxis is recommended.

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

­

Read more about prophylaxis of pneumocystis jiroveci (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 tests

FBC, EUC, LFTs, LDH at baseline, prior to each treatment and regularly throughout treatment. Methotrexate levels to be monitored every 24 hours until level is less than 0.05 µ/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
Commence next cycle on day 21 or when WCC is greater than or equal to 2 x 109/L and platelets are greater than 60 x 109/L, whichever is earlier.
Subsequent courses are given either on day 21 or when the total WCC is greater than or equal to 2.0 x 109/L and platelets are greater than 60 x 109/L, whichever is earlier.
Renal impairment
Creatinine clearance (mL/min)
10 to 50 Reduce methotrexate by 50%
less than 10 Contraindicated

Cytarabine to be reduced to 1000 mg/m2 in patients over 60 years

Note: an increased risk of neurotoxicity has been associated with high dose cytarabine when creatinine clearance is less than 60 mL/min

Hepatic impairment
Hepatic dysfunction
Mild No dose modifications necessary
Moderate No dose modifications necessary
Severe Reduce methotrexate by 25%
Mucositis, stomatitis and diarrhoea
Grade 3 or Grade 4 Diarrhoea and ulcerative stomatitis require interruption of therapy otherwise, hemorrhagic enteritis and death from intestinal perforation may occur; reduce methotrexate by 25%

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:  

Cytarabine
No specific clinically significant drug-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 treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Prime IV line(s).

Access CVAD.

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Commence corticosteroid eye drops prior to the first dose of cytarabine.

Methotrexate 

Prehydration:
  • administer 100 mL sodium bicarbonate 8.4% in 1000 mL glucose 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.

Note: A large volume of intravenous fluid is 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 is present review by medical officer (diuretics may be required).

First dose of methotrexate
  • administer via IV infusion over 2 hours
  • the starting time of the methotrexate infusion must be documented as the calcium folinate (leucovorin) rescue is to commence exactly 36 hours after the commencement of the methotrexate and continue until the methotrexate level is less than 0.05  micromol/L.
Second dose of methotrexate (to commence immediately after the first dose):
  • administer via  IV infusion over 22 hours
  • flush with ~50 mL of sodium chloride 0.9%
  • Stop the methotrexate infusion after 22 hours even if the infusion is not completed
​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)

Day 2

General patient assessment prior to each treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

  • continue daily weight
  • continue to monitor pH on all urine output
  • strict fluid balance input and output
  • continue corticosteroid eye drops as prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Cytarabine

Prior to administration:

Ensure corticosteroid eye drops have been administered before starting cytarabine. Please see ocular toxicities associated with high dose cytarabine for more information. 

Verify that cytarabine neurological assessment has been performed prior to administration of cytarabine:

  • if the patient scores 0 then administer cytarabine as charted
  • if the patient scores 1 or above, do not administer the cytarabine and immediately notify medical officer.
Administer cytarabine:
  • via IV infusion over 3 hours
  • flush with ~50 mL of sodium chloride 0.9%.
Administer second dose of cytarabine 12 hours after first dose.

Calcium Folinate (Leucovorin)

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

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

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

Day 3

General patient assessment prior to each treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

  • continue daily weight
  • continue to monitor pH on all urine output
  • strict fluid balance input and output
  • continue corticosteroid eye drops as prescribed

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Continue corticosteroid eye drops.

Note: Continue to administer calcium folinate (leucovorin) every 6 hours until methotrexate level is less than 0.05 micromol/L.

Cytarabine 

Prior to administration:

Verify that cytarabine neurological assessment has been performed prior to administration of cytarabine:

  • if the patient scores 0 then administer cytarabine as charted
  • if the patient scores 1 or above, do not administer the cytarabine and immediately notify medical officer.
Administer cytarabine:
  • via IV infusion over 3 hours
  • flush with ~50 mL of sodium chloride 0.9%.
Administer second dose of cytarabine 12 hours after first dose.

Deaccess CVAD.

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

Day 4

Continue corticosteroid eye drops for 72 hours after completion of the last dose of cytarabine.

Pegfilgrastim

  •  administer subcutaneously at least 24 hours post chemotherapy.

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Corticosteroid eye drops
  • Continue corticosteroid eye drops for at least 72 hours after completion of final cytarabine dose.
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 
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Bone pain

Bone pain, usually in the lower back or pelvis, associated with G-CSF.
Cytarabine (Ara-C) syndrome

Flu-like symptoms including fever, myalgia and malaise can occur 6 to 12 hours after cytarabine administration. Symptoms generally resolve within 24 hours of completing therapy.
Headache
Neurotoxicity

High dose cytarabine has been associated with acute cerebellar syndrome and diffuse cerebral dysfunction.

Read more about neurotoxicity associated with high dose cytarabine
Ocular toxicities

Reversible corneal toxicity (keratitis), haemorrhagic conjunctivitis, vision loss and other ocular side effects can occur with high dose cytarabine.  Corticosteroid eye drops must be administered concurrently with treatment. 

Read more about ocular toxicities associated with cytarabine
Taste and smell alteration

Read more about taste and smell changes

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 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
Diarrhoea

Read more about treatment induced diarrhoea
Fatigue

Read more about fatigue
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
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
Peripheral neuropathy

Typically symmetrical sensory neuropathy, affecting the fingers and toes, sometimes progressing to the hands and feet.  It is associated with several classes of anti-cancer drugs. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

Read more about peripheral neuropathy

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
Anaemia

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

Read more about anaemia

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

The following evidence pertains to the use of Hyper-CVAD in mantle cell lymphoma. Specific evidence is not cited for use in other aggressive lymphomas, and use of Hyper-CVAD will be at the physician's discretion in most cases.

Hyper-CVAD alternating with methotrexate and cytarabine is an aggressive chemotherapy regimen which has proven effective in patients with aggressive histopathological variants of mantle cell lymphoma (MCL). The evidence for this regimen in the treatment of MCL comes from three prospective trials:

  1. Khouri et alr reported a prospective phase II trial that included 45 patients aged 65 years or younger, with newly diagnosed or previously treated MCL evaluating Hyper-CVAD followed by autologous or allogeneic HCT. Complete response (CR) after four cycles of Hyper-CVAD was reported at 38%, while partial response (PR) was reported at 55.5%.
  2. Romaguera et alrr reported a prospective open-label phase II trial of six cycles of Hyper-CVAD plus rituximab in newly diagnosed MCL. Of the 97 assessable patients (aged 41-80 years; median age 61 years), 87% achieved CR or unconfirmed CR. No patients went on to receive HCT. At a median follow-up of 40 months, three-year failure-free survival was 64% and overall survival was 82%. In a subsequently published Short Report in 2010, at 10 years of follow up (median of 8 years), the median overall survival for all patients had not been reached and the time to treatment failure was 4.6 years. On subset analysis, patients 65 years or younger had significantly higher rates of overall survival at eight years (68 versus 33 percent) when compared with older patients.
  3. Merli et alr reported a prospective, multicentre trial of 8 cycles of Hyper-CVAD plus rituximab in 63 patients with newly diagnosed MCL. The overall response and complete response rates were 83% and 72% respectively. After a median follow up of 46 months the estimated 5 years overall survival and progression-free survival rates were 73% and 61% respectively. However, this study reported significant toxicity with only 37% of patients completing the full 8 cycles and 3 patients died during therapy.

The addition of rituximab to chemotherapy has shown to be beneficial with a 2007 meta-analysisr of rituximab plus chemotherapy for patients with indolent NHL or MCL finding those treated with rituximab plus chemotherapy had superior overall survival, response and disease control than those that were treated with chemotherapy alone. However, only three small studies for MCL were available for inclusion. Consideration should be given to the addition of rituximab to each cycle of Hyper-CVAD.

Efficacy

Overall survival r

© Journal of Clinical Oncology 2005

Toxicity

© Journal of Clinical Oncology 2005

© Journal of Clinical Oncology 2005

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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
24/01/2022 Pulmonary toxicity added to side effects.

Version 4

Date Summary of changes
20/04/2007 Reformatting and minor editing
28/05/2008 Renaming cycles 1, 3, 5 and 7 as part A and cycles 2, 4, 6 and 8 as part B as requested in feedback
06/11/2008 Revision and reformatting of patient sheet
08/09/2009 Reviewed and transferred to eviQ
21/03/2011 New format to allow for export of protocol information.
Protocol version number changed to V.2.
Antiemetics and premedications added to the treatment schedule.
Additional Clinical Information, Key Prescribing table and Key Administration table combined into new section titled Clinical Considerations.
Drug specific information placed behind the drug name link.
19/08/2011 Review at Reference Committee meeting (RCM)
23/11/2011 Removal of methylprednisolone from treatment schedule as was not included in original published papers for NHL (Khouri et al 1998 and Thomas et al 2004).
16/11/2012 Addition of further administration instructions for calcium leucovorin to the treatment schedule summary
21/11/2012

Protocol updates included and protocol republished:

  • frequency and cycle numbers for LBL and MCL amended as per RCM
  • CNS prophylaxis link added as per RCM
  • addition of statement regarding use of rituximab
  • inclusion of CNS prophylaxis link per RCM
  • evidence section rewritten with addition updated references - Romaguera et al 2010 and Merli et al 2012
  • addition of links to POMP and Part A protocols
11/09/2015

Protocol updates included and protocol republished:

  • frequency and cycle numbers for LBL deleted as per RCM
  • added link to Hyper CVAD overview for Lymphoblastic Leukaemia as per RCM
  • added note under drug schedule suggesting that patients being treatment for Lymphoblatic Lymphoma should use the Hyper CVAD Lymphoblastic Leukaemia protocol
  • removed Lymphoblastic Lymphoma from the indications
  • removed link to POMP maintenance as per RCM
  • removed the paragraph on Lymphoblastic Lymphoma from the evidence and efficacy section (added to the protocol Lymphoblastic Leukaemia ID:788)
  • removed Cortelazzo et al 2011 and Thomas et al 2004 from the reference list
10/11/2016 Peripheral neuropathy dose modification removed.
31/05/2017

Transferred to new eviQ website. Version number change to V.4.
25/05/2018 Reviewed by Haematology Reference Committee with no significant changes, review in 2 years
25/06/2018 Antiemetics updated to be in line with international guidelines. Note to dexamethasone added.
25/10/2018 Link added to high dose methotrexate-induced toxicity document in clinical information.
10/10/2019  Clinical information updated with PBS expanded indications for G-CSF. 
27/03/2020 Reviewed by Haematology Reference Committee with no changes, review in 2 years

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/225

31 Mar 2023