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Mantle cell lymphoma R-HiDAC (rituximab and cytarabine)

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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Cycle 2 and 4

Drug Dose Route Day
Rituximab 375 mg/m2 IV infusion * 1
Cytarabine (Ara-C) 3,000 mg/m2 TWICE a day (2000 mg/m2 TWICE a day if greater than 60 years) IV infusion 1 and 2

Cycle 6

Drug Dose Route Day
Rituximab 375 mg/m2 IV infusion * 1 and 9
Cytarabine (Ara-C) 3,000 mg/m2 TWICE a day (2000 mg/m2 TWICE a day if greater than 60 years) IV infusion 1 and 2
Filgrastim 10 micrograms/kg in divided doses for PBSC mobilisation Subcut 3 and continue daily until stem cells have been harvested

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

Frequency:
21 days 
Cycles:
3. Alternate R-maxi-CHOP (cycles 1, 3, 5) with R-HiDAC (cycles 2, 4, 6) every 3 weeks.
Notes:
  • CT staging after cycle 4 (i.e after 2 cycles of maxi-CHOP and 2 cycles of HiDAC) to assess response.
  • Stem cell harvesting to commence post cycle 6 (i.e. post final dose of high dose cytarabine).
  • Rituximab is given on day 9, cycle 6 post HiDAC as part of the in vivo purging prior to stem cell harvest.
  • Only patients that have shown an adequate response after 4 cycles of chemotherapy (greater than or equal to 50% reduction in disease) should be considered for autologous transplant.
  • Post cycle 2 and 4, consider the use of G-CSF 24 hours after last dose of chemotherapy for secondary prophylaxis or consider primary prophylaxis as per institution until recovery.
Drug status:

Rituximab SC: TGA registered but not PBS listed.

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

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 2 and 4

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Dexamethasone 8 mg (PO) ONCE a day 60 minutes before treatment, with or after food.
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day. Each dose to be 12 hours apart (4 doses in total).
Day 2
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day. Each dose to be 12 hours apart (4 doses in total).
Day 3
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 3 may not be required and may be reduced or omitted at the clinician's discretion. **

Cycle 6

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Dexamethasone 8 mg (PO) ONCE a day 60 minutes before treatment, with or after food.
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day. Each dose to be 12 hours apart (4 doses in total).
Day 2
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day. Each dose to be 12 hours apart (4 doses in total).
Day 3
Filgrastim 10 micrograms/kg (Subcut) inject subcutaneously in divided doses (morning and evening) until stem cells have been harvested
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 3 may not be required and may be reduced or omitted at the clinician's discretion. **
Day 9
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

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

Frequency:
21 days 
Cycles:
3. Alternate R-maxi-CHOP (cycles 1, 3, 5) with R-HiDAC (cycles 2, 4, 6) every 3 weeks.

Cycle 2 and 4

Drug Dose Route Day
Rituximab 375 mg/m2 IV infusion * 1
Cytarabine (Ara-C) 3,000 mg/m2 TWICE a day (2000 mg/m2 TWICE a day if greater than 60 years) IV infusion 1 and 2

Cycle 6

Drug Dose Route Day
Rituximab 375 mg/m2 IV infusion * 1 and 9
Cytarabine (Ara-C) 3,000 mg/m2 TWICE a day (2000 mg/m2 TWICE a day if greater than 60 years) IV infusion 1 and 2
Filgrastim 10 micrograms/kg in divided doses for PBSC mobilisation Subcut 3 and continue daily until stem cells have been harvested

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

Frequency:
21 days 
Cycles:
3. Alternate R-maxi-CHOP (cycles 1, 3, 5) with R-HiDAC (cycles 2, 4, 6) every 3 weeks.
Notes:
  • CT staging after cycle 4 (i.e after 2 cycles of maxi-CHOP and 2 cycles of HiDAC) to assess response.
  • Stem cell harvesting to commence post cycle 6 (i.e. post final dose of high dose cytarabine).
  • Rituximab is given on day 9, cycle 6 post HiDAC as part of the in vivo purging prior to stem cell harvest.
  • Only patients that have shown an adequate response after 4 cycles of chemotherapy (greater than or equal to 50% reduction in disease) should be considered for autologous transplant.
  • Post cycle 2 and 4, consider the use of G-CSF 24 hours after last dose of chemotherapy for secondary prophylaxis or consider primary prophylaxis as per institution until recovery.
Drug status:

Rituximab SC: TGA registered but not PBS listed.

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

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 2 and 4

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Dexamethasone 8 mg (PO) ONCE a day 60 minutes before treatment, with or after food.
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day. Each dose to be 12 hours apart (4 doses in total).
Day 2
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day. Each dose to be 12 hours apart (4 doses in total).
Day 3
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 3 may not be required and may be reduced or omitted at the clinician's discretion. **

Cycle 6

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Dexamethasone 8 mg (PO) ONCE a day 60 minutes before treatment, with or after food.
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day. Each dose to be 12 hours apart (4 doses in total).
Day 2
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day. Each dose to be 12 hours apart (4 doses in total).
Day 3
Filgrastim 10 micrograms/kg (Subcut) inject subcutaneously in divided doses (morning and evening) until stem cells have been harvested
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 3 may not be required and may be reduced or omitted at the clinician's discretion. **
Day 9
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

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

Frequency:
21 days 
Cycles:
3. Alternate R-maxi-CHOP (cycles 1, 3, 5) with R-HiDAC (cycles 2, 4, 6) every 3 weeks.
  • Previously untreated mantle cell lymphoma (stage II-IV), with intention to proceed to autologous stem cell transplantation
  • This is a highly intensive protocol and therefore patient fitness is crucial prior to commencing this regimen.
Venous access required

IV cannula (IVC) or 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 rituximab.
Premedication

The product information states that premedication is required for this treatment.

Please refer to the treatment schedule for suggested premedication regimen. This may be substituted to reflect institutional policy.
Emetogenicity MODERATE

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

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
Subcutaneous rituximab

Please note that subcutaneous rituximab is no longer subsidised by the Pharmaceutical Benefit Scheme and is currently unavailable in Australia.

All patients must always receive their first dose of rituximab by intravenous administration. Subcutaneous (SC) rituximab must only be given at the second or subsequent doses. From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. If patient was not able to receive one full rituximab intravenous infusion dose, they should continue the subsequent dose with intravenous rituximab until a full IV dose is successfully administered.

Premedication consisting of an analgesic/antipyretic and an antihistamine should always be administered before each dose of rituximab SC. Premedication with glucocorticoids should also be considered, particularly if rituximab SC is not given in combination with steroid-containing chemotherapy.

 Read more about Non-Hodgkin lymphoma subcutaneous rituximab 
Rituximab rapid infusion

This regimen is not in line with the product monograph, however published literature indicates that it can be completed safely.

Read more about the rapid infusion of rituximab
Progressive multifocal leukoencephalopathy

Use of monoclonal antibodies may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal opportunistic viral infection of the brain. Patients must be monitored for any new or worsening neurological symptoms.

Read more about progressive multifocal leukoencephalopathy and the Therapeutic Goods Administration Medicines Safety update on progressive multifocal leukoencephalopathy from the Australian Government, Department of Health.
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.
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

Read more about 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.
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
Biosimilar drug

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

FBC, EUC, LFTs and LDH at baseline, and prior to each cycle and as clinically indicated.
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
Dose reductions for haematological toxicity not usually recommended. Discuss with Haematologist.
Renal impairment
Creatinine clearance (mL/min)
less than 60 Increased risk of neurotoxicity has been associated with high dose cytarabine
Hepatic impairment
Hepatic dysfunction
Moderate to severe Consider reducing cytarabine by 50%
Age older than 60 years
Reduce cytarabine dose to 2000 mg/m2 TWICE a dayr

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
Rituximab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to the rituximab infusion
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 dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Hydration if prescribed

Rituximab

Prior to administration:
  • check baseline observations
  • check for previous adverse events during previous infusions
  • verify premedication has been taken. If not, administer 30 to 60 minutes prior to rituximab administration:
    • paracetamol 1000 mg orally AND
    • loratadine 10 mg orally (or similar antihistamine)
    • a steroid may also be included as a premed according to local guidelines
Initial infusion:
  • commence rituximab infusion at 50 mg/hr for 30 minutes
  • repeat observations prior to each rate increase
  • increase rate by 50 mg/hr every 30 minutes, up to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have completely resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Transient hypotension may occur. Consider withholding antihypertensive medication for 12 hours before and during infusion.

Subsequent infusions:

If an adverse event was experienced with initial infusion recommence infusion at the same rate as initial infusion

  • commence rituximab infusion at 100 mg/hr
  • repeat observations prior to each rate increase
  • increase rate by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Read more about rapid infusion rituximab

Read more about subcutaneous rituximab

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.

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

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

Day 2

General patient assessment prior to each day of treatment.

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Hydration if prescribed

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.

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

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

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
  • Post cycle 2 and 4, arrangements for administration until neutrophil recovery (if prescribed).
  • Post cycle 6, arrangements for administration and detailed instructions of when to present for blood tests/monitoring.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) e.g. PJP prophylaxis, antifungals, antivirals.
Patient information
  • Ensure patient receives patient information sheet.

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).

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Hydration if prescribed

Rituximab

Prior to administration:
  • check baseline observations
  • check for previous adverse events during previous infusions
  • verify premedication has been taken. If not, administer 30 to 60 minutes prior to rituximab administration:
    • paracetamol 1000 mg orally AND
    • loratadine 10 mg orally (or similar antihistamine)
    • a steroid may also be included as a premed according to local guidelines
Initial infusion:
  • commence rituximab infusion at 50 mg/hr for 30 minutes
  • repeat observations prior to each rate increase
  • increase rate by 50 mg/hr every 30 minutes, up to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have completely resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Transient hypotension may occur. Consider withholding antihypertensive medication for 12 hours before and during infusion.

Subsequent infusions:

If an adverse event was experienced with initial infusion recommence infusion at the same rate as initial infusion

  • commence rituximab infusion at 100 mg/hr
  • repeat observations prior to each rate increase
  • increase rate by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Read more about rapid infusion rituximab

Read more about subcutaneous rituximab

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.

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

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

Day 2

General patient assessment prior to each day of treatment.

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Hydration if 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.

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

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

Day 3

Filgrastim

Growth factor administration cycle 6:
  • filgrastim is to be administered commencing on day 3 of cycle 6 via subcutaneous injection in divided doses (morning and evening) until stem cells have been harvested
  • it should be clearly documented and communicated to the persons responsible for monitoring the CD34+ counts and notifying the patient and all other appropriate healthcare professionals when collection is anticipated.
  • arrangements regarding leukapheresis are usually made by the BMT Coordinator or designated nurse.

Day 9

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).

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Hydration if prescribed

Rituximab

Prior to administration:
  • check baseline observations
  • check for previous adverse events during previous infusions
  • verify premedication has been taken. If not, administer 30 to 60 minutes prior to rituximab administration:
    • paracetamol 1000 mg orally AND
    • loratadine 10 mg orally (or similar antihistamine)
    • a steroid may also be included as a premed according to local guidelines
Initial infusion:
  • commence rituximab infusion at 50 mg/hr for 30 minutes
  • repeat observations prior to each rate increase
  • increase rate by 50 mg/hr every 30 minutes, up to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have completely resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Transient hypotension may occur. Consider withholding antihypertensive medication for 12 hours before and during infusion.

Subsequent infusions:

If an adverse event was experienced with initial infusion recommence infusion at the same rate as initial infusion

  • commence rituximab infusion at 100 mg/hr
  • repeat observations prior to each rate increase
  • increase rate by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Read more about rapid infusion rituximab

Read more about subcutaneous rituximab

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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
  • Post cycle 2 and 4, arrangements for administration until neutrophil recovery (if prescribed).
  • Post cycle 6, arrangements for administration and detailed instructions of when to present for blood tests/monitoring.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) e.g. 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)
Bone pain

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

Symptoms include fever, chills, rigors, diaphoresis, malaise, myalgia, arthralgia, loss of appetite, dry cough and headache.
Headache
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
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Neurotoxicity

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

Read more about neurotoxicity associated with high dose cytarabine
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
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.

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
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
Palmar-plantar erythrodysaesthesia (PPE) - hand-foot syndrome (HFS)

Bilateral erythema, tenderness, pain, swelling, tingling, numbness, pruritus, dry rash, or moist desquamation and ulceration of the palms and soles. It is also known as hand-foot syndrome (HFS). Symptoms appear to be dose dependent and palms are affected more than soles.

Read more about hand-foot syndrome associated with chemotherapy
Diarrhoea

Read more about treatment induced diarrhoea
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
Injection-site reaction

Inflammation of or damage to the tissue surrounding the area where a drug was injected.

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) 
Anaemia

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

Read more about anaemia
Progressive multifocal leukoencephalopathy (PML)

A rare opportunistic viral infection of the brain, usually leading to death or severe disability, can occur with monoclonal antibodies (e.g. rituximab, obinutuzumab, ofatumumab, brentuximab vedotin) and other targeted therapies (e.g. ibrutinib, ruxolitinib, idelalisib). Onset may occur up to months after the final dose.  

Read more about progressive multifocal leukoencephalopathy (PML)

Mantle cell lymphoma represents 3-10% of non-Hodgkin's lymphomas. It has been considered incurable with standard chemotherapy. However, in recent years the overall survival for mantle cell lymphoma has improved. The optimal treatment approach is contentious. The respective roles of watchful waiting, chemo-immunotherapy alone or followed by consolidation with autologous stem cell transplantation is beyond the scope of this document.

The Nordic MCL 2 study was a prospective multi centre study performed by the Nordic Lymphoma group. It enrolled 160 untreated patients with mantle cell lymphoma under the age of 66 between 2000 and 2006. MCL 2 followed on from the MCL 1 study, which originally used four cycles of maxi-CHOP followed by BEAM or BEAC autograft for newly diagnosed mantle cell lymphoma. The results of MCL 1 were disappointing with an 18% EFS at 4 years. The MCL 2 study incorporated rituximab and alternated three cycles of maxi-CHOP with 3 cycles of high dose cytarabine prior to transplant, with results compared to the historical controls from the MCL 1 study. Importantly MCL 2 also allowed for pre-emptive treatment at molecular relapse post transplant with up to 4 doses of single agent rituximab, which was received by 26 patients. Nevertheless the MCL 2 study resulted in a significant improvement in EFS of 63% and OS of 81% at 4 years.r

The data from the MCL 2 study continues to mature. The 15 year follow up of the MCL 2 study continued to show impressive results, with mean OS and PFS being 12.7 and 8.5 years across all patient groups overall on an intent to treat basis. High risk patients on the basis of MIPI score did significantly worse, with OS and PFS of 4 and 2.5 years respectively. Disappointingly even in low and medium risk patients with long durations of response, survival curves never appear to have plateaued, emphasizing the ongoing risk of late relapse despite intensive therapy.r

The majority of patients received only 4 doses of rituximab. This appeared to be adequate in terms of providing in vivo purging of the stem cell product. There was no difference in EFS between 4 and 6 doses of rituximab.r

Treatment with the MCL2 study protocol should be undertaken with the view to autologous transplantation in CR1 or PR1 after 6 cycles of chemo-immunotherapy. Further chemo-immunotherapy beyond cycle 6 was undertaken in some patients pending transplant. This was associated with increased cardiotoxicity and as such should be avoided if possible.rr

Alternative induction chemotherapy prior to autograft with BEAM or TBI based conditioning have also been described. Dreyling et al conducted the only randomised control trial of autologous transplant in mantle cell lymphoma. This compared CHOP followed by interferon or autologous transplant. This showed improved PFS but not OS at 3 years with TBI/Cyclophosphamide autograft following CHOP chemotherapy and Dexa-BEAM to mobilise stem cells.r

Since the publication of the MCL2 data, a variety of alternative induction therapies incorporating cytarabine have been published. Two of these have used either sequential or alternating R-CHOP and R-DHAP followed by TBI based conditioning. This approach resulted in EFS of 84 and 88 months.rr The 5 year OS was 75% with the sequential approach.r A third trial utilised 4 cycles of R-DHAP (or R-DHAC at the investigators choice) followed by R-BEAM and autologous transplant in patients with a PR. Patients were then randomized to maintenance rituximab every 2 months for 18 doses or placebo. Rates of OS and PFS at 4 years in the maintenance group were 89% and 83% respectively, whilst in the observation group they were 80% and 64%. These studies have highlighted the activity of cytarabine in the treatment of mantle cell lymphoma. It should be noted the Nordic MCL 5 study using single agent cytarabine as induction was prematurely terminated due to lack of response.r 

Khouri et al conducted TBI/Cyclophosphamide autograft following hyperCVAD + Methotrexate/cytarabine induction. Obtaining 5yr OS and DFS of 77% and 43% respectively.r

Romaguera reported impressive results with Rituximab-HyperCVAD+ Methotrexate/Cytarabine with 87% achieving CR/Cru, without autologous transplant. The 10 year survival was 64% and failure free survival 52%. These results are very similar to the 10 year follow up of the MCL 2 study. However, the multi centre SWOG 0213 using Rituximab hyper CVAD+ Methotrexate Cytarabine was less impressive with a median survival of 6.8 years after 4.8 years of follow up.rr

Efficacy

Survival

Updated follow-up for the Nordic MCL 2 trial (A) Overall survival (OS), (B) progression-free survival (PFS) and (C) cumulative incidence of relapse (CIR) after an intent-to-treat principle.r

© British Journal of Haematology 2016

Overall survival and progression free survival according to prognostic scores. (A, B) Mantle Cell Lymphoma International Prognostic Index (MIPI), (C, D) biological MIPI including Ki-67 expression (MIPI-B) and (E, F) MIPI algorithm including miR-18b expression (MIPI-B-miR).r

© British Journal of Haematology 2016

Overall survival and time to failure in 97 patients treated with R-hyperCVAD alternating with R- methotrexate-cytarabiner

© British Journal of Haematology 2010

Reports of trials for untreated MCL including more than 20 patients.r

© British Journal of Haematology 2010

Toxicity

The hospitalisation rate for grade 3 or 4 toxicities was 17% with maxi-CHOP and 12% with cytarabine. The majority of these, 80%, were due to febrile neutropenia. 15 patients failed to proceed to high dose therapy; 5 due to toxicity, 4 due to failed mobilisation and 6 for unresponsive disease. There were 8 deaths due to non relapse mortality. 4 occurred during high dose therapy (1 graft failure, 3 infectious). 4 later deaths; 3 from cardiac failure and one PE.r

This compares favourably with the toxicity of R hyper CVAD + Methotrexate/Cytarabine in which up to 29% patients had sufficient toxicity to stop therapy. This compares with 3% in the MCL2 study.r

At 15 year follow-up there had been identified 15 cases of solid organ malignancies (excluding non-melanoma skin cancers) and 5 cases of haematological malignancies (3 myelodysplastic syndromes and 2 cases of AML).r

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Version 5

Date Summary of changes
09/03/2020 Biosimilar rituximab added to clinical information. Version number changed to V.5    
01/10/2021 Drug status updated: rituximab SC is TGA registered but no longer PBS listed.

Version 4

Date Summary of changes
02/09/2011 New protocol taken to BMT Reference Committee meeting.
21/10/2011 Approved and published on eviQ.
13/12/2011 PHC role permission created.
29/05/2015

Protocol reviewed:
- changed emetogenicity preclin from multiday to moderate.
- ondansetron changed to palonosetron and prednisolone changed to hydrocortisone in treatment schedule.
- evidence updated.
21/01/2016 Reviewed at BMT Chairs Meeting: No change, review in 2 years.
31/05/2017 Transferred to new eviQ website. Version number change to V.3.
13/03/2018

Added:

  • Link to subcutaneous​ rituximab document underneath the treatment schedule.
  • Clinical information block on subcutaneous rituximab
  • Link to the subcutaneous rituximab document into administration section
  • Injection-site reaction side effect
  • Note about subcutaneous rituximab to the patient information
  • Version number changed to V.4.
25/06/2018 Antiemetics updated to be in line with international guidelines. Note to dexamethasone added.
19/07/2018

Protocol reviewed and presented at the May 2018 eviQ Lymphoma and CLL Reference Committee meeting. Discussion continued over email and document approved for publication with the following changes: 

  • Evidence section updated 
  • To be reviewed in 2 years 
13/03/2019 Reviewed by Haematology Reference Committee, no changes made. Review in 5 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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31 Mar 2023