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Non-Hodgkin lymphoma R-DHAOx (rituximab dexamethasone cytarabine oxaliplatin)

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.

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Cycle 1 and 2

Drug Dose Route Day
Dexamethasone 40 mg ONCE a day IV/PO 1 to 4
Rituximab 375 mg/m2 IV infusion * 1
Oxaliplatin 130 mg/m2 IV infusion 1
Cytarabine (Ara-C) 2,000 mg/m2 IV infusion 2 and 3 **

* 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.

** Cytarabine may be administered TWICE daily on day 2 (12 hours apart) as per the Lignon et al. study.r

Frequency:
21 days 
Cycles:
2 to 6 until disease progression or unacceptable toxicity.
Notes:

The dose of oxaliplatin has been changed to align with the Witzig et al. study.​r

Drug status:

Rituximab SC: TGA registered but not PBS listed.

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

Cost:
~ $1,600 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
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Dexamethasone 40 mg (IV/PO) ONCE a day orally in the morning with food OR by IV infusion on days 1 to 4.*
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate **
Netupitant 300 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron 0.5 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with netupitant)
Oxaliplatin 130 mg/m2 (IV infusion) in 250 mL to 500 mL glucose 5% over 2 hours
Day 2 and 3
Dexamethasone 40 mg (IV/PO) ONCE a day orally in the morning with food OR by IV infusion on days 1 to 4.*
Cytarabine (Ara-C) 2,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours
Day 4
Dexamethasone 40 mg (IV/PO) ONCE a day orally in the morning with food OR by IV infusion on days 1 to 4.*

* Dose for day 1 should be given 30 minutes prior to rituximab infusion.

** 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:
2 to 6 until disease progression or unacceptable toxicity.

Cycle 1 and 2

Drug Dose Route Day
Dexamethasone 40 mg ONCE a day IV/PO 1 to 4
Rituximab 375 mg/m2 IV infusion * 1
Oxaliplatin 130 mg/m2 IV infusion 1
Cytarabine (Ara-C) 2,000 mg/m2 IV infusion 2 and 3 **

* 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.

** Cytarabine may be administered TWICE daily on day 2 (12 hours apart) as per the Lignon et al. study.r

Frequency:
21 days 
Cycles:
2 to 6 until disease progression or unacceptable toxicity.
Notes:

The dose of oxaliplatin has been changed to align with the Witzig et al. study.​r

Drug status:

Rituximab SC: TGA registered but not PBS listed.

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

Cost:
~ $1,600 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
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Dexamethasone 40 mg (IV/PO) ONCE a day orally in the morning with food OR by IV infusion on days 1 to 4.*
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate **
Netupitant 300 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron 0.5 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with netupitant)
Oxaliplatin 130 mg/m2 (IV infusion) in 250 mL to 500 mL glucose 5% over 2 hours
Day 2 and 3
Dexamethasone 40 mg (IV/PO) ONCE a day orally in the morning with food OR by IV infusion on days 1 to 4.*
Cytarabine (Ara-C) 2,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours
Day 4
Dexamethasone 40 mg (IV/PO) ONCE a day orally in the morning with food OR by IV infusion on days 1 to 4.*

* Dose for day 1 should be given 30 minutes prior to rituximab infusion.

** 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:
2 to 6 until disease progression or unacceptable toxicity.
  • Relapsed/refractory CD20 positive B-cell non-Hodgkin lymphoma
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 oxaliplatin and rituximab
Premedication

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

Note: a corticosteroid is included as part of this treatment and therefore additional corticosteroid may not be required as premedication.

Please refer to the treatment schedule for the 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.

A NK1 receptor antagonist and a 5HT3 receptor antagonist in combination with dexamethasone are available on the PBS for primary prophylaxis of oxaliplatin induced nausea and vomiting.

Note: as a steroid has been included as part of this protocol, additional antiemetic steroids are not 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
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.
Laryngopharyngeal dysaesthesia associated with oxaliplatin

Sensation of loss of breathing related to oxaliplatin without objective evidence of respiratory distress. Symptoms are often precipitated by exposure to cold.

Read more about laryngopharyngeal dysaesthesia associated with oxaliplatin
Peripheral neuropathy

Assess prior to each treatment and dose reduce if appropriate.

Read more about peripheral neuropathy

Link to chemotherapy-induced peripheral neuropathy screening tool
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

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.
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, LDH and BSL at baseline, prior to each cycle and regularly throughout treatment 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 are recommended. Discuss with Haematologist. Consider adding G-CSF
Renal impairment
No specific dose modifications recommended for cytarabine in renal impairment, but please note an increased risk of neurotoxicity has been associated with high dose cytarabine with creatinine clearance less than 60 mL/min.
Hepatic impairment
Elevations in liver function tests occur with both standard and high dose cytarabine. Significant liver function abnormalities may require discontinuation or a dose reduction.
Peripheral neuropathy
Grade 2 which is present at the start of the next cycle Reduce oxaliplatin by 25%,
if persists, omit oxaliplatin until recovery
Grade 3 or Grade 4 Omit oxaliplatin
Acute laryngo-pharyngeal dysaesthesia Increase oxaliplatin infusion time to 6 hours

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
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
NK-1 antagonist e.g. aprepitant, fosaprepitant, netupitant
  Interaction Clinical management
Dexamethasone Increased effects/toxicity of dexamethasone due to inhibition of its metabolism via CYP3A4

Reduce dose of antiemetic dexamethasone by approximately 50% when adding a NK-1 antagonist. For protocols that already recommend a NK-1 antagonist, the dose reduction of antiemetic dexamethasone has already been taken into account.

If dexamethasone is part of the chemotherapy protocol, dose reduction as per the product information is not routinely recommended in clinical practice and no additional dexamethasone is required for antiemetic cover. 
Warfarin

Reduced anticoagulant efficacy of warfarin due to increased clearance (aprepitant induces CYP2C9). *Note interaction only applicable to aprepitant/ fosaprepitant

INR should be monitored in the 2 week period, particularly at 7 to 10 days following the administration of aprepitant/ fosaprepitant
Combined oral contraceptive Reduced contraceptive efficacy due to increased clearance. *Note interaction only applicable to aprepitant/ fosaprepitant Alternative non-hormonal methods should be used during and for 1 month after stopping aprepitant/ fosaprepitant
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of NK-1 antagonist possible due to increased clearance Avoid combination or monitor for decreased antiemetic effect. Consider using an alternative antiemetic regimen
CYP3A4 inhibitors (e.g. azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of NK-1 antagonist possible due to reduced clearance Avoid combination or monitor for increased adverse effects of NK-1 antagonist (e.g. headache, hiccups, constipation)
Drugs metabolised by CYP3A4 (e.g. etoposide, imatinib, irinotecan, midazolam, paclitaxel, vinblastine, vincristine etc.) Increased effects/toxicity of these drugs possible due to inhibition of CYP3A4 by NK-1 antagonist Avoid combination or monitor for increased toxicity especially with orally administered drugs
Oxaliplatin    
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal function closely
Neurotoxic drugs (e.g. vincristine, paclitaxel) Additive neurotoxicity Monitor closely for neuropathy if combination used
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

Approximate treatment time: 8 hours (initial); 4 to 6 hours (subsequent) 

General patient assessment prior to each day of treatment.

Peripheral neuropathy assessment tool

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.

  • baseline weight

Dexamethasone

  • administer orally ONCE a day in the morning with food OR
  • via IV infusion over 15 minutes on days 1 to 4
  • flush with ~ 50mL sodium chloride 0.9%

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

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: dexamethasone (part of this protocol) or hydrocortisone 100 mg IV
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

If no adverse event experienced with initial infusion:

  • perform baseline observations and repeat observations prior to each rate increase
  • commence rituximab infusion at 100 mg/hr
  • 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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Oxaliplatin

  • Oxaliplatin is only compatible with glucose 5%, ensure IV lines are flushed with glucose 5% pre and post administration.
Administer oxaliplatin (irritant with vesicant properties):
  • via IV infusion over 2 hours
  • risk of laryngopharyngeal dysaesthesia
    • patients should not drink cold fluids
  • monitor for signs of hypersensitivity
  • flush with ~ 100 mL glucose 5%
  • if patient has laryngopharyngeal dysaesthesia or a hypersensitivity reaction - stop infusion and obtain medical officer review. If rechallenge indicated, premedicate patient and administer oxaliplatin at a slower rate (up to 6 hours).

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

Days 2 and 3

Approximate treatment time: 3 to 4 hours 

General patient assessment prior to each day of treatment.

Prime IV line(s).

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Dexamethasone

  • administer orally ONCE a day in the morning with food OR
  • via IV infusion over 15 minutes on days 1 to 4
  • flush with ~ 50mL sodium chloride 0.9%

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

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%.

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)

Day 4

This is an oral treatment

Dexamethasone

  • administer orally ONCE a day in the morning with food OR
  • via IV infusion over 15 minutes on days 1 to 4
  • flush with ~ 50mL sodium chloride 0.9%

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

Discharge information

Dexamethasone tablets
  • Dexamethasone tablets with written instructions on how to take them.
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 
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.
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Headache
Laryngopharyngeal dysaesthesia

The sensation of difficulty breathing or an inability to swallow. This is associated with oxaliplatin and can occur during, and for up to 48 hours after treatment.

Read more about laryngopharyngeal dysaesthesia
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
Injection-site reaction

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

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

Read more about anaemia
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) 
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)

A search of the literature found limited evidence to support the use of R-DHAOx for the treatment of relapsed or refractory non-Hodgkin lymphoma (NHL). Velasquez et al.r demonstrated that R-DHAP (cisplatin, high dose cytarabine and dexamethasone) was an effective salvage regimen for recurrent NHL. Of the 90 patients reported in this study, 58 had diffuse large B cell histology (DLBCL). Seventeen of these patients achieved complete remission (CR), and fourteen achieved partial remission (PR). These platinum-containing regimes, whilst providing effective results, had associated toxicities that often resulted in discontinuation of treatment. These included peripheral neuropathy, renal toxicity and severe myelosuppression.r

Oxaliplatin is a third-generation platinum derivative of the diaminocyclohexamine (DACH) family. It has a 1,2 DACH carrier ligand which confers a different spectrum of cytotoxic activity compared to cisplatin.rr It has no auditory or renal toxic effects.

Two single-centre phase II studies have reported on the use of DHAOx for relapsed or refractory lymphoma. In one study by Machover et al.r of 15 patients with relapsed/refractory NHL demonstrated a 73% response rate, with 53% attaining CR and 20% attaining PR. 27% failed to respond. The median follow up period was 17 months, and no relapses from the complete responders were noted. Another study by Chau et al.r recruited 24 patients with intermediate or high-grade NHL and demonstrated an objective response rate of 50% (17% CR and 33% PR) with median duration of response 8.7 months. They also reported that response rate was 77% in those at first relapse compared to 29% for second or subsequent relapse and no responses in patients who were refractory to initial treatment. Median survival was 10.6 months, and median progression-free survival (PFS) was 3.5 months with PFS probability of 46.8% at 1 year.

The addition of rituximab to DHAOx (R-DHAOx) was initially demonstrated in a phase II study of 22 patients with relapsed or refractory follicular lymphoma. Twenty-one patients (95%) achieved CR with one PR. Long term efficacy was seen with 84% PFS at 38 months.r

A more recent single-centre phase II study recruited 45 patients with relapsed or refractory aggressive NHL and administered R-DHAOx. Rituximab was given weekly for the first cycle and subsequently on day 1 only from cycle 2. Cytarabine administration was also modified to daily for two doses to facilitate outpatient administration. An overall response rate of 71% was seen (27% CR and 44% PR), with 44% of patients proceeding to autologous transplant. Median overall survival (OS) was 26 months, with median PFS 11 months. The rate of grade 3-4 neuropathy was low at 4%.r

A multicentre retrospective analysis of 70 patients with refractory/relapsed NHL of DLBCL (67%) and Hodgkin lymphoma (HL) (33%) demonstrated a response rate of 73% (51 of 70) with 43% CR and 30% PR. Overall response rate according to subtype was 72% for NHL and 74% for HL. Further, 83% of patients planned for high dose consolidation or autograft proceeded to this.r

Another retrospective case series of 91 patients with relapsed/refractory NHL from a single institution demonstrated an overall response rate of 75% with CR of 57%. Median follow up of 23 months demonstrated 2 year OS probability of 75% and PFS probability of 43%.r

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Machover et al. 2001r Yes  No 

Relapsed/refractory NHL (n=15).

Dexamethasone 40 mg (days 1 to 4), oxaliplatin 130 mg/m2 (day 1) and cytarabine 2 g/m2  for two doses (day 2). Treatment was repeated every 21 days.
Chau et al. 2001r Yes  No

Relapsed/refractory NHL intermediate or high grade (n=24).

Dexamethasone 40 mg (days 1 to 4), oxaliplatin 130 mg/m2 (day 1) and cytarabine 2 g/m2 for two doses (day 2). Treatment was repeated every 21 days.
Machover et al. 2010r  Yes Yes

Relapsed/refractory follicular lymphoma (n=22).

Rituximab 375 mg/m2 (day 1), dexamethasone 40 mg (days 1 to 4), oxaliplatin 130 mg/m2 day 1 and cytarabine 2 g/m2 for two doses (day 2). Treatment was repeated every 21 days. 
Witzig et al. 2017r  Yes No

Relapsed/refractory aggressive NHL (n=45).

Rituximab 375 mg/m2 (day 1,8,15,22 cycle 1, then day 1 from cycle 2), dexamethasone 40 mg (days 2 to 5), oxaliplatin 130 mg/m2 (day 2) and cytarabine 2 g/m2  for 2 doses (days 2 to 3). Treatment was repeated every 21 days.
Multicentre retrospective analysis Rigacci et al. 2010r Yes  Yes

Relapsed/refractory NHL (DLBCL n=47) or HL (n=23).

Rituximab 375 mg/m2 (day 0), oxaliplatin 130 mg/m2 (day 1), cytarabine 2 g/m2 for two doses (days 2 and 3) and dexamethasone 40 mg (days 1 to 4). Treatment was repeated every 21 days for 2 to 6 cycles.
Retrospective studies  Lignon et al. 2010r Yes No 

Relapsed/refractory NHL (DLBCL n=42; FL n=30).

Rituximab 375 mg/m2 (day 1), oxaliplatin 100 mg/m2(day 1), cytarabine 2 g/m2 twice a day (day 2) and dexamethasone 40 mg (days 1 to 4). Treatment was repeated every 21 days. 
Guidelines Date published / revised  Supports Use Is the dose and regimen consistent with the protocol?  Comments 
NCCN B-Cell Lymphomas v5. 2021 Yes  Yes -
BCCA - N/A N/A -
CCO  - N/A N/A - 

Efficacy

© Cancer 2010 

Toxicity


© Cancer 2010

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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.
22/10/2021 Reviewed by Haematology Reference Committee with minor changes. Review due in 4 years.
20/01/2022 Interactions updated.

Version 4

Date Summary of changes
01/11/2019

Reviewed by the Haematology Reference Committee with the following changes: 

  • Dose of oxaliplatin changed to 130 mg/m2 
  • Administration of cytarabine changed to daily on days 2 and 3 to facilitate outpatient administration  
  • Evidence section updated 
  • Protocol to be reviewed in 2 years 
  • Version number changed to v.4. 

Version 3

Date Summary of changes
20/05/2016 New protocol taken to reference committee meeting.
24/05/2016 Published on eviQ.
31/05/2017

Transferred to new eviQ website. Version number changed to v.2.

Antiemetic change: A NK1 receptor antagonist and a 5HT3 receptor antagonist in combination with dexamethasone has been added as available on the PBS for primary prophylaxis of oxaliplatin induced nausea and vomiting.
12/03/2018

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.3.
25/05/2018 Reviewed by Haematology Reference Committee with no significant changes, 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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31 Mar 2023