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Non-Hodgkin lymphoma R-DHAP (rituximab dexamethasone cytarabine ciSplatin)

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 1 to 3

Drug Dose Route Day
Dexamethasone 40 mg ONCE a day IV/PO 1 to 4
Rituximab 375 mg/m2 IV infusion * 1
ciSplatin 100 mg/m2 IV infusion over 24 hours 1
Cytarabine (Ara-C) 2,000 mg/m2 TWICE a day (12 hours apart) IV infusion 2

* 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 then plan for peripheral blood stem cell harvest and autologous stem cell transplant (ASCT) as indicated.
Notes:
  • Velasquez et al.r modified the cytarabine dose for patients aged older than 70 years to 1 g/m2.
Drug status:

Rituximab SC: TGA registered but not PBS listed.

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

Dexamethasone is available as 0.5 mg and 4 mg tablets

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 to 3

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)
ciSplatin 100 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours
Day 2
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 TWICE a day (12 hours apart)
Day 3 and 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 to 60 minutes before 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.

Note:

  •  Velasquez et al.r modified the cytarabine dose for patients aged older than 70 years to 1 g/m2.

Frequency:
21 days 
Cycles:
3 then plan for peripheral blood stem cell harvest and autologous stem cell transplant (ASCT) as indicated.

Cycle 1 to 3

Drug Dose Route Day
Dexamethasone 40 mg ONCE a day IV/PO 1 to 4
Rituximab 375 mg/m2 IV infusion * 1
ciSplatin 100 mg/m2 IV infusion over 24 hours 1
Cytarabine (Ara-C) 2,000 mg/m2 TWICE a day (12 hours apart) IV infusion 2

* 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 then plan for peripheral blood stem cell harvest and autologous stem cell transplant (ASCT) as indicated.
Notes:
  • Velasquez et al.r modified the cytarabine dose for patients aged older than 70 years to 1 g/m2.
Drug status:

Rituximab SC: TGA registered but not PBS listed.

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

Dexamethasone is available as 0.5 mg and 4 mg tablets

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 to 3

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)
ciSplatin 100 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours
Day 2
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 TWICE a day (12 hours apart)
Day 3 and 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 to 60 minutes before 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.

Note:

  •  Velasquez et al.r modified the cytarabine dose for patients aged older than 70 years to 1 g/m2.

Frequency:
21 days 
Cycles:
3 then plan for peripheral blood stem cell harvest and autologous stem cell transplant (ASCT) as indicated.
  • Relapsed CD20 positive B-cell non-Hodgkin lymphoma
  • Newly diagnosed mantle cell non-Hodgkin lymphoma prior to autologous stem cell transplant
Venous access

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

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

High risk with 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 HIGH

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

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.
Ototoxicity

Ototoxicity may occur with platinum-based therapy; patients should be monitored for signs and symptoms. Platinum compounds should be used with caution in patients with pre-existing conditions or risk factors.

Ototoxicity may become more severe in patients being treated with other drugs with nephrotoxic potential e.g. aminoglycosides.

An audiometry test should be performed if symptoms develop.

Read more about ototoxicity - tinnitus and hearing loss
Cisplatin hydration

Hydration helps to prevent cisplatin-induced nephrotoxicity. Mannitol 10% may be used as per institutional policy; there is much variation in the use of mannitol and although there is no conclusive evidence that mannitol should be used, many sites have used it routinely without renal toxicity.

The routine use of frusemide to increase urine flow is not recommended. Refer to your institutional guidelines and medical orders.

The default regimen is appropriate for patients with normal electrolytes, renal function, fluid status etc. and should be adjusted according to individual requirements.

Read more about cisplatin hydration regimens
Peripheral neuropathy

Assess prior to each treatment. If a patient experiences grade 2 or greater peripheral neuropathy, a dose reduction, delay, or omission of treatment may be required; review by medical officer before commencing treatment.

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, calcium, magnesium, phosphate and BSL at baseline, and prior to each treatment and/or 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. 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.
Creatinine clearance (mL/min)
greater than or equal to 70 No dose modifications necessary
50 to less than 70 Reduce cisplatin by 25%
30 to less than 50 Reduce cisplatin by 50%
less than 30 Withhold treatment

Refer to Nephrotoxicity associated with cisplatin for more information

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, Grade 3 or Grade 4 Omit cisplatin

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:  

Cisplatin
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal function closely
Ototoxic drugs (e.g. aminoglycosides, frusemide, NSAIDs) Additive ototoxicity Avoid combination or perform regular audiometric testing
Neurotoxic drugs (e.g. vincristine, paclitaxel) Additive neurotoxicity Monitor closely for neuropathy if combination used
Paclitaxel Administration schedule may influence the development of myelosuppression Minimise toxicity by administering paclitaxel first in regimens using the combination
Carbamazepine, phenytoin, valproate Decreased antiepileptic plasma levels Monitor antiepileptic serum levels and seizure frequency for efficacy; adjust dosage as appropriate or select alternative antiepileptic (e.g. clonazepam, diazepam, lorazepam)
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
Rituximab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to the rituximab infusion
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
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.

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).

Access CVAD.

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

  • baseline weight
  • baseline urinalysis
  • strict fluid balance input and output

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

Dexamethasone

  • administer orally ONCE a day in the morning with food OR
  • via IV infusion over 15 minutes
  • flush with ~ 50mL sodium chloride 0.9%
  • patients may receive dexamethasone on day 3 and 4 orally as an outpatient or administered via IV infusion if still an inpatient

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.

Cisplatin 

Commence prehydration for cisplatin:
  • administer 10 mmol magnesium sulphate (MgSO4) in 1000 mL sodium chloride 0.9% over 60 minutes
  • followed by 200 mL of mannitol 20% over 15 minutes 
    • mannitol should be administered via a controlled infusion
  • mannitol 10% may be used as per institutional policy; there is much variation in the use of mannitol and although there is no conclusive evidence that mannitol should be used, many sites have used it routinely without renal toxicity. The routine use of frusemide to increase urine flow is not recommended. Refer to your institutional guidelines and medical orders.
  • ensure patient has passed urine prior to cisplatin administration as per institutional policy.
Administer cisplatin (irritant):
  • via IV infusion over 24 hours
  • flush with 100 mL of sodium chloride 0.9%.
Post hydration:
  • 1000 mL sodium chloride 0.9% over 60 minutes.

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 delay of treatment and review by medical officer before commencing treatment.

  • daily weight
  • daily urinalysis
  • strict fluid balance input and output

Hydration if prescribed

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
  • flush with ~ 50mL sodium chloride 0.9%
  • patients may receive dexamethasone on day 3 and 4 orally as an outpatient or administered via IV infusion if still an inpatient

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%.
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)

Days 3 and 4

General patient assessment prior to each day of treatment.

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

Dexamethasone

  • administer orally ONCE a day in the morning with food OR
  • via IV infusion over 15 minutes
  • flush with ~ 50mL sodium chloride 0.9%
  • patients may receive dexamethasone on day 3 and 4 orally as an outpatient or administered via IV infusion if still an inpatient

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

Deaccess CVAD.

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)
Headache
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Neurotoxicity

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

Read more about neurotoxicity associated with high dose cytarabine
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.
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)
Fatigue

Read more about fatigue
Hypomagnesaemia, hypokalaemia, hypocalcaemia

Abnormally low levels of magnesium, potassium and calcium in the blood.
Nephrotoxicity

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

Tinnitus and hearing loss may occur due to damage in the inner ear. Tinnitus is usually reversible, while hearing loss is generally irreversible. Hearing loss is dose-related, cumulative and may be worse in those with pre-existing hearing problems.

Read more about ototoxicity - tinnitus and hearing loss
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.
Thrombocytopenia

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

Read more about thrombocytopenia
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
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
Diarrhoea

Read more about treatment induced diarrhoea
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
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
Anaemia

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

Read more about anaemia
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)

In 1988 Velasquez et al showed that DHAP (cisplatin, high dose cytarabine and dexamethasone) was shown to be an effective salvage regimen for recurrent non Hodgkin lymphoma (NHL). Of the 90 patients reported in this study, 58 had diffuse large B cell histology (DLBCL). Seventeen of these patients achieved CR and fourteen achieved PR.rr

DHAP was employed as the salvage chemotherapy regimen in the PARMA trial published in NEJM in 1995. This randomised trial examined the role of autologous bone marrow transplantation (ABMT) compared to conventional salvage chemotherapy in relapsed, but chemotherapy sensitive NHL.rr

Randomisation occurred after two cycles of DHAP – patients showing no response were excluded – to either 4 additional courses of DHAP or ABMT. Bone marrow was harvested after cycle 1 in all patients except those with clearly progressive disease, or in those who had marrow harvested previously.rr

Involved field radiation therapy up to 26 Gy was allowed, as per defined indications, in both groups, and was administered prior to high dose chemotherapy (BEAC – carmustine, etoposide, cytarabine and cyclophosphamide) in the ABMT group.rr

A total of 215 patients were enrolled, with a median age of 43 and median follow up of 63 months. There were 163 with ‘intermediate grade’ histology (DLBCL in 37), and 52 with ‘high grade’ histology. Note this is a comparatively favourable group of patients, with only 36 out of 105 having a raised LDH. Nevertheless, there was a highly significant advantage in favour of ABMT in EFS as well as OSrr– see below in ‘Efficacy’ section.

Vose in a review in 1998rr commented that DHAP followed by high dose chemotherapy and autologous haemopoietic stem cell transplant was then the standard of care for relapsed or refractory DLBCL

DHAP + Rituximab (R-DHAP)

With the widespread use of rituximab in frontline as well as in salvage treatment for various types of CD-20 positive NHL, it is logical to examine the role of incorporating rituximab with DHAP. In this regard, one of the first abstracts on R-DHAP was from Guibert et al in 2006. This report described 24 patients with newly diagnosed mantle cell lymphoma treated with 4 to 6 courses of R-DHAP followed by autologous stem cell transplantation (ASCT) for patients under 65 (group 1); those over 65 were treated with R-DHAP alone (group 2). In group 1, 16 out of 17 attained CR or CRu; fourteen were scheduled to have ASCT. Blood stem cells were harvested after 3 to 4 courses, with 3 failures. Ten patients in total proceeded to ASCT using BEAM (carmustine, etoposide, cytarabine and melphalan), after a total of 4 to 6 courses of R-DHAP. On intention-to-treat, 3-year OS and EFS were 75% and 76% respectively. In group 2, six of seven patients entered CR or CRu after 4 courses of R-DHAP; five received an additional two courses.r

Addition of rituximab to DHAP type chemotherapy in re-induction of relapsed, or progressive aggressive CD20+ NHL was reported in the HOVON-44 trial in 2008. Chemotherapy consisted of DHAP alternating with VIM (etoposide, ifosfamide, methotrexate), with the sequence DHAP – VIM – DHAP. Patients proceeded to blood stem cell mobilisation on the back of the third chemotherapy cycle (DHAP number 2). If required, a fourth cycle, VIM, can be given. The experimental arm consisted of the same, plus rituximab. Patients in CR or PR after two cycles of chemotherapy are candidates for ASCT (BEAM). Radiation therapy following ASCT is allowed. The following is the schema for the trial:rr

© Blood 2008

Efficacy

The PARMA trial provided excellent data on the role of DHAP in treatment of relapsed NHL, with or without high dose chemotherapy followed by ABMT. At the end of the first two cycles of DHAP, 109 patients (41% in CR, and 59% in PR) were randomised to either BEAC followed by ABMT, or continuing with up to 4 more cycles of DHAP.r

The following points are worth noting:

  • the group was by and large a favourable group, with the aim at that time to test the toxicities of ABMT
  • source of stem cells was unstimulated (no G-CSF) bone marrow
  • involved field radiation therapy was built into the protocol for both arms of the study, according to predefined criteria (bulky disease = 5cm or extranodal T3 or T4 lesions as defined by EORTC)
  • the study was conducted well before the rituximab era.r

Comparing the ABMT arm vs chemotherapy:

  • response rate (CR+PR) 84% vs 44% at completion of all treatment
  • EFS 46% vs 12% (p=0.001)
  • OS at 5 years 32% vs 13% (p=0.038)2

© New England Journal of Medicine 1995

Time to first relapse is correlated with response after the first two cycles of DHAP, as well as 8-year survival rates in the PARMA trial.r Age adjusted IPI at relapse is correlated with OS in the DHAP group but it has no effect in the BEAC group. In addition, ABMT was not superior in patients with an age adjusted IPI of 0.r

In the HOVON-44 trial comparing DHAP to R-DHAP, 14 out of 239 patients enrolled, were excluded from analysis. A total of 225 patients were analysed on ITT basis – 112 in DHAP arm, and 113 in R-DHAP arm. The majority of the patients had DLBCL and had received CHOP-like first line treatment. Only 4 patients in each arm had prior exposure to rituximab. The two groups were well balanced in prognostic factors and demographics.r

Response rate following chemotherapy favoured the R-DHAP arm: 75% vs 54%. Patients showing response were eligible to proceed to ASCT. Inadequate blood PBSC harvest was observed in 1 patient in the DHAP arm, and 3 in the R-DHAP arm. Six patients in DHAP and 7 in the R-DHAP arm respectively progressed prior to ASCT and went off protocol. Radiation therapy after ASCT was given to 3 patients in the DHAP arm and 9 patients in the R-DHAP arm. The overall response rates were: DHAP – CR 35%, PR 15%; R-DHAP – CR 46% and PR 27%.r

Median follow up was 31 months. At 24 months, FFS was 24% in DHAP arm, and 50% in the R-DHAP arm (p<0.001). PFS at 24 months were: 31% vs 52% (p<0.002). OS at 24 months were: 52% vs 59% (p=0.15).r

© Blood 2008

Thus, in this essentially rituximab-naïve group of patients, addition of rituximab to DHAP-like salvage regimen prior to ASCT led to significant improvement in EFS and PFS, without significant increase in toxicities or delay in haemopoietic recovery following ASCT (data not shown). However, the benefit for OS cannot be demonstrated with confidence.r This may be due to successful third line salvage treatment. Note (1) there were only 3 doses in total of rituximab in the R-DHAP arm, and (2) patients relapsing or progressing after rituximab-containing front line therapy are not adequately examined in this study (see CORAL study, below).

R-DHAP vs R-ICE (ifosfamide, carboplatin, etoposide) was examined in the CORAL study, a phase III multicentre randomised trial in relapsed or primary refractory DLBCL.rr Of a total of 396 patients (median age 55 years), 62% had received prior rituximab. Overall efficacy measurements were similar between R-DHAP and R-ICE, with different toxicity profiles. Overall, 3-year EFS was inferior in patients with prior rituximab treatment (21% vs 47%). Of interest, patients with initial CR >12 months after diagnosis had similar EFS whether they had received rituximab (D below). This suggests patients with early relapses after rituximab-containing front-line therapy constitute a prognostically adverse group (C below).r Data for rituximab maintenance was not sufficiently mature for analysis at time of publication.

© Journal of Clinical Oncology 2010

A GELA phase 2 study examining R-DHAP, alternating with R-CHOP 21, followed by ASCT in mantle cell lymphoma patients younger than 66 years was reported in 2013. Patients had at least stage-3 disease. Sixty patients were enrolled, with a median age of 57 years. This study examines the role of adding high dose cytarabine and 4 doses of rituximab to this particular chemotherapy backbone in mantle cell lymphoma, which has been investigated previously by GELA.r The following table shows the demographics:

© Blood 2013

The following is the treatment schedule

© Blood 2013

Peripheral blood stem cells were harvested after the third cycle of R-DHAP. ASCT conditioning included TBI of 10 Gy over 3 days in twice daily fractions, high dose cytarabine and high dose melphalan. Primary end point was EFS. Of 53 patients still on study at the end of induction, 49 proceeded to ASCT. BEAM was used in 7 patients because of unavailability of TBI, or induction toxicity. At end of induction, 57% of patients were in CR and 30% in PR. There was a notable proportion who converted from PR after R-CHOP to CR after R-DHAP. For patients who received the entire planned treatment, including ASCT, CR was 96% and PR 4%. On ITT analysis for the entire cohort, CR was 78%, and ORR 82%.r

Median follow-up from diagnosis was 67 months. Median EFS was 83.9 months with 5-year EFS estimate of 64%. Relapse or progression occurred in 16 patients. Median PFS was 84 months, and median OS was not reached. OS rate at 5 years was 75%.r

Toxicity

In the PARMA trial there were 6 (out of 55 patients) early toxic deaths in the BEAC arm. Of these, 22 had received radiation therapy. There were no early toxic deaths in 54 patients in the DHAP arm. Out of these, 12 had received radiation therapy. As expected, the BEAC arm also had much higher adverse events such as infections and mucositis, one case of septic shock, and one had grade 4 cardiac toxicity.r

A high incidence of second malignancies was observed in the GELA (R-DHAP) study. With the limited follow-up, 11 of 60 patients were diagnosed with a second malignancy, mostly renal cancer. No cases of MDS or acute leukaemia were observed.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     
06/07/2020

Note added for modified cytarabine dose for patients aged older than 70 years to 1g/m2 .​
Reviewed by Haematology Reference Committee, nil significant changes, review in 4 years.
01/10/2021 Drug status updated: rituximab SC is TGA registered but no longer PBS listed.
20/01/2022 Interactions updated.

Version 4

Date Summary of changes
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.4.
25/05/2018 Reviewed by Haematology Reference Committee with no significant changes, review in 2 years
13/09/2019 Reviewed by Haematology Reference Committee, no changes made. Review in 5 years.
10/10/2019 Clinical information updated with PBS expanded indications for GCSF. 

Version 3

Date Summary of changes
11/10/2013 Presented at Haematology reference committee meeting (new Protocol).
11/11/2013 Published on eviQ.
18/08/2014 Added link to ALLG, ANZCTR and Lymphoma Australia website with statement 'Patients with NHL should be considered for inclusion into clinical trials'.
11/09/2015 Reviewed at reference committee meeting, no changes. Review in 2 years. Updated cost of drugs for treatment.
20/06/2016 Drug status updated as per PBS: Removed 'NB: Rituximab is not on the PBS for mantle cell lymphoma'.
31/05/2017

Transferred to new eviQ website. Version number change to V.3.

Antiemetic change: Netupitant/palonosetron combination has replaced aprepitant and a 5HT3 receptor antagonist in combination with dexamethasone for all highly emetogenic regimens.

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31 Mar 2023