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Waldenstrom macroglobulinaemia DRC (dexamethasone rituximab CYCLOPHOSPHamide)

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 to 6

Drug Dose Route Day
Dexamethasone 20 mg IV infusion 1
Rituximab 375 mg/m2 IV infusion 1
CYCLOPHOSPHamide 100 mg/m2 TWICE a day PO 1 to 5
Frequency:
21 days 
Cycles:
6 
Notes:
  • Although the multicentre studies by Dimopoulos et al.rr recommend this therapy as first line management with good efficacy, it has demonstrated efficacy in the relapsed setting, and has been considered as a second line management option in the NCCN guidelinesr as well as the Eighth International Workshop on WM.r Bendamustine-rituximab is likely to be the most commonly used alternative front-line therapy, and whilst it is TGA licensed in the relapsed setting, is not currently PBS reimbursed for this indication.
  • The incidence of an initial IgM flare was low at 32% with the DRC protocol compared to other studies. Of these, only 11% of patients experienced an increase in IgM equal to or greater than 25%. The IgM flare did not have clinical consequences such as resulting in symptoms or signs of hyperviscosity in any patient in the study.r It is thought that the concomitant administration of cyclophosphamide may explain the lower incidence. However, in patients who present with high serum IgM monoclonal paraproteins, pheresis may need to be considered before administration of rituximab-based therapies.
Drug status:

All drugs in this protocol are on the PBS general schedule

Cyclophosphamide is available as 50 mg tablets

Cost:
~ $640 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 6

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Dexamethasone 20 mg (IV infusion) in 100 mL sodium chloride 0.9% over 15 minutes
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9%

as per graded administration rate
CYCLOPHOSPHamide 100 mg/m2 (PO) TWICE a day on days 1 to 5
Day 2 to 5
CYCLOPHOSPHamide 100 mg/m2 (PO) TWICE a day on days 1 to 5
Frequency:
21 days 
Cycles:
6 

Cycle 1 to 6

Drug Dose Route Day
Dexamethasone 20 mg IV infusion 1
Rituximab 375 mg/m2 IV infusion 1
CYCLOPHOSPHamide 100 mg/m2 TWICE a day PO 1 to 5
Frequency:
21 days 
Cycles:
6 
Notes:
  • Although the multicentre studies by Dimopoulos et al.rr recommend this therapy as first line management with good efficacy, it has demonstrated efficacy in the relapsed setting, and has been considered as a second line management option in the NCCN guidelinesr as well as the Eighth International Workshop on WM.r Bendamustine-rituximab is likely to be the most commonly used alternative front-line therapy, and whilst it is TGA licensed in the relapsed setting, is not currently PBS reimbursed for this indication.
  • The incidence of an initial IgM flare was low at 32% with the DRC protocol compared to other studies. Of these, only 11% of patients experienced an increase in IgM equal to or greater than 25%. The IgM flare did not have clinical consequences such as resulting in symptoms or signs of hyperviscosity in any patient in the study.r It is thought that the concomitant administration of cyclophosphamide may explain the lower incidence. However, in patients who present with high serum IgM monoclonal paraproteins, pheresis may need to be considered before administration of rituximab-based therapies.
Drug status:

All drugs in this protocol are on the PBS general schedule

Cyclophosphamide is available as 50 mg tablets

Cost:
~ $640 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 6

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Dexamethasone 20 mg (IV infusion) in 100 mL sodium chloride 0.9% over 15 minutes
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9%

as per graded administration rate
CYCLOPHOSPHamide 100 mg/m2 (PO) TWICE a day on days 1 to 5
Day 2 to 5
CYCLOPHOSPHamide 100 mg/m2 (PO) TWICE a day on days 1 to 5
Frequency:
21 days 
Cycles:
6 
  • Symptomatic relapsed/refractory Waldenstrom macroglobulinaemia
Caution with oral anti-cancer drugs

Select links for information on the safe prescribing, dispensing and administration of orally administered anti-cancer drugs. 

Read more about the COSA guidelines and oral anti-cancer therapy
Venous access required

IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.

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

High risk with rituximab.
Premedication

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

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.
Antiemetics for multi-day protocols

Antiemetic therapy should be administered throughout the duration of the chemotherapy protocol and to cover delayed nausea. The acute and delayed emetic risk of multi-day chemotherapy protocols will overlap depending on the individual drugs and their sequence of administration. More or less antiemetic cover may be required. 

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
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.
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
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

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

PJP prophylaxis is recommended e.g. trimethoprim/sulfamethoxazole 160/800 mg PO one tablet twice daily, twice weekly (e.g. on Mondays and Thursdays) OR one tablet three times weekly (e.g. on Mondays, Wednesdays and Fridays).

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

Antiviral prophylaxis is recommended.

Read more about antiviral prophylaxis drugs and doses
Antifungal prophylaxis

The use of prophylaxis should be at the discretion of the treating clinician and based on patient risk factors and local guidelines.

Read more about antifungal prophylaxis drugs and doses.
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).
Haematological toxicity
Dose reductions for haematological toxicity not usually recommended. Discuss with Haematologist.

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:  

Cyclophosphamide
  Interaction Clinical management
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Increased toxicity of cyclophosphamide possible due to increased conversion to active (and inactive) metabolites Avoid combination or monitor for cyclophosphamide toxicity
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Reduced efficacy of cyclophosphamide possible due to decreased conversion to active (and inactive) metabolites Avoid combination or monitor for decreased clinical response to cyclophosphamide
Amiodarone Possible additive pulmonary toxicity with high-dose cyclophosphamide (i.e. doses used prior to stem cell transplant; 60 mg/kg daily or 120 to 270 mg/kg over a few days) Avoid combination or monitor closely for pulmonary toxicity
Allopurinol, hydrochlorothiazide, indapamide Delayed effect. Increased risk of bone marrow depression; probably due to reduced clearance of active metabolites of cyclophosphamide Avoid combination, consider alternative antihypertensive therapy or monitor for myelosuppression
Ciclosporin Reduced efficacy of ciclosporin due to reduced serum concentration Monitor ciclosporin levels; adjust dosage as appropriate; monitor response to ciclosporin
Suxamethonium Prolonged apnoea due to marked and persistent inhibition of cholinesterase by cyclophosphamide Alert the anaesthetist if a patient has been treated with cyclophosphamide within ten days of planned general anaesthesia
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
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: 4 to 6 hours (initial); 3 to 4 hours (subsequent) 

General patient assessment prior to each treatment.

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

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

  • weigh patient on each visit
  • urinalysis each visit

Dexamethasone

  • administer via IV infusion over 15 minutes
  • flush with ~ 50mL sodium chloride 0.9%.

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 IV (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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Cyclophosphamide

  • administer orally TWICE a day, on days 1 to 5 of each cycle
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • patients should be well hydrated and be encouraged to void frequently during treatment to prevent cyclophosphamide induced bladder irritation.

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Days 2 to 5

This is an oral treatment

General patient assessment prior to each treatment.

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Cyclophosphamide

  • administer orally TWICE a day, on days 1 to 5 of each cycle
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • patients should be well hydrated and be encouraged to void frequently during treatment to prevent cyclophosphamide induced bladder irritation.

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

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

Discharge information

Cyclophosphamide tablets
  • Cyclophosphamide tablets with written instructions on how to take them.
Antiemetics
  • Antiemetics as 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 
Flu-like symptoms
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting

Early (onset days to weeks)
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.
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
Constipation
Fatigue

Read more about fatigue
Oral mucositis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiation therapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT).

Read more about oral mucositis
Haemorrhagic cystitis

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

Read more about haemorrhagic cystitis

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
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)

Delayed (onset months to years)
Pulmonary toxicity

Pulmonary toxicity may include damage to the lungs, airways, pleura and pulmonary circulation. 

Read more about pulmonary toxicity associated with anti-cancer drugs

Waldenstrom Macroglobulinaemia (WM) is a distinct B cell lymphoma with lymphoplasmacytic bone marrow infiltration and presence of an IgM monoclonal paraprotein. Patients with asymptomatic WM with a low Beta2MG and Hb greater than120 g/L, may have an indolent course and not require therapy. Symptomatic patients with WM should be considered for immediate treatment to control symptoms, as well as to reverse or prevent complications of WM.

The Fourth International Workshop on WM, held in June 2007 in Kos, Greece, recommended through their consensus panel of experts that the use of extended-dose rituximab as well as combination therapy with alkylating agents and/or nucleoside analogs were reasonable choices for the first-line or salvage treatment of WM in comparison to single agent therapy.r However, randomized studies to address the efficacy and impact of such novel regimens were recommended, and that individually tailored therapy including eligibility for autologous transplantation would impact on the choice of first line and salvage therapy of such patients. For patients eligible for autologous transplantation, exposure to alkylating agents and nucleoside analogs should be limited due to risk of stem cell damage by these agents.rr

A multicentre, prospective trial was conducted by Dimopoulos et. al between 2002 to 2006. 72 patients were enrolled and received the DRC regimen as first line therapy for symptomatic WM. Courses were repeated every 21 days for 6 courses. Patients median age was 69 years. The majority of these patients had advanced disease with a median serum monoclonal paraprotein of 36 g/L (range 3 to 117 g/L) which was predominantly kappa in 78%. Treatment consisted of dexamethasone 20 mg intravenously followed by rituximab 375 mg/m2 intravenously on day 1 and cyclophosphamide 100 mg/m2 orally twice a day on days 1 to 5 (total dose 1000 mg/m2). Patients who achieved stable disease or no disease progression were observed.r

Complete response was defined as a complete disappearance of disease at all involved sites and a negative serum immunofixation. Partial response was defined as a greater than 50% reduction of serum monoclonal paraprotein along with a greater than 50% reduction of tumour burden at all sites of involvement. A minor response was defined as an equal to 25% but less than a 50% reduction in serum monoclonal paraprotein and no new signs of active disease.r

Longer-term follow-up of these data have been published.r After a minimum follow-up of 7 years for all patients,83% achieved a response, with median progression-free survival of 35 months. This data was felt to compare favourably with results achieved in other front-line studies.

No randomized comparative data of DRC against other therapies has been published. At ASH2016 Paludo et al.rr presented a retrospective review of patients treated at the Mayo clinic between January 2007 and December 2014. This analysis looked at the outcomes in WM patients who received DRC (n=50) and Bendamustine-Rituximab (BR; n =44). Patients achieved similar overall response rates (ORR) with both regimens, although there was a non-significant trend to more rapid achievement of best response in the BR group (11 v 6.1 months, p=0.13). 2 year progression free survival was not statistically different, but with a strong trend favouring the BR group (53% v 66%, p=0.08).

This study also investigated the role of DRC in the relapsed setting. 50 patients had a median time to best response of 6.8 months, with an ORR of 87%, (68% ≥ PR). Median PFS was 32 months.

The 8th International Workshop on Waldenstrom’s Macroglobulinaemia considered DRC to be an appropriate first-line combination therapy, especially in frail patients. Furthermore, they agreed, in general terms, that DRC could be considered in the relapsed setting for patients treated with an alternative therapy in first-line, or where first-line DRC was associated with a prolonged response duration (> 2 years).

Australian relevance

Although the multicentre study by Dimopoulos et. alrr recommends this therapy as first line management with good efficacy, it has demonstrated efficacy in the relapsed setting,  and has been considered  as a second line management option in the NCCN guidelines as well as the Eighth International Workshop on WMr. Bendamustine-rituximab is likely to be the most commonly used alternative front-line therapy, and whilst it is TGA licensed in the relapsed setting, is not currently PBS reimbursed for this indication.

Source Study & year published Supports use Is the dose and regimen consistent with the protocol? Comments
Phase II trials

Dimopoulos et al., 2007

Kastritis et al., 2015

 Yes Yes Trial performed in previously untreated patients with symptomatic WM
Case series Paludo et al., 2016 Yes N/A Previously untreated and relapsed/refractory patients with WM
Observational studies N/A N/A N/A -
Guidelines Date published/revised Supports use Is the dose and regimen consistent with the protocol? Comments
NCCN Jan 2014 Yes N/A -
BCCA N/A N/A N/A -
ESMO 2013 Yes N/A -

Efficacy

On an intent-to-treat basis, 83% of patients (95% CI, 73 to 91%) achieved a response, including 7% complete, 67% partial and 9% minor responses. The median time to response was 4.1 months. The 2 year progression-free survival rate for all patients was 67%; and for patients who responded to DRC, it was 80%. The 2 year disease-specific survival rate was 90%.r

© Journal of Clinical Oncology 2007

Toxicity

Treatment was well tolerated, with 9% of patients experiencing grade 3 to 4 neutropenia and approximately 20% of patients experienced rituximab related toxicity.r

© Journal of Clinical Oncology 2007

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Version 4

Date Summary of changes
09/03/2020 Biosimilar rituximab added to clinical information. Version number changed to V.4    
27/03/2020 Reviewed by Haematology Reference Committee with no significant changes, review in 4 years
20/01/2022 Interactions updated.
24/01/2022 Pulmonary toxicity added to side effects.

Version 3

Date Summary of changes
27/06/2014 New protocol taken to Haematology Reference Committee meeting.
20/11/2014 Approved and published on eviQ.
20/06/2016 Drug status updated as per PBS: Replaced 'Rituximab is TGA registered but not PBS listed for this indication' with 'Rituximab: (PBS authority)'.
31/05/2017

Transferred to new eviQ website. Version number change to V.2.
24/11/2017

Reviewed at Haematology Reference Committee meeting:

  • Treatment schedule: notes section update to reflect current practice
  • Evidence updated

Version number change to V.3.
13/09/2019 Reviewed by Haematology Reference Committee, no changes made. Review in 5 years.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/1654

31 Mar 2023