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Chronic lymphocytic leukaemia FCR (fludarabine CYCLOPHOSPHamide rituximab)

Patients with leukaemia should be considered for inclusion into clinical trials. Link to ALLG website and ANZCTR website.

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Cycle 1

Drug Dose Route Day
Rituximab * 375 mg/m2 IV infusion 0
Fludarabine 25 mg/m2 IV infusion *** 1 to 3
CYCLOPHOSPHamide 250 mg/m2 IV infusion *** 1 to 3

Cycle 2 to 6

Drug Dose Route Day
Rituximab 500 mg/m2 IV infusion ** 1
Fludarabine 25 mg/m2 IV infusion *** 1 to 3
CYCLOPHOSPHamide 250 mg/m2 IV infusion *** 1 to 3

* The dose of rituximab can be split over 2 days or be administered later in the cycle.

** From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,600 mg. For more information see the Chronic lymphocytic leukaemia subcutaneous rituximab  document.

*** For oral dosing of fludarabine and cyclophosphamide refer to the evidence section.

Frequency:
28 days 
Cycles:
6. Depending on response and toxicity less cycles may be given.
Notes:

This is a very immunosuppressive therapy; caution required in pre-treated patients, those with pre-existing cytopenias, those with a history of opportunistic infections and the elderly.

Concomitant treatment with steroids (excluding those used as antiemetics and rituximab premedication) should be avoided where possible due to the heightened risk of opportunistic infections.

It is the consensus of the Haematology Reference Committee that a 5HT3 antagonist should be given on each day of treatment, all patients should receive antiviral and PJP prophylaxis for the duration of treatment and a minimum of 3 to 6 months subsequently and antifungal prophylaxis is not routine.

Drug status:

Rituximab: (PBS authority)

Fludarabine and cyclophosphamide are available on the PBS general schedule

Cost:
~ $3,320 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 antineoplastic 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 antineoplastic 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

Day 0
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *
Day 1
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Fludarabine 25 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 30 minutes **
CYCLOPHOSPHamide 250 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Day 2 and 3
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Fludarabine 25 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 30 minutes **
CYCLOPHOSPHamide 250 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Day 4 and 5
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 4 to 5 may not be required and may be reduced or omitted at the clinician's discretion. ***

Cycle 2 to 6

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 500 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate ****
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Fludarabine 25 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 30 minutes **
CYCLOPHOSPHamide 250 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Day 2 and 3
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Fludarabine 25 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 30 minutes **
CYCLOPHOSPHamide 250 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Day 4 and 5
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 4 to 5 may not be required and may be reduced or omitted at the clinician's discretion. ***

* The dose of rituximab can be split over 2 days or be administered later in the cycle.

** For oral dosing of fludarabine and cyclophosphamide refer to the evidence section​.

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

**** From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,600 mg. For more information see the Chronic lymphocytic leukaemia subcutaneous rituximab  document.

Frequency:
28 days 
Cycles:
6. Depending on response and toxicity less cycles may be given.

Cycle 1

Drug Dose Route Day
Rituximab * 375 mg/m2 IV infusion 0
Fludarabine 25 mg/m2 IV infusion *** 1 to 3
CYCLOPHOSPHamide 250 mg/m2 IV infusion *** 1 to 3

Cycle 2 to 6

Drug Dose Route Day
Rituximab 500 mg/m2 IV infusion ** 1
Fludarabine 25 mg/m2 IV infusion *** 1 to 3
CYCLOPHOSPHamide 250 mg/m2 IV infusion *** 1 to 3

* The dose of rituximab can be split over 2 days or be administered later in the cycle.

** From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,600 mg. For more information see the Chronic lymphocytic leukaemia subcutaneous rituximab  document.

*** For oral dosing of fludarabine and cyclophosphamide refer to the evidence section.

Frequency:
28 days 
Cycles:
6. Depending on response and toxicity less cycles may be given.
Notes:

This is a very immunosuppressive therapy; caution required in pre-treated patients, those with pre-existing cytopenias, those with a history of opportunistic infections and the elderly.

Concomitant treatment with steroids (excluding those used as antiemetics and rituximab premedication) should be avoided where possible due to the heightened risk of opportunistic infections.

It is the consensus of the Haematology Reference Committee that a 5HT3 antagonist should be given on each day of treatment, all patients should receive antiviral and PJP prophylaxis for the duration of treatment and a minimum of 3 to 6 months subsequently and antifungal prophylaxis is not routine.

Drug status:

Rituximab: (PBS authority)

Fludarabine and cyclophosphamide are available on the PBS general schedule

Cost:
~ $3,320 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 antineoplastic 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 antineoplastic 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

Day 0
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *
Day 1
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Fludarabine 25 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 30 minutes **
CYCLOPHOSPHamide 250 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Day 2 and 3
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Fludarabine 25 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 30 minutes **
CYCLOPHOSPHamide 250 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Day 4 and 5
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 4 to 5 may not be required and may be reduced or omitted at the clinician's discretion. ***

Cycle 2 to 6

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 500 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate ****
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Fludarabine 25 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 30 minutes **
CYCLOPHOSPHamide 250 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Day 2 and 3
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Fludarabine 25 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 30 minutes **
CYCLOPHOSPHamide 250 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Day 4 and 5
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 4 to 5 may not be required and may be reduced or omitted at the clinician's discretion. ***

* The dose of rituximab can be split over 2 days or be administered later in the cycle.

** For oral dosing of fludarabine and cyclophosphamide refer to the evidence section​.

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

**** From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,600 mg. For more information see the Chronic lymphocytic leukaemia subcutaneous rituximab  document.

Frequency:
28 days 
Cycles:
6. Depending on response and toxicity less cycles may be given.

Indication:

  • CD20 positive B-cell chronic lymphocytic leukaemia (CLL)
    • Alternative therapy should be considered for patients with 17p deletion

Contraindication:

  • Fludarabine treatment is contraindicated if creatinine clearance is < 30mL / min​
Venous access required

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

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

High risk with rituximab.
Premedication

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

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

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

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO or 12.5 mg IV every 6 hours when necessary.

Read more about preventing antineoplastic induced nausea and vomiting
Subcutaneous rituximab (CLL)

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 1,600 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 Chronic lymphocytic leukaemia rituximab subcutaneous
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.
Infection risk

It is the consensus of the haematology reference committee that, if patients are hypogammaglobulinemic with recurrent infections consider intravenous immunoglobulin replacement therapy as per the Australian Red Cross Blood services guidelines (ARCBS).

Read more about the Australian Red Cross Blood services guidelines
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

Read more about prevention and management of tumour lysis syndrome.
Pneumocystis jiroveci 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

There are no specific recommendations for the use of antifungal with this treatment. 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.
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
Autoimmune haemolytic anaemia

The use of fludarabine in patients with CLL may increase the risk of autoimmune haemolytic anaemia (AIHA).
Irradiated blood components

Irradiation of blood components is recommended.

Read more about the indications for the use of irradiated blood components
Biosimilar rituximab

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

FBC, EUC, LFTs and LDH at baseline, and prior to each cycle and as clinically indicated.
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy.

Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations

Live vaccines, including BCG, MMR, zoster and varicella 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.
Effects of cancer treatment on fertility

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment.

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 antineoplastic 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 and reference committee consensus. 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.

Note: All dose reductions are calculated as a percentage of the starting dose

Haematological toxicity
ANC x 109/L (pre-treatment blood test)
Less than 1.0 or previous episode of febrile neutropenia Delay treatment until recovery and consider adding G-CSF for subsequent cycles.
Consider reducing fludarabine by 25% for repeat grade 3 or 4 neutropenia (on Day 1 of cycle).
Platelets x 109/L (pre-treatment blood test)
Less than 75 Delay treatment until recovery. No dose reduction if decreased platelet count is due to disease.
Consider reducing fludarabine by 25% for repeat grade 3 or 4 thrombocytopenia (on Day 1 of cycle).
Renal impairment
Creatinine clearance (mL/min)
30 - 60 Reduce fludarabine to 20mg/m2
less than 30 Use alternative treatment

Note: Landmark trials excluded patients with CrCl <70mL/min.  ​Other clinical trials have used FCR without dose reduction with CrCl as low as 40mL/min, however increased toxicity may be expected.  There are few data on efficacy/toxicity with dose reduction due to CrCl for this regimen.

Hepatic impairment
Hepatic dysfunction
No dose modifications recommended
Peripheral neuropathy
Consider delaying or discontinuing fludarabine if neurotoxicity occurs

References & Disclaimer

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
Fludarabine
  Interaction Clinical management
Dipyridamole Reduced efficacy of fludarabine possible due to inhibition of adenosine uptake Avoid combination or monitor for decreased clinical response to fludarabine
Rituximab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to the rituximab infusion
General
  Interaction Clinical management
Warfarin Antineoplastic agents 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 antineoplastic 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 Antineoplastic agents 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 antineoplastic 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 antineoplastic 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

Day 0

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Insert IV cannula or access port or CVC.

  • baseline weight 
  • baseline urinalysis 

Note: Rituximab is given on day 0 of cycle 1 and then on day 1 of cycles 2 to 6.

Rituximab

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

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

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

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

Subsequent infusions:

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

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

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

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

Read more about rapid infusion rituximab

Read more about subcutaneous rituximab

Days 1 to 3

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Fludarabine

Administer fludarabine:
  • via IV infusion over 30 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.

Cyclophosphamide

Administer cyclophosphamide:
  • via IV infusion over 30 to 60 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%
  • rapid infusion can cause dizziness, rhinitis, nausea and perioral numbness. If symptoms develop, slow infusion rate.

Remove IV cannula and/or deaccess port or CVC.

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

Discharge information

Antiemetics
  • Antiemetics as prescribed.
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.

Day 1

Approximate treatment time: 4 to 6 hours (initial); 3 to 4 hours (subsequent) 

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Insert IV cannula or access port or CVC.

  • baseline weight 
  • baseline urinalysis 

Pre treatment medication

Rituximab

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

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

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

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

Subsequent infusions:

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

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

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

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

Read more about rapid infusion rituximab

Read more about subcutaneous rituximab

Verify antiemetics taken or administer as prescribed.

Fludarabine

Administer fludarabine:
  • via IV infusion over 30 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.

Cyclophosphamide

Administer cyclophosphamide:
  • via IV infusion over 30 to 60 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%
  • rapid infusion can cause dizziness, rhinitis, nausea and perioral numbness. If symptoms develop, slow infusion rate.

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

Days 2 and 3

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Fludarabine

Administer fludarabine:
  • via IV infusion over 30 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.

Cyclophosphamide

Administer cyclophosphamide:
  • via IV infusion over 30 to 60 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%
  • rapid infusion can cause dizziness, rhinitis, nausea and perioral numbness. If symptoms develop, slow infusion rate.

Remove IV cannula and/or deaccess port or CVC.

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

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Growth factor support
  • Arrangements for administration if prescribed.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.
Patient information
  • Ensure patient receives patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Flu-like symptoms

Early (onset days to weeks)
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 antineoplastic agents. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

Read more about peripheral neuropathy
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 neutropenia
Constipation
Thrombocytopenia

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

Read more about thrombocytopenia
Fatigue

Read more about fatigue
Diarrhoea

Read more about treatment induced diarrhoea
Oral mucositis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiotherapy 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 radiotherapy. 

Read more about haemorrhagic cystitis
Injection-site reaction

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

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)

The chemoimmunotherapy combination of fludarabine, cyclophosphamide and rituximab (FCR or R-FC) is recommended for young or fit, elderly patients with previously untreated chronic lymphocytic leukaemia (CLL).

The German CLL study group CLL8 study, a phase 3 randomised controlled trial comparing the combination of rituximab, fludarabine and cyclophosphamide (R-FC, n=408 patients) to FC alone (n=409), demonstrated superior response rates (Table 1), progression-free survival and overall survival for patients who received R-FC.r The overall response rate (ORR) was 90% (FCR) compared to 80% (FC, p<0.0001) including a complete response rate (CR) of 44% (FCR) versus 22% (FC, p<0.0001). The hazard ratios for PFS and OS were 0.56 [95%CI: 0.46 – 0.69] and 0·67 [0·48–0·92] respectively.

The MD Anderson group updated their outcomes with the FCR regimen.r The 6-year median overall survival of 77% and failure-free survival of 51% suggest that a significant proportion of patients may achieve long-lasting remissions with this chemoimmunotherapy regimen. Both studies demonstrated that patients with 17p deletions were less likely to achieve long-lasting responses following either FC or FCR.

Table 1r

  FC   FCR  
  CR ORR CR ORR
All Patients 22 80 44 90
Less than 65 years 20 79 45 89
Greater than or equal to 65 years 24 83 43 93
FISH Result        
13q deletion 23 80 48 96
11q deletion 15 87 51 93
Trisomy 12 19 84 71 100
17p deletion 0 34 5 68
No abnormality 28 91 35 89

The GCLLSG CLL10 confirms the superiority of FCR over bendamustine-rituximab as first-line therapy in fit patients, with higher CR rate (40% vs 31%) and improved median PFS (55 vs 42 months), though no difference in overall survival.r  However in subgroup analysis of age > 65, the difference in PFS was not evident.

The ECOG-ACRIN E1912 randomised control trial compared 6 cycles of ibrutinib and rituximab followed by ongoing ibrutinib until progression or toxicity with FCR.  In this FCR demonstrated statistically inferior 3-year PFS (73% vs 89%) and OS (92% vs 99%), most marked in patients with unmutated IgHV.r

FCR may also be used in the relapsed CLL setting. The REACH studyr demonstrated superior responses and progression-free survival of FCR over FC in patients with CLL in first relapse who had received prior fludarabine or alkylator-based therapy. Patients who had received prior FC or rituximab were excluded. There was no statistical difference in overall survival between the two groups at a median follow-up time of 25 months.r

The MD Anderson group updated their experience with FCR in a phase 2 single arm study of FCR for patients with relapsed CLL. This study demonstrated good responses (ORR 74% and CR 30% for all patients) and progression-free survival (21 months) following administration of FCR in this population. CLL patients who had received more than 3 prior treatments, were fludarabine-refractory, or patients with chromosome 17 abnormalities experienced suboptimal responses and short progression-free survival.r

Efficacy

Progression-free survival (A) and overall survival (B) in all patients with Previously Untreated Chronic leukaemia receiving chemoimmunotherapy (FCR) compared to chemotherapy (FC)r(GCLLSG CLL8 study)

© Lancet 2010

A meta-analysis conducted by Nunes et al. comparing FC and FCR in patients with CLL, the PFS was 32.8 months in the FC group and 51.8 months in the FCR group. The difference between the two groups was statistically significant (p<0.05).r

The subgroup analysis conducted by Thompson et al. found long-term disease-free survival after FCR therapy in patients with mutated immunoglobulin heavy chain variable (IGHV) gene (IGHV-M). The original patient cohort (n=300) who received FCR in the phase 2 study was reviewed to identify long-term disease-free survivors.r

© Blood 2016

Median PFS was not reached (NR) for patients with IGHV-M and 4.2 years for patients with IGHV-UM (P<.001). Progression-free survival at 12.8 years was 53.9% for patients with IGHV-M versus 8.7% for patients with unmutated IGHV (IGHV-UM). Furthermore, 50.7% of patients with IGHV-M who achieved MRD-negativity posttreatment had a PFS of 79.8% at 12.8 years. No relapses occurred beyond 10.4 years in 42 patients (total follow-up 105.4 patient-years) with IGHV-M, which resulted in a plateau on the PFS curve.r

Although IGHV-UM patients had inferior PFS compared to the IGHV-M patients, 9 of 126 patients with IGHV-UM remained in clinical remission beyond 10 years. The difference in PFS translated into a significant survival advantage for patients with IGHV-M. Patients who achieved MRD-negativity by PCR at completion of treatment had prolonged PFS of a median of 13.7 years compared to patients who remained MRD-positive with a median PFS of 4.0 years. Furthermore, patients with IGHV-M who were PCR negative at end-of-treatment had a 12.8-year PFS of 79.8% as opposed to a PFS of 36.9% if patients were MRD-positive.r

© Blood 2016

The median overall survival (OS) for the total cohort was 12.7 years. Survival was significantly inferior for patients with IGHV-UM compared with IGHV-M (median, 9.4 years vs NR and 12.8-years, 32.2% vs 65.5%; P < .001). Also, B2-microglobulin (B2M) ≥4.0 was predictive of inferior survival regardless of whether patients had IGHV mutation or not (IGHV-UM P = .002 and IGHV-M P = .011).r

MRD-negativity was associated with superior long-term survival in patients with IGHV-M only. A survival of 87.2% for MRD-negative patients and 56.5% for MRD-positive patients was observed at 12.8 years. MRD status did not affect IGHV-UM patients according to MRD status (P = .146).r

Toxicity

In the German CLL8 study 76% of patients experienced at least one grade 3 or 4 adverse event following chemoimmunotherapy with FCR (table 2). The majority of these events were haematological toxicity (56%) with neutropenia (34%) being most common. Chemoimmunotherapy with FCR was associated with a higher rate of grade 3 or 4 neutropenia compared to FC (34% versus 21% respectively, P<0.0001); however, the rates of severe infections were similar (25% versus 21%, p=0.18).

In the GCLLSG CLL10 study FCR was more toxic than bendamustine-rituximab with increased neutropenia (84% vs. 59%) and severe infections (39% vs. 25%).r  In the ECOG-ACRIN E1912 trial grade 3+ infections were higher in the FCR arm (20%) than ibrutinib-rituximab.r

Similar rates of grade 3 or 4 complications were noted in the REACH study (Table 3).r Almost all patients experienced grade 3 or 4 neutropenia during the study with a slightly higher incidence in the FCR arm (FCR 89% vs. FC 84%). Despite this, the overall incidence of infections (FC 51% and FCR 49%) and grade 3 or 4 infections (FC 19% and FCR 18%) did not differ between arms. Fatal adverse events occurred in 10% (FC) and 14% (FCR) of patients, mostly related to serious infections. In the phase 2 MD Anderson trial for relapsed CLL, patients older than 70 years with relapsed CLL were less likely to complete therapy and had a higher incidence of serious infections and myelosuppression.r

This regimen should be used with caution in elderly patients and patients with co-morbidities including reduced creatinine clearance.  Landmark trials demonstrating efficacy and survival for the FCR regimen excluded patients with CrCl <70 mL/min.rr  Other clinical trials have included patients with creatinine clearance as low as 40 mL/min without dose modification.r  There are no clear data on the efficacy and toxicity when modifying dose due to renal dysfunction.

Table 2: Grade 3 or 4 toxicity of FCR as initial therapy for chronic lymphocytic leukaemiar

© Lancet 2010

Table 3: Toxicity of FCR as first salvage therapy of relapsed chronic lymphocytic leukaemiar

© American Society of Clinical Oncology 2010

In a more recent trial conducted by Benjamini et al., the risk of second cancers was found to be 2.38 times higher than the expected risk in the general population (40% had other cancers before and 28% after FCR). Second cancer risk after frontline FCR is mainly due to high rates of acute myeloid leukaemia / myelodysplastic syndrome (t-AML/MDS) (5.1%) and Richter transformation (RT) (9%) while solid tumors were not increased. The survival of affected patients is shorter.r

Oral FCR

Early studies incorporating single agent fludarabine confirmed similar pharmokinetic data for IV fludarabine 25mg and oral fludarabine 40mg. Retrospective reviews of studies in fludarabine and cyclophosphamide demonstrate comparable efficacy, however increased gastrointestinal toxicity when substituting oral fludarabine.r  With these data oral FCR has been incorporated into clinical trials, though there are no head-to-head trials of IV and oral FCR. The ARCTIC and ADMIRE studies used the regimen of fludarabine 24 mg/m2 daily and cyclophosphamide 150 mg/m2 daily for 5 days with similar outcomes to historical IV FCR.rr  The CLL2007 SA studyr used oral fludarabine 40 mg/m2 and cyclophosphamide 250 mg/m2 for 3 days and ICORG 07-01 studyr allowed IV or oral formulations, however cycle numbers were limited to 4, and direct comparisons can not be made.  Oral fludarabine and cyclophosphamide utilising modified dosing may be considered.

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Version 7

Date Summary of changes
27/03/2020

Protocol reviewed at Haematology Reference Committee meeting with the following changes:

  • Note regarding fludarabine and cyclophosphamide oral dosing added
  • Dose modifications updated
  • Evidence updated
  • Review in 2 years

Version 6

Date Summary of changes
09/03/2020

Biosimilar rituximab added to clinical information. Version number changed to V.6

Version 5

Date Summary of changes
30/11/2009 Reviewed and transferred to eviQ
13/07/2010 Amendment of rituximab dosing to reflect current evidence and TGA licensing for use in CLL ie 375 mg/m2 day 1 cycle 1, then 500 mg/m2 day 1 cycle 2 to 6
08/04/2012 New format to allow for export of protocol information
Protocol version number changed to V.2
Antiemetics and premedications added to the treatment schedule
Additional Clinical Information, Key Prescribing table and Key Administration table combined into new section titled Clinical Considerations
Drug specific information placed behind the drug name link
13/04/2012 Addition of information on PML associated with rituximab (preclinical information and side effect)
Update of rituximab PBS authority status
10/05/2013 Taken to Haematology Reference Committee Meeting (HRCM) review changes made and republished.
11/09/2015

Reviewed at HRCM:

  • treatment schedule updated- Rituximab cycle one changed administration day to day 0 as per Hallek and Robak et al. papers. Number of cycles updated to 'Cycles: 6. Depending on response and toxicity less cycles may be given.'
  • drug status section updated
  • clinical information- emetogenicity preclin updated
  • evidence section updated to include two new references Nunes et al. 2015 and Benjamini et al. 2015
04/07/2016 Removed rapid infusion link for Rituximab as there is limited evidence for 500 mg/m2
31/05/2017

Transferred to new eviQ website. Version number change to V.4.
13/03/2018

Added:

  • Link to subcutaneous​ rituximab document underneath the treatment schedule.
  • Clinical information block on subcutaneous rituximab
  • Link to the subcutaneous rituximab document into administration section
  • Injection-site reaction side effect
  • Note about subcutaneous rituximab to the patient information
  • Version number changed to V.5.
25/07/2018

Reviewed by Haematology Reference Committee with updates to:

  • Antiemetic dexamethasone updated to be in line with international guidelines. 
  • Evidence updated.
  • Review in 5 years.
10/10/2019 Clinical information updated with PBS expanded indications for G-CSF. 

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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11 Jul 2020