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Non-Hodgkin lymphoma rituximab maintenance

Patients with lymphoma should be considered for inclusion into clinical trials. Link to ALLG website, ANZCTR website and Lymphoma Australia website.

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Cycle 1 to 8

Drug Dose Route Day
Rituximab 375 mg/m2 IV infusion * 1

* 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:
84 days (3 monthly) or 56 days (2 monthly) depending on the indication
Cycles:
8 (3 monthly) or 12 (2 monthly)
Drug status:

Rituximab: (PBS authority)

Note: the PBS restriction for rituximab maintenance is limited to follicular lymphoma, in the front-line and relapsed setting.

Cost:
~ $2,180 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 or other supportive medications), 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 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 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 to 8

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 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *

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

Frequency:
84 days (3 monthly) or 56 days (2 monthly) depending on the indication
Cycles:
8 (3 monthly) or 12 (2 monthly)

Cycle 1 to 8

Drug Dose Route Day
Rituximab 375 mg/m2 IV infusion * 1

* 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:
84 days (3 monthly) or 56 days (2 monthly) depending on the indication
Cycles:
8 (3 monthly) or 12 (2 monthly)
Drug status:

Rituximab: (PBS authority)

Note: the PBS restriction for rituximab maintenance is limited to follicular lymphoma, in the front-line and relapsed setting.

Cost:
~ $2,180 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 or other supportive medications), 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 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 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 to 8

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 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *

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

Frequency:
84 days (3 monthly) or 56 days (2 monthly) depending on the indication
Cycles:
8 (3 monthly) or 12 (2 monthly)
  • Relapsed/refractory CD20 positive low grade or follicular B-cell non-Hodgkin lymphoma following immunochemotherapy
  • Newly diagnosed CD20 positive Stage III or IV follicular B-cell non-Hodgkin lymphoma following immunochemotherapy
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 MINIMAL

No antiemetics should be routinely administered before treatment in patients without a history of nausea and vomiting. If patients experience nausea and/or vomiting, consider using the low antiemetic prophylaxis regimen.

Read more about preventing treatment induced nausea and vomiting
Subcutaneous rituximab

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.
Antiviral prophylaxis

­

Read more about antiviral prophylaxis drugs and doses
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. For more information see dosing considerations & disclaimer.

No dose modifications required

References & Disclaimer

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 (e.g. LMWH or unfractionated heparin)
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 1

General patient assessment prior to each day of treatment.

Prime IV line(s).

Insert IV cannula or access port or CVC.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Rituximab

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

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

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

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

Subsequent infusions:

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

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

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

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

Read more about rapid infusion rituximab

Read more about subcutaneous rituximab

Remove IV cannula and/or deaccess port or CVC.

Discharge information

Prophylaxis medication
  • Prophylaxis medication (if prescribed) i.e. 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 
Headache
Flu-like symptoms

Early (onset days to weeks)
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
Skin rash

Antineoplastic agents can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. 

Read more about skin rash
Injection-site reaction

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

Late (onset weeks to months)
Anaemia

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

Read more about anaemia
Progressive multifocal leukoencephalopathy (PML)

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

Read more about progressive multifocal leukoencephalopathy (PML)

Follicular B cell lymphoma

In 2006 the EORTC 20981 intergroup studyr randomised 474 patients with relapsed or resistant follicular B cell lymphoma (grade 1 to 3A), maximum of two prior non-anthracycline or immunotherapy containing regimens, to R-CHOP or CHOP for six cycles following randomisation to maintenance (375 mg/m2 every 3 months for two years) or observation.

R-CHOP significantly increased overall response rate compared to CHOP (85.1% versus 72.3%, p < 0.01). Rituximab maintenance was associated with a median PFS of 51.5 months versus 14.9 months (P< 0.01). In addition, overall survival was superior with rituximab maintenance over observation only (OS at 3 years of 85% versus 77%, P=0.011, HR 0.52). In 2010, these results were updated,r and remained highly significant. Comparing maintenance with no maintenance, PFS was 3.7 versus 1.3 years.

The PRIMA (Primary RItuximab and MAintenance) study randomised 1,217 patients with previously untreated follicular lymphoma, following immunochemotherapy (R-CHOP, R-CVP or R-FCM) to observation or maintenance rituximab (375 mg/m2) every 8 weeks for two years.r

At 36 months median follow up, the progression free survival (PFS) in the maintenance arm was 74.9% versus 57.6% in the observation only arm (P<0.0001). Overall survival was not significantly different and there was an increase in grade 3 or 4 adverse events (24% versus 17%, P=0.0026) in the maintenance arm and grade 2-4 infective episodes (39% versus 24%, P < 0.0001). The ECOG1496r study (included de novo small lymphocytic as well as follicular grade 1 and 2) showed a significant PFS advantage to rituximab maintenance (given as weekly X 4 repeated every six months for two years) of 68% versus 33% at 3 years.

There was no significant difference in OS. Modelling of the PRIMA data yielded an increased mean PFS of 1.5 years, OS by 1.21 years, and QALYs gained by 1.11 years.r

In a study of 280 patients with relapsed rituximab-naive follicular NHL, which also involved rituximab "purging" pre autograft, patients randomised to post transplant rituximab demonstrated improved PFS (10 years 54% v 37%) but not OS. Maintenance was administered 4 times at 2 monthly interval.r

The SAKK 35/03 trial randomised 165 patients with untreated, relapsed, stable or chemotherapy-resistant follicular lymphoma to receive short-term (n=82) or long-term (n=83) rituximab maintenance therapy. Rituximab 375 mg/m2 was administered intravenously every 2 months as four doses for short-term therapy and for a maximum of 5 years or until relapse, progression or unacceptable toxicity occurred for long term therapy. The primary end point was EFS and secondary end points PFS, OS and toxicity.r

At a median follow-up period of 6.4 years, in the short-term arm the median EFS was 3.4 years (95% CI, 2.1 to 5.3) and in the longer-term arm it was 5.3 years (95% CI, 3.5 to not available) (P = .14). More adverse effects were experienced in patients who received long term rituximab treatment compared to those who received four doses, with 76% v 50% of patients with at least one adverse event (P , .001), five versus one patient with grade 3 and 4 infections, and three versus zero patients discontinuing treatment because of unacceptable toxicity, respectively. There was no difference in OS between the two groups.r

A retrospective analysis found maintenance rituximab to improve PFS in patients who were treated with bendamustine and rituximab induction therapy on the BRIGHT study. Randomised controlled studies may be required to further test maintenance rituximab after BR therapy.r

A meta-analysis of seven trials including 2315 patients treated with rituximab maintenance (n=1145) for follicular lymphoma had improved overall survival compared with observation (n=1170). Median overall survival in the rituximab maintenance group was 12 years (95% CI 11.5 to not yet reached) compared to 11.5 years in the observation group. PFS was improved by rituximab maintenance compared to observation for patients with follicular lymphoma (HR 0.57, 95% CI 0.51-0.64).r

Rituximab was associated with a higher risk of adverse events, with infection being the major toxicity. Infection occurred in 33.6% (7.1% grade 3-4) of patients on maintenance rituximab and 23.6% (4.9% grade 3-4) of the observation group.r

Mantle cell lymphoma

Rituximab has been used as maintenance therapy following initial chemotherapy for mantle cell lymphoma and may be a reasonable alternative in transplant ineligible patients.r

It has also been used in transplant eligible patients in a phase 3 trial involving 299 patients was conducted by Le Gouill et al. between September 2008 through August 2012. The role of rituximab maintenance therapy given after autologous stem-cell transplantation (AuSCT) in patients with untreated mantle cell lymphoma (MCL) was investigated.r

Four courses of induction R-DHAP (rituximab, dexamethasone, cytarabine, and a platinum derivative) immunochemotherapy given every 21 days, was followed by the R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan) conditioning regimen prior to AuSCT. Patients who had a partial response received a rescue induction therapy with four courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 14 days. Only patients who had a response (confirmed or unconfirmed complete remission (CR) or a partial response (PR)) were eligible to undergo transplantation. The overall response rate was 89%, and the complete response rate 77% and transplantation was performed in 257 patients. After AuSCT, 240 patients were randomised to receive maintenance therapy (n=120) with intravenous rituximab 375 mg/m2 every 2 months for 3 years, or to undergo observation (n=120). The primary end point was event-free survival (EFS).r

The rate of EFS at 4 years from start of randomisation was 79% (95% confidence interval [CI], 70 to 86) in the rituximab group versus 61% (95% CI, 51 to 70) in the observation group (P=0.001).
PFS at 4 years was 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P<0.001). OS rate was 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P=0.04). The rate of overall survival at 4 years was higher in the rituximab group than in the observation group (hazard ratio for death, 0.50; 95% CI, 0.26 to 0.99; P=0.04) according to a Cox regression unadjusted analysis.r

Conclusions

Maintenance rituximab significantly improves OS and PFS in patients re-treated with chemotherapy for relapsed or resistant follicular B cell lymphoma (375 mg/m2 every 12 weeks for 2 years in the EORTC study).r

In patients with untreated follicular B cell lymphoma, maintenance therapy every eight weeks significantly improves PFS although the benefits in overall survival are less certain.r

In patients with mantle-cell lymphoma who were younger than 66 years of age at diagnosis, rituximab maintenance therapy after transplantation prolonged event-free survival, progression-free survival, and overall survival.r

Eight weekly versus 12 weekly delivery schedules have not been cross compared in the two patient populations. The duration of maintenance in the EORTC and PRIMA studies was 2 years. Ongoing studies are examining the optimal duration of maintenance.r

The role of maintenance rituximab in other indolent lymphomas is less clear.

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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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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/1385

13 Dec 2018

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