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Chronic lymphocytic leukaemia idelalisib and rituximab

 Infection and pneumonitis risk:

Idelalisib can cause serious infections and/or fatal pneumonitis. See 'Pneumocystis jirovecii pneumonia (PJP) prophylaxis' and 'CMV monitoring' in the Clinical information section below for more information.

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

The anticancer drug(s) in this protocol have been updated with the ADDIKD guideline recommendations (if applicable). Recommendations may differ from other protocols which have not been updated. For further information refer to the dedicated eviQ ADDIKD guideline webpage.

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Cycle 1

Drug Dose Route Day
Idelalisib 150 mg TWICE a day PO 1 to 28
Rituximab 375 mg/m2 IV infusion 1
Rituximab 500 mg/m2 IV infusion 15

Cycle 2

Drug Dose Route Day
Idelalisib 150 mg TWICE a day PO 1 to 28
Rituximab 500 mg/m2 IV infusion 1 and 15

Cycle 3 to 6

Drug Dose Route Day
Idelalisib 150 mg TWICE a day PO 1 to 28
Rituximab 500 mg/m2 IV infusion 1
Frequency:
28 days 
Cycles:
6. After completion of cycle 6, continue idelalisib 150 mg TWICE a DAY until disease progression or unacceptable toxicity.
Notes:
  • G-CSF may be required to maintain the schedule of this protocol.
Drug status:

Idelalisib: (PBS authority)

Rituximab is on the PBS general schedule

Idelalisib is available as 100 mg and 150 mg tablets

Cost:
~ $5,640 (cycle 1); $5,760 (cycle 2); $5,274 (cycle 3 to 6) "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). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

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.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

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

Day 1
Idelalisib 150 mg (PO) TWICE a day with or without food
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 2 to 14
Idelalisib 150 mg (PO) TWICE a day with or without food
Day 15
Idelalisib 150 mg (PO) TWICE a day with or without food
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
Day 16 to 28
Idelalisib 150 mg (PO) TWICE a day with or without food

Cycle 2

Day 1
Idelalisib 150 mg (PO) TWICE a day with or without food
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
Day 2 to 14
Idelalisib 150 mg (PO) TWICE a day with or without food
Day 15
Idelalisib 150 mg (PO) TWICE a day with or without food
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
Day 16 to 28
Idelalisib 150 mg (PO) TWICE a day with or without food

Cycle 3 to 6

Day 1
Idelalisib 150 mg (PO) TWICE a day with or without food
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
Day 2 to 28
Idelalisib 150 mg (PO) TWICE a day with or without food
Frequency:
28 days 
Cycles:
6. After completion of cycle 6, continue idelalisib 150 mg TWICE a DAY until disease progression or unacceptable toxicity.

Cycle 1

Drug Dose Route Day
Idelalisib 150 mg TWICE a day PO 1 to 28
Rituximab 375 mg/m2 IV infusion 1
Rituximab 500 mg/m2 IV infusion 15

Cycle 2

Drug Dose Route Day
Idelalisib 150 mg TWICE a day PO 1 to 28
Rituximab 500 mg/m2 IV infusion 1 and 15

Cycle 3 to 6

Drug Dose Route Day
Idelalisib 150 mg TWICE a day PO 1 to 28
Rituximab 500 mg/m2 IV infusion 1
Frequency:
28 days 
Cycles:
6. After completion of cycle 6, continue idelalisib 150 mg TWICE a DAY until disease progression or unacceptable toxicity.
Notes:
  • G-CSF may be required to maintain the schedule of this protocol.
Drug status:

Idelalisib: (PBS authority)

Rituximab is on the PBS general schedule

Idelalisib is available as 100 mg and 150 mg tablets

Cost:
~ $5,640 (cycle 1); $5,760 (cycle 2); $5,274 (cycle 3 to 6) "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). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

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.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

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

Day 1
Idelalisib 150 mg (PO) TWICE a day with or without food
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 2 to 14
Idelalisib 150 mg (PO) TWICE a day with or without food
Day 15
Idelalisib 150 mg (PO) TWICE a day with or without food
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
Day 16 to 28
Idelalisib 150 mg (PO) TWICE a day with or without food

Cycle 2

Day 1
Idelalisib 150 mg (PO) TWICE a day with or without food
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
Day 2 to 14
Idelalisib 150 mg (PO) TWICE a day with or without food
Day 15
Idelalisib 150 mg (PO) TWICE a day with or without food
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
Day 16 to 28
Idelalisib 150 mg (PO) TWICE a day with or without food

Cycle 3 to 6

Day 1
Idelalisib 150 mg (PO) TWICE a day with or without food
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
Day 2 to 28
Idelalisib 150 mg (PO) TWICE a day with or without food
Frequency:
28 days 
Cycles:
6. After completion of cycle 6, continue idelalisib 150 mg TWICE a DAY until disease progression or unacceptable toxicity.
  • CD20 positive B-cell chronic lymphocytic leukaemia (CLL) / small lymphocytic lymphoma (SLL) in patients who have relapsed and chemo-immunotherapy is not considered suitable
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
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 Cancer Council Australia guidelines and oral anti-cancer therapy
Hypersensitivity/infusion related reaction

High risk with rituximab.

Read more about Hypersensitivity reaction
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 or low

No routine prophylaxis required. If patients experience nausea and/or vomiting, consider using the low emetogenic risk regimen.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Pneumonitis

Pneumonitis, including organising pneumonia, some with a fatal outcome have occurred with idelalisib. Treatment may be interrupted in patients presenting with pulmonary symptoms or radiographic appearances. Patient should be assessed for an explanatory etiology, considering infectious causes (e.g. CMV). If pneumonitis is suspected the patient should be treated accordingly.

If moderate-severe symptomatic pneumonitis or organising pneumonia is diagnosed, appropriate treatment should be initiated and idelalisib should be permanently discontinued.
Gastrointestinal toxicity

Severe diarrhoea or colitis (grade 3 or higher) and intestinal perforation has been associated with idelalisib treatment in clinical trials. Some fatal outcomes were observed. 

Severe diarrhoea or colitis can be delayed or occur at any time during treatment.

Infectious causes (e.g.Clostridum difficile, CMV) should be excluded when assessing patients with colitis. Interruption of idelalisib and additional treatment (e.g. antidiarrhoeal and anti-inflammatory agents such as enteric budesonide) may be recommended.

Assess hydration status for all patients with diarrhoea, especially in those with increased risk for dehydration (eg. pre-existing renal failure). Monitor patients for any new or worsening abdominal pain, chills, fever, nausea or vomiting and advise them to promptly report symptoms.

Discontinue idelalisib permanently in patients who experience intestinal perforation.
Hepatotoxicity

Hepatotoxicity has been observed with this treatment. Onset of hepatic dysfunction typically occurs within 3 months of starting treatment.

Monitor for abnormal liver function tests (LFTs), jaundice and tiredness. Refer to blood tests and dose modification sections for specific recommendations.
Skin toxicity

Severe or life-threatening (grade ≥ 3) cutaneous reactions have been reported in patients treated with idelalisib.

Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have occurred when patients were treated with idelalisib administered concomitantly with other medications associated with SJS-TEN.

Idelalisib may be interrupted or discontinued.
Lymphocytosis

A transient increase in lymphocyte counts has been observed with idelalisib therapy. Lymphocytosis associated with idelalisib should not be considered progressive disease in the absence of other clinical findings. 
Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) has been reported in one idelalisib study in a CLL patient, who had received rituximab previously.

In any patient receiving idelalisib who reports the new onset of, or changes in pre-existing neurologic signs and symptoms, a diagnosis of PML should be considered.

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.
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
CMV monitoring

All patients should have cytomegalovirus (CMV) status assessed before starting idelalisib.

Monitor closely for laboratory and clinical evidence of CMV infection. If patient is CMV positive or has evidence of a history or CMV infection at baseline, at least monthly clinical and laboratory monitoring for CMV infection is recommended. 

Use of idelalisib may need to be interrupted or stopped.

For patients with asymptomatic CMV viraemia, monitor for evidence of high or rising viral load and if confirmed, consider interrupting idelalisib and commence antiviral therapy to prevent invasive disease. 

For patients with symptomatic CMV viraemia, initiate antiviral therapy and consider interrupting idelalisib until CMV disease has resolved. Pre-emptive CMV therapy should be considered if benefits of resuming idelalisib outweigh the risks. Patients with fever and/or other signs of infection should be evaluated promptly and treated accordingly.
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 in all patients during idelalisib treatment 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).

Post-treatment prophylaxis should continue for 2 to 6 months after the discontinuation of idelalisib and be based on clinical judgement, taking into account the patient's risk factors (e.g. concomitant corticosteroid treatment and prolonged neutropenia).

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
Growth factor support

G-CSF (short or long-acting) is available on the PBS for chemotherapy induced neutropenia depending on clinical indication and/or febrile neutropenia risk.  

Access the PBS website
Biosimilar drug

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

FBC, EUC, eGFR, LFTs, and LDH at baseline then every 2 weeks for the first 12 weeks, every 4 weeks between weeks 12 and 24, every 6 weeks between weeks 24 and 48, and then every 12 weeks or as clinically indicated.
Hepatitis B screening and prophylaxis

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

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

Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease.

Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.

Read more about COVID-19 vaccines and cancer.
Fertility, pregnancy and lactation

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. There is a risk of foetal harm in pregnant women. A pregnancy test should be considered prior to initiating treatment in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and adequate contraception timeframe should be discussed with all patients of reproductive potential. Possibility of infant risk should be discussed with breastfeeding patients.

Read more about the impact 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.
Haematological toxicity
ANC x 109/L (pre-treatment blood test)
0.5 to less than 1.0 No dose reduction required. Monitor ANC at least weekly and consider adding G-CSF
less than 0.5 Delay treatment until recovery
Monitor ANC at least weekly until ANC is greater than or equal to 0.5, then resume idelalisib at 100 mg TWICE a day. Consider adding G-CSF
Platelets x 109/L (pre-treatment blood test)
25 to less than 50 No dose reduction required. Monitor platelet counts at least weekly
less than 25 Delay treatment until recovery
Monitor platelet count at least weekly. May resume idelalisib at 100 mg TWICE a day when platelets are greater than or equal to 25
Kidney dosing recommendations 
  • Suggested dose modifications are based on the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).
  • Where one or more drugs in a protocol is recommended to be avoided, consider using a clinically appropriate alternative treatment protocol instead.
  • Before dose adjusting or omitting a drug, consider treatment intent.
  • In kidney replacement therapy consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing. 
  • For complete information on individual drug recommendations please review the individual drug monograph in the ADDIKD guideline.
eGFR
(mL/min/1.73m2)		 Rituximab Idelalisib*
≥ 60

Full dose

No dose adjustment required in kidney dysfunction

 

 

 

 

 
45 - 59

Full dose
30 - 44

Full dose
15 - 29

Full dose
< 15
(without kidney replacement therapy)

Full dose

* This drug was not included in the ADDIKD guideline.
Hepatic impairment
Hepatic dysfunction (ALT/AST)

> 3-5 x ULN

 No dose reduction required. Monitor as least weekly until ≤ 1 x ULN.
> 5-20 x ULN 

Delay treatment and monitor at least weekly until ≤ 1 x ULN, then resume idelalisib at 100 mg TWICE a day.

If no recurrence, the dose can be re-escalated to 150 mg TWICE a day at the discretion of the treating clinician.

If there is recurrence, delay treatment until return to grade 1 or below. Consider resuming idelalisib at the discretion of the treating clinician.
> 20 x ULN Discontinue idelalisib permanently. 
Bilirubin

> 1.5-3 x ULN

No dose reduction required. Monitor as least weekly until ≤ 1 x ULN.
>  3-10 x ULN 

Delay treatment and monitor at least weekly until ≤ 1 x ULN, then resume idelalisib at 100 mg TWICE a day.
> 10 x ULN Discontinue idelalisib permanently. 
Diarrhoea

Grade 2

No dose reduction required. Monitor as least weekly until recovery.
Grade 3

Delay treatment and monitor at least weekly until recovery, then resume idelalisib at 100 mg TWICE a day.

If no recurrence, the dose can be re-escalated to 150 mg TWICE a day at the discretion of the treating clinician.
Grade 4 Discontinue idelalisib permanently. 
Rash
Grade 1 or 2 No dose reduction required. Monitor until resolved.
Grade 3 or 4

Delay treatment until recovery to ≤ grade 1 and resume idelalisib at 100 mg TWICE a day at the discretion of the treating clinician. 

If no recurrence, the dose can be re-escalated to 150 mg TWICE a day at the discretion of the treating clinician.

If SJS or TEN is suspected interrupt idelalisib immediately. 

Permanently discontinue idelalisib if there is a severe cutaneous reaction.
CMV infection
Patients with positive baseline CMV serology

Monitor patients with CMV viraemia (positive polymerase (PCR) or antigen test).

Consider delaying idelalisib until the infection has resolved. Provide treatment according to established clinical guidelines.
Patients with CMV viraemia without associated clinical signs of CMV infections

Careful monitoring is recommended.
If the benefits of resuming idelalisib outweigh the risks, consider pre-emptive CMV therapy.
Pneumonitis
Symptomatic pneumonitis (any grade)

Discontinue idelalisib. 

However, if re-treatment is appropriate once pneumonitis has resolved, consider resuming idelalisib at 100 mg TWICE a day, at the discretion of the treating physician.
Organising pneumonia Permanently discontinue idelalisib
Intestinal perforation

Permanently discontinue idelalisib.

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:  

For more information see References & Disclaimer.

Idelalisib
  Interaction Clinical management
CYP3A inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin, grapefruit juice etc.) Increased toxicity of idelalisib possible due to reduced clearance Avoid combination or monitor for idelalisib toxicity
CYP3A inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort, dexamethasone etc.)  Reduced efficacy of idelalisib possible due to increased clearance Avoid combination or monitor for decreased clinical response to idelalisib
CYP3A substrates (e.g. atorvastatin, benzodiazepines, calcineurin inhibitors, clarithromycin, dihydroergotamine, simvastatin, etc.) Increased toxicity of these drugs possible due to inhibition of CYP3A by idelalisib resulting in reduced clearance Avoid combination or monitor for increased toxicity of the interacting drugs. 
Rituximab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to the rituximab infusion
Immunosuppressants (eg. abatacept and baricitinib etc.) Increased risk of infection Concurrent use not recommended. If an immunosuppressant must be used, monitor closely for signs of infection
General
  Interaction Clinical management
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 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.

  • baseline weight

Insert IV cannula or access TIVAD or CVAD.

This is a continuous oral treatment

Idelalisib

  • administer orally TWICE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food

Note: if a dose is missed and it is less than 6 hours late, it should be taken as soon as the patient remembers. If it is more than 6 hours late, the patient should not take the missed dose.

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 ~ 50 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 ~ 50 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

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Days 2 to 14

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.

This is a continuous oral treatment

Idelalisib

  • administer orally TWICE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food

Note: if a dose is missed and it is less than 6 hours late, it should be taken as soon as the patient remembers. If it is more than 6 hours late, the patient should not take the missed dose.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Day 15

Approximate treatment time: 3 to 4 hours 

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.

Insert IV cannula or access TIVAD or CVAD.

This is a continuous oral treatment

Idelalisib

  • administer orally TWICE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food

Note: if a dose is missed and it is less than 6 hours late, it should be taken as soon as the patient remembers. If it is more than 6 hours late, the patient should not take the missed dose.

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 ~ 50 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 ~ 50 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

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Days 16 to 28

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.

This is a continuous oral treatment

Idelalisib

  • administer orally TWICE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food

Note: if a dose is missed and it is less than 6 hours late, it should be taken as soon as the patient remembers. If it is more than 6 hours late, the patient should not take the missed dose.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Idelalisib tablets
  • Idelalisib tablets with written instructions on how to take them.
Antiemetics
  • Antiemetics as prescribed.
Antidiarrhoeals
  • Antidiarrhoeals 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.

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: 3 to 4 hours 

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.

  • baseline weight

Insert IV cannula or access TIVAD or CVAD.

This is a continuous oral treatment

Idelalisib

  • administer orally TWICE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food

Note: if a dose is missed and it is less than 6 hours late, it should be taken as soon as the patient remembers. If it is more than 6 hours late, the patient should not take the missed dose.

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 ~ 50 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 ~ 50 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

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Days 2 to 28

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.

This is a continuous oral treatment

Idelalisib

  • administer orally TWICE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food

Note: if a dose is missed and it is less than 6 hours late, it should be taken as soon as the patient remembers. If it is more than 6 hours late, the patient should not take the missed dose.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge

Idelalisib tablets
  • Idelalisib tablets with written instructions on how to take them.
Antiemetics
  • Antiemetics as prescribed.
Antidiarrhoeals
  • Antidiarrhoeals 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
Headache
Flu-like symptoms

Symptoms include fever, chills, rigors, diaphoresis, malaise, myalgia, arthralgia, loss of appetite, dry cough and headache.

Early (onset days to weeks)
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about immediate management of neutropenic fever
Thrombocytopenia

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

Read more about thrombocytopenia
Abdominal pain

Dull ache, cramping or sharp pains are common with some anti-cancer drugs. These are caused by either increased or decreased gastrointestinal motility and can be associated with diarrhoea or constipation.
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Fatigue

Read more about fatigue
Skin rash

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

Read more about skin rash
Constipation
Gastrointestinal perforation

A rupture of the wall of the stomach, small intestine or large bowel. Symptoms include acute abdominal pain, tenderness and signs of sepsis. 
Arthralgia and myalgia

Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation. 

Read more about arthralgia and myalgia
Respiratory tract infection
Dizziness

Feeling faint or lightheaded, weak or unsteady. Advise patients to stand up slowly from sitting down or lying down positions and increase fluid intake if dehydrated.
Dyspnoea
Hepatotoxicity

Anti-cancer drugs administered either alone or in combination with other drugs and/or radiation may cause direct or indirect hepatotoxicity. Hepatic dysfunction can alter the metabolism of some drugs resulting in systemic toxicity.
Fluid retention and oedema

An excess amount of fluid around the cells, tissues or serous cavities of the body, leading to swelling.
Electrolyte imbalance

Hypokalaemia, hypercalcaemia, hyponatraemia and hyperuricaemia may occur with idelalisib.
Hyperlipidaemia and hypercholesterolaemia

Abnormally elevated levels of lipids and cholesterol in the blood.
Hypoalbuminaemia

Abnormally low levels of albumin in the blood.

Late (onset weeks to months)
Anaemia

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

Read more about anaemia
Diarrhoea

Read more about treatment induced diarrhoea
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
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)

Between May 2012 and August 2013, 220 patients with relapsed Chronic Lymphocytic Leukaemia (CLL) were recruited from 90 centres across the United States and Europe to participate in a phase 3 randomised, double blinded placebo controlled study to assess the efficacy and safety of idelalisib (versus placebo) in combination with rituximab.r

All eligible patients had CLL that had progressed within 24 months after their last treatment, and were not able to receive cytotoxic agents for specific reasons, namely: Grade 2-3 cytopenias secondary to previous therapy, poor renal function (eGFR<60ml/min), of CIRS>6. All patients were previously treated with at least two previous cytotoxic treatments, or one treatment including a CD20 monoclonal antibody.r

Idelalisib was administered at a dose of 150 mg twice a day. Rituximab was planned at an initial dose of 375 mg/m2 followed by 500 mg/m2 every 2 weeks for four doses, then every 4 weeks for three doses (total of eight infusions).r

The primary end point of the trial was progression free survival. Secondary end points were rates of overall and complete response, lymph node response and overall survival.r

Efficacy

The overall response rate (ORR) was 81% in the idelalisib  group compared to 13% in the placebo group (p<0.001). There was also a significant higher lymph node response in the idelalisib group.r

At 24 weeks, the progression free survival (PFS) rate was 93% in the idelalisib group compared to 46% in the placebo group (HR 0.15, 95% CI 0.08-0.28 p<0.001). The median duration of PFS in the idelalisib group was not reached, compared to 5.5 months in the placebo group. This trend favouring idelalisib was similar in all subgroups, including stratification for 17p deletion and IGHV mutational status.r

The overall survival (OS) in the idelalisib groups was superior at 12 months (92% versus 80%).r

© N Engl J Med 2014

Of note: Idelalisib has been shown to cause a peripheral lymphocytosis when it is administered as a single agent. The addition of rituximab to idelalisib blunted and shortened the duration of the lymphocytosis; in this study, the lymphocytosis peaked at week 2 and majority were resolved by week 12 in the idelalisib group.r

Toxicity

More than 90% of the patients had at least one adverse event. The most common adverse events were pyrexia, fatigue, nausea, chills and diarrhoea. Grade 3 diarrhoea were reported in 4% of patients receiving idelalisib/rituximab combination, and a grade 3 Rash in 2%.r

Raised transaminases were common in the idelalisib group (35%), with grade 3 of higher elevations in 5%; onset was approximately at 8-16 weeks. In majority of these cases, idelalisib was withheld and successfully re-initiated once LFTs returned to baseline.r

The most frequent serious adverse events were pneumonia, pyrexia and febrile neutropenia.r

Adverse events leading to study drug discontinuation were reported in 8% of the idelalisib group (most frequently gastrointestinal and skin disorders) and 10% of the placebo group (most frequently infections and respiratory disorders).r

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Version 4

Date Summary of changes
26/10/2023

Protocol updated with ADDIKD guideline recommendations. New kidney dosing recommendation table added to dose modification section.

PDF of previous protocol.

Version number changed to V.4.

Version 3

Date Summary of changes
05/06/2023 Subcutaneous rituximab information removed from the following sections – treatment schedule, clinical information, administration, patient information. Increased to version 3.

Version 2

Date Summary of changes
09/03/2020 Biosimilar rituximab added to clinical information. Version number changed to V.2     
27/03/2020 Reviewed by Haematology Reference Committee with no significant changes, review in 4 years.
01/10/2021 Drug status updated: rituximab SC is TGA registered but no longer PBS listed.
21/12/2021

Changed antiemetic clinical information block to minimal or low, to align with new categories. See ID 7 Prevention of anti-cancer therapy induced nausea and vomiting (AINV) v5.

Version 1

Date Summary of changes
25/05/2018 New Protocol discussed at Haematology Reference Committee meeting.
25/07/2018 Approved and published on eviQ.
10/10/2019 Clinical information updated with PBS expanded indications for G-CSF.

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

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https://www.eviq.org.au/p/3466

16 Apr 2024