364-Hairy cell leukaemia cladribine

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 may have been included in the ADDIKD guideline. Dose recommendations in kidney dysfunction have yet to be updated to align with the ADDIKD guideline. Recommendations will be updated once the individual protocol has been evaluated by the reference committee. For further information refer to the ADDIKD guideline. To assist with calculations, use the eviQ Estimated Glomerular Filtration Rate (eGFR) calculator.

Drug	Dose	Route	Day
Cladribine	0.14 mg/kg	IV infusion	1 to 5

Cycles:: 1. Response is usually manifested after a single course of cladribine. If a second course is necessary it should be given after resolution of all haematological toxicities.

Notes:

Various regimens for cladribine in hairy cell leukaemia have been reported:
- Continuous IV infusion of 0.1 mg /kg /day for seven days^r ^r ^r ^r
- IV infusion of 0.14 mg/kg /day over 2 hours for five days,^r ^r
- IV infusion of 0.15 mg/kg over 2 hours weekly for six weeks^r and
- Subcutaneous bolus administration of 0.085 mg /kg /day for seven days^r

The eviQ Reference committee believes that each of these regimens are reasonable option. The 5 day IV protocol ^r ^r has been selected for its feasibly, as it is able to be administered in the outpatient setting within a short discrete treatment timeframe. However, it is acknowledged that clinicians may prefer to use one of the other regimens.

Drug status:: Cladribine: (PBS authority)

Cost:: ~ $3,480 per cycle "How this cost is calculated"
The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m²; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Day 1 to 5
Cladribine	0.14 mg/kg (IV infusion)	in 100 mL to 500 mL sodium chloride 0.9% over 2 hours

Cycles:: 1. Response is usually manifested after a single course of cladribine. If a second course is necessary it should be given after resolution of all haematological toxicities.

Treatment schedule - Overview

Drug	Dose	Route	Day
Cladribine	0.14 mg/kg	IV infusion	1 to 5

Cycles:: 1. Response is usually manifested after a single course of cladribine. If a second course is necessary it should be given after resolution of all haematological toxicities.

Notes:

Various regimens for cladribine in hairy cell leukaemia have been reported:
- Continuous IV infusion of 0.1 mg /kg /day for seven days^r ^r ^r ^r
- IV infusion of 0.14 mg/kg /day over 2 hours for five days,^r ^r
- IV infusion of 0.15 mg/kg over 2 hours weekly for six weeks^r and
- Subcutaneous bolus administration of 0.085 mg /kg /day for seven days^r

Drug status:: Cladribine: (PBS authority)

Cost:: ~ $3,480 per cycle "How this cost is calculated"
The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m²; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

Treatment schedule - Detail

Day 1 to 5
Cladribine	0.14 mg/kg (IV infusion)	in 100 mL to 500 mL sodium chloride 0.9% over 2 hours

Cycles:: 1. Response is usually manifested after a single course of cladribine. If a second course is necessary it should be given after resolution of all haematological toxicities.

Indications and patient population

Hairy cell leukaemia

Clinical information

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
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 anti-cancer therapy induced nausea and vomiting
Opportunistic infections	Cladribine produces profound and prolonged immunosuppression due to reduction of CD4 and CD8 T-lymphocytes. An increased incidence of opportunistic infections is expected during and six months following therapy with cladribine. Monitor for signs and symptoms of opportunistic infections. Prophylactic antimicrobials recommended.
Tumour lysis risk	Assess patient for risk of developing tumour lysis syndrome. A daily oral dose of allopurinol 100 mg, starting on the first day of chemotherapy is recommended for a period of 2 weeks. Read more about the prevention and management of tumour lysis syndrome.
Pneumocystis jirovecii pneumonia (PJP) prophylaxis	Read more about prophylaxis of pneumocystis jiroveci (carinii) in cancer patients
Antiviral prophylaxis	Read more about antiviral prophylaxis drugs and doses
Irradiated blood components	The use of irradiated of blood components is recommended for patients receiving this treatment. Read more about the indications for the use of irradiated blood components
Blood tests	FBC, EUC and LFTs at baseline, then FBC weekly (during and after treatment), and defer further therapy until haematological recovery has occurred. Repeat EUC and LFTs as clinically indicated.
Hepatitis B screening and prophylaxis	Routine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy. Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations	Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease. Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook. Read more about COVID-19 vaccines and cancer.
Fertility, pregnancy and lactation	Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. There is a risk of foetal harm in pregnant women. A pregnancy test should be considered prior to initiating treatment in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and adequate contraception timeframe should be discussed with all patients of reproductive potential. Possibility of infant risk should be discussed with breastfeeding patients. Read more about the effect of cancer treatment on fertility

Dose modifications

Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

The dose recommendations in kidney dysfunction (i.e.renal impairment) displayed may not reflect those in the ADDIKD guideline and have been included for historical reference only. Recommendations will be updated once the individual protocol has been evaluated by the reference committee, with this version of the protocol then being archived. Clinicians are expected to refer to the ADDIKD guideline prior to prescribing in kidney dysfunction.
International Consensus Guideline for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).

Haematological toxicity
Cladribine produces severe myelosuppression. Monitor hematologic function regularly especially during the first 4 to 8 weeks after therapy. Red blood cell or platelet transfusion may be necessary.
ANC x 10⁹/L, platelets x 10⁹/L (pre-treatment blood test)
ANC less than 1.5 and/or platelets less than 100	Delay treatment until recovery unless disease related, then use clinical judgement

Renal impairment
Insufficient data available on dose modification for renal impairment. Patients with known or suspected renal insufficiency should be treated carefully and monitored regularly for haematological and non-haematological toxicity.

Hepatic impairment
Insufficient data in this patient population. Decision to treat is based on clinical judgement.

Interactions

Drug interactions in eviQ protocols are under review and being updated to align with current literature. Further site-wide updates and changes will occur in due course. References & Disclaimer

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources:

MIMS - interactions tab (includes link to a CYP-450 table) (login required)
Australian Medicines Handbook (AMH) – interactions tab (login required)
Micromedex Drug Interactions (login required)
Cancer Drug Interactions
Cytochrome P450 Drug Interactions

Cladribine
No specific or clinically significant drug-drug interactions reported. Exercise caution when administering with other known myelosuppressive agents.

General
	Interaction	Clinical management
Warfarin	Anti-cancer drugs may alter the anticoagulant effect of warfarin.	Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran	Interaction with both CYP3A4 and P-gp inhibitors /inducers. DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).	Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. Dabigatran: avoid combination with strong P‑gp inducers and inhibitors. If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin	Anti-cancer drugs can damage the lining of the intestine; affecting the absorption of digoxin.	Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics	Both altered antiepileptic and anti-cancer drug levels may occur, possibly leading to loss of efficacy or toxicity.	Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate. Also monitor closely for efficacy of the anti-cancer therapy.
Antiplatelet agents and NSAIDs	Increased risk of bleeding due to treatment related thrombocytopenia.	Avoid or minimise combination. If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine)	Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.)	Avoid combination. If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia). For more information link to TGA Medicines Safety Update
Vaccines	Diminished response to vaccines and increased risk of infection with live vaccines.	Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy. For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Administration

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.

Days 1 to 5

Approximate treatment time: 2 hours

Safe handling and waste management

Safe administration

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Administer antiemetics if required

Chemotherapy - Time out

Cladribine

administer via IV infusion over 2 hours
flush with ~ 100 mL of sodium chloride 0.9%.

Remove IV cannula and/or deaccess TIVAD or CVAD.

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

Discharge information

Prophylaxis medications

Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.

Patient information

Ensure patient receives patient information sheet.

Side effects

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)
Nausea and vomiting	Read more about prevention of treatment induced nausea and vomiting
Taste and smell alteration	Read more about taste and smell changes

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
Anorexia	Loss of appetite accompanied by decreased food intake. Read more about anorexia
Fatigue	Read more about fatigue
Diarrhoea	Read more about treatment induced diarrhoea
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

Late (onset weeks to months)
Anaemia	Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. Read more about anaemia
Alopecia - partial	Hair thinning and/or patchy hair loss. 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

Evidence

The Hairy Cell Leukaemia Foundation has developed the following “Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia".^r

Various methods of administration of cladribine in hairy cell leukaemia have been investigated. These include a single course of a seven day continuous IV infusion of 0.1mg /kg /day, ^r ^r ^r ^r IV infusion of 0.14 mg/kg /day over 2 hours for five days,^r ^r weekly 2 hour IV infusion of 0.15 mg/kg for six weeks^r and subcutaneous bolus administration of 0.085 mg /kg /day for seven days.^r

These different regimens have not been directly compared though they appear to have comparable results. Each is considered to be a reasonable option in the above Hairy Cell Leukaemia guidelines.

It is noted that Liliemark et al studied the bioavailability of cladribine by treating 10 patients with alternate days of IV infusion (2 hours) or SC cladribine at a dose of 0.14 mg/kg/day.^r It was concluded that the bioavailability of SC cladribine was 100% (SC route gives a high peak concentration of short duration with AUC identical to that of IV) and no local toxicity was noted.

Efficacy

The following table gives some example results of studies using the various regimens listed above.

Regimen		Patient Number	Response	Remission duration or relapse figures
Dose	Route and duration	Patient Number	Response	Remission duration or relapse figures
0.1 mg/kg^r	IV continuous infusion daily for seven days	207	PR-5% CR-95%	37% of patients relapsed OS 97% at 108 months
0.14 mg/kg^r	IV infusion over 2 hours daily for five days	50 (arm A of a study comparing to weekly)	PR-50% CR-28%	EFS: 77% at five years
0.15 mg/kg^r	IV infusion over 2 hours weekly for 6 courses	30	PR-27% CR-73%	16.7% had relapsed at 35 months
0.085 mg/kg^r	SC daily for seven days	73	PR-7% CR-81%	No relapses at 20 months

Note that the eviQ Reference committee believes that each of these is a reasonable option.

Note on response assessment

Given that time to marrow recovery is often prolonged, it is recommended that marrow remission assessment is not done until 4-6 months after therapy. It is found that complete response is associated with longer disease free survival.^r However, it is not thought that HCL is cured with current regimens. Furthermore, it is noted that patients with partial response may remain asymptomatic for many years. Therefore it is unclear whether further therapy is warranted in patients who have not achieved CR with the first course, let alone in those who have demonstrable MRD. Some groups choose to administer a second course of cladribine if CR is not achieved after the first course.

Note on rituximab

There have been trials investigating the use purine analogue (PA) combined with Rituximab.

In one study in the upfront setting, PA was followed 1 month later by rituximab 375 mg/m2 IV weekly for 8 weeks.^r There was a 100% CR rate and the median survival duration was not reached.

Another large case series by Else et al, followed 233 patients for a median duration of 16 years.^r In the subset of 79 patients who were in relapse, 12/79 were given rituximab in additional to pentastatin or cladribine. The complete response rates to PA alone was 50-69%, whereas the addition of rituximab increased CR rate was 92%. The achievement of CR was associated with superior relapse-free survival.

Rituximab is available on the PBS. Please refer to the PBS website for further information.

Toxicity

The main toxicities are haematological and infectious. In the Zenhausern study (5 days of IV cladribine), 90% developed grade 3-4 neutropenia. 44% developed any grade of infection. 38% required hospitalisation at some point in their therapy. 22% required packed cell transfusion while 8% required platelets.^r

References References

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History

Version 4

Date	Summary of changes
04/07/2007	Reformatting and additional extra information
09/11/2008	Review and reformatting of patient information sheet
30/03/2010	Review and update of evidence and transferred to eviQ
04/04/2012	New format to allow for export of protocol information Protocol version number changed to V.2 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
11/03/2013	Decision of the CLL group to categorise protocol ID:364 to a group 2, no new evidence, review again in 2 years.
16/07/2014	PHC view removed
17/12/2014	Removed from notes section: "Administration of cladribine once weekly for 6 weeks has been shown to reduce haematological toxicity and infectious complications" as recent literature is indicative of no significant difference in the toxicity between cladribine administered daily for 5 days versus weekly cladribine.(Robak 2007, Grever 2010)
11/09/2015	Reviewed at RCM, added the use of Rituximab into the evidence section, updated drug costs. Review in 2 years.
31/05/2017	Transferred to new eviQ website. Version number change to V.4.
21/09/2018	Protocol reviewed at Haematology Reference Committee meeting. Evidence and interaction sections updated. Review in 5 years.

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

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First approved:: 11 July 2006
Last reviewed:: 21 September 2018
Review due:: 30 June 2023

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/364

31 May 2023