NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE

Technology Appraisal Guidance No. 28

Guidance on the use of fludarabine for B-cell chronic lymphocytic leukaemia

Issue Date: September 2001 Review Date: August 2004

Ordering Information:

Copies of this guidance can be obtained from the NHS Response Line by telephoning 0870 1555 455 and quoting ref: N0025. A patient version of this document can be obtained by quoting ref: N0027. A bi-lingual patient leaflet is also available, ref: N0028.

This document has been circulated to the following:

• Health Authority Chief Executives in England and Wales
• NHS Trust Chief Executives in England and Wales
• PCG Chief Executives
• Local Health Group General Managers
• Medical and Nursing Directors in England and Wales
• Consultant Oncologists in England and Wales
• Consultant Haematologists in England and Wales
• Chief Pharmacists, Heads of Drug Purchasing, Heads of Drug Information, Pharmaceutical Advisors, GP Prescribing Advisors and Purchase Advisors in England and Wales
• NHS Director Wales
• Chief Executive of the NHS in England
• NHS Executive Regional Directors
• Special Health Authority Chief Executives
• Community Health Councils in England and Wales
• Patient advocacy groups
• Commission for Health Improvement
• NHS Clinical Governance Support Team
• Chief Medical, Nursing Officers and Pharmaceutical Officers in England and Wales
• Medical Director & Head of NHS Quality - National Assembly for Wales
• Representative bodies for health services, professional organisations and statutory bodies, Royal Colleges

This guidance represents the view of the Institute which was arrived at after careful consideration of the available evidence. Health professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.

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Copyright National Institute for Clinical Excellence September 2001. All rights reserved. This material may be freely reproduced for educational and not for profit purposes within the NHS. No reproduction by or for commercial organisations is permitted without the express written permission of the Institute.

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This section (Section 1) constitutes the Institute's guidance on the use of fludarabine for B-cell chronic lymphocytic leukaemia. The remainder of the document is structured in the following way:

2. Clinical Need
3. The Technology
4. Evidence
5. Implications for the NHS
6. Implementation
7. Further Research
8. Review of Guidance

Appendix A: Appraisal Committee
Appendix B: Sources of evidence
Appendix C: Information for patients
Appendix D: Staging systems

 

1.Guidance
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	1.1.		Oral fludarabine is recommended as second line therapy for B-cell chronic lymphocytic leukaemia (CLL) for patients who have either failed, or are intolerant of, first line chemotherapy, and who would otherwise have received combination chemotherapy of either:
		1.1.1.	cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)
		1.1.2.	cyclophosphamide, doxorubicin and prednisolone (CAP) or
		1.1.3.	cyclophosphamide, vincristine and prednisolone (CVP)g
	1.2.		The oral formulation of fludarabine is preferred to the intravenous formulation on the basis of more favourable cost effectiveness. Intravenous fludarabine should only be used when oral fludarabine is contra-indicated.
	2. Clinical Need and Practice
		2.1.	Chronic lymphocytic leukaemia (CLL) is a malignant disorder of the white blood cells (lymphocytes). CLL causes abnormal lymphocytes to proliferate, thus impairing the production and function of red blood cells, platelets and normal lymphocytes. This in turn causes anaemia, failure of the blood to clot and increased susceptibility to infection.
		2.2.	There are two main types of lymphocytes called B-cells and T-cells. B-cell CLL comprises about 95% of all CLL.
		2.3.	Often, the disease goes undiagnosed either until it is well advanced, or until a chance test shows abnormally high levels of lymphocytes in the blood.
		2.4.	CLL is a chronic, life-threatening and incurable disease. It is the most common form of leukaemia in the Western world, affecting about 2.7 people in every 100,000. Predominantly, it is a disease of older people, with 75% of those diagnosed being over the age of 60 years, although 6% are below the age of 50 years. Twice as many men as women are affected.
		2.5.	Life expectancy depends on the stage at which the disease is diagnosed (see Table 2, Appendix D for definition of stages). For those in the early stages of the disease, median life expectancy is over 10 years, while for patients with advanced disease it is only 6 to 9 months. Other adverse prognostic factors include early age of onset.
		2.6.	Despite the apparently better prognosis in early disease, there is no evidence that early treatment is beneficial, and it may indeed be harmful. Since many patients have limited disease, they do not require anything more than general observation, referred to as 'watchful waiting'.
		2.7.	When the disease progresses, a hierarchy of treatments is used. There is a trade-off between the likelihood of halting or reversing progression of the disease and the side-effects of drug treatment.
		2.8.	Response rates to chemotherapy of about 70% are seen in intermediate-stage disease, dropping to about 30% in later stages. In patients at intermediate or advanced stages of their disease an alkylating agent such as chlorambucil (with or without corticosteroids), cyclophosphamide or fludarabine (currently unlicensed in this indication) has been used as a first-line treatment.
		2.9.	When patients relapse or fail to respond to one of the first-line treatments (usually chlorambucil or, occasionally, cyclophosphamide), either combination treatment (such as CHOP, CAP or CVP) or fludarabine monotherapy is employed. A single cycle of combination therapy usually consists of drugs given by both the intravenous route (day 1) and orally (for a further 4 days). Cycles are repeated monthly for up to six months. Fludarabine is sometimes used as third-line treatment after combination therapy has failed.
3. The Technology
	3.1		Fludarabine is a cytotoxic agent of the antimetabolite class. It is currently licensed for patients with B-cell CLL with sufficient bone marrow reserve and who have not responded to, or whose disease has progressed during or after, treatment with at least one standard alkylating-agent containing regimen.
	3.2		It is administered either as an intravenous infusion (over 30 minutes) or orally. This is repeated each day for 5 days, and this cycle is then repeated every 28 days for up to 6 cycles. The drug acquisition cost (for either intravenous or oral formulation) of a course of 6 cycles is about £3,900. Each intravenous infusion requires a day-case admission to hospital, while the oral preparation usually needs only a small number of hospital visits.
	3.3		Although the immediate side effects of fludarabine (nausea, vomiting, alopecia) are less troublesome than those of CHOP, there are frequent haematological adverse events (granulocytopenia, anaemia and thrombocytopenia), as well as other important long-term effects. Of these, the principal effect is T-cell immunosuppression, leading to a recommendation for prophylactic antibiotic treatment against Pneumocystis carinii pneumonia, and irradiation of all blood products given to the patient to prevent transfusion-related graft-versus-host disease. Concurrent corticosteroids increase this risk due to the additive lymphocytic activity and should therefore be avoided unless otherwise indicated. Additionally, autoimmune haemolytic anaemia is relatively common in patients with CLL. It occurs in about 1% to 5% of patients receiving fludarabine as a second line treatment. The haemolysis is often severe, may be difficult to treat, and is potentially fatal.
	3.4		Nevertheless, on a day-to-day basis, fludarabine is generally tolerated better than conventional second line chemotherapy regimens, particularly in patients currently considered too frail to withstand combination therapies.
4 Evidence
	4.1 Clinical effectiveness
		4.1.1	There are two randomised controlled trials (RCT) evaluating intravenous fludarabine as a second line agent in CLL. In one of these, comparing fludarabine with cladribine, an unknown number of patients had B-cell CLL. It is not possible therefore to derive from this study results, relevant to the indication under consideration.
		4.1.2	The second RCT compared fludarabine with CAP. Only 96 of 196 patients studied had been previously treated with a first line agent. Response rates (RR) for these previously treated patients were 48% with fludarabine versus 27% with CAP (95% confidence interval on the difference of 21 percentage points was 2 to 40 percentage points). The fludarabine response rate was much higher than that seen in the case series (see below). Mostly, the responses were partial, with just 13% complete responses for fludarabine versus 6% for CAP (the difference is not statistically significant). Time to progression for previously treated patients (responders only) had a median of 324 days for fludarabine versus 179 days for CAP (the difference is not statistically significant). In addition there were 9 deaths in 48 patients with fludarabine compared with 3 out of 48 in the control arm (the difference is not statistically significant). No data on quality of life were collected as part of the trial. Adverse events, mostly haematological, were common in both arms of the trial.
		4.1.3	For intravenous fludarabine, six case series with an aggregate population size of almost 1000 were found. Response rates averaged 32%. The response rate appears to decline in patients who have been treated more heavily prior to treatment with fludarabine, and is generally lowest for patients for whom fludarabine is the treatment of last resort. Where reported, mild or moderate side effects were common although 72% of patients experienced severe haematological adverse events (based on laboratory results). The degree and length of response in these studies is greater than those of comparable studies for combination therapy, although it is not known whether there is an impact on length of survival. The quality of all such studies is lower than that of randomised controlled trials, due to the possibility of unrepresentative or biased patient selection, heterogeneity between studies, and placebo effects of unknown size.
		4.1.4	Quality of life data have not been formally collected as part of these studies. Some evidence, however, is available from the Lymphoma Association, whose survey showed that 74% of patients consider that they are in as good or better health during fludarabine treatment as they would have been with other chemotherapy.
		4.1.5	Recent data from the MRC-sponsored CLL3 study show that, for patients who failed to respond to first-line treatment with chlorambucil or chlorambucil plus epirubicin at 6 months, 80% responded to fludarabine (17% complete, 63% partial). This evidence is in general supportive of the use of fludarabine second line. It is, however, subject to the biases of being an uncontrolled case series, the difficulty in defining non-responders and the variation in times to recruitment into the study following 'failure' of first line treatment.
		4.1.6	Other evidence in the form of four randomised controlled trials for fludarabine alone against other chemotherapeutic agents for first line treatment (for which fludarabine is not currently licensed) shows that fludarabine gives higher rates of remission and longer remission than CAP, CHOP, or chlorambucil plus prednisolone, but no demonstrated survival advantage. For fludarabine against chlorambucil, one study favours fludarabine as above, but the other finds no difference between the two drugs. Assuming that a high positive correlation exists between the relative performance of fludarabine against its comparators in first and second line therapies, this evidence supports the case for the use of fludarabine in second-line therapy.
		4.1.7	For oral fludarabine, an open study of 78 previously treated patients with CLL showed that 46% of patients responded (20% complete and 26% partial remission). Evidence on the bioavailability of the oral formulation and equivalence of blood levels of oral fludarabine with those of the intravenous preparation indicates that orally administered fludarabine is likely to have similar clinical efficacy to the intravenously administered preparation.
	4.2. Cost effectiveness
		4.2.1	No single piece of evidence is strong enough to establish whether fludarabine is a clinically effective agent for second line treatment of CLL. When the evidence is taken in aggregate, however, it is supportive of fludarabine as a clinically effective drug for this indication. The assessment of cost effectiveness, however, is also subject to considerable uncertainty, because reliable figures for the costs of dealing with adverse side effects are not available.
		4.2.2	Three sources have been used to examine the costs of overcoming adverse events in using fludarabine and CHOP. The first (described as the low estimate), submitted by the manufacturer, is based on very small numbers of patients, and is therefore subject to large sampling error. The second (described as the high estimate) was submitted by a different manufacturer for the treatment of a different type of lymphoma, and was also based on a small sample. This source yielded cost estimates over six times as high as the first source, much of which appears to be attributable to the disease having advanced much further, on average, in patients from the second source. The third was from the MRC trial CLL3, which may have included costs associated with the disease per se, as well as of side effects of fludarabine, yielded costs comparable with those of the high estimate.
		4.2.3	The cost effectiveness estimates have been examined separately for oral and intravenous fludarabine, and for both of these against the comparators of CHOP and of no treatment, for both high and low estimates of the cost of side effects.
		4.2.4	Oral fludarabine is less costly to administer than intravenous fludarabine. The estimated combined cost of acquisition and administration, based on an average of 4.1 cycles administered, is £3,000 for oral fludarabine (comprising £2,700 for acquisition and £300 for administration) against £5,300 for intravenous fludarabine (£2,700 acquisition, £2,600 administration).
		4.2.5	The mean cost per year of remission from CLL of oral fludarabine against no treatment is estimated to be £9,000 (low cost of treating side effects) or £21,000 (high cost of treating side effects); for intravenous fludarabine, the corresponding estimates are £14,000 and £28,000; and for CHOP are £22,000 and £67,000.
		4.2.6	The mean incremental cost-effectiveness ratio for oral fludarabine against CHOP is estimated to be £2,700 per year of remission (low cost of treating side-effects) and £200 per year of remission (high cost of treating side-effects) (the latter figure is smaller than the former because the cost of treating side-effects for CHOP is also much higher in the high-cost scenario). The corresponding estimates for intravenous fludarabine against CHOP are £10,600 and £10,500. Even if there is no increase in overall survival using fludarabine compared with that of CHOP, it is probable that oral fludarabine is cost effective against CHOP.
		4.2.7	In clinical practice it is likely that if fludarabine were not given, then patients who would otherwise have been prescribed it would be prescribed CHOP or an equivalent combination. In this situation oral fludarabine is both a more clinically effective and a more cost effective drug than its alternatives, as well as being more likely to be acceptable to patients.
5. Implications for the NHS
	5.1		This guidance is not expected to result in a net increase in NHS expenditure in England and Wales, because fludarabine is already in common use. Increases in drug acquisition costs are likely to be offset by the transfer to the oral formulation, and because the switch from combination therapies to fludarabine should reduce the costs of treating adverse side effects.
	5.2	(a)	For each patient already being treated with fludarabine, it can be expected that cost savings in drug administration in switching from intravenous to oral fludarabine will be about £2,300 per course of an average 4 cycles (there was an average of 4 cycles of oral fludarabine given in one of the key trials).
		(b)	For each patient new to fludarabine therapy who would otherwise have been prescribed combination chemotherapy (CHOP, CAP or CVP), the increased drug acquisition cost of fludarabine should be partially or fully offset by cost savings from avoiding the necessity of treating the side effects of combination drug therapy. For this group of patients, the net cost effect, on average, is likely to have a range of zero to £2,000, although this does not include the further costs of those who might subsequently also be treated with combination chemotherapy.
		(c)	For each patient new to fludarabine therapy who would not have been able to tolerate combination chemotherapy, the additional costs are likely to be of the order of £6,000 to £9,000 per patient.
6. Implementation
	6.1		Clinicians with responsibility for treating people with CLL should review their current practice in line with the guidance set out in Section 1.
	6.2		To enable clinicians to audit their own compliance with this guidance it is recommended that treatment plans are recorded for each patient.
	6.3		This information should be incorporated into local audit data recording systems and consideration given (if not already in place) to the establishment of appropriate categories in routine electronic record keeping systems used in hospitals and the multi-disciplinary groups working in support of patients with CLL.
	6.4		Relevant clinical guidelines and protocols for CLL should be reviewed in the light of this guidance.
	6.5		Prospective clinical audit programmes should record the proportion of treatments adhering to this guidance. Such programmes are likely to be more effective in improving patient care when they form part of the organisation's formal clinical governance arrangements and where they are linked to specific post-graduate activities.
7. Further Research
	7.1.		Further appropriately constructed clinical trials should assess impact on quality of life directly.
	7.2.		Further research into fludarabine as a first line therapy, either singly or in combination with current first line drugs, would be of value. Recruitment of patients to the current CLL4 trial is recommended.
	7.3.		More comprehensive research, in the form of an adequately powered randomised controlled trial, to determine with greater certainty whether oral fludarabine is as clinically effective as intravenous fludarabine, is required.
8. Review of guidance
	8.1.		This advice will be reviewed in August 2004.
Andrew Dillon
Chief Executive
September 2001

APPENDIX A - Appraisal Committee Members

The appraisal committee is a statutory committee whose members sit for 3 years. Two meetings are held per month and the majority of members attend one of the other. Declared interest may also exclude a member from individual technology appraisals. The committee are supplemented by technology specific experts as indicated in Appendix B.

 

Professor R. L. Akehurst
Dean, School of Health Related Research
Sheffield University

Professor David Barnett (Chairman)
Professor of Clinical Pharmacology
University of Leicester

Professor Sir Colin Berry
Professor of Morbid Anatomy
St Bartholomew's and Royal London School of Medicine

Dr Sheila Bird
MRC Biostatistics Unit,
Cambridge

Professor Martin Buxton
Director of Health Economics Research Group
Brunel University

Dr Karl Claxton
Lecturer in Economics
University of York

Professor Duncan Colin-Jones
Professor of Gastroenterology
University of Southampton

Professor Sarah Cowley
Professor of Community Practice Development
Kings College, London

Dr Nicky Cullum
Reader in Health Studies
University of York

Mr Chris Evennett
Chief Executive
Mid-Hampshire Primary Care Group

Professor Terry Feest
Clinical Director and Consultant Nephrologist
Richard Bright Renal Unit and
Chairman of the UK Renal Registry

Ms Jean Gaffin
Formerly Executive Director
National Council for Hospice and Specialist Palliative Care Service

Mrs Sue Gallagher
Chief Executive
Merton, Sutton and Wandsworth Health Authority

Dr Trevor Gibbs
International Medical Operations Director
GlaxoWellcome R&D Ltd

Mr John Goulston
Director of Finance
The Royal Free Hampstead NHS Trust

Professor Philip Home
Professor of Diabetes Medicine
University of Newcastle

Dr Terry John
General Practitioner
The Firs, London

Dr Diane Ketley
Clinical Governance Programme Leader
Leicester Royal Infirmary

Dr Mayur Lakhani
General Practitioner,
Highgate Surgery, Leicester and
Lecturer, University of Leicester

Mr M Mughal
Consultant Surgeon
Chorley and South Ribble NHS Trust

Mr James Partridge
Chief Executive
Changing Faces

Professor Philip Routledge
Professor of Clinical Pharmacology
University of Wales

Professor Andrew Stevens
Professor of Public Health
University of Birmingham

APPENDIX B

Sources of Evidence

 

1.			The following documentation and opinion was made available to the Committee:
	a.		Assessment Report prepared by the Department of Public Health and Epidemiology, University of Birmingham (Fludarabine as second line therapy for B-Cell chronic lymphocytic leukaemia, January 2001)
			Assessment Report Annexe prepared by the Department of Public Health and Epidemiology, University of Birmingham (Fludarabine as second line therapy for B-Cell chronic lymphocytic leukaemia: Effectiveness Annexe, May 2001)
			Assessment Report Cost-Effectiveness Annexe prepared by Dr A J Fischer, NICE Appraisals Team, May 2001
	b.		Manufacturer/Sponsor submissions:
		1.	Schering Health Care Ltd
	c.		Professional/Specialist Group, Patient/Carer Group and Trade Association submissions:
		1.	British National Lymphoma Investigation and UK CCCR
		2.	British Committee for Standards in Haematology (BCSH)
		3.	CancerBACUP
		4.	Lymphoma Association
		5.	Macmillan Cancer Relief
		6.	Royal College of Pathologists
	d.		External expert and patient advocate submissions:
		1.	Dr Andrew MacMillan, Oncologist, Mount Vernon Hospital
		2.	Dr Peter Hoskin, Consultant Clinical Oncologist, Mount Vernon Hospital
		3.	Dr Tracey Murray, Lecturer/Practitioner, St George's Healthcare NHS Trust
		4.	Catriona Moore, Policy Officer, CancerBACUP
		5.	Judith Brodie, Head of Cancer Support Services, CancerBACUP
		6.	Catriona Gilmour Hamilton, Assistant Head of Information Services, The Lymphoma Association

.Appendix C - Patient Information

Guidance on the use of fludarabine as second line therapy for B-cell chronic lymphocytic leukaemia

The patient information in this appendix has been designed to support the production of your own information leaflets. You can download it from our website at www.nice.org.uk where it is available in English and Welsh. If you would like printed copies of the leaflets please ring the NHS Response Line on 0870 1555 455 and quote reference number N0027 for the English patient leaflet and N0028 for the bi-lingual patient leaflet.

What is NICE Guidance?

The National Institute for Clinical Excellence (NICE) is a part of the NHS. It produces guidance for both the NHS and patients on medicines, medical equipment, diagnostic tests and clinical and surgical procedures, and how and when they should be used.

When the Institute evaluates these things, it is called an appraisal. Each appraisal takes around 12 months to complete and involves the manufacturers of the drug or device, the professional organisations and the groups who represent patients and their carers. NICE was asked to look at the available evidence on fludarabine and provide guidance that would help the NHS in England and Wales decide where it should be used in the management of B-cell chronic lymphocytic lymphoma.

What is chronic lymphocytic leukaemia?

Cancer is a disease of the body's cells. Normally, all cells divide and reproduce themselves in an orderly and controlled manner. In cancer, cells multiply without proper control. Chronic lymphocytic leukaemia (CLL) is cancer of the white blood cells (lymphocytes). People with CLL have abnormal white blood cells that prevent the red blood cells, the normal white blood cells and the platelets (particles that have a role in the clotting of blood) from working properly. This can stop the blood from clotting, cause anemia (lack of iron in the blood) and expose people with CLL to infections.

CLL is the most common form of leukaemia. It affects mainly older people - about 7 out of 10 people diagnosed with CLL are over the age of 60. Twice as many men as women are affected. The length of time people live with CLL depends on how far the disease has progressed when it is first diagnosed.

The type of treatment given for a cancer depends on many factors. These include:

• the type of cancer
• where in the body it started
• what the cancer cells look like under the microscope
• how far they have spread, if at all
• the general health of the patient

Treatments for CLL vary depending on the stage of the disease. For people at an early stage, there is no evidence that treatment with drugs has any benefits, rather, it may cause harm. Initial treatment is usually 'watchful waiting', during which the condition is carefully monitored for any change. If the disease progresses, or if diagnosis is made at a later stage, a series of treatments using combinations of chemotherapy drugs are available. Chemotherapy drugs are anti-cancer drugs that are used to destroy cancer cells. These treatments can themselves sometimes cause harm to the person taking them. Doctors and patients will therefore want to discuss the benefits and the possible disadvantages of treatment before starting.

What is fludarabine?

Fludarabine is a chemotherapy drug. It works by preventing cancer cells reproducing and can therefore slow down the progression of the disease. It can be given either by a drip into a blood vessel or by tablet. This treatment is given every day for 5 days and is called a 'treatment cycle'. The treatment cycle is then repeated every 28 days for up to 6 cycles. If the drug is given by a drip, then the person with CLL usually has to visit hospital on each day of the cycle. If it is given as a tablet then the person with CLL may need to visit the hospital less often.

Side effects of fludarabine include nausea (feeling sick), vomiting and hair loss. There can also be some more severe long-term side effects relating to the blood and ability to fight infection.

What has NICE recommended about the use of fludarabine?

NICE has recommended to the NHS that:

People with B-cell chronic lymphocytic leukaemia (CLL) who have had to stop their first chemotherapy treatment (for example because it was causing side effects or their disease had progressed), may be treated with fludarabine tablets.

may be introduced at the stage where people with CLL might have previously been offered one of the following combination treatments:

• cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)
• cyclophosphamide, doxorubicin and prednisolone (CAP), or
• cyclophosphamide, vincristine and prednisolone (CVP)

People with CLL should only be given fludarabine by a drip when their condition is such that they are unable to take the tablets.

What should I do?

If you, or someone you care for, has CLL then you may wish discuss this advice with the doctor or nurse at your next appointment.

Will NICE review its guidance?

Yes. The guidance will be reviewed August 2004.

Further Information:

Further information on NICE, and the full guidance issued to the NHS is available on the NICE web site (www.nice.org.uk).

The guidance can also be requested from 0870 1555 455, quoting reference N0025.

If you have access to the Internet and would like to find out more about cancer visit the NHS Direct website: www.nhsdirect.nhs.uk. If you would like to speak to NHS direct please call them on 08 45 46 47.

APPENDIX D - Staging Systems

Rai	Characteristics	Median Survival
Stage 0	Lymphocytosis in blood and bone marrow only	12 years
Stage I	Lymphocytosis plus lymphadenopathy	7 years
Stage II	Lymphocytosis plus splenomegaly or hepatomegaly
Stage III	Lymphocytosis plus anaemia (Hb < 110="" g/l)="">	< 1="">
Stage IV	Lymphocytosis plus thrombocytopenia (platelets < 100="" x="">9/L)
Binet*
Stage A	< 3="" sites="" involved,="" hb=""> 100 g/L, platelets > 100 x 109/L	9 years
Stage B	> 3 sites involved, Hb > 100 g/L, platelets > 100 x 109/L	5 years
Stage C	Hb < 100="" g/l,="" platelets=""> 100 x 109/L	2 years

· Involved sites are liver, spleen and lymph nodes in inguinal, axilliary and cervical regions.