Cll Guideline 2005

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Guidelines on the diagnosis and management of chronic

lymphocytic leukaemia

Methods

The purpose of this guideline is to provide a rational approach

to the diagnosis and management of patients with chronic

lymphocytic leukaemia (CLL).

This guideline has been compiled by the Guidelines

Working Group of the UK CLL Forum on behalf of the

British Committee for Standards in Haematology (BCSH).

Recommendations are based on a review of the literature using

Medline/Pubmed searches under the heading, CLL, up to

October 2003 and data presented at the American Society ofHematology in 2003 and at the 10th International Workshop

on CLL in 2003. The results of meta-analyses and phase 3

studies that have been published or presented in abstract form

are included. Treatment recommendations were influenced by

current and proposed clinical trials in the UK and by guidance

from The National Institute for Clinical Excellence (NICE). A

draft guideline was reviewed by members of the UK CLL

Forum, patient representatives, members of the BCSH and

a panel of approximately 60 UK haematologists. Their

comments were incorporated where appropriate. To ensure

widespread dissemination, the guideline is available on the

BCSH website.Criteria for levels of evidence and grades of recommenda-

tion are shown in Table I. The guideline will be reviewed and

updated in 2005, and a full guideline revision is planned for

2007.

Epidemiology

Chronic lymphocytic leukaemia is the most common type of

leukaemia in the western world, accounting for 40% of all

leukaemias in individuals over the age of 65 years. The median

age of presentation is between 65 and 70 years. CLL is

extremely rare below the age of 30 years but 2030% of

patients present under the age of 55 years. The overall

incidence is approximately 3 per 100 000 per year. Studies

on the racial and geographic distribution show that CLL is

2030 times commoner in Europe, Australasia and North

American white and black populations than in India, China

and Japan. The male/female ratio in all populations is

approximately 2:1 (Sgambati et al, 2001).

There is no good evidence that exposure to chemicals or

radiation, diet, cigarette smoking, viral infections or auto-

immune disease are risk factors for the development of CLL.

However, there is an increase in both lymphoid malignancies,

including CLL, and a subclinical monoclonal B-cell expansion

in first and second degree relatives of patients with CLL

(Houlston et al, 2002; Rawstron et al, 2002). The phenomenon

of anticipation in which the disease presents earlier and in a

more severe form in successive generations is seen in manyfamilies with CLL (Yuille et al, 1998).

The incidence of second malignancies is increased both in

treated and untreated CLL.

Diagnosis and prognostic factors

Diagnostic investigations

Patients may present with lymphadenopathy, systemic symp-

toms such as tiredness, night sweats and weight loss or the

symptoms of anaemia or infection. However, 7080% of

patients are now diagnosed as an incidental finding on aroutine full blood count. The initial clinical evaluation

should seek to elicit a family history of lymphoid malig-

nancy, susceptibility to infection, significant co-morbid

conditions, and the presence of peripheral lymphadenopathy,

hepatosplenomegaly and bulky intra-abdominal lymphaden-

opathy.

A definitive diagnosis of CLL is based on the combination of

a lymphocytosis and characteristic lymphocyte morphology

and immunophenotype.

Blood count. Current criteria for the diagnosis of CLL

require a lymphocytosis of >5 109/l. Patients whose

routine blood count shows a lower level of lymphocytosis

may subsequently develop clinically significant CLL. Options

for adult patients with a lymphocytosis of between 3 and

5 109/l and lymphocyte morphology consistent with CLL

include immunophenotyping or a follow-up blood count.

However, there is no evidence that early diagnosis of

asymptomatic patients with minimal lymphocytosis confers

clinical benefit.Correspondence: BCSH Secretary, British Society for Haematology,

100 White Lion Street, London N1 9PF, UK.

E-mail: [email protected]

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Lymphocyte morphology. Two subgroups of CLL can be

distinguished using morphological criteria (Bennett et al,

1989). In typical CLL >90% of cells are small or medium

sized lymphocytes with clumped chromatin, indistinct or

absent nucleoli and scanty cytoplasm. In 15% of patients, the

morphology is atypical; due to the presence of >10%

prolymphocytes (CLL/PL) or >15% of cells showing

lymphoplasmacytoid differentiation and/or cleaved nuclei.

Immunophenotyping. Immunophenotyping should be performedin all cases requiring treatment and is of particular value in the

following situations: (i) in cases with low lymphocyte counts to

confirm the diagnosis of CLL and exclude reactive

lymphocytosis; and (ii) in patients with atypical lymphocyte

morphology to exclude other B- or T-cell lymphoproliferative

disorders. Typically, CLL cells express weak monotypic surface

immunoglobulin, CD5 CD19, CD23 and weak or absent

CD79B, CD22 and FMC7. A recommended panel of

monoclonal antibodies and scoring system for the diagnosis

of CLL is shown in Table II (Moreau et al, 1997). Using this

scoring system, 92% of CLL cases score 4 or 5, 6% score 3 and

2% score 1 or 2. Most other chronic B-cell lymphomas and

leukaemias score 1 or 2, but a minority score 3.

Additional investigations

Additional investigations that may be helpful either at

presentation and/or during the course of the disease include:

direct antiglobulin test (DAT) (essential in all anaemic

patients and before starting treatment);

reticulocyte count;

renal and liver biochemistry (including urate levels);

serum immunoglobulins;

chest X-ray;

bone marrow aspirate and trephine biopsy.

Although marrow examination is not usually essential for the

diagnosis of CLL, the presence of proliferation centres and

absence of paratrabecular foci and cyclin D1 nuclear staining

support a diagnosis of CLL in cases with atypical morphology

and a low immunophenotype score. Marrow examination is

also valuable for determining the cause of cytopenias, providing

prognostic information and assessing the response to therapy.

Lymph node biopsy. Lymph node histology is not required for

the diagnosis of typical CLL but may be indicated where the

diagnosis is uncertain, in patients who develop bulky

lymphadenopathy (particularly if localized to one lymph

node area) and to exclude transformation to lymphoma or

an unrelated cause of lymphadenopathy.

Cytogenetic/fluorescence in situ hybridization (FISH) analysis. As

with bone marrow and lymph node biopsy, genetic studies are

not essential for the diagnosis of typical CLL. However, they

may be helpful when there is diagnostic uncertainty. It is

particularly important to exclude a t(11;14) translocation in

CD5 positive cases with a low immunophenotype score.

Computed tomography scan and/or ultrasound. These

investigations may be helpful when the presence of

splenomegaly is uncertain on physical examination, where

Table I. Criteria for (A) levels of evidence and (B) grades of recom-

mendation.

(A) Levels of evidence

Level Type of evidence

Ia Evidence obtained from meta-analysis of randomized

controlled trialsIb Evidence obtained from at least one randomized controlled

trial

IIa Evidence obtained from at least one well designed

controlled study without randomization

IIb Evidence obtained from at least one other

type of well designed quasi-experimental study

III Evidence obtained from well-designed non-experimental

descriptive studies, such as comparative studies, correlation

studies and casecontrol studies

IV Evidence obtained from expert committee reports or opinions

and/or clinical experiences of respected authorities

(B) Grades of recommendation

Grade Evidence level Recommendation

A Ia, Ib Required at least one randomized

controlled trial as part of the body

of literature of overall good quality

and consistency addressing specific

recommendation

B IIa, IIb, III Required availability of well-conducted

clinical studies but no randomized clinical

trials on the topic of recommendation

C IV Required evidence obtained from expert

committee reports or opinions and/or

clinical experiences of respects authorities

Indicates absence of directly applicable

clinical studies of good quality

Table II. Scoring system for the diagnosis of chronic lymphocytic

leukaemia (CLL).

Marker

Score points

1 0

Smlg Weak Strong

CD5 Positive NegativeCD23 Positive Negative

FMC7 Negative Positive

CD22 or CD79b Weak Strong

Scores in CLL are usually >3, in other B-cell malignancies the scores

are usually


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the finding of intrathoracic or bulky intra-abdominal disease

would influence the need for, or choice of, therapy and to

determine remission status following treatment in patients

with bulky nodes prior to therapy.

Prognostic factors

The variable clinical course in CLL is a consequence of the

frequency with which the disease is diagnosed in a preclinical

phase, differences in the rate of disease progression between

cases and the varying response to treatment.

The median survival is approximately 10 years but this figure

is of little value to an individual patient due to the extraordin-

ary heterogeneity in the natural history of this disorder. Two

studies have shown that the median survival of CLL is

independent of whether patients present above or below 50

55 years (Montserrat et al, 1991; Moreau et al, 1997; Mauro

et al, 1999). However, younger patients are more likely to die of

CLL-related causes while older patients more commonly die of

unrelated causes including second primary malignancies. Datafrom the Medical Research Council (MRC) CLL trials have

consistently shown that response rates to treatment and

survival is better in women than in men (Catovsky et al,

1989). Established prognostic factors and more recent tests,

which appear to provide additional prognostic information, are

shown in Table III and include the following.

Clinical stage. The clinical staging systems devised by Binet

et al (1981) and Rai et al (1975) are the simplest and best-

validated means of assessing prognosis (Table IV). It is

important to exclude haemolysis and unrelated causes of

anaemia or thrombocytopenia before assigning a patient to

Binet stage C or the Rai high-risk group. Limitations of both

systems include the choice of a single (but different)

haemoglobin level to define marrow failure regardless of

the sex of the patient, and the inability to predict the rate of

disease progression in patients presenting with a low tumour

burden. A subgroup of patients with Binet stage A disease

who have smouldering CLL can be identified based on the

following parameters (Monteserrat et al, 1988; French

Co-operative Group on Chronic Lymphocytic Leukaemia,

1990a):

haemoglobin >13 g/dl;

lymphocyte count 12 months.

In one study, only 15% of these patients showed disease

progression after 5 years and 80% were alive at 10 years

(Monteserrat et al, 1988).

Patients entered into the MRC 3 trial with progressive

stage A disease have a similar life expectancy to those

presenting with stage B disease.

Serum markers. These include b2 microglobulin, lactate

dehydrogenase (LDH), serum thymidine kinase and soluble

CD23 (Knauf et al, 1997; Hallek et al, 1999; Di Raimondoet al, 2001; Schwarzmeier et al, 2002). All have been shown to

predict progression and survival in Binet stage A patients, but

their value is currently limited either by the lack of a standard

assay method, variable cut-off points between series or the lack

of validation in a prospective study.

CD38 expression. Many studies have shown that a high level

and/or intensity of CD38 expression on leukaemic lymphocytes

is a poor prognostic factor both in univariate analysis and in

patients of known clinical stage and b2 microglobulin levels

(Damle et al, 1999; Del Poeta et al, 2001; Ibrahim et al, 2001;

Durig et al, 2002; Hamblin et al, 2002; Ghia et al, 2003). The

optimum cut-off level with greatest prognostic significance is

uncertain. Different studies have chosen values of 7%, 20% or

Table III. Prognostic factors in chronic lymphocytic leukaemia.

Factor Low risk High risk

Gender Female Male

Clinical stage Binet A Binet B or C

Rai OI Rai II, III, IV

Lymph ocyte morphology Typical Atypical

Pattern of marrow

trephine infiltration

Non-diffuse Diffuse

Lymphocyte doubling time >12 months


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30%. CD38 expression may vary during the course of the

disease (Hamblin et al, 2002) and although there is a

correlation between high CD38 expression and unmutated

IgVH genes, CD38 is not a surrogate marker for VH gene status.

IgVH gene status. There is a highly significant difference in the

survival between patients with or without mutated IgVH genes

(Damle et al, 1999). In one study, patients with mutated IgVH

genes had a median survival of 25 years compared with 8 years

for patients with unmutated IgVH genes (Hamblin et al,

1999). However, there is still controversy as to the percentage

of mutations which best correlates with clinical outcome

(between 98% and 95% homology to the germline gene) (Lin

et al, 2002). Recent data suggest that the use of particular IgVH

gene segments such as the VH 3.21 gene may confer a poor

prognosis regardless of mutational status (Tobin et al, 2002).

Preliminary data suggest that expression of ZAP70mRNA and

ZAP70 protein, measured using flow cytometry, correlates

closely with IgVH gene mutation status (Crespo et al, 2003;

Wiestner et al, 2003; Orchard et al, 2004).

Cytogenetic abnormalities. Cytogenetic analysis has shown

correlations between chromosome abnormalities and clinical

features in CLL. Patients with a normal karyotype or an

isolated deletion of chromosome 13q have a better prognosis

than those with trisomy 12 as the sole abnormality or with a

complex karyotype (Juliusson et al, 1990). Subsequently, both

chromosome 11q deletions and structural abnormalities of

chromosome 17p were shown to be associated with short

survival (Dohner et al, 1995, 1997). In a univariate analysis,

using a panel of FISH probes, patients with an isolated deletion

of 13q, trisomy 12, deletion of 11q, or of loss of one copy of the

p53 gene on 17p had a median survival of 133, 114, 79 and

32 months respectively (Dohner et al, 2000).

Drug sensitivity testing. Non-randomized studies have

suggested that pretreatment drug sensitivity testing using the

apoptosis by morphology using octospot [AMO; previously

the differential staining cytotoxicity (DiSC)] assay can identify

drug sensitivity and resistance in individual cases (Bosanquet

et al, 1999). The value of the assay in guiding second line

therapy is being evaluated in the MRC/Leukaemia Research

Fund (LRF) CLL4 trial.

Although the finding of good risk prognostic factors can be

reassuring to asymptomatic stage A patients, evidence that theapplication of the prognostic factors discussed above improves

clinical outcome is currently lacking. This is being addressed in

ongoing trials such as the MRC CLL4 study and the German

CLL trials. In the interim, the choice of prognostic markers

should take account of the following considerations:

1 Ideally prognostic markers should be inexpensive, widely

available, quality controlled, validated in phase 3 clinical

trials and shown to provide additional information to

markers in current use.

2 The value of prognostic factors differs for different treat-

ments, e.g. p53 abnormalities predict a poor response to

alkylating agents, purine analogues (Dohner et al, 1995)

and rituximab monotherapy (Byrd et al, 2003a)3 but not to

high-dose steroids or alemtuzumab (Campath 1H).

3 Some prognostic markers, such as VH gene status, remain

constant throughout the disease while others, such as

cytogenetic abnormalities and high CD38 expression, may

be acquired during the disease.Boththe timing and frequency

of testing for prognostic factors are therefore important.

4 Many prognostic markers are closely linked and their value

can only be assessed in multivariate analyses. Two recent

multivariate analyses, which included assessment of cyto-

genetic and genetic abnormalities, CD38 expression and VH

gene status, both showed that only VH gene status and loss

or mutation of the p53 gene had independent prognostic

significance using a cut-off of 98% homology to the

germline sequence to define IgVH gene mutational status.

Deletion of chromosome 11q was also significant in one

study when a cut-off of 97% VH gene homology was chosen(Krober et al, 2002; Oscier et al, 2002).

Management of CLL

Indications for referral

The management of CLL requires a collaborative approach

between primary care and a haematology department. Input

from a palliative care team may sometimes be valuable in the

management of terminal drug resistant patients.

Indications for referral to a haematology department

include: symptomatic disease, the presence of lymphadenop-athy or hepatosplenomegaly and the investigation of a

lymphocytosis, particularly if the lymphocyte count is high

or there is anaemia or thrombocytopenia. The subsequent

management of these patients should be discussed at a multi-

disciplinary team meeting.

The follow-up of patients seen initially in hospital, who do

not require treatment, may be organized in primary care,

hospital outpatients or via a homecare service depending on

local resources and patient wishes. Asymptomatic elderly

patients, with a slight lymphocytosis only, may be managed by

primary care teams, providing indications for referral to a

haematology department are clearly documented.

Communicating with patients

Chronic lymphocytic leukaemia is characteristically a condi-

tion for which the natural history is measured in years and it is

therefore particularly important that patients are able to

establish a relationship and trust with the clinician managing

their condition. Patients who are referred for a haematological

opinion and subsequent management decision will expect and

are entitled to be honestly informed about their disease.

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A frequent dilemma is whether to convey the diagnosis of CLL

to an elderly asymptomatic patient with low count stage A

disease diagnosed on a routine blood count. Anxiety generated

by the use of the word leukaemia can almost always be

prevented by a clear and careful explanation of the benign

nature of the condition. If a decision not to inform a patient is

taken this must be very clearly documented to ensure that

other health care workers do not subsequently impart the

diagnosis without explaining its significance.

The majority of patients benefit from, and should be offered,

information about CLL in general and about their specific

management. The latter might include details of the topogra-

phy of the haematology unit, the staff involved in their care,

who to contact if problems arise, details of local support

groups and whether their treatment may be influenced by

NICE guidelines or budgetary constraints.

General information may be obtained from a wide variety of

sources, as follows:

Books and pamphlets. CANCERBACUP publishes a wide rangeof pamphlets, including one on understanding CLL and others

on living with cancer. For further information go to http://

www.cancerbacup.org.uk4 .

The LRF also produces a range of booklets and pamphlets.

These tend to be rather more technical than those published by

CANCERBACUP. A list of their publications is found at http://

dspace.dial.pipex.com/lrf-//publications/index.htm.

There are three books from the USA that offer comprehen-

sive guides for patients.

Non-Hodgkins Lymphoma by Lorraine Johnson, published

by OReilly.

Adult Leukemia by Barbara Lackritz, published by OReilly. Bone Marrow and Blood Stem Cells Transplants: A Guide

for Patients by Susan Stewart, published by Bone Marrow

information, http://www.bmtinfonet.org/books.html.

Video and audio. CANCERBACUP has several UK-based

videos and audio programmes. It also produces a CD-ROM

that contains a comprehensive guide to all aspects of cancer.

The remaining sources are from the USA. There are several

organizations that produce video or audio programmes for

patients. They are kept current and usually involve well-known

doctors. They are a source of reliable information.

Healthology at http://www.healthology.com/html/splash.htm.

Healthtalk International CLL education network at http://

www.healthtalk.com/cllen/index.html.

Lymphomafocus at http://www.lymphomafocus.org/.

General internet sites. There are numerous sites. It is suggested

that patients should be directed to a few that are known to

be reliable. These sites do contain links to other sources

of information for patients who wish to extend their

knowledge.

GrannyBarbs Leukemia Links, CLL at http://www.acor.org/

leukemia/cll.html. An early site developed by Barbara

Lackritz.

CLL FAQs, Glossary of terms and an ABC of acronyms at

http://www.acor.org/leukemia/cll/cllfaq/cover.html.

Summary of CLL research information at http://www.

acor.org/leukemia/medical_news.htm.

American Cancer Society at http://www3.cancer.org/

docroot/lrn/lrn_0.asp.

UK Cancer resources at http://www.cancerindex.org/

clinks44.htm.

National Cancer Institute (NCI) site at http://www.can-

cer.gov/cancerinfo/.

The patients guide to CLL from the NCI at http://

www.cancer.gov/templates/doc_pdq.aspx?versionpatient

&cdrid62684.

On-line discussion groups. Some patients may wish to join a

group of others with the same condition where they can share

their experience. There is a large international group for CLL, for

moreinformationon thisand other groupsthat maybe of interest

the contact is http://www.acor.org/mailing.html. Patients may

also join the UK CLL Forum, which publishes a newsletter.

Indications for treatment

The indications for treatment recommended by the NCI

sponsored working group are shown in Table V (Cheson et al,

1996). These criteria will encompass the majority of patients

with Binet stage B or C disease anda proportion of patients with

Binet stage A disease, showing features of disease progression.

Stage A patients who develop autoimmune haemolytic anaemia(AIHA) or immune thrombocytopenic purpura (ITP) should be

treated for their autoimmune cytopenia but may not require

anti-leukaemic therapy. The minority of patients who present

with either Binet stage B disease, with generalized non-bulky

lymphadenopathy and/or minimal hepatosplenomegaly, or with

Table V. Indications for treatment.

Progressive marrow failure: the development or worsening of anaemia

and/or thrombocytopenia

Massive (>10 cm) or progressive lymphadenopathy

Massive (>6 cm) or progressive splenomegaly

Progressive lymphocytosis>50% increase over 2 months

Lymphocyte doubling time 10% in previous 6 months

Fever >38C for 2 weeks

Extreme fatigue

Night sweats

Autoimmune cytopenias

*It is important to exclude other causes for these symptoms, such as

infection.

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stage C disease and mild cytopenias and who are asymptomatic,

may be observed without treatment until there is evidence of

symptomatic or progressive disease.

Hyperviscosity due to extreme lymphocytosis is very rare in

CLL and a high lymphocyte count in the absence of a rapid

lymphocyte doubling time is not an indication for treatment.

Neither asymptomatic hypogammaglobulinaemia nor the

presence of a paraprotein are reasons for treatment.

Assessment of response

The criteria for assessing complete response (CR) or partial

response (PR) to treatment recommended by the NCI working

group are shown in Table VI (Cheson et al, 1996). Patients

who fulfil the criteria for a CR but whose bone marrow

trephines contain lymphoid nodules have been designated as

having a nodular PR.

Since the publication of the NCI criteria, new methods have

become available for assessing minimal residual disease (MRD).A variety of techniques are available to detect MRD. A flow

cytometric assay that differentiates CLL cells from normal

B cells based on expression of CD19/CD5/CD20 and CD79b is

rapid, applicable to all patients and can detect one CLL cell in

105 normal cells when 5 105 cells are analysed (Rawstron

et al, 2001). Comparable sensitivity may be achieved using real-

time quantifiable allele-specific oligonucleotide polymerase

chain reaction (PCR) (Pfitzner et al, 2002). However, this

technique is labour intensive and expensive.

Newer therapeutic approaches can result in MRD negative

remissions. The presence of detectable MRD in patients who

achieve a complete remission by NCI criteria followingtreatment with purine analogues, monoclonal antibodies or

autologous transplantation predicts for clinical relapse. How-

ever, patients who initially remain MRD positive after

allogeneic transplantation may subsequently become MRD

negative (Esteve et al, 2002).

A treatment strategy for CLL

Before initiating treatment, consideration must be given to

(i) patient-related factors, such as age, performance status,

co-morbid conditions and patient wishes; (ii) disease-related

factors, such as the severity of symptoms and the presence of

adverse prognostic factors; and (iii) treatment-related factors

including the degree and duration of response to prior

treatments and contra-indications to, and side-effects from,

particular treatment modalities. Pharmacoeconomic consider-

ations (Table VII) are also important.

Chronic lymphocytic leukaemia presents significant man-

agement problems by virtue of the heterogeneity in both the

age of presentation, in the natural history of the disease and

also the frequency with which CLL is diagnosed in a

preclinical phase. The median survival of patients with

advanced CLL is usually superior to that seen in many other

haematological malignancies and solid tumours. In the

absence of a curative treatment, most patients receive a

number of different treatment modalities during the course

of the disease. The response to a particular treatment varies

according to its place in the overall treatment strategy, such

that treatments which produce high response rates whenused as initial therapy may also make a substantial contri-

bution to prolonging survival when given later in the disease,

particularly if they are administered after less active agents.

Table VI. Response criteria.

Criteria Complete response Partial response Progressive disease

Symptoms None

Lymph nodes None >50% decrease >50% increase or new nodes

Liver/spleen Not palpable >50% decrease >50% increase or new nodes

Haemoglobin

(untransfused)

>110 g/dl >110 g/dl or >50% improvement from baseline

Neutrophils >15 109/l >15 109/l or >50% improvement from baseline

Lymphocytes 50% decrease >50% increase

Platelets >100 109/l >100 109/l or >50% improvement from baseline

Marrow aspirate


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The latter phenomenon is seen in trials in which the design

permits crossover between two treatment arms for patients

who have not responded to their initial therapy. Although it

is relatively easy to measure the rates of response to any

given therapy, proving that this ultimately translates into a

survival advantage is more difficult.

Current strategies for the management of CLL, particularly

in those patients with good performance status, mirror those

adopted in other haematological malignancies and seek to

achieve MRD negative responses. An important consideration

on beginning treatment in CLL is whether to adopt a palliative

approach and treat symptomatic disease with regimens causing

minimal treatment-related toxicity, or to aim for prolonged

disease-free survival in the hope that this will translate into

superior overall survival.

Initial treatment

Treatment of early stage CLL. In 1998, the French Co-operative

Group on CLL reported the outcome of two trials comparinginitial or deferred treatment until disease progression in Binet

stage A CLL (Dighiero et al, 1998).

One trial included 609 patients, randomized to receive either

no treatment or chlorambucil 01 mg/kg/d until drug resis-

tance. The second trial randomized 926 patients to no

treatment or to chlorambucil 03 mg/kg and prednisolone

40 mg/m2 daily for 5 d per month for 3 years.

Early treatment with chlorambucil slowed the rate of disease

progression but there was no difference in overall survival in

either trial between early and delayed treatment. A subsequent

meta analysis of 2048 patients in six trials of immediate

treatment with chlorambucil plus or minus prednisolone

vs. deferred treatment showed no significant difference in

10 years survival (CLL Trialists Collaborative Group, 1999).

In the untreated arm of the first French Co-operative Group

Trial 51% of patients showed disease progression and 27% of

stage A patients died of disease-related causes. There is current

interest in conducting clinical trials to evaluate whether

asymptomatic stage A patients with poor risk disease might

benefit from newer and more effective treatments than

chlorambucil. The choice of prognostic markers and treatment

options is currently under discussion.

Treatment of early stage disease with chlorambucil is not

indicated (grade A recommendation, level Ia evidence).

Treatment of advanced or progressive disease

There are no randomized studies comparing treatment versus

no treatment in patients with advanced disease stage. Evidence

indicating the need for treatment comes indirectly from the

obvious symptomatic and clinical improvement, as well as the

survival advantage, seen in those patients who respond to

therapy compared with non-responders (Robak & Kasznicki,

2002).

Alkylating agents. Early studies used low dose chlorambucil

with or without prednisolone/prednisone. The combined CR

and PR rates ranged from 4586%. In no study was there any

advantage in terms of progression-free interval or overall

survival with the addition of prednisolone/prednisone to

chlorambucil (Han et al, 1973). Similarly, there was no

difference between continuous and intermittent chlorambucil

therapy (Sawitsky et al, 1979). Patients who are intolerant of

chlorambucil may respond to low dose daily

cyclophosphamide.

Four randomized studies have compared chlorambucil with

COP (cyclophosphamide, vincristine, prednisolone) in 630

patients (Montserrat et al, 1985; French Co-operative Group

on Chronic Lymphocytic Leukaemia, 1990b5 ; Catovsky et al,

1991; Raphael et al, 1991). COP resulted in more rapid

responses and a higher response rate, but there was no

difference in progression-free interval and overall survival.

In 1986, the French Co-operative Study Group reported a

significant survival advantage for patients with previously

untreated advanced disease stage using a modified CHOPregimen (cyclophosphamide, adriamycin, vincristine, predn-

isolone) utilizing a lower dose of adriamycin than the CHOP

regimen introduced for the treatment of lymphoma, compared

with COP (French Co-operative Group on Chronic Lymph-

ocytic Leukaemia, 1990b). In this study, however, the COP

arm fared worse than in previously reported studies. A meta-

analysis of 2022 patients in 10 trials, comparing combination

therapy with chlorambucil with or without prednisolone,

showed an identical 5-year survival of 48% in both groups

(CLL Trialists Collaborative Group, 1999). Six of the 10

studies included an anthracycline and a subgroup analysis of

these trials also showed no survival advantage compared with

chlorambucil.

A number of studies have evaluated the role of higher dose

chlorambucil in CLL. A total of 279 patients were randomized

to either high-dose chlorambucil (15 mg daily) or intermittent

chlorambucil (75 mg every 4 weeks) with prednisolone.

Patients receiving continuous high-dose treatment achieved a

higher remission rate (70% vs. 30%) and longer median

survival (6 years vs. 3 years, P < 001) (Jaksic & Brugiatelli,

1988).

A subsequent study randomized 228 previously untreated

patients to either high-dose chlorambucil at a fixed dose of

15 mg/d until either a CR, grade 3 toxicity or to a maximum of

6 months (Jaksic et al, 1997). This induction phase was thenfollowed by maintenance therapy with chlorambucil given at a

dose of 515 mg twice weekly according to haematological

tolerability. The other arm of the study comprised the CHOP

regimen using the doses proposed by the French Co-operative

Group on CLL. Six cycles of induction treatment were given

followed by maintenance therapy with six additional courses

given at three monthly intervals. High-dose chlorambucil

resulted in a higher overall response rate (ORR) (89% vs. 75%)

and prolonged median survival (68 months vs. 47 months)

after a median follow-up of 37 months. Studies on high-dose

Guideline



8/24

chlorambucil were excluded from the meta-analysis of rand-

omized trials described above. They are difficult to evaluate in

comparison with other phase 3 trials of chlorambucil, as they

utilize non-standard response criteria: namely a total tumour

mass score (Jaksic & Vitale, 1981) and a diagnosis of marrow

failure based on a haemoglobin of


9/24

(Robak et al, 2000a6 ). Sixty-seven per cent of patients resistant

to chlorambucil respond to cladribine, but only 27% of

patients who failed cladribine benefited from second line

treatment with chlorambucil.

Although these results were broadly similar to those

achieved with fludarabine, the extent of the evidence is

considerably less and it is currently not possible to recommend

cladribine as a routine alternative to fludarabine for the initial

therapy of CLL.

To prevent transfusion related graft versus host disease

(GVHD), all patients treated with a purine analogue should

receive irradiated blood products indefinitely thereafter

(BCSH, 1996).

Steroids. There is no evidence that prolonged treatment with

low, intermediate or high-dose steroids is an effective initial

treatment for CLL. However, it is recommended that patients

with stage C disease should be given a short course of

prednisolone before receiving chlorambucil (grade C

recommendation, level IV evidence).

Monoclonal antibodies. Alemtuzumab, given intravenously to

nine previously untreated patients resulted in three CR and

five PR (Osterborg et al, 1997). A subsequent phase 2 trial, in

which alemtuzumab was given subcutaneously at a dose of

30 mg three times per week for up to 18 weeks to 41 patients,

produced an ORR of 81% with 19% CR (Table IX). The

median time to treatment failure has not been reached

(>18 months) (Lundin et al, 2002). Alemtuzumab therapy

results in high ORR in untreated CLL but follow-up is short

and benefit over conventional therapy has not been

demonstrated. Ten per cent of patients develop

cytomegalovirus (CMV) reactivitation. Use of irradiated

blood products is recommended following alemtuzumab.

Single agent rituximab therapy induces short-term PRs in

previously untreated patients. The use of subsequent

maintenance treatment with rituximab in patients responding

to initial treatment with the same agent is being evaluated

(Hainsworth et al, 2003). A randomized phase 2 study,

comparing fludarabine given with either concurrent or

sequential rituximab, showed a higher overall and CR rate

for the concurrent regime but the median response duration

and survival have not been reached for either arm after a

median follow-up of 23 months (Byrd et al, 2003b).

Response rates to rituximab in combination with fludara-

bine and cyclophosphamide are better than historical controls

using any previously reported regimen (Table X). In a study

of 135 patients, complete remission was demonstrated in

67%, and 57% were in molecular remission using a PCR

technique. Thirteen of 41 evaluable PCR negative patients

became PCR positive, usually within 6 months of follow-up

but longer follow-up is required to assess the clinical

benefit of attaining a PCR negative response (Keating et al,

2002a).

Summary of recommendations for initial treatment

For the majority of patients who are ineligible for a transplant

procedure and in whom there is no contraindication to

fludarabine (severe renal impairment or an autoimmune

cytopenia), entry into the MRC CLL4 study should be offered.

This trial randomizes patients to either chlorambucil, fludara-

bine, or fludarabine and cyclophosphamide and assesses the

value of prognostic factors and quality of life issues as well as

outcome. Both fludarabine and chlorambucil are options for

patients who do not wish to enter the study.

Patients in whom fludarabine is contraindicated and for

whom a palliative approach has been adopted should be

treated with chlorambucil (grade A recommendation, level Ia

evidence).

There is no survival advantage for including an anthra-

cycline with chlorambucil in the initial treatment of advanced

CLL (grade A recommendation, level Ia evidence).

Table IX. Use of alemtuzumab alone or in combination in untreated and previously treated chronic lymphocytic leukaemia.

Study Treatment Regimen

No. of patients

OR (%) CR (%)Untreated Treated

Osterborg et al (1996) Alemtuzumab 30 mg, 3 weekly s.c. or i.v. for up to 18 weeks 9 0 89 33

Lundin et al (2002) Alemtuzumab 30 mg, 3 weekly s.c. for up to 18 weeks 41 0 87 19

Osterborg et al (1997)30 Alemtuzumab 30 mg, 3 weekly i.v. for up to 12 weeks 0 29 42 3Kennedy et al (2001) Alemtuzumab 30 mg, 3 weekly i.v. 0 77 44 25

Rai et al (2001) Ale mtuzumab 3 0 mg, 3 weekly i.v. for up to 12 weeks 0 136 40 7

Keating et al (2002c) Alemtuzumab 30 mg, 3 weekly i.v. to maximum response 0 93 33 2

Kennedy et al (2002) Alemtuzumab 30 mg, 3 weekly i.v. 0 6 66 16

Fludarabine 25 mg/m2, 3 d monthly till maximum response

Nabhan et al (2001) Alemtuzumab 330 mg, 3 weekly 0 9 0 0

Rituximab 375 mg/m2, 4 weekly for 5 weeks

Faderl et al (2001) Alemtuzumab 330 mg, 3 weekly 0 22 45 5

Rituximab 375 mg/m2 weekly

OR, overall response; CR, complete remission.

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10/24

Further studies using standard response criteria are required

before high-dose chlorambucil can be recommended as an

initial treatment for CLL (grade C recommendation, level IV

evidence).

Where a patient is considered suitable for entry into the

MRC CLL5 trial or for allogeneic transplantation, then an

initial treatment, such as fludarabine or fludarabine and

cyclophosphamide, which is likely to result in a complete or

very good partial remission, should be chosen (grade C

recommendation, level IV evidence).

Alemtuzumab is not recommended for untreated CLL

(grade B recommendation, level IIb evidence).

Rituximab monotherapy is not recommended in untreated

CLL (grade C recommendation, level III evidence).

Rituximab combined with fludarabine (with or without

cyclophosphamide) requires further evaluation in untreated

CLL (grade B recommendation, level Ib evidence).

Second line and subsequent treatment

There has been only a single randomized study comparing

treatments for patients with relapsed or refractory disease.

Evidence of benefit is largely based on historical control data

and the results of randomized trials of initial treatment in

which patients who fail to respond to one arm of the study arecrossed over to another arm. The inclusion of patients who

may be either minimally or heavily pretreated, and who may

have drug resistant or responsive disease, makes the results of

many second line studies difficult to interpret.

The indications for second line and subsequent treatments

are symptomatic and/or progressive disease, as for initial

therapy, although treatments with curative rather than

palliative intent such as allogeneic transplantation, may be

considered in early relapse, or in first remission. The

response to second line treatments depends on a variety of

factors including clinical stage, adverse biological prognostic

factors, the number of prior therapies and critically,

refractoriness to the last treatment. The second randomiza-

tion in the CLL4 study is designed to evaluate the

effectiveness of the AMO assay in predicting optimal therapy

for patients relapsing after initial treatment. Therapeutic

options are listed below and a therapeutic strategy is shown

in Fig 1.

Alkylating agents alone or in combination

Patients who have responded to an alkylating agent such as

chlorambucil can often be successfully retreated on one or

more occasions. However, the quality and duration of

response is usually inferior to that achieved with the initial

treatment and multiple courses of treatment often result in

the emergence of drug resistance (Galton et al, 1961; Ezdinli

et al, 1969). The response rate to chlorambucil in patients

relapsing after initial treatment with purine analogues is

low. In the US intergroup study, only 7% of patients

responded to chlorambucil after failing fludarabine therapy

(Rai et al, 2000). In a randomized trial between cladrabine

and prednisolone versus chlorambucil and prednisolone,

27% of patients who failed cladrabine subsequently respon-

ded to chlorambucil (Robak et al, 2000b). COP is notsuperior to chlorambucil and prednisolone in patients

relapsing after initial therapy with chlorambucil (Montserrat

et al, 1985).

Anthracycline-containing combination therapy

Although widely used, evidence for the value of anthracy-

cline-containing regimens in previously treated patients is

limited. A randomized phase 3 study comparing CAP with

fludarabine, in patients who had received an alkylating agent

Table X. Use of Rituximab combined with other agents in untreated and previously treated chronic lymphocytic leukaemia.

Study Treatment Regimen

No. of patients

OR (%) CR (%)Untreated Treated

Byrd et al (2003b) Rituximab (i) Concurrent 51 0 90 47

Fludarabine (ii) Sequential 53 0 77 28

Schulz et al (2002) Rituximab 375 mg/m2

* 20 11 87 34Fludarabine 25 mg/m2*

Keating et al (2002a) Rituximab 500 mg/m2 135 0 95 67

Fludarabine 25 mg/m2

Garcia-Manero et al (2001) Rituximab 500 mg/m2 0 167 73 23

Fludarabine 25 mg/m2

Cyclophosphamide 250 mg/m2

Gupta et al (2001) Rituximab Four weekly until maximum response 0 22 77 36

Cyclophosphamide

Dexamethasone

OR, overall response; CR, complete remission.

*For four cycles.

For six cycles.

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11/24

for more than 6 months and less than 3 years, showed an

ORR of 27% in the CAP arm compared with 48% in the

fludarabine arm (P 0036) (French Co-operative Group on

CLL, 1996). A subsequent study conducted by the French

collaborative group (Leporrier et al, 2001) randomized

patients between fludarabine and either CAP or CHOP;

39% of patients failing fludarabine subsequently responded

to CHOP.The above data suggest that anthracycline-containing reg-

imens are less effective than purine analogues in patients

previously treated with chlorambucil, but do have activity in

patients relapsing after purine analogue therapy.

Purine analogues

Numerous phase 1 and phase 2 studies have evaluated the

response of previously treated patients to fludarabine (Grever

et al, 1988; Keating et al, 1988, 1989, 2000, 2002b; Sorensen

et al, 1997). ORR range from 13% to 73% and CR rates from

0% to 37%. Response rates are highest in patients who have

not been heavily pretreated, were not resistant to their

last treatment, have a normal serum albumin and are


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the response rate falls to 12% in patients who are refractory to

previous fludarabine therapy.

Cladrabine has been less extensively evaluated than

fludarabine and there are differences in opinion as to its

correct schedule of administration. However, response rates

are broadly similar to that achieved with fludarabine (Piro

et al, 1988; Saven et al, 1991; Juliusson & Liliemark, 1993,

1994, 1996). The results of a small case series which

reported benefit from cladrabine therapy in three patients

who were refractory to fludarabine (Juliusson et al, 1992)

was not confirmed by the experience of other investigators.

However, a recent study sponsored by the cancer and

leukemia group B (Byrd et al, 2003c) achieved responses in

nine of 28 patients (ORR 32%) for cladrabine in fludarabine

refractory patients.

Small phase 2 studies show that when purine analogues are

administered in combination with other chemotherapeutic

agents to previously treated patients, the response rates are

higher than those achieved with purine analogues alone.

Examples are shown in Table XI.

High-dose methyl prednisolone (HDMP)

Although widely used, there is little published data on the

efficacy of HDMP in relapsed CLL. A study of HDMP given

intravenously or orally at a dose of 1 gm/m2/d for 5 d each

month was performed in 25 patients, 15 of whom were

refractory to fludarabine (Thornton et al, 20037 ). An ORR of

77% was achieved with a median duration of 12 months.

Responses were seen in five of 10 patients with loss and/or

mutation of the p53 gene. The event-free and overall survival

was significantly better in responders than in non-responders.

Patients who relapse after HDMP frequently respond

to further courses of the same treatment. HDMP is contra-

indicated in patients with an active gastric or duodenal ulcer

and should be used with caution in patients with diabetes or

heart failure.

Monoclonal antibodies

Alemtuzumab. A total of 341 patients refractory to fludarabine

have been treated with alemtuzumab in five non-randomized

studies (Table IX). The ORR was 39% (9 4% CR and 30% PR)

with a prolonged median survival compared with historical

data on fludarabine-resistant patients. In the pivotal study of

92 patients with fludarabine-resistant disease, best responses

were seen in patients with a low b2 microglobulin, platelet

count >50 109/l and 5 cm achieved complete resolution of

lymphadenopathy (Keating et al, 2002b). Alemtuzumab may

be effective in some patients with p53 mutations refractory to

purine analogues (Stilgenbauer & Dohner, 2002).

Preliminary data suggest that the combination of fludar-

abine and alemtuzumab may be effective in patients resistant

to both agents given alone (Kennedy et al, 2002).Alemtuzumab has been administered to patients with

residual disease following treatment with fludarabine (OBrien

et al, 2003), and prior to stem cell mobilization (Montillo et al,

2002). Although CRs and MRD-negative responses have been

achieved, some patients have experienced prolonged myelo-

suppression following standard doses of alemtuzumab, and

this sequential regimen should only be used in a clinical trial

setting.

Rituximab. Although rituximab has some efficacy in CLL,

the response rates to rituximab monotherapy in previously

treated patients are poor. Even at very high doses (up to six

times the standard dose), all the responses are partial.

Response rates to rituximab, in combination with

fludarabine or with fludarabine and cyclophosphamide,

given to patients with relapsed or refractory CLL are

superior to those seen with standard second line therapies

such as fludarabine or CHOP (Table X). The use of

fludarabine, cyclophosphamide and rituximab has been

reported in 167 patients with previously treated CLL, of

whom 102 were evaluable with more than 6 months of

follow-up. Fifteen per cent of patients had received

alkylating agents only, 59% had been sensitive to

fludarabine-containing regimens and 26% had been

resistant to fludarabine. Complete remissions, using NCIcriteria, were achieved in 20% of patients who had received

alkylating agents only, 30% of fludarabine-sensitive patients

and 7% of fludarabine-resistant cases (Garcia-Manero et al,

2001). A historical comparison of previously treated patients

receiving either fludarabine, with or without prednisolone,

fludarabine and cyclophosphamide, or fludarabine,

cyclophosphamide and rituximab showed a CR rate and

median survival of 13% and 19 months, 12% and 31 months

and 28% and not reached respectively (Wierda et al, 2003).

Table XI. Combination of a purine analogue with other chemo-

therapeutic agents in previously treated chronic lymphocytic leukae-

mia.

Study

No. of

patients Regimen

Overall

response

rate (%)

Rummel et al (1999) 25 Fludarabine +

epirubicin

60

OBrien et al (2001) 20 Fludarabine +

cyclophosphamide

85

Hallek et al (2001) 18 Fludarabine +

cyclophosphamide

94

Bosch et al (2002) 37 Fludarabine +

cyclophosphamide +

mitoxantrone

78

Montillo et al (2003) 23 Pentostatin +

cyclophosphamide

95

Guideline



13/24

Transplantation in CLL

The majority of patients with CLL are elderly and in older

patients the increased morbidity and mortality of high-dose

chemo-radiotherapy with allogeneic or autologous stem cell

rescue do not justify this approach. About 20% of patients are

aged


14/24

both the higher treatment-related mortality associated with

allografting and the selection of higher risk drug resistant

patients.

Although most patients have received stem cells from

human leucocyte antigen (HLA)-matched siblings, younger

patients with high-risk disease have obtained a durable CR

following transplantation from an unrelated HLA-matcheddonor.

The observations that patients with MRD after allogeneic

transplantation may subsequently become MRD negative

(Esteve et al, 2002), and the clinical benefit of donor lympho-

cyte infusions, strongly suggests that the long-term disease-free

survival achievable following allogeneic transplantation is

immunologically mediated (Ritgen et al, 2002). These data,

together with the high treatment-related mortality associated

with standard allogeneic transplantation, have provided the

impetus for studies using low intensity conditioning regimens.

Treatment-related mortality is reduced but the non-relapse

morbidity and mortality remains high in older patients with

advanced disease. Disabling GVHD can result in considerable

reduction in quality of life. The optimal conditioning regimen

and approach to GVHD control is currently uncertain. In vivo

T-cell depletion using Campath IH significantly reduces

GVHD at the expense of a high incidence of CMV reactivation.

In a study of 129 patients with lymphoproliferative disorders

receiving a sibling non-myelo-ablative transplant and condi-

tioning with fludarabine and melphalan, there was no differ-

ence in event-free or overall survival between patients receiving

either Campath 1H and ciclosporin A or methotrexate and

ciclosporin A for GVHD prophylaxis (Perez-Simon et al,

2002). A recent overview of 77 low intensity transplants for

CLL in Europe has shown a cumulative treatment-relatedmortality of 18% (95% CI 927) with event-free and overall

survival at 24 months of 56% (CI 4369) and 72% (CI 6183)

respectively (Dreger et al, 2003).

Radiotherapy

Lymphoid neoplasms are exquisitely sensitive to the effects of

ionizing radiation, although the systemic nature of CLL has

meant that cytotoxic chemotherapy is the principal treatment

approach. Radiotherapy, however, continues to play an

important although limited role in the palliation of patients

with this group of diseases.

Splenic irradiation. Splenic irradiation was first reported in the

treatment of CLL in 1903. For many years, it remained the only

available anti-neoplastic therapy for leukaemias. With the

advent of systemic chemotherapy, it has become restricted tothe treatment of symptomatic splenomegaly unresponsive to

chemotherapy, where splenectomy is contraindicated. Splenic

irradiation remains a useful, generally well-tolerated and

effective palliative treatment with 5090% of patients

experiencing a reduction in splenic size and relief of

abdominal pain and discomfort. A complete haematological

remission has been reported in 38% of patients in one series

(Catovskyet al, 1991).

The early MRC 1 and 2 trials reported equivalent survival

for patients treated with splenic irradiation and conventional

chemotherapy (Catovsky et al, 1991). The mean duration of

response is typically 718 months and benefit may be seen

with a further short course of splenic irradiation.

Adverse effects include fatigue, nausea and transient thromb-

ocytopenia and neutropenia. Cytopenia is not, however, a

contraindication to therapy as all haematological indices

generally improve following a response to radiotherapy

(Chisesi et al, 1991). Remarkably low doses of irradiation

may be effective and doses of 051 Gray (Gy) one to three

times per week has become the conventional practice, as no

significant dose response is seen above 10 Gy (Van Mook

et al, 2001).

External beam radiotherapy for bulky nodal masses. A dose of

3040 Gy in 2 Gy fractions has traditionally been used forbulky lymph node masses in the palliation of CLL. However,

the radiosensitivity of this disease means that doses of 20 Gy or

less may be effective in achieving this goal. A sustained ORR of

81%, with a dose of 4 Gy in two fractions over 3 d to an

involved field, can be achieved in this setting (Girinsky et al,

2001). Based on these results, it is clear that lower doses than

are conventionally given may be effective in palliation of nodal

masses with a consequent reduction in treatment-related

morbidity.

Table XIII. Allografting in chronic lymphocytic leukaemia.

Study No. of patients Median age

Donor

Conditioning TRM (%) OSRelated Unrelated

Gribben et al (1998) 23 44 23 0 Standard 22 50% (4 years)

Michallet et al (1999) 134 45 80 20 Standard 40 54% (3 years)

Horowitz et al (2000) 242 47 88 12 Standard 25 GVDH27 treatment related

45% (3 years)

Dreger and Montserrat (2002) 38 44 0 38 Standard 39 41% (3 years)

Dreger et al (2001) 63 81 19 Low Intensity 19

TRM, treatment-rated mortality; OS, overall survival; GVHD, graft versus host disease.

Guideline



15/24

Splenectomy

Indications for splenectomy are as follows:

Symptomatic massive splenomegaly.

Refractory cytopenias.

Autoimmune cytopenias.

Hypersplenism.There have been no randomized studies comparing splen-

ectomy with other treatments for CLL.

A case-controlled study in which 55 patients undergoing

splenectomy were matched (sex, age, albumin and Hb levels,

Rai stage, number of prior therapies, time from diagnosis) with

55 patients receiving fludarabine, showed no survival advant-

age in favour of either treatment (Seymour et al, 1997).

In a series of studies each comprising more than 40

patients, the operative mortality ranged from 159% with a

morbidity (particularly infections) of 2654% (Christensen

et al, 1977; Pegourie et al, 1987; Delpero et al, 1990; Neal

et al, 1992; Cusack et al, 1997). No consistent predictivefactors for morbidity or mortality were identified. For

patients (many of whom were drug resistant) undergoing

splenectomy to relieve anaemia or thrombocytopenia, the

response rates were 5077% and 6188% respectively. These

responses are durable, frequently lasting beyond 3 years. No

predictive factors for haematological response have been

consistently identified.

Summary of recommendations for second line and

subsequent treatment

Patients who relapse after an initial response to low dose

chlorambucil may be treated with a further course of

chlorambucil (grade B recommendation, level IIb evidence).

Patients refractory to low dose chlorambucil should be

treated with fludarabine. CHOP is an alternative treatment for

patients unsuitable for fludarabine (grade B recommendation,

level IIb evidence).

Patients who develop progressive disease more than 1 year

after receiving fludarabine and whose CLL responded to

fludarabine initially, may be treated again with fludarabine

alone (grade B recommendation, level IIb evidence).

Patients who develop progressive disease within 1 year of

previous fludarabine therapy may be treated with a combina-

tion of fludarabine and cyclophosphamide (grade B recom-mendation, level IIb evidence).

Patients who are refractory or become resistant to fludara-

bine currently have a poor prognosis. Therapeutic options

include the following:

High-dose methyl prednisolone is recommended as a

treatment option for patients who are resistant to fludara-

bine, particularly in cases with bulky lymphadenopathy

and/or p53 abnormalities (grade B recommendation, level

III evidence).

Alemtuzumab is licensed for and recommended in patients

without bulky lymphadenopathy, previously treated with

alkylating agents and refractory to fludarabine (grade B

recommendation, level IIb evidence).

Rituximab monotherapy is not recommended for previ-

ously treated CLL (grade C recommendation, level IIb

evidence). Rituximab combined with fludarabine (with or

without cyclophosphamide) may be effective in refractory

CLL and warrants further evaluation in this setting (grade B

recommendation, level IIb evidence).

Autologous transplantation should be considered for

patients in complete or good partial remission who are able

to withstand high-dose chemotherapy and TBI. Autologous

transplantation should be performed in the context of a

randomized trial, such as the MRC CLL5 trial.

The possibility of an allogeneic transplant procedure should

be considered for younger patients with good performance

status who have been previously treated and have poor risk

disease. Suitable patients should be discussed with a transplant

centre at an early stage in their disease before the development

of drug resistant disease for inclusion into a clinical research

protocol (grade B recommendation, level III evidence).

Splenectomy may be beneficial in relieving symptomatic

splenomegaly and in improving peripheral cytopenias secon-

dary to hypersplenism or autoantibodies (grade B recommen-

dation, level IIa evidence).

Management of complications

Prophylaxis and treatment of infections

Infective complications are a common clinical problem in CLL,with an incidence of 026047 per patient year, accounting for

up to 50% of all CLL-related deaths. The increased

susceptibility to infection is both intrinsic to the disease and

therapy-related, resulting from multiple factors including

hypogammaglobulinaemia, neutropenia, impaired T and nat-

ural killer cell function and defective complement activity

(Molica, 1994). Risk factors for infection include advanced age,

number of previous treatments and ongoing treatment (Per-

kins et al, 2002; Hensel et al, 2003).

Most infections are bacterial (pneumococcus, haemophilus

influenzae, staphylococcus) with upper and lower respiratory,

septicaemia, pyelonephritis, soft tissue and urogenital infec-

tions being the most common. Fungal, viral and opportunistic

infections were historically rare but are becoming increasingly

prevalent with the introduction of purine analogues, HDMP,

alemtuzumab and transplantation (Morrison, 2001).

Prophylaxis

Antibiotic therapy. Although the use of cycling antibiotics as

infective prophylaxis is widely used for patients with

recurrent chest infections due to bronchiectasis, or

Guideline



16/24

recurrent urinary tract infections, there are no large studies to

assess the efficacy and cost-effectiveness of this approach in

patients with CLL.

Prophylaxis against Pneumocystis carinii with septrin or

nebulized pentamidine should be administered routinely for all

patients receiving purine analogues or alemtuzumab, and

continued for a minimum of 6 months after stopping purine

analogues or alemtuzumab (grade C recommendation, level IV

evidence).

Prophylaxis against herpes zoster/simplex and fungal infec-

tions should also be considered for patients receiving purine

analogues or alemtuzumab, particularly if there is a previous

history of herpetic or fungal infection. Patients treated with

high-dose methylprednisolone should receive prophylaxis

against candidiasis with fluconazole. Reactivation of CMV

occurs in 10% of patients treated with alemtuzumab, with the

peak incidence of reactivation occurring 26 weeks after

starting treatment. Regular weekly monitoring with CMV

PCR testing should be performed in patients receiving

alemtuzumab. A positive quantifiable CMV PCR result is anindication for treatment with intravenous ganciclovir.

Granulocyte colony-stimulating factor may be useful in

reducing the incidence of infection in patients receiving

myelotoxic regimens such as fludarabine and cyclophospha-

mide, and in the early weeks of alemtuzumab treatment during

which neutropenia is common (OBrien et al, 1997).

Intravenous immunoglobulin (IVIG). Hypogammaglobulinaemia

occurs in 2070% of unselected patients with CLL, being more

common in patients with advanced disease stage and in those

with a long disease duration (Montserrat & Rozman, 1993). The

incidence of infection, particularly withencapsulatedorganisms,

correlates with serum immunoglobulin levels (Chapel & Bunch,

1987).

Early studies using prophylactic intramuscular immunoglo-

bulin failed to show consistent benefit. Randomized studies

using IVIG have differed in both the dose and duration of

immunoglobulin replacement therapy. In a double blind trial,

84 patients with IgG levels of


17/24

commonly during the course of the disease, particularly in

patients with advanced disease stage. Several studies have

reported an association between AIHA and treatment with

purine analogues. The incidence of AIHA following fludara-

bine ranges from 2% in previously untreated patients to

more than 20% in heavily pretreated patients. There have

been no controlled trials comparing different treatments for

autoimmune cytopenias in CLL. In a recent study of 52 cases

of AIHA, the rare cases with an IgM warm autoantibody had

the poorest prognosis (Mauro et al, 2000). It is recommen-

ded that patients with warm AIHA or ITP are treated

according to the protocols used for patients with idiopathic

AIHA or ITP (grade C recommendation, level IV evidence).

Autoimmune cytopenias developing following purine ana-

logue therapy are frequently severe and may be fatal (Myint

et al, 1995; Weiss et al, 1998). The majority of patients who

have developed AIHA post fludarabine have had recurrent

haemolysis on re-exposure to fludarabine. There have been

reports of small numbers of patients in whom fludarabine

has been re-introduced successfully while patients are onciclosporin A (Cortes et al, 2001).

However, retreatment with a purine analogue cannot be

recommended in a patient who has previously developed a

purine analogue-related immune cytopenia (grade B recom-

mendation, level IIa evidence).

The risk of AIHA in patients with a positive DAT without

features of haemolysis associated with purine analogue therapy

is unknown. Haemolysis does not inevitably occur but purine

analogues should be used with caution in this situation, with

regular monitoring of the haemoglobin and DAT.

There are anecdotal reports of patients with autoimmune

PRCA responding to steroids, ciclosporin A, IVIG and

alemtuzumab (Castelli et al, 2002; Ru & Liebman, 2003).

Recent case reports suggest that rituximab can be effective in

patients with AIHA, ITP and PRCA refractory to other

treatments (Ghazal, 2002; Gupta et al, 2002; Hegde et al,

2002).

Lymphomatous transformation

The occurrence of lymphomas in 510% of patients with CLL

was originally described by Richter (1928). A minority are

diagnosed concurrently with CLL, but most are diagnosed

during the course of the disease. In the largest reported series

of 39 patients, 64% had progressive lymphadenopathy, 23%asymptomatic abdominal mass, 38% had extra nodal involve-

ment, 54% had either fever or weight loss and 80% had a

>2-fold elevation of LDH. Histologically most cases are

diagnosed as a diffuse large cell lymphoma but ReedStern-

berg-like cells are present in 1015%. Lymphomas may arise as

a transformation of the CLL clone or be clonally unrelated. The

pathogenesis of lymphomatous transformation is poorly

understood but the EpsteinBarr virus has been detected in

the ReedSternberg-like cells in lymphomas developing fol-

lowing treatment with purine analogues.

Studies of the treatment of lymphomas developing in the

context of CLL are largely anecdotal or consist only of small

case series. The experience at the MD Anderson Cancer Center

has been reported in greater detail (Giles et al, 1998). It

suggests that treatment of patients whose histology is diffuse

large B-cell lymphoma achieve a response rate of about 40%

with CHOP-like therapy, and that response duration and

survival are short, at


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