guideline
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 of
Hematology 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 20–30% 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
20–30 times commoner in Europe, Australasia and North
American white and black populations than in India, China
Correspondence: BCSH Secretary, British Society for Haematology,
100 White Lion Street, London N1 9PF, UK.
E-mail: janice@b-s-h.org.uk
doi:10.1111/j.1365-2141.2004.04898.x ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
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 many
families 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, 70–80% of
patients are now diagnosed as an incidental finding on a
routine 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.

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 trials
Ib 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 case–control 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
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 performed
in 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
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Guideline
Table II. Scoring system for the diagnosis of chronic lymphocytic
leukaemia (CLL).
Score points
Marker 1 0
Smlg Weak Strong
CD5 Positive Negative
CD23 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 <3.
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
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the finding of intrathoracic or bulky intra-abdominal disease who have smouldering CLL can be identified based on the
would influence the need for, or choice of, therapy and to following parameters (Monteserrat et al, 1988; French
determine remission status following treatment in patients Co-operative Group on Chronic Lymphocytic Leukaemia,
with bulky nodes prior to therapy. 1990a):
• haemoglobin >13 g/dl;
Prognostic factors • lymphocyte count <30 · 109/l;
• minimal, or no lymphadenopathy;
The variable clinical course in CLL is a consequence of the
• non-diffuse pattern of bone marrow involvement;
frequency with which the disease is diagnosed in a preclinical
• a lymphocyte doubling time of >12 months.
phase, differences in the rate of disease progression between
cases and the varying response to treatment. In one study, only 15% of these patients showed disease
The median survival is approximately 10 years but this figure progression after 5 years and 80% were alive at 10 years
is of little value to an individual patient due to the extraordin- (Monteserrat et al, 1988).
ary heterogeneity in the natural history of this disorder. Two Patients entered into the MRC 3 trial with progressive
studies have shown that the median survival of CLL is stage A disease have a similar life expectancy to those
independent of whether patients present above or below 50– presenting with stage B disease.
55 years (Montserrat et al, 1991; Moreau et al, 1997; Mauro
et al, 1999). However, younger patients are more likely to die of Serum markers. These include b2 microglobulin, lactate
CLL-related causes while older patients more commonly die of dehydrogenase (LDH), serum thymidine kinase and soluble
unrelated causes including second primary malignancies. Data CD23 (Knauf et al, 1997; Hallek et al, 1999; Di Raimondo
from the Medical Research Council (MRC) CLL trials have et al, 2001; Schwarzmeier et al, 2002). All have been shown to
consistently shown that response rates to treatment and predict progression and survival in Binet stage A patients, but
survival is better in women than in men (Catovsky et al, their value is currently limited either by the lack of a standard
1989). Established prognostic factors and more recent tests, assay method, variable cut-off points between series or the lack
which appear to provide additional prognostic information, are of validation in a prospective study.
shown in Table III and include the following.
CD38 expression. Many studies have shown that a high level
Clinical stage. The clinical staging systems devised by Binet and/or intensity of CD38 expression on leukaemic lymphocytes
et al (1981) and Rai et al (1975) are the simplest and best- is a poor prognostic factor both in univariate analysis and in
validated means of assessing prognosis (Table IV). It is patients of known clinical stage and b2 microglobulin levels
important to exclude haemolysis and unrelated causes of (Damle et al, 1999; Del Poeta et al, 2001; Ibrahim et al, 2001;
anaemia or thrombocytopenia before assigning a patient to Durig et al, 2002; Hamblin et al, 2002; Ghia et al, 2003). The
Binet stage C or the Rai high-risk group. Limitations of both optimum cut-off level with greatest prognostic significance is
systems include the choice of a single (but different) uncertain. Different studies have chosen values of 7%, 20% or
haemoglobin level to define marrow failure regardless of
Table IV. Staging systems in chronic lymphocytic leukaemia.
the sex of the patient, and the inability to predict the rate of
disease progression in patients presenting with a low tumour Features % of patients
burden. A subgroup of patients with Binet stage A disease
Binet stage
A <3 lymphoid areas* 60
Table III. Prognostic factors in chronic lymphocytic leukaemia.
B >3 lymphoid areas 30
Factor Low risk High risk C Haemoglobin < 10Æ0 g/dl or 10
platelets < 100 · 109/l
Gender Female Male Rai stage
Clinical stage Binet A Binet B or C 0 Lymphocytosis only 30
Rai OI Rai II, III, IV I Lymphadenopathy 25
Lymphocyte morphology Typical Atypical II Hepato or splenomegaly ± 25
Pattern of marrow Non-diffuse Diffuse lymphadenopathy
trephine infiltration III§ Haemoglobin < 11Æ0 g/dl 10
Lymphocyte doubling time >12 months <12 months IV§ Platelet < 100 · 109/l 10
Serum markers* Normal Raised
CD38 expression <20–30% >20–30% *The five lymphoid areas comprise unilateral or bilateral cervical,
Genetic abnormalities None del 11q23 axillary and inguinal lymphadenopathy, hepatomegaly and spleno-
del 13q (sole) Loss/mutation of p53 megaly.
IgVH gene status Mutated Unmutated Risk group at low level.
Risk group at intermediate level.
*See text for details. §Risk group at high level.

296 ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317

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 ZAP70 mRNA 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 the
application 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.
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Guideline
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)
3 and rituximab monotherapy (Byrd et al, 2003a) 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. Both the 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 range
of pamphlets, including one on understanding CLL and others
on living with cancer. For further information go to http://
4 www.cancerbacup.org.uk.
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-Hodgkin’s Lymphoma by Lorraine Johnson, published
by O’Reilly.
• Adult Leukemia by Barbara Lackritz, published by O’Reilly.
• 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.
298 ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
• GrannyBarb’s Leukemia Links, CLL at http://www.acor.org/
leukemia/cll.html. An early site developed by Barbara
Lackritz.
• CLL FAQ’s, 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?version¼patient
&cdrid¼62684.
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
more information on this and other groups that may be 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 and a 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 <6 months
Systemic symptoms*
Weight loss >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.
 Guideline

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 >11Æ0 g/dl >11Æ0 g/dl or >50% improvement from baseline
(untransfused)
Neutrophils >1Æ5 · 109/l >1Æ5 · 109/l or >50% improvement from baseline
Lymphocytes <4Æ0 · 109/l >50% decrease >50% increase
Platelets >100 · 109/l >100 · 109/l or >50% improvement from baseline
Marrow aspirate <30% lymphocytes
Marrow trephine No interstitial or nodular infiltrate May be residual lymphoid nodules

stage C disease and mild cytopenias and who are asymptomatic, co-morbid conditions and patient wishes; (ii) disease-related
may be observed without treatment until there is evidence of factors, such as the severity of symptoms and the presence of
symptomatic or progressive disease. adverse prognostic factors; and (iii) treatment-related factors
Hyperviscosity due to extreme lymphocytosis is very rare in including the degree and duration of response to prior
CLL and a high lymphocyte count in the absence of a rapid treatments and contra-indications to, and side-effects from,
lymphocyte doubling time is not an indication for treatment. particular treatment modalities. Pharmacoeconomic consider-
Neither asymptomatic hypogammaglobulinaemia nor the ations (Table VII) are also important.
presence of a paraprotein are reasons for treatment. 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
Assessment of response
also the frequency with which CLL is diagnosed in a
The criteria for assessing complete response (CR) or partial preclinical phase. The median survival of patients with
response (PR) to treatment recommended by the NCI working advanced CLL is usually superior to that seen in many other
group are shown in Table VI (Cheson et al, 1996). Patients haematological malignancies and solid tumours. In the
who fulfil the criteria for a CR but whose bone marrow absence of a curative treatment, most patients receive a
trephines contain lymphoid nodules have been designated as number of different treatment modalities during the course
having a nodular PR. of the disease. The response to a particular treatment varies
Since the publication of the NCI criteria, new methods have according to its place in the overall treatment strategy, such
become available for assessing minimal residual disease (MRD). that treatments which produce high response rates when
A variety of techniques are available to detect MRD. A flow used as initial therapy may also make a substantial contri-
cytometric assay that differentiates CLL cells from normal bution to prolonging survival when given later in the disease,
B cells based on expression of CD19/CD5/CD20 and CD79b is particularly if they are administered after less active agents.
rapid, applicable to all patients and can detect one CLL cell in
105 normal cells when 5 · 105 cells are analysed (Rawstron Table VII. Cost of chemotherapy in chronic lymphocytic leukaemia.
et al, 2001). Comparable sensitivity may be achieved using real- Route of Approximate
time quantifiable allele-specific oligonucleotide polymerase Drug administration cost (£)
chain reaction (PCR) (Pfitzner et al, 2002). However, this
technique is labour intensive and expensive. Chlorambucil p.o. 730
Newer therapeutic approaches can result in MRD negative Fludarabine p.o. 5245
i.v. 4290
remissions. The presence of detectable MRD in patients who
Fludarabine and p.o. 3280
achieve a complete remission by NCI criteria following
cyclophosphamide
treatment with purine analogues, monoclonal antibodies or
i.v. 2800
autologous transplantation predicts for clinical relapse. How- Rituximab
ever, patients who initially remain MRD positive after Fludarabine p.o./i.v.
allogeneic transplantation may subsequently become MRD Cyclophosphamide 15 110
negative (Esteve et al, 2002). Alemtuzumab (12 weeks) i.v. 11 985
High-dose methylprednisolone i.v. 730

A treatment strategy for CLL
Before initiating treatment, consideration must be given to
(i) patient-related factors, such as age, performance status,
The costs are those for the chemotherapy alone, based on 6 months’
treatment (apart from alemtuzumab) using standard regimens for a
patient with a surface area of 2 m2. The figures do not represent the
total cost of administering these treatments.

ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317 299
Guideline
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 comparing
initial 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 0Æ1 mg/kg/d until drug resis-
tance. The second trial randomized 926 patients to no
treatment or to chlorambucil 0Æ3 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).
300 ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
Alkylating agents. Early studies used low dose chlorambucil
with or without prednisolone/prednisone. The combined CR
and PR rates ranged from 45–86%. 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
5 on Chronic Lymphocytic Leukaemia, 1990b; 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 CHOP
regimen (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 < 0Æ01) (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 then
followed by maintenance therapy with chlorambucil given at a
dose of 5–15 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

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 <10Æ5 g/dl for men or <9Æ5 g/
dl for women and/or a platelet count of <100 · 109/l. There is
no requirement for bone marrow examination post-therapy.
Purine analogues. Fludarabine. Fludarabine produces ORR of
70–80% with a CR rate of approximately 30% and a median
survival of 73 months when given as a single agent at a dose of
25 mg/m2 intravenously for 5 d each month. Factors
predicting prolonged survival included age <70 years,
intermediate rather than high-risk disease and response to
therapy, particularly the attainment of a molecular complete
remission (Keating et al, 1998).
The addition of prednisolone has no effect on overall
survival (O’Brien et al, 1993). Oral fludarabine at a dose of
40 mg/m2/d for 5 d achieves a comparable remission rate with
intravenous administration (Boogaerts et al, 2001).
Three studies (Table VIII) have compared fludarabine with
regimens including an alkylating agent with or without an
anthracycline (Johnson et al, 1996; Rai et al, 2000; Leporrier
et al, 2001). In each case fludarabine produced a higher ORR,
CR rate and longer duration of response than CAP (cyclo-
phosphamide, adriamycin, prednisolone) or chlorambucil.
However, there was no statistically significant difference in
the survival for patients receiving fludarabine. In the above
studies of Rai et al (2000) and Leporrier et al (2001), this was
related to the crossover nature of the studies and the high
response rate to second line treatment with fludarabine in
patients who had failed CHOP, CAP or chlorambucil. The risk
of severe infection was lower with chlorambucil than with
fludarabine, or in combination chemotherapy regimens inclu-
ding an anthracycline, while the latter were associated with a
higher incidence of nausea, vomiting and alopecia.
In the USA intergroup study the incidence of therapy-
related myeloid leukaemia was 3Æ5% in patients receiving
fludarabine and chlorambucil, 0Æ5% in patients given fludara-
bine alone and 0% in patients treated with chlorambucil alone
(Morrison et al, 2002).
An European Organisation for Research and Treatment of
Cancer study comparing fludarabine with continuous high-
dose chlorambucil has reported similar response rates and
comparable response duration and survivals (Zittoun et al,
1999).
An interim analysis of a phase 3 German CLL study group
trial, comparing chlorambucil with fludarabine in previously
untreated patients over the age of 65 years with advanced CLL,
shows a higher overall and CR rate in the fludarabine arm, but
no difference in progression-free survival with a median
follow-up of 11 months. Myelotoxicity was greater in patients
receiving fludarabine, but there was no difference in the
incidence of severe infections (Eichhorst et al, 2003a).
An interim analysis of the CLL4 study of the German CLL
Study Group, which randomized 375 patients aged <65 years
with progressive Binet stage A or stage B/C disease to
fludarabine alone or in combination with cyclophosphamide,
has shown that the combined treatment results in a higher
ORR (94% vs. 85%), a higher CR rate (20% vs. 9%), prolonged
progression-free survival (28 months vs. 23 months) and a
lower incidence of severe anaemia, but more severe neutro-
penia and thrombocytopenia. There was no difference in the
incidence of severe infections (Eichhorst et al, 2003b).
Cladribine. The use of cladribine in previously untreated
patients results in ORR of approximately 75% with 38% CR
(Saven et al, 1995; Juliusson et al, 1996). The duration of
response is about 2 years. A phase 3 randomized study
comparing cladribine + prednisone with chlorambucil
(12 mg/m2 for 7 d) + prednisolone, resulted in a higher
ORR, CR rate and progression-free survival for patients
receiving cladribine but no advantage in overall survival

Table VIII. Comparison of fludarabine with

alkylating agents (alone or in combination Median
therapy) in previously untreated chronic No. of Duration survival
lymphocytic leukaemia. Study Regimen patients CR (%) PR (%) (months) (months)

Johnson et al (1996) Fludarabine 52 23 48 Not reached Not reached

vs. 48 17 43 6Æ9 52Æ6
CAP
Rai et al (2000) Fludarabine 170 20 43 25 66
vs. 181 4 33 14 56
Chlorambucil
Leporrier et al (2001) Fludarabine 341 40Æ1 31Æ0 31Æ7 69
vs. 240 15Æ2 43Æ0 27Æ7 70
CAP
vs. 357 29Æ6 41Æ9 29Æ5 67
CHOP

CHOP, cyclophosphamide, adriamycin, vincristine, prednisolone; CAP, cyclophosphamide,

adriamycin, prednisolone; CR, complete remission; PR, partial remission.

ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317 301
 Guideline

6 (Robak et al, 2000a). 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
Table IX. Use of alemtuzumab alone or in combination in untreated and previously treated chronic lymphocytic leukaemia.
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).

No. of patients

Study Treatment Regimen Untreated Treated OR (%) CR (%)

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
30 Osterborg et al (1997) Alemtuzumab 30 mg, 3· weekly i.v. for up to 12 weeks 0 29 42 3
Kennedy et al (2001) Alemtuzumab 30 mg, 3· weekly i.v. 0 77 44 25
Rai et al (2001) Alemtuzumab 30 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 3–30 mg, 3· weekly 0 9 0 0
Rituximab 375 mg/m2, 4· weekly for 5 weeks
Faderl et al (2001) Alemtuzumab 3–30 mg, 3· weekly 0 22 45 5
Rituximab 375 mg/m2 weekly

OR, overall response; CR, complete remission.

302 ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
 Guideline

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

No. of patients

Study Treatment Regimen Untreated Treated OR (%) CR (%)

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 34
Fludarabine 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.

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 are
crossed 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 not
superior 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

ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317 303
Guideline

Fig 1. Treatment options in CLL. CLL4 trial and CLL5 autograft trial are current UK trials. Proposed UK CLL Forum trials are: (i) poor risk stage A
CLL; (ii) Alemtuzumab ± fludarabine for patients resistant to fludarabine; and (iii) reduced intensity conditioning Allograft Study. Treatment
strategy for patients who are refractory or become resistant to fludarabine or fludarabine + cyclophosphamide therapy is shown in shaded boxes.
chlor ¼ chlorambucil; F ¼ fludarabine; FC ¼ fludarabine + cyclophosphamide; RIC ¼ reduced intensity conditioning; HDMP ¼ high-dose methyl
prednisolone; CHOP ¼ cylophosphomide, adriamycin, vincristine, prednisolone; FCR ¼ fludarabine, cyclophosphamide and rituximab.

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 ¼ 0Æ036) (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
<70 years old.
Response rates to fludarabine in patients previously respon-
sive to an alkylating agent range from 60% to 68%, whereas
response rates in patients refractory to alkylating agents range
from 20% to 49% (O’Brien et al, 1993; Montserrat et al, 1996;
Keating et al, 2000). Durable responses to fludarabine are seen
in 40% of patients who failed to respond to CHOP as first line
therapy (Leporrier et al, 2001). NICE guidance recommends
fludarabine alone as second line therapy for patients who have
failed, or are intolerant of first line therapy with an alkylating
agent and who would otherwise receive CHOP, COP or CAP
(NICE, 2001).
Eighty-five per cent of patients previously responsive to
fludarabine respond to retreatment with the same agent but

304 ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
 Guideline

the response rate falls to 12% in patients who are refractory to and should be used with caution in patients with diabetes or
previous fludarabine therapy. heart failure.
Cladrabine has been less extensively evaluated than
fludarabine and there are differences in opinion as to its
Monoclonal antibodies
correct schedule of administration. However, response rates
are broadly similar to that achieved with fludarabine (Piro Alemtuzumab. A total of 341 patients refractory to fludarabine
et al, 1988; Saven et al, 1991; Juliusson & Liliemark, 1993, have been treated with alemtuzumab in five non-randomized
1994, 1996). The results of a small case series which studies (Table IX). The ORR was 39% (9Æ4% CR and 30% PR)
reported benefit from cladrabine therapy in three patients with a prolonged median survival compared with historical
who were refractory to fludarabine (Juliusson et al, 1992) data on fludarabine-resistant patients. In the pivotal study of
was not confirmed by the experience of other investigators. 92 patients with fludarabine-resistant disease, best responses
However, a recent study sponsored by the cancer and were seen in patients with a low b2 microglobulin, platelet
leukemia group B (Byrd et al, 2003c) achieved responses in count >50 · 109/l and <3 cm lymphadenopathy. No case with
nine of 28 patients (ORR 32%) for cladrabine in fludarabine lymph nodes >5 cm achieved complete resolution of
refractory patients. lymphadenopathy (Keating et al, 2002b). Alemtuzumab may
Small phase 2 studies show that when purine analogues are be effective in some patients with p53 mutations refractory to
administered in combination with other chemotherapeutic purine analogues (Stilgenbauer & Dohner, 2002).
agents to previously treated patients, the response rates are Preliminary data suggest that the combination of fludar-
higher than those achieved with purine analogues alone. abine and alemtuzumab may be effective in patients resistant
Examples are shown in Table XI. to both agents given alone (Kennedy et al, 2002).
Alemtuzumab has been administered to patients with
residual disease following treatment with fludarabine (O’Brien
High-dose methyl prednisolone (HDMP)
et al, 2003), and prior to stem cell mobilization (Montillo et al,
Although widely used, there is little published data on the 2002). Although CRs and MRD-negative responses have been
efficacy of HDMP in relapsed CLL. A study of HDMP given achieved, some patients have experienced prolonged myelo-
intravenously or orally at a dose of 1 gm/m2/d for 5 d each suppression following standard doses of alemtuzumab, and
month was performed in 25 patients, 15 of whom were this sequential regimen should only be used in a clinical trial
7 refractory to fludarabine (Thornton et al, 2003). An ORR of setting.
77% was achieved with a median duration of 12 months.
Responses were seen in five of 10 patients with loss and/or Rituximab. Although rituximab has some efficacy in CLL,
mutation of the p53 gene. The event-free and overall survival the response rates to rituximab monotherapy in previously
was significantly better in responders than in non-responders. treated patients are poor. Even at very high doses (up to six
Patients who relapse after HDMP frequently respond times the standard dose), all the responses are partial.
to further courses of the same treatment. HDMP is contra- Response rates to rituximab, in combination with
indicated in patients with an active gastric or duodenal ulcer 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
Table XI. Combination of a purine analogue with other chemo-
fludarabine, cyclophosphamide and rituximab has been
therapeutic agents in previously treated chronic lymphocytic leukae-
mia. reported in 167 patients with previously treated CLL, of
whom 102 were evaluable with more than 6 months of
Overall follow-up. Fifteen per cent of patients had received
No. of response alkylating agents only, 59% had been sensitive to
Study patients Regimen rate (%)
fludarabine-containing regimens and 26% had been
Rummel et al (1999) 25 Fludarabine + 60 resistant to fludarabine. Complete remissions, using NCI
epirubicin criteria, were achieved in 20% of patients who had received
O’Brien et al (2001) 20 Fludarabine + 85 alkylating agents only, 30% of fludarabine-sensitive patients
cyclophosphamide and 7% of fludarabine-resistant cases (Garcia-Manero et al,
Hallek et al (2001) 18 Fludarabine + 94 2001). A historical comparison of previously treated patients
cyclophosphamide receiving either fludarabine, with or without prednisolone,
Bosch et al (2002) 37 Fludarabine + 78 fludarabine and cyclophosphamide, or fludarabine,
cyclophosphamide + cyclophosphamide and rituximab showed a CR rate and
mitoxantrone
median survival of 13% and 19 months, 12% and 31 months
Montillo et al (2003) 23 Pentostatin + 95
and 28% and not reached respectively (Wierda et al, 2003).
cyclophosphamide

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 Guideline
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 <65 years. In these younger patients, it may well be
justifiable to consider a more aggressive approach when
standard treatment with alkylating agents or purine analogues
offers a poor outlook. To date, the only potentially curative
therapy for CLL is allogeneic transplantation.
Autologous transplantation. Autologous transplantation is
based on the premise that for some chemotherapeutic
regimens, there is a dose effect and that superior anti-
tumour efficacy can be achieved by dose escalation. There is
some logic to this in CLL, as conventional dose escalation
results in increased response rates (Gale & Montserrat, 1993).
There are no randomized studies comparing autologous
transplantation with other forms of treatment for CLL. The
first published studies of autografting came from Boston
(Rabinowe et al, 1993) and were subsequently extended
(Gribben et al, 1998). In this series, patients with CLL were
transplanted after achievement of a good response to prior
(unspecified) chemotherapy. The conditioning regimen was
cyclophosphamide and total body irradiation (TBI), and the
stem cell source was bone marrow purged in vivo with a
cocktail of monoclonal antibodies (B5, anti-CD10 and anti-
CD20). The procedure-related mortality was 10%, but the
most striking observation was that the disease-free survival
was 63% at 4 years and the overall survival was 85%.
Subsequent reviews have shown that transplant-related
mortality ranges from 4–10% to 65–94% of patients are
8 alive at 4 years from transplantation (Van Besien et al, 2001;
Dreger & Montserrat, 2002) (Table XII). Evaluation of this
data is complicated by heterogeneity in patient selection,
choice of conditioning regimen and use of in vitro or in vivo
purging. In addition, the majority of studies report data
either from the time of stem cell mobilization or from the
date of transplantation. This introduces a substantial bias, as
only approximately 50% of patients for whom an autograft
Table XII. Autografting in chronic lymphocytic leukaemia.
No. of TRM 2-year 4-year 4-year
Study patients (%) EFS (%) EFS (%) OS (%)
Gribben et al (1998) 81 10 – 63 – undergoing allogeneic transplantation have received several
Dreger et al (2000a) 370 10 – – 69
Esteve et al (2001) 124 6 69 37 65
Dreger et al (2000b) 77 4 87 69 94
Dreger and 105 5 88 – –
Montserrat (2002)
TRM, treatment-related mortality; EFS, event-free survival; OS, overall
survival.
306 ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
is intended actually receive the transplant, either because of
a poor response to pretransplant chemotherapy or
inadequate stem cell mobilization (Forsyth et al, 2000).
Difficulty with stem cell harvesting is related to the heavy
marrow involvement with disease and chemotherapy-
induced stem cell damage. European Bone Marrow
Transplantation group data have shown that more than six
cycles of fludarabine is associated with improved stem cell
mobilization, as is a delay of more than 2 months between
completing chemotherapy and attempting mobilization
(Michallet et al, 2000). The optimal mobilization and
conditioning regimens and the value of peripheral blood
or bone marrow purging remain uncertain. Granulocyte
colony-stimulating factor appears insufficient to mobilize
peripheral blood stem cells in patients treated
with fludarabine and cyclophosphamide (Tournilhac et al,
2004).
Evidence for the benefit of autologous transplantation is
based on the longer duration of remissions that are achievable
compared with those obtained with previous second line
treatments in the same patients. In addition, a matched pair
analysis showed improved survival of poor risk patients with
unmutated IgVH genes who received an autologous transplant
rather than conventional chemotherapy (Dreger et al, 2002).
The outcome after autologous transplantation appears to be
better in patients with mutated IgVH genes (Ritgen et al,
2003), in those who are in CR at the time of autograft and in
patients who received a TBI-based conditioning regimen
(Dreger et al, 2000a). Patients with del 11q23 have a lower
chance of achieving an MRD negative state, postautograft
(Stilgenbauer et al, 2000). The lack of a plateau in survival
curves and the high risk of clinical relapse in patients who
either fail to achieve a molecular CR or who develop a
molecular recurrence, suggests that autologous transplantation
is not curative in CLL.
The optimal timing of autologous transplantation is
uncertain. This is being investigated in the MRC CLL5 trial,
which compares immediate with the possibility of deferred
autologous transplantation in patients who achieve a com-
plete, very good or nodular PR to first or second line
treatments.
Allogeneic transplantation. There have been no controlled
trials evaluating the role of allogeneic transplantation in
CLL. The results of registry data and larger single centre
studies are shown in Table XIII (Van Besien et al, 2001;
Dreger & Montserrat, 2002). The majority of patients
previous types of chemotherapy and many are drug resistant.
In contrast to autologous transplantation, allografting is a
potentially curative procedure in CLL, based on the long-
term disease-free survival of some patients who have
achieved a complete remission. The inferior 4-year overall
survival in registry data of patients who have undergone
allogeneic compared with autologous transplantation, reflects

Table XIII. Allografting in chronic lymphocytic leukaemia.
Study No. of patients Median age
Gribben et al (1998) 23 44
Michallet et al (1999) 134 45
Horowitz et al (2000) 242 47
Dreger and Montserrat (2002) 38 44
Dreger et al (2001) 63 – 81
TRM, treatment-rated mortality; OS, overall survival; GVHD, graft versus host disease.
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-matched
donor.
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-related
mortality of 18% (95% CI 9–27) with event-free and overall
survival at 24 months of 56% (CI 43–69) and 72% (CI 61–83)
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
ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
Guideline
Donor
Related Unrelated Conditioning TRM (%) OS
23 0 Standard 22 50% (4 years)
80 20 Standard 40 54% (3 years)
88 12 Standard 25 GVDH 45% (3 years)
27 treatment related
0 38 Standard 39 41% (3 years)
19 Low Intensity 19
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 to
the treatment of symptomatic splenomegaly unresponsive to
chemotherapy, where splenectomy is contraindicated. Splenic
irradiation remains a useful, generally well-tolerated and
effective palliative treatment with 50–90% 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
(Catovsky et 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 7–18 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 0Æ5–1 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
30–40 Gy in 2 Gy fractions has traditionally been used for
bulky 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.
307
Guideline
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 1Æ5–9% with a
morbidity (particularly infections) of 26–54% (Christensen
et al, 1977; Pegourie et al, 1987; Delpero et al, 1990; Neal
et al, 1992; Cusack et al, 1997). No consistent predictive
factors 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 50–77% and 61–88% 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).
308 ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
• 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 0Æ26–0Æ47 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

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 2–6 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 an
indication 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 (O’Brien et al, 1997).
Intravenous immunoglobulin (IVIG). Hypogammaglobulinaemia
occurs in 20–70% 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 with encapsulated organisms,
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 <50% of the lower limit of
normal, or a history of one or more serious infections since
diagnosis, received IVIG 400 mg/kg every 3 weeks for 1 year or
placebo (Griffiths et al, 1989). Patients receiving IVIG had
significantly fewer bacterial infections (23 vs. 42, P ¼ 0Æ01),
and a longer period from the time of entering the study to that
of first infection. The benefit of IVIG at this dose was
confirmed in a crossover study, in which 12 patients received
IVIG for 1 year before being transferred to placebo.
A multicentre multinational study randomized 34 patients to
receive IVIG at a dose of either 500 or 250 mg/kg every
4 weeks for 1 year (Chapel et al, 1994). There was no
significant difference in the number or severity of infections
between the two therapeutic groups. Similarly in a Danish
prospective study, 15 patients received low dose IVIG at a dose
of 10 g every 3 weeks for 1 year. Compared with the
12 months prior to IVIG therapy, patients required fewer
ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
Guideline
hospital admissions and had fewer febrile episodes (31 vs. 63,
P ¼ 0Æ004) (Jurlander et al, 1994).
No study has demonstrated an effect on the incidence of
viral or fungal infections or on overall survival (Weeks et al,
1991).
Although there is little doubt about the efficacy of IVIG
therapy in selected patients with CLL there has been debate
about its cost-effectiveness.
Patients with hypogammaglobulinaemia and recurrent bac-
terial infections, especially those in whom prophylactic anti-
biotics have proved ineffective, should be treated with
prophylactic IVIG (grade A recommendation, level Ib evi-
dence).
Immunization. Patients with CLL have been shown to have a
suboptimal response to vaccination against diphtheria,
typhoid, mumps, influenza, pneumococcus and
haemophilus (Gribabis et al, 1994). Most vaccines are
unconjugated and hence thymus independent. Conjugation
to a carrier protein renders vaccines thymus dependent and
more immunogenic. A recent study showed 21% of CLL
patients had baseline immunity to haemophilus influenzae,
but following vaccination with a conjugated haemophilus
influenzae type b vaccine, this rose to 54% (Sinisalo et al,
2001). In contrast, pneumococcal antibody baseline levels
were similar between CLL patients and normal controls, but
whereas the latter responded to vaccination (with an
unconjugated vaccine) most CLL patients did not. A new
protein conjugated form of pneumococcal vaccination has
recently been introduced but no data as to its potential
benefit in CLL are available.
While it is standard practice to recommend annual influenza
vaccination for patients with CLL, the efficacy of this measure
is uncertain, and further studies on vaccination against
infections in CLL are required (Sinisalo et al, 2003)
Treatment of infections
Patients and their carers need to be educated about the risks of
infection and the necessity to seek immediate medical atten-
tion as soon as suggestive symptoms occur. Patients with
minor infections can be treated as outpatients, but those with
major infections will require hospitalization and access to full
resuscitation including respiratory support. As many infections
are potentially life threatening, broad spectrum antibiotics
covering the common likely pathogens should be started as
soon as all essential cultures have been taken.
Autoimmune cytopenias
The incidence of autoimmune cytopenias is significantly
higher than in the general population. Warm AIHA, ITP and
pure red cell aplasia (PRCA) occur with the incidence of
4–40%, 1–2% and <1% respectively (Hamblin, 2001). These
complications may be diagnosed at presentation, or more
309
Guideline
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 on
ciclosporin 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 5–10% 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 Reed–Stern-
berg-like cells are present in 10–15%. Lymphomas may arise as
a transformation of the CLL clone or be clonally unrelated. The
pathogenesis of lymphomatous transformation is poorly
understood but the Epstein–Barr virus has been detected in
the Reed–Sternberg-like cells in lymphomas developing fol-
lowing treatment with purine analogues.
310 ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
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 <6 months (Robertson et al, 1993).
Increasing the intensity of treatment by using cisplatin/
fludarabine based chemotherapy is not associated with higher
response rates (Giles et al, 1999), but the use of highly
intensive treatment may generate improved overall survival
(Dabaja et al, 2001). In the small number of cases in which
treatment of transformations resembling Hodgkin’s disease has
been reported, the use of standard regimens such as ABVD
(adriamycin, bleomycin, vincristine, dacarbazine) is associated
with response rates of 40% or less and overall survival of
12–18 months. However, these results are not significantly
different from those reported in patients with de novo
Hodgkin’s disease who are over 60 years old with stage III or
IV disease (Giles et al, 1998).
No standard treatment can be recommended for Richter’s
transformation of CLL; existing clinical reports fail to identify
consistently effective therapy (grade C recommendation, level
IV evidence).
Disclaimer
Whilst the advice and information contained in this guideline
are believed to be true and accurate at the time of going to
press, neither the authors nor the publisher can accept any
legal responsibility or liability for any errors or omissions that
may be made.
D. Oscier1
C. Fegan2
P. Hillmen3
T. Illidge4
S. Johnson5
P. Maguire6
E. Matutes7
D. Milligan2
1
Department of Haematology, Royal Bournemouth Hospital,
Bournemouth, 2Department of Haematology, Heartlands
Hospital, Birmingham, 3Department of Haematology,
Pinderfields General Hospital, Wakefield, 4Department of
Oncology, Southampton General Hospital, Southampton,
5
Department of Haematology, Taunton and Somerset Hospital,
Taunton, 6181 Main Street, Nottingham, and 7Academic
Department of Haematology and Cytogenetics, Royal Marsden
Hospital, London, UK

References
BCSH Blood Transfusion Task Force (1996) Guidelines on gamma
irradiation of blood components for the prevention of transfusion-
associated graft-versus-host disease. Transfusion Medicine, 6,
261–271.
Bennett, J.M., Catovsky, D., Daniel, M.T., Fladrin, G., Galton,
D.A.G., Gralnick, H.R. & Sultan, C. (1989) The French–American–
British (FAB) proposal for the classification of chronic (mature) B
and T lymphoid leukaemias. Journal of Clinical Pathology, 42, 567–
584.
Binet, J.L., Auquier, A., Dighiero, G., Chastang, C., Piguet, H.,
Goasguen, J., Vaugier, G., Potron, G., Colona, P., Oberling, F.,
Thomas, M., Tchernia, G., Boivin, P., Lesty, C., Duault, M., Mon-
conduit, M., Belabbes, S. & Gremy, F. (1981) A new prognostic
classification of chronic lymphocytic leukaemia derived from a
multivariate survival analysis. Cancer, 48, 198–206.
Boogaerts, M.A., Van Hoof, A., Catovsky, D., Kovacs, M., Montillo,
M., Zinzani, P.L., Binet, J.L., Feremans, W., Marcus, R., Bosch, F.,
Verhoef, G. & Klein, M. (2001) Activity of oral fludarabine phos-
phate in previously treated chronic lymphocytic leukemia. Journal of
Clinical Oncology, 19, 4252–4258.
Bosanquet, A.G., Johnson, S.A. & Richards, S.M. (1999) Prognosis for
fludarabine therapy of chronic lymphocytic leukaemia based on
ex vivo drug response by DiSC assay. British Journal of Haematology,
106, 71–77.
Bosch, F., Ferrer, A., Lopez-Guillermo, A., Gine, E., Bellosillo, B.,
Villamor, N., Colomor, D., Cobo, F., Esteve, J., Altes, A., Besalduch,
J., Ribera, J. & Montserrat, E. (2002) Fludarabine, cyclophosphanide
and mitoxauthrone in the treatment of resistent or relapsed chronic
lymphocytic leukaemia. British Journal of Haematology, 119, 976–
984.
Byrd, J.C., Smith, L., Hackbarth, M.L., Flinn, I.W., Young, D., Proffitt,
J.H. & Heerema, N.A. (2003a) Interphase cytogenetic abnormalities
in chronic lymphocytic leukemia may predict response to rituximab.
Cancer Research, 63, 36–38.
Byrd, J.C., Peterson, B.L., Morrison, V.A., Park, K., Jacobson, R., Hoke,
E., Vardiman, J.W., Rai, K., Schiffer, C.A. & Larson, R.A. (2003b)
Randomized phase 2 study of fludarabine with concurrent versus
sequential treatment with rituximab in symptomatic, untreated
patients with B-cell chronic lymphocytic leukemia: results from
Cancer and Leukemia Group B 9712 (CALGB 9712). Blood, 101,
6–14.
Byrd, J.C., Peterson, B., Piro, L., Saven, A., Vardiman, I.W., Larson,
R.A. & Schiffer, C. (2003c) A phase II study of cladribine treatment
for fludarabine refractory B-cell chronic lymphocytic leukemia:
results from CALGB study 9211. Leukemia, 17, 323–327.
Castelli, R., Vismara, A., Pavia, G., Dagani, R. & Porro, T. (2002)
Relapsing pure red cell aplasisa associated with B-cell chronic lym-
phocytic leukemia successfully treated by intravenous
immunoglobulin concentrate. Annali Italiani de Medicini Interna,
17, 47–50.
Catovsky, D., Fooks, J. & Richards, S. (1989) Prognostic factors in
chronic lymphocytic leukaemia: the importance of age, sex and
response to treatment in survival. British Journal of Haematology,
72, 141–149.
Catovsky, D., Richards, S., Fooks, J. & Hamblin, T. (1991) CLL trials in
the United Kingdom. The Medical Research Council CLL Trials
9 1,2,3. Leukemia and Lymphoma, (Suppl.), 105–107.
ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
Guideline
Chapel, H.M. & Bunch, C. (1987) Mechanisms of infection in chronic
lymphocytic leukemia. Seminars in Hematology, 24, 291–296.
Chapel, H., Dicato, M., Gamm, H., Brennan, V., Ries, F., Bunch, C. &
Lee, M. (1994) Immunoglobulin replacement in patients with
chronic lymphocytic leukaemia: a comparison of two dose regimes.
British Journal of Haematology, 88, 209–212.
Cheson, B.D., Bennett, J.M., Grever, M., Kay, N., Keating, M.J.,
O’Brien, S. & Rai, K.R. (1996) National Cancer Institute-spon-
sored Working Group guidelines for chronic lymphocytic leuke-
mia: revised guidelines for diagnosis and treatment. Blood, 87,
4990–4997.
Chisesi, T., Capnist, G. & Dal Fior, S. (1991) Splenic irradiation in
chronic lymphocytic leukemia. European Journal of Haematology,
46, 202–204.
Christensen, B.E., Hansen, M.M. & Videbaek, A. (1977) Splenectomy
in chronic lymphocytic leukaemia. Scandanavian Journal of Hae-
matology, 18, 279–287.
CLL Trialists’ Collaborative Group (1999) Chemotheraputic Options
in Chronic Lymphocytic Leukemia: a Meta-analysis of the Rand-
omized Trials. CLL Trialists’ Collaborative Group. Journal of
National Cancer Institute, 91, 861–868.
Cortes, J., O’Brien, S., Loscertales, J., Kantarjian, H., Giles, F., Thomas,
D., Koller, C. & Keating, M. (2001) Cyclosporin A for the treatment
of cytopenia associated with chronic lymphocytic leukemia. Cancer,
92, 2016–2022.
Crespo, M., Bosch, F., Villamor, N., Bellosillo, B., Colomer, D., Roz-
man, M., Marce, S., Lopez-Guillermo, A., Campo, E. & Montserrat,
E. (2003) ZAP-70 expression as a surrogate for immunoglobulin-
variable-region mutations in chronic lymphocytic leukemia. New
England Journal of Medicine, 348, 1764–1775.
Cusack, Jr, J.C., Seymour, J.F., Lerner, S., Keating, M.J. & Pollock, R.E.
(1997) Role of splenectomy in chronic lymphocytic leukemia.
Journal of American College of Surgery, 185, 237–243.
Dabaja, B.S., O’Brien, S.M., Kantarjian, H.M., Cortes, J.E., Thomas,
D.A., Albitar, M., Schlette, E.S., Faderl, S., Sarris, A., Keating, M.J. &
Giles, F.J. (2001) Fractionated cyclophosphamide, vincristine, lipo-
somal daunorubicin (daunoXome), and dexamethasone
(hyperCVXD) regimen in Richter’s syndrome. Leukemia and Lym-
phoma, 42, 329–337.
Damle, R.N., Wasil, T., Fais, F., Ghiotto, F., Valetto, A., Allen, S.L.,
Buchbinder, A., Budman, D., Dittmar, K., Kolitz, J., Lichtman, S.M.,
Schulman, P., Vinciguerra, V.P., Rai, K.R., Ferrarini, M. & Chior-
azzi, N. (1999) Ig V gene mutation status and CD38 expression as
novel prognostic indicators in chronic lymphocytic leukemia. Blood,
94, 1840–1847.
Del Poeta, G., Maurillo, L., Venditti, A., Buccisano, F., Epiceno, A.M.,
Capelli, G., Tamburini, A., Suppo, G., Battaglia, A., Del Principe,
M.I., Del Moro, B., Masi, M. & Amadori, S. (2001) Clinical sig-
nificance of CD38 expression in chronic lymphocytic leukemia.
Blood, 98, 2633–2639.
Delpero, J.R., Houvenaeghel, G., Gastaut, J.A., Orsoni, P., Blache, J.L.,
Guerinel, G. & Carcassonne, Y. (1990) Splenectomy for hypers-
plenism in chronic lymphocytic leukaemia and malignant non-
Hodgkin’s lymphoma. British Journal of Surgery, 77, 443–449.
Di Raimondo, F., Giustolisi, R., Lerner, S., Cacciola, E., O’Brien, S.,
Kantarjian, H. & Keating, M.J. (2001) Retrospective study of the
prognostic role of serum thymidine kinase level in CLL patients with
active disease treated with fludarabine. Annals of Oncology, 12,
621–625.
311
Guideline
Dighiero, G., Maloum, K., Desablens, B., Cazin, B., Navarro, M., Leblay,
R., Leporrier, M., Jaubert, J., Lepeu, G., Dreyfus, B., Binet, J.L. &
Travade, P. (1998) Chlorambucil in indolent chronic lymphocytic
leukemia. French Co-operative Group on Chronic Lymphocytic
Leukemia. New England Journal of Medicine, 338, 1506–1514.
Dohner, H., Fischer, K., Bentz, M., Hansen, K., Benner, A., Cabot, G.,
Diehl, D., Schlenk, R., Coy, J., Stilgenbauer, S., Volkmann, M., Galle,
P., Poustka, A., Hunstein, W. & Lichter, P. (1995) p53 gene deletion
predicts for poor survival and non-response to therapy with purine
analogs in chronic B-cell leukemias. Blood, 85, 1580–1588.
Dohner, H., Stilgenbauer, S., James, M.R., Benner, A., Weilgum, T. &
Bentz, M. (1997) 11q deletions identify a new subset of B-cell
chronic lymphocytic leukaemia characterised by extensive nodal
involvement and inferior prognosis. Blood, 89, 2616–2522.
Dohner, H., Stilgenbauer, S., Benner, A., Leupolt, E., Krober, A.,
Bullinger, L., Dohner, K., Bentz, M. & Lichter, P. (2000) Genomic
aberrations and survival in chronic lymphocytic leukemia. New
England Journal of Medicine, 343, 1910–1916.
Dreger, P. & Montserrat, E. (2002) Autologous and allogeneic stem cell
transplantation for chronic lymphocytic leukemia. Leukemia,
16, 985–992.
Dreger, P., van Biezen, A., Brand, R., Esteve, J., Gratwohl, A., Kimby,
E., Michallet, M., Milligan, D.W. & Niederwieser, D. (2000a)
Prognostic factors for survival after autologous stem cell trans-
plantation for chronic lymphocytic leukemia (CLL): the EMBT
experience. Blood, 96(Suppl. 1), 482a.
Dreger, P., von Neuhoff, N., Sonnen, R., Kuse, R., Seyfarth, B., Glass,
B. & Schmitz, N. (2000b) Feasibility and efficacy of autologous stem
cell transplantation for poor risk CLL. Blood, 96(Suppl. 1), 483a.
Dreger, P., van Biezen, A., Brand, R., Hansz, J., Corradini, P., Finke, J.,
Lambertenghi-Deliliers, G., Russell, N., Michallet, M. & Nied-
erwieser, D. (2001). Allogenic stem cell transplantation (SCT) for
chronic lymphocytic leukaemia using intensisty-reduced condi-
tioning. An EMBT survey. Blood, 98, 743a.
Dreger, P., Stilgenbauer, S., Benner, A., Ritgen, M., Schmitz, N. &
Dohner, H. (2002) High-dose therapy with autologous stem cell
transplantation (ASCT) prolongs survival of patients with chronic
lymphocytic leukemia (CLL): a matched-pair analysis. Blood,
100(Suppl. 1), 217a.
Dreger, P., Brand, R., Hansz, J., Milligan, D., Corradini, P., Finke, J.,
Deliliers, G., Martino, R., Russell, N., Van Biezen, A., Michallet, M.
& Niederwieser, D. (2003) Treatment related mortality and graft
versus leukemia effect after allogeneic stem cell transplantation for
chronic lymphocytic leukemia using intensity reduced conditioning.
Leukemia, 17, 841–848.
Durig, J., Nascher, M., Schmucker, U., Renzing-Kohler, K., Huttmann,
A. & Duhrsen, U. (2002) CD38 expression is an important prog-
nostic marker in chronic lymphocytic leukaemia. Leukemia, 16,
30–35.
Eichhorst, B., Busch, R., Stauch, M., Kneba, M., Ritgen, M., Soling, U.,
Burkhard, O., Bergmann, M., Wendtner, M., Hiddermann, W.,
Emmerich, B. & Hallek, M. (2003a) Fludarabine induces higher
response rates in first line therapy of older patients with advanced
chronic lymphocytic leukemia than chlorambucil: interim analysis
of a phase 111 study of the German CLL study group. Blood,
102(Suppl. 1), 109a.
Eichhorst, B., Busch, R., Hopfinger, G., Pasold, R., Hensel, M., Soling,
U., Siehl, S., Steinbrecher, C., Jager, U., Bergmann, M., Wendtner,
M., Hiddermann, W., Emmerich, B. & Hallek, M. (2003b)
312 ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
Fludarabine plus cyclophosphamide induces higher remission rates
and longer progression free survival than fludarabine alone in first line
therapy of advanced chronic lymphocytic leukemia: results of a phase
111 study of the German CLL study group. Blood, 102(Suppl. 1),
72a.
Esteve, J., Montserrat, E., Dreger, P., Meloni, G., Pavletic, S., Catovsky,
D., Dearden, D., Scime, C., Sutton, L., Michallet, M., Desablens, B.,
Kimby, E., Coiffier, B., Brunet, S., Sanz, M.A., Besalduch, J.,
Cabellero, D., Juliusson, G., Conde, E., Del Potro, E. & Schmitz, N.
(2001) Stem cell transplantation (SCT) for chronic lymphocytic
leukemia (CLL): outcome and prognostic factors after autologous
and allogenic transplants. Blood, 98(Suppl. 1), 482a.
Esteve, J., Vilamor, N., Colomer, D. & Montserrat, E. (2002) Different
clinical value of minimal residual disease after autologous and
allogenic stem cell transplantation for chronic lymphocytic leuke-
mia. Blood, 99, 1873–1874.
Ezdinli, E., Stutzman, L., William August, C. & Firat, D. (1969) Cor-
ticosteriod therapy for lymphomas and chronic lymphocytic leu-
kemia. Cancer, 23, 900–909.
Faderl, S., Thomas, D.A., O’Brian, S., Giles, F., Koller, C.A., Beran, M.,
Williams, M., Garcia-Manero, G., Kantarjian, H.M. & Keating, M.J.
(2001) An exploratory study of the combination of monoclonal
antibodies CAMPATH-1H and rituximab in the treatment of CD52-
and CD20-positive chronic lymphoid disorders. Blood, 98(Suppl. 1),
365a.
Forsyth, P., Milligan, D. & Davies, F.E. (2000) High dose chemor-
adiotherapy with autologous stem cell rescue for patients with CLL
is an effective and safe means of inducing molecular responses: an
MRC pilot study. Blood, 96(Suppl. 1), 843a.
French Co-operative Group on Chronic Lymphocytic Leukaemia
(1990a) Natural history of stage A chronic lymphocytic leukaemia
untreated patients. British Journal of Haematology, 76, 45–57.
French Co-operative Group on Chronic Lymphocytic Leukaemia
(1990b) A randomized clinical trial of chlorambucil versus COP in
stage A chronic lymphocytic leukaemia. French Co-operative Group
on Chronic Lymphocytic Leukaemia. Blood, 75, 1422–1425.
French Co-operative Group on CLL, Johnson, S., Smith, A.G., Loffler,
H., Osby, E., Juliusson, G., Emmerich, B., Wyld, P.J. & Hiddemann,
W. (1996) Multicentre prospective randomised trial of fludarabine
versus cyclophosphamide, doxorubicin and prednisone (CAP) for
treatment of advanced stage chronic lymphocytic leukaemia. Lancet,
347, 1432–1438.
Gale, R.P. & Montserrat, E. (1993) Intensive therapy of chronic lym-
phocytic leukaemia. Bailliere’s Clinical Haematology, 6, 879–885.
Galton, D., Wiltshire, E., Szur, J. & Dacie, J. (1961) The use of
chlorambucil and steriods in the treatment of chronic lymphocytic
leukaemia. British Journal of Haematology, 7, 73–98.
Garcia-Manero, G., O’Brien, S., Cortes, J., Faderl, S., Giles, F., Albitar,
M., Lerner, S., Kantarjian, H. & Keating, M. (2001) Update of results
of the combination of fludarabine, cyclophosphamide and rituximab
for previously treated patients with chronic lymphocytic leukaemia
(CLL). Blood, 98(Suppl. 1), 633a.
Ghazal, H. (2002) Successful treatment of pure red cell aplasia with
rituximab in patients with chronic lymphocytic leukemia. Blood,
99, 1092–1094.
Ghia, P., Guida, G., Stella, S., Gottardi, D., Guena, M., Strola, G.,
Scielzo, C. & Caligaris-Cappio, F. (2003) The pattern of CD38
expression defines a distinct subset of chronic lymphocytic leukemia
(CLL) patients at risk of disease progression. Blood, 101, 1262–1269.

Giles, F.J., O’Brien, S.M. & Keating, M.J. (1998) Chronic lymphocytic
leukemia in (Richter’s) transformation. Seminars in Oncology, 25,
117–125.
Giles, F.J., O’Brien, S.M., Santini, V., Gandhi, V., Plunkett, W., Sey-
mour, J.F., Robertson, L.E., Kantarjian, H.M. & Keating, M.J. (1999)
Sequential cis-platinum and fludarabine with or without arabinosyl
cytosine in patients failing prior fludarabine therapy for chronic
lymphocytic leukemia: a phase II study. Leukemia and Lymphoma,
36, 57–65.
Girinsky, T., Guillot-Vals, D., Koscielny, S., Cosset, J.M., Ganem, G.,
Carde, P., Monhonval, M., Pereira, R., Bosq, J., Ribrag, V., Vantelon,
J.M. & Munck, J.N. (2001) A high and sustained response rate in
refractory or relapsing low-grade lymphoma masses after low-dose
radiation: analysis of predictive parameters of response to treatment.
International Journal of Radiation Oncology, Biology, Physics, 51,
148–155.
Grever, M.R., Kopecky, K.J., Coltman, C.A., Files, J.C., Greenberg,
B.R., Hutton, J.J., Talley, R., Von Hoff, D.D. & Balcerzak, S.P.
(1988) Fludarabine monophosphate: a potentially useful agent in
chronic lymphocytic leukaemia. Nouvelle Revue Francaise d’Hema-
tologie, 30, 457–459.
Gribabis, D.A., Panayiotidis, P., Boussiotis, V.A., Hannoun, C. &
Pangalis, G.A. (1994) Influenza virus vaccine in B-cell chronic
lymphocytic leukaemia patients. Acta Haematologica, 91, 115–118.
Gribben, J.C., Neuberg, D., Soiffer, R.J., Fischer, D.C., Schlossman, R.,
Alyea, E.P., Kuhlman, C., Ritz, J. & Nadler, L.M. (1998) Autologous
versus allogenic bone marrow transplantation for patients with poor
prognosis CLL. Blood, 92(Suppl.), 322a.
Griffiths, H., Brennan, V., Lea, J., Bunch, C., Lee, M. & Chapel, H.
(1989) Crossover study of immunoglobulin replacement therapy in
patients with low-grade B-cell tumors. Blood, 73, 366–368.
Gupta, N.K., Patel, D., Kavuru, S., Janson, D., Hoffman, M., Rama-
doss, U., Ahmed, S. & Rai, K. (2001) Rituximab, cyclophosphamide
and decadron (RCD) is effective in previously treated advanced
chronic lymphocytic leukaemia (CLL). Journal of Clinical Oncology,
20, page 284a (abstract no. 1133).
Gupta, N.K., Kavuru, S., Patel, D., Janson, D., Driscoll, N. & Ahmed, S.
(2002) Rituximab-based chemotherapy for steroid-refractory auto-
immune hemolytic anemia of chronic lymphocytic leukemia. Leu-
kemia, 10, 2092–2095.
Hainsworth, J., Litchy, S., Barton, J., Houston, G., Hermann, F., Bra-
dof, J. & Greco, F. (2003) Single agent rituximab as first line and
maintenance treatment for patients with chronic lymphocytic leu-
kemia or small lymphocytic lymphoma: a phase II trial of the
Minnie Pearl Cancer Research Network. Journal of Clinical Oncology,
21, 1746–1751.
Hallek, M., Langenmayer, I., Nerl, C., Knauf, W., Dietzfelbinger, H.,
Adorf, D., Ostwald, M., Busch, R., Kuhn-Hallek, I., Thiel, E. &
Emmerich, B. (1999) Elevated serum thymidine kinase levels
identify a subgroup at high risk of disease progression in early,
nonsmoldering chronic lymphocytic leukemia. Blood, 93, 1732–
1737.
Hallek, M., Schmitt, B., Wilhelm, M., Busch, R., Krober, A., Fostitsch,
H.P., Sezer, O., Herold, M., Knauf, W., Wendtner, C.M., Kuse, R.,
Freund, M., Franke, A., Schriever, F., Nerl, C., Dohner, H., Thiel, E.,
Hiddemann, W., Brittinger, G., Emmerich, B. & the German
Chronic Lymphocytic Leukaemia Study Group (2001) Fludarabine
plus cyclophosphamide is an efficient treatment for advanced
chronic lymphocytic leukaemia (CLL): results of a phase II study of
ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
Guideline
the German CLL Study Group. British Journal of Haematology, 114,
342–348.
Hamblin, T. (2001) Autoimmune Disease and Its Management in
Chronic Lymphocytic Leukemia. In: Chronic Lymphoid Leukemias
(ed. by B.D. Cheson), pp. 435–458. Marcel Dekker, New York.
Hamblin, T.J., Davis, Z., Gardiner, A., Oscier, D.G. & Stevenson, F.K.
(1999) Unmutated Ig V(H) genes are associated with a more
aggressive form of chronic lymphocytic leukemia. Blood, 94, 1848–
1854.
Hamblin, T.J., Orchard, J.A., Ibbotson, R.E., Davis, Z., Thomas, P.W.,
Stevenson, F.K. & Oscier, D.G. (2002) CD38 expression and
immunoglobulin variable region mutations are independent prog-
nostic variables in chronic lymphocytic leukemia, but CD38 expres-
sion may vary during the course of the disease. Blood, 99, 1023–1029.
Han, T., Ezdinli, E.Z., Shimaoka, K. & Desai, D.V. (1973) Chlor-
ambucil vs. combined chlorambucil-corticosteroid therapy in
chronic lymphocytic leukemia. Cancer, 31, 502–508.
Hegde, U.P., Wyndham, H.W., White, T. & Cheson, B.D. (2002)
Rituximab treatment of refractory fludarabine-associated immune
thrombocytopenia in chronic lymphocytic leukemia. Blood, 100,
2260–2262.
Hensel, M., Kornacker, M., Yammeni, S., Egerer, G. & Ho, A. (2003)
Disease activity and pretreatment rather than hypogammaglobuli-
naemia, are major risk factors for infectious complications in
patients with chronic lymphocytic leukaemia. British Journal of
Haematology, 122, 600–606.
Horowitz, M.M., Montserrat, E., Sobocinski, K., Giralt, S., Khouri, I.F.
& Schmitz, N. (2000) Haemopoietic stem cell transplantation for
chronic lymphocytic leukaemia. Blood, 96(Suppl. 1), 522a.
Houlston, R., Catovsky, D. & Yuille, M. (2002) Genetic susceptibility
to chronic lymphocytic leukemia. Leukemia, 16, 1008–1014.
Ibrahim, S., Keating, M., Do, K.A., O’Brien, S., Huh, Y.O., Jilani, I.,
Lerner, S., Kantarjian, H.M. & Albitar, M. (2001) CD38 expression
as an important prognostic factor in B-cell chronic lymphocytic
leukemia. Blood, 98, 181–186.
Jaksic, B. & Brugiatelli, M. (1988) High dose continuous chlorambucil
vs intermittent chlorambucil plus prednisone for treatment of
B-CLL–IGCI CLL-01 trial. Nouvelle Review Francais d’Hematologie,
30, 437–442.
Jaksic, B. & Vitale, B. (1981) Total tumour mass score (TTM): a new
parameter in chronic lymphocyte leukaemia. British Journal of
Haematology, 49, 405–413.
Jaksic, B., Brugiatelli, M., Krc, I., Losonczi, H., Holowiecki, J., Planinc-
Peraica, A., Kusec, R., Morabito, F., Iacopino, P. & Lutz, D. (1997)
High dose chlorambucil versus Binet’s modified cyclophosphamide,
doxorubicin, vincristine, and prednisone regimen in the treatment
of patients with advanced B-cell chronic lymphocytic leukemia.
Results of an international multicenter randomized trial. Interna-
tional Society for Chemo-Immunotherapy, Vienna. Cancer, 79,
2107–2114.
Johnson, S., Smith, A.G., Loffler, H., Osby, E., Juliusson, G., Emme-
rich, B., Wyld, P. & Hiddemann, W. (1996) Multicentre prospective
randomised trial of fludarabine versus cyclophosphamide, doxir-
ubicin, and prednisilone (CAP) for the treatment of advanced-stage
chronic lymphocytic leukaemia. The French Co-operative Group on
CLL. Lancet, 347, 1432–1438.
Juliusson, G. & Liliemark, J. (1993) High complete remission rate from
2-chloro-2¢-deoxyadenosine in previously treated patients with
B-cell chronic lymphocytic leukaemia: response predicted by rapid
313
Guideline
decrease of blood lymphocyte count. Journal of Clinical Oncology,
11, 679–689.
Juliusson, G. & Liliemark, J. (1994) Retreatment of chronic lympho-
cytic leukaemia with 2-chlorodeoyadenosine (CdA) at relapse fol-
lowing CdA-induced remission: no acquired resistance. Leukemia
and Lymphoma, 13, 75–80.
Juliusson, G. & Liliemark, J. (1996) Long-term survival following
cladribine (2-chlorodeoxyadenosine) therapy in previously treated
patients with chronic lymphocytic leukaemia. Annals of Oncology, 7,
373–379.
Juliusson, G., Oscier, D.G., Fitchett, M., Ross, F.M., Stockdill, G.,
Mackie, M.J., Parker, A.C., Castoldi, G.L., Cuneo, A., Knuutila, S.,
Elonen, E. & Gahrton, G. (1990) Prognostic subgroups in B-cell
chronic lymphocytic leukaemia defined by specific chromosomal
abnormalities. New England Journal of Medicine, 323, 720–724.
Juliusson, G., Elmhorn-Rosenborg, A. & Liliemark, J. (1992) Response
to chlorodeoxyadenosine in patients with B-cell chronic lympho-
cytic leukemia resistant to fludarabine. New England Journal of
Medicine, 327, 1056–1061.
Juliusson, G., Christiansen, I., Hansen, M.M., Johnson, S., Kimby, E.,
Elmhorn-Rosenborg, A. & Liliemark, J. (1996) Oral cladribine as
primary therapy for patients with B-cell chronic lymphocytic
leukemia. Journal of Clinical Oncology, 14, 2160–2166.
Jurlander, J., Geisler, C.H. & Hansen, M.M. (1994) Treatment of
hypogammaglobulinaemia in chronic lymphocytic leukaemia by
low-dose intravenous gammaglobulin. European Journal of Hema-
tology, 53, 114–118.
Keating, M.J., Kantarjian, H., Talpaz, M., Redman, J. & McCredie, K.B.
(1988) Fludarabine therapy in chronic lymphocytic leukaemia
(CLL). Nouvelle Revue Francaise d’Hematologie, 30, 461–466.
Keating, M.J., Kantarjian, H., Talpaz, M., Redman, J., Koller, C.,
Barlogie, B., Velasquez, W., Plunkett, W., Freireich, E.J. & McCredie,
K.B. (1989) Fludarabine: a new agent with major activity against
chronic lymphocytic leukaemia. Blood, 74, 19–25.
Keating, M.J., O’Brien, S., Lerner, S., Koller, C., Beran, M., Robertson,
L.E., Freireich, E.J., Estey, E. & Kantarjian, H. (1998) Long-term
follow-up of patients with chronic lymphocytic leukemia
(CLL) receiving fludarabine regimens as initial therapy. Blood, 92,
1165–1171.
Keating, M.J., Smith, T.L., Lerner, S., O’Brien, S., Robertson, L.E.,
Kantarjian, H. & Freireich, E.J. (2000) Prediction of prognosis fol-
lowing fludarabine used as secondary therapy for chronic lympho-
cytic leukaemia. Leukemia and Lymphoma, 37, 71–85.
Keating, M.J., Manshouri, T., O’Brien, S., Wierda, W., Kantarjian, H.,
Washington, L., Lerner, S. & Abitar, M. (2002a) A high proportion
of molecular remission can be obtained with a fludarabine, cyclo-
phosphamide, rituximab combination (FCR) in chronic lympho-
cytic leukaemia (CLL). Blood, 100(Part 1), 205a.
Keating, M.J., O’Brien, S., Kontoyiannis, D., Plunkett, W., Koller, C.,
Beran, M., Lerner, S. & Kantarjian, H. (2002b) Results of first salvage
therapy for patients refractory to a fludarabine regimen in chronic
lymphocytic leukaemia. Leukemia and Lymphoma, 43, 1755–1762.
Keating, M.J., Flinn, I., Jain, V., Binet, J.L., Hillmen, P., Byrd, J.,
Albitar, M., Brettman, L., Santabarbara, P., Wacker, B. & Rai, K.R.
(2002c) Therapeutic role of alemtuzumab (Campath-1H) in patients
who have failed fludarabine: results of a large international study.
Blood, 99, 3554–3561.
Kennedy, B., Rawstron, A., Haynes, A., Fegan, C., Leach, M., Tighe, J.,
Rassam, S., Hale, G., Morgan, G. & Hillmen, P. (2001) Eradication
314 ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
of detectable minimal residual disease with Campath-1H therapy
results in prolonged survival in patients with refractory B-CLL.
Blood, 98(Suppl. 1), 365a.
Kennedy, B., Rawstron, A., Carter, C., Ryan, M., Speed, K., Lucas, G. &
Hillmen, P. (2002) Campath-1H and fludarabine in combination are
highly active in refractory chronic lymphocytic leukemia. Blood, 99,
2245–2247.
Knauf, W.U., Ehlers, B., Mohr, B., Thiel, E., Langenmayer, I., Hallek,
M., Emmerich, B., Adorf, D., Nerl, C. & Zwingers, T. (1997)
Prognostic impact of the serum levels of soluble CD23 in B-cell
chronic lymphocytic leukemia. Blood, 89, 4241–4242.
Krober, A., Seiler, T., Benner, A., Bullinger, L., Bruckle, E., Lichter, P.,
Dohner, H. & Stilgenbauer, S. (2002) V(H) mutation status, CD38
expression level, genomic aberrations, and survival in chronic lym-
phocytic leukemia. Blood, 100, 1410–1416.
Leporrier, M., Chevret, S., Cazin, B., Boudjerra, N., Feugier, P., De-
sablens, B., Rapp, M.J., Jaubert, J., Autrand, C., Divine, M., Dreyfus,
B., Maloum, K., Travade, P., Dighiero, G., Binet, J.L. & Chastang, C.
(2001) Randomized comparison of fludarabine, CAP, and ChOP in
938 previously untreated stage B and C chronic lymphocytic leu-
kemia patients. Blood, 98, 2319–2325.
Lin, K., Sherrington, P.D., Dennis, M., Matrai, Z., Cawley, J.C. &
Pettitt, A.R. (2002) Relationship between p53 dysfunction, CD38
expression, and IgV(H) mutation in chronic lymphocytic leukemia.
Blood, 100, 1404–1409.
Lundin, J., Kimby, E., Bjorkholm, M., Broliden, P.A., Celsing, F.,
Hjalmar, V., Mollgard, L., Rebello, P., Hale, G., Waldmann, H.,
Mellstedt, H. & Osterborg, A. (2002) Phase II trial of subcutaneous
anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as
first-line treatment for patients with B-cell chronic lymphocytic
leukemia (B-CLL). Blood, 100, 768–773.
Mauro, F.R., Foa, R., Giannarelli, D., Cordone, I., Crescenzi, S., Pes-
carmona, E., Sala, R., Cerretti, R. & Mandelli, F. (1999) Clinical
characteristics and outcome of young chronic lymphocytic leukemia
patients: a single institution study of 204 cases. Blood, 94, 448–454.
Mauro, F.R., Foa, R., Cerretti, R., Giannarelli, D., Coluzzi, S., Mandelli,
F. & Girelli, G. (2000) Autoimmune hemolytic anemia in chronic
lymphocytic leukemia: clinical, therapeutic, and prognostic features.
Blood, 95, 2786–2792.
Michallet, M., Carreras, E., Cornelissen, J.J., Dreger, P., Einsele, H.,
Gratwohl, A., Kimby, E., Niederwieser, D. & Apperley, J. (1999)
Allotransplants and autotransplants in CLL (abstract). Bone Marrow
Transplantation, 23, S53.
Michallet, M., Thiebaud, A., Dreger, P., Remes, K., Milpied, N., San-
tini, G., Hamon, M., Bjorkstrand, B., Kimby, E., Belhabri, A., Tan-
guy, M. & Apperley, J. (2000) Peripheral blood stem cell
mobilisation and transplantation after fludarabine therapy in chro-
nic lymphocytic leukaemia: a report of the EBMT CLL Subcom-
mittee on behalf of the EBMT Chronic Leukaemia Working Party.
21 British Journal of Haematology, 108, 595–601.
Molica, S. (1994) Infections in chronic lymphocytic leukemia: risk
factors, and impact on survival, and treatment. Leukemia and
Lymphoma, 13, 203–214.
Monteserrat, N., Vinolas, N., Reverter, J.C. & Rozman, C. (1988)
Natural history of chronic lymphocytic leukaemia: on the progres-
sion and prognosis of early stages. Nouvelle Review Francais d’He-
matologie, 30, 359–361.
Montillo, M., Tedeschi, A., Cafro, A.M., Rossi, V., D’Avanzo, G.,
Pungolino, E., Cairoli, R., Oreste, P., Veronese, S., Brando, B. &

Morra, E. (2002) Sequential subcutaneous administration of
CAMPATH-1H as treatment of minimal residual disease in CLL
patients responding to fludarabine (FAMP). Blood, 100(Suppl. 1),
805a.
Montillo, M., Tedeschi, A., O’Brien, S., DiRaimondo, F., Lerner, S.,
Ferrajoli, A., Morra, E. & Keating, M. (2003) Phase 11 study of
cladribine and cyclophosphamide in patients with chronic lym-
phocytic leukemia and prolymphocytic leukemia. Cancer, 79, 114–
120.
Montserrat, E. & Rozman, C. (1993) Chronic lymphocytic leukaemia:
prognostic factors and natural history. Bailliere’s Clinical Haema-
tology, 6, 849–866.
Montserrat, E., Alcala, A., Parody, R., Domingo, A., Garcia-Conde, J.,
Bueno, J., Ferran, C., Sanz, M.A., Giralt, M. & Rubio, D. (1985)
Treatment of chronic lymphocytic leukemia in advanced stages. A
randomized trial, comparing chlorambucil plus prednisone versus
cyclophosphamide, vincristine, and prednisone. Cancer, 56, 2369–
2375.
Montserrat, E., Gomis, F., Vallespi, T., Rios, A., Romero, A., Soler, J.,
Alcala, A., Morey, M., Ferran, C., Diaz-Mediavilla, J., Flores, A.,
Woessner, S., Batille, J., Gonzales-Aza, C., Rovira, M., Reverter, J. &
Rozman, C. (1991) Presenting features and prognosis of chronic
lymphocytic leukemia in younger adults. Blood, 78, 1545–1551.
Montserrat, E., Lopez-Lorenzo, J.L., Manso, F., Martin, A., Prieto, E.,
Arias-Sampedro, J., Fernandez, M.N., Oyarzabal, F.J., Odriozola, J.,
Alcala, A., Garcia-Conde, J., Guardia, R. & Bosch, F. (1996) Flu-
darabine in resistant or relapsing B-cell chronic lymphocytic leu-
kemia: the Spanish Group experience. Leukaemia and Lymphoma,
21, 467–472.
Moreau, E.J., Matutes, E., A’Hern, R.P., Morilla, A.M., Morilla, R.M.,
Owusu-Ankomah, K.A., Seon, B.K. & Catovsky, D. (1997)
Improvement of the chronic lymphocytic leukemia scoring system
with the monoclonal antibody SN8 (CD79b). American Journal of
Clinical Pathology, 108, 378–382.
Morrison, V.A. (2001) Infections in Patients with Chronic Lympho-
cytic Leukemia: Pathogenesis, Spectrum and Theraputic Approa-
ches. In: Chronic Lymphoid Leukemias (ed. by B.D. Cheson),
22 pp. 505–523. Marcel Dekker, New York.
Morrison, V.A., Rai, K.R., Peterson, B.L., Kolitz, J.E., Elias, L.,
Appelbaum, F.R., Hines, J.D., Shepherd, L., Larson, R.A. & Schiffer,
C.A. (2002) Therapy-related myeloid leukemias are observed in
patients with chronic lymphocytic leukemia after treatment with
fludarabine and chlorambucil: results of an intergroup study, cancer
and leukemia group B 9011. Journal of Clinical Oncology, 20, 3878–
3884.
Myint, H., Copplestone, J.A., Orchard, J., Craig, V., Curtis, D., Pren-
tice, A.G., Hamon, M.D., Oscier, D.G. & Hamblin, T.J. (1995)
Fludarabine-related autoimmune haemolytic anaemia in patients
with chronic lymphocytic leukaemia. British Journal of Haematology,
91, 341–344.
Nabhan, C., Tallman, M.S. & Riley, M.B. (2001) Phase 1 study of
rituximab and Campath-1H in patients with relapsed or refractory
chronic lymphocytic leukaemia. Blood, 98(Suppl. 1), 365a.
National Institute for Clinical Excellence (2001) Guidance on the use of
fludarabine for B-cell lymphocytic leukaemia. Technology Appraisal
Guidance 29. National Institute for Clinical Excellence, London.
Neal, Jr, T.F., Tefferi, A., Witzig, T.E., Su, J., Phyliky, R.L. & Nagorney,
D.M. (1992) Splenectomy in advanced chronic lymphocytic leuke-
ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
Guideline
mia: a single institution experience with 50 patients. American
Journal of Medicine, 93, 435–440.
O’Brien, S., Kantarjian, H., Beran, M., Smith, T., Koller, C., Estey, E.,
Robertson, L.E., Lerner, S. & Keating, M. (1993) Results of fludar-
abine and prednisone therapy in 264 patients with chronic lym-
phocytic leukemia with multivariate analysis-derived prognostic
model for response to treatment. Blood, 82, 1695–1700.
O’Brien, S., Kantarjian, H., Beran, M., Koller, C., Talpaz, M., Lerner, S.
& Keating, M.J. (1997) Fludarabine and granulocyte colony-stimu-
lating factor (G-CSF) in patients with chronic lymphocytic leuke-
mia. Leukemia, 11, 1631–1635.
O’Brien, S.M., Kantarjian, H.M., Cortes, J., Beran, M., Koller, C.A.,
Giles, F.J., Lerner, S. & Keating, M. (2001) Results of the fludarabine
and cyclophosphamide combination regimen in chronic lympho-
cytic leukemia. Journal of Clinical Oncology, 19, 1414–1420.
O’Brien, S.M., Kantarjian, H.M., Thomas, D.A., Cortes, J., Giles, F.J.,
Wierda, W.G., Koller, C.A., Ferrajoli, A., Browning, M., Lerner, S.,
Abitar, M. & Keating, M.J. (2003) Alemtuzumab as treatment for
residual disease after chemotherapy in patients with chronic lym-
phocytic leukemia. Cancer, 98, 2657–2663.
Orchard, J.A., Ibbotson, R.E., Davis, Z.A., Gardiner, A.C., Hamblin,
T.J. & Oscier, D.G. (2004) Zap-70 evaluation by flow cytometry is a
significant prognostic marker in B-CLL. Lancet, 363, 105–111.
Oscier, D.G., Gardiner, A.C., Mould, S.J., Glide, S., Davis, Z.A.,
Ibbotson, R.E., Corcoran, M.M., Chapman, R.M., Thomas, P.W.,
Copplestone, J.A., Orchard, J.A. & Hamblin, T.J. (2002) Multivariate
analysis of prognostic factors in CLL: clinical stage, IGVH gene
mutational status, and loss or mutation of the p53 gene are
independent prognostic factors. Blood, 100, 1177–1184.
Osterborg, A., Fassas, A.S., Anagnostopoulos, A., Dyer, M.J., Catovsky,
D. & Mellstedt, H. (1996) humanized CD52 monoclonal antibody
Campath-1H as first-line treatment in chronic lymphocyitic leu-
23 kaemia. British Journal of Haematology, 93, 151–153.
Osterborg, A., Dyer, M.J., Bunjes, D., Pangalis, G.A., Bastion, Y.,
Catovsky, D. & Mellstedt, H. (1997) Phase II multicenter study of
human CD52 antibody in previously treated chronic lymphocytic
leukemia. European Study Group of CAMPATH-1H Treatment in
Chronic Lymphocytic Leukemia. Journal of Clinical Oncology, 15,
1567–1574.
Pegourie, B., Sotto, J.J., Hollard, D., Michallet, M. & Sotto, M.F. (1987)
Splenectomy during chronic lymphocytic leukemia. Cancer, 59,
1626–1630.
Perez-Simon, J.A., Kottaridis, P.D., Martino, R., Craddock, C.,
Caballero, D., Chopra, R., Garcia-Conde, J., Milligan, D.W., Schey,
S., Urbano-Ispizua, A., Parker, A., Leon, A., Yong, K., Sureda, A.,
Hunter, A., Sierra, J., Goldstone, A.H., Linch, D.C., San Miguel, J.F.
& Mackinnon, S. (2002) Nonmyeloablative transplantation with or
without alemtuzumab: comparison between 2 prospective studies in
patients with lymphoproliferative disorders. Blood, 100, 3121–3127.
Perkins, J.G., Flynn, J.M., Howard, R.S. & Byrd, J.C. (2002) Frequency
and type of serious infections in fludarabine-refractory B-cell
chronic lymphocytic leukemia and small lymphocytic lymphoma:
implications for clinical trials in this patient population. Cancer, 94,
2033–2039.
Pfitzner, T., Reiser, M., Barth, S., Borchmann, P., Schulz, H., Schink-
othe, T., Oberhauser, F., Wessels, J., Tur, M., Diehl, V. & Engert, A.
(2002) Quantitative molecular monitoring of residual tumor cells in
chronic lymphocytic leukemia. Annals of Hematology, 81, 258–266.
315
Guideline
Piro, L.D., Carrera, C.J., Beutler, E. & Carson, D.A. (1988) 2-Chlor-
odeoxyadenosine: an effective new agent for the treatment of
chronic lymphocytic leukemia. Blood, 72, 1069–1073.
Rabinowe, S.N., Soiffer, R.J., Gribben, J.G., Daley, H., Freedman, A.S.,
Daley, J., Pesek, K., Neuberg, D., Pinkus, G. & Leavitt, P.R. (1993)
Autologous and allogeneic bone marrow transplantation for poor
prognosis patients with B-cell chronic lymphocytic leukemia. Blood,
82, 1366–1376.
Rai, K.I., Sawitsky, A., Cronkite, E.P., Chanana, A., Levy, R. & Pas-
ternak, B. (1975) Clinical staging of chronic lymphocytic leukaemia.
Blood, 46, 219–234.
Rai, K.R., Peterson, B.L., Appelbaum, F.R., Kolitz, J., Elias, L., Shep-
herd, L., Hines, J., Threatte, G.A., Larson, R.A., Cheson, B.D. &
Schiffer, C.A. (2000) Fludarabine compared with chlorambucil as
primary therapy for chronic lymphocytic leukemia. New England
Journal of Medicine, 343, 1750–1757.
Rai, K., Coutre, S., Rizzeri, D., Gribben, J., Flinn, I., Rabinowe, S. &
Keating, M. (2001) Efficacy and safety of alemtuzumab (Campath-
1H) in refractory B-CLL patients treated on a compassionate basis.
Blood, 98(Suppl. 1), 365a.
Raphael, B., Andersen, J.W., Silber, R., Oken, M., Moore, D. & Ben-
nett, J. (1991) Comparison of chlorambucil and prednisone versus
cyclophosphamide, vicristine and prednisone as an initial treatment
for chronic lymphocytic leukaemia: a long term follow up of an
Eastern Co-operative Oncology Group randomised clinical trial.
Journal of Clinical Oncology, 9, 770–776.
Rawstron, A.C., Kennedy, B., Evans, P.A., Davies, F.E., Richards, S.J.,
Haynes, A.P., Russell, N.H., Hale, G., Morgan, G.J., Jack, A.S. &
Hillmen, P. (2001) Quantitation of minimal disease levels in chronic
lymphocytic leukemia using a sensitive flow cytometric assay im-
proves the prediction of outcome and can be used to optimize
therapy. Blood, 98, 29–35.
Rawstron, A.C., Yuille, M.R., Fuller, J., Cullen, M., Kennedy, B.,
Richards, S.J., Jack, A.S., Matutes, E., Catovsky, D., Hillmen, P. &
Houlston, R.S. (2002) Inherited predisposition to CLL is detectable
as subclinical monoclonal B-lymphocyte expansion. Blood, 100,
2289–2290.
Richter, M.N. (1928) Generalised reticular cell sarcoma of lymph
nodes associated with lymphocytic leukemia. American Journal of
Pathology, 4, 285–292.
Ritgen, M., Dreger, P., Humpe, A., Stilgenbauer, S., Döhner, H. &
Kneba, M. (2002). Quantitative PCR demonstrates effective graft
versus host leukemia activity after allogeneic stem cell transplanta-
tion using reduced intensity conditioning in patients with chronic
lymphocytic leukemia. Blood, 100(Suppl. 1), 854a.
Ritgen, M., Lange, A., Stilgenbauer, S., Dohner, H., Bretscher, C.,
Bosse, H., Stuhr, A., Kneba, M. & Dreger, P. (2003) Unmutated
immunoglobulin variable heavy-chain gene status remains an ad-
verse prognostic factor after autologous stem cell transplantation for
chronic lymphocytic leukemia. Blood, 101, 2049–2053.
Robak, T. & Kasznicki, M. (2002) Alkylating agents and nucleoside
analogues in the treatment of B cell chronic lymphocytic leukemia.
Leukemia, 16, 1015–1027.
Robak, T., Blonski, J.Z., Kasznicki, M., Blasinska-Morawiec, M., Kry-
kowski, E., Dmoszynska, A., Mrugala-Spiewak, H., Skotnicki, A.B.,
Nowak, W., Konopka, L., Ceglarek, B., Maj, S., Dwilewicz-Trojaczek,
J., Hellmann, A., Urasinski, I., Zdziarska, B., Kotlarek-Haus, S.,
Potoczek, S. & Grieb, P. (2000a) Cladribine with prednisone versus
chlorambucil with prednisone as first-line therapy in chronic lym-
316 ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
phocytic leukemia: report of a prospective, randomized, multicenter
trial. Blood, 96, 2723–2729.
Robak, T., Blonski, J.Z., Kasznicki, M., Konopka, L., Ceglarek, B.,
Dmoszynska, A., Soroka-Wojtaszko, M., Skotnicki, A.B., Nowak,
W., Dwilewicz-Trojaczek, J., Tomaszewska, A., Hellman, A.,
Lewandowski, K., Kuliczkowski, K., Potoczek, S., Zdziarska, B.,
Hansz, J., Kroll, R., Komarnicki, M., Holowiecki, J. & Grieb, P.
(2000b) Cladribine with or without prednisone in the treatment of
previously treated and untreated B-cell chronic lymphocytic leu-
kaemia – updated results of the multicentre study of 378 patients.
British Journal of Haematology, 108, 357–368.
Robertson, L.E., Pugh, W., O’Brien, S., Kantarjian, H., Hirsch-Gins-
berg, C., Cork, A., McLaughlin, P., Cabanillas, F. & Keating, M.J.
(1993) Richter’s syndrome: a report on 39 patients. Journal of
Clinical Oncology, 11, 1985–1989.
Ru, X. & Liebman, H. (2003) Successful treatment of refractory pure
red cell aplasia associated with lymphoproliferative disorders with
the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H).
British Journal of Haematology, 123, 278–281.
Rummel, M.J., Kafer, G., Pfreundschuh, M., Jager, E., Reinhardt, U.,
Mitrou, P.S., Hoelzer, D. & Bergmann, L. (1999) Fludarabine and
epirubicin in the treatment of chronic lymphocytic leukaemia: a
German Multicentre phase II study. Annals of Oncology, 10, 183–
188.
Saven, A., Carrera, C.J., Carson, D.A., Beutler, E. & Piro, L.D. (1991)
2-Chlorodeoxyadenosine treatment of refractory chronic lympho-
24 cytic leukaemia. Leukemia and Lymphoma, 5(Suppl.), 133–138.
Saven, A., Lemon, R.H., Kosty, M., Beutler, E. & Piro, L.D. (1995)
2-Chlorodeoxyadenosine activity in patients with untreated chronic
25 lymphocytic leukaemia. Journal of Clinical Oncology, 14, 2160–2166.
Sawitsky, A., Rai, K.R., Glidewell, O. & Silver, R.T. (1979) Comparison
of daily versus intermittent chlorambucil and prednisone therapy in
the treatment of patients with chronic lymphocytic leukemia. Blood,
50, 1049–1059.
Schulz, H., Klein, S.K., Rehwald, U., Reiser, M., Hinke, A., Knauf,
W.U., Aulitzky, W.E., Hensel, M., Herold, M., Huhn, D., Hallek, M.,
Diehl, V. & Engert, A. (2002) Phase 2 study of a combined immu-
nochemotherapy using rituximab and fludarabine in patients with
chronic lymphocytic leukemia. Blood, 100, 3115–3120.
Schwarzmeier, J.D., Shehata, M., Hilgarth, M., Marschitz, I., Louda, N.,
Hubmann, R. & Greil, R. (2002) The role of soluble CD23 in dis-
tinguishing stable and progressive forms of B-chronic lymphocytic
leukemia. Leukemia and Lymphoma, 43, 549–554.
Seymour, J.F., Cusack, J.D., Lerner, S.A., Pollock, R.E. & Keating, M.J.
(1997) Case/control study of the role of splenectomy in chronic
lymphocytic leukemia. Journal of Clinical Oncology, 15, 52–60.
Sgambati, M.T., Linet, M.S. & Devesa, S.S. (2001) Chronic Lympho-
cytic Leukemia: Epidemiological, Familial, and Genetic Aspests. In:
Chronic Lymphoid Leukemias (ed. by B.D. Cheson), pp. 33–62.
26 Marcel Dekker, New York.
Sinisalo, M., Aittoniemi, J., Oivanen, P., Kayhty, H., Olander, R.M. &
Vilpo, J. (2001) Response to vaccination against different types of
antigens in patients with chronic lymphocytic leukaemia. British
Journal of Haematology, 114, 107–110.
Sinisalo, M., Aittoniemi, J., Kayhty, H. & Vilpo, J. (2003) Vaccination
strategies against infections in chronic lymphocytic leukemia.
Leukemia and Lymphoma, 44, 649–652.
Sorensen, J.M., Vena, D.A., Fallavollita, A., Chun, H.G. & Cheson, B.D.
(1997) Treatment of refractory chronic lymphocytic leukaemia with

fludarabine phosphate via the Group C Protocol mechanism of the
National Cancer Institute: five-year follow-up report. Journal of
Clinical Oncology, 15, 458–465.
Stilgenbauer, S. & Dohner, H. (2002) Campath-1H-induced complete
remission of chronic lymphocytic leukemia despite p53 gene mu-
tation and resistance to chemotherapy. New England Journal of
Medicine, 347, 452–453.
Stilgenbauer, S., Neuhoff, N., Bullinger, L., Krober, A., Lichter, P.,
Dreger, P. & Dohner, H. (2000) Deletion 11q23 identifies B-CLL
patients at high risk for molecular disease persistance after high dose
therapy and autografting. Blood, 96(Suppl. 1), 715a.
Thornton, P.D., Matutes, E., Bosanquet, A.G., Lakhani, A.K., Grech,
H., Ropner, J.E., Joshi, R., Mackie, P.H., Douglas, I.D., Bowcock, S.J.
& Catovsky, D. (2003) High dose methyl prednisolone can induce
remissions in CLL patients with p53 abnormalities. Annals of
27 Hematology, Oct 10, (E-pub ahead of print).
Tobin, G., Thurnberg, U., Johnson, A., Thorn, I., Soderberg, O.,
Hultdin, M., Botling, J., Enblad, G., Sallstrom, J., Sundstrom, C.,
Roos, G. & Rosenquist, R. (2002) Somatically mutated Ig VH3–21
genes characterize a new subset of chronic lymphocytic leukemia.
Blood, 99, 2262–2264.
Tournilhac, O., Cazin, B., Lepretre, S., Devine, M., Maloum, K., Del-
mer, A., Grosbois, B., Feugier, P., Maloisel, F., Villard, F., Ville-
magne, B., Bastit, D., Belhadj, K., Azar, N., Michallet, M., Manhes,
G. & Travade, P. (2004). Impact of frontline fludarabine and cy-
clophosphamide treatment on peripheral blood stem cell mobilisa-
28 tion in B cell chronic lymphocytic leukemia. Blood, 103, 363–365.
Van Besien, K., Keralavarma, B., Devine, S. & Stock, W. (2001) Allo-
geneic and autologous transplantation for chronic lymphocytic
leukemia. Leukemia, 15, 1317–1325.
Van Mook, W.N., Fickers, M.M. & Verschueren, T.A. (2001) Clinical
and immunological evaluation of primary splenic irradiation in
ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294–317
Guideline
chronic lymphocytic leukemia: a study of 24 cases. Annals of
Hematology, 80, 216–223.
Weeks, J.C., Tierney, M.R. & Weinstein, M.C. (1991) Cost effectiveness
of prophylactic intravenous immune globulin in chronic lympho-
cytic leukemia. New England Journal of Medicine, 325, 81–86.
Weiss, R.B., Freiman, J., Kweder, S.L., Diehl, L.F. & Byrd, J.C. (1998)
Hemolytic anemia after fludarabine therapy for chronic lymphocytic
leukemia. Journal of Clinical Oncology, 16, 1885–1889.
Wierda, W., O’Brien, S., Fader, S., Ferrajoli, A., Lerner, S., Wang, X.,
Thomas, D., Garcia-Manero, G., Cortes, J., Kantarjian, H. & Keat-
ing, M. (2003) Improved survival in patients with relapsed-refract-
ory chronic lymphocytic leukemia (CLL) treated with fludarabine,
cyclophosphamide, and rituximab (FCR) combination. Blood,
102(Suppl. 1), 110a.
Wiestner, A., Rosenwald, A., Barry, T.S., Wright, G., Davis, E., Hen-
rickson, S., Zhao, H., Ibbotson, R., Orchard, J., Davis, Z., Stetler-
Stevenson, M., Raffeld, M., Arthur, D.C., Marti, G., Wilson, W.H.,
Hamblin, T., Oscier, D. & Staudt, L. (2003) ZAP-70 expression
identifies a chronic lymphocytic leukemia subtype with unmutated
immunoglobulin genes, inferior clinical outcome, and distinct gene
29 expression profile. Blood, 101, 4944–4951.
Yuille, M.R., Houlston, R.S. & Catovsky, D. (1998) Anticipation
in familial chronic lymphocytic leukaemia. Leukemia, 12,
1696–1698.
Zittoun, R., de Witte, T., et al, (1999) A randomized phase II trial of
high-dose chlorambucil vs. fludarabine in patients with advanced
B-chronic lymphocytic leukemia. Hematology and Cell Therapy, 41,
127–136.
Keywords: chronic lymphocytic leukaemia, guidelines, man-
agement.
317