LEUKAEMIAS

Chronic lymphocytic Key points

leukaemia C Chronic lymphocytic leukaemia (CLL) is the most common
leukaemia in the developed countries and is a disease of the
Stephen Devereux elderly
Kirsty Cuthill
C Clinical features arise from infiltration of the lymph nodes,
liver, spleen and bone marrow compartments and from
disruption of the normal immune system
Abstract
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in
C CLL is highly heterogeneous, and biomarkers are useful in
developed countries. It is a disease of the elderly, usually incurable and
prognostication
characterized by significant clinical and biological heterogeneity. Many
patients are diagnosed after the incidental finding of a sustained lympho-
C Treatment is reserved for patients who have symptoms of
cytosis, while others present with symptomatic disease requiring treat-
progressive disease
ment. Clinical features arise from immune dysfunction and tissue
infiltration, and include fatigue, infections, lymphadenopathy, hepatos-
C CLL harbouring TP53 deletions or mutations respond poorly to
plenomegaly and cytopenias. Key diagnostic tests are peripheral blood
conventional therapy and should be treated accordingly
morphology and immunophenotyping. Clinical staging, lymphocyte
doubling time and biomarkers are useful in assessing prognosis. Overall,
C The introduction of targeted therapies is improving clinical
median survival is 10 years. Patients with CLL undergo regular moni-
outcomes, particularly in patients with poor prognosis
toring, and therapy is reserved for those with symptomatic or rapidly pro-
relapsed or refractory disease
gressive disease. Early intervention has no impact on outcome and can
encourage drug resistance. Consideration must be given to the patient’s
fitness for treatment and the management of co-morbidities. Supportive
care includes prevention and treatment of infection, transfusion support
developed countries, with an incidence rising from 0.7 to 21 per
and treatment of autoimmune cytopenias. Chemo-immunotherapy con-
100,000 per year between the ages of 40 and 70 years. There is a
tinues to be the mainstay of front-line treatment for standard-risk disease.
male predominance (1.7:1), and both a genetic and ethnic pre-
However, treatment of CLL has rapidly evolved over recent years with the
disposition, with a 5.7-fold risk in first-degree relatives and a
introduction of targeted therapies that inhibit signalling downstream of
lower incidence in Far-Eastern populations.
the B cell receptor, second-generation monoclonal antibodies and
A pre-leukaemic disorder, termed monoclonal B lymphocy-
BCL2B Cell Lymphoma 2 (BCL2) antagonists.
tosis (MBL), affecting 5% of healthy individuals aged >60 years,
Keywords Aetiology; B cell chronic lymphocytic leukaemia; bio- has been described. Patients with MBL are estimated to have a
markers; blood; diagnosis; drug therapy; epidemiology; genetics; pa- 1% chance per year of developing symptomatic CLL.
thology; prognosis

Introduction
Chronic lymphocytic leukaemia (CLL) is a common and highly
heterogeneous tumour caused by the expansion of a clone of
mature B lymphocytes. It is the most common leukaemia in
Stephen Devereux PhD FRCP FRCPath is a Consultant Haematologist
at King’s College Hospital and a Professor of Lymphoma Biology at
King’s College London, UK. He trained at the Hammersmith, Royal
Free and University College Hospitals, London. His main clinical
interest is in the treatment of lymphoid malignancy, specifically
chronic lymphocytic leukaemia (CLL). He leads a laboratory research
group focused on the biology of CLL, and a large clinical trials
portfolio. He is a member of the UK-CLL Forum Executive and the
Bloodwise Trials Committee. Competing interests: none declared.
Kirsty Cuthill MRCP FRCPath is a locum Consultant Haematologist at
King’s College Hospital, London, UK. She trained at Guy’s and St
Thomas’ Hospitals, London, and has recently completed PhD studies
in chronic lymphocytic leukaemia under the supervision of Professor
Devereux at King’s College London. Competing interests: none
declared.
Pathogenesis
As with other cancers, CLL arises because of an imbalance be-
tween the proliferation and death of the malignant clone. Pro-
liferation takes place in the lymph node compartment, where
CLL cells interact with components of the tumour microenvi-
ronment including activated CD4 T cells, stromal cells and
endothelial cells. Within the lymph node compartment, signal-
ling through the B cell receptor (BCR) plays a major role in the
survival and proliferation of tumour cells and has recently been
found to be a highly effective therapeutic target (Figure 1c).
Disease progression is associated with clonal evolution that
renders the disease more aggressive and resistant to therapy.
Whole-genome sequencing studies have identified a number of
mutations in the tumour cells that can become therapeutic
targets.1
Clinical and diagnostic features
In many patients, CLL is diagnosed following the incidental
detection of an isolated lymphocytosis. A diagnosis of CLL re-
quires the presence of a clonal B lymphocytosis of
5  109/litre
sustained over 3 months. Small lymphocytic lymphoma is a

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j.mpmed.2017.02.001
 LEUKAEMIAS
a b
CD19
CD5
Figure 1 (a) Blood film demonstrating small, round mature lymphocytes with clumped chromatin and scanty cytoplasm and smear cells. (b) Flow
cytometry plot demonstrating CLL cells that co-express CD5 and CD19. (c) Schema of drug targets downstream of the BCR in CLL cells.
lymphoid tumour with the morphology and immunophenotype
of CLL without a leukaemic component.
When symptoms are present, they arise as a consequence of
immune dysfunction and tissue infiltration, as outlined in
Table 1.
The differential diagnosis includes other types of low-grade B
lymphoproliferative disorder and reactive and leukaemic T cell
disorders.
The diagnosis of CLL is made on the basis of a typical blood
film appearance and a characteristic immunophenotype
(Figure 1a, b).
Prognostic factors
Clinical stage
Clinical staging systems (Table 2) reflect disease bulk and the
degree of bone marrow failure. They can be used to estimate
prognosis.
Biomarkers
The following biomarkers have been shown to correlate with
clinical outcome:
 Mutational status of immunoglobulin heavy chain vari-
able genes e in normal lymph node germinal centres, the
variable portion of the immunoglobulin heavy chain genes
(IgVH ) undergoes mutation to generate high-affinity anti-
body. Approximately half of patients with CLL have mutated
IgVH genes, and this correlates with a good prognosis.
 CD38 expression: increased tumour expression of this
activation marker is associated with faster disease pro-
gression and reduced overall survival (OS).
 Fluorescence in situ hybridization (FISH)/cytogenetics:
TP53 (tumour protein p53) abnormalities (deletions, mu-
tations) and 11q deletion are poor prognostic markers.
Patients with an isolated 13q deletion have a favourable
prognosis.2
With the exception of TP53 abnormalities (chromosome 17p),
which predict resistance to chemotherapy, these markers are not
currently used to guide patient management. TP53 status should
be assessed by FISH and/or sequencing before commencing
chemotherapy.
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c
BCR
SYK
Ibrutinib BTK
Idelalisib PI3K
NFκB BCL2 Ventoclax
Management
CLL has traditionally been considered to be incurable with
chemotherapy, so the goals of therapy are to prolong survival
and manage symptoms. The diagnosis of CLL can have pro-
found effects on quality of life even in the earliest stages of the
disease, and accurate information and appropriate support are
essential. Many patients with CLL are elderly with multiple co-
morbidities that limit the feasibility of myelosuppressive
chemotherapy.
The recent introduction of targeted therapies, including ide-
lalisib3 and ibrutinib,4 that inhibit signalling downstream of the
BCR has revolutionized the treatment of particularly challenging
groups of patients; these include patients with TP53 abnormal-
ities and those who relapse quickly after front-line therapy. Ide-
lalisib (a phosphatidylinositol 3-kinase) inhibitor and ibrutinib (a
Bruton’s tyrosine kinase antagonist) are oral, potent, small-
molecule inhibitors of BCR signalling that inhibit the activa-
tion, proliferation and homing of CLL cells (Figure 1c). They are
associated with higher response rates and are generally well
tolerated; however, long-term safety data are not yet available
and unexpected toxicities may emerge.
Stage A disease
The use of alkylating agents in this setting does not prolong
survival. These patients should be monitored for disease pro-
gression and educated regarding immunizations and the mea-
sures to reduce the risk of secondary malignancy.
Stage B/C disease
Treatment should be reserved for those with symptomatic or
rapidly progressive disease as outlined below:
 progressive bone marrow failure, manifest as anaemia,
neutropenia or thrombocytopaenia not resulting from
autoimmunity
 massive, progressive or symptomatic splenomegaly or
lymphadenopathy
 rapidly progressive lymphocytosis (e.g. doubling in <6
months)
 autoimmune cytopenias, which are poorly responsive to
corticosteroids
2 Ó 2017 Published by Elsevier Ltd.
 LEUKAEMIAS

When therapy becomes necessary, patients should be offered

Key clinical features and suggested investigations the option of being treated as part of a clinical trial. If this is not
Definition C 5  109/litre MBL persistent over 3 months possible, the following options should be considered according to
Diagnosis C Blood film e small round mature lympho- the fitness of the patient and the presence of co-morbidities.
cytes with scanty cytoplasm, smear cells
Previously untreated patients
C Peripheral blood immunophenotyping. CLL
 Fludarabine, cyclophosphamide þ rituximab (FCR):
cells co-express CD19, a B cell marker, and
recommended by the National Institute for Health and Care
CD5, which is normally found on T cells.
Excellence (NICE) for patients fit to be given fludarabine þ
Mantle cell lymphoma, the other
cyclophosphamide (FC). The landmark CLL8 trial
CD5þCD19þ lymphoma, is characterized by
demonstrated a significant progression-free survival (PFS)
the t(11:14) translocation and expression
and OS advantage associated with the addition of ritux-
of cyclin D1
imab to FC (5-year PFS, 46.8% versus 25.5%; 5-year OS,
Clinical features Immune dysfunction
78.7% versus 66.9%). The benefit of FCR was most pro-
C Recurrent infections
nounced in patients with IgVH-mutations, in whom the 5-
C Autoimmune haemolytic anaemia or
year PFS and OS were 66.6% and 86.3%, respectively.5
thrombocytopaenia
FCR is associated with an increased risk of toxicities,
C Constitutional symptoms including mal-
particularly neutropenia and severe infection, and is
aise, fever and weight loss
generally reserved for patients aged <70 years.
Tissue infiltration
 Bendamustine þ rituximab: a treatment option for pa-
C Lymphadenopathy
tients who are aged >65 years and not fit for FCR. It has
C Hepatosplenomegaly
reduced efficacy compared with FCR (median PFS, 41.7
C Bone marrow failure
versus 55.2 months) but less neutropenia and fewer in-
Further investigations C Renal and liver function tests
fections in the elderly.
C Direct antiglobulin test
 Chlorambucil þ obinutuzumab: recommended by NICE
C Reticulocyte count
for patients who are elderly and/or have co-morbidities
C Serum immunoglobulins
and are not fit for bendamustine. The combination of
C Hepatitis B surface antigen and core anti-
chlorambucil with the type II glycoengineered monoclonal
body, hepatitis C and HIV serology
antibody obinutuzumab has recently been found to be
C Bone marrow biopsy e only indicated
superior to chlorambucil þ rituximab (median PFS, 26.7
when there is diagnostic uncertainty or to
versus 15.2 months).
investigate cytopenias
Untreated CLL with TP53 abnormality: CLL with TP53 deletion or
C Lymph node biopsy e in the event of
mutation is rare in the upfront setting but is poorly responsive to
diagnostic uncertainty or if high-grade
chemoimmunotherapy. BCR antagonists are the treatment of
transformation is suspected
choice in this setting, subject to availability.
C CT scanning not mandatory but can be
Relapsed and refractory disease: the treatment of relapsed CLL
used to confirm remission or in the context
is rapidly evolving and increasingly involves the use of targeted
of a clinical trial
therapies. The choice of therapy depends upon the response to
Prognosis C Clinical staging (Rai, Binet (Table 2))
previous therapy and the patient’s fitness to undertake treatment;
C Lymphocyte doubling time
TP53 abnormalities are more common in the relapsed setting,
C Biomarkers: IgVH gene sequencing, CD38
and again they must be ruled out.
expression, FISH, cytogenetics, TP53
Idelalisib þ rituximab is approved by NICE for patients who
sequencing
have a relapse within 24 months of therapy and affords a 26-
Table 1 month PFS of 93% in the absence of high-risk cytogenetics.
Ibrutinib is currently undergoing NICE appraisal for this
 severe disease-related symptoms including weight loss, indication.
fatigue, fever and night sweats. Richter’s transformation: CLL is estimated to transform to
Supportive therapies are directed at the treatment and pro- high-grade non-Hodgkin lymphoma in 2e8% of patients. This is
phylaxis of infection and the management of autoimmune cyto- heralded by the onset of constitutional symptoms and rapidly
penias and bone marrow failure: progressive lymphadenopathy. Lymph node biopsy must be
 infection: patients should be given annual influenza performed if this is suspected. The outlook for these patients is
vaccination. Bacterial infections should be treated with generally poor, and novel therapies are urgently needed.
appropriate antibiotic therapy. Immunoglobulin replace- Transplantation: in suitable patients, allogeneic haemopoietic
ment reduces the frequency of recurrent infection in stem cell transplantation should be considered for patients with
hypogammaglobulinaemic patients very high-risk disease and to consolidate remission in patients
 autoimmune disorders: corticosteroids with Richter’s transformation. Overall treatment-related mortal-
 bone marrow failure: transfusion. ity is high, at 15e25%.

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 LEUKAEMIAS

Clinical staging of CLL

Binet Clinical features Median overall Rai stage Clinical features Median overall
stage survival (months) survival
(months)
A 2 lymph node areas 0 Isolated lymphocytosis >150 Cervical

B
3 lymph node areas 84 I Lymphadenopathy 101

Axillary
C Haemoglobin 10 g/dl, 24 II Splenomegaly 60
platelets 100  109/litre
L S
III Lymphadenopathy þ 19
splenomegaly
IV Haemoglobin 10 g/dl, 19 Inguinal

Platelets 100  109/litre

Cervical, axillary, liver/spleen and inguinal regions each represent one lymphoid area.

Table 2

The future KEY REFERENCES

1 Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing
Our understanding of CLL biology and the therapeutic landscape
identifies recurrent mutations in chronic lymphocytic leukaemia.
have changed radically in recent years. Several novel agents are
Nature 2011; 475: 101e5.
now in routine use and have transformed the outlook for patients
2 Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations
with resistant disease. There are, however, a number of unan-
and survival in chronic lymphocytic leukemia. N Engl J Med 2000;
swered questions and important areas of unmet need.
343: 1910e6.
Outstanding issues include whether novel agents should be used
3 Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab
alone or in combination, the duration of therapy and how those
in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370:
who relapse should be best treated. Patients with TP53 abnor-
997e1007.
malities or with Richter’s transformation continue to have a poor
4 Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in
outcome, and new therapies are urgently needed for these
previously treated chronic lymphoid leukemia. N Engl J Med 2014;
groups.
371: 213e23.
Further novel therapies including small molecules, engineered
5 Fischer K, Bahlo J, Fink A-M, et al. Long-term remissions after FCR
antibodies and cellular therapies are on the horizon, and fitting
chemoimmunotherapy in previously untreated patients with CLL:
these into the treatment algorithm may be a major challenge.
updated results of the CLL8 trial. Blood 2016; 127: 208e15.
Affordability and providing access for patients when required
may be the most important of these issues. A

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.

Question 1
A 65-year-old man attended for annual review of his type 2
diabetes mellitus. He was well and had no new symptoms.
Clinical examination was unremarkable.
Investigations
 Haemoglobin 140 g/litre (130e180)
 White cell count 12  109/litre (4.0e11.0)
 Lymphocytes 7  109/litre (1.5e4.0)
 Platelets 200  109/litre (150e400)
These changes persisted over 3 months
 Peripheral blood immune phenotyping confirmed 4 109/
litre clonal B lymphocytes that co-expressed CD5 and CD19

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 LEUKAEMIAS
What is the most likely diagnosis?
A. Stage A chronic lymphocytic leukaemia
B. Reactive lymphocytosis
C. B cell non-Hodgkin lymphoma
D. Monoclonal B lymphocytosis with risk of Richter’s trans-
formation of 1% per year
E. Monoclonal B lymphocytosis with a risk of progression to
symptomatic chronic lymphocytic leukaemia of 1% per
year
Question 2
A 55-year-woman presented with increasing fatigue. Twelve
months previously, she had been diagnosed with chronic lym-
phocytic leukaemia.
On clinical examination, there was 1.5 cm lymphadenopathy in
both axillae, which had not changed in size. She had a perfor-
mance status of 1.
Investigations
 Haemoglobin 110 g/litre (115e165)
 White cell count 55  109/litre (4.0e11.0)
 Lymphocytes 50  109/litre (1.5e4.0)
 Platelets 120  109/litre
Investigations 6 months previously had shown:
 Haemoglobin 115 g/litre
 White cell count 45  109/litre
 Lymphocytes 40  109/litre
 Platelets 130  109/litre (150e400)
 At diagnosis, fluorescence in situ hybridization performed
on peripheral blood had revealed a TP53 deletion in 20%
of the chronic lymphocytic leukaemia cells
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What is the most appropriate management?
A. Treat with alemtuzumab and methylprednisolone
B. Treat with fludarabine, cyclophosphamide and rituximab
C. Continue active surveillance
D. Treat with idelalisib and rituximab
E. Perform bone marrow examination to assess the degree of
infiltration by chronic lymphocytic leukaemia cells
Question 3
An 80-year-old man presented with anorexia, weight loss, night
sweats and severe fatigue. He had also developed early satiety
and abdominal discomfort. He had a history of stage C chronic
lymphocytic leukaemia previously treated with chlorambucil. He
had recently started treatment with ibrutinib.
On clinical examination, his temperature was 38.5  C, pulse 86
beats/minute and blood pressure 138/88 mmHg. There were
axillary lymph nodes measuring 4 cm  3 cm, and the spleen
extended 8 cm below the costal margin. Neither of these had
previously been detected.
Investigations
 Haemoglobin 95 g/litre (130e180)
 White cell count 12  109/litre (4.0e11.0)
 Lymphocytes 10  109/litre (1.5e4.0)
 Platelets 73  109/litre (150e400)
What is the most likely cause of his presentation?
A. Richter’s transformation
B. Development of resistance to ibrutinib
C. Sepsis
D. Adverse drug reaction
E. Progression of chronic lymphocytic leukaemia
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