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inside
Chronic
lymphocytic
leukaemia
Follicular
lymphoma
Managing patients
receiving
chemotherapy

The authors

DR SARAH KAMEL,
advanced trainee in clinical and
laboratory haematology, division
of cancer medicine, Peter
MacCallum Cancer Centre, East
Melbourne, Victoria.

Lymphoproliferative disorders
Part 2 Chronic lymphocytic leukaemia and
follicular lymphoma
Last week, Part 1 of this two-part series discussed the most common of the aggressive types of lymphoma. This week, Part 2 focuses
on two of the indolent lymphoproliferative diseases chronic lymphocytic leukaemia and follicular lymphoma. We discuss diagnosis and management for these conditions, after patients have been referred to a haematologist. The outlook for these malignancies
today is also reviewed.

PROFESSOR JOHN F SEYMOUR,

consultant haematologist, head of
haematology department, division
of cancer medicine, Peter
MacCallum Cancer Centre, East
Melbourne, Victoria.

PROFESSOR H MILES PRINCE,

consultant haematologist, division
of cancer medicine, Peter
MacCallum Cancer Centre, East
Melbourne, and Cabrini Hospital,
Malvern, Victoria.

Background
THE lymphoproliferative diseases
are a heterogeneous group of
haematological disorders characterised by malignant clonal proliferation of cells derived from their
normal lymphoid counterparts.
They are classified according to distinct clinicopathological features.
This group of disorders is distinct
from myeloid disorders, which are

malignancies that derive from cells

destined to form neutrophils, monocytes, etc. (eg, chronic myeloid
leukaemia, myeloproliferative diseases and myelodysplasia) (figure 1,
page 30.).
The lymphoproliferative diseases
comprise the lymphomas and the
chronic lymphoid leukaemias. The
latest edition of the WHO Classifiwww.australiandoctor.com.au

cation of Tumours of Haematopoietic and Lymphoid Tissues lists

more than 40 different types of nonHodgkin lymphoma (NHL). These
can broadly be divided into B- and
T-cell disorders and further subdivided into clinically aggressive
high-grade and clinically indolent
low-grade malignancies.
contd next page
8 April 2011 | Australian Doctor |

29

HOW TO TREAT Lymphoproliferative disorders Part 2

from previous page

The two most common indolent

lymphoproliferative diseases are
chronic lymphocytic leukaemia
(CLL) and follicular lymphoma
(FL), both of B-cell origin. Included
with the term CLL is small lymphocytic lymphoma (SLL), which
is essentially a lymphomatous presentation of CLL.
First, to clarify a few terms,
low-grade implies a slow-growing
indolent tumour. Both CLL and
FL are in this category. However,
both may (albeit unusually) transform into a more aggressive lymphoma. In the case of CLL this is
referred to as a Richters transformation. Once this occurs, the
prognosis for these patients is
much bleaker than for de novo
aggressive lymphomas such as
those discussed in Part 1, and cure
is not attainable with currently

Figure 1: Ontogeny of haematopoietic cells.

B cells
Common
lymphoid
progenitor cell

T cells

LPDs
originate from
B or T cells

NK (natural killer) cells

Pluripotent
stem cell

Neutrophilis

Common
myeloid
progenitor cell

Myeloblast

Monocytes
Eosinophils

Platelets

Red cells

Basophils

LPD = lymphoproliferative disease

available therapies.
Broadly speaking, indolent lymphoproliferative diseases can

grumble on for years, even for

more than a decade in some
patients. In many cases they can

be observed for a period of time

before therapy is required. The
flipside of their indolent nature is
that they are generally incurable,
although in selected patients, an
allogeneic bone marrow transplant may offer the hope of a
cure. Similarly, localised FL is curable with radiotherapy. When discussing FL, we focus be on disseminated disease, as this is by far
the more common presentation.

Epidemiology
Many of you will have been
involved in the care of lymphoma
patients in your practice. According to Australian Institute of
Health and Welfare data for 2005,
lymphomas were the fifth most
commonly diagnosed group of
cancers in both men and women.
This translates to 4400 new cases
of lymphoma, or an incidence of

21/100,000 Australians per year,

which equates to just over 4% of
all cancer diagnoses.
Of these cases, CLL/SLL and FL
were each diagnosed in almost
1000 Australians in 2005, with
incidences of 4.5 and 4.3
cases/100,000 people, respectively.
For CLL the incidence climbs
steeply in people over 65, with 2230/100,000 people in this age
group diagnosed each year with
the disease.
By comparison, prostate cancer
comprised 16.3% of all cancers,
with an annual incidence in men
of 164/100,000. Breast cancer
made up 12.2% of new cancers
and was diagnosed in 111/100,000
women. Other frequently diagnosed malignancies such lung
cancer and colorectal cancer comprised 9.1% and 13% of all cancer
diagnoses, respectively.

Chronic lymphocytic leukaemia

CLL is the most common
type of leukaemia in Western societies and is less
common in people of Asian
descent. It is characterised
by the protracted but progressive accumulation of
small, relatively slow-growing lymphocytes. The
median age at diagnosis is
70.

Figure 2: A smear or smudge cell seen in patients with chronic lymphocytic lymphoma (CLL).
These cells are fragile and are damaged in the process of blood slide preparation. The presence of
these cells should alert the treating doctor that CLL is a possible diagnosis. They may be present
even when the absolute lymphocyte count is normal.

Flow cytometry

Prognosis
Median patient survival is
10 years. However, this
number does not take into
account the heterogeneity
seen in the CLL patient population. Many patients will
have a very indolent course
and ultimately succumb to
an illness other than their
CLL, while a small proportion of patients will have
aggressive disease and live
only 1-2 years from diagnosis. Apart from initial staging
of the disease, a variety of
prognostic markers has been
recognised that aid in riskstratifying patients and guiding clinicians as to who is
likely to require treatment
and when.

Two intact CLL cells

A smear cell

Presentation
Many laboratories with a
large referral base of GPs
will often encounter routine
FBCs as part of annual
health checks that show a
mild lymphocytosis (5-10
109 cells/L), but are otherwise unremarkable. In most
cases, this lymphocytosis is
reactive and thus transient
(see box, right, for causes of
lymphocytosis). Lymphocyte
counts >15 109 cells/L are
more concerning. Many GPs
will prudently repeat the
FBC in a few weeks or
months and in a minority of
cases the lymphocytosis will
be persistent.
It is essential to assess the
patient clinically for lymphadenopathy and splenomegaly. With regard to their
blood tests, the presence of
an anaemia or thromboycytopenia is more suggestive of
underlying malignancy. If

30

| Australian Doctor | 8 April 2011

ther characterise the cell

population in question. The
request slip should state as
much clinical information as
possible and stipulate that
CLL/NHL is being considered.

any of these clinical or laboratory features are present,

further investigations should
be pursued.
Rarely, patients can present with a lymphocyte count
of >50 10 9 cells/L. This
magnitude of lymphocytosis
is almost always malignant.
A good laboratory will
always make an urgent
blood film and review the
lymphocyte morphology in
addition to performing further tests, if required, to
exclude an acute leukaemia.

Diagnosis
A peripheral blood film
should be examined by a
laboratory haematologist to
look for abnormal lymphocytes. CLL cells classically
look like small mature lymphocytes. Due to their

fragility, the cell membrane

can easily tear when a drop
of blood is smeared across a
glass slide. This results in the
laboratory artefact of a
smear or smudge cell
(figure 2).
Morphology is generally
not sufficient to define the
malignant nature of the cells
or that the lymphoproliferative disease is CLL and not
another disorder (such as
mantle-cell or marginal-zone
lymphoma, T-cell or natural
killer (NK) cell proliferations).
If CLL is suspected based
either on a persistent lymphocytosis, abnormal lymphoid morphology or presence of lymphadenopathy or
splenomegaly, flow cytometry of the peripheral blood
should be performed to fur-

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Flow cytometry, also known

as cell surface markers, has
a rapid turnaround time and
can definitively establish the
presence of an abnormal
population of cells in the
peripheral blood, bone
marrow, excised lymph
nodes and even CSF or pleural fluid.
The principle of flow
cytometry is to measure the
light-scatter characteristics
of a stream of cells in single
file, which run past a laser
(figure 3, see page 32). Additionally, the light emission of
fluorescent markers (fluorochromes) tagged to antibodies that attach to various
cluster-of-differentiation
(CD) cell surface markers is
characterised (figure 4, see
page 32).
All haematopoietic cells
express CD markers, which
perform different cellular
functions. Different cell
types have their own typical
pattern of normal CD
expression a phenotype.
Malignant lymphocytes
express an aberrant lymphocyte phenotype. For example, all B cells are CD19 positive (CD19+) and this
includes CLL cells. What
defines the CLL cells as
abnormal is they are also
CD5+, whereas normal B
cells are CD5-.
The classic phenotype of
CLL cells is CD19+ CD5+
CD10-, with either lambda
or kappa light chain restriction. The term light chain
restriction implies that all
cells in a given population
express the same light chain
type (ie, kappa or lambda)
because they are clonal.
Flow cytometry is invaluable not only for the diagcontd page 32

Differential diagnosis of
a lymphocytosis (other
than a lymphoproliferative disease)
Viral infection (eg, influenza,
EpsteinBarr virus (EBV),
cytomegalovirus (CMV),
HIV, toxoplasmosis
Stress-related
lymphocytosis (during an
MI, post-trauma)
Some bacterial infections
(eg, pertussis, brucellosis,
tuberculosis)
Post-splenectomy
Allergic reaction to a
medication
Post-seizure

HOW TO TREAT Lymphoproliferative disorders Part 2

from page 30

nosis of haematological
malignancies but also for
detecting minimal residual
disease (MRD) post-therapy
with a sensitivity of up to
1/10,000 abnormal cells in
some laboratories. Additionally, markers of poor prognosis, such as CD38 and
ZAP-70 expression in CLL
can also be identified.

Figure 3: Schematic of a flow cytometer.

Figure 4: CD19+ cell tagged by a fluorochrome.

Fluorochrome
conjugated to antiCD19 antibody

Single file of cells in sheath fluid

CD19

Detector

Monoclonal B lymphocytosis

It should be noted that the

presence of cells in the
peripheral blood with a
CLL phenotype is not
enough to diagnose CLL. If
the total abnormal lymphocyte population is <5 109
cells/L and there is no evidence of lymphadenopathy
or organomegaly, the patient
is considered to have a
monoclonal B lymphocytosis, which is essentially preCLL. This pattern occurs in
at least 3% of people aged
60-80 years.
The International Workshop on Chronic Lymphocytic Leukaemia (IWCLL)
guidelines state that to diagnose CLL there must be an
absolute peripheral blood
lymphocytosis (of phenotypically abnormal cells) of >5
109 cells/L. This lymphocytosis must be present for at
least three months.
The progression of monoclonal B lymphcytosis to
frank CLL is at the rate of 12% of patients per annum,
and these patients typically
have very indolent disease,
with only about 15% ever
requiring therapy. In general
they should be monitored on
an annual basis.

Light scatter
comprised of forward
and side scatter

Detector
Fluorescent emission
Laser strikes cell

After a patient
has been
diagnosed with
CLL, the first
thing to decide is
how extensively
they need to be
investigated.

marrow involvement is so
extensive that normal
haematopoiesis is compromised and the patient develops cytopenias anaemia
(stage III) and thrombocytopenia (stage IV).
Table 1, adapted from
the original 1975 article by
Rai, describes each stage of
disease. With the increasing
utilisation of blood tests in
the community, up to 60%
of patients may present
with isolated lymphocytosis.

Prognostic markers

Small lymphocytic lymphoma

SLL is considered biologically the same disease as

CLL and is treated in the
same way. Patients diagnosed with SLL have lymphadenopathy
and/or
splenomegaly but lack the
peripheral blood lymphocytosis of >5 109 cells/L that
is required for a diagnosis of
CLL. The different presentation of what is essentially the
same disease may be due to
different expression of adhesion proteins that result in
SLL manifesting in a more
lymphomatous rather than
leukaemic form.

Staging
Who should be investigated?

After a patient has been

diagnosed with CLL, the first
thing to decide is how extensively they need to be investigated. It is our practice to
address this issue by first
asking how will this alter
management. In other words,
if the patient is over 60 and
asymptomatic, a watch and
wait approach is appropriate.
In almost all cases, specialist
referral should be sought, as
patient investigation and management needs to be individualised.
Before referring a patient it
is helpful to order a Coombs

32

| Australian Doctor | 8 April 2011

test (to assess for autoimmune haemolysis). Baseline

immunoglobulin levels are
helpful to assess the degree
of underlying immunosuppression.
In early-stage CLL we recommend three-monthly
reviews in the first year primarily to assess the tempo
of disease. The peripheral
blood lymphocyte doubling
time (the time for the baseline lymphocyte count to
double) is one of the most
useful prognostic measures,
as doubling in less than six
months confers a poor prognosis.
Conversely, if the patient
clearly needs treatment in the
foreseeable future (eg, cytopenias, lymphadenopathy,
organomegaly or constitutional symptoms are present),
immediate staging will help
prognosticate for that
patient. The staging approach
described below applies to
such patients.
Staging investigations

Generally, if therapy is
being considered in patients
with cytopenias, a bone

marrow biopsy is performed. This will distinguish between cytopenias

caused by marrow infiltration by CLL and autoimmune cytopenias, which are
seen in about 7% of
patients with CLL. In the
presence of an autoimmune
cytopenia there will be
robust marrow production
of the affected cell lineage,
indicating that there is
peripheral destruction of
cells. An autoimmune
cytopenia does not upstage the disease and the
presence of autoimmune
cytopenias does not confer
a worse overall survival. A
bone marrow biopsy will
also help with prognostication, as the extent of
marrow infiltrate and cytogenetic abnormalities influence prognosis.
Most patients will also
have CT to assess for the
presence of lymphadenopathy, splenomegaly and
hepatomegaly. About onequarter of patients with no
clinically detectable lymphadenopathy have occult
abdominal lymphadenopa-

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thy on CT, which has been

shown to confer a worse
prognosis.
Both the Rai and Binet
staging systems for CLL are
used by clinicians. The Rai
classification is comprised
of five stages, which
describe the progressive
increase in disease burden
over time. In the earliest
stage (stage 0), CLL is
purely leukaemic; there
are only circulating malignant lymphocytes in the
peripheral blood.
The stage after this
involves the lymph nodes
(stage I). An involved
lymph node will contain an
infiltrate of malignant lymphocytes that are morphologically the same as the
cells circulating in the
peripheral blood.
As the disease progresses,
the spleen and liver become
engorged with malignant
lymphocytes, leading to
organomegaly (stage II).
At all stages in CLL, the
bone marrow will contain
malignant cells. However,
in the most advanced stages
(III and IV), the burden of

The Rai staging system has

limitations with regard to
its ability to risk-stratify
patients, as there are
patients within Rai 0 or I
disease, who only live 1-2
years from the time of diagnosis. In addition to lymphocyte doubling time and
staging, several new prognostic markers have been
identified (table 2), of
which the most important
is the presence of a chromosome 17p deletion, identified by standard cytogenetics.
In addition, CD38 and
ZAP-70 (by flow cytometry) are thought to have
prognostic utility because
of their correlation with
unmutated immunoglobulin variable heavy chain
(IgVH) status, which is an
indicator of more aggressive disease. These latter
tests are variably used and
their place in CLL management is still being investigated.

Treatment
As with most incurable diseases, the treatment paradigm for CLL is not uniform; there is no single
one-size-fits-all treatment.
In patients with early-stage
disease, treatment may not
be indicated. Indeed, even in
young patients a period of
observation is recommended
to gauge the tempo of disease. Moreover, early intervention does not improve

AD_ 0 3 3 _ _ _ APR0 8 _ 1 1 . p d f

survival, and indeed premature and prolonged exposure

to unnecessary therapy may
lead to drug resistance.
Chemotherapy

For patients who ultimately

require chemotherapy, the
predominant indications
are:
Progressive marrow failure (ie, symptoms of
anaemia, progressive
thrombocytopenia or
infections).
Constitutional symptoms
such as weight loss or
fatigue.
Progressive symptomatic
lymphadenopathy.
Symptoms such as fever
or sweats are quite rare.
When deciding on the
treatment plan, the patients
age and fitness for therapy
are paramount (table 3).
Consideration should always
be given to enrolling eligible
patients in a clinical trial.
In older patients, less
intensive oral therapy with
alkylating agents such as
chlorambucil or cyclophosphamide is often used for
symptom control.
In younger patients and
selected older patients we
generally aim to get a deep
response, as this generally
translates into more prolonged remissions. As such,
more intensive therapy with
fludarabine-based regimens
is frequently used. Recently,
the addition of the antiCD20 antibody rituximab
has improved patient survival when used in combination with chemotherapy.
This progressive improvement has led to drug combinations such as FCR (fludarabine, cyclophosphamide
and rituximab) being used
relatively early in the disease
course.

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Reference: 1. American
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Table 1: Rai staging system for CLL

Stage (at time
of diagnosis)

Description

Comments

Peripheral blood
lymphocytosis

Lymphadenopathy

II

Organomegaly

III and IV

Cytopenias due to
the burden of marrow
involvement. Hb
<110g/L or platelets
<100 109 cells/L

When deciding
on the treatment
plan, the patients
age and fitness
for therapy are
paramount.

In the modern era

about 60% of
patients present in
this way

Autoimmune
cytopenias are not
included as stage III
or IV disease

Table 2: New prognostic markers in CLL

Prognostic marker

Example
A deletion of the short arm of chromosome
17 (del17p) confers a poor prognosis and
resistance to chemotherapy (median
survival 32 months). Trisomy 12 and
deletion of chromosome 13 confer a better
prognosis

CD38 (surrogate marker

for unmutated IgVH
status)

The presence of CD38 on

CLL cells is detected by
flow cytometry

CD38 positivity indicates a worse prognosis

ZAP-70, a tyrosine
kinase not normally
found in B cells

Expression of ZAP-70 can

be readily detected using
flow cytometry

The presence of ZAP-70 suggests a worse

prognosis but the assay is notoriously
unreliable in inexperienced hands

Allogeneic stem cell

transplant

An allogeneic stem cell transplant (SCT), or allograft, is

considered in patients under
55 (keeping in mind that the
median age for CLL is 70).
Allogeneic SCT is different
from autologous SCT
(described in Part 1 of this
article) in several important
ways. Firstly, the stem cells
are not the patients own
cells; they are obtained from
a donor who is HLA (human
leukocyte antigen) matched
as closely as possible to the
patient.
Secondly, the aim of infusing donor stem cells is not
only to rescue the patient
from lethal bone marrow
failure resulting from highdose chemotherapy, as is the
case in autologous transplant. In allogeneic SCT, the
infused stem cells are themselves an important element
of treatment. Once they
repopulate the patients
bone marrow (engraftment),
the patient effectively has a
new immune system, which
ideally will recognise as foreign and kill the patients
malignant cells. This is a
therapeutic form of graft

Detection

Cytogenetics/fluorescent The malignant cell

in situ hybridisation
karyotype is analysed.
(FISH)
Several cytogenetic
abnormalities
are recognised in CLL that
help determine prognosis

Table 3: Treatment options in patients with CLL

Patient type

Goal of treatment

The elderly patient

with comorbidities

Symptom control/quality of life. Any Observe, or gentle oral chemotherapy

therapy must be balanced against with chlorambucil or
comorbidities
cyclophosphamide

The robust older

patient

Quality of life always paramount.

Aim for tumour bulk-reduction with
deepest response achievable, ie,
reduced lymphadenopathy and
reduced marrow infiltrate

Observe if asymptomatic. However, if

treatment is required, use up-front
multidrug chemotherapy + rituximab
(eg, fludarabine-based combination
therapy) to achieve prolonged
remission

The younger patient

As above. However, consider for

allogeneic bone marrow transplant
as part of therapy

As above

versus host disease.

Thirdly, the chemotherapy
(with or without radiotherapy) used in allogeneic SCT
(termed conditioning) not
only directly treats the disease (as in autologous SCT)
but also prepares the bone
marrow to receive the donor
stem cells, and suppresses the
patients immune system to
prevent graft rejection.
A recent study of patients
with CLL undergoing
reduced-intensity, conditioning allogeneic stem cell trans-

First-line treatment options

plants showed that for a

subset of patients, no evidence of relapse was
detectable for up to 96
months (the period of
follow-up of this study). For
appropriately
selected
patients, allografting can
offer long-term disease-free
survival and possibly cure.
IV immunoglobulin

It is well recognised that

patients with CLL are often
hypogammaglobulinaemic,
that is, they have low levels

of IgG, IgA and IgM. In

patients with severe recurrent
infections, monthly infusions
of IV immunoglobulin (IVIg)
are administered to increase
baseline immunoglobulin
levels. There are small studies
that show reduced numbers
of infections in these
patients.1,2 In Australia, CLL
with recurrent bacterial
infection
due
to
hypogammaglobulinaemia is
an approved indication for
periodic IVIg infusions.
contd next page

Wouldnt you treat the whole thing?

Depression may manifest as a variety of emotional,
somatic and other associated symptoms.1

HOW TO TREAT Lymphoproliferative disorders Part 2

Follicular lymphoma
Epidemiology
WITH an annual incidence in
Australia of at least four per
100,000 people, FL is the next
most common NHL after diffuse large B-cell lymphoma
(discussed in Part 1). The
median age of diagnosis is in
the sixth decade and the disease is generally more prevalent in women, with a
female:male ratio of 1.7:1.
Eighty per cent of patients
present with Ann Arbor stage
III or IV disease (ie, disseminated disease) and half have
bone marrow involvement
(for a description of Ann
Arbor staging, please refer to
Part 1). Despite being generally considered incurable,
there has been an improvement in overall survival in
these patients in recent years,
which has been attributed to
the introduction of the monoclonal antibody against CD20,
rituximab.

Pathology
The malignant lymphocytes in
FL are derived from germinal
centre (follicle centre) B cells. B
cells in germinal centres of
lymph nodes normally
undergo immunoglobulin class
switching, switching from IgM
to IgG or IgA. In FL the
immunoglobulin heavy chain
gene (IgH) on chromosome 14
is translocated and abuts the
anti-apoptotic gene, bcl-2, on
chromosome 18. This translocation is designated as
t(14;18). The bcl-2 gene is
already switched on in germinal centre cells, as its antiapoptotic function (preventing
programmed cell death) is
important in the development
of normal memory B cells.
Eighty-five per cent of FL cases
have a detectable t(14;18) and
the translocation is also found
in 30% of diffuse large B-cell
lymphomas.

Diagnosis
Unfortunately, laboratories are
frequently sent tissue samples
from patients with suspected
lymphoma who have had
only fine-needle aspirates of
an accessible node. This is not
a practice we generally support, for two reasons. The
first is that the limited volume
of diagnostic tissue obtained
by aspiration risks not captur-

Figure 5: Bone marrow involvement with follicular lymphoma (note the lymphomatous infiltrate
along bony trabeculae).

Follicular lymphoma
infiltrate

ing malignant tissue in the

sample. The second is that
nodal architecture cannot be
assessed and thus the histological grade of FL cannot be
determined.
FL is graded 1-3, with
grades 1-2 indicating a more
indolent lymphoma and grade
3 being a more aggressive disease, which in some cases will
lead the treating haematooncologist to pursue more
intensive chemotherapy regimens.
The practice of most clinicians would be to obtain an
excisional node biopsy (or at
least a core biopsy if accessibility is an issue, such as with
retroperitoneal lymphadenopathy).

Staging and prognostic

markers
As previously described,
anatomical staging is performed according to the Ann
Arbor staging system. Stages I
and II are considered earlystage disease and such a presentation is uncommon in FL.
It is critical to accurately stage
all patients, as distinguishing
stage I, II (and some stage III)
will identify a potentially curable group who can achieve
long-term disease-free survival
with radiotherapy.
Thus, most patients will
have staging CT in addition
to a bone marrow biopsy.

recently been updated (FLIPI2). The five adverse prognostic

markers that comprise this
score are:
Age >60.
Hb <120g/L.
Beta2 microglobulin level
higher than the upper limit
of normal.
Largest involved node >6cm
diameter.
Bone marrow involvement.
Patients can then be riskstratified into one of three
groups (low, intermediate or
high risk) based on whether
they have none/one, two, or
three or more risk factors,
respectively (table 4).
Several trials have now
shown improved response
rates, time to progression and
overall survival when patients
with newly diagnosed FL are
treated with upfront rituximab plus chemotherapy
versus chemotherapy alone.3,4
This new index showed a fiveyear overall survival rate of
98%, 88% and 77% in each
respective risk group and is
more reflective of survival
rates in the current rituximab
era (table 4).

Treatment

Table 4: Overall survival of patients with follicular

lymphoma based on FLIPI-2 prognostic scoring
system
Risk group

Number of
risk factors

Percentage of Five-year
patients
overall
survival

Low

20

98%

Intermediate

1-2

53

88%

High

27

77%

Regardless of the CT findings,

if the bone marrow is involved
the patient is deemed to have
stage IV disease (figure 5). 18Ffluorodeoxyglucose positron
emission tomography (18FFDG-PET) is being used
increasingly to help separate

early- versus late-stage disease.

A prognostic score, the Follicular Lymphoma specific
International Prognostic Index
(FLIPI), was devised a few
years ago using data collected
on almost 5000 patients with
FL. This scoring system has

In the 20% of patients with

stage I-II FL, local radiotherapy can achieve long-term
remissions and potentially
cure in 50% or more of stage
I patients. A retrospective
study of patients with stages I
and II FL treated with radiotherapy showed that at 10
years 40% of patients were
relapse-free.5
However, for most patients
with stage III or IV disease,
FL remains an incurable disease. The frequently indolent
nature of FL in some patients
means it can be viewed in
many cases as a chronic disease. However, some patients
with FL undergo large cell
transformation, which carries
a dismal prognosis.
In patients with asymptomatic disease, the watch-andwait approach is usually
appropriate, as there is no evidence that treating these
patients early improves survival. Studies assessing the
early use of rituximab are
underway.
The indications for treatment are similar to those of

CLL and include painful or

cosmetically unappealing
nodal disease or constitutional
symptoms of fatigue and
malaise. Fever and sweats are
rare presenting features of
low-grade NHL.
Generally, multi-agent
chemotherapy in combination
with rituximab is the standard
approach to front-line therapy. The two most commonly
used regimens are R-CVP (rituximab combined with
cyclophosphamide and vincristine)
or
R-CHOP
(cyclophosphamide, hydroxydaunorubicin, vincristine
[Oncovin] and prednisolone
with rituximab) which is
R-CVP with hydroxydaunorubicin (doxorubicin)
added. R-CHOP is generally
used in younger patients.
These agents are given sequentially on the same day in an
ambulatory setting. Five days
of oral prednisolone 100mg is
also administered.
Dosing is spaced at threeweekly intervals to allow time
for the bone marrow to
recover. The goal is to administer six cycles of therapy, providing the lymphoma is
chemotherapy sensitive and
the patient is able to tolerate
the treatment without significant toxicity. Again, as for
CLL, less intensive regimens
using alkylating agents can be
used for frailer patients.
Recently, results from a
large international trial
showed that initial chemotherapy with ongoing single-agent
rituximab maintenance therapy every three months for
two years led to improved
progression-free survival at a
medium follow-up of 36
months of 75% in the maintenance arm versus 58% in
patients not receiving threemonthly rituximab.6
When relapse occurs, a variety of treatment options are
available, including:
Repeating the above therapy.
Rituximab alone.
Fludarabine-based therapy
(as for CLL).
Radioimmunotherapy
(radioisotope linked to a
monoclonal antibody).
Autologous or allogeneic
stem transplantation for
younger patients.

Managing patients receiving chemotherapy

Neutropenia
MANY of the chemotherapeutic
regimens used in patients with lymphoproliferative disorders will result
in a period of neutropenia. The nadir
of this neutropenia is generally 7-12
days after the first day of chemotherapy administration.
Haematology staff provide education on the expected effects of
chemotherapy and tell patients that if
they feel unwell or have a fever they
must call their haematologist or
oncologist immediately and present
to an ED for prompt assessment.

34

| Australian Doctor | 8 April 2011

Neutropenic patients can deteriorate

rapidly, so the time to the first dose
of antibiotics must be minimised.
As part of supportive care
throughout chemotherapy, patients
are given additional medications for
some regimens. Granulocyte colony
stimulating factor (G-CSF) is given
to minimise the period of neutropenia. This is a cytokine that stimulates
the marrow production of neutrophils. Pegfilgrastim is a pegylated
long-acting form of G-CSF, which is
given as a one-off injection each
cycle. Regardless of whether they
www.australiandoctor.com.au

have received such cytokine support,

any patient with fever post-treatment
must be assessed without delay.

Immunosuppression
Reactivation of herpes simplex virus I
and II as well as varicella zoster is
not uncommon during this time,
and many patients are prescribed
prophylactic antiviral therapy.
Additionally, oral candidiasis is
common in immunosuppressed
patients, and some patients are also
prescribed prophylactic antifungal
agents. Antibiotics to prevent Pneu-

mocystis jirovecii (previously P.

carinii [PCP]) infection are used in
selected patients, especially if
steroids are used.
All patients with a new diagnosis
of lymphoma should be tested for
hepatitis B, hepatitis C and HIV.
This is because the latter two infections may be aetiologically linked
to the development of the patients
lymphoma. Hepatitis B is particularly important to diagnose because
chemotherapy with high-dose
steroids can lead to a fulminant
flare of the disease. Patients with

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are up-to-date with their five-yearly

pneumococcal vaccine. As to
whether these two vaccines should
be administered before starting
chemotherapy or after completion,
no studies have been conducted that
answer this question. Ideally we like
to have vaccines administered
months before chemotherapy. However, this is not feasible in patients
requiring more immediate treatment.
It should also be appreciated that
the immune response an individual
mounts to vaccination may be suboptimal. There is no evidence to suggest that in significantly immunocompromised patients a second
vaccination will result in a more successful response. Live attenuated vaccines such as MMR and varicella

quiescent hepatitis B are prescribed

suppressive antiviral therapy
throughout their treatment.

Vaccinations
Patients with indolent haematological malignancies, particularly CLL,
are well recognised to be chronically
immunosuppressed, primarily due to
impaired humoral immunity.
Chemotherapy agents, especially
purine analogues such as fludarabine
(which can impair T-cell immunity)
and monoclonal antibodies can exacerbate any underlying immune suppression.
These patients should receive the
annual influenza virus vaccine, which
is comprised of inactivated virus.
GPs should also ensure these patients

vaccines should be avoided in

patients receiving chemotherapy or
those with advanced disease.
For patients receiving autologous
or allogeneic SCTs, revaccination
with the diphtheriatetanuspertussis
vaccine, in addition to inactivated
polio, haemophilus influenzae type
b, hepatitis B, pneumococcal and
influenza vaccines, is required.
Administration of the MMR and
varicella vaccines is deferred until 24
months post-transplant, the decision
as to whether a patient is appropriate for these vaccines being made by
the treating haematologist. At many
transplant centres both patients and
their GPs are provided with a list of
which vaccinations are required at
what time.

Leichhardt, NSW

Case study
MR RW is a longstanding
patient of the practice. He is a
resident of a local boarding
house and suffers both from
chronic schizophrenia, for
which he receives risperdone,
and also from type 2 diabetes,
for which he requires Mixtard
insulin. He is looked after primarily by the boarding-house
team and community-support
liaison psychiatry.
He presented to us in 2006
with new-onset enlargement
of the lymph glands in his left
axilla. This was associated
with only mild local discomfort but he had many constitutional symptoms, with drench-

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References: 1. Hirschfeld
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2. American Psychiatric
Association, Diagnostic

THE patient diagnosed

today with CLL or FL has a
better prognosis than
patients diagnosed 10 years
ago. This is largely due to
the introduction of rituximab into modern treatment
regimens. For most patients,
these malignancies can be
viewed as chronic illnesses
with the goal of therapy to
achieve the best possible
quality of life. In younger
patients, more aggressive
treatment modalities may be
appropriate.

References

GPs contribution

DR DIANNE CHAMBERS

Conclusion

Available on request from

julian.mcallan
@reedbusiness.com.au

ing night sweats, hot flushes

at night and a 10kg weight
loss. He was not able to tell
us over what period his glands
had become swollen but he
did mention that he had also
noticed lesser swellings in his
neck and groin. Although his
sleep and appetite were good,
he had noticed weight loss,
having to tighten his belt several notches.
On examination he had
bilateral cervical, axillary and
inguinal lymphadenopathy.
The largest lymph node was
in the left axilla and measured
3 3cm. It was mobile and
non-tender. He did not have
any organomegaly.
His initial white cell count
was 42 109 cells/L, which fell
to 28.7 109 cells/L. Haemoglobin and platelets were
normal. He was initially
treated with chlorambucil. All
symptoms settled and lymph
nodes regressed. However,
with further deterioration his
chemotherapy has been
changed on several occasions

over the last five years.

The most recent CT scan in
February 2011 showed widespread lymphadenopathy, with
the largest node being a 4cm
left axillary node. The spleen is
enlarged at 16.9cm, but the
liver is clear.

Questions for the author

Mr RW was initially prescribed chlorambucil and

prednisone (gentle chemotherapy). This seemed to work for
a period although he continued to have palpable lymph
nodes. After some time his
WCC became considerably
elevated and he was started on
fludarabine, first as singleagent therapy and then combined with rituximab. On
what criteria was Mr RWs
lymphoma deemed suitable for
gentle chemotherapy?
We presume Mr RW has
CLL with lymphocytosis and
organomegaly. Importantly
the initial red cell and platelet
counts are preserved. In general, treatment is indicated for

symptomatic relief, marrow

suppression or constitutional
symptoms,
particularly
fatigue. A rapid lymphocyte
doubling time or poor-risk
cytogenetics may also influence the decision towards
chemotherapy. This patient
had notable weight loss and
constitutional symptoms and
therefore required treatment.
Indeed, such a presentation
can sometimes indicate an
underlying transformation to
a more aggressive lymphoma
(Richters transformation).
There has been a shift away
from the use of gentle, less
intensive chemotherapy in an
attempt to achieve deeper and
longer responses. However,
such an approach is not for
frail elderly patients and
patients with multiple co-morbidities, such as Mr RW.
While the disease tends to
improve in the majority of
patients receiving chlorambucil monotherapy, less than 5%
achieve a deep prolonged
response. The average dura-

tion of response is typically

less than two years. A more
usual approach in a patient
able to tolerate more aggressive treatment is the use of
FCR (fludarabine, cyclophosphamide and rituximab),
which results in a complete
remission rate of almost 90%
and a superior overall survival. In patients not suitable
for FCR, a combination of
chlorambucil and rituximab
would be the favoured
approach.

Online resources
A comprehensive list of
useful websites can be found
at: www.petermac.org/
haematologyinformation

Are their any new treatment

regimens in the pipeline for
RW?
Newer next generation
CD20 antibodies have
recently been developed. One
such drug is ofatumumab,
which appears to have greater
potency than rituximab in
patients with relapsed/refractory CLL. Bendamustine is
effective in CLL and follicular lymphoma and has a particularly good toxicity profile
contd next page

THINK BROAD. TREAT BROAD.

Targeting many of the symptoms of depression DSM-IV.2

HOW TO TREAT Lymphoproliferative disorders Part 2

from previous page

but is not yet approved in

Australia. Alemtuzumab, a
CD52 antibody, which can be
used in relapsed or refractory
CLL is useful in fit, younger
patients. When all conventional options have been
exhausted, motivated and
compliant patients can be considered for enrolment in clinical trials. One such agent currently undergoing clinical
trials in Australia is ABT-263,
an inhibitor of bcl-2, which is
dysregulated in CLL.

General questions for

the author

Patients with febrile neutropenia may present to GPs. Can

you give more advice as to
what would be a critical level
and what is the appropriate
antibiotic? Or do these
patients all need G-CSF and
hospitalisation?
It is hard to tell a patient
who is sitting in your clinic
with no apparent symptoms
of impending sepsis, other
than a temperature of 38
degrees, that he or she needs
to go to hospital. An absence
of neutrophils generally means

an absence of suppuration, so
there are often no localising
signs. Many patients will
declare that they feel fine.
Unfortunately, febrile neutropenic patients can deteriorate remarkably quickly,
sometimes within the space of
a few hours. As a general rule,
a febrile neutropenic patient
should come into hospital for
intravenous antibiotic therapy
+/- G-CSF. We use a broad
spectrum antibiotic such as
piperacillin/tazobactam. If an
infected intravenous cannula
site or central venous catheter
is suspected as the source of
infection, vancomycin is
added to cover MRSA (methicillin resistant Staphylococcus
aureus). Recent Australian
guidelines have been published on the management of
febrile neutropenia in cancer
patients.1
Part 1 of your article advises
that both mantle cell and
Burkitts lymphoma are associated with a characteristic
chromosomal translocation. Is
the chromosome abnormality
the primary cause for these
lymphomas, or does it just

represent an increased susceptibility. If it is the primary

cause, are we moving towards
genetic screening and anticipatory care?
The chromosomal translocations that occur in haematological malignancies such as
those associated with Burkitts
lymphoma (involving the cmyc gene) and mantle cell
lymphoma (involving the
cyclin D1 locus) are mutations
that occur within malignant
cells only and are the main
pathogenic steps in the development of these lymphomas.
These translocations are not
constitutional abnormalities
(present in the germ line of the
patient), rather they are
acquired random genetic
events in B-lymphocytes. Consequently, there is no role for
screening for these translocations in the absence of clinical disease.
In Part 1, you advise there is a
20% risk of subsequent breast
cancer risk in those who have
had mantle radiotherapy. This
is news to me. You also mention that this radiotherapy
was the standard of care

How to Treat Quiz

Lymphoproliferative disorders
Part 2 8 April 2011
1. Which TWO statements are correct?
a) If an indolent lymphoma transforms into a
more aggressive lymphoma, the prognosis is
much better than for de novo aggressive
lymphomas
b) Indolent lymphomas are generally regarded
as curable
c) On routine FBC, lymphocyte counts above
15 109 cells/L should be a cause for concern
d) Lymphocytosis with lymphadenopathy,
splenomegaly, anaemia or thrombocytopenia
is suggestive of underlying malignancy
2. Which TWO statements are correct
regarding chronic lymphocytic leukaemia
(CLL)?
a) Lymphocyte morphology on the blood film is
sufficient for the diagnosis of CLL
b) Flow cytometry identifies the cell surface
markers present on the cell population of
interest
c) Flow cytometry is used only for the cells in
peripheral blood
d) Flow cytometry can detect minimal residual
disease after treatment and can identify
markers of poor prognosis
3. Which TWO statements are correct?
a) The presence of <5 109 cells/L with the CLL
phenotype in peripheral blood without
lymphadenopathy or organomegaly has no
clinical significance
b) Patients with monoclonal B cell
lymphocytosis (pre-CLL) should be monitored
annually

about 15 or more years ago. I

suspect that these patients
may no longer be under the
care of haematology units and
would be seeing their GPs.
These patients warrant aggressive breast surveillance. You
state that the method of investigation is under discussion. In
the meantime, would you suggest MRI (which has MBS
funding for breast cancer
screening in high-risk
patients), ultrasound, mammogram or a combination?
Due to the multitude of
late effects that can occur, we
recommend that all patients
treated for HL (and indeed
all long-term lymphoma survivors) are followed up in the
long term by their haematologist/oncologist or in specialised multidisciplinary
clinics dedicated to the management of the long-term
effects associated with cancer
treatment. Depending on
risks, a review every 1-5
years may be appropriate.
We suggest annual mammography and ultrasound
for patients with exposure of
breast tissue to radiation.
However, the young age of

some patients makes mammography a less sensitive

modality due to density of
breast tissue. Given the sensitivity of breast MRI for
detecting abnormalities, it
may be desirable to use this
modality for very select
patients at high risk of subsequent breast cancer (eg, significant radiation exposure
and young age); however,
currently patients would
have to self-fund for this
investigation. The original
treating team should be consulted in order to establish
treatment details and to seek
advice on subsequent breast
cancer risk.
Table 1 in Part 1 alerts us to
the need to manage Helicobacter pylori and Chlamydia psittaci infections as effective treatment of extranodal
disease in MALToma. What
is the risk for lymphoma
development in these illnesses?
What is thought to be the
pathophysiological effect of
these organisms?
Given the high prevalence
of H. pylori infection (about
half of the worlds population)

and the relative rarity of gastric MALToma, the percentage of patients infected with
H. pylori who will go on to
develop gastric MALToma is
extremely low. While the
exact pathogenesis of extranodal MALToma is still being
elucidated, the current
hypothesis is that H. pylori or
C. psittaci induces abnormal
aggregations of lymphoid
tissue, which (through chronic
antigen stimulation) eventually develop a degree of
autonomous growth.
In the early stages of disease, the lymphocyte proliferation is still partially dependent on the presence of
bacterial antigen, so removing
the organism may result in
resolution of the lymphoma.
However, as the disease progresses, the B-lymphocytes
acquire further genetic abnormalities that lead to further
autonomy, independence from
bacterial antigen stimulation
and frank malignant behaviour.

Reference
1. Internal Medicine Journal
2011; 41:75-81.

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c) Small cell lymphocytic lymphoma is

essentially the same disease as CLL but
without the leukaemic component
d) An asymptomatic patient over 60 with CLL
always requires full investigation and
immediate treatment
4. Which TWO statements are correct
regarding CLL?
a) Before referring an anaemic patient with CLL,
the GP should arrange a Coombs test to
assess for autoimmune haemolysis
b) Baseline immunoglobulin levels do not usually
reflect the degree of immunosuppression
c) A lymphocyte doubling time of 12 months
confers a poor prognosis
d) The need for treatment of CLL is determined
by the presence of cytopenias,
lymphadenopathy, organomegaly or
constitutional symptoms
5. Which TWO statements are correct
regarding CLL?
a) A bone marrow biopsy will make the
important distinction between autoimmune
cytopenias and cytopenias due to marrow
infiltration
b) The extent of bone marrow infiltrate and
cytogenetic abnormalities does not influence
prognosis in CLL
c) Patients without clinically detectable
lymphadenopathy are unlikely to have occult
abdominal lymphadenopathy on CT
d) One of the most important prognostic
markers for CLL is the presence of a

chromosome 17p deletion

6. Which TWO statements are correct
regarding CLL?
a) Early treatment improves survival
b) Indications for chemotherapy include
symptomatic anaemia, infections, weight loss
or fatigue
c) In older patients, less intensive oral therapy
(chlorambucil or cyclophosphamide) is often
used for symptom control
d) The combination of fludarabine,
cyclophosphamide and rituximab improves
symptoms but does not improve survival in
younger patients
7. Which TWO statements are correct?
a) In allogeneic stem cell transplant (SCT), the
patients own stem cells are transplanted
b) In allogeneic SCT the transplanted stem cells
do not themselves have an anti-cancer effect
c) For appropriately selected patients, allogeneic
SCT can offer long-term disease-free survival
and possibly cure
d) In patients with CLL, IV immunoglobulin may
decrease the number of infections associated
with hypogammaglobulinaemia
8. Which TWO statements are correct
regarding follicular lymphoma (FL)?
a) Most patients with FL present with
early-stage disease
b) Fine-needle aspiration of lymph nodes
is the preferred method of obtaining
tissue for diagnosis

c) Excisional biopsy of a lymph node provides

an adequate tissue sample and the nodal
architecture is preserved for analysis
d) Adverse prognostic markers include age >60,
involved lymph node >6cm, and bone marrow
involvement
9. Which THREE statements are correct?
a) Patients with early-stage FL can achieve longterm remissions and possible cure with local
radiotherapy
b) The indications for chemotherapy for FL
include painful or cosmetically unappealing
nodal disease, fatigue and malaise
c) After chemotherapy a patient with malaise or
fever should be assessed urgently for febrile
neutropenia
d) Patients who have received granulocyte
colony stimulating factor (G-CSF) with
chemotherapy are not at risk of febrile
neutropenia
10. Which TWO statements are correct?
a) Antiviral treatment for hepatitis B is
contraindicated in lymphoma patients
receiving chemotherapy with high-dose
steroids
b) Patients with lymphoma should receive
annual influenza and five-yearly
pneumococcal vaccines
c) Live attenuated vaccines (eg, MMR, varicella)
should be avoided in patients with lymphoma
receiving chemotherapy or those with
advanced disease
d) Re-vaccination is contraindicated after SCT

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complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post or
fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.

HOW TO TREAT Editor: Dr Giovanna Zingarelli

Co-ordinator: Julian McAllan
Quiz: Dr Giovanna Zingarelli

NEXT WEEK More than one-quarter of the population have some hearing impairment, while in the 70+ age group, the prevalence rises to 87.5%, making this yet another condition that one is likely to see
more of as the population ages. The next How to Treat tackles hearing loss in the ageing patient. The authors are Dr Phil Sale, cochlear implant research fellow, Kolling Deafness Research Centre,
University of Sydney, NSW; and Clinical Associate Professor Nirmal Patel, clinical director, Northside Cochlear Implant Clinic, and Director, Kolling Deafness Research Centre, University of Sydney, NSW.

36

| Australian Doctor | 8 April 2011

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