1. health and fitness
2. disease

Guidelines on the investigation and management of
follicular lymphoma
British Committee for Standards in Haematology
Address for correspondence:
BCSH Administrator
British Society for Haematology
100 White Lion Street
London N1 9PF
e-mail [email protected]
Writing group:
C McNamara1 , J Davies2, M Dyer3, P Hoskin4, T Illidge5, M Lyttelton6, R
Marcus7, S Montoto8, A Ramsay9, W Wong4, K Ardeshna9
Disclaimer:
While the advice and information in these guidelines is believed to be true and
accurate at the time of going to press, neither the authors, the British Society for
Haematology nor the publishers accept any legal responsibility for the content of
these guidelines.
Date of publication: September 2011
BCSH will review this guideline on an annual basis to ensure it remains up-to-date
guidance. Please see the website at www.bcshguidelines.com to see if the guideline
has been updated or amendments added. The website will also show the date the
guideline was last reviewed.
1 The Royal Free Hospital, London
2 Western General Hospital, Edinburgh
3 Leicester Royal Infirmary, Leicester
4 Mount Vernon Cancer Centre, Northwood
5 Christie Hospital, Manchester
6 Kettering General Hospital, Northamptonshire
7 Kings College Hospital, London
8 Barts Cancer Institute, London
9 University College London Hospital, London
1
Table of Contents
Methodology .....................................................................................................3
Summary of key recommendations ..................................................................4
1.
Introduction ...............................................................................................6
2.
Diagnosis ..................................................................................................7
3.
Initial investigation ...................................................................................11
4.
Prognostic scoring systems .....................................................................15
5.
Management of newly diagnosed patients ..............................................24
6.
Management of patients with relapsed FL...............................................28
7.
Management of patients with transformed FL .........................................35
8.
The role of autolgous and allogeneic transplant ......................................37
9.
Follow up and monitoring ........................................................................40
Acknowledgements and declarations of interest ............................................43
Appendix 1: Method of calculating FLIPI and FLIPI2 indices ........................44
Appendix 2: Grades of evidence and strength of recommendations .............45
References .....................................................................................................47
Table 1: Architecture patterns in FL .........................................................9
Table 2: Grading of FL ...........................................................................11
Table 3: FLIPI and FLIPI2 scoring system .............................................18
Table 4: First line treatment - immunochemotherapy Phase III trials .....25
Table 5: Outcomes after RIC -allotransplant for FL.................................40
2
METHODOLOGY
The guideline group was selected to be representative of UK based medical experts.
MEDLINE and EMBASE were searched systematically for publications in English
from 1980-2010 using key words follicular lymphoma, non-Hodgkin lymphoma and
low-grade lymphoma. The writing group produced the draft guideline which was
subsequently revised by consensus by members of the Haemato-oncology Task
Force of the British Committee for Standards in Haematology. The guideline was
then reviewed by a sounding board of approximately 50 UK haematologists, the
BCSH (British Committee for Standards in Haematology) and the British Society for
Haematology Committee and comments incorporated where appropriate. The
objective of this guideline is to provide healthcare professionals with clear guidance
on the management of patients with follicular lymphoma. The guidance is not
appropriate for patients with other lymphoma subtypes and in all cases individual
patient circumstances may dictate an alternative approach.
GRADING OF EVIDENCE
These guidelines have used the GRADE (Grading of Recommendations
Assessment, Development and Evaluation) nomenclature for assessing levels of
evidence and providing recommendations in guidelines. See appendix 2.
3
SUMMARY OF KEY RECOMMENDATIONS:

Lymph node excision or adequate core biopsy is required for the
diagnosis of follicular lymphoma (FL) - histology enables an assessment
of the tumour grade and the exclusion of transformation to a more
aggressive histological subtype (1B).

All cases should be subject to routine central review by an experienced
haematopathologist (1B).

All patients with newly diagnosed FL should undergo a comprehensive
clinical, laboratory and imaging assessment to characterise the stage of
disease and the physiologic status of the patient, prior to any
consideration of therapy (1B).

The Follicular Lymphoma International Prognostic Index (FLIPI) indices
should be recorded for all patients at diagnosis (2B).

Involved field radiotherapy delivering a dose of 24 Gray (Gy) in 12 daily
fractions should be regarded as the standard of care for patients with
newly diagnosed, limited stage disease (1A). Outside of a clinical trial,
lower doses of radiotherapy can only be recommended for palliation or
re-treatment where radiation tolerance may be a concern.

Observation following total excision of all macroscopic disease may be
suggested in selected patients with negative staging after discussion
with a radiation oncologist (2C).

Observation
remains
an appropriate
approach in
patients
with
asymptomatic, advanced stage follicular lymphoma in an attempt to
delay the need for chemotherapy. This is particularly the case for
patients over 70 years of age (1A).

Rituximab in combination with chemotherapy should be used in patients
with newly diagnosed, symptomatic advanced stage FL (1A). There is
currently no strong evidence to support one chemotherapy regimen
over another.
4

Rituximab maintenance after successful induction therapy prolongs
progression-free survival (PFS) and is recommended in patients
responding to first-line rituximab-based chemotherapy (1B).

Patients with Mann and Berard histological grade 3b FL should be
treated as if they have diffuse large B-cell lymphoma as there may be
important clinical and biologic differences between this group and FL
patients with lower grades (2B).

Autologous stem cell transplantation has no role in first line therapy for
FL (which has no evidence of histological transformation) outside the
setting of a clinical trial (1B).

Patients with known FL who present with features of relapsed disease
should undergo a biopsy procedure, wherever practicable (1B).

The combination of chemotherapy with rituximab is the standard for
those patients who require treatment at the point of relapse and are
rituximab naïve as the combination improves all clinically meaningful
outcomes, including overall survival (OS), compared to chemotherapy
alone (1A).

Chemotherapy and rituximab should also be the standard for relapsed
FL patients who have received prior rituximab if the patient had
previously responded to rituximab (1C).

Rituximab maintenance prolongs PFS substantially in patients with
relapsed/refractory FL who are rituximab-naïve and respond to reinduction therapy with single agent rituximab, chemotherapy or
chemotherapy and rituximab and should be offered to all patients in this
setting (1A).

Radioimmunotherapy with 90Y-Ibritumomab tiuxetan is an active
treatment approach in patients with relapsed follicular lymphoma and
should be considered in older patients and those that are refractory to
or intolerant of chemotherapy and rituximab (2B).

All patients with FL should be monitored for evidence of disease
recurrence and for the late effects of therapy (1C).
5
1
INTRODUCTION
Follicular Lymphoma (FL) is the most common of the low grade lymphomas in the
United Kingdom. Its incidence increases with age, with a median presentation
between 60-65 years and a slight female: male predominance (Friedberg et al,
2009).
FL has commonly been seen as a chronic, relapsing, indolent tumour with a median
survival of 7-10 years in the pre-rituximab era. Approximately 85% of patients have
advanced disease at presentation. Symptoms may include B symptoms, fatigue, the
local mass effect of lymph node enlargement, as well as those of bone marrow
failure. Many patients, however, are relatively asymptomatic at presentation. The
disease has been seen as incurable apart from in the relatively infrequent patient
with early stage disease.
The course of the disease is heterogeneous. A minority of patients have indolent
disease with little or no progression over several decades. Lymphadenopathy is
variable and patients may enter spontaneous and prolonged remissions (Horning
and Rosenberg, 1984). Some patients are observed without treatment according to a
"Watch & Wait" policy (see section 5) and will never require systemic treatment. In
contrast to this, over a period of years, 20-30% of patients will die following
transformation of their disease to high grade lymphoma (Montoto et al, 2007).
Prognostic indices may help discriminate between risk groups.
Survival of patients with FL has improved over the last 30 years. Single institution
series show up to 30% improvement in 5 year OS (Fisher et al, 2005; Liu et al 2006).
A United States population-based registry study of over 14000 patients between
1978 and 1999 showed an increase in median survival from 84 to 93 months
(Swenson et al, 2005). Improvement in failure-free survival (FFS) was only seen
following the introduction of anti-CD20 combinations. The introduction of anti-CD20
antibody therapy in 1997 in the USA and 2004 in the UK, therefore, represents a
watershed. Some OS improvement is seen prior to 1997 probably due to the
combined effect of different treatment options as well as advances in supportive
care.
Treatment plans for an individual patient should be, whenever possible, part of a
long term strategy and planned after review of all the evidence at a lymphoma
6
multidisciplinary team meeting with lymphoma specialists, specialist
haematopathologist, radiologists, nuclear medicine physician and radiation
oncologist. Many modalities are available for treatment but some of these may
compromise future choices e.g. nucleoside analogues and autologous stem cell
harvesting. Risk of other long term complications such as myelodysplastic
syndromes, other secondary cancers, cardiac toxicity and effects on fertility must
also be considered, given the extended and now increasing survival of many
patients.
Detailed discussions with the patient of different treatment options are of particular
importance in the management of the patient with FL. The relative benefits and
objectives of the different treatment options must be clearly presented. The different
treatment objectives to be considered include impact on symptoms, attainment of
sustained remission, prolongation of survival and, less commonly, the potential for a
curative treatment such as allogeneic transplantation. Psychological support from the
clinical team and other bodies such as patient groups is particularly important in the
face of the chronic relapsing nature of this disease and the multiplicity of treatment
choices available to the patient and physician.
2
DIAGNOSIS
(Note: The reader is also referred to the BCSH guideline entitled Best Practice in
Lymphoma Diagnosis and Reporting for further information on diagnosis.)
2.1
Morphology
Recognised in the 1920s (Brill et al, 1925; Symmers, 1927), FL is a B-cell neoplasm
derived from germinal (follicle) centre cells. Involved nodes show replacement of the
normal architecture by closely-packed neoplastic follicles which are uniform in size,
lack tingible body macrophages, and possess poorly-formed mantle zones. Reactive
germinal centres contain a mixture of centroblasts and centrocytes organised into
well-defined zones, whereas germinal centres in FL contain a monomorphic
population (usually of centrocytes) and lack any evidence of zonation. FL may be
focally follicular, follicular and diffuse, or even completely diffuse (Table 1) (Swerdlow
et al, 2008).
7
Table 1: Architecture patterns in FL
FL Pattern
Architecture
Follicular
>75% follicular
Follicular and diffuse
25 – 75% follicular
Focally follicular
<25% follicular
Diffuse
0% follicular
The cells between the follicles make up the interfollicular component of FL (Dogan et
al, 1998). These cells are normally small centrocytes, and can show phenotypic
differences from the cells within the neoplastic follicles (see below).
Approximately half of all FL cases show bone marrow involvement at presentation
(Conlan et al, 1990) typically consisting of paratrabecular aggregates of lymphoid
cells showing follicle centre cell morphology.
2.2
Immunohistochemistry
Follicle centre cells express B-cell lineage markers and the germinal centre cell
antigens CD10 and BCL6. The interfollicular component of the FL (Dogan et al,
1998) and bone marrow disease often shows downregulation or loss of these
markers. High grade (Grade 3) FL can lose CD10 expression, although BCL6 is
often retained (Eshoa et al, 2001). The underlying networks of follicular dendritic
cells (FDC) can be shown with CD21.
Normal germinal centre cells are BCL2 negative; in 85% of cases the neoplastic cells
in FL are BCL2 positive. At the molecular level FL shows a characteristic t(14;18)
translocation which relocates the BCL2 anti-apoptosis gene so that it is adjacent to
an immunoglobulin promoter leading to the over-expression of BCL2 protein. BCL2
staining may be negative in high grade (grade 3) FL and in some cases showing an
alternative translocation (see below). The tumour cells in FL will show light chain
restriction.
8
All cases of FL require a histological diagnosis. A fine needle aspirate is not
appropriate; whilst FL cells can be detected in cytology specimens (Saikia et al,
2002), with confirmation by polymerase chain reaction (PCR) and fluorescent in situ
hybridization (FISH), and by flow cytometry in some cases, histology is needed to
grade the tumour and to exclude transformation to diffuse large B-cell lymphoma
(DLBCL).
2.3 Molecular investigations
The typical IgH/BCL2 translocation can be detected by PCR or by FISH using a
break-apart probe for the BCL2 gene (Gu et al, 2008). Some cases, particularly
those in the Grade 3 category, can show an alternative translocation involving BCL6
(Katzenberger et al, 2004; Bosga-Bouwer et al, 2005). PCR studies will show a
clonal IgH rearrangement.
2.4 Grading of FL
The grading of FL relies on the proportion of centroblasts in neoplastic follicles, but
the reproducibility of this method has been questioned (Non-Hodgkin's Lymphoma
Classification Project, 1997). This Mann-Berard system defines 3 grades, but the
latest World Health Organisation (WHO) classification (Swerdlow et al, 2008)
merged grade 1 and 2 into a single low-grade category of grade 1-2 (Table 2). Grade
3 lesions are further subdivided according to the presence or absence of
centrocytes, so that Grade 3B FL is composed solely of centroblasts. Grade 3B
lymphomas show areas histologically indistinguishable from DLBCL, and a diagnosis
of grade 3B FL is clinically regarded as equivalent to a diagnosis of DLBCL (BosgaBouwer et al, 2006).
9
Table 2: Grading of FL (Swerdlow et al, 2008)
Grade
Criteria
Grade 1-2 (WHO 2008)
0 – 15 centroblasts per high power field (HPF)
Grade 1
0 – 5 centroblasts per HPF
Grade 2
6 – 15 centroblasts per HPF
Grade 3
> 15 centroblasts per HPF
Grade 3A
Centrocytes present
Grade 3B
Centrocytes absent
HPF = high power field
Grading can present problems in some cases. Histological identification of
centroblasts is not always straightforward; counting the absolute number of
centroblasts in a x40 high power field from 10 follicles is time consuming and prone
to error. Small specimens such as needle core biopsies may not be representative.
Of interest is a 2007 paper reporting tumour sclerosis to be a more useful prognostic
marker than Mann-Berard grading in advanced-stage FL (Klapper et al, 2007).
2.5 Pitfalls and differential diagnosis
Difficult cases include those with atypical morphology, those lacking a follicular
architecture, and where BCL2 is negative. Needle core biopsies may consist solely
of diffuse areas of FL, or may be composed predominantly of the interfollicular
component. With such difficult cases specialist review is mandatory, with addition of
PCR and FISH where required.
The differential diagnosis of FL includes nodular lymphocyte predominant Hodgkin
lymphoma (NLPHL), chronic lymphocytic leukaemia/small lymphocytic lymphoma
(CLL), mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL). The
nodules of NLPHL contain small lymphocytes and scattered large Error! Bookmark
not defined.cells rather than follicle centre cells. CLL shows sheets of small B
lymphocytes that are CD5 and CD23 positive and CD10 and BCL6 negative. MCL
10
has a monomorphic appearance and the cells express CD5 and cyclin-D1. Nodal
MZL can colonise pre-existing follicles (Naresh, 2008), and may need FISH to
exclude a BCL2 translocation. FL at extra-nodal sites can form lymphoepithelial
lesions (Tzankov et al, 2002) and so can mimic mucosa-associated lymphoid tissue
(MALT) lymphoma, and MALT lymphoma can show a proliferation of follicular
dendritic cells (FDC) that may mimic FL (Fellbaum et al, 1993). However MALT
lymphoma is CD10 and BCL6 negative, and FISH will fail to show a BCL2
translocation.
Recommendations :

Biopsy is required for the diagnosis of FL, as histology enables an
assessment of the tumour grade and the exclusion of transformation to
DLBCL (1B).

FL is composed of germinal centre B cells that normally express CD10,
BCL6 and BCL2. The follicular architecture is confirmed by using CD21
to identify FDC networks (1B).

All cases should be subject to routine central review, as with any
malignant lymphoma, as expert/specialist opinion is required to
establish a firm diagnosis (1B).

Molecular investigations including PCR and FISH are required in cases
with atypical clinical and/or pathological features (1B).
3
INITIAL INVESTIGATIONS FOLLOWING A DIAGNOSIS OF FL
Appropriate investigation following diagnostic biopsy in FL serves two purposes.
Firstly, staging investigations allow initial assessment of disease extent, including
determination of the Ann Arbor stage, identification of sites of bulk disease and
derivation of prognostic scoring systems such as the Follicular Lymphoma
International Prognostic Index (FLIPI). Staging also provides a rational basis for
treatment, allows for appropriate on-going disease monitoring and facilitates
comparative post-treatment assessment of disease sites.
11
3
IMAGING GUIDELINES IN FL
Computed Tomography (CT) is the established technique for assessing FL (Kwee et
al, 2008). Functional imaging with 18-F fluoro-deoxy-glucose positron emission
tomography computed tomography (FDG PET CT) is an emerging new technique
whose precise role is yet to be defined for this patient group. The frequency of follow
up imaging which involves radiation exposure needs careful consideration.
It must
always be justified in terms of likely clinical benefit to avoid unnecessary potential
risk due to ionizing radiation exposure.
3.1.2 Use of Imaging at Diagnosis
3.1.2.1 Computed Tomography (CT)
CT should include the neck, thorax, abdomen and pelvis and extend from the skull
base to the pubic symphysis. Imaging of the central nervous system is not
performed routinely. All studies should be performed with administration of oral
contrast to differentiate between loops of bowel and abdominal nodal masses.
Intravenous contrast is also recommended, unless there is a contraindication such
as renal failure, to distinguish between blood vessels and lymph nodes and to
increase sensitivity for detecting extra-nodal disease in the liver and spleen.
CT may be used to identify the most appropriate lesion for biopsy and to assist the
radiologist localise lesions during percutaneous needle biopsies.
3.1.2.2 Magnetic Resonance Imaging (MRI)
MR is the imaging of choice in the rare FL patient with suspected lymphoma in the
central nervous system including brain, leptomeninges and spinal cord,
complimented by examination of CSF. Intravenous gadolinium increases sensitivity
and should be considered in patients with a high risk of central nervous system
(CNS) disease and a negative MRI.
3.1.2.3 Ultrasonography (USS)
USS is of limited value in the staging of FL. It shows lymphadenopathy in the cervical
regions of the neck, around the coeliac axis, splenic hilum, porta hepatis and in the
12
inguinal regions. It demonstrates disease in the liver and spleen. However, the
entire retroperitoneum cannot be assessed and mediastinal and retropharyngeal
nodal enlargement cannot be detected.
3.1.2.4 Positron Emission Tomography (PET)
For patients with potentially curable conditions, such as Hodgkin lymphoma,
functional imaging with PET utilising the glucose analogue fluoro-deoxyglucose
(FDG) has become a routine investigation for the staging and assessment of posttreatment residual masses (Burton et al, 2004; Hutchings and Barrington, 2009).
There is substantial evidence that most cases of FL are visualised on FDG-PET,
irrespective of grade (Karam et al, 2006; Newman et al, 1994; Moog et al, 1997;
Stumpe et al, 1998; Jerusalem et al, 2001; Wöhrer et al, 2006).One of the main
factors that influence prognosis in patients with FL is the number of nodal regions
containing disease. In the FLIPI involvement of more than 4 nodal areas is an
adverse prognostic factor (Solal-Céligny et al, 2004). FDG-PET, compared with CT,
more accurately diagnoses nodal disease and detects unexpected sites of extranodal disease. However, whether small volume disease detected on PET but not CT
is important prognostically is uncertain. The number of patients correctly diagnosed
as having limited disease is increased when FDG-PET is included (Jerusalem et al,
2001; Karam et al, 2006; Wirth et al, 2008; Janikova et al, 2008).
FDG-PET is of limited value for the detection of bone marrow disease and is not a
substitute for bone marrow biopsy (Jerusalem et al, 2001; Elstrom et al, 2003)
Detection of bowel involvement with FDG PET CT is a challenge as normal bowel
wall shows FDG uptake (Elstrom et al, 2003).
There is considerable debate about the clinical value of FDG-PET CT in patients with
FL; therefore, the results of FDG-PET scanning should not be used to make clinical
decisions regarding therapy and the utility of this technique should be further
evaluated for FL patients within a prospective clinical trial.
3.2 PATIENT ASSESSMENT
A number of additional investigations may be undertaken to determine disease
extent and prognosis in patients with biopsy proven FL. The recommendations below
13
are based either on the requirements for staging and prognostic scoring (Federico et
al, 2009) or as part of good clinical practice allowing the detection of relevant
disease- related and patient specific co-morbidities. Some elements are considered
core while others are discretionary depending on the clinical context. It should be
recognised that specific areas of controversy exist. For example virological testing
for hepatitis B and C is recommended before the start of immunotherapy either alone
or in combination while HIV testing is subject to local incidence patterns since the
incidence of FL does not appear to be increased in patients with HIV infection (Artz
et al, 2010; Cave et al, 2009; Vajdic et al, 2010). An assessment of the impact of
any proposed therapy on fertility should always be made in younger patients. If
clinically appropriate, referral to a specialist in reproductive medicine should be
made prior to treatment so that options to preserve fertility can be discussed.
Recommendations:

A full clinical history and examination including determination of
performance status and any other relevant co-morbidity scores (1B).

Full blood count and blood film examination, with immunophenotyping
by flow cytometry where there is a peripheral blood lymphocytosis (1B).

Urea, creatinine and electrolytes (1B).

Liver function tests, Lactate Dehydrogenase (LDH) and β2 microglobulin
(1B).

Calcium, albumin, urate and phosphate (1B).

Immunoglobulins and quantitation of monoclonal band if present (1B).

Bone marrow examination to include aspirate, trephine biopsy and
immunophenotyping by flow cytometry and immuno-histochemistry
(1B).

Cytogenetic analysis of involved bone marrow should not be considered
routine but may be helpful where there is diagnostic uncertainty (2B).
14

Molecular detection of a clonal B-cell population in marrow or blood
should not be considered standard but may form part of studies
directed specifically at detection of minimal residual disease (2B).

As part of the staging process of patients with newly diagnosed FL, CT
is the established initial imaging investigation and should include the
neck, chest, abdomen and pelvis. Oral and intravenous contrast should
be administered unless there is a specific contraindication (1B).

At the current time, FDG-PET is of uncertain value in FL. Routine use
should be considered only in the setting of a clinical trial (1B).

In addition to staging the head and neck, MRI is the diagnostic
procedure of choice for rare patients with suspected disease in the
central nervous system disease including brain, leptomeninges and
spinal cord (1B).
Additional recommended investigations:

Standard assessment of relevant cardiac, respiratory or other general
medical co-morbidities may be required in order to determine patient
fitness for particular treatment (1B).

Pregnancy testing should be undertaken in women of child bearing age
prior to administration of relevant treatment (1B).

Virological testing for hepatitis B and hepatitis C should be undertaken
at baseline and in all patients considered at risk of virus reactivation in
whom immunotherapy is the treatment of choice (1B).

Clinical assessment and virological testing for HIV, as indicated by local
protocols (2C).
4
PROGNOSTIC SCORING SYSTEMS IN FL
Several prognostic indices or scores, including the International Prognostic Index
(IPI) for aggressive lymphoma, have been used to better define risk groups in
patients with follicular lymphoma (FL) (Leonard et al, 1991; Cameron et al, 1993;
15
Romaguera et al, 1991; Lopez-Guillermo et al, 1994; Federico et al, 2000). However,
none of these have been adopted into routine clinical practice, either because of
being too complicated (Leonard et al, 1991; Cameron et al, 1993; Romaguera et al,
1991), or lacking the ability to identify patients with poor prognosis (Lopez-Guillermo
et al, 1994). In 2004 an international collaborative study including 4167 patients
resulted in the publication of the Follicular Lymphoma International Prognostic Index
(FLIPI) (Solal-Celigny et al, 2004), a prognostic score specifically designed for
patients with FL. This index includes the following adverse variables: age >60 years,
haemoglobin concentration <120 g/l, LDH >upper normal value, stage III-IV, and >4
involved nodal areas, and stratifies the patients in 3 groups (low, intermediate and
high-risk) well balanced in terms of the proportion of patients in each group and with
a clearly different outcome (5-year overall survival: 91%, 78% and 52%, respectivelysee table 3). Furthermore, the FLIPI at diagnosis identifies patients with a higher risk
of histological transformation (Gine et al, 2006; Montoto et al, 2007b). Although this
index was designed in the pre-rituximab era, its prognostic value has recently been
confirmed in the rituximab era (Federico et al, 2007) and in patients receiving
rituximab as part of the first-line therapy (Buske et al, 2006; Marcus et al, 2008) and
its use has spread worldwide. However, at present the FLIPI has not yet been
validated prospectively to guide therapeutic decisions for patients with FL and should
only be used to guide prognosis and treatment decisions in the setting of clinical
trials. Notwithstanding, it is recommended that the FLIPI index should be recorded
for all patients at diagnosis.
More recently, another international collaborative study was launched with a two-fold
intention: a) to prospectively validate the FLIPI and b) to prospectively design a
prognostic index for FL patients treated in the rituximab era. The modified FLIPI2
(Federico et al, 2008; Federico et al, 2009) includes age, serum β2-microglobulin,
haemoglobin concentration, bone marrow involvement and tumour burden. Although
the latter was calculated using a complex mathematical formula, it correlates with the
longest diameter of the largest involved lymph node, which can be used as a
surrogate for tumour burden (with one point being scored if this is over 6 cm),
making the FLIPI2 relatively easy to calculate. It is recommended that the FLIPI2
index should be recorded in routine clinical practice (see table 3 and appendix 1).
16
Prognostic indicators at relapse are not established. Data on the value of the FLIPI
at the time of relapse is scarce, although its ability to predict survival from
progression has been confirmed in retrospective series (Montoto et al, 2004) and in
clinical trials (Sacchi et al, 2007).
Recommendations:

FLIPI and FLIPI2 should be recorded at diagnosis (2B).
Table 3: Prognostic scoring systems in FL- FLIPI and FLIPI2
FLIPI
FLIPI2
Age, stage, Hb,
Age, Hb, BM, β2M, nodal
LDH, nodal areas
size
Risk
Low
Intermediate High
Low
Intermediate High
groups
(0-1)
(2)
(> 3)
(0-1)
(2)
(> 3)
%
36
37
27
20
53
27
5-yr OS
91
78
52
98
88
77
Variables
Adverse factors: age >60 years; stage: III-IV; Hb- haemoglobin concentration <120
g/L; LDH elevated above the upper limit of normal; nodal areas > 5; beta 2
microglobulin (β2M) elevated above the upper limit of normal; bone marrow (BM)
involvement; longest diameter of largest node > 6 cm (see appendix 1).
5
MANAGEMENT OF PATIENTS WITH NEWLY DIAGNOSED FL
5.1 Guidelines for the management of early stage disease
It is particularly important in the case of early stage disease to gain as much
information as possible to exclude more advanced disease which would result in a
change in management. The FLIPI index is also of value in predicting outcome in
this group (Plancarte et al, 2006) and should be recorded, as recommended above.
17
5.1.1 Radiotherapy
Conventionally, early stage follicular lymphoma comprising Ann Arbor stage 1 and
stage 2 disease, where the involved nodes are contiguous, has been treated with
local radiotherapy. Follicular lymphomas are highly radiosensitive and a number of
case series in the literature confirm a high response rates with around 80% of
patients having long term disease control at 5 and 10 years (MacManus and Hoppe,
1996; Wilder et al, 2001; Guadnogolo et al, 2006; Pugh et al, 2010). Examination of
the patterns of relapse in these patients reveals that the majority relapse outside the
irradiated field (Reddy et al, 1989; Eich et al, 2009). Involved field or involved site
radiotherapy is the usual management. Conventional doses of 30 to 40 Gy that were
used in the past are now recognised to be higher than necessary for local disease
control and the current standard dose of 24 Gy in 12 fractions is recommended
outside of a clinical trial. Even lower doses have proved to be effective with a
schedule of 4 Gy in 2 fractions reported from several centres (Sawyer and Timothy,
1997; Johansson et al, 2002; Haas et al, 2003; Haas et al, 2005; Murthy et al, 2008;
Luthy et al, 2008) The largest series from The Netherlands has a total of 98 patients
with follicular lymphoma receiving either 4 Gy in 2 fractions or a single fraction of 4
Gy (Haas et al, 2003, 2005). The overall response rate was 92% and complete
response rate was achieved in 61% lasting up to 77 months with a median time to
local progression 25 months. The comparison of the UK standard dose of 24 Gy in
12 fractions versus 4 Gy in 2 fractions, is now the subject of a randomised trial in the
United Kingdom (FORT). At present in the absence of high quality evidence such low
doses can only be recommended for palliation or re-treatment where radiation
tolerance may be a concern.
5.1.2 Combined modality treatment
Since the majority of relapses occur outside the radiation field and are seen in up to
50% of patients, combined modality treatment may be an alternative approach.
There is limited and conflicting data to date. The largest study from Melbourne
reported on 102 patients with stage I or stage II “low grade” lymphoma (Seymour et
al, 2003). They received 10 cycles of COP-BLEO or CHOP-BLEO with 30 to 40 Gy
involved field radiotherapy. Ninety-nine per cent of patients achieved complete
remission; in those with follicular lymphoma there was a median follow up of 10
18
years and the freedom from failure rate was 72% and overall survival 80%. The
International Prognostic Index (IPI) was found to be predictive of outcome in this
series. This is now the subject of an ongoing phase III randomised trial. Pending
the results of this, combined modality treatment cannot be recommended routinely.
5.1.3 Observation alone in early stage FL
There are no randomised studies comparing no initial therapy with immediate
treatment in patients with early stage FL. A retrospective analysis of 43 patients with
stage 1a and 2a grade 1/2 FL suggests that this is an acceptable approach with 10
year overall survival of 86% which is not inferior to that of patients treated with
radiotherapy (Advani et al, 2004)). In this study 56% of patients had still not received
any therapy by 10 years. Another observation alone study of 26 patients with stage I
FL in whom the tumour had been fully excised at biopsy (stage I 0) (Soubeyran et
al,1996) had not relapsed with median follow-up of 4.6 years, 6 relapsed in the same
site (median 4.2yr (0.6-9y)) and 7 relapsed outside the original site (median 1yr (0.55.5yr). Five year overall survival for the 26 patients was 82.5% once again
suggesting that an observation policy in patients with stage I 0 FL is reasonable.
There may therefore be a case for patients with limited stage FL with no residual
disease following excision biopsy to be observed without treatment , especially if
there are concerns with regards side effects of involved field radiotherapy e.g. fertility
preservation in young women, elderly frail patients where significant morbidity, such
as xerostomia, might be expected.
Recommendations:

Involved field radiotherapy delivering a dose of 24 Gy in 12 daily
fractions is the standard of care (1A).

Observation of patients with early stage disease is acceptable if
radiotherapy is thought to be undesirable or due to patient choice.
These patients should be discussed with a radiation oncologist (2C).
19

Combined modality treatment and immunotherapy are at present
investigational approaches which should only be considered within a
formal clinical trial (2C).
5.2 Treatment of Advanced Stage Disease
5.2.1 Advanced stage, asymptomatic FL
Three randomised studies of varying quality have shown that there is no advantage
to immediate treatment in patients with advanced stage asymptomatic FL compared
with a watchful waiting approach in terms of overall survival (Ardeshna et al, 2003;
Brice et al, 1997; Young et al, 1988) and cause-specific survival (Ardeshna et al,
2003). The majority of patients in these studies had histology which would be
classified today as FL grade 1/2. The treatment arm in the studies consisted of
chlorambucil (Ardeshna et al, 2003), prednimustine or interferon (IFN) (Brice et al,
1997) and aggressive combined modality therapy with ProMACE-MOPP +total nodal
irradiation (Young et al, 1988). In 2 of the studies low dose radiotherapy to
symptomatic nodes was allowed in one (Young et al, 1988) or both (Ardeshna et al,
2003) of the arms. In the largest study of 309 patients with a median 16 years of
follow up conducted by the British National Lymphoma Investigation (BNLI), the
criteria for patients being eligible for a watch and wait approach were defined as the
absence of the following:
1) Pruritus or B symptoms
2) Rapid generalised disease progression in the preceding 3 months
3) Life-endangering organ involvement
4) Significant bone marrow infiltration resulting in bone marrow depression
sufficient to warrant immediate chemotherapy. This was defined as an
haemoglobin concentration <100g/l, a white cell count <3.0 x 109/l or a
platelet count <100x109/l, having excluded other causes of such cytopenias
5) Localised bone lesions detected on X-ray or isotope scan because of
concern over the development of pathological fractures
6) Renal infiltration (even if the renal function was well preserved)
7) „Macroscopic‟ as opposed to „microscopic‟ liver involvement.
20
Bulk disease per se was not an exclusion criterion.
A more restrictive set of criteria which defined low tumour burden FL were
established by the Groupe d‟Etude des Lymphomes Folliculaires (GELF), largely as
criteria for trial entry. Low tumour burden was defined as:
1) LDH within normal range
2) Largest nodal or extra-nodal mass less than 7cm diameter
3) No more than 3 nodal sites with a diameter more than 3cm
4) No significant serous effusions detectable clinically or on chest radiography
(small, clinically non-evident effusions on CT scan are not deemed significant)
5) Spleen enlargement less than or equal to 16 cm by CT.
Normal β2 microglobulin has now been added to the GELF definition of low tumour
burden.
In clinical practice a watchful waiting approach does not need to be limited to
patients with low tumour burden though it is likely patients with higher tumour
burdens will have a shorter interval until disease progression necessitates treatment.
Watchful waiting is able to defer the initiation of systemic therapy by 2-3 years
(Ardeshna et al, 2003; Brice et al, 1997; Young et al, 1998). In the BNLI study, 40%
of patients over 70 years had not received chemotherapy or died of lymphoma at 10
years after study entry. This fell to 16% in those patients under 70 years. Thus there
is little justification for immediate treatment in patients with asymptomatic advanced
stage FL. Patients who undergo observation do not have an increased risk of high
grade transformation (Brice et al, 1997; Horning et al, 1984; Al-Tourah et al, 2008)
compared to those who start treatment immediately.
The presumed advantage of a watchful waiting approach is that patients are spared
toxic side effects of chemotherapy. There is anecdotal evidence that at least for
some patients this strategy may lead to a worse quality of life as patients can find
being diagnosed with a malignant condition and not receiving treatment
psychologically distressing. Preliminary results of a three arm international
randomised study comparing watchful waiting with immediate treatment with
rituximab using the standard 4 week induction with or without maintenance rituximab
21
administered 2 monthly for 2 years, in patients with advanced stage asymptomatic
FL with low tumour burden have recently been reported after a median follow up of
32 months. The primary endpoint was time to initiation of new therapy. Three years
after randomisation 49% of patients in the watch and wait arm had not received
further therapy whereas 80% of patient in the rituximab induction arm and 91% of
patients in the rituximab induction and maintenance arm had not initiated new
therapy. There was no difference in overall survival with 95% of patients alive at 3
years. The quality of life data remains to be analysed but if this does not show a
detriment in the rituximab arms, initial treatment with rituximab in asymptomatic
patients with advanced stage, low tumour burden FL may be an alternative option
especially in patients in whom deferring chemotherapy is thought to be
advantageous. Whether early exposure to rituximab will mean responses to
chemotherapy combined with rituximab will be inferior will remain to be determined.
5.2.2 Treatment of symptomatic advanced stage FL
Note that patients with grade 3b FL, using the Mann and Berard grading system,
may have clinical and biological differences from other grades FL and should be
treated as DLBCL (Bosga-Bouwer et al, 2006).
Patients with advanced stage symptomatic FL are treated with the expectation that
the disease will pursue a relapsing and remitting course and may require several
lines of treatment during the course of the disease. For many years standard first
line treatment was alkylator based, frequently in combinations including vinca
alkaloids, corticosteroids and anthracyclines.
Attempts to increase the intensity of chemotherapy by addition of an anthracycline
failed to show a survival advantage. A study by Kimby randomised 259 patients with
untreated, symptomatic low grade NHL between ChP (chlorambucil + prednisolone)
and CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) (Kimby et
al, 1994). The 5 year overall survival was equivalent in the two arms (54% vs. 59%).
Peterson, randomised 228 patients with previously untreated FL to receive either
daily oral cyclophosphamide or CHOP-bleomycin; no significant differences in either
complete response (CR) (66% vs. 60%), 10 year time to treatment failure (TTF)
(25% vs. 33%) or overall survival (OS) (44% vs. 46%) were seen (Peterson et al,
22
2003). Any improvement in response with anthracycline-containing combinations
must be balanced against the inevitable increase in toxicity and the preclusion of
anthracycline as a therapeutic agent in the event of subsequent transformation to
high grade disease.
The purine analogue fludarabine has activity in follicular lymphoma as first line
treatment used as both a single agent and in combination (Velasquez et al, 2003).
No trial identified a survival advantage over single agent alkylator therapy: in a
prospective randomised trial fludarabine was compared to cyclophosphamide,
vincristine and prednisolone (CVP) in 381 previously untreated patients with follicular
lymphoma. Although higher responses were observed in the fludarabine arm this did
not translate into an improved progression-free or overall survival (Hagenbeek et al,
2006). In the immediate pre-rituximab era fludarabine containing combinations
demonstrated high complete remission rates (79%) and PFS rates of 52% at 5
years in younger patients falling to 29% in the over 60s (Tsimberidou et al, 2002).
The first-line use of fludarabine may, however, have a detrimental effect on
mobilising haematopoietic stem cells for autologous transplantation. Its use also
carries an increased risk of opportunistic infection and it may be associated with an
increased risk of secondary AML/MDS. Finally, patients receiving nucleoside
analogues require irradiated blood products to avoid the risk of transfusionassociated graft versus host disease.
IFN has also been studied in FL; (Solal-Celigny et al, 1993). In the French pivotal
trial 242 patients were randomised between cyclophosphamide, doxorubicin,
teniposide (vm 26) and prednisone (CHVP) or CHVP followed by interferon
maintenance (CHVPI). The 123 who received interferon had a PFS of 34 compared
to 19 months . Consequently CHVP-I was used as the control arm in the later study
that compared CHVP-I to CHVP-I with the addition of rituximab ( see below ).
Ten trials examined the role of IFN either as an adjunct to induction therapy or as
maintenance. In a meta-analysis (Rohatiner et al, 2005) a modest improvement in
overall survival and remission duration were seen.
Five phase III trials have now confirmed the efficacy of rituximab in combination with
an alkylator-containing regimen both with and without the inclusion of anthracycline
(table 4).
23
There is a suggestion in these studies that the duration of response in patients
treated with anthracycline-based therapies might be superior to that obtained with
less intensive regimens utilising alkylators. This has led to the widespread adoption
of R-CHOP as a standard regimen as first line therapy for follicular lymphoma but
recent data (Rummel et al, 2009) add to the uncertainty as to the benefits of
incorporating anthracyclines into first line therapy. In this study of 513 patients with
symptomatic low grade lymphoma, half of whom had FL, were randomized to either
2 doses of bendamustine (see below) and 1 dose of rituximab (BR) every 28 days, or
to the standard R-CHOP regimen every 21 days, for a maximum of 6 cycles. BR
patients had a PFS of 54.8 months, compared to 34.8 months with R-CHOP
The survival benefit of combined immunochemotherapy as first line treatment of FL
has been confirmed by a Cochrane meta-analysis (Shulz et al, 2007). This combined
survival data from the above randomised trials. This analysis favoured
immunochemotherapy with a hazard ratio of 0.57 (95% CI: 0.43 – 0.77)
Note that due to the paucity of reports of primary or secondary involvement of the
CNS by FL, CNS chemoprophylaxis is not recommended at first presentation or in
the setting of disease relapse. Patients who have histological transformation of FL
(see section 7.0) may require CNS chemoprophylaxis, according to
recommendations for the histological subtype.
24
Table 4 First-Line Treatment: Immunochemotherapy Phase III trials
FLIPI
Regimen
Phase
Pts
ORR
Duration
Reference
R-CHOP
III
428
96%
TTF: (2y85%)
Hiddeman,
(LR/IR/HR)
14/41/45
Blood „04
-/42/46
R-CHOP
III
540
91.3%
R-Benda
7/37/56
R-MCP-
PFS: 46.7m (FL) Rummel,
PFS: n.r.
III
201
92%
PFS:n.r.(4y71%) Herold,
>IFN
19/41/40
R-CVP
ASH „09
JCO „07
III
331
81%
TTP:34mo
Marcus,
Blood „05
19/35/46
RCHVP+IFN
III
358
85%
PFS: n.r.(5y
Salles, Blood
53%)
„08
n.r., not reached; PFS, progression-free survival; TTF, time to failure; TTP, time to
progression; LR/IR/HR, low risk, intermediate risk, high risk.
5.2.3 Rituximab maintenance following first line chemo-immunotherapy.
Maintenance therapy with rituximab is aimed at preventing the re-establishment of
malignant cells thereby prolonging the time until relapse, improving survival and
maximizing the patient‟s quality of life (Ardeshna, 2007).
There is evidence from randomised studies that rituximab maintenance significantly
prolongs median event-free survival (EFS) in previously untreated patients who
respond to single agent rituximab induction (36 months vs 19months p=0.009)
(Ghielmini et al, 2004) and significantly improves PFS and OS in patients who
respond to CVP chemotherapy without rituximab (4 yr PFS 56% vs 33%
p=0.0000003; 4 yr OS 88%vs 72% p=0.03) (Hochster et al, 2005). The current
standard induction therapy is chemotherapy combined with rituximab. The PRIMA
study randomised patients with high tumour burden FL who achieved at least a
25
partial response (PR) to R-chemotherapy (R-CVP, R-CHOP or R-FCM) to either
observation or rituximab maintenance 375mg/m2 every 2 months for 2 years. With a
median follow up of 3 years the PFS in those responding to induction was 75% in the
rituximab maintenance group and 58% in the observation group (p<0.0001). The
time to initiation of next anti lymphoma therapy was also significantly longer in the
maintenance arm. There was an increase in grade 2-4 infections in the maintenance
group (39% vs 24% p<0.0001). These were mainly bronchitis, upper respiratory tract
infections, sinusitis, urinary tract infections and nasopharyngitis, Grade 3-4
infections were 4% in the maintenance arm and 1% in the observation arm. There
was no difference in quality of life between the two arms nor was there a difference
in overall survival with 95% of patients alive at 3 years. NICE (the National Institute
of Clinical Excellence) has recently approved rituximab maintenance as an option for
patients responding to induction therapy in the newly diagnosed setting (TA226).
5.2.4 Autologous stem cell transplantation (ASCT) and newly diagnosed FL.
(Please see section 8.0 for a summary of the evidence)
5.2.5 Radioimmunotherapy (RIT) in the newly diagnosed FL patient
A phase II trial has examined the role of
131
I-tositumomab in the treatment of
previously untreated FL (Kaminski et al, 2005). 76 patients with stage III/IV FL
received a single one week course of 131I-tositumomab. Overall response rate (ORR)
was 95% and CR was 75%. Molecular responses were seen in 80% of patients
achieving a complete response. At a median follow-up of 5.1 years the PFS was
59% and median PFS was 6.1 years. Patients tolerated the treatment without
problems and no case of therapy related-myelodysplastic syndrome (MDS) was
seen. Whilst the ORR and PFS quoted are extremely impressive the study included
patients with a very favourable profile; the median age was 49 years and less than
50% of patients had bulky disease. The SWOG studied the use of
131
I-tositumomab
as consolidation after CHOP chemotherapy in 90 previously untreated patients with
FL (Press et al, 2003). Treatment was well tolerated and myelosuppression was
more severe with chemotherapy than the RIT. The ORR was 90% including 67%
26
complete response. 57% of patients who failed to achieve a CR with CHOP
converted to CR after RIT. The two year PFS was estimated to be 81%.
A prospective phase III randomized trial demonstrated that Y90 – ibrutumomab RIT
after standard chemotherapy induction prolongs PFS (Morschhausser et al, 2008)
The trial compared a single treatment with RIT to observation in 414 patients with
advanced (stage 3 or 4) follicular lymphoma who had achieved partial or complete
remission after first-line chemotherapy. The choice of which chemotherapy regimen
to use for induction was left to the physicians' discretion, and various combinations
were used, including CVP, CHP, fludarabine, chlorambucil and rituximab. The
primary end point of median progression-free survival was 37 months in the group
receiving Y90 – ibritumomab and 13.5 months in the control group (P < .0001); longer
term overall survival advantages remain unproven. This study predated Rchemotherapy becoming established as the “standard” and as result only a small
minority of patients received rituximab as part of induction therapy. High conversion
rates (77%) from partial to complete response rates were seen in all treatment
groups including the rituximab-containing chemotherapy. There is a concern that Y90
– ibritumomab consolidation may not confer the same improvement in PFS in
patients who receive rituximab-based induction.
Recommendations:

Observation remains an appropriate approach in patients with
asymptomatic, advanced stage follicular lymphoma in an attempt to
delay the need for chemotherapy (1B).

Rituximab, in combination with chemotherapy, should be used in
patients with newly diagnosed, symptomatic advanced stage FL who
require therapy (1A). There is no strong evidence to support one
regimen over another (1B).

Rituximab maintenance after successful induction therapy prolongs PFS
and is recommended in patients responding to first-line rituximab based
chemotherapy (1B).

Autologous stem cell transplantation has no role in first line therapy for
follicular lymphoma outside a clinical trial (1B).
27

There is no conclusive evidence that radio-immunotherapy prolongs OS
in patients and insufficient data to routinely recommend RIT after
receiving rituximab based induction therapy (2C).
6
MANAGEMENT OF RELAPSED FOLLICULAR LYMPHOMA
6.1 Aims of therapy
Although chemotherapy in combination with rituximab has improved outcomes in the
newly diagnosed setting, patients with FL almost always relapse and require a
succession of therapies over many years Hiddemann et al, 2005; Herold et al, 2007;
Marcus et al, 2008). Modalities of therapy for patients with relapsed disease have
altered significantly in recent years and are likely to change further with controlled
trial data on newer agents becoming available.
The overall aim of therapy is similar to that at diagnosis - to optimise overall survival
while at the same time preserving health-related quality of life. In the relapsed setting
the cumulative effects of previous therapies are particularly relevant.
6.2 Patient assessment
Before commencing therapy in patients with symptoms or signs consistent with
relapsed FL it is strongly recommended that a repeat biopsy and histopathological
reassessment be carried out, wherever practicable. This is because of the risk of
histological transformation of FL to a more aggressive lymphoma subtype and the
adverse prognostic implications of this event (Bastion et al, 1997; Montoto et al,
2007; Al Tourah et al, 2008). If histological transformation has been excluded
decisions regarding therapy will depend on a combination of the following factors:
1. The indications for therapy - there is no evidence that intervention will
improve outcomes for patients with relapsed but asymptomatic FL. For
example, recurrent asymptomatic nodal disease detected on routine
clinical examination should not necessarily result in re-treatment
2. Patient fitness for therapy
3. Previous treatments received and the duration of response to these.
28
6.3 Chemo-immunotherapy
Those patients with relapsed, symptomatic FL who are rituximab naive should
always receive rituximab, in combination with chemotherapy, as the combination
improves all meaningful outcomes in relapsed FL, compared with chemotherapy
alone, including OS (Forstpointner et al, 2006; Van Oers et al, 2006; Shulz et al,
2007). The optimal chemotherapy regimen at the point of relapse has not been
determined; options include alkylating agents with or without anthracyclines and
nucleoside analogues. The decision to use an anthracycline combination should be
based on patient characteristics such as cardiac function and the response duration
of previous therapies. For example, patients who have relapsed late following single
agent alkylator based treatment administered in the pre-rituximab era may be treated
with an alkylator-rituximab based combination (e.g. cyclophosphamide, vincristine,
prednisolone, rituximab).This is based on the competitive response rates seen with
this regimen in previously untreated patients and the concern about potential cardiotoxicity of anthracycline use and its preclusion from further use due to accumulated
dose exposure later in the course of the disease or in disease transformation.
In those patients who are resistant to or who have relapsed early following
anthracycline-based chemotherapy or who have contra-indications to their use,
alternate agents should be considered. Nucleoside analogues are active in FL
patients who have been heavily pre-treated (Bosch, 1997). Fludarabine-based
chemotherapy regimens and rituximab produce high response rates and prolong
PFS in patients who are refractory to previous therapies. Forstpointner and
colleagues randomised 65 patients who had failed to respond to previous
chemotherapy (but who were rituximab naïve), including autologous stem cell
transplantation (ASCT), to receive fludarabine, cyclophosphamide and mitoxantrone
with or without rituximab (R-FCM v FCM) (Forstpointner et al, 2004). The ORR was
94% in the R-FCM group with a CR rate of 40% and the median PFS was not
reached after 3 years of follow-up. Grade 3 or 4 infections were seen in less than 2%
of R-FCM treated patients; there was no long term follow-up reported in this study
that might inform on the risk of secondary myelodysplasia.
Many patients with relapsed FL will have had rituximab containing chemotherapy
previously. Re-treatment of patients with rituximab is effective in patients who have
29
experienced disease progression and has acceptable side-effects (Davis, et al,
2000; Coiffier, et al, 2002; Hainsworth, et al, 2005).
Although rituximab has been used as monotherapy in the relapsed setting
(McClaughlin et al, 1998) the response rates and PFS are markedly improved with
the addition of chemotherapy. It is therefore recommended that patients who require
therapy be treated with the combination of immunotherapy and chemotherapy. For
those patients who are intolerant of chemotherapy, due to co-morbidities or other
reasons, rituximab monotherapy can be considered.
6.4 Radio-immunotherapy
Most of the data for RIT in the setting of relapsed FL is derived from Phase II studies
in patients treated after 2 or more relapses. There are no randomised trials
demonstrating the efficacy of RIT compared to R-chemotherapy regimens. Two
radioimmunoconjugates, namely 131I-tositumomab and 90Y Ibritumomab have been
used in relapsed FL. However, only 90Y-ibritumomab tiuxetan RIT is approved for
treatment within the European Union and it is the only drug that can be prescribed in
the UK.
90
Y-Ibritumomab has demonstrated clinical activity in heavily pre-treated
populations, including disease refractory to both chemotherapy and rituximab (Witzig
et al, 2002a, Witzig et al, 2003) leading to durable responses for some patients
(Gordon et al, 2004). Around 70 % of patients who have previously failed 2 lines of
therapy or one course of anthracycline-containing chemotherapy who achieve a CR
following RIT remain in remission for more than 3 years (Gordon et al, 2004; Witzig,
2003). This patient cohort had not received rituximab previously. An analysis of longterm responders, defined as patients who had a PFS of more than 12 months,
demonstrated that 90Y-ibritumomab tiuxetan achieved durable remissions with a
median duration of response approaching 2 years and responses lasting over 6
years in some patients. Higher response rates and longer duration of responses
were observed when RIT was used earlier in the therapy schedule (Gordon et al,
2004). The only clinical parameter found to correlate to clinical response in RIT is
the maximum dimension of the largest tumour. Patients with tumours with a
maximum dimension of < 5 cm had an ORR 90% (p<0.001), whereas bulky tumours
were less likely to respond (Witzig et al, 2003).
30
90
Y-Ibritumomab RIT appears to be safe with manageable and predictable
myelotoxicity (Witzig et al, 2003). With more than 10 years of follow-up data there
does not appear to be a significant increase in late AML / MDS, although there is a
suggestion that this might be increased after previous exposure to fludarabine to
around 3.8% (Czuczman et al, 2007). The high response rates achieved with
minimal interruption to patient‟s lives and associated high quality of life for patients
receiving the therapy make RIT an attractive treatment option for patients with
relapsed FL especially those who are refractory to rituximab or chemotherapy and
for those who are intolerant or unwilling to have further chemotherapy.
6.5 Novel agents
Bendamustine is a DNA alkylating agent with novel properties that has been studied
in FL patients who are rituximab refractory (Friedberg et al, 2008). Phase II trials of
bendamustine in combination with rituximab in relapsed FL have reported ORRs of
92% and a median PFS of 23 months (Robinson et al, 2008). A recent multi-centre
single arm study treated 62 patients with rituximab-refractory FL (Kahl et al, 2010).
Patients had between 1 and 3 previous therapies including CVP-R (38%), CHOP-R
(37%), purine analogue-based chemotherapy with rituximab (44%) and
radioimmunotherapy (24%). Twenty nine percent of patients had a high risk FLIPI.
The ORR was 74% with a 15% CRR. The median PFS was 9.3 months. Grade 3 or
4 haematological toxicity was common; neutropenia was seen in 61% and
thrombocytopenia in 25 %. The most common non-haematological toxicity was
gastro-intestinal. There were seven toxicity-related deaths, many of which were
attributable to myelosuppression. There was one case of MDS detected in a patient
more than a year following therapy - this patient had also received fludarabine and
mitoxantrone previously. Randomised studies of bendamustine and rituximab with
or without other novel agents, in comparison with conventional alkylator and
anthracycline-based-therapies are ongoing and may further inform decision making.
A range of BCL2 small molecule inhibitors, novel monoclonal antibodies and
immunomodulators are being assessed in clinical trials. These therapies are the
consequence of a better understanding of the biology of FL and may herald an era
where additional therapies extend the duration of remission without adding further
toxicity.
31
6.6 Maintenance therapy in relapsed FL
Two randomised studies of rituximab maintenance following standard rituximab
induction in previously treated patients who were rituximab naïve have been reported
and both show a PFS/ EFS benefit in the maintenance arm. (Ghielmini, et al, 2004;
Hainsworth, et al, 2005). Of more relevance are the two randomised studies which
demonstrate the benefit of rituximab maintenance following re-induction with
chemotherapy combined with rituximab (van Oers, et al, 2006; Forstpointner, et al,
2006).
In the EORTC 20981 Intergroup study, 465 rituximab naive patients with
relapsed/refractory FL were reported (van Oers, et al 2006). The study design
involved 2 randomisations. Patients were initially randomised to receive CHOP or RCHOP induction chemotherapy. Response was assessed after 3 courses; patients
with progressive disease (PD) or stable disease (SD) went off study and responders
went on to receive a further 3 courses of induction therapy. A second randomisation
took place at completion of induction therapy between observation and maintenance
rituximab (administered once every 3 months for a maximum of 2 years). The
primary endpoint of the first randomisation was response whilst that of the second
randomisation was PFS.
The ORR was significantly better in the group that received R-CHOP induction
(85.1% vs 72.3%, P<0.0001), as was the CR rate (29.5% vs 15.6%, P<0.0001); PR
rates were similar (55.6% vs 56.7%). With a median follow up of 39.4 months from
first randomisation there was a significant increase in median PFS in the R-CHOP
group (33.1 vs 20.2 months, P=0.003) without a significant increase in OS at 3 years
(82.5% vs 71.9%, P=0.096). 334 patients were randomised to receive maintenance
rituximab or observation. With a median follow up from second randomisation of 33.3
months, the median PFS was significantly greater in the rituximab maintenance
group (51.5 vs 14.9 months, P<0.0001), equating to a gain of 3 years in PFS. A gain
in PFS of approximately 2.5 years was present whether patients received CHOP
induction (42.2 vs 11.6 months, P<0.0001) or R-CHOP induction (51.8 vs 23 months,
P=0.0043), indicating that the anti-lymphoma effect of rituximab is not exhausted
during induction. Importantly rituximab maintenance was also found to confer a
32
significant overall survival benefit at 3 years when compared to observation, with the
risk of dying being reduced by one-third (85.1% vs 77.1%, P=0.0111). No breakdown
of OS benefit conferred by rituximab maintenance according to induction regimen
was given as the study was not powered to determine this.
Maintenance rituximab resulted in a non-significant increase in grade 3 and 4
neutropenia (10.8% vs 5.4%) which probably accounted for the significant increase
in grade 3 and 4 infections (mainly ear, nose and throat infections) in this group (9%
vs 2.4%, P=0.009). Six of 167 patients withdrew from the maintenance arm because
of toxicity, 4 due to infection.
It thus appears that in patients with relapsed and refractory FL, maintenance
rituximab improves median PFS more than 3-fold when compared with observation.
This is achieved with minimal increase in toxicity. Even when rituximab maintenance
follows R-CHOP induction the median PFS is more than doubled. In addition a
significant overall survival benefit to rituximab maintenance is seen at 3 years.
There is currently no evidence from randomised studies that clearly demonstrates
the benefit of rituximab maintenance in patients with relapsed/refractory FL who
have been exposed to prior rituximab. NICE guidance however recommends the use
of rituximab as maintenance treatment in this situation as well as in patients who
were previously rituximab naïve.
Many different schedules of rituximab maintenance have been used. It is not clear
which schedule is optimal. Gordon et al treated patients with rituximab 375 mg/m2
weekly for 4 weeks (Gordan, et al, 2005). Further rituximab was administered only
when the plasma concentration fell below 25μg/ml (a level which correlated with
response in a previous study). The median time to the next infusion to achieve this
was 2-5 months, with 50% of patients achieving this level with a dosing interval of 3
months and almost all with a dosing interval of 2 months. This suggests that 2-3
monthly dosing is probably optimal.
The duration of maintenance is also uncertain. Further rituximab benefit has been
noticed even after 2 years. However it is worth bearing in mind that in patients with
low tumour burden who received rituximab 375mg/m2 weekly for 4 weeks, 24% of
responders maintained their response at 5 years and 15% at 7 years without any
further therapy. Of course, the longer the maintenance period the greater the
33
financial cost and the greater the possibility that continued B-cell depletion will result
in significant adverse effects.
Unfortunately none of the randomised studies of maintenance rituximab have
measured patient-related quality of life. It is generally assumed that a patient has a
better quality of life if periods of remission are prolonged. However, for some patients
repeated visits to receive therapy when they are otherwise well can be a constant
reminder of their disease and actually have a significant negative impact on their
quality of life. If rituximab is given every two or three months the infusion can be
given on the same day as a scheduled follow up visit thus minimising the disruption
to the patient‟s life.
Recommendations:

Patients who are being reassessed with features of relapsed FL should
undergo a biopsy procedure, wherever practicable (1B).

The combination of chemotherapy with rituximab should become the
standard for those patients who require treatment at the point of relapse
and are rituximab naïve as the combination improves all clinically
meaningful outcomes, including overall survival, compared to
chemotherapy alone (1A).

Chemotherapy and rituximab should also be the standard for relapsed
FL patients who have received prior rituximab if the patient had
previously responded to rituximab (1C).

The choice of chemotherapy will depend on characteristics of the
patient. Both anthracycline and nucleoside analogue based therapies
are active in patients with relapsed and refractory disease (1A).

Rituximab maintenance prolongs PFS substantially in patients with
relapsed/refractory FL who are rituximab-naïve and respond (partial or
complete response) to re-induction therapy with single agent rituximab,
chemotherapy or chemotherapy and rituximab (1A).
34

90
Y-Ibritumomab tiuxetan is an active treatment approach in patients
with relapsed FL and should be considered in older patients and those
that are refractory or intolerant to chemotherapy and rituximab (2B).

The benefits of high dose therapy with ASCT in relapsed FL need to be
balanced against the long term risks of the procedure and considered in
the setting of emerging therapies (1B;see section 8.0).

Patients with localised, symptomatic disease should be considered for
palliative radiotherapy, delivering doses of 4 Gy to 24 Gy (1B; see
section 5.1.1).
7
MANAGEMENT OF PATIENTS WITH TRANSFORMED FL (TFL)
Histological transformation (HT) into an aggressive lymphoma is a frequent event in
the natural history and clinical course of patients with FL (Montoto et al, 2007b; AlTourah et al, 2008). In general, patients with transformed FL (tFL) have adverse
clinical features (i.e. poor performance status, high LDH, low haemoglobin level,
high-risk according to both the IPI and the FLIPI), but the relationship between poor
clinical characteristics and HT is not absolute, making a tissue biopsy mandatory to
diagnose HT. Furthermore, FL occasionally transforms to Burkitt or to lymphoblastic
lymphoma which require different treatment protocols. A recent study has
demonstrated that the prognosis of patients with adverse clinical characteristics at
relapse suggestive of HT (a sudden increase in the LDH level, rapid discordant nodal
growth, new extra-nodal sites of disease or hypercalcaemia) but without histological
confirmation is as poor as that in patients with biopsy-confirmed HT and, if obtaining
a tissue biopsy is not feasible, these patients should be treated as patients with tFL
(Al-Tourah et al, 2008).
The outcome following HT is dismal with a median survival from transformation of
around 1 year (Montoto et al, 2007b; Al-Tourah et al, 2008). Data regarding the
optimal treatment for patients with HT are scarce, as these patients are frequently
excluded both from FL and DLBCL trials. Patients with tFL are generally managed
with anthracycline-containing regimens, if they have not received them early in the
35
course of the disease, or with chemotherapy regimens used as salvage therapy in
relapsed DLBCL such as ICE, ESHAP or DHAP, co-administered with rituximab.
In patients achieving a response after salvage treatment, this is frequently followed
by consolidation with high-dose treatment (HDT) and autologous stem cell rescue.
Some studies demonstrate that the outcome of patients with tFL who receive such
treatment is similar to that of patients who have HDT with autologous stem cell
rescue for either FL or DLBCL (Williams et al, 2001; Foran et al, 1998). Whether this
proves the benefit of HDT in tFL or it is only a consequence of the selection of
patients that actually get HDT (i.e. those with a good response to salvage treatment)
remains to be seen. Nonetheless, it has to be taken into account when considering
the outcome after transformation that most of the studies include patients treated in
the pre-rituximab era. In this regard, a study by the Stanford University presented in
abstract form but not yet published (Tan et al, 2008), suggested that the outcome of
patients after transformation has considerably improved in more recent eras, with a
median OS of 3.3 years. In that series, patients who had not received any treatment
before presenting HT had a significantly better outcome than those previously
treated, which has also been reported in other studies (Yuen et al, 1995). The other
important variable that predicts outcome after transformation is the stage at the time
of HT, so that patients with localised disease (i.e. the transformed component is of
limited stage, according to the Ann Arbor classification, after full staging
investigations) have a prolonged survival (Gine et al, 2006; Al-Tourah et al, 2008;
Yuen et al, 1995) supporting a less intensive treatment (i.e. avoiding HDT) in this
population, as well as in those untreated at the time of HT.
Recommendations:

Rituximab-naïve patients with HT of FL should receive rituximabchemotherapy as treatment of the HT (1B).

FL patients with HT who have previously been exposed to rituximab
should receive rituximab chemotherapy as treatment of the HT (1C).

Anthracycline-naïve patients should receive a doxorubicin-containing
regimen; otherwise, a second-line therapy of the type used for DLBCL is
recommended (1B).
36

HDT with autologous stem cell rescue should be considered in younger
and fit patients responding to salvage therapy for HT ( 2B).

Chemotherapy-naïve patients at the time of HT and those with
localised/limited stage disease may have better outcomes and may not
require intensification with HDT (2B).
8
THE ROLE OF AUTOLOGOUS AND ALLOGENEIC TRANSPLANT IN FL
Three randomised studies have compared HDT (all with cyclophosphamide-total
body irradiation as the conditioning regimen) and autologous stem cell rescue with
conventional chemotherapy as first-line therapy of FL (Lenz et al, 2004; Deconinck et
al, 2005; Sebban et al, 2006). No differences in OS are detected in any of the
studies, but two of them (Lenz et al, 2004; Deconinck et al, 2005) show a significant
improvement in PFS for patients receiving HDT. However, the long-term toxicity with
an increased risk of secondary malignancies is considerable and, as a result, HDT
with autologous stem cell rescue is not recommended for FL as first-line therapy
outside the setting of a clinical trial.
In contrast, HDT is considered amongst the standard options for patients with
relapsed FL. Several studies in the pre-rituximab era have demonstrated an
improvement in the outcome of patients treated with HDT in comparison with
historical controls treated with conventional chemotherapy (Brice et al, 2000;
Apostolidis et al, 2000). This has been confirmed in a randomised study,
demonstrating an advantage in terms of OS and PFS for patients with relapsed FL
who receive HDT over those treated with conventional chemotherapy (Schouten et
al, 2003). Three recent studies with a long follow-up show a plateau in the PFS
curve, with around one third of patients being alive without disease 10 years after
treatment (Montoto et al, 2007a; Kornacker et al, 2009; Rohatiner et al, 2007). It is
likely that HDT remains an effective procedure in the rituximab era; a cohort of
relapsed FL patients receiving in vivo rituximab purging and rituximab maintenance
reported an overall survival of 80 % at 8 years (Pettengell, et al, 2010). The main
discrepancy lies in the appropriate timing for this strategy. The toxicity supports
reserving HDT for late in the course of the disease. As discussed above, the
introduction of maintenance rituximab prolonging PFS in patients with relapsed FL
37
also favours delaying the use of HDT (van Oers et al, 2006). On the other hand, the
prognosis after HDT correlates with the number of lines of treatment before
transplant. In addition, the risk of secondary MDS/AML seems to be associated with
the use of total-body irradiation in the conditioning regimen (Montoto et al, 2007a)
and with the number of previous relapses (Rohatiner et al, 2007). High risk features
at relapse may also help in identifying patients with a poor prognosis as candidates
for an intensive treatment early in the course of the disease (Montoto et al, 2004).
Historical studies show that myeloablative allogeneic stem cell transplantation is a
curative treatment but has a high associated mortality. The advent of reducedintensity conditioning (RIC) regimens has broadened the use of allogeneic transplant
in FL by reducing its toxicity. Thus, RIC-allotransplants are considered a suitable
clinical option for relapsed FL in specific circumstances (Ljungman et al, 2006). Most
of the published series report a consistent relapse rate of around 20% at 3 years
and a 3-year transplant-related mortality ranging from 30 to 40%, resulting in a 3year OS and PFS of 50-65% and 43-55%, respectively (Table 5) (Robinson et al,
2007; Morris et al, 2004; Vigouroux et al, 2007; Rezvani et al, 2008; Hari et al, 2008;
Ingram et al, 2008; Khouri et al, 2008; Thomson et al, 2010). Recently, excellent
results have been published following RIC-allotransplants with T-cell depletion with
alemtuzumab (Thomson et al, 2010).
The heterogeneity in the outcomes reported account for differences in the
populations treated and in the characteristics of the procedures in different studies.
The comparison of RIC allogeneic stem cell transplantation with HDT with
autologous stem cell rescue is hampered by the fact that these two procedures are
normally performed in very different populations; in the absence of the results of any
prospective RCTs and given their toxicity, RIC-allotransplants are frequently
performed in patients who relapse after HDT with autologous stem cell support
(Khouri et al, 2008). However, some studies suggest that having failed a previous
autologous transplant increases the mortality of the procedure (Rezvani et al, 2008).
Chemo-refractory disease appears consistently in most of series as an adverse
prognostic factor (Robinson et al, 2007; Morris et al, 2004; Vigouroux et al, 2007;
Rezvani et al, 2008; Hari et al, 2008; Ingram et al, 2008).
There are no definitive trial results supporting either autologous or allogeneic
transplant and the decision regarding timing and donor source varies from centre to
38
centre based on expert opinion, local experience and retrospective registry data.
Consideration should be given to high dose therapy with autologous stem cell
support or RIC allogeneic transplantation in selected patients in second or later
remission. The decision should be based on previous remission duration, patient
fitness, FLIPI index at relapse and choice of donor. If the first remission is less than 2
years it is reasonable to proceed to transplant in second remission. If the first
remission is over 5 years then further immunochemotherapy is a reasonable option.
If first remission is between 2 and 5 years therapeutic options include autologous
transplant, especially if the patient has received rituximab maintenance in first
remission, or RIC allogeneic transplantation if a sibling or fully matched unrelated
donor is available in patients under 60.
Recommendations:

Autologous stem cell transplantation has no role in first line therapy for
follicular lymphoma outside the setting of a clinical trial (1B).

The benefits of HDT with ASCT in relapsed FL need to be balanced
against the long term risks of the procedure and considered in the
setting of emerging therapies (1B).

The patients suitable for transplantation with shorter durations of
response following first line therapy should be considered for early
referral (2C).

RIC-allogeneic transplants should be considered for younger FL
patients with early relapse (1B).
39
Table 5: Outcomes after RIC-allotransplant for FL
Series
3-yr TRM
3-yr RR
3-yr OS
3-yr EFS/PFS
Robinson, 2002*
31%
20%
65%
54%
Morris, 2004
11%
44%
73%
65/49%
Vigourox, 2007
40%
10%
56%
51%
Rezvani, 2007
42%
14%
52%
43%
Khouri, 2008
NR
NR
85%
83%
Hari, 2008
28%
17%
62%
55%
Ingram, 2008
20%
20%
69%
58%
Thomson, 2010**
15%
26%
76%
76%#
TRM: transplant-related mortality; RR: relapse risk; OS: overall survival; EFS: eventfree survival; PFS: progression-free survival; * at 2 years; ** at 4 years; #current PFS.
9
FOLLOW-UP AND MONITORING OF PATIENTS WITH FL
9.1 Use of Imaging to Evaluate Response at the Completion of Treatment
CT is currently the standard imaging tool for assessing treatment response. The
role of FDG PET-CT in determining response at the conclusion of treatment in FL is
unclear and not routinely recommended (Juweid et al, 2007). A recent study in
immunochemotherapy treated patients, presented in abstract form, suggested that a
post-treatment FDG PET-CT is a powerful predictor of PFS (Trotman et al, 2010).
Although there was no central review of scans carried out in this analysis, the results
invite further studies of the utility of functional imaging and assessment of whether
this modality can be used to guide therapy in FL based on response quality.
9.2 Follow-up of patients undergoing watchful waiting
There is no agreed follow-up strategy for patients undergoing watchful waiting; follow
up is aimed at detecting the development of symptoms or significant disease
progression. A follow up appointment 4-6 weeks after initial diagnosis is suggested
40
to assess the rate of disease progression. If after several visits there has been no
change, the intervals between appointments can be lengthened.
Clinics should be operated to allow patients to be seen at short notice if there is a
change in their condition. At each visit an enquiry about symptoms should be made
as well as a physical examination being done. Results of full blood count, renal, liver
and bone tests should be available. Any concern may warrant a repeat CT scan or
other imaging as appropriate. Standard indications for considering therapy are
described in section 5.2.1. A rising LDH is not in itself an indication to initiate therapy
but may trigger further investigations. What is most difficult to define is what degree
of lymph node enlargement would warrant the initiation of therapy if the patient
remains asymptomatic. Clearly the rate of nodal growth will be important. For the
purpose of clinical trials a lymphoma mass >7 cm is suggested as a threshold for
therapy, provided it has increased in size by at least 25% or more than 3 sites with
diameter >5 cm, but ultimately the decision will be left to the physician to make in
conjunction with the patient.
9.3 Follow-up of previously treated patients, including surveillance for late
effects of therapy
Due to considerable variability in the rate of progression of FL, there are no set
standard guidelines for routine patient follow-up after therapy. The frequency of
follow up visits and the means used to monitor disease progression should therefore
be tailored to the individual patient‟s disease and expectations, as well as possible
subsequent treatment modalities. It is probably necessary to continue to follow up
all patients indefinitely.
Most patients with progressive disease will die with uncontrolled FL rather than
complications of therapy. Patients receiving chemotherapy regimens or ASCT need
to be monitored for the development of MDS and the effects of cardiotoxic agents.
9.4 Molecular monitoring of FL
It is widely assumed that the depth of remission of FL is related to the duration of
clinical response; this has been demonstrated in several subtypes of both acute and
chronic leukaemia. Similar approaches using either peripheral blood or bone
41
marrow cells have been designed for FL, but their utility may be limited, firstly by the
lymph nodal origin of FL, and secondly by the fact that transformation can occur at
any stage in the disease process. A further complication of using molecular methods
as a marker of the depth of response to therapy is the lack of reproducibility of PCR
reactions between different laboratories. In summary, molecular monitoring of the
BCL2 translocation cannot be currently recommended for routine FL follow-up.
Recommendations for follow up of FL patients:

CT scanning is currently the appropriate method of response
assessment following therapy for FL (1B).

History and clinical examination performed at least 3 monthly for the
first year following therapy and then tailored to an individual patient's
circumstances e.g. 4 to 6 monthly for 4 years and yearly thereafter (2C).

A full blood count, urea and creatinine, LFT and LDH at each clinical
visit (2C).

Thyroid function yearly in patients who have undergone irradiation of
the neck (1B).

Cross-sectional imaging following treatment is instigated only on
suspicion of relapse requiring therapy. There is no role for routine
scanning of patients following therapy (1C).
For patients on watchful waiting the above may be further modified as follows:

History and clinical examination should be performed 3 monthly until
disease progression (2C).

Full blood count, urea and creatinine, liver function tests and LDH
should be taken 3 monthly (2C).

Cross sectional imaging post-treatment is instigated on suspicion of
progression requiring therapy (2C).
42
ACKNOWLEDGEMENTS AND DECLARATIONS OF INTEREST
Kirit Ardheshna‟s work on this guideline was supported by the UCL/ UCLH
Comprehensive Biomedical Research Centre. C McNamara, K Ardeshna, R Marcus
and T Illidge have received travel support and honoraria from Roche. C McNamara
and T Illidge have received remuneration for advisory board work for Roche. S
Montoto has received research support from Genentech. All authors submitted forms
to the Chair of BCSH and the Chair of the Haemato-oncology Task Force listing any
sums received (either directly or funding for research or members of staff) from any
organisation that could in any way gain or lose financially from the recommendations
in this guideline. Having reviewed the submissions none of the authors of the
guideline are considered to have a conflict of interest. Task force membership at the
time of approving this guideline was J Wimperis, F Matthey, J Bird, M Lyttleton, K
Ardeshna, G Jones, A Clark and S Kinsey.
43
Appendix 1: Method of calculation of FLIPI and FLIPI2 indices
Variable
Adverse factors
FLIPI
FLIPI2
Age
> 60 years
> 60 years
Ann Arbor stage
III-IV
-
Haemoglobin level
<120 g/l
<120 g/l
Serum LDH level
> ULN#
-
Number of nodal sites
>4
-
Bone marrow
-
+
B2M
-
> UNL
LoDLIN*
-
> 6 cm
ULN#– upper limit of normal
*LoDLIN: longest diameter of the largest involved node
44
Appendix 2: Strength of recommendations and levels of evidence:
GRADE
GRADE stands for: Grading of Recommendations Assessment, Development and
Evaluation (GRADE). Details of the GRADE system are available at the working
group website: http://www.gradeworkinggroup.org/index.htm.
STRENGTH OF RECOMMENDATION
Strong (grade 1):
Strong recommendations (grade 1) are made when there
is confidence that the benefits do or do not outweigh harm and burden. Grade 1
recommendations can be applied uniformly to most patients. Regard as
'recommend'.
Weak (grade 2): Where the magnitude of benefit or not is less certain a weaker
grade 2 recommendation is made. Grade 2 recommendations require judicious
application to individual patients. Regard as 'suggest'.
QUALITY OF EVIDENCE AND DEFINITIONS
The quality of evidence is graded as high (A), moderate (B) or low (C). To put this in
context it is useful to consider the uncertainty of knowledge and whether further
research could change what we know or our certainty.
(A) High Further research is very unlikely to change confidence in the estimate
of effect. Current evidence derived from randomised clinical trials without
important limitations.
(B) Moderate
Further research may well have an important impact on
confidence in the estimate of effect and may change the estimate. Current
evidence derived from randomised clinical trials with important limitations (e.g.
inconsistent results, imprecision - wide confidence intervals or methodological
flaws - e.g. lack of blinding, large losses to follow up, failure to adhere to intention
to treat analysis), or very strong evidence from observational studies or case
series (e.g. large or very large and consistent estimates of the magnitude of a
treatment effect or demonstration of a dose-response gradient).
(C) Low Further research is likely to have an important impact on confidence in
the estimate of effect and is likely to change the estimate. Current evidence from
observational studies, case series or just opinion.
45
SUGGESTED TOPICS FOR AUDIT
1. What proportion of FL patients have their pathological material
reviewed by a specialist haematopathologist?
2. Rituximab use, in combination with chemotherapy, in previously
untreated FL patients, with firm indications to commence treatment?
3. Rituximab use, in combination with chemotherapy, in relapsed FL
patients with firm indications to commence treatment?
4. Biopsy rate in patients presenting with symptoms and signs suggestive
of relapsed FL?
5. What is the current approach to imaging of FL patients, including
functional studies, and do they concur with recommendations made?
6. What proportion of patients with relapsed FL, who respond to reinduction therapy, progress to receive two years of rituximab
maintenance?
46
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