Follicular Lymphoma [autosaved]

Dr.PRATTUSHA MUKHERJEE
(1st yr resident)
DNB RADIOTHERAPY

HISTORY
 35 years old, male, software professional,
resident of .......... ,presented with a swelling
over the left inguinal region 3-4months back.
 The swelling was painless and gradually
increasing in size
 No h/o fever or weight loss
 No h/o any addiction
 No significant past history
 No family h/o any cancers

He got himself evaluated with the
following investigations:
1. CBC
• Hb- 14.3gm/dl
• TLC- 6190
• Neutrophils- 53%
• Lymphocytes- 37
• Serum LDH- 92.5 U/L
• Serum Albumin- 4.2gm/dl
• Serum Creatinine-1.05mg/dl

2.SEROLOGY
HbsAg – Negative
HIV I,II – Non Reactive
Anti HCV – Non Reactive
3. CT scan of Abdo-pelvis
Multiple small lymph nodes in periaortic,
paracaval,aorotocaval region of retroperitoneum.
Enlarged lymph node in the inguinal region. Multiple
small subcm lymph nodes along the rest of the small
bowel mesentery and in the right iliac fossa.
Mild hepatomegaly

4. WHOLE BODY PET-CT SCAN
Increased FDG uptake in the following regions:
 Right axillary node measuring 1.6x1.2cm
SUVmax-9
Mesenteric lymph nodes, largest measuring
1.9x2.5x5cm SUVmax-7.5
Left inguinal lymph node 3.4x4x4.7cms
SUVmax-4.7

Follicular Lymphoma [autosaved]

5. BIOPSY
Non Hodgkin’s Lymphoma of Follicular type
grade I/II (WHO 2008)
Express CD 20,CD 10, bcl-6 & bcl-2 and are
immunonegative for CD3, CD5 & CD 23
FINAL DIAGNOSIS:NHL of Follicular type

Clinical examination
• Patient was alert,conscious,cooperative and obeying all
commands
• KPS 100%
• Systemic examination:
Chest- clear, breath sounds normal
CVS- S1,S2 audible, no abnormal heart sounds
P/A- soft, no palpable organomegaly
CNS- no neurodeficits
Bladder/bowel- Normal
• Local examination: A scar over the left inguinal region
No palpable lymph nodes

DISCUSSION
• A brief overview of FL
(CLASSIFICATION,PATHOLOGY)
• DIAGNOSTIC WORK-UP
• MANAGEMENT OF EARLY STAGE FL
• MANAGEMENT OF ADVANCED STAGE
FOLLICULAR LYMPHOMAS

It is the second most common lymphoma
diagnosed in the U.S.
20% of all Non Hodgkin’s Lyphomas & 70% of
all indolent Lymphomas
Median age at diagnosis is 60 years
Slight female preponderance
FOLLICULAR LYMPHOMA

PATHOBIOLOGY
Cell of origin – Germinal centre B cells
(centrocytes & centroblasts)
•Follicular Lymphomas recapitulates the architecture of normal germinal
centres of secondary lymphoid follicles.
• The tumor is comprised of variable numbers of small,cleaved
cells(centroytes) and larger,blastoid cells(centroblasts)
• WHO GRADING : Based on no.of large cells/hpf
GRADE I : 0-5 centroblasts/hpf
GRADE II: 6-15 centroblasts/hpf
GRADE III: >15 centroblasts/hpf IIIa (centrocytes predominate)
IIIb (sheets of centroblasts)
(IIIb is an aggressive disease and tends to have a higer relapse rate)

Genetics and Immunophenotype
•BCL-2 is an oncogene that blocks programmed
cell death
•Approximately 85% of FL’s have BCL2
overexpression
•In a vast majority of cases,FL is associated with
translocation between BCL-2 and one of the
three immunoglobulin(Ig) genes.
•Deep sequencing studies have established other
genetic mutations.
Most cases involving MLL-2 protein (mixed
lineage leukemia 2protein)- a gene encoding
histone H3 methylase.
•Other recent studies suggest that
Tumor microenvironment, comprising of
T cells and dendritic cells also contibute to
the development of FL

MOLECULAR MARKERS AND
PROFILING

CLINICAL FEATURES
• Painless peripheral lymphadenopathy with waxing and waning
throughout
• Bone marrow involvement is present in about 70% of the cases
• 20% patients present with B-symptoms(high grade fever,
drenching night sweats, unintentional weightloss)
• Involvement of other non-lymphoid organs is uncommon
• Small subset of patients present with a raised serum LDH
• 10-70% patients show a histologic transformation from FL to
DLBCL.

AJCC 8th edition
LIMITED STAGE DISEASE
STAGE I : Involvement of a SINGLE lymph node region OR
IE: Involvement of a SINGLE EXTRALYPMHATIC site/organ
STAGE II: Involvement of TWO or more lymph node regions on the
SAME SIDE of the diaphragm OR
IIE: Involvement of ONE lymph region and one CONTIGUOUS
EXTRALYMPHATIC organ/site on the SAME side of the diaphragm

ADVANCED STAGE DISEASE
STAGE III : Involvement of lymph node regions on BOTH SIDES of the diaphragm OR
IIIS: Involvement of lymph node regions ABOVE the diaphragm along with
involvement of the SPLEEN
STAGE IV : Diffuse/ disseminated involvement of one or more extralypmhatic
organs/site with/without nodal involvement
OR
NON CONTIGUOUS EXTRALYMPHATIC ORGAN involvement with nodal STAGE II
disease
OR
Any extralymphatic involvement with nodal STAGE III
Involvement of any of these:
•CSF
•BONE MARROW
•LIVER
•LUNGS

ADVERSE FACTORS
 Age > 60yrs
 No.of nodal sites involved >4
 LDH>upper limit of normal
 Ann Arbor Stage III-IV
 Heamoglobin <12gm/dl
No.of Factors Risk Group 5-year OS(%) 10-yr OS(%) Prognosis
0-1 Low 91 71 Good
2 Intermediate 78 51 Moderate
3-5 High 52 36 Poor
Solal-Celigny et al, Blood 2004

Management
• DIAGNOSTIC WORK-UP
1. Pathological evaluation wit a biopsy to confirm the
histology and the grade
2. Lab studies: CBC, LFT, RFT, Serum electrolytes,
Serum LDH
3. Serology
4. Bone marrow biopsy may be performed prior to
initiation of the therapy

6. Echocardiogram should be performed if chemotherapy
is planned and the regimen includes cardiotoxic drugs
7. Men and women of child bearing potential should be
counselled about the effect on their fertility and options
for fertility preserving measures
5. Baseline imaging with a CECT or a WHOLE BODY
PET-CT which will help us determine the areas of
involvement and the extent
Documentation of the precise histology,stage and grade of
the disease, FLIPI score and the performance status should
be done for determining the treatment strategy and
predicting the outcome.

LIMITED STAGE DISEASE
STAGE I,II
STAGE I/II
NON-BULKY,
CONTIGUOUS
DISEASE
BULKY OR
NON-
CONTIGUOUS
IMMUNOTHERAPY+
/-CT
IMMUNOTERAPY+/-
CHEMOTHERAPY +/- RT
IFRT ALONE
OBSERVATION
NCCN 2017 GUIDELINES

First Author
(year) Institution
Number of
Patients Treatment
Freedom from
Relapse (10 y)
Overall
Survival (10 y)
Soubeyran, 1988
Fondation Bergonié,
France 103 RT ± CT 49% 56%
Kelsey, 1994 BNLI 148 RT + CT 42% 42%
RT 33% 52%
Vaughan Hudson,
1994 BNLI 208 RT 47% 64%
Pendlebury, 1995
Royal Marsden
Hospital, London 58 RT 43% 79%
MacManus, 1996 Stanford 177 RT 44% 64%
Wilder, 2001 MDAH 80 RT 41% (15 y) 43% (15 y)
Seymour, 2003 MDAH 83 RT + CT 72% 80%
Petersen, 2004
Princess Margaret
Hospital 460 RT 51% 62%
Guadagnolo, 2006 JCRT, Boston 106 RT ± CT 46% 75%
IFRT +/- Chemotherapy for Stage I & II
follicular lymphomas

STANFORD STUDY
FOLLOW-UP(yrs) OS(%) FFR(%)
5 82 55
10 64 44
15 44 40
20 35 37

Despite the heterogeneity in the patient population and the lack of
uniformity in data reporting, certain conclusions which can be drawn
are:
 5 and 10 yr OS is high with RT (75-90%)
 >90% local control rates can be achieved with IFRT alone
Long median survival of approximately 19years
Field sizes varied widely, however prophylactic coverage of
uninvolved lymph node regions didn't reduce overall risk
Toxicities depend upon the site of disease,radiation field and dose
A dose of 24 Gy @ 2Gy per fraction is the standard
recommendation. A higher dose upto 30Gy can be considered for
bulky diseases.

Observation is a reasonable alternative to RT if significant
morbidity is expected from RT based on the location of the tumour
or if patient chooses against it.
Chemoimmunotherapy or immunotherapy with or without RT as
been reserved for patients wit advanced stage disease and also for
limited stage disease when they present with a bulky(>5cm)
disease
In Pre-Rituximab era, systemic therapy dint add any benefit after
local RT
Addition of chemotherapy has improved PFS but has not been
shown to improve OS.

ADVANCED STAGE
DISEASE(III/IV)
• 70-85% patients present with advanced stage
disease .
• They are usually not cured with conventional
treatment. Remissions can be attained but
repeated relapses are common.
Principles of treatment are:
1. Alleviation of the symptoms
2. Reversal of the cytopenias
3. Improvement of the quality of life

INDICATIONS FOR THERAPY
IN ADVANCED STAGE FL
• Cytopenias secondary to bone marrow infiltration
• Threatened end-organ function
• Symptoms attributable to bulky nodal disease
• Bulky at presentation
• Steady progression during > 6 months of observation
• Presentation with concurrent histologic transformation
• Massive splenomegaly
• Presence of B symptoms
• Presence of symptomatic extranodal disease
• Patient preference
• Candidate for clinical trial

CONSIDER
PET-CT SCAN
MANAGEMENT OF ADVANCED
STAGE
STAGE III/IV
NO INDICATIONS
OBSERVE
INDICATIONS
PRESENT
CHEMOIMMUNOTH
ERAPY
PALLIATIVE LOCAL
RT
NCCN 2017 GUIDELINES

ASYMPTOMATIC PATIENTS
Several large randomized trials comparing chemotherapy and
watch and wait strategy followed by chemo at the time of
progression as been done.
Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic,
non-bulky follicular lymphoma: an open-label randomised phase 3 trial
Ardeshna, Kirit M et al.
An International phase III trial, recruited 379 patients wit advanced stage follicular
lymphoma, asymptomatic, non-bulky FL and divided into three groups: i) Watchful waiting
ii)Rituximab induction (375mg/m2 weekly X 4) iii)Rituximab induction followed by
maintenance Rituximab(every 2m for 2yrs)
RESULTS were as follows:
i)Poor accrual resulted in early closure of the Rituximab induction arm
ii)Rituximab therapy was associated with improved ratings on quality of life, decrease in
anxiety.
iii)18 patients developed serious adverse events related to Rituximab
iv)Greater number of watchful wait patients required subsequent interventions
v) There was no significant difference in overall survival or histologic transformation
between the 3 groups
WATCHFUL WAITING CAN BE DONE FOR ADVANCED STAGE
PATIENTS WHO ARE ASYMPTOMATIC WITH WITH A LOW VOLUME
DISEASE. WITHOUT JEOPARDIZING THEIR SURVIVAL.
IT WOULD PROVIDE AVOIDANCE OF COST,COMPLICATIONS AND
DRUG RESISTANCE.
CHEMO-IMMUNOTHERAPY CAN BE RESERVED FOR DISEASE WITH
PROGRESSION

CHEMOTHERAPY BASED TREATMENT
No Advantage of Alternative Chemotherapy over CHOP
Freedom from
Treatment Failure
Overall Survival

IMMUNOTHERAPY
• Lack of evidence that the natural history of FL
is greatly altered by chemotherapy stimulated
search for newer agents.
• RITUXIMAB an anti-CD 20 molecule was
the first drug to be used in the treatment of FL.

Several chemo regimens in combination with
RITUXIMAB were studied:
•CVP vs R-CVP[1]
•CHOP vs R-CHOP[2]
•MCP vs R-MCP[3]
All of them showed an improvement in OS when Rituximab
was added to a combination chemo regimen
1. Marcus R, et al. J Clin Oncol. 2008;26:4579-4586.
2. Hiddemann W, et al. Blood. 2005;106:3725-3732.
3. Herold M, et al. J Clin Oncol. 2007;25:1986-1992
DFS(%) PFS(5yrs)(%) OS(%)
CHOP 55 30 45
R-CHOP 66 54 58

STiL TRIAL( Study group indolent lympoma)
Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for
patients with indolent and mantle-cell lymphomas: an open-label, multicentre,
randomised, phase 3 non-inferiority trial
Rummel, Mathias J et al.
The Lancet , Volume 381 , Issue 9873 , 1203 – 1210
BRIGT STUDY
Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of
indolent NHL or MCL: the BRIGHT study
Ian W. Flinn et al.
Blood 2014 123:2944-2952; doi: https://doi.org/10.1182/blood-2013-11-531327
•The complete response rate for first-line bendamustine/rituximab was statistically
noninferior to R-CHOP or R-CVP in indolent NHL
•The safety profile of bendamustine/rituximab is distinct from that of R-CHOP/R-
CVP.

SINGLE AGENT RITUXIMAB
• An acceptable initial treatment for patients with co-
morbid conditions that make them poor candidates for
chemotherapy and for those with a low tumor burden and
progressing slowly.
• DOSES:
375mg/m2 IV per week X 4 doses
375mg/m2 IV per week X 4 doses followed by 4
additional doses administered evrery two months
A lot of studies has been done which suggest that single
agent Rituximab is associated with low toxicity and high
response rates.

PRIMA STUDY : Rituximab maintenance for 2 years in
patients with high tumour burden follicular lymphoma
responding to rituximab plus chemotherapy (PRIMA): a
phase 3, randomised controlled trial.
INFERENCE: 2 years of rituximab maintenance therapy
after immunochemotherapy as first-line treatment for
follicular lymphoma significantly improves PFS.
RITUXIMAB MAINTAINANCE

John Francis Seymour et al. Blood 2013;122:509
UPDATED 6YR FOLLOW-UP CONFIRMED THE BENEFIT OF
MAINTENANCE RITUXIMAB

WHAT’S NEW??
The GALLIUM STUDY( OCT,2017)
OBINUTUZUMAB VS RITUXIMAB FOR
ADVANCED STAGE FOLLICULAR
LYMPHOMA
INTERPRETATION: OBINUTUZUMAB
HAD MORE ADVERSE EFFECTS BUT
RESULTED IN SUPERIOR PROGRESSION
FREE SURVIVAL

Other Consolidation Strategies
• Interferon
• Radiolabeled antibodies
• Hematopoietic stem cell transplantation
• Vaccines

SPECIAL THANKS TO:
DR.SHARMILA AGARWAL
DR.NIKHIL KALYANI

Follicular Lymphoma [autosaved]

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