Treatment of low grade lymphoma

1. TREATMENT OF LOW GRADE NON-HODGKIN LYMPHOMA
Presenter- Dr Hardik Sharma
Moderator- Dr Shikha Goyal

2. INTRODUCTION
• Heterogenous group of malignancies of the lymphoid system characterized by an abnormal clonal proliferation of B cells,
T cells or NK cells
• Increase in incidence has been related to environmental factors, including occupational exposures, longevity
• Accounts for up to 3% of all malignancies
• In INDIA,
● B-cell lymphomas (80%–85%)
● T-cell (15%–20%)
● NK cell are rare

3. B & T Cell development & cell of origin of lymphomas

5. ETIOLOGY- Risk factors and diseases associated with NHL

6. NHL: CLASSIFICATION
• Historically
• Gail and Mallory 1940s
• Rappaport 1950s
• Lukos-collins 1970s
• Keil 1970s
• Working 1982
• Real 1994
• WHO 2001,2008, 2016 & 2022
6
Indolent Aggressive Very Aggressive
CLL/SLL PLL Precursor B-
lymphoblastic
lymphoma
Lymphoplasmacytic Plasmacytoma/multipl
e myeloma
Burkitt’s lymphoma
Primary cutaneous
anaplastic cell
lymphoma
MCL Plasma cell leukemia
Splenic marginal zone
lymphoma
Follicle centre, grade
III
MZL-
• Extranodal
(MALT)
• Nodal
DLBCL
Follicle centre
lymphoma, follicular
grade I-II
Primary mediastinal
lymphoma

7. Indolent Aggressive NHL
Proportion 40-50% 50-60%
Growth Slow Fast
Description Often, no symptoms at
diagnosis
Symptoms are likely before
diagnosis & progress is
relatively quick
Treatment Because growth is slow,
treatment is sometimes not
needed immediately
Because growth is fast,
treatment is often needed
straight away
Outcome Responds very well to
treatment, however eventual
relapse is likely. Patients can
live normally for many years
Responds very well to
treatment, more likely to be
cured

8. Low Grade Non-Hodgkin Lymphoma
CLL/SLL
Follicular lymphoma
Grade I-II Marginal cell lymphoma
Hairy cell lymphoma
splenic marginal
zone lymphoma
Lymphoplamscytic
lymphoma
WHO CLASSFICATION- 5th edition haemotolymphoid neoplasms Subtypes distinguish based
on
a) Morphology
b) Phenotype
c) Genetic
d) Clinical behaviour

9. NON-HODGKIN LYMPHOMA- INCIDENCE
Al-Hamadani et al, American journal of oncology

10. FOLLICULAR LYMPHOMA- INTRODUCTION
• Is a heterogenous group derived from germinal center B cells, both centrocytes and Centroblasts
• Second most common subtype of NHL
• Most common type of indolent NHL’s
• Incidence increases with age
• Most frequently presents in middle-aged & elderly
• Median age diagnosis – 65 yrs
• Richter’s transformation in 30% cases
• Extranodal prentation is uncommon

11. PATHOGENESIS
● Variable clinical course
• Incurable with standard therapy;
multiple remission and relapses
• Histological transformation
● t(14;18) (q32;21)- oncogene
bcl-2-(85%) FL
● 80-90%- KMT2D gene
mutation

12. CLINICAL FEATURES
• Most patients presents with painless peripheral adenopathy
• Commonly - waxing and waning course
• Some present with relatively large abdominal masses, with or without evidence of GIT/GU obstruction
• 20% of the patients presents with B symptoms
• Pediatric-type FL- rare with characteristics
a) Low stage disease (stage I/II)
b) Frequent involvement of the head & neck region
c) Predominance of grade 3 histology
d) Absence of BCL2 gene rearrangements & infrequent BCL2 protein expression
e) Presence of activating mutations involving MAP2K1 & mutation affecting TNFRSF14
f) High rate of apparent cure

13. PATHOLOGY
• On histology,
• Growth pattern
• Cell morphology
a) Centrocytes- cleaved follicle center cells
b) Centroblasts- non-cleaved follicle center cells
Grade Characteristic
Grade 1 0-5 centroblasts/hpf
Grade 2 6-15 centroblasts/hpf
Grade 3 > 15 centroblasts/hpf
3a Centrocytes present
3b Solid sheets of centroblasts

14. STAGING 14 Lymph nodal regions in lymphoma

15. DIAGNOSIS- WORK-UP
Classical FL
Large BCL
with IRF4
BCL2-R
negative,CD
23 +ve FL
Pediatric
type-FL
ESSENTIAL SELECTED CASES ADDITIONAL TESTING (FL)
Physical exam: node bearing
areas, size of liver & spleen
2D-ECHO Immunophenotyping
CD20,CD3,CD5,CD10,BCL2,BCL
6,CD21 or CD23
Performance status Beta-2 microglobulin
(FLIPI-2)
Molecular analysis – Ig gene
rearrangements; BCL2
rearrangements
CBC/RFT/LFT/LDH Uric acid Karyotype/FISH: t(14;18),
BCL6,IRF4/MUM1
rearrangements- F.L. grade-3
Excisional/ incisional biopsy Hepatitis C IHC panel: ki-67,cyclin D-1
Comprehensive metabolic panel
(ca2+,po4,uric acid, k+,mg2+)
NGS panel-: EZH2, TNFRSF14 &
STAT6 mutation
Hepatitis B
PET-CT or CECT(T+A+P
Bone marrow biopsy

16. VARIANTS OF FOLLICLUAR LYMPHOMA
• 2016 WHO classification of tumors recognizes four additional clinical variants of FL
a) Pediatric follicular lymphoma
b) Intrafollicular neoplasia/”in situ” follicular neoplasm
c) Duodenal-type follicular lymphoma
d) Predominantly diffuse follicular lymphoma with IRF4 rearrangement

17. EXCISIONAL BIOPSY
• The biopsy should be obtained before administration of steroids
• Analysis – diagnosis and classification of lymphoma requires
a) Histology- microscopic appearance of malignant cells
b) Immunophenotype- by flow cytometry or by immunohistochemistry
c) Cytogenetics- conventional karyotype or FISH
d) Molecular analysis- for mutations, gene arrangements and gain or loss of certain genes by PCR, DNA
sequencing

18. ROLE OF PET-CT
• PET-CT has greater sensitivity for extra nodal
involvement
• May lead to change in stage (8-20% patients)
• The lesions typically have low metabolic activity
• Low FDG uptake or no uptake & can miss the bone
marrow uptake in low grade NHL
• PET/CT also has the potential to detect transformation
of a low-grade lymphoma to a more aggressive
subtype (Richter transformation) based on the degree
of FDG avidity
• SUV value more than 10 is predictor of aggressive B-
cell lineage or presence of aggressive histology
20XX 18

19. PROGNOSTIC INDEX
PARAMETER FLIPI-1 FLIPI-2 PRIMA-PI
(advanced
FL)
Nodal sites >4 LN
regions
Diameter>6cm
lymph node
Age > 60yrs >60yrs
Serum marker Elevated
LDH
(> UNL)
Elevated B2M Elevated
B2M (< or >
3mg/l)
Stage III-IV
advance
d stage
Bone marrow
involvement
Bone marrow
involvement
haemoglobin <12g/dl <12g/dl
Score – FLIPI-1 10yr OS % 2yr OS%
• 0-1- low risk 71 98
• 2- intermediate risk 51 94
• 3 or more- high risk 36 87
Score – FLIPI-2 3yr PFS % 3yr OS%
• 0- low risk 91 99
• 1-2- intermediate risk 69 96
• 3 or more- high risk 51 84
Score – PRIMA-PI 5yr OS %
• 0- low risk 95
• 1-2- intermediate risk 91
• 3 or more- high risk 78
• M7-FLIPI –EZH2, ARID1A, MEF2, EP300,
FOXO1, CREBBP & CARD11
• Able to identify patients at risk of for early
progression
• Low-risk - FFS (5yr) – 78%
• High-risk – FFS (5yr) - 22%

20. MANAGEMENT

21. STAGE I-II FOLLICULAR LYMPHOMA
Stage I or
contiguous II
Non-
contiguous II
ISRT
(preferred)
• ISRT + anti CD-
20 antibody +/-
chemo
• Anti CD-20
antibody +/-
chemo
• CR/PR • NR
• Follow-
up
• Progress
ive
disease
• Anti-CD antibody +/- chemo +/- ISRT
OR
• Observation
• CR • PR/NR
• ISRT if not given
before
• NR
NCCN
Stage 1 grade
1,2 3a

22. STAGE III-IV FOLLICULAR LYMPHOMA
Evaluate for indications
for treatment-
Candidate for trial
Symptoms
Threatened end-organ
function
Progressive cytopenia
Clinically significant
bulky disease
Steady or rapid
progression
No indication Observe Follow-up
• Progressive disease
• Histologic transformation
Indication PET-CT
• Suggested
regime of
chemoimmunoth
erapy
• Clinical trial
and/or
palliative ISRT
NCCN

23. GELF CRITERIA
• Involvement of >3 nodal sites, each with
diameter of >3cm
• Any nodal or extranodal tumor mass with a
diameter of >7cm
• B symptoms
• Splenomegaly
• Pleural effusion or peritoneal ascites
• Cytopenias
• Leukemia
• Elevated LDH or b-2-microglobuliny
NCCN guidelines
Advanced stage low burden FL-
consider observation
Any one present signifies a high
tumor burden

24. ADVANCED STAGE III/IV FL
Asymptomatic pt with
low burden
Asymptomatic pt with
high burden
Symptomatic pt with
low burden
Symptomatic pt with
high burden
Observation
Or
rituximab
Observation
Or
Rituximab + chemotherapy
Rituximab +
chemotherapy
Or
Rituximab
Rituximab +
chemotherapy
with
maintenance
rituximab

25. RADIOTHERAPY IN FOLLICULAR LYMPHOMA
• Radiation therapy results 10yr OS rates of 60-80%; median OS 19 yrs
• SEER data, RT was used as the initial treatment, OS and DFS was improved with RT and local relapse at an
irradiated area is rare
• Relapse usually occur in distant sites & rare after 10 yrs
• Risk factor for relapse are age (>60yrs), abnormal LDH and bulky disease
Data supports ES –FL – may
be cured with RT alone
Retrospective analysis
• Stage I/II FL (1998-2012)
• OS improved with RT VS no RT
• 10yr OS (68%) VS (54%)
• RT gives better benefit over chemo
• Adding chemo to RT provides little
benefit ( Kaplan-meier )

26. RT DOSE- FOLLICULAR LYMPHOMA
Interpretation- No diff in OS, PFS,LF
• 30Gy dose is appropriate for aggressive
NHL
• 24Gy dose for indolent NHL
Methods (67% stage I-II)
• Aggressive NHL- 30Gy/15#
• Indolent NHL 24Gy/12#
• For all – 40-45Gy/20-23#

27. • Stage I-II FL- 30 Gy vs 30Gy + R-CVP
• Adding R-CVP to IFRT improves PFS but
OS is unchanged
• Systemic therapy after IFRT reduced
relapse outside radiation field.
• Without definitive data showing survival
advantage with CMT, ISRT remains the
preferred treatment for most of the
patients with FL

28. ILROG GUIDELINES FOR INDOLENT LYMPHOMA
• Historically IFRT was used as a sole treatment for localized FL, NMZL
• Nowdays, ISRT volume includes radiologically evident disease sites plus an expansion to encompass potential adjacent
microscopic disease sites
• Volume includes
a) GTV- PET positive nodes and should include enlarged or equivocal nodes
b) CTV- GTV plus extend bouandaries of the involved nodal compartment in axial and craniocaudal plane
c) PTV- CTV to 0.5 cm margin
• 24Gy to 30Gy in 12-15# remains the standard dose for curative therapy of localized FL
• 2 to 4Gy in 1-2# palliation of advanced disease ( which may be repeated as needed)

29. BOOM-BOOM REGIMEN
• Follicular/ MZL- indolent type
• 24gy vs 4Gy for FL or MZL
• 2yr local PFS – 94% VS 80%
• 24 Gy leads to better LC than 4Gy but
there is no difference in OS
• 2*2 allows for repeat treatment , may still
opt for the regimen
• But improvement in LC, still short course
of 12# , strongly supports for many
2Gy*2 still used for palliation, as 50% pts achieved a CR and 81% of patients showed partial response

30. CHEMOTHERAPY
• Multiple chemotherapy ( CHOP, CVP, Fludarabine) in combination with rituximab- no drug has demonstrated superiority
over another
• Recently, bendamustine ( alkylating agent) with rituximab has been introduced in FL
Bendamustine + rituximab vs R-CHOP showed increasy efficacay , PFS &
fewer toxic effects

31. • Follicular lymphoma grade 1, 2 & 3a
• Rituximab maintenance therapy after induction immunochemotherapy provides
a significant long term PFS but not OS , benefit over observation

32. • Follicular lymphoma grade 1, 2 & 3a & advanced disease
• Improved PFS was observed for G plus chemotherapy for all three chemotherapy
backbones
• Increased risk of mortality from oppurunistic infections receiving bendamustine
• Prophylaxis with PJP & VZV vaccine should be administered
• Prophylaxis

33. • Stage III/1V FL with CD20+
• Consolidation of first remission with 90Y-ibritumomab tiuxetan in advanced-
stage follicular lymphoma is highly effective with no unexpected toxicities,
prolonging PFS by 2 years and resulting in high PR-to-CR conversion rates
regardless of type of first-line induction treatment

34. CHEMOTHERAPY COMBINATION WITH RITUXIMAB
SAMPLE FOOTER TEXT 20XX 34
Showed improved median
PFS with rituximab

35. PEDIATRIC-TYPE FOLLICULAR LYMPHOMA IN ADULTS
• PET-CT
• Bone marrow
biopsy
Stage I,II
Excision
Or
ISRT
Or
RCHOP for pts
with extensive ds
who are not
candidates for
excision or ISRT
Observe
Restage with PET-CT
CR
Observe
• NR
• Progressive disease

37. RELAPSE OR REFRACTORY FOLLICULAR LYMPHOMA
• A biopsy should be taken
• The previous lines of treatment
• What is the current situation?
a) Patient age/comorbidities
b) Disease-related symptoms
c) Tumor burden
Evaluate patients for
treatment

38. RESPONSE ASSESSMENT

39. • Relapsed or refractory indolent lymphoma
• Lenalidomide improved efficacy of rituximab in patients with recurrent indolent
lymphoma, with an acceptable safety profile.

40. FDA APPROVED LINES OF CHEMOTHERAPY- FOLLICULAR
LYMPHOMA
Bendamustine causes grade 3-4 lymphocytopenia,
bimonthly CD4 T-helper cells and initiation of P.
jiroveci pneumonia prophylaxis for counts <200/
microlitre (T. septran)

41. MARGINAL ZONE LYMPHOMA
● 10% of all cases of NHL
● Approximately half of the people diagnosed with marginal zone lymphoma are over the
age of 60 at the time of diagnosis.
● 3 types
● Nodal marginal zone lymphoma- widespread nodal involvement, if localized- RT
● Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT)-
m/c
● Splenic marginal zone lymphoma- mostly stage IV but indolent.
• Asymptomatic - observation
• Symptomatic - splenectomy, Rituximab or chemoimmunotherapy
• Patients have a history of autoimmune disorder ( Sjogren syndrome, SLE)

42. • Sjogren syndrome increase in risk of MZL (30 fold) & 1000 times increase risk of parotid
INCIDENCE- SITES OF MALTOMA
SAMPLE FOOTER TEXT 20XX 42

43. ETIOLOGY-PATHOLOGY
• Characterized by centrocyte like B
cells, small lymphocytes, and plasma
cells
• In epithelial tissue, marginal zone B
cells typically infiltrate the
epithelium defined by invasion and
partial obstruction of mucosal glands
by tumor cells
• Achromobacter xylooxidans- lung EMZL

44. CHRONIC AG STIMULATION CHRONIC INFLAMMATION

45. IMMUNOPHENOTYPE CYTOGENETIC NGS
MZL (CD20,CD19,CD79A) +ve
(CD5,CD23,CD10,CD43) –VE
BCL2+ve, Cyclin D-1
7q del - 45%
MALTOMA t(11;18), t(14;18)
t(1;14), t(3;14)
SPLENIC MZL +3,+18,+12, del 6q NOTCH2 (10-20%)
NODAL MZL +3,+19,+12, del 6q,-7

46. EXTRANODAL MALTOMA
• Two-thirds of the patients have stage I-II disease
• MALT is a collection of lymphocytes in the mucosa, which is rich in B cells, can form in the mucosa in
response to inflammation to help protect the body from disease and infection
• MALT lymphoma can develop almost anywhere in the body where there is lymphoid tissue
• Gastric (stomach) type
• Non-gastric type
• Most common sites- stomach, orbit , bone & less common were parotid, breast, thyroid and lung

47. GASTRIC MALT LYMPHOMA
• Median age at diagnosis – 60 yrs
• Equal in men and women
• 2/3rd of the patients with stage I/II disease with B symptoms & bone marrow involvement rare
• MALT lymphomas can transform into more aggressive lymphoma but occurs rarely
• Most common transformation into ABC- like DLBCL
• Nearly half of the lymphomas involves gastric mucosa
• 60% associated with an H. pylori infection
• Normal T-cells in gastric mucosa attract B-cell population, rise to lymphoid follicles which further lead to
prolonged stimulation lead to lymphomas

48. SIGNS & SYMPTOMS- GASTRIC MALTOMA
• Heart burn & indigestion
• Nausea
• Vomiting
• Loss of appetite
• Unexplained weight loss
• Gastric bleeding
• A mass or irregularity present during an endoscopy

49. DIAGNOSTIC CRITERIA – DAWSON’S CRITERIA
Used for labelling primary gastrointestinal lymphomas
• Absence of peripheral lymphadenopathy at the time of diagnosis
• Lack of enlarged mediastinal lymph nodes
• Normal total and differential WBC count
• Predominance of bowel lesion at the time of laparotomy with only lymph node obviously affected in the
immediate vicinity
• No lymphomatous involvement of liver and spleen

51. PROGNOSTIC FACTORS & DIAGNOSIS
• Disease site
• Paired organs ( orbit , salivary gland) have a high risk of relapse
• Medical history and physical examination
• Upper endoscopy for biopsy
a) Testing for H.pylori
b) Flow cytometry
c) Molecular testing
● Hepatitis B & C test
• Stains- giemsa
• Urea breath test
• Rapid urease test
• Culture
• Serological based
studies

52. HISTOPATHOLOGY
• Closely resemble the normal malt
• Expansion of marginal zone around reactive follicles
• Dutcher bodies may be seen
• Variable plasma cell infiltrate in 1/3rd of the MALT
lymphomas
• Infiltration of neoplastic cells into gland/crypt epithelium
with destruction of architecture

53. DIFFERENTIAL DIAGNOSIS
• Reactive lesions ( H. pylori gastritis, lymphoepithelial sialadenitis)- early phases of MALToma resemble
reactive process and immunophenotypic & IGH rearrangements by molecular techniques
• Follicular lymphoma- CD10+, aberrant expression of bcl-2 protein
• Mantle cell lymphoma- CD5+,cyclin-D1 staining
• CLL/SLL- CD5+/CD23+
• Burkitt lymphoma- CD19,CD20,CD22,surface IgM +ve, 60-80% of cases CD10+ve

54. • Complete response – 80% , of those who received CR, EFS 98% of the pts
• Interpretation- Antibiotics in H. pylori +ve gastric MALT lead to excellent
control

55. MANAGEMENT- STAGE I & II 1/ STAGE IE/T1-3N0M0
H. Pylori +ve, t(11;18)
negative or t(11;18)
unknown
H.Pylori +ve, t(11;18)
+ve
H.Pylori negative
Antibiotic therapy
Then evaluate with
endoscopy
• Antibiotic therapy with
ISRT ( preferred)
Or
• Rituximab ( ISRT is
contraindicated)
• ISRT (preferred)
Or
• Rituximab ( ISRT is
contraindicated)
Evaluate with
endoscopy

56. MANAGEMENT- STAGE II 2/ STAGE IIE- IV/T1-3N2M0/T1-4N1-3M0-1
Evaluate for indication
for Rx-
a) Candidate for trial
b) Symptoms
c) GI bleeding
d) End organ
function
e) Clinically bulky
disease
f) Steady or rapid
progression
observe
Indication present
First line
chemotherapy
Palliative ISRT
• Evaluate with
endoscopy, if
evidence of
recurrence (MZL)
• If histologic
transformation

57. RADIOTHERAPY IN MALTOMA
• t(11;18) (q21;q21) translocation and lack of response to antibiotic therapy are the two main indications to treat with
definitive radiotherapy
• Prospective trial British National Lymphoma Investigation – phase III RCT lead to adoption of 24-30Gy as the
appropriate dose of curative treatment of FL
• For MZL, published data reflect the results of whole organ irradiation ( eg, stomach, salivary glans , thyroid)
• For conjunctival MZL, irradiation confined to conjunctival sac is highly effective
• For lacrimal gland, treatment may be confined to the lacrimal gland only
ILROG

58. ILROG GUIDELINES- ISRT EXTRANODAL MZL
• GTV- PET positive lesion & PET positive adjacent nodes ( additional information from CT, MRI & endoscopy)
• CTV- entire involved organ or compartment – gastric MZL whole organ is irradiated
• Equivocally adjacent lymph nodes should be included in CTV
• For conjunctival MZL , the entire conjunctival sac is irradiated with no need to irradiate the whole orbit
• Partial organ irradiation may be considered in some cases where whole organ irradiation is not feasible (i.e lung, skin,
breast)
• Adequate ITV/PTV expansion must be used to account for organ motion
• Dose- 24-30 Gy is standard for MZL, with 24 Gy used for sensitive sites such as the orbit
• Lower doses 2-4 Gy found to be very effective in palliative or advanced FL with response rates of 80-90% with
median duration of response 22-4 months.

60. FOLLOW-UP 3MONTH RESTAGING & ENDOSCOPY
Restage at 3mo with
endoscopy/biopsy for H.
pylori after antibiotics
(restage earlier than 3mo
if symptomatic)
H. Pylori –ve,
Lymphoma -ve
H. Pylori –ve,
Lymphoma +ve
H. Pylori +ve,
Lymphoma -ve
H. Pylori +ve,
Lymphoma +ve
Asymptomatic
Symptomatic
Observe for another
3mo or ISRT
ISRT
Second-line
antibiotic treatment
Stable disease
Progressive or
symptomatic ds
ISRT & Second-line
antibiotic treatment
Follow-up
Endoscopy

61. FOLLOW-UP 3-6 MONTH RESTAGING & ENDOSCOPY
Restage at 3mo with
endoscopy & biopsy
after ISRT or rituximab
H. Pylori –ve,
Lymphoma -ve
H. Pylori +ve,
Lymphoma -ve
H. Pylori -ve,
Lymphoma +ve
H. Pylori +ve,
Lymphoma +ve
Consider antibiotic
treatment
First line
therapy for
MZL
Evaluate
for
indications
for Rx
Relapse
Indications
+nt
No
indication
observe
Second line
therapy for
MZL
Follow-up
Endoscopy

62. FOLLOW-UP - MZL
Repeat
endoscopy
after 3mo
CR
NR
Follow-up every 3-6
mo for 5yrs and then
yearly
Recurrence post ISRT Indication for
treatment
No
indication
observation
Indication
present
Second line
chemo
Recurrence post
antibiotic
Systemic
recurrence
Local
recurrence
Locoregional ISRT
Relapse
Previous ISRT
Previous
antibiotic Rx
First line chemo Relapse
Locoregional ISRT
Indication for
treatment
Indication
present
No
indication
First line
chemo
observation

63. • RCT-III trial- Low tumor burden indolent lymphoma
• In low tumor burden SLL and MZL patients responding to R induction, MR
significantly improved TTTF as compared with RR

64. CHEMOTHERAPY REGIMEN

65. SITE-SPECIFIC WORKUP IN NON-GASTRIC MALT LYMPHOMA

66. MANAGEMENT- NON-GASTRIC MALT LYMPHOMA
Stage IE or
Contiguous Stage
IIE
ISRT (preferred)
Surgery may be
considered for some sites
+ve margins
-ve margins
Consolidative ISRT
Observe
Follow-up
Rituximab in selected
cases
Observation in selected cases
Stage IV
ISRT
Observation
Manage per advanced NMZL

67. FOLLOW-UP NON-GASTRIC MALT LYMPHOMA
Clinical follow-up
every 3-6mo for
5yr & then yearly
or as clinically
indicated
Local
recurrence
Systemic
recurrence
If histologic
transformation
ISRT if not previously treated or manage as advanced stage NMZL
Evaluate for indication for Rx-
a) Candidate for trial
b) Symptoms
c) GI bleeding
d) End organ function
e) Clinically bulky disease
f) Steady or rapid
progression
No indication
Indication
present
observation
First line or second
line chemotherapy

68. SPLENIC MARGINAL ZONE LYMPHOMA
● The spleen is a soft, spongy organ above the stomach and under the ribs on the left side, about the size of a
fist. It is part of the lymphatic system, and it performs several critical functions including:
• Filtering out and destroying old, damaged blood cells
• Storing red blood cells and platelets
• Producing lymphocytes (a type of white blood cell) that fight infection and disease
● The cause of splenic marginal zone lymphoma in unknown in most cases. It is more common in people who
have been infected with hepatitis C virus or who have an autoimmune condition.
● The median age at diagnosis is 65 to 70 years

69. PATHOGENESIS- SMZL
• Arise from the post germinal center, memory B cell of splenic type
• Molecular studies showed alterations to pathways , result in proliferation and commitment of mature B cells to marginal
zone differentiation
GENES Percentage in population
Notch pathway 40%
NF-KB pathway 35-40%
KLF2 20-40%
MYD88 3-15%
CARD11 5-10%
KMT2D 7%

70. CLINICAL FEATURES- SMZL
• Symptoms of an enlarged spleen include:
• Pain in the left upper abdomen that may spread to the left shoulder
• Feeling full after eating only a small amount (from the enlarged spleen pressing on the stomach)
• Decreased appetite
• Unexplained weight loss
● Splenic marginal zone lymphoma often spreads to the bone marrow, the soft tissue inside of certain bones,
causing low red blood cells and platelet counts

71. PATHOLOGY
Peripheral smear show small lymphoid cells with
dark round nuclei
Section of spleen- follicles with expanded mantle &
marginal zones
• Bone marrow- if present, mild and can be subtle
• Lymph node- splenic hilar lymph nodes often involved
• Immunophenotype- IgM, IgD, CD 19,CD20,CD22 & BCL2 with LFA-
1,CD29 &ICAM-1

72. WORK-UP - SMZL
• Excisional/ incisional biopsy
• Hepatitis B/ hepatitis C
• Bone marrow biopsy +/- aspirate
• SPEP for qualitative Ig levels
• IHC & Molecular testing
• Prognostic model
Adverse
factors
Value Risk
group
5yr cause specific
survival
Hemoglobin <9.5g/dl A(0) 88%
Albumin <3.5g/dl B (1) 73%
LDH More than
ULN
C(2-3) 50%

73. MANAGEMENT- SPMZL
Criteria to indicate treatment of Splenic
MZL
• Progressive or symptomatic
splenomegaly
• Cytopenia
a) HB- <10g/dl
b) Neutrophils<1*10 9/L
c) Progressive thrombocytopenia
• Constitutional symptoms
• Progressive nodal disease
• Autoimmune haemolytic anaemia

74. FOLLOW-UP – SPLENIC MARGINAL ZONE LYMPHOMA
Clinically follow-up
every 3-6mo for 5yr
& then yearly or as
clinically indicated
Recurrence
If histologic
transformation
Evaluate for
indications for Rx:
• Candidate for
clinical trial
• Symptoms
• Cytopenias
• Clinically
significant bulky
disease
• Steady or rapid
progression
No induction
Indication
present
No induction
First line /
second line
chemotherapy

75. FOLLOW-UP – SPLENIC MARGINAL ZONE LYMPHOMA
• Pneumococcal and meningococcal
vaccinations at least two weeks
before the splenectomy Vaccination
against
• Haemophilus influenzae type b
(HiB), should also be considered

76. NODAL MARGINAL ZONE LYMPHOMA
• Rare , slow-growing type of MZL
• Lymphomas are primarily nodal diseases without evidence of extranodal involvement
• Approximately 1% of NHL
• Median age at diagnosis 70yrs
• Male > female
• Pediatric NMZL is a distinct entity with excellent prognosis

77. CLINICAL FEATURES
• B symptoms
• Anemia- 25%
• Thrombocytopenia- 10%
• Elevated LDH- 12-48%
• Increased beta-2 microglubin- 29-45%
• Monoclonal immunoglobin- 6-33%

78. DIAGNOSTIC WORK UP- NMZL
• Excisional biopsy
• Cell assessment via flow cytometry with CD20+ve, CD5-ve, CD10-ve
• Molecular analyses – MYD88 mutation , CXCR4 mutation
• Hepatitis B & C
• If patient with localized nodal involvement, with high suspicious of marginal zone lymphoma of extranodal primary site
a) Axillary node- evaluate for lung, breast,, etc
b) Mediastinal node- lung, breast
c) Abdominal node- splenic & gastrointestinal
d) Neck node- evaluate for parotid, ocular, thyroid,,etc

79. TREATMENT- STAGE I, II NMZL
Stage I-
II
Stage I
Or
contiguous
stage II
ISRT ( Preferred)
ISRT + anti CD-
20 mab +/- chemo
anti CD-20 mab
+/- chemo
CR/PR
NR STAGE III,
IV
CR/PR
NR
Progressive
disease
● Clinical
• H&P & labs
every 3-6mo
for 5 yr and
then
annually
● Surveillance
imaging
• Upto to 2yr
post
completion
of Rx-
C/A/P CT
evety 6
months
• >2yr- no
more than
annually
Non-
contiguous
stage II
anti CD-20 mab
+/- chemo +/-
ISRT for local
palliation
observation
CR
PR or
NR
Consider ISRT
if not previously
given
CR/PR
NR

80. STAGE – III-IV NMZL
Evaluate for indication
• Candidate for
clinical trial
• Symptoms
• Threatened end-
organ function
• Clinically significant
cytopenia
• Clinically significant
bulky
• Steady or rapid
progression
No indication
Indication +nt
PET-CT
scan
Suggested
regimen (MZL-
A)
Clinical trial
Palliative ISRT
Response
assessment &
additional Rx
Indication +nt
Clinical
• H&P and labs – 3-6 mo for
5yr & then annually or as
clinically indicated
Surveillance imaging
• Upto 2yr- C/A/P CT no
more than every 6 mo
• >2yr- CT scan no more than
annually
• Progres
sive
disease
• Histolo
gic
transfor
mation

81. FOLLOW-UP NODAL MZL
CT (C+A+P)
CR
PR
NR
Maintenance
therapy for
patients
related with
rituximab
Or observe
● Clinical
• H&P & labs every 3-6mo
for 5 yr and then
annually
● Surveillance imaging
• Upto to 2yr post
completion of Rx- C/A/P
CT evety 6 months
• >2yr- no more than
annually
• Relapse or
progression
• If histologic
transformation
Evaluate for indications for Rx:
• Candidate for clinical trial
• Symptoms
• Cytopenias
• Clinically significant bulky
disease
• Steady or rapid progression
No indication
observe
Rebiopsy
• Third line
chemo/ CART-
T cell therapy
• If histologic
transformation
PET-CT
Chemotherapy/
palliative ISRT

82. HISTOLOGICAL TRANSFORMATION OF INDOLENT LYMPHOMA
FL/MZL to DLBCL after minimal or no prior therapy
With double hit Without double hit
MZL to DLBCL
Treat as a DLBCL schedule
Carry a poor prognosis
• Occurs in approximately 2-3% of patients per year & associated with a poor clinical outcome
• Canadian trial, treated with after transformation by induction chemotherapy f/b HDC & ASCT, a 5yr survival 65%
reported

83. FL/MZL TRANSFORMATION TO DLBCL
• Histologic transformation of FL & MZL to DKBCL ( after multiple lines of prior therapy)

84. SMALL LYMPHOCYTIC LYMPHOMA/CLL
• Mature peripheral B-cell malignancy
• Difference between SLL vs CLL, clinical presentation, with non-leukemic presentation in SLL
• SLL represents <5% of all NHLs
• Median age at diagnosis 65ys
• At least 80% have stage IV disease due to bone marrow involvement at diagnosis

85. PATHOLOGY
• Small lymphocytes with condensed chromatin, round nuclei, sometimes with large lymphoid cells with
prominent nucleoli can be seen
• Larger lymphoid cells are clustered to form proliferative centers, which are pathognomic
• 60% have Ig genes , that showed evidence of significant somatic mutation
• Express low level of IgM or IgD, HLA-DR, CD19,CD20 and CD23 with tyrosine kinase ZAP70 also
• Recurrent mutation which involve the NOTCH 1, SF3B1, TP53, ATM, & MYD88 genes
• Cytogenetic abnormalities include trisomy 12, 13q deletions ( most favorable prognosis), 17p deletions(
unfavorable prognosis), 11q deletions

86. CLINICAL FEATURES
• Painless generalized lymphadenopathy, present for several years
• B symptoms are rare
• Hepatosplenomegaly present in <50% patients
• Peripheral blood smear- showed normal or mild lymphocytosis
• ANC <5000/microlitre
• Hypogammaglobinemia- present at 40%
• Both SLL/CLL may develop autoimmune hemolytic anemia, pure red cell aplasia
• Elevated LDH is uncommon
• Raised level of serum b-2 macroglobulin, marker for disease burden
• ( Richter syndrome- present with rapidly growing masses, elevated LDH and B symptoms)

87. TREATMENT
• Stage 1 treated with IFRT only
• Stage II-III treated with chemotherapy regimens used for SLL
• For advanced stage who do not need systemic therapy, but causing symptoms, low dose palliative RT ( 2Gy *2#) but local
control rates are not high as seen with FL

88. LYMPHOPLASMACYTIC LYMPHOMA-PATHOLOGY
• 1% of all NHLs, with mixed cryoglubulinemia, related with concurrent
Hep C infection
• Mixture of small lymphocytes, lymphoplasmacytic cells and plasma
cells with Russell bodies/ Dutcher bodies are seen
• Occasionally cases may also contain frequent larger immunoblastic-
like cells
• IHC- CD19, CD20, & surface IgM , do not express CD10 or CD23
• Waldenstrom macroglobulinemia (high level of IgM) associated with
LPL
• MYD88 & CXCR4 are associated mutations but are not specific to it

89. CLINICAL PRESENTATION
• Similar to SLL
• Median age – 60yrs
• Nearly all patients have stage IV disease by virtue of bone marrow involvement
• Lymph nodes & spleen involvement are common
• Patients with waldenstrom macroglubinemia may transform to a more aggressive NHL
• B symptoms & serum LDH are uncommon

90. • Lymphoplasmacytic lymphoma
I. Neoplasm of small B cell,
plasmacytoid lymphocytes&
plasma cells
II. Involving bone marrow &
sometimes LN and spleen
III. Does not fulfill criteria of any
other small B-cell lymphoid
neoplasm
WHO CRITERIA- LPL AND WALDENSTROM MACROGLOBULINEMIA
• Waldenstorm macroglubinemia
I. IgM monoclonal antibody
II. Bone marrow infiltration of
small B lymphocytes, plasma
cells
III. Diffuse, interstitial or nodular
bone marrow infiltration
IV. (CD19,CD20, CD5, IgM,
CD10, CD23) positivity
Revised IPSS criteria WM

91. TREATMENT- LPL
• At least 25% of patients have no indication for therapy at initial presentation
Asymptomatic
or minimally
symptomatic
Risk score
• Bone marrow
inv(%)
• S. IgM
• S. beta 2-
microglobulin
• S.albumin
• Low risk
MTP- 9.2yrs
• Intermediate
risk
MTP- 4.8yrs
• High risk
MTP-1.8yrs
• Low risk
Every 12 mo with
CBC, metabolic
panel, SPEP, S.Ig
• Intermediate risk
Every 6 mo with CBC,
metabolic panel, SPEP,
S.Ig
• High risk
Every 3 mo with CBC,
metabolic panel, SPEP,
S.Ig
Indication for treatment
Follow-up
Symptoms related to:
• Hyperviscosity
• Neuropathy
• Organomegaly
• Amyloidosis
• Cold agglutinin
• Cryoglobulinemia
• Anemia
• Cytopenias
• Bulky adenopathy
• B symptoms

92. PRIMARY MANAGEMENT - LPL
Plasmapheresis for
symptomatic
hyperviscosity &
Primary therapy
Or
Clinical trial
Treat with
chemoimmunotherapy
regimen
Observe until
progressive disease
Observe until
progressive disease
Consider
previous
regimen, if
well
tolerated
Treated with BTK
inhibtors
Continue Rx until disease
progression or toxicity
If persistent symptoms
• No response
• Progressive disease
• Choose alternative
therapy
• If transformation occur
(B cell lymphoma)

93. SUMMARY- LOW GRADE NHL
Localised (S-I/II) indolent/low grade
lymphoma
Standard therapy:
ISRT-24-30Gy
Investigational:
Combined
modality Rx
Advanced (S-III/IV) indolent/low
grade lymphoma
Asymptomatic:
Observation with
delayed therapy
Symptomatic:
Chemotherapy or
palliative RT

94. CONCLUSION- LOW GRADE NHL
• Low grade NHL – heterogeneous group, indolent course
• Histology – cornerstone of diagnosis
• PET – lesser role than in aggressive NHL or HL
• Follicular NHL – B-cell origin – comprises >30% of all NHL
• Primarily a disease of older age
• Treatment depends on stage and other prognostic factors
• No single therapeutic standard exists
• Early stage: RT preferred; Advanced stage: Observation or systemic therapy
• MZL – Nodal, Extranodal, Splenic
• Stomach MALToma – even H pylori eradication may suffice as therapy in early stage; for advanced stage,
therapy depends on indication
• RT doses for low grade NHL – 24 Gy in curative setting, 4 Gy in palliative setting
94

95. THANK YOU
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