This document provides an overview of non-Hodgkin lymphomas (NHL). Key points include: - NHL are a heterogeneous group of malignancies characterized by abnormal proliferation of B, T, or NK cells. - The main subtypes seen in India are B-cell lymphomas (80-85%) and T-cell lymphomas (15-20%). - Diagnostic workup involves clinical evaluation, laboratory/radiologic testing, and tissue biopsy for classification. - Staging and risk stratification inform treatment selection which may include chemotherapy, immunotherapy, radiation, stem cell transplant, or observation depending on the NHL subtype and stage.

2. NHL are heterogenous group of
malignancies of the lymphoid
system characterised by an
abnormal clonal proliferation of B
cells, Tcells or NK cells

3. ● Non-Hodgkin lymphomas are neoplastic transformations
of B, T, and natural killer (NK) cells.
● Current classification is based on the cell of origin.
In India,
● B-cell lymphomas (80%–85%)
● T-cell (15%–20%)
● NK cell are rare.

6. Risk factors and diseases associated with NHL

7. REAL classification

10. NCI classification

12. Clinical presentation
● Old age
● M > F
● Painless neck mass
● Waxing and waning LN ( seen in follicular lymphoma)
● B symptoms are less common
● Bone marrow involment ( seen in follicular lymphoma)
● Extranodal involvement seen in 50% cases of DLBCL
● Extranodal presentation is a rule in Marginal zone lymphoma
● Testicular DLBCL – chances of spread to C/L testis and CNS

13. Clinical, Laboratory and Radiologic Evaluation of Patients

15. Modified Ann Arbor Staging Of NHL

16. ● Tonsils,Waldeyer ring,and spleen are considered nodal tissue.
● Definition of bulky disease in DLBCL not validated but 6 to 10
cm generally accepted.

17. PET CT SCAN
● Sensitivity 95% in detecting unsuspected metastasis
or differentiating active v/s uninvolved nodes
Uses
● Diagnostic purpose
● Response assessment – CR, PR, SD, PD
● Detection early relapses

18. ● If PET-CT indicates bone marrow involvement in DLBCL, confirmatory bone marrow biopsy is
not recommended
● End of treatment assessment is probably most accurate and most meaningful

19. Response Assessment

20. 1. DS 1, 2, 3 = complete metabolic response
2. DS 4, 5 = partial metabolic response but with reduce uptake
compared to previous scan
3. Stable disease is no change in FDG uptake
4. Progressive disease is increase in uptake

21. DS 4or 5
Treatment failure
Confirm histologically by
biopsy

22. 1. Many studies of interim PET CT have been carried out in
DLBCL suggesting that interim positive PET CT predicts
worse outcome
However there is no conclusive evidence that
changing treatment according to interim PET findings
improves outcome
2. In FL, Interim PET CT donot suggest any benefit

23. Treatment options
1. Chemotherapy
2. Radiotherapy
3. Immunotherapy
4. Stem cell transplantation
5. Observation

24. Overview of management of NHL

27. DLBCL
● DLBCL is neoplasm
of large , transformed
cells with diffuse
growth pattern that
totally or partially
effaces nodal
architecture
DLBCL
ABC GCB PMBCL
Molecular
subgroups

28. Markers of DLBCL
● Pan B cell marker
CD 19, 20, 79a
sIg, cIg
MYC, BCL2, BCL6
● Double or triple hit= GCB
type (10-15%)
● Overexpressors = ABC type
● Prognosis= triple hit >
overexpressors > double hit
MYC, BCL2,
BCL6
Gene
rearrangement
MYC + BCL2/
BCL6
Double hit
MYC
+BCL2+BCL6
Triple hit
overexpression
MYC
+BCL2/BCL6
Double or triple
hit expressors

29. DLBCL
• Most common NHL –30%
• Median age 64 years
• M>F
• 1/3rd have B symptoms
• Half patients with localised disease with extranodal disease

30. International prognostic index
IPI was designed in prerituximab era. Adding approx 10%
survival to each IPI subgroup approximately outcomes when
rituximab is added to combination chemotherapy

31. Stage 1 to 2 DLBCL
● Pre chemo era
● RT was only treatment
● Dose= 30-60 Gy
● IFRT was used
● PFS >80%
● OS 30-60%
INTRODUCTION OF COMBINED
CHEMOTHERAPY IMPROVED OS AND
PFS
Whether RT was
necessary?

32. Brief chemotherapy may be
insufficient systemic treatment
for most patients with DLBCL
RT provides benefit even after
extended chemotherpay

33. ● None of the trial used rituximab nor functional imaging
● Chemo +RT = PFS 90% and OS 80%
● Advantage of combined modality therapy has been observed
using large databases (SEER, NCCN, NCDB)

34. Advanced stage DLBCL
● Current recommendation RCHOP
● 5yr OS is 60%
GELA trial
• 8 cycles of
RCHOP superior
to CHOP alone in
terms of PFS, OS
and DFS
RICOVER trial
• 6-8 cycles of
RCHOP or CHOP
(14 days cycle)
• RCHOP superior
to CHOP (70%vs
57%)
• No benefit of
8cycles over 6
cycles
UNFOLDER trial
• Prematurely
closed as RCHOP
arm not receiving
consolidative RT
had excess
relapse at site of
bulky disease

35. RCHOP- 3 weekly
● Rituximab -375mg/m² i/v D1
● Cyclophosphamide – 750mg /m² i/v D1
● Doxorubicin – 50mg /m² i/v D1
● Vincristine – 1.4mg/m² i/v D1
● Prednisolone – 100 mg/m² orally D1-D5
Salvage chemotherapy
R-ICE (rituximab, ifosfamide, carboplatin, etoposide)
or
R-DHAP (rituximab,dexamethasone, cytarabine, cisplatin).

40. DLBCL: early-stage
SWOG 8736
UNFOLDER
Adapted from NCCN
guidelines,2021

41. DLBCL : Advanced stage

42. Relapsed or refractory cases
Relapsed or
refractory
cases
Second line
therapy
CR HDCT + ASCT +/-
ISRT
PR
Anti CD19 CAR Tcell
therapy
Or HDCT + ASCT +/-
ISRT
PD or no
response
Anti CD19 CAR Tcell
therapy
Or
Palliative ISRT
Role of RT in patients undergoing ASCT is undefined. The rationale for RT
lies in the observation that most treatment filures occur at the site of initial
involvement

43. Radiotherapy
DOSE
● Stage I and II disease, dose 20-30 Gy in 10-15# when complete response (Deauville 1 to 3)
has been achieved by PET-CT after chemo immunotherapy, typically RCHOP
● British National Lymphoma Investigation randomized study showed no difference in
freedom from local progression, PFS, or OS between 30 Gy and 40Gy to 45Gy.
● Patients having persistent PET-positive disease (Deauville 4),higher doses of consolidation
RT may be required to achieve optimal local control (≥40 Gy)
● There is little evidence for doses above 40Gy.

44. ISRT
Involved-site radiation therapy (ISRT)
CTV that consists of the pre chemotherapy extent of disease,
● Adjusted to exclude normal tissues after chemotherapy
● Expanded to account for uncertainties in recreating the pre chemotherapy extent of
disease (anatomical changes, patient positioning differences between and imaging
uncertainties).
● PTV account for setup variation and potential organ motion.
● Stage I - II- all sites of original involvement should be treated.
● Stage III –IV – only bulky disease

45. Palliative RT
● Doses of 24 to 30 Gy in 12 – 15# are most commonly utilized
● Low-dose RT (2Gy×2) maybe reasonable in select circumstances.
● Response rates of 50% to 80% have been reported with 2Gy×2 with a median
time to progression of about 1 year.

46. Follicular Lymphoma
● Most common indolent lymphoma
● 80% generalized disease
● Female preponderance
● B symptoms – rare
● Bone marrow involvement
● Richter’s transformation in
30% cases
● Extranodal prentation is uncommon
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
 Treat as G1-2, or as G3B
 Treat as DLBCL

47. Prognostic indices

48. Stage I and II FL
Stage I or
contiguous
stage II
ISRT preferred
Rituximab +/-
ISRT
Non
contiguous
stage II
Rituximab +/-
CTH
+/- ISRT for
palliation
observation
CR/PR= follow up
NR= treat as stage III and IV

49. Stage III or IV FL
● Considered as incurable disease
● Indolent nature
● Observation as suggested by Stanford university and later confirmed by
multiple randomised trial
● NCCN recommends observation in low burden advanced FL

50. GELF criteria (any one positive indicates high tumor burden)
3 nodal site >/= 3 cm
Single nodal site >/= 7cm
Symptomatic spleenomegaly
Pleural effusion or ascitis
Organ compression or compromise
B symptoms
Raised LDH or beta-2- microglobulin

51. Stage III and IV FL
Advanced
FL
asymptomatic
Low
burden
Observation or
single agent
Rituximab
High
burden
Observation
or R +
chemotherapy
symptomatic
Low
burden
Single
agent
rituximab
High
burden
Rituximab containing
chemotherapy with
maintainance
rituximab

52. Chemotherapy used in FL are
1. RCHOP
2. R + bendamustine
3. R + CVP
4. R + lenalidomide

53. Radiotherapy
● ISRT DOSES
● 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.

54. Marginal Zone Lymphoma
• 10% of all cases of NHL
• 3 types
• Nodal marginal zone lymphoma- widespread nodal involvement, if localized- RT
• Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
(MALT)
• Splenic marginal zone lymphoma- mostly stage IV but indolent.
• Asymptomatic - observation
• Symptomatic - splenectomy, Rituximab or chemoimmunotherapy
Cells express pan B cell associated antigens-CD19, CD20, CD22,and CD79a.
 Lack of CD5 (positive in CLL/SLL and MCL),CD10 (positive in FL), and
cyclin D1 (positive in MCL) expression helps distinguish MALT from other
small B-cell lymphomas

55. • Indolent; usually present stage IE or
IIE
• 60-70% present with stage I or II
• >90% LC with RT
• Common Sites
• Stomach
• H-Pylori
• Represents 65% of MALT
lymphomas
• Orbital
• Skin
• Salivary glands
OTHER SITES:
• Parotid, breast,thyroid,lung
Site Infectious agent
Stomach H. Pylori (92%)
Ocular adnexa Chlamydia psittaci
Small intestine Campylobacter jejuni
Spleen HCV
Skin Borrelia burgdorferi
Prognosis depends on the site .
MALT in paired organs have high risk of
relapse than single.

56. ● For H pylori associated – antibiotics- omeprazole 20mg BD, metronidazole 400mg
TDS,and clarithromycin 250 or 500mg BD; for 2 weeks CR -80%
● Serial endoscopy for response evaluation, may take upto 2 years, hence wait and watch.
● Factors associated with a lower chance of achieving and maintaining complete response
after antibiotic therapy include deep gastric wall invasion,nodal involvement, and
translocation t(11;18)
● If patient relapses after antibiotics, treatment is by RT

57. MALT of Non-Gastric sites:
• Ocular Adnexa, Salivary glands, Lung,Skin
• Definitive treatment for early stage localized disease is RT alone
• RT dose 24-30Gy in 12-15#: CR =approx. 100%
Lower doses for ocular and salivary gland lesions
• 24 Gy in 12 fractions
• Can avoid toxicity
• In Stage III/IV patients, can consider 4Gy in 1-2 fractions for local
control
• Antibiotic response rates of 35-50% documented
• Takes 6-24 months to see response

58. Mantle Cell Lymphoma
● It is neoplasm of small to medium sized B cells with irregular nuclei that resembels
centrocytes of germinal centres
● CD 5+, CD 20+
● T (11;14) involving BCL-1 gene with overexpression of cyclin D1
● Median age 63years
● M>F
● 80% have stage III or IV
● Most common organ involved is bone marrow

59. TREATMENT
● Clinical trial
● Multi drug chemotherapy
● ISRT
For refractory cases
HDC with ASCT
Haematopoietic stem cell transplant
Chemoimmunotherapy is standard
initial treatment.
No standard regimen for MCL
Choice of chemotherapy is guided by
age and PS
Stage 1 and 2, consolidative RT after
chemoimmunotherapy is recommended
to a dose of 30Gy

60. Primary CNS Lymphoma
● PCNSL comprises all primary intracerebral or intraocular lymphomas
● Associated with HIV 1 and EBV
● MRI is the investigation of choice
● Diffuse parenchymal infiltration present- surgery has no role
● Age and KPS – prognostic factors
MSKCC prognostic
model
Factors Median Survival in
years
Class 1 Age <50yrs 8.5
Class 2 Age > 50, KPS >/=70 3.2
Class 3 Age > 50, KPS <70 1

61. Biopsy proven PCNSL
( extensive surgery
doesnot improve OS)
KPS >40
RFT= normal
High dose
methotrexate
CR
WBRT 23.4Gy
PR
WBRT 30-36Gy
+ boost upto
45Gy
KPS <40 or
RFT= abnormal
WBRT
WBRT 24-36Gy +
boost upto 45Gy
Or
Non MTx chemo
If spinal MRI or CSF
cytology positive,
consider for intrathecal
chemo
If ocular examination
positive, consider for
intraocular chemo
If spinal MRI or CSF
cytology positive,
consider for intrathecal
chemo and focal spinal
RT
If ocular examination
positive, consider for
RT to globe

62. Treatment
RT
● The posterior globes are included in the field.
● Inferior border of the field should is at the C1/C2 vertebral body to cover the obex,
where the fourth ventricle narrows to become the central canal of the spinal cord
● Prophylactic RT to the spine is not recommended.
Non MTx chemotherapy
Cytarabine, procarbazine, vincristine, carmustin

63. BURKITT’S LYMPHOMA(BL)
Highly aggressive B-cell neoplasm, 0.8% of all B-cell lymphomas.
● Uncommon in adults
Tumor etiologically associated with
• Epstein-Barr virus,
• A specific chromosomal translocation t(8;14) , t (8;22)– by karyotyping, FISH
It presents in three clinically distinct forms:
• Endemic - most common, affects facial bones, pediatric population
• Sporadic- MC involved sites are terminal ileum, caecum and intra-abdominal lymph
nodes
• Immunodeficiency associated- HIV positive, autoimmune disease patients, transplant
patients

64. ● Immunophenotyping
 Positive for CD10 ,CD19, CD20, CD22, and
CD79a
 BCL 6 +ve
 BCL 2 -ve
 Ki67 +ve
 Lack CD5 and CD23.
EBV : +ve in 98 percent of endemic
30 percent of sporadic
30 to 40 percent of HIV-associated

65. Treatment
● CODOX-M/IVAC is among most commonly used regimens
● 2 years event free survival (EFS) 81% , overall survival 83%
● Rituximab has also been combined with CODOX-M/IVAC, with promising initial
results
● 3 Year EFS by adding rituximab - 74% Vs 61% without rituximab
● 3 year OS by adding rituximab – 77% Vs 66 % without rituximab
RELAPSED CASES
● ASCT
● HDC

66. Peripheral T cell lymphoma NOS
● PTCL, NOS(not otherwise specified), resembles DLBCL in its clinical
characteristics and presentation
● Most common PTCL subtype (25%)
● IPI tends to be worse
● Approximately half of patients have B symptoms.
● Treatment is similar to that used for DLBCL.
● Rituximab, however, has no role, as this is a T-cell lymphoma
For minority of patients who
presents with stage I and II
PTCL, consolidative RT is
recommended

67. Follow up and routine surveillance
• NCCN guideline suggests history and physical and routinr laboratory
assessment every 3-6 months for 5 years and then annually indicated
• Routine surveillance with PET CT not recommended
• Role of CT is unclear
• Detection of relapse is most relevant in DLBCL where ASCT is option
and in MZL where second line therapy is given. However, role of
early detection and improved survival is unclear (NCCN)