1. TREATMENT
OF
INDOLENT LYMPHOMAS
DR ARNAB BOSE
Dept. of Radiotherapy
NRS Medical College, Kolkata

2.  The World Health Organization classification provides a biologic
framework for lymphomas, but it is not specifically organized
with treatment in mind.
 Thus, in presenting clinical management,
Non- Hodgkin’s Lymphomas and can be organized into clinically
relevant groups according to their natural history
(i.e. Indolent versus Aggressive).
 While such clinical groupings provide a framework for
management, each case must be considered individually.

3. Indolent Lymphomas
 Follicular Lymphoma, grades I , II , IIIa
 Marginal Zone B-cell Lymphoma
 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
 Lymphoplasmacytic Lymphoma
 Mycosis Fungoides /Sezary Syndrome

4. Follicular Lymphoma Grade I/II/IIIa
 Follicular lymphomas (F L )are classified into 3 grades based on
the number of centroblasts per high-power field.
 Generally, grades 1 and 2 are indolent, whereas grade 3 can be
more aggressive.
 It is now recognized that grade 3 disease is biologically diverse
and includes both follicular lymphoma, termed grade 3a, and
large B-cell lymphoma, termed grade 3b, which has a follicular
growth pattern but is clinically like Diffuse Large B Cell
Lymphoma and should be treated like DLBCL.

5. Follicular Lymphoma Grade I/II/IIIa
STAGE I/II
Initial Therapy
 Involved Field Radiotherapy :
Preferred treatment option for clinical stage I & contiguous stage
II Dose: 24 to 30 Gy
36 Gy for bulky disease
 Observation :
May be an option in cases where toxicity of IFRT outweighs
potential clinical benefit

6.  Complete/Partial Response to initial therapy :
Clinical Follow up with Laboratory assessment
every 3 to 6 months for first 5 years and then annually or
as clinically indicated
 No Response to initial therapy :
Managed as patients with advanced disease

7. Follicular Lymphoma Grade I/II/IIIa
STAGE II X/III/IV
 Indications for Treatment
Symptomatic patients
Threatened end organ function
Cytopenia secondary to lymphoma
Bulky disease
Steady progression
Candidates for Clinical Trials

8. GELF Criteria for initiating treatment
 Involvement of 3 or more nodal sites each with
a diameter of 3 cm or more
 Any nodal or extra nodal tumor mass with
a diameter of 7 cm or more
 B Symptoms
 Splenomegaly
 Pleural or Peritoneal effusion
 Cytopenias ( leukocytes < 1.0x109/L and/or
platelets < 100x109/L )
 Leukemia ( >5.0x109/L malignant cells )

9. Indications absent
 Observation :
Clinical Follow up with Laboratory assessment
every 3 to 6 months for first 5 years and then annually or
as clinically indicated

10. Indications present
 First Line Therapy :
i) R CHOP ii) R CVP iii) R FND
iv) Rituximab v) Bendamustine + Rituximab
vi) Radioimmunotherapy
vii) Single agent Alkylating agents
(Chlorambucil/Cyclophosphamide) with/without Rituximab
 Radiotherapy : Local RT for palliation of advanced stage low
grade lymphomas with 2Gy x 2 fractions ( may be repeated )
 Clinical Trials : Given incurability with conventional treatment
investigational treatment can be considered for first line therapy

11.  R – CHOP
Cyclophosphamide 750 mg/m2 IV day 1
Doxorubicin 50 mg/m2 IV day 1
Vincristine 1.4 mg/m2 (max. 2 mg) IV day 1
Prednisone 100mg PO day 1- day 5
Rituximab 375 mg/m2 IV day 1
Cycle repeated every 21 days
 The addition of Rituximab has consistently improved the ORR,
response duration and PFS; also OS in some studies.
 The superiority of R-CHOP to CHOP was established in the GLSG
study. R- CHOP was associated with 60% reduction in relative
risk for treatment failure, significantly prolonged TTF, higher
ORR and prolonged duration of remission.

12.  R- CVP (Rituximab + Cyclophosphamide,Vincristine,Prednisone)
Addition of Rituximab to CVP chemotherapy has significantly
improved outcome in previously untreated FL with no
significant increase in toxicity.
 R-FND (Rituximab + Fludarabine,Mitoxantrone,Dexamethasone)
Addition of Rituximab to FND chemotherapy resulted in
improved outcome.
 Bendamustine (alkylating agent consisting of purine
benzimidazole ring and a nitrogen mustard moiety) as a single
agent or in combination with Rituximab (BR ) has shown
promising results with acceptable toxicity in newly diagnosed
as well as heavily pre-treated patients of relapse/refractory
indolent lymphomas.

13.  Rituximab is a chimeric anti CD 20 antibody consisting of
human IgG constant regions and variable regions from the
murine monoclonal anti CD 20 antibody. It targets the CD
20
antigen which is expressed on >90% of all B cell NHLs.
Binding of antibodies to CD 20 induces a trans membrane
signal that blocks cell activation and cell cycle activation.
 Rituximab in combination with CHOP , CVP , FND
chemotherapy as first line therapy are all recommended and
acceptable.
 Single agent Rituximab is the preferred first line therapy in
elderly and infirm patients.
 Single agent alkylating agent
(Cyclophosphamide/Chlorambucil)

14.  Complete/Partial Response to First Line Therapy :
A) Consolidation or Extended Therapy
i) Chemotherapy followed by Radioimmunotherapy
ii) Rituximab Maintenance 375mg/m2 one dose
every 8 weeks up to 2 years for patients initially
presenting with high tumor burden
B) Observation
 No Response to First Line Therapy :
Managed as Progressive Disesase

15. Progressive Disease (Relapse/Refractory Cases)
 Early stage disease
i) treated previously with Initial Therapy & showing
Complete/Partial Response: on follow up > Progressive disease
ii) showing no response to Initial Therapy and
managed as cases of advanced disease :
a) on observation with follow up > Progressive disease
b) treated with First Line Therapy
but showing no response > Progressive disease

16.  Advanced stage disease
i) on observation: follow up > Progressive disease
ii) treated with First Line Therapy
but showing no response > Progressive disease
iii) showing Complete/Partial response to First Line Therapy
and on observation: follow up > Progressive disease
iv) showing Complete/Partial response to First Line Therapy
& receiving Consolidation Therapy and on observation :
follow up > Progressive disease

17. Progressive disease (Relapse/Refractory Cases)
 Should always be histologically documented
 Histological transformation to Diffuse Large B Cell Lymphoma to
be ruled out before further treatment
 Indications for treatment as for Advanced stage disease
If no indications for treatment Observation is an option
Second Line Therapy is the treatment option for those cases
with indications for treatment

18.  Second Line Therapy
i) Chemoimmunotherapy ( as in First Line Therapy)
ii) Radioimmunotherapy iii) FCMR
iv) Fludarabine + Rituximab
 Second Line Consolidation or Extended Therapy
i) Rituximab Maintenance 375mg/m2 one dose
every 12 weeks for 2 years
ii) High Dose Chemotherapy with Autologous Stem Cell Rescue
iii) Allogenic Stem Cell Transplant

19.  Radio Immuno Therapy (RIT):
i) I 131 Tositumomab is a radiolabeled monoclonal
antibody
which is a radio-iodinated derivative of tositumomab that
has been covalently linked to I131 .
The antibody moiety is Tositumomab which targets
the CD 20 antigen while ionizing radiation from Iodine
radioisotope results in cell death (Beta 0.6 MeV,2.3 mm
tissue range) and gamma ~0.33 MeV).

20. ii) Y 90 Ibritumomab tiuxetan is the immuno conjugate
consisting of a stable covalent bond between the monoclonal
antibody Ibritumomab and the linker-chelator tiuxetan.
This linker – chelator provides a high affinity conformally
restricted site for Yttrium90 .
The antibody moiety Ibritumomab targets the CD 20 antigen
while Beta emission ( pure beta 2.3 MeV ,1.1cm tissue range)
from Yttrium radioisotope induces cellular damage.

21.  FCMR (Fludarabine,Cyclophosphamide,Mitoxantrone,Rituximab)
Addition of Rituximab to Fludarabine based regimens is
associated with superior results compared to those without
Rituximab in relapse/refractory cases.
 High-Dose Therapy with Autologous Hematopoietic Stem Cell
Rescue ( HDT/ASCR) for indolent lymphoma has been tested as
consolidation in first response, relapse, and transformation.
Patients who undergo transplantation early in their disease
course have the best outcome.

22.  Rituximab Maintenance :
A number of studies have also investigated the use of
Rituximab maintenance treatment either as monotherapy or
following chemotherapy.
When used as a single agent, maintenance treatment following
initial therapy with either a single infusion every 2–3 months
over a period of 8–12 months or four infusions every 6 months
over 2 years, results in improved response rate and PFS.
However, whether the long-term results of this
approach are superior to Watch and Wait or conventional
chemotherapy is unknown.

23.  Histological Transformation to DLBCL :
Transformation to DLBCL in patients with FL occurs at a rate
of approximately 2-3% per year for at least 15 years and the
risk falls after that time. It is generally associated with poor
clinical outcome.
However, patients with limited disease with no previous
exposure to chemotherapy can have the favourable outcomes
similar to de novo DLBCL.
In patients with multiple prior therapies , the prognosis
is
much poorer and enrollment in clinical trial is the preferrred
option. Otherwise treatment options include RIT,
chemotherapy with/without Rituximab, IFRT or Best
Supportive Care. HDT/ASCR may be considered in patients
responding to initial treatment.

24. If the patient has had minimal (IFRT alone or single agent
chemotherapy including Rituximab) or no prior
chemotherapy Anthracycline based chemotherapy with
Rituximab with/without Radiotherapy is the treatment option.
Patients responding to initial treatment can be considered for
HDT/ASCR. Patients with no response or progressive disease
after initial therapy can be treated with RIT or Best Supportive
Care.

25. Marginal Zone Lymphoma
 Extra Nodal Marginal Zone Lymphoma of Mucosa
Associated Lymphoid Tissue (MALT)
Gastric :
Non Gastric : typical sites include
small & large intestine, breast, head & neck, lung,
ocular adnexa, ovary, prostate and salivary glands
 Nodal Marginal Zone Lymphoma
 Splenic Marginal Zone Lymphoma

26. Gastric MALT Lymphoma
Stage I E /II E H Pylori positive :
 Initial Therapy with Antibiotic Therapy for H Pylori >
Evaluate
for H pylori eradication with endoscopy
t(11;18) is a predictor of lack of response to antibiotics > these
patients to be considered for alternative therapy
 After antibiotic therapy
Restage at 3 months with endoscopy/biopsy
for H Pylori/Lymphoma ( Restage earlier if symptomatic)

27.  Restaging leads to following groups
H Pylori negative/Lymphoma negative > Observation
H Pylori negative/Lymphoma positive > Radiotherapy
H Pylori positive/Lymphoma negative > Second Line Antibiotic
Therapy
H Pylori positive/Lymphoma positive > Second Line Antibiotic
Therapy + Radiotherapy
 Radiotherapy
Field : the involved organ alone i.e. the whole of stomach
Dose : 30 Gy

28. Stage I E/II E H Pylori negative :
 Initial Therapy with Radiotherapy
 After Radiotherapy
Restage at 3 to 6 months with endoscopy / biopsy
 Restaging leads to following groups
H Pylori negative/Lymphoma negative > Observation
H Pylori negative/Lymphoma positive >
Chemoimmunotherapy as per regimens for
advanced stage FL I/II

29. Stage III E/IV disease :
 Indications for Treatment
Symptomatic patients
Threatened end organ function
Cytopenia secondary to lymphoma
Bulky disease
Steady progression
Candidates for Clinical Trials
 If indicated for treatment options are
Chemoimmunotherapy as per regimens for advanced stage FL
I/II Radiotherapy
 If not indicated for treatment > Observation

30.  Follow up endoscopy in Stage I E/II E disease
Repeat endoscopy after 3 months for all patients treated with
antibiotic therapy, radiotherapy or kept under observation
 If Complete Response > clinical follow up every 3 months
for 5 years and then annually or as clinically indicated >
If Recurrence occurs in post Radiotherapy cases :
treated along the lines of progressive FL I/II
If Recurrence occurs in post Antibiotic Therapy cases :
for local Recurrence Radiotherapy to be considered &
for systemic Recurrence treated along the lines of
progressive FL I/II

31.  If No Response >
in post Radiotherapy cases :
treated along the lines of progressive FL I/II
in post Antibiotic Therapy cases :
Radiotherapy to be considered
 Follow up endoscopy in Stage III E /IV disease
If Recurrence occurs >
treated along the lines of progressive FL I/II

32. Non Gastric MALT Lymphoma
Stage I/II
 Initial Therapy with Involved Field Radiotherapy
 Surgery may be considered for certain sites
( Lung, Breast [lumpectomy], Thyroid, Colon, Small Bowel)
If margins positive on histology > Locoregional Radiotherapy
If margins negative on histology > Observation
 Radiotherapy
Field: involved organ alone
Dose: 24 to 30 Gy depending upon the site with lower doses
for Eye involvement

33.  All patients to undergo clinical follow up every 3 months
for 5 years and then annually or as clinically indicated
 If local Recurrence > Radiotherapy is an option if previously
treated by surgery or may be treated along the lines of advanced
stage FL I/II
 If systemic Recurrence > treated along the lines of advanced
stage FL I/II
Stage III/IV
 Treated along the lines of advanced stage FL I/II

34. Nodal Marginal Zone Lymphoma
 This is a rare disease, mainly of older women. Most patients
present with lymphadenopathy, often in the neck.
 There is little consensus about treatment, management being
dictated by the site that is involved and the age of the patient. In
general, however, the principles of therapy that were described
for advanced stage FL I/II can be applied.

35. Splenic Marginal Zone Lymphoma
 In patients with chronic Hepatitis C infection, treatment of the
Hepatitis with Interferon-α alone or in combination with the
antiviral agent Ribavirin is associated with regression of
disease.
 Hepatitis C virus–negative patients do not respond to this therapy.
 Historically, splenectomy was often required to establish the
diagnosis, and prolonged responses are often observed.
 Rituximab is highly effective and should also be considered before
splenectomy.

36. Small Lymphocytic Lymphoma /
B-Cell Chronic Lymphocytic Leukemia
 The same principles of management are applied to these
subtypes of lymphoma as to Follicular Lymphoma, therapy
being recommended only if it is clinically indicated. Because the
patient population is generally older and more likely to have
co morbid problems, there has to date been less enthusiasm for
aggressive intervention.
 Purine analogs (i.e.,Fludarabine, Cladribine, and
Pentostatin)
alone and in combination have held the greatest promise
in
terms of new chemotherapy for SLL/B-CLL.

37.  Several studies investigating combinations of Fludarabine with
Cyclophosphamide or with Mitoxantrone and high doses of
Dexamethasone have been encouraging, although substantial
toxicity has been seen.
 The combination of Fludarabine with Cyclophosphamide and
Rituximab has yielded a high proportion of complete remissions,
previously a rare outcome in this disease.
 The relative seniority of many of the patients as well as the
incompleteness of clearance of bone marrow infiltration makes
high-dose therapy with hematopoietic stem cell support
inappropriate for the majority.

38. Lymphoplasmacytic Lymphoma
 Lymphoplasmacytic lymphomas are generally treated like other
advanced-stage indolent lymphomas.
 When these lymphomas present with a significant
immunoglobulin M paraprotein and bone marrow disease, they
are also known as Waldenström’s macroglobulinemia and may
present with splenomegaly.
 Patients with acute symptoms from hyperviscosity might require
emergency plasmapheresis.
 Alkylating agents, Purine analogs, and Rituximab are
quite
effective in this disorder.

39. Evidence for Treatment Recommended
Early Stage Indolent Lymphoma
 Princess Margaret Hospital (ASCO 2004):
460 patients with clinical stage I–II FL treated with
IFRT alone. Median follow-up 12.5 years.
Ten-year DFS and OS were 41 and 62%.
Late relapses after 10 years were infrequent.

40. Advanced Stage Indolent Lymphoma
 GLSG (Hiddemann et al. 2005):
428 patients with symptomatic stage III–IV FL grades I–II
randomized to either CHOP vs. R-CHOP. Median follow-
up
18 months. R-CHOP significantly improved Time to
treatment failure (TTF) and 2-year OS (95 vs. 90%).
 CVP ± R (Marcus et al. 2008):
321 patients with symptomatic stage III–IV FL grades I–II
randomized to CVP vs. R-CVP. Median follow-up 53
months. TTF and OS (83 vs. 77%) were significantly
improved with R- CVP vs. CVP.

41.  Ibritumomab Trial (Morschhauser et al. 2008):
Phase III trial of 414 patients with advanced FL treated
with first-line chemotherapy with a complete or partial
response were randomized to receive Y-90-Ibritumomab
or no further treatment . Median observation of 3.5
years.
Y-90-Ibritumomab significantly prolonged PFS in all
patients (36.5 vs. 13.3 months); no difference between
CR or PR after first-line chemotherapy. 77% of patients with
PR converted to CR. Main toxicity was grade III–IV
hematologic toxicity.

42.  The PRIMA Trial (2011) prospectively evaluated the role of
Rituximab maintenance in patients responding to first
line
chemotherapy with Rituximab.
1,018 eligible patients responding to first line R-CHOP,
R-CVP or R-FCM were randomized to observation or
Rituximab maintenance.
After a median follow up of 36 months 3 year PFS was 75%
in the Rituximab arm and 58% in the observation arm.
However the OS was not significantly different in the two
groups – follow up is ongoing to evaluate the role of
Rituximab on OS.

43.  Low Dose IFRT (Haas et al. 2003):
Phase II study was of 109 patients (304 total sites) with
recurrent indolent B-cell NHL. 90% of patients had
Follicular NHL. 94% had prior systemic therapy, 28%
had prior radiotherapy.
27% had 4 Gy in 1 fraction;
73% had 4 Gy in 2 fractions
Overall response rate of 92%: 61% achieved complete
response (CR) and 31% had partial response (PR)
Median time to local progression was 25 months; median
time to local or distant progression was 14 months.

44. Response definitions for NHL
 Complete Remission (CR)
Disappearance of all evidence of disease
If previously PET avid nodal disease or with palpable
spleen or liver, disease is now PET negative and not palpable
Regression of lymph nodes to normal size
If involved prior to treatment, bone marrow biopsy shows
no disease
 Partial remission (PR)
Regression of disease and no new sites
≥50% decrease in size of up to 6 largest masses
One or more previously involved sites remain FDG avid
No increase in the size of the liver or spleen

45.  Stable disease (SD)
Failure to attain CR, PR, or PD
One or more previously involved sites remain FDG avid
No change in size of previous lesions
 Relapsed or Progressive disease (PD)
New lesions or an increase of disease
New lesions ≥1.5 cm or ≥50% increase in any diameter
of a previously involved site
≥50% increase in size of liver or spleen at their nadir size
during treatment
New or recurrent bone marrow involvement

46. Conclusion
 Indolent B-cell lymphomas are clinically diverse.
 Symptomatic patients who do not achieve a durable initial
remission will often require intermittent therapy to control
clinical signs and symptoms.
 There are many effective drug classes that provide disease
control, including purine analogs , alkylators,
anthracyclines ,
and rituximab. Furthermore, targeted agents and
immunotherapy with idiotype vaccines and alpha
interferon
hold promise and are under investigation.
 Observation is an important option for asymptomatic

47.  Newer approaches, such as early use of monoclonal antibodies
and development of patient-specific idiotype vaccines, have
changed the natural history of follicular lymphoma,
making the decision when to initiate treatment challenging.
 For the present, treatment of these lymphomas is generally
initiated for constitutional symptoms, organ compromise,
and/or evidence of rapid tumor growth or bulk during the
initial observation period. Symptomatic patients are usually
those with bulky disease, diffuse bone marrow infiltration
resulting in abnormal blood counts, and threatened organ
function.

48. Extra Nodal Marginal Zone Lymphoma of Conjunctiva
thank you