TREATMENT TREATMENT OF OF

INDOLENT INDOLENT LYMPHOMASLYMPHOMAS

DR ARNAB BOSEDept. of RadiotherapyNRS Medical College, Kolkata

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.

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

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.

Follicular Lymphoma Grade I/II/IIIa

STAGE I/IIInitial 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

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

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

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 )

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

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

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.

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.

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) with/without Rituximab is an alternative for these patients.

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

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

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

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

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

Radio Immuno Therapy (RIT):

i) I131 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).

ii) Y90 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.

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.

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.

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.

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.

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

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)

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

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

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

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

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

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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

patients, since early treatment has not been shown to improve survival.

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.

thank you

Extra Nodal Marginal Zone Lymphoma of Conjunctiva