MANAGEMENT OF INDOLENT LYMPHOMA

• FOLLICULAR LYMPHOMA GRADE 1-2

• Marginal zone lymphoma (MZL): Extranodal (MALT lymphoma)

NodalSplenic

• Lymphoplasmacytic Lymphoma

FOLLICULAR LYMPHOMA GRADE 1-2

• second most common lymphoma

• 30% of all NHLs and up to 70% of low-grade lymphomas reported

• affects predominantly older adults, with a slight female predominance

• Most patients have widespread disease at diagnosis,

• Despite the advanced stage, the clinical course is generally indolent; however, the disease is not usually curable with available treatment

• has a favorable outcome in the intermediate term, with 5- to 8-year survival rates from 70% to 80%

• relapse rate of 15% to 20% per year

• follicular lymphomas eventually evolve into aggressive lymphomas

• transformation risk of 28% in 10 years

Workup

Staging

Lymph node regions

• stage remains important

• for selection of treatment strategy

• predicting prognosis in each histologic category.

Follicular Lymphoma: Stages I/II

• The treatment historically for stage I/II FL has been RT alone

• 20% of FL patients present with localized (stage I and stage II) disease and are largely curable with radiation therapy

Clinical evidence of treatment of limited-stage indolent NHL

• The reported series were accumulated over a long period

• Patients stage differently

• Treated with varying doses and field

• Different lymphoma in older pathologic classifications.

Common results• Five- and 10-year OS is high 75% to 90%

• Early deaths from lymphoma in this group are quite uncommon.

• The FFS rate is less, 40% to 80%.

• Stage 1 better than 2

• Radiation doses and field varied widely.

• The local control rate was greater than 90%with no dose response demonstrated above 30 Gy

• No evidence of improved survival with field size

• DOSE-

• most current radiotherapy series for stage I and II indolent lymphomas usually employ 30 to 40 Gy

• in-field recurrences have been uncommon

ROLE OF CHEMOTHERAPY

• Randomized studies conducted in the 1970s failed to demonstrate that non adriamycin-containing combination chemotherapy regimens plus RT were superior to RT alone

• British national lymphoma study compared RT vs RT chlorambucil

• No OS or DFS

• A single-arm study of 91 stage I to II patients treated at the M. D. Anderson Hospital with COP OR CHOP

• In addition RT improved DFS compared to historical control but no increase in OS

OBSERVATION ALONE?• The Stanford group -43 patients with early stage follicular

lymphoma who were not immediately treated with XRT.

• Reasons for no initial therapy included physician choice, large abdominal radiation field required, advanced age, concern for xerostomia, and patient refusal.

• At a median follow-up of 86 months, 27 patients (63%) had not required any therapy

• OS comparable with immediately treated with RT

Rx SUMMARY OF FL GR 1-2 STAGE 1-2

• 1 Most patients have a good prognosis after local-regional RT alone.

• 2 Selected patients may be initially observed without initial intervention.

• 3 For patients whose prognosis is less certain, such as those with stage II disease with multiple sites of involvement or bulky nodes

• chemotherapy followed by involved-field irradiation may provide more durable remissions

Therapy of Disseminated Follicular Lymphoma

• Advance stage generally considered incurable

• The optimal treatment strategy for patients with advanced-stage follicular lymphoma is unclear

• Many years of clinical investigation have failed to prove that immediate aggressive therapy improves survival compared with conservative therapy.

• The NCI initiated a prospective randomized study

• comparing conservative treatment (no initial therapy) VS

• Aggressive combined modality therapy with ProMACE (prednisone, methotrexate-leucovorin, doxorubicin, cyclophosphamide, etoposide)/MOPP (mechlorethamine, vincristine, procarbazine, prednisone) chemotherapy

• followed by low-dose (24 Gy) total lymphoid RT

• The disease-free survival was significantly higher in the combined modality therapy group at 4 years (51% vs. 12%)

• no differences in OS were seen.

WHEN TO CONSIDER TREATMENT• Symptomatic disease

• Threatened end organ function

• Cytopenia secondary to lymphoma

• Bulky disease (single > 7 cm or 3 or more >3 cm)

• Splenomegaly or steady progression over at least 6 months

CHEMOTHERAPY REGIMEN

• FL is quite responsive to a variety of systemic agents,

• alkylating agents• Anthracyclines• purine analogs• vinca alkaloids• Corticosteroids• monoclonal antibodies

• single alkylating agents (cyclophosphamide or chlorambucil) are directly compared with

• combinations of three drugs (COP), significant differences in long-term outcome, including survival, are not observed

• Southwest Oncology Group of 415 patients

• doxorubicin-containing treatment did not prolong the overall median survival

• compared with results with less aggressive regimen

• Why combination therapy?

• speed of response

• possibly prolonged disease-free interval compared with less intense programs

• Combinations of fludarabine with mitoxantrone have demonstrated very high response rates

Role of rituximab• Hainsworth et al.used rituximab (375 mg/m2 iv per week for 4

consecutive weeks) as initial therapy

• Patients who did not progress received an additional 4-week course of rituximab every 6 months for 2 years.

• In 62 chemotherapy-naive patients, most of whom had stage III or IV disease

• 37% complete remissions and median PFS was 34 months

Chemotherapy-Biologic Combinations

• Marcus et al. randomized previously untreated patients with advanced stage follicular lymphoma

• 8 cycles of CVP plus rituximab (R-CVP) or CVP alone.

• Overall and complete response rates were 81% and 41% in the R-CVP arm versus 57% and 10% in the CVP arm.

• At a median follow-up of 30 months, patients treated with R-CVP had a very significantly prolonged time to progression (median 32 months vs. 15 months for CVP)

• a randomized trial comparing mitoxantrone, chlorambucil, and prednisone (MCP) alone with rituximab plus MCP (R-MCP).

• Also showed superior result on addition of rituximab

• Bendamustine along with rituximab

• Higher PFS and CR

• Similar ORR

• The use of the radiolabeled monoclonal antibody iodine-131 tositumomab in previously untreated patients has also been reported to produce a high CR rate

• chemoimmunotherapeutic approach

• combining standard induction chemotherapy (CHOP) followed by consolidation with 131I tositumomab

• CR PFS better than chemo alone

CHEMOTHERAPY REGIMENS

• R COP or R CHOP preferred

• BR

• Single agent Rituximab or oral cyclophosphomide in elderly frail patients

Consolidation

• Who had CR or PR

• Remission Maintenance: Role of Rituximab

• Rituximab maintenance after chemotherapy alone provides significant benefit as far as PFS and borderline OS benefit

• Maintenance therapy with Rituximab once in 8 week for 2 years

Rx for relapsed or progressive ds

• Histologically document to r/o transformation

• R-FCM regimen

• RIT( RADIO IMMUNOTHERAPY)

• radiolabeled monoclonal antibody iodine-131 tositumomab and yttrium-90 ibritumomab tiuxetan

Role of RT

Extranodal Marginal Zone B-Cell Lymphoma

• Low-Grade B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue

• accounts for the majority of low-grade gastric lymphomas and almost 50% of all gastric lymphomas

• ocular adnexa, they make up approximately 40% of the cases, and they account for the majority of low-grade pulmonary lymphomas

• Patients are usually older adults

• female predominance has been reported .

• The majority of patients present with localized stage I or II extranodal disease

• The stomach is the most frequent site

• salivary glands, skin, orbit, conjunctiva, lung, thyroid, larynx, breast, kidney, liver, bladder, prostate, urethra, small intestine, rectum, pancreas, and even in the intracranial dura

• Twenty-five percent of gastric MALT lymphomas and 46% of nongastric MALT lymphomas had evidence of disseminated disease

• Many patients have a history of autoimmune disease

• Sjogren's syndrome or Hashimoto's thyroiditis

• Helicobacter gastritis in the case of gastric MALT lymphoma

• Mediterranean abdominal lymphoma, a heavy-chain and immunoproliferative small intestinal disease- C Jejni

• Gastric MALT lymphoma

• C/F- Dyspepsia ,abdominal pain, reflux, nausea, weight loss

• Endoscopic biopsy

• Erythema, erosion and ulceration

Therapy of Mucosa-Associated Lymphoid Tissue Lymphomas

• these diseases tend to remain localized for long periods of time

• local treatment (surgery or radiation therapy [RT]) is effective at long-term control of disease

• low doses of RT (30 Gy) almost always control sites of disease

• Local control rates ranged from 97% to 100%

• 5-year PFS and OS were approximately 76% and 91%, respectively

• Gastric MALT lymphoma is frequently associated with chronic gastritis and H. pylori infection.

• antibiotics against H pylori

• 70% of patients remained in complete remission

• If PR further antibiotics should be considered

• RT ?

• NO response with abx

• Negative for H pylori(t 11: 18)

• local control and relief of symptoms in greater than 90% of patients

• Dose 30- 35 Gy 1.8-2 Gy per fraction

• Sx good result but increased morbidity

• Role of chemotherapy

• In local disease chemo inferior to RT

• Disseminated ds got similar role as in FL

• NON GASTRIC MALT LYMPHOMA

• Stage 1-2 IFRT 24-30 Gy

• Observation if diagnostic biopsy excisional

Nodal Marginal Zone B-Cell Lymphoma

• monocytoid B-cell lymphomas

• rare disorder, accounting for 1% of the cases

• presented with isolated or generalized nodal disease

• Peripheral nodes involved in > 95%

• Thoraccic or abdominal in 50%

• bone marrow was involved in 30%

• Patients are frequently treated with regimens that are used for follicular lymphoma

Splenic Marginal Zone Lymphoma• commonly seen in elderly men, the disease can occur in both

genders and in young patients

• Patients typically present with weakness, fatigue, or symptoms related to splenomegaly

• splenomegaly in almost all patients

• hepatomegaly in up to 40% of patients

• Peripheral lymphadenopathy is rare but splenic hilar nodes usually involved

• Thoracic or abdominal nodes in 30%

• Lymphocytosis is a uniform finding, but extreme lymphocytosis is unusual.

• Anemia and thrombocytopenia are present in a minority of patients

• Most have stage IV disease, principally because of bone marrow involvement(85%)

• prognostic factors

• hemoglobin level less than 12 g/dL• LDH level greater than normal• albumin level less than 3.5 g/dL

• low-risk group (41%) with no adverse factors(88%)

• intermediate-risk group (34%) with one adverse factor(73%)

• high-risk group (25%) with 2 or 3 adverse factors(50%).

Treatment

• Observation – asymptomatic with out cytopenia and splenomegaly

• HCV infection in 35% of SMZL

• IF +ve anti HCV Therapy with ribavirine and INF @

• HCV –ve

• Splenectomy (80-90% Overall response and MS 93 Months)

• R or R COP

Follow up

RADIATION THERAPY TECHNIQUE

• Extended radiation treatment fields for NHL

Involved-fi eld radiation therapy (IFRT)

Lymphoplasmacytic lymphoma

• neoplasm of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells

• involving bone marrow, lymph nodes, and spleen,

• lacking CD5, usually with a serum monoclonal protein with hyperviscosity or cryoglobulinemia.

• Cells may contain intranuclear inclusions of periodic acid Schiff positive IgM (Dutcher bodies).

• The cells have surface and cytoplasmic (some cells) Ig, usually of IgM type; usually lack IgD;

• strongly express B-cell associated antigens (CD19, CD20, CD22, CD79a).

• The cells are CD5, CD10, CD23; CD25 or CD11c may be faintly positive in some cases

• the median age was 63 years and 53% were men;

• most (73%) had bone marrow involvement.

• Lymph node and splenic involvement is common

• A monoclonal serum paraprotein of IgM type, with or without hyperviscosity syndrome in most cases

• Most cases of mixed cryoglobulinemia have been shown to be related to HCV infection

Treatment

• Treatment of patients with HCV and cryoglobulinemia with interferon to reduce viral load has been associated with regression of the lymphoma.

• chlorambucil with or without prednisone

• Fludarabine with or with out rituximab

• Thalidomide and bortezomib