indolent lymphoma-management
TRANSCRIPT
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MANAGEMENT OF INDOLENT LYMPHOMA
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• FOLLICULAR LYMPHOMA GRADE 1-2
• Marginal zone lymphoma (MZL): Extranodal (MALT lymphoma)
NodalSplenic
• Lymphoplasmacytic Lymphoma
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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,
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• 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
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Workup
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Staging
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Lymph node regions
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• stage remains important
• for selection of treatment strategy
• predicting prognosis in each histologic category.
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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
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Clinical evidence of treatment of limited-stage indolent NHL
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• The reported series were accumulated over a long period
• Patients stage differently
• Treated with varying doses and field
• Different lymphoma in older pathologic classifications.
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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
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• DOSE-
• most current radiotherapy series for stage I and II indolent lymphomas usually employ 30 to 40 Gy
• in-field recurrences have been uncommon
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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
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• 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
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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
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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
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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.
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• 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
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• 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.
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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
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CHEMOTHERAPY REGIMEN
• FL is quite responsive to a variety of systemic agents,
• alkylating agents• Anthracyclines• purine analogs• vinca alkaloids• Corticosteroids• monoclonal antibodies
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• 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
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• 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
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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
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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)
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• 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
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• 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
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CHEMOTHERAPY REGIMENS
• R COP or R CHOP preferred
• BR
• Single agent Rituximab or oral cyclophosphomide in elderly frail patients
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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
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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
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Role of RT
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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 .
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• 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
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• 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
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• Gastric MALT lymphoma
• C/F- Dyspepsia ,abdominal pain, reflux, nausea, weight loss
• Endoscopic biopsy
• Erythema, erosion and ulceration
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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
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• 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
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• 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
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• Sx good result but increased morbidity
• Role of chemotherapy
• In local disease chemo inferior to RT
• Disseminated ds got similar role as in FL
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• NON GASTRIC MALT LYMPHOMA
• Stage 1-2 IFRT 24-30 Gy
• Observation if diagnostic biopsy excisional
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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%
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• bone marrow was involved in 30%
• Patients are frequently treated with regimens that are used for follicular lymphoma
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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
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• 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%)
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• 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%).
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Treatment
• Observation – asymptomatic with out cytopenia and splenomegaly
• HCV infection in 35% of SMZL
• IF +ve anti HCV Therapy with ribavirine and INF @
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• HCV –ve
• Splenectomy (80-90% Overall response and MS 93 Months)
• R or R COP
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Follow up
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RADIATION THERAPY TECHNIQUE
• Extended radiation treatment fields for NHL
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Involved-fi eld radiation therapy (IFRT)
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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).
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• 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.
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• 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
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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