Follicular Lymphoma. 1. Introduction. 2. Diagnosis. 3. Baseline Investigations

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1 Follicular Lymphoma Follicular Lymphoma Treatment policy prepared by Dr. Louise Bordeleau 1. Introduction Follicular lymphoma is the second most frequent type of non-hodgkin s lymphoma. These lymphomas are classified as follicular small cleaved cell, follicular mixed cell and follicular large cell lymphoma in the Working Formulation [1]. According to the WHO classification, this entity is classified as follicle center cell lymphoma, follicular grade 1 (small cleaved cell), grade 2 (mixed small and large cell) and grade 3 (large cell) [2]. 2. Diagnosis The diagnosis of follicular lymphoma is dependent on an adequate biopsy specimen (preferable open surgical biopsy) with immunohistochemistry. This lymphoma is composed of follicle center cells, usually a mixture of centrocytes (cleaved follicle center cells) and centroblasts (large non-cleaved follicle center cells). The pattern is at least partially follicular, but diffuse areas may be present. The tumor cells are usually surface immune globulin +, B-cell-associated antigen + (CD 19, 20, 79a). Lack of CD5 and CD43 is useful in distinguishing follicle center lymphoma from mantle cell lymphoma and the presence of CD10 can be useful in distinguishing it from marginal zone cell lymphomas [2]. 3. Baseline Investigations The following investigations are indicated for most patients with follicular lymphoma: Pathology review CBC, differential, blood film Serum electrolytes and creatinine Liver function tests Serum LDH Serum protein electrophoresis Serum uric acid Chest x-ray CT chest, abdomen and pelvis Unilateral bone marrow biopsy Toronto-Sunnybrook Regional Cancer Centre Hematology Site Group - Treatment Policies 1/10

2 Patients who will be managed with palliative intent may have more limited staging investigations with a focus on identification of disease that is likely to require symptomatic management. Bone marrow biopsy may not be necessary in patients who are not eligible for experimental treatments or curative radiotherapy. HIV Serology As follicular lymphoma is not usually associated with HIV infection, testing should be limited to patients at risk of such an infection especially if choice of treatment would be affected. Cardiac Assessment A cardiac assessment should be performed in all patients planned to receive an anthracycline-based chemotherapy (such as CHOP). MUGA scan or 2Dechocardiogram should be performed for those patients if known to have a history of: Age > 60 years Hypertension Congestive heart failure Peripheral vascular disease Cerebrovascular disease Angina Cardiac arrhythmia Myocardial infarction Gallium Scan Gallium scans are not routinely recommended, but may be required for patients on experimental therapy. 4. Staging Patients with follicular lymphoma should be staged according to both the Ann Arbor and the IPI staging systems. Ann Arbor Stage The Ann Arbor staging system continues to be in use in follicular lymphoma. This system provides limited prognostic information, but is of use in determining therapeutic management. All patients should have an Ann Arbor stage assigned. 2/10

3 Follicular Lymphoma Stage Definition I II III IV Involvement of a single lymph node region or a single extranodal site. Involvement of two or more lymph nodes on the same side of the diaphragm or localized involvement of an extra lymphatic organ or site and one or more lymph nodes on the same side of the diaphragm. Involvement of lymph node regions on both sides of the diaphragm that may also be accompanied by involvement of the spleen or by localized involvement of an extra lymphatic organ or site or both. Diffuse or disseminated involvement of one or more extra lymphatic organs or tissues, with or without associated lymph node involvement. The absence or presence of fever > 38.5 C, drenching night sweats, and/or unexplained weight loss of 10 percent or more body weight in the six months preceding admission are to be denoted in all cases by the suffix A or B respectively. The International Prognostic Factor Index The International Prognostic Index (IPI) for aggressive non-hodgkin s lymphomas has been found to be an important prognostic tool in low-grade lymphomas [3, 4]. The IPI index is dependent on five prognostic factors: age, Ann Arbor stage, performance status, LDH and number of extranodal sites. Based on the IPI, tenyear overall survival rates for the risk groups are as follows: low, 73.6%; lowintermediate, 45.2%; high-intermediate, 53.5%; and high, 0% (P, 0.001) [3]. In patients with stage III-IV, B symptom(s), age greater than 60 years, and at least three nodal sites greater than 3cm were significant prognostic variables on multivariate analysis. The IPI used in patients with stage III-IV was also significant for progression-free and overall survival [4]. The main limitation of the IPI in patients with follicular lymphoma is that prognostic subgroups do not have a good discriminating power [5]. A number of other prognostic factors have also been studied. Presence of helper T- cell infiltrates and normal hemoglobin have been associated with a favorable prognosis, whereas absence of inter-follicular fibrosis, increased nuclear proliferation, cytogenetics abnormalities, male gender, bulky tumor, hepatosplenomegaly, > 20% bone marrow involvement and a B2 microglobulin > 3 have been associated with unfavorable prognosis. The prognosis value of the number of large cells and the architecture remains equivocal [6]. Toronto-Sunnybrook Regional Cancer Centre Hematology Site Group - Treatment Policies 3/10

4 (A) Survival curves of 125 patients according to the International Index (low v low-intermediate v high-intermediate v high risk: P <.001; low-intermediate risk: not significant). (B) Survival curves after merging groups with low-intermediate and high-intermediate risk (P <.001) [3]. 5. Management of Follicular Grade I-II Patients with localized disease at presentation (stage I-II) may be cured by radiotherapy. Relapse free survival (RFS) is found to be ranging from 55-60% at 5 years and 40-55% at 10 years [7]. Over 25% of patients treated with radiotherapy are unlikely to relapse at any time in the future with RFS of 55% +/- 15% at 15 years for patients with stage I disease and 29% +/- 14% for patients with stage II disease [8]. Long-term disease control within radiation fields can be achieved in a significant number of patients by using doses of radiation that usually range from 2,500 to 4,000 cgy to involved sites or to extended fields, which cover adjacent nodal sites [9,10,11,8]. The value of adjuvant chemotherapy, in addition to radiation to decrease relapse, has not been proven conclusively [12,13]. Most patients will be treated to a dose of 3600 cgy in 18 fractions. For patients with involvement not encompassable by radiation therapy or patients for whom radiation therapy is contraindicated, we recommend treatment as described for the advanced stage. 4/10

5 Follicular Lymphoma Advanced Stage Disease The majority of patients with follicular lymphoma have disseminated disease at presentation and remain incurable with present therapeutic approaches. Current management strategies includes a watch and wait policy, the use of oral alkylating agents (such as chlorambucil or cyclophosphamide), newer purine analogues (fludarabine, 2-CDA) and combination chemotherapy with or without interferon. The optimal treatment is controversial, as the vast majority of patients with advanced stages of follicular lymphoma are not cured with the current therapeutic options. In addition, prolongation of survival has been difficult to demonstrate. Innovative approaches are under clinical evaluation. Watch and Wait Policy: Early intervention has shown no survival advantage to the watch and wait policy [14,15]. This watch and wait policy requires symptomatic disease, before institution of therapy. Once symptomatic, local or systemic therapy is indicated. Systemic Therapy: Systemic therapy should be initiated in symptomatic patients. A variety of treatment options are available: (a) Oral Alkylating Agents (with or without steroids): Chlorambucil and subsequently cyclophosphamide have almost invariably been included in first line treatment of follicular lymphoma since the efficacy of the drugs was first reported [16,17]. (b) Purines Analogues: The treatment efficacy of single-agent purine analogues (fludarabine, 2-chlorodeoxyadenosine) approaches that of the alkylating agents [18,19,20]. (c) Combination Chemotherapy: Combination chemotherapy, such as CVP (cyclophosphamide, vincristine and prednisone) have also been compared to single alkylating agent in the treatment of follicular lymphomas. Although CVP was found to prolong the duration of first remission, the overall response rate and overall survival were equivalent to single agent therapy [21,22]. The addition of adriamycin to CVP (i.e. CHOP) has resulted in a higher remission rate with no significant influence on survival [23]. We recommend watch and wait in asymptomatic patients (+/- bulk). In symptomatic patients with life-threatening disease or rapid progression, we recommend CVP. Other patients should be offered chlorambucil +/- prednisone as initial therapy. CHOP is almost never used as initial therapy. The Role of Interferon Alpha CCO EBR 6-10 Data for the use of interferon maintenance therapy suggest prolonged disease-free survival, but no consistent overall survival benefit [24,25,26]. The role for interferon in patients with follicular lymphoma remains under clinical evaluation. Toronto-Sunnybrook Regional Cancer Centre Hematology Site Group - Treatment Policies 5/10

6 The Role of Dose Intense Therapy with Stem Cell Support The use of autologous bone marrow transplantation in first remission remains investigational. Assessment of Response Responses are classified according to the Cheson criteria (Appendix C). Treatment objectives are to achieve symptomatic control of the disease as well as to prevent potential complications. The achievement of complete remission is not a treatment goal. Management of Incomplete Responders Unless symptomatic, patients with incomplete response should be observed carefully. Treatment (systemic or local) should be offered at the time of disease progression. Follow Up For advanced disease, recurrence is inevitable. The median time to progression is 31 months, with an overall median survival of 6 to 10 years [27,23]. Patients should be followed every 3-4 months for the first 2 years and every 6-12 months thereafter. Assessment should consist of: History & physical exam CBC and differential Liver function tests Creatinine Serum LDH Imaging of involved areas with US +/- CXR should be performed after completion of treatment as a baseline for future comparison. Routine surveillance imaging is an inefficient means of identifying relapse and should be restricted to patients felt to be at high risk of vital organ compromise. Patients wishes should be considered when planning follow up investigations. 6. Follicular Grade III (Follicular Large Cell) Follicular large cell lymphoma (FLCL) is a rare disease that represents ~ 3% of all NHL [2]. FLCL is supposed to have an intermediate prognosis between other follicular lymphomas and the more aggressive diffuse large-cell lymphoma [28]. FLCLs may have sustained remission after standard anthracycline-based chemotherapy (such as CHOP) and therefore are often treated as aggressive lymphomas [28]. This remains an area of controversy. Patients with follicular large cell NHL should be treated similarly to those with diffuse large B-cell lymphoma (see Diffuse Large B-Cell Lymphoma). 6/10

7 Follicular Lymphoma 7. Management of Relapsed Disease Relapse with follicular low-grade non-hodgkin s lymphoma is inevitable in patients with advanced disease and common in patients with localized disease. Although patients often respond again to the same or a similar induction regimen, the quality of their response becomes worse and the duration shorter. Favorable survival after relapse has been associated with age younger than 60 years, complete remission rather than partial remission, and duration of response longer than 1 year [29]. Relapse with both indolent or aggressive histology (histologic conversion) may occur. Biopsy should be performed if the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, has rapid growth or discordant growth between various disease sites. Relapse with Indolent Lymphoma CCO EBR 6-8 Patients who experience a relapse with indolent lymphoma can often have their disease controlled with palliative radiation or systemic therapy. Consideration to experimental therapies should be given at this time. Otherwise, we recommend chlorambucil +/- prednisone if remission duration > 1 year. If remission duration is < 1 year, combination chemotherapy such as CVP can be used first. Significant activity for purine analogues has also been demonstrated in relapsed low-grade lymphomas, either as a single agent [30,31,18] or in combination with other drugs [32]. An anti-cd20 monoclonal antibody results in a 40-50% response rate in patients who relapse with indolent B-cell lymphomas [33]. Radio-labeled monoclonal antibodies are presently under investigation. Bone marrow transplantation is still under evaluation, but can be considered [34]. The therapy of relapsed follicular low-grade lymphoma should be individualized. A sequence appropriate for most patients would consist of the following: Chlorambucil CVP Fludarabine Rituximab Relapse with Histologic Conversion Patients with histologic conversions should be treated with the regimens described in the aggressive, recurrent adult NHL section (CHOP X 6 cycles). A subset of patients with histologic transformation enjoys relatively long-term survival. Patients with limited disease and no previous exposure to chemotherapy have the most favorable prognosis [35]. The addition of radiotherapy can also be considered in patients with residual localized low-grade NHL. Toronto-Sunnybrook Regional Cancer Centre Hematology Site Group - Treatment Policies 7/10

8 8. References 1. Armitage JO, Weisenburger DD. New approach to classifying non-hodgkin s lymphomas: clinical features of the major histologic subtypes. J Clin Oncol Aug;16(8): Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study group. Blood Sep 1;84(5): Lopez-Guillermo A, Montserrat E, Bosch F, et al. Applicability of the International Index for aggressive lymphomas to patients with low-grade lymphoma. J Clin Oncol Jul;12(7): Decaudin D, Lepage E, Brousse N, et al. Low-grade stage III-IV follicular lymphoma; multivariate analysis of prognostic factors in 484 patients--a study of the groupe d Etude des lymphomes de l Adulte. J Clin Oncol Aug;17(8): Bastion Y, Coiffier B. Is the International Prognostic Index for Aggressive Lymphoma patients useful for follicular lymphoma patients? J Clin Oncol Jul;12(7): Horning SJ. Natural history of and therapy for the indolent non-hodgkin s lymphomas. Semin Oncol Oct;20(5 Suppl 5): Pendlebury S, el Awadi M, Ashley S, et al. Radiotherapy results in early stage low grade nodal non-hodgkin s lymphoma. Radiother Oncol Sep;36(3): Denham JW, Denham E, Dear KB, Hudson GV. The follicular non-hodgkin s lymphomas--i. The possibility of cure. Eur J Cancer Mar;32A(3): Mac Manus MP, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol Apr;14(4): Lawrence TS, Urba WJ, Steinberg SM, et al. Retrospective analysis of stage I and II indolent lymphomas at the National Cancer Institute. Int J Radiat Oncol Biol Phys Mar;14(3): Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, et al. Clinical stage 1 non-hodgkin s lymphoma: long-term follow-up patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer Jun;69(6): Kelsey SM, Newland AC, Hudson GV, Jelliffe AM. A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-hodgkin s lymphoma. Med Oncol. 1994;11(1): /10

9 Follicular Lymphoma 13. Seymour JF, McLaughlin P, Fuller LM, et al. High rate of prolonged remissions following combined modality therapy for patients with localized low-grade lymphoma. Ann Oncol Feb;7(2): Young RC, Longo DL, Glatstein E, et al. The treatment of indolent lymphomas; watchful waiting v aggressive combined modality treatment. Semin Hematol Apr;25(2 Suppl 2): Portlock CS, Rosenberg SA. No initial therapy for stage III and IV non-hodgkin s lymphomas of favorable histologic types. Ann Intern Med Jan;90(1): Portlock CS, Rosenberg SA, Glatstein E, Kaplan HS. Treatment of advanced non- Hodgkin s lymphomas with favorable histology: preliminary results of a prospective trial. Blood May;47(5): Rosenberg SA. Karnofsky memorial lecture. The low-grade non-hodgkin s lymphomas: challenges and opportunities. J Clin Oncol Mar;3(3): Redman JR, Cabanillas F, Velasquez WS, et al. Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low-grade lymphoma. J Clin Oncol May;10(5): Solal-Celigny P, Brice P, Brousse N, et al. Phase II trial of fludarabine monophosphate as first-line treatment in patients with advanced follicular lymphoma: a multicenter study by the Groupe d Etude des Lymphomes de l Adulte. J Clin Oncol Feb;14(2): Saven A, Emanuele S, Kosty M, et al. 2-Chlorodeoxyadenosine activity in patients with untreated, indolent non-hodgkin s lymphoma. Blood Sep 1;86(5): Hoppe RT, Kushlan P, Kaplan HS, et al. The treatment of advanced stage favorable histology non-hodgkin s lymphoma: a preliminary report of a randomized trial comparing single agent chemotherapy, combination chemotherapy, and whole body irradiation. Blood Sep;58(3): Ezdinli EZ, Anderson JR, Melvin F, et al. Moderate versus aggressive chemotherapy of nodular lymphocytic poorly differentiated lymphoma. J Clin Oncol Jun;3(6): Dana BW, Dahlberg S, Nathwani BN, et al. Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol Apr;11(4): Hagenbeek A, Carde P, Meerwaldt JH, et al. Maintenance of remission with human recombinant interferon alfa-2a in patients with stages III and IV low-grade malignant non-hodgkin s lymphoma. European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol Jan;16(1):41-7. Toronto-Sunnybrook Regional Cancer Centre Hematology Site Group - Treatment Policies 9/10

10 25. Peterson BA, Petroni GR, Oken MM, et al. Cyclophosphamide versus cyclophosphamide plus interferon alfa-2b in follicular low-grade lymphomas: an intergroup phase III trial (CALGB 8691 and EST 7486). Proc Am Soc Clin Oncol 16, A-48, 14a, Arranz R, Garcia-Alfonso P, Sobrino P, et al. Role of interferon alfa-2b in the induction and maintenance treatment of low-grade non-hodgkin s lymphoma: results from a prospective, multicenter trial with double randomization. J Clin Oncol Apr;16(4): Johnson PW, Rohatiner AZ, Whelan JS, et al. Patterns of survival in patients with recurrent follicular lymphoma: a 20-year study from a single center. J Clin Oncol Jan;13(1): Bartlett NL, Rizeq M, Dorfman RF, et al. Follicular large-cell lymphoma: intermediate or low grade? J Clin Oncol Jul;12(7): Weisdorf DJ, Andersen JW, Glick JH, Oken MM. Survival after relapse of low-grade non-hodgkin s lymphoma: implications for marrow transplantation. J Clin Oncol Jun;10(6): Hochster HS, Kim K, Green MD, et al. Activity of fludarabine in previously treated non-hodgkin s low-grade lymphoma: results of an Eastern Cooperative Oncology Group Study. J Clin Oncol Jan;10(1): Kay AC, Saven A, Carrera CJ, et al. 2-Chlorodeoxyadenosine treatment of lowgrade lymphomas. J Clin Oncol Mar;10(3): McLaughlin P, Hagemeister FB, Romaguera JE, et al. Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma. J Clin Oncol Apr;14(4): McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-cd20 monoclonal antibody therapy for relapsed indolent lymphoma; half of patients respond to a four-dose treatment program. J Clin Oncol Aug;16(8): Laport GF, Williams SF. The role of high-dose chemotherapy in patients with Hodgkin s disease and non-hodgkin s lymphoma. Semin Oncol Aug;25(4): Yuen AR, Kamel OW, Halpern J, Horning SJ. Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol Jul;13(7): /10