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Follicular Lymphoma: Expanding Therapeutic Options

Follicular Lymphoma: Expanding Therapeutic Options

The most common indolent lymphoma, follicular lymphoma comprises 35% of adult non-Hodgkin’s lymphoma (NHL) in the United States and 22% worldwide. Features associated with adverse outcome include age, male gender, disease stage, and performance status, with the International Prognostic Index being the most widely used risk classification system. Long-term disease-free survival is possible in select patient subgroups after treatment, but very late relapses suggest that quiescent lymphoma cells might be harbored for long periods of time. Radiation therapy is the mainstay of treatment for limited-stage follicular lymphoma, but there is some experience with chemotherapy and combined chemoradiation. When to initiate treatment in patients with advanced disease is controversial, but options include various combined chemotherapy regimens, monoclonal antibodies, radiolabeled antibodies, and bone marrow or stem cell transplantation. Future directions in the treatment of follicular lymphoma include vaccines, antisense therapy, and proteasome inhibitors.

Follicular lymphoma is a type of non-Hodgkin's lymphoma (NHL) that arises from the follicle center B lymphocytes and has a follicular pattern on histopathologic examination.[1] It is the most common indolent lymphoma, comprising 35% of adult NHL in the United States and 22% worldwide.[2] It most commonly is seen in middle-aged individuals and the elderly, with a median age of diagnosis of 59 years, as compared to 64 years for patients with diffuse large B-cell lymphoma. Females (52%) are slightly more often affected than males (48%).[3,4] Morphologically, follicular lymphoma is composed of a mixture of centrocytes (cleaved follicle center cells) and centroblasts (large noncleaved follicle center cells), with centrocytes being the predominant cell type and centroblasts being in the minority.[ 5] The most reproducible method of grading follicular lymphoma, as described by Berard and Mann, is based on the absolute number of centroblasts in 10 neoplastic follicles, expressed per 40* high power field (hpf): grade 1 is defined as 0-5 centroblasts/ hpf; grade 2, as 6-15 centroblasts/ hpf; and grade 3, as > 15 centroblasts/hpf.[6] Clinically, the behavior and outcome of grades 1 and 2 follicular lymphoma are similar, and both are considered indolent lymphomas. In contrast, grade 3 is a more aggressive disease.[7] Patients usually present with diffuse, painless, persistent, generalized lymphadenopathy, and except for bone marrow involvement, extranodal disease is uncommon. The size of the lymph nodes may vary with time, and complete disappearance followed by reappearance has been reported. The Ann Arbor staging system developed in 1971 for Hodgkin's disease has been adapted for staging NHL as well.[8,9] In a retrospective analysis, Anderson et al found that clinically, 66% of patients had stage III disease, whereas pathologically, 84% of patients had stage III/IV disease at presentation.[10] Prognostic Features A large number of features have been associated with an adverse outcome in follicular lymphoma, including increased age, male gender, stage of disease, performance status, presence of B symptoms, elevated levels of serum lactate dehydrogenase (LDH), serum beta-2 microglobulin, and hemoglobin, as well as bulk disease and extranodal involvement. The most widely used system is the International Prognostic Index (IPI). According to the IPI, age > 60 years, stage III/IV disease, Eastern Cooperative Oncology Group (ECOG) performance status < 2, involvement of more than two extranodal sites, and elevated serum LDH levels are considered adverse prognostic factors.[ 11] In a Spanish study, 10-year overall survival rates were 74% for low, 45% for low-intermediate, 54% for high-intermediate, and 0% for high-risk groups based on IPI score (P < .001).[12] In 1991, Romaguera et al developed a model based on the tumor burden to predict outcomes in follicular lymphoma. The investigators included number of extranodal sites involved, degree of bone marrow involvement, and lymph node size in this model, and found that patients with a low tumor burden had a 10-year survival of 73% as compared to 24% for those with a high tumor burden.[ 13] Decaudin et al studied 484 patients with stage III/IV follicular lymphoma, identifying three prognostic factors for poor overall survival: B symptoms, age greater than 60 years, and at least three nodal sites greater than 3 cm.[14] Frederico et al devised a prognostic model based on age, gender, number of extranodal sites, B symptoms, serum LDH level, and erythrocyte sedimentation rate. They found a 5- and 10-year survival rate of 90% and 65% for patients at low risk, respectively; 75% and 54% for patients at intermediate risk; and 38% and 11% for those at high risk.[15] In a recent retrospective analysis of 810 patients treated with anthracycline- based chemotherapy and adjuvant radiotherapy to sites of initial bulky nodal disease, only three factors- age > 60 years, presence of B symptoms, and involvement of more than two extranodal sites-were found to influence overall and progressionfree survival. When the IPI was applied to these patients, no statistical differences were observed in outcomes between the various groups. This suggests a lack of uniform prognostic factors for follicular lymphoma, indicating an urgent need for multicentric international clinical analysis to define prognostic factors.[16] Recently, an international group looked at a variety of prognostic factors in a large number of patients with follicular lymphoma and found that age ≥ 60 years, stage III/IV disease, elevated LDH level, hemoglobin < 12 g/dL, and number of nodal sites ≥ 5 had a significant adverse effect on survival. They designed an index based on these factors: the Follicular Lymphoma International Prognostic Index (FLIPI). Based on the FLIPI, patients could be divided into three prognostic groups: good (0-1 adverse prognostic factor), intermediate (2 factors), and poor (≥ 3 factors). The 10-year overall survival was 70.7%, 50.9%, and 35.5%, respectively for the three groups (Table 1).[17] The role of histopathology in predicting outcome is much more controversial. It is generally agreed that the presence of large cells confer a more aggressive nature to follicular lymphoma.[18,19] The degree of nodularity has also been studied as a prognostic factor. In an ECOG study, a pure nodular pattern (defined as nodularity involving 75% or more of the cross-sectional area) was found to be an important favorable prognostic indicator as compared with a nodulardiffuse pattern.[20] Similarly, Hu et al from Stanford University found that patients with focally follicular areas (ie, < 25% of the histologic section) had significantly worse outcomes compared with patients with a predominantly follicular architecture (ie, > 50% of the section).[21] Another recent study from the University of Nebraska found that cases of follicular lymphoma (grade 3) with a predominant diffuse component (> 50%) had a significantly worse overall and event-free survival (similar to diffuse large B-cell lymphoma) than those without.[22] Martin et al studied the prognostic value of proliferative index in 106 patients with follicular lymphoma. They determined the proliferative index quantitatively using an automated image analyzer and found that patients with a low proliferative index (< 40%) had a significantly longer overall survival than those with a high proliferative index (≥ 40%), but the proliferative index did not predict failure-free survival.[23] Clinical Course Horning and Rosenberg studied 83 asymptomatic patients with low-grade NHL (most of whom had follicular lymphoma), in whom the advanced disease was initially managed without therapy. The 5- and 10-year actuarial survival rates were 82% and 73%, respectively, and spontaneous regressions occurred in 19 untreated patients.[ 24] Portlock and Rosenberg retrospectively studied 44 asymptomatic patients with stage III/IV NHL who received no initial treatment. They found that the median time to treatment was 31 months, and the median survival was 121 months. The 4-year actuarial survival was 77.3%.[25] More recently, in a retrospective study conducted at Stanford University, Advani et al studied 43 patients with stage I/II follicular lymphoma who were not treated initially. They showed in this study that deferred therapy is an acceptable approach for patients with early-stage disease.[26] Some authors have stated that conventional chemotherapy is neither curative nor does it substantially modify the natural course of follicular lymphoma.[ 27] Patients with disseminated disease ultimately die from the disease, with a median survival time of 8 to 10 years.[28] However, longterm disease-free survival (relapsefree survival of ~50%) has been noted in a number of settings, ie, limitedstage disease, grade 3 follicular lymphoma (unpublished data), achievement of complete remission following chemotherapy or concomitant chemotherapy and radiation therapy (RT), and following autologous stem cell transplantation.[29-34] Whether one considers follicular lymphoma to be curable depends on the definition of cure. If one considers clinical cure (ie, the absence of a clinically obvious relapse) as the criterion, this has been demonstrated in various groups of patients who have had a long-term disease-free survival following various interventions as mentioned above. However, since follicular lymphomas have an extremely indolent course, it is very difficult to determine if clinical cure corresponds to complete elimination of all lymphoma cells. In addition, patients in clinical remission can have small numbers of circulating lymphocytes exhibiting t(14;18) translocations that are considered pathognomonic of follicular lymphoma.[35] However, these cells can also be identified in the peripheral blood of healthy individuals. Schuler et al found that if the sensitivity of the assay used for detection was high enough in almost all healthy individuals, one or multiple cell clones carrying the t(14;18) translocation could be found.[36] Thus, long-term disease-free survival is possible after treatment of patients with follicular lymphoma, but it is impossible to be sure that this corresponds to the absence of even a single lymphoma cell in the patient. Very late relapses suggest that some patients might harbor quiescent lymphoma cells for very long periods of time. Treatment of Limited-Stage Disease No Initial Treatment
In a French study, Brice et al randomized 193 newly diagnosed follicular lymphoma patients with a low tumor burden to no initial treatment, prednimustine, or interferon alfa-2b (Intron A) and found no difference in the overall survival rate at 5 years among the three groups.[37] In the Stanford study described above, Advani et al found that at a median follow-up of 86 months, 27 patients (63%) had not yet required treatment.[26] Radiation Therapy
Radiation therapy has been the mainstay of treatment for limited-stage grade 1 and 2 follicular lymphoma. Table 2 presents an overview of the clinical trials that have used RT as the major modality for treatment.[38-49] The results of these studies uniformly show that involved-field RT confers a 10-year failure-free survival of approximately 45% in patients presenting with early-stage disease. Chemotherapy
The role of chemotherapy alone in the treatment of early-stage follicular lymphoma is not exactly clear. Jeffery et al treated 30 patients with nonbulky stage I, nodal, intermediate-grade NHL with RT. They then compared the outcomes in 11 patients with bulky stage I disease treated with combination chemotherapy. They found that the 5-year actuarial survival for the 30 patients treated with RT was 86%, as compared to a 60% 4-year actuarial survival in the 11 patients treated with chemotherapy.[50] In contrast, Teczan et al evaluated 40 patients with previously untreated follicular lymphoma and found that stage IA patients treated with chemotherapy (with or without RT) showed a better trend for 10-year event-free survival as compared to RT alone. There was, however, no difference in the estimated 10-year overall survival.[51] Combined Chemoradiation
In a study conducted at Memorial Sloan-Kettering Cancer Center, Yahalom et al randomized 44 patients with clinical or pathologic stage I intermediate-grade or low-grade NHL to receive regional RT alone or regional RT followed by six cycles of CHOP chemotherapy (cyclophosphamide [Cytoxan, Neosar]/doxorubicin HCl/vincristine [Oncovin]/prednisone). They found an 83% actuarial relapse-free survival rate for the RT-plus-CHOP group at 7 years, compared with 47% for the RT-alone group. The overall survival for the two groups was 88% and 66%, respectively. However, in patients with low-grade NHL, the addition of adjuvant CHOP did not improve outcomes.[52] McLaughlin et al prospectively treated 44 patients with stage I/II lowgrade lymphoma with sequential chemotherapy and involved-field RT. At a median follow-up of 32 months, they had 5-year overall and failurefree survival rates of 89% and 74%, respectively.[53] Seymour et al studied 102 eligible patients with stage I/II low-grade lymphoma (85 patients with follicular lymphoma) treated with chemotherapy and involved-field RT. They found that the 10-year time to treatment failure and overall survival rates in patients with follicular lymphoma were 72% and 80%, respectively.[ 54] These results constitute a marked improvement in the 10-year disease-free survival of 41% to 64% reported by the various studies involving RT alone described above. Richards et al retrospectively studied 202 patients with clinical stage I/II NHL between 1972 and 1985. They found that although the duration of remission was better in patients who received adjuvant chemotherapy than in those treated with RT alone, there was no difference in overall survival between the two groups of patients. Since neither of these were randomized trials, it is unclear whether the addition of chemotherapy would improve the outcomes obtained by RT alone.[55] Treatment of Advanced Disease No Initial Treatment
The exact time to initiate treatment in this setting is controversial, since these patients have a prolonged survival despite frequent relapses. In an effort to answer the question of whether early aggressive therapy is superior to watchful waiting, the National Cancer Institute (NCI) conducted a study in 104 patients with advanced indolent lymphomas. They randomly assigned 44 patients to the watchful waiting group, in which only carefully defined, limited RT was administered if necessary; 45 were randomly assigned to aggressive combinedmodality treatment with ProMACEMOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine [Mustargen], vincristine, procarbazine [Matulane], prednisone), followed by total nodal irradiation. They found no difference in overall survival at 5 years (> 75% in each group), but diseasefree survival was better in the group that received initial therapy.[56] In a recently published British study, Ardeshna et al randomized 309 patients with asymptomatic, advancedstage, low-grade NHL (204 patients with follicular lymphoma) to immediate systemic chemotherapy with chlorambucil (Leukeran), 10 mg/d continuously, vs an initial policy of observation with systemic therapy delayed until disease progression. However, in contrast to the above study, they found that overall survival and cause-specific survival did not differ between the two groups.[57] Chemotherapy

  • CVP-Systemic chemotherapy is the mainstay of treatment in patients with advanced-stage follicular lymphoma. Hoppe et al randomized 51 patients with favorable-histology NHL (pathologic stage III/IV disease) to single-alkylating agent chemotherapy, combination chemotherapy with CVP (cyclophosphamide, vincristine, prednisone), or fractionated wholebody irradiation followed by low-dose involved-field irradiation. They found an actuarial survival of 84% at 4 years, with similar survival observed for each of the three treatment options.[58]
  • Kennedy et al randomized 58 patients with advanced lymphoma to the CVP combination or these same three agents given separately in succession. They demonstrated a complete remission rate of 81% with the combination and 46% with sequential use of the three agents.[59] Portlock et al randomized 63 previously untreated patients with stage IV NHL with favorable histologies to three groups: CVP alone, split-course CVP and total lymphoid irradiation, or single- alkylating agent therapy. The actuarial probability of obtaining a complete remission was greater than 80% in all three groups. In contrast to the above findings of Kennedy et al, they found no statistically significant differences among the groups in terms of the probability of disease-free or overall survival.[60]

  • CHOP-Peterson et al randomized 228 patients with stage III/IV follicular lymphoma to cyclophosphamide or the CHOP-B combination (cyclophosphamide, doxorubicin, vincristine, prednisone, bleomycin [Blenoxane]). These investigators observed complete responses in 66% of those treated with cyclophosphamide and in 60% of those treated with CHOP-B. They found no difference in overall survival between the two groups. However, in an unplanned subgroup analysis, patients with follicular mixed lymphoma who received the combination experienced improved disease control and survival.[61]
  • Jones et al compared two CHOP regimens (CHOP with either low-dose bleomycin or bacille Calmette-Gurin [BCG] by scarification) to COP-Bleo (cyclophosphamide/vincristine/prednisone, with low-dose bleomycin). In patients with follicular lymphoma, they found no difference in complete response rates, relapse-free survival, and overall survival among the three groups.[62]

  • Other Combinations-In an effort to improve outcomes in this setting, other regimens have been tried. Ezdinli and associates analyzed 252 patients with advanced-stage favorable NHL treated with moderate-CP (cyclophosphamide, prednisone)-vs intensive- BCVP (carmustine [BCNU, Gliadel], cyclophosphamide, vincristine, prednisone) or COPP (cyclophosphamide, vincristine, procarbazine, prednisone)-chemotherapy regimens. They found an overall complete response rate of 57% and a median duration of remission of 88 weeks. There was no difference in the response rate, response duration, or survival rate among the various groups.[63]
  • In a recent Italian study, Zinzani et al performed a comparative trial of FM (fludarabine [Fludara], mitoxantrone [Novantrone]) with CHOP as front-line chemotherapy, with and without sequential rituximab (Rituxan). They randomized 140 previously untreated patients with grades 1 and 2 follicular lymphoma to either CHOP or FM. The overall clinical response was the same in both groups (FM: 96%; CHOP: 98%). However, the complete response rate was higher in the FM arm (68% vs 42%; P = .003). They also found that the percentage of patients with a negative bcl-2/immunoglobulin heavy chain (IgH) status by qualitative polymerase chain reaction was higher in the FM group (47% vs 29%; P = .03). These results seem to indicate that FM may be superior to CHOP for front-line therapy of follicular lymphoma. However, it is unclear whether this superiority translate into superior progression-free or overall survival.[64]

  • Interferon-Interferon has been tried alone and in combination with cytotoxic chemotherapy for the treatment of advanced follicular lymphoma. The individual studies are summarized in Table 3.[37,65-72] Rohatiner et al performed a meta-analysis of these clinical trials involving interferon. Their initial meta-analysis showed an overall survival difference in favor of interferon, but a significant heterogeneity effect suggested significant differences between trials.
  • The investigators then divided the trials based on the interferon dose used and found that trials using a more intensive therapy showed a large and significant survival advantage in favor of interferon, with a 14% survival difference at 5 years (74% vs 60%) and a 19% survival difference at 8 years (57% vs 38%). However, trials that used a low-intensity interferon regimen showed no survival difference.[ 73] The results with the use of interferon are mixed, thereby leading to controversy about the exact role of interferon in the treatment of advanced follicular lymphoma.

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