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. It is the most common indolent lymphoma, comprising 35% of adult NHL in the United States and 22% worldwide. 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. 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. 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. 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). 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. 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. 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. 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). 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. 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). 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. 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. 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%. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.
- 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.
- 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.
- 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.
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. 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.
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.
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.
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.
Dr. Armitage is a speaker for Genentech, GlaxoSmithKline, and Corixa. The other authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Armitage JO, Mauch PM, Harris NL, et al: Non-Hodgkin’s lymphomas, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 6th ed, pp 2256-2316. Philadelphia, Lippincott Williams & Wilkins, 2001.
2. A clinical evaluation of the International Lymphoma Study Group classification of non- Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood 89:3909-3918, 1997.
3. Armitage JO, Weisenberger DD: New approach to classifying non-Hodgkin’s lymphomas: Clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 16:2780-2795, 1998.
4. National Cancer Institute-sponsored study of classification of non-Hodgkin’s lymphomas: Summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathological Classification Project. Cancer 49:2112-2135, 1982.
5. Nathwani BN, Harris NL, Weisenberger DD, et al: Follicular lymphoma, in Jaffe ES, Haris NL, Stein H, et al (eds): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, pp 162- 168. Lyon, IARC Press, 2001.
6. Mann RB, Berard CW: Criteria for the cytologic classification of follicular lymphomas: A proposed alternative method. Hematol Oncol 1:187-192, 1983.
7. Harris NL, Jaffe ES, Diebold J, et al: World Health Organization classification of neoplastic diseases haematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol 17:3835-3849, 1999.
8. Rosenberg SA: Validity of the Ann Arbor staging classification for the non-Hodgkin’s lymphomas. Cancer Treat Rep 61:1023-1027, 1977.
9. Moormeier JA, Williams SF, Golomb HM: The staging of non-Hodgkin’s lymphomas. Semin Oncol 17:43-50, 1990.
10. Anderson T, Chabner BA, Young RC, et al: Malignant lymphoma. 1. The histology and staging of 473 patients at the National Cancer Institute. Cancer 50:2699-2707, 1982.
11. A predictive model for aggressive non- Hodgkin’s lymphoma. The International Non- Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 329:987-994, 1993.
12. 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 12:1343-1348, 1994.
13. Romaguera JE, McLaughlin P, North L, et al: Multivariate analysis of prognostic factors in stage IV follicular low-grade lymphoma: A risk model. J Clin Oncol 9:762-769, 1991.
14. 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 17:2499- 2505, 1999.
15. Federico M, Vitolo U, Zinzani PL, et al: Prognosis of follicular lymphoma: A predictive model based on a retrospective analysis of 987 cases. Intergruppo Italiano Linfomi. Blood 95:783-789, 2000.
16. Aviles A, Neri N, Cuadra I, et al: Lack of prognostic factors in follicular lymphoma. Leuk Lymphoma 44:143-147, 2003.
17. Solal-Celigny P, Roy P, Colombat P, et al: Follicular lymphoma international prognostic index. Blood 104:1258-1265, 2004.
18. Kantarjian HM, McLaughlin P, Fuller LM, et al: Follicular large cell lymphoma: Analysis and prognostic factors in 62 patients. J Clin Oncol 2:811-809, 1984.
19. Rodriguez J, McLaughlin P, Hagemeister FB, et al: Follicular large cell lymphoma: An aggressive lymphoma that often presents with favorable prognostic features. Blood 93:2202- 2207, 1999.
20. Ezdinli EZ, Costello WG, Kucuk O, et al: Effect of the degree of nodularity on the survival of patients with nodular lymphomas. J Clin Oncol 5:413-418, 1987.
21. Hu E, Weiss LM, Hoppe RT, et al: Follicular and diffuse mixed small-cleaved and large-cell lymphoma—a clinicopathologic study. J Clin Oncol 3:1183-1187, 1985.
22. Hans CP, Weisenburger DD, Vose JM, et al: A significant diffuse component predicts for inferior survival in grade 3 follicular lymphoma, but cytologic subtypes do not predict survival. Blood 101:2363-2367, 2003.
23. Martin AR, Weisenburger DD, Chan WC, et al: Prognostic value of cellular proliferation and histologic grade in follicular lymphoma. Blood 85:3671-3678, 1995.
24. Horning SJ, Rosenberg SA: The natural history of initially untreated low-grade non- Hodgkin’s lymphomas. N Engl J Med 311:1471-1475, 1984.
25. Portlock CS, Rosenberg SA: No initial therapy for stage III and IV non-Hodgkin’s lymphomas of favorable histologic types. Ann Intern Med 90:10-13, 1979.
26. Advani R, Rosenberg SA, Horning SJ: Stage I and II follicular non-Hodgkin’s lymphoma: Long term follow-up of no initial therapy. J Clin Oncol 22:1454-1459, 2004.
27. Hunault-Berger M, Ifrah N, Solal- Celigny P: Groupe Ouest-Est des Leucemies Aiguee et des Maladies du Sang (GOELAMS): Intensive therapies in follicular non-Hodgkin lymphomas. Blood 100:1141-1152, 2002.
28. Horning SJ: Follicular lymphoma: Have we made any progress? Ann Oncol 11:23-27, 2000.
29. Gospodarowicz MK, Bush RS, Brown TC, et al: Prognostic factors in nodular lymphomas: A multivariate analysis based on the Princess Margaret Hospital experience. Int J Radiat Oncol Biol Phys 10:489-497, 1984.
30. Maartense E, Le Cessie S, Kluin- Nelemans HC, et al: Age-related differences among patients with follicular lymphoma and the importance of prognostic scoring systems: Analysis from a population-based non- Hodgkin’s lymphoma registry. Ann Oncol 13:1275-1284, 2002.
31. Paryani SB, Hoppe RT, Cox RS, et al: Analysis of non-Hodgkin’s lymphomas with nodular and favorable histologies, stages I and II. Cancer 52:2300-2307, 1983.
32. Denham JW, Denham E, Dear KB, et al: The follicular non-Hodgkin’s lymphomas—I. The possibility of cure. Eur J Cancer 32A:470- 479, 1996.
33. Aviles A, Delgado S, Fernandez R, et al: Combined therapy in advanced stages (III and IV) of follicular lymphoma increases the possibility of cure: Results of a large controlled clinical trial. Eur J Haematol 68:144-149, 2002.
34. Corradini P, Ladetto M, Zallio F, et al: Long-term follow-up of indolent lymphoma patients treated with high-dose sequential chemotherapy and autografting: Evidence that durable molecular and clinical remission frequently can be attained only in follicular subtypes. J Clin Oncol 22:1460-1468, 2004.
35. Ngan BY, Chen-Levy Z, Weiss LM, et al: Expression in non-Hodgkin’s lymphoma of the bcl-2 protein associated with the t(14;18) chromosomal translocation. N Engl J Med 318:1638-1644, 1988.
36. Schuler F, Hirt C, Dolken G: Chromosomal translocation t(14;18) in healthy individuals. Semin Cancer Biol 13:203-209, 2003.
37. Brice P, Bastion Y, Lepage E, et al: Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: A randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 15:1110- 1117, 1997.
38. 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 14:1282-1290, 1996.
39. Wilder RB, Jones D, Tucker SL, et al: Long-term results with radiotherapy for stage I-II follicular lymphomas. Int J Radiat Oncol Biol Phys 51:1219-1227, 2001.
40. Ott OJ, Rodel C, Gramatzki M, et al: Radiotherapy for stage I-III nodal low-grade non-Hodgkin’s lymphoma. Strahlenther Onkol 179:694-701, 2003.
41. Sack H, Hoederath A, Stuschke M, et al: Radiotherapy of follicle center lymphoma. Results of a German multicenter and prospective study. Members of the Study Group “NHL-early stages.” Strahlenther Onkol 174:178-185, 1998.
42. Taylor RE, Allan SG, McIntyre MA, et al: Low grade stage I and II non-Hodgkin’s lymphoma: Results of treatment and relapse pattern following therapy. Clin Radiol 39:287-290, 1988.
43. Pendlebury S, el Awadi M, Ashley S, et al: Radiotherapy results in early stage low grade nodal non-Hodgkin’s lymphoma. Radiother Oncol 36:167-171, 1995.
44. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, et al: Clinical stage I non- Hodgkin’s lymphoma: Long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer 69:1088-1093, 1994.
45. Neumann H, Blanck H, Koch R, et al: Follicle Centre Lymphoma: Treatment results for stage I and II. Strahlenther Onkol 179:840- 846, 2003.
46. Stuschke M, Hoederath A, Sack H, et al: Extended field and total central lymphatic radiotherapy in the treatment of early stage lymph node centroblastic-centrocytic lymphomas: Results of a prospective multicenter study. Study Group NHL-fruhe Stadien. Cancer 80:2273-2284, 1997.
47. McLaughlin P, Fuller LM, Velasquez WS, et al: Stage I-II follicular lymphoma. Treatment results for 76 patients. Cancer 58:1596- 1602, 1986.
48. 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 14:417- 424, 1988.
49. Soubeyran P, Eghbali H, Bonichon F, et al: Localized follicular lymphomas: Prognosis and survival of stages I and II in a retrospective series of 103 patients. Radiother Oncol 13:91-98, 1988.
50. Jeffery GM, Mead GM, Whitehouse JM, et al: Involved field radiotherapy or chemotherapy in the management of stage I nodal intermediate grade non-Hodgkin’s lymphoma. Br J Cancer 64:933-937, 1991.
51. Tezcan H, Vose JM, Bast M, et al: Limited stage I and II follicular non-Hodgkin’s lymphoma: The Nebraska Lymphoma Study Group experience. Leuk Lymphoma 34:273-285, 1999.
52. Yahalom J, Varsos G, Fuks Z, et al: Adjuvant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy after radiation therapy in stage I low-grade and intermediate- grade non-Hodgkin lymphoma. Results of a prospective randomized study. Cancer 71:2342-2350, 1993.
53. McLaughlin P, Fuller L, Redman J, et al: Stage I-II low-grade lymphomas: A prospective trial of combination chemotherapy and radiotherapy. Ann Oncol 2(suppl):137-140, 1991.
54. Seymour JF, Pro B, Fuller LM, et al: Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin’s lymphoma. J Clin Oncol 21:2115-2122, 2003.
55. Richards MA, Gregory WM, Hall PA, et al: Management of localized non-Hodgkin’s lymphoma: The experience at St. Bartholomew’s Hospital 1972-1985. Hematol Oncol 7:1-18, 1989.
56. Young RC, Longo DL, Glatstein E, et al: The treatment of indolent lymphomas: Watchful waiting v aggressive combined modality treatment. Semin Hematol 25(suppl 2):11-16, 1988.
57. Ardeshna KM, Smith P, Norton A, et al: British National Lymphoma Investigation. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: A randomised controlled trial. Lancet 362:516-522, 2003.
58. 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 58:592-598, 1981.
59. Kennedy BJ, Bloomfield CD, Kiang DT, et al: Combination versus successive single agent chemotherapy in lymphocytic lymphoma. Cancer 41:23-28, 1978.
60. Portlock CS, Rosenberg SA, Glatstein E, et al: Treatment of advanced non-Hodgkin’s lymphomas with favorable histologies: Preliminary results of a prospective trial. Blood 47:747- 756, 1976.61. Peterson BA, Petroni GR, Frizzera G, et al: Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: A study of the Cancer and Leukemia Group B. J Clin Oncol 21:5-15, 2003.
62. Jones SE, Grozea PN, Metz EN, et al: Superiority of Adriamycin-containing combination chemotherapy in the treatment of diffuse lymphoma: A Southwest Oncology Group study. Cancer 43:417-425, 1979.
63. Ezdinli EZ, Costello WG, Silverstein MN, et al: Moderate versus intensive chemotherapy of prognostically favorable non- Hodgkin’s lymphoma: A progress report. Cancer 46:29-33, 1980.
64. Zinzani PL, Pulsoni A, Perrotti A, et al: Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol 22:2654-2661, 2004.
65. Price CG, Rohatiner AZ, Steward W, et al: Interferon alfa-2b in addition to chlorambucil in the treatment of follicular lymphoma: Preliminary results of a randomized trial in progress. Eur J Cancer 27(suppl 4):S34-S36, 1991.
66. Chisesi T, Congiu M, Contu A, et al: Randomized study of chlorambucil (CB) compared to interferon (alfa-2b) combined with CB in low-grade non-Hodgkin’s lymphoma: An interim report of a randomized study. Non- Hodgkin’s Lymphoma Cooperative Study Group. Eur J Cancer 27(suppl 4):S31-33, 1991.
67. Solal-Celigny P, Lepage E, Brousse N, et al: Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. Groupe d’Etude des Lymphomes de l’Adulte. N Engl J Med 329:1608-1614, 1993.
68. Ozer H, Anderson JR, Peterson BA, et al: Combination trial of subcutaneous recombinant alpha 2b interferon and oral cyclophosphamide in follicular low-grade non-Hodgkin’s lymphoma. Med Pediatr Oncol 22:228-235, 1994.
69. Solal-Celigny P, Lepage E, Brousse N, et al: Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: Final analysis of survival and toxicity in the Groupe d’Etude des Lymphomes Folliculaires 86 Trial. J Clin Oncol 16:2332- 2338, 1998.
70. Coiffier B, Neidhardt-Berard EM, Tilly H, et al: Fludarabine alone compared to CHVP plus interferon in elderly patients with follicular lymphoma and adverse prognostic parameters: A GELA study. Groupe d’Etudes des Lymphomes de l’Adulte. Ann Oncol 10:1191- 1197, 1999.
71. Rohatiner A, Radford J, Deakin D, et al: A randomized controlled trial to evaluate the role of interferon as initial and maintenance therapy in patients with follicular lymphoma. Br J Cancer 85:29-35, 2001.
72. Neri N, Aviles A, Cleto S, et al: Chemotherapy plus interferon-alpha 2b versus chemotherapy in the treatment of follicular lymphoma. J Hematother Stem Cell Res 10:669- 674, 2001.
73. Rohatiner AZ, Gregory W, Peterson B, et al: A meta-analysis (MA) of randomised trials evaluating the role of interferon (IFN) as treatment for follicular lymphoma (FL). Proc Am Soc Clin Oncol 17:4a, 1998.
74. McLaughlin P, Hagemeister FB, Swan F Jr, et al: Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma. J Clin Oncol 12:575- 579, 1994.
75. 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 14:514-519, 1996.
76. Emmanouilides C, Rosen P, Rasti S, et al: Treatment of indolent lymphoma with fludarabine/mitoxantrone combination: A phase II trial. Hematol Oncol 16:107-116, 1998.
77. Zinzani PL, Magagnoli M, Moretti L, et al: Randomized trial of fludarabine versus fludarabine and idarubicin as frontline treatment in patients with indolent or mantle-cell lymphoma. J Clin Oncol 18:773-779, 2000.
78. Crawley CR, Foran JM, Gupta RK, et al: A phase II study to evaluate the combination of fludarabine, mitoxantrone and dexamethasone (FMD) in patients with follicular lymphoma. Ann Oncol 11:861-865, 2000.
79. Rohatgi N, LaRocca RV, Bard V, et al: Phase II trial of sequential therapy with fludarabine followed by cyclophosphamide, mitoxantrone, vincristine, and prednisone for low-grade follicular lymphomas. Am J Hematol 70:181-185, 2002.
80. Klasa R, Meyer R, Shustik C, et al: Fludarabine versus CVP in previously treated patients with progressive low grade non- Hodgkin’s lymphomas (lg-NHL) (abstract 28). Proc Am Soc Clin Oncol 18:9a, 1999.
81. Hainsworth JD. Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin’s lymphoma: Interim follow- up of a multicenter phase II trial. Semin Oncol 29(1 suppl 2):25-29, 2002.
82. Hainsworth JD, Litchy S, Burris HA 3rd, et al: Rituximab as first-line and maintenance therapy for patients with indolent non- Hodgkin’s lymphoma. J Clin Oncol 20:4261- 4267, 2002.
83. Colombat P, Salles G, Brousse N, et al: Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: Clinical and molecular evaluation. Blood 97:101- 106, 2001.
84. Foran JM, Gupta RK, Cunningham D, et al: A UK multicentre phase II study of rituximab (chimaeric anti-CD20 monoclonal antibody) in patients with follicular lymphoma, with PCR monitoring of molecular response. Br J Haematol 109:81-88, 2000.
85. Jaeger G, Neumeister P, Brezinschek R, et al: Rituximab (anti-CD20 monoclonal antibody) as consolidation of first-line CHOP chemotherapy in patients with follicular lymphoma: A phase II study. Eur J Haematol 69:21-26, 2002.
86. Maloney DG, Press OW, Braziel RM, et al: A phase II trial of CHOP followed by rituximab chimeric monoclonal anti-CD20 antibody for treatment of newly diagnosed follicular non-Hodgkin’s lymphoma: SWOG 9800 (abstract 3502). Blood 98:843a, 2001.
87. Czuczman MS, Grillo-Lopez AJ, LoBuglio AI, et al: Patients with low-grade NHL treated with rituximab + CHOP experience prolonged clinical and molecular remission (abstract 1493). Blood 102:411a, 2003.
88. Hiddemann W, Dreyling MH, Forstpointner R, et al: Combined immuno-chemotherapy (R-CHOP) significantly improves time to treatment failure in first line therapy of follicular lymphoma: Results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG) (abstract 352). Blood 102:104a, 2003.
89. Marcus R, Imrie K, Belch A, et al: An international multi-centre, randomized, openlabel, phase III trial comparing rituximab added to CVP chemotherapy to CVP chemotherapy alone in untreated stage III/IV follicular non- Hodgkin’s lymphoma (abstract 87). Blood 102:28a, 2003.
90. Witzig TE, Gordon LI, Cabanillas F, et al: Randomized controlled trial of yttrium- 90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 20:2453-2463, 2002.
91. Wiseman GA, Gordon LI, Multani PS, et al: Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: A phase II multicenter trial. Blood 99:4336-4342, 2002.
92. Witzig TE, Flinn IW, Gordon LI, et al: Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol 20:3262-3269, 2002.
93. Vose JM, Bierman PJ, Lynch JC, et al: Phase I clinical trial of Zevalin (90Yibritumomab) in patients with B-cell non- Hodgkin’s lymphoma (NHL) with relapsed disease following high-dose chemotherapy and autologous stem cell transplantation (ASCT) (abstract 92). Blood 102:30a, 2003.
94. Vose JM, Wahl RL, Saleh M, et al: Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade Bcell non-Hodgkin’s lymphomas. J Clin Oncol 18:1316-1323, 2000.
95. Kaminski MS, Estes J, Zasadny KR, et al: Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: Updated results and long-term follow-up of the University of Michigan experience. Blood 96:1259-1266, 2000.
96. Kaminski MS, Zelenetz AD, Press OW, et al: Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol 19:3918-3928, 2001.
97. Coleman M, Kaminski MS, Knox SJ, et al: The BEXXAR therapeutic regimen (tositumomab and iodine I 131 tositumomab) produced durable complete remissions in heavily pretreated patients with non-Hodgkin s lymphoma (NHL), rituximab-relapsed/refractory disease, and rituximab-naive disease (abstract 89). Blood 102:29a, 2003.
98. Davies AJ, Rohatiner AZ, Howell S, et al: Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 22:1469-1479, 2004.
99. Press OW, Unger JM, Braziel RM, et al: A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911. Blood 102:1606- 1612, 2003.
100. Kaminski M, Estes J, Tuck M, et al: Iodine I 131 Tositumomab therapy for previously untreated follicular lymphoma (FL) (abstract 11). Proc Am Soc Clin Oncol 19:5a, 2000.
101. Colombat P, Binet C, Linassier C, et al: High dose chemotherapy with autologous marrow transplantation in follicular lymphomas. Leuk Lymphoma 7(suppl):3-6, 1992.
102. Rohatiner AZ, Freedman A, Nadler L, et al: Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for follicular lymphoma. Ann Oncol 5(suppl 2):143-146, 1994.
103. Colombat P, Donadio D, Fouillard L, et al: Value of autologous bone marrow transplantation in follicular lymphoma: A France Autogreffe retrospective study of 42 patients. Bone Marrow Transplant 13:157-162, 1994.
104. Bastion Y, Brice P, Haioun C, et al: Intensive therapy with peripheral blood progenitor cell transplantation in 60 patients with poorprognosis follicular lymphoma. Blood 86:3257-3262, 1995.
105. Haas R, Moos M, Mohle R, et al: Highdose therapy with peripheral blood progenitor cell transplantation in low-grade non- Hodgkin’s lymphoma. Bone Marrow Transplant 17:149-155, 1996.
106. Bociek RG, Bierman PJ, Lymch JC, et al: High-dose therapy with autologous hematopoietic stem cell transplantation for follicular non-Hodgkin’s lymphoma: Long term results (abstract 8). Proc Am Soc Clin Oncol 18:3a, 1999.
107. Foran JM, Apostolidis J, Papamichael D, et al: High-dose therapy with autologous haematopoietic support in patients with transformed follicular lymphoma: A study of 27 patients from a single centre. Ann Oncol 9:865- 869, 1998.
108. Lopez R, Martino R, Sureda A, et al: Autologous stem cell transplantation in advanced follicular lymphoma. A single center experience. Haematologica 84:350-355, 1999.
109. Freedman AS, Neuberg D, Mauch P, et al: Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 94:3325-3333, 1999.
110. Apostolidis J, Gupta RK, Grenzelias D, et al: High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: Long-term clinical and molecular follow-up. J Clin Oncol 18:527-536, 2000.
111. Brice P, Simon D, Bouabdallah R, et al; Groupe d’Etude des Lymphomes de l’Adulte (GELA): High-dose therapy with autologous stem-cell transplantation (ASCT) after first progression prolonged survival of follicular lymphoma patients included in the prospective GELF 86 protocol. Ann Oncol 11:1585-1590, 2000.
112. Horning SJ, Negrin RS, Hoppe RT, et al: High-dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial remission: Results of a phase II clinical trial. Blood 97:404-409, 2001.
113. Ladetto M, Corradini P, Vallet S, et al: High rate of clinical and molecular remissions in follicular lymphoma patients receiving highdose sequential chemotherapy and autografting at diagnosis: A multicenter, prospective study by the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Blood 100:1559-1565, 2002.
114. Recher C, Huynh A, Huguet F, et al: Tandem transplant for follicular lymphoma in patients under 60 years (abstract 871). Blood 102:248a, 2003.
115. Gopal AK, Gooley TA, Maloney DG, et al: High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: A multivariable cohort analysis. Blood 102:2351- 2357, 2003.
116. van Besien K, Loberiza FR Jr, Bajorunaite R, et al: Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 102:3521-3529, 2003.
117. Schouten HC, Qian W, Kvaloy S, et al: High-dose therapy improves progression-free survival and survival in relapsed follicular non- Hodgkin’s lymphoma: Results from the randomized European CUP trial. J Clin Oncol 21:3918-3927, 2003.
118. van Besien K, Sobocinski KA, Rowlings PA, et al: Allogeneic bone marrow transplantation for low-grade lymphoma. Blood 92:1832-1836, 1998.
119. Juckett M, Rowlings P, Hessner M, et al: T cell-depleted allogeneic bone marrow transplantation for high-risk non-Hodgkin’s lymphoma: Clinical and molecular follow-up. Bone Marrow Transplant 21:893-899, 1998.
120. Stein RS, Greer JP, Goodman S, et al: High-dose therapy with autologous or allogeneic transplantation as salvage therapy for small cleaved cell lymphoma of follicular center cell origin. Bone Marrow Transplant 23:227-233, 1999.
121. Khouri IF, Saliba RM, Giralt SA, et al: Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: Low incidence of toxicity, acute graft-versus-host disease, and treatmentrelated mortality. Blood 98:3595-3599, 2001.
122. Forrest DL, Thompson K, Nevill TJ, et al: Allogeneic hematopoietic stem cell transplantation for progressive follicular lymphoma. Bone Marrow Transplant 29:973-978, 2002.
123. Yakoub-Agha I, Fawaz A, Folliot O, et al: Allogeneic bone marrow transplantation in patients with follicular lymphoma: A single center study. Bone Marrow Transplant 30:229- 234, 2002.
124. Ho AY, Devereux S, Mufti GJ, et al: Reduced- intensity rituximab-BEAM-CAMPATH allogeneic haematopoietic stem cell transplantation for follicular lymphoma is feasible and induces durable molecular remissions. Bone Marrow Transplant 31:551-557, 2003.
125. Verdonck LF, Dekker AW, Lokhorst HM, et al: Allogeneic versus autologous bone marrow transplantation for refractory and recurrent low grade non-Hodgkin’s lymphoma. Blood 90:4201-4205, 1997.
126. Deshpande AT, Bociek RG, Bierman PJ, et al: Long term outcome following autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Biol Blood Marrow Transplant 10(suppl):28, 2004.
127. van Besien KW, de Lima M, Giralt SA, et al: Management of lymphoma recurrence after allogeneic transplantation: The relevance of graft-versus-lymphoma effect. Bone Marrow Transplant 19:977-982, 1997.
128. Mandigers CM, Verdonck LF, Meijerink JP, et al: Graft-versus-lymphoma effect of donor lymphocyte infusion in indolent lymphomas relapsed after allogeneic stem cell transplantation. Bone Marrow Transplant 32:1159-1163, 2003.
129. Hsu FJ, Caspar CB, Czerwinski D, et al: Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma: Long-term results of a clinical trial. Blood 89:3129-3135, 1997.
130. Timmerman JM, Czerwinski DK, Davis TA, et al: Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: Clinical and immune responses in 35 patients. Blood 99:1517- 1526, 2002.
131. Vose JM, Chiu BC, Cheson BD, et al: Update on epidemiology and therapeutics for non-Hodgkin’s lymphoma. Hematology (Am Soc Hematol Educ Program) pp 241-262, 2002.
132. Leonard JP, Coleman M, Ketas JC, et al: Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin’s lymphoma. J Clin Oncol 21:3051-3059, 2003.
133. Postema EJ, Raemaekers JM, Oyen WJ, et al: Final results of a phase I radioimmunotherapy trial using (186) Re-epratuzumab for the treatment of patients with non-Hodgkin’s lymphoma. Clin Cancer Res 9:3995S-4002S, 2003.
134. Gingrich RD, Dahle CE, Hoskins KF, et al: Identification and characterization of a new surface membrane antigen found predominantly on malignant B lymphocytes. Blood 75:2375-2387, 1990.
135. Press OW, Leonard JP, Coiffier B, et al: Immunotherapy of non-Hodgkin’s lymphomas. Hematology (Am Soc Hematol Educ Program) 221-240, 2001.
136. Link BK, Wang H, Byrd JC, et al: Phase I study of Hu1D10 monoclonal antibody in patients with B-cell lymphoma (abstract 1135). Proc Am Soc Clin Oncol 20:284a, 2001.
137. Czuczman M, Witzig TE, Vose JM, et al: Results of a phase I/II multicenter trial of galiximab (IDEC-114, anti-CD80 antibody) therapy for relapsed or refractory follicular lymphoma (abstract 2393). Blood 102:647a-648a, 2003.
138. Gordon LI, Moore JO, Cheson BD, et al: Phase I results from a multicenter trial of galiximab (anti-CD80 Antibody, IDEC-114) in combination with rituximab for the treatment of follicular lymphoma (abstract 4951). Blood 102:307b, 2003.
139. Webb A, Cunningham D, Cotter F, et al: BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet 349:1137- 1141, 1997.
140. Freedman AS, Friedberg JW, Mauch PM, et al: Non-Hodgkin’s Lymphomas, pp 367- 388. Philadelphia, Lippincott Williams & Wilkins, 2003.
141. Waters JS, Webb A, Cunningham D, et al: Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol 18:1812-1823, 2000.
142. Kisselev AF, Goldberg AL: Proteasome inhibitors: From research tools to drug candidates. Chem Biol 8:739-758, 2001.
143. Orlowski RZ, Eswara JR, Lafond- Walker A, et al: Tumor growth inhibition induced in a murine model of human Burkitt’s lymphoma by a proteasome inhibitor (abstract). Cancer Res 58: 4342-4348, 1998.
144. O’Connor O, Wright J, Moskowitz CH, et al: Promising activity of the proteasome inhibitor bortezomib (Velcade) in the treatment of indolent non-Hodgkin’s lymphoma and mantle cell lymphoma (abstract 2346). Blood 102:636a, 2003.
145. Warren TL, Dahle CE, Weiner GJ: CpG oligodeoxynucleotides enhance monoclonal antibody therapy of a murine lymphoma. Clin Lymphoma 1:57-61, 2000.
146. Friedberg JW, Kim H, McCauley M, et al: Combination immunotherapy for non- Hodgkin’s lymphoma (NHL) with CpG oligonucleotide (1018 ISS) and rituximab: Biologic responses through interferon-alpha/beta-inducible gene expression without significant toxicity (abstract 232). Blood 102:69a, 2003.
147. Chopra R, Goldstone AH, Pearce R, et al. Autologous versus allogeneic bone marrow transplantation for non-Hodgkin’s lymphoma: A case-controlled analysis of the European Bone Marrow Transplant Group registry data. J Clin Oncol 10:1690-1695, 1992.
148. Khouri IF, Saliba RM, Giralt SA, et al: Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: Low incidence of toxicity, acute graft-versus-host disease, and treatmentrelated mortality. Blood 98:3595-3599, 2001.