Advances in molecular biology diagnostic and treatment of B-cell malignancies: indolent B-cell lymphoma

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1 Annals of Oncology 16 (Supplement 2): ii99 ii104, 2005 doi: /annonc/mdi724 Advances in molecular biology diagnostic and treatment of B-cell malignancies: indolent B-cell lymphoma M. Dreyling, C. Buske & W. Hiddemann Department of Internal Medicine III, Grosshadern Hospital, Ludwig-Maximilians University, Munich, Germany Clinical presentation Follicular lymphoma (FL) represents 60% of indolent lymphoma (15 30% of all malignant lymphomas) and is thus one the most frequent lymphoma subtypes, with a rapidly increasing incidence in Western countries [1]. The clinical course is characterized by a slowly progressive disease but continuous relapse pattern, with a median overall survival of 5 10 years. The vast majority of patients presents with advanced stages III or IV (Ann Arbor classification) at initial diagnosis; accordingly, conventional chemotherapy is only palliative [2]. Therefore, a watch and wait strategy is generally recommended in patients with low tumor burden and no clinical symptoms, because various randomized trials have demonstrated that earlier initiation of cytoreductive therapy is not superior to observation with regard to overall survival [3 5]. When FL becomes symptomatic chemotherapy induces remissions in the vast majority of patients, but does not prevent recurrent relapses and finally refractory disease. In addition, the survival of these patients has remained essentially unchanged despite intensive clinical research and exploration of different therapeutic strategies over the last 30 years [2]. Recently, a new prognostic score (Follicular Lymphoma International Prognostic Index, FLIPI) of five risk factors including number of nodal areas, lactate dehydrogenase, stage, age, and hemoglobin level has been proposed to predict the outcome of individual patients with newly diagnosed FL, which will allow more risk-adapted therapeutic strategies in future trials [6]. However, so far, validating data from prospective studies are limited [7]. Purine analogs like fludarabine represent a non-cross-resistant alternative to alkylating agents. Fludarabine monotherapy is not clearly superior to alkylating combinations. In relapsed FL, fludarabine monotherapy achieved a slightly improved PFS (10.9 months) in comparison with CVP chemotherapy (9.2 months) (P = 0.03), but there were no differences in response rates (fludarabine 64%, CVP 52%) or median OS (fludarabine 57 months, CVP 44 months) between the two treatment groups [10]. In contrast, the efficacy of fludarabine combinations, especially in relapsed or refractory indolent lymphoma, has been demonstrated with impressive remission rates (70 100%). The most widely investigated fludarabine combinations contain either cyclophosphamide, mitoxantrone or both [11 15]. Although fludarabine is generally well tolerated and its toxicity profile seems to be comparable to other regimens, the drug is associated with immunosuppression, and physicians should be aware of an increased risk of opportunistic infections. Additionally, the cumulative stem cell toxic effect (especially of more than three cycles fludarabine) has to be considered if an autologous stem cell transplantation is planned. Bendamustine, which is chemically related to the alkylating agents but has a partially different mechanism of action, is another interesting drug in the treatment of indolent lymphoma without cross-resistance to other alkylating agents. Combination chemotherapy with mitoxantrone showed promising response rates in a multicenter phase I/II study in patients with refractory or relapsed indolent lymphoma [16]. Conventional chemotherapy The alkylating agents chlorambucil and cyclophosphamide have been the standard treatment approach for indolent lymphoma for decades. Both, daily chlorambucil or repeated courses of CVP or COP (cyclophosphamide, vincristine and prednisone) result in similar progression-free survival (PFS) and overall survival (OS) [8]. The addition of doxorubicin (CHOP) led to higher response rates and a longer PFS [9]. However, OS remained unaffected and the potential cardiotoxic effect of doxorubicin has to be considered in a predominantly elderly population. q 2005 European Society for Medical Oncology Monoclonal antibody therapy (rituximab) Single-agent therapy Rituximab is a chimeric anti-cd20 monoclonal antibody (mab) that displays an intrinsic anti-lymphoma effect but also initiates complement-dependent cytotoxicity and antibodydependent cellular cytotoxicity, the efficacy of the latter being strongly dependent on the activation of effector cells via the Fcg receptor [17]. Accordingly, two polymorphisms of this receptor were shown to predict response rate and freedom from progression after rituximab monotherapy [18].

2 ii100 Figure 1. Event-free survival after rituximab maintenance versus observation. Patients with advanced follicular lymphoma without progress after antibody induction were randomized into an observation arm (n = 78) or rituximab maintenance [20]. The high anti-lymphoma activity of this antibody combined with its low toxicity profile was confirmed in the pivotal study of 166 patients with refractory or relapsed indolent lymphoma (mainly follicular-type) achieving an overall response rate of 48% [6% complete response (CR), 42% partial response (PR)] and a median time to progression of 13 months. Side-effects were moderate and consisted mainly of infusion-associated flu-like symptoms [19]. These promising results were confirmed in several subsequent clinical trials achieving response overall of 70% and CR rates of 20% in first-line treatment of indolent lymphoma. However, despite these encouraging results, response duration in patients treated with rituximab monotherapy at relapse is limited (12 17 months). One possibility to further improve treatment outcome in these patients is an extended antibody maintenance schedule. The feasibility and efficacy of this approach was investigated in a phase III clinical trial by the Swiss study group SAKK, randomizing FL patients who did not progress after 4 weekly rituximab infusions to a rituximab maintenance arm (single infusions after 3, 5, 7 and 9 months) versus an observation arm [20]. After a median observation time of 35 months the event-free interval was 23 months in the maintenance arm versus 12 months in the watch and wait group, respectively (Figure 1), with an even more pronounced difference in first-line patients. Similar results have been reported for a different rituximab maintenance regime (4 weekly rituximab infusions every 6 months) [21]. In a retrospective comparison, the median PFS after rituximab maintenance (34 months) was superior to a control cohort of patients treated with rituximab induction only (12 months). Combined immunochemotherapy Table 1. Rituximab plus chemotherapy in first line therapy of advanced stage follicular lymphoma Based on their different mode of action, in vitro data suggested a synergic activity of conventional chemotherapy and rituximab, which has been meanwhile confirmed in several clinical studies. In a small phase II trial the combination of CHOP and rituximab induced responses in all evaluable patients, with a CR rate of 63% and an impressive median PFS of 82 months, with 19 of 38 patients still in ongoing remissions [22]. In four large randomized phase III studies combined immunochemotherapy has been compared with chemotherapy alone (Table 1). In the trial of the German Low-grade lymphoma Study Group (GLSG), patients with previously untreated advanced FL received either six to eight cycles of rituximab plus CHOP (R-CHOP) or chemotherapy alone [23]. R-CHOP was superior with regard to overall response rate (96% versus 90%; P = 0.01), as well as PFS (P <0.0001) (Figure 2). This Author Regimen P value Hiddemann et al. [23] CHOP (n = 205) R-CHOP (n = 223) Response rate 90% 96% Median time to treatment failure 31 months Not reached < Marcus et al. [24] CVP (n = 159) R-CVP (n = 162) Response rate 57% 81% < Median time to treatment failure 7 months 27 months < Herold et al. [25] MCP (n = 96) R-MCP (n = 105) Response rate 75% 92% <0.001 Median event-free survival 19 months Not reached < Salles et al. [26] CHVP/IFN-a (n = 175) R-CHVP/IFN-a (n = 184) Response rate (CR/CRu) 85% (49%) 94% (76%) < Median event-free survival Not reached Not reached CHOP, cyclophosphamide, doxorubicin, vincristine and prednisone; R, rituximab; CVP, cyclophosphamide, vincristine and prednisone; MCP, mitoxantrone, chlorambucil and prednisone; CHVP, cyclophosphamide, doxorubicin, etoposide and prednisone; IFN, interferon; CR, complete response; CRu, CR unconfirmed.

3 ii101 Figure 2. Time to treatment failure in follicular lymphoma: rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R- CHOP) versus CHOP in first line therapy [23]. Patients with advancedstage follicular lymphoma were randomized to rituximab plus CHOP (n = 271) or CHOP (n = 259) as first-line therapy. advantage of the immunochemotherapy was evident in both younger (<60 years) and older patients, as well as low-risk [International Prognostic Index (IPI) score 0 2] and high-risk patients. A slight increase of grade 3/4 granulocytopenias was observed in the R-CHOP arm, but rates of (clinically more relevant) infections or other therapy-associated toxicity were similar. In another phase III trial, the addition of rituximab to the moderately intensive CVP regimen resulted in a significant improvement of response rates (81% versus 57%; P <0.0001) as well as PFS (P <0.0001) as compared with CVP alone [24]. These results were also confirmed by two other randomized trials evaluating the additional effect of rituximab in combination with a more effective chemotherapy schedule (mitoxantrone, chlorambucil and prednisone, MCP) by Herold et al. [25] or a chemotherapy-interferon schedule [6 CHVP: cyclophosphamide 600 mg/m 2, doxorubicin 25 mg/m 2, etoposide 100 mg/m 2 day 1, prednisone 40 mg/m 2 day 1 5 and interferon-a (IFN-a)] by the French group GELA [26], respectively. The superiority of an immunochemothrapy consisting of rituximab and standard chemotherapy compared with chemotherapy alone was also shown in patients with recurrent lymphoma. In a prospective study, this combined approach (R-FCM: fludarabine 25 mg/m 2 day 1 3, cyclophosphamide 200 mg/m 2 day 1 3, mitoxantrone 8 mg/m 2 day 1) resulted not only in significantly improved response rates (overall response/cr 94%/44% versus 75%/25%; P = 0.047) and prolonged median PFS, but more importantly, also the OS [27]. In summary, clinical trials have convincingly demonstrated that combined immunochemotherapy is superior to conventional chemotherapy and should be considered as standard approach in first-line as well as salvage therapy of patients with advanced-stage FL. Radioimmunotherapy Because of the high radiosensitivity of FL and the curative effect of external radiation in localized stages, radioimmunotherapy represents an especially promising concept in this disease. Such radioimmunoconjugates are able to deliver highenergy radiation directly to lymphoma cells and also eliminate neighboring bystander cells by a crossfire effect. The antigen most widely targeted so far in radioimmunotherapy is CD20, which is neither shed nor internalized and thus an appealing target for radioimmunotherapy in B-cell lymphomas. Most encouraging results were reported for the 90 Y-labeled murine antibody ibritumomab (Zevalin w ) and the 131 iodinelabeled antibody tositumomab (Bexxar w ). Zevalin is a pure b-emitter of high energy with a short half-life of 64 h, and therefore suitable for outpatient treatment. The Bexxar conjugate delivers both b and g irradiation with a half-life of 8 days, therefore shielding of contact persons is necessary. In general, both constructs may be applied in a conventional as well as myeloablative dosage. In the non-myeloablative approach both conjugates demonstrated comparable activity, with 60 80% overall response and CR/CR unconfirmed (CRu) rates between 15% and 44% [28]. In a randomized trial a single infusion of 90 Y-ibritumomab was superior to a standard 4 weekly infusion of rituximab with regard to overall response (80% versus 56%) and CR rate (30% versus 16%), although the median PFS was not different in the total cohort. However, patients achieving a CR after 90 Y-ibritumomab infusion seemed particularly to achieve a long-term benefit [29]. Both the 90 Y-ibritumomab as well as 131 I-tositumomab induces considerable myelosuppression with a delayed onset 6 10 weeks post-treatment. Thus, in case of reduced platelet counts ( /mm 3 ) appropriate dose reduction is recommended. Additionally, bone marrow infiltration by lymphoma cells should not exceed 25%, because of severe and prolonged myelosuppression. Another attractive approach is radioimmunochemotherapy consolidation after initial chemotherapy induction. Press et al. [30] reported a phase II study in previously untreated FL patients, who achieved 67% CR/CRu and 23% PR. Importantly, in 27 of the 47 patients (57%) the remission status after initial cytoreduction was converted to CR after the infusion of the radioconjugate. After a median follow-up of 2.3 years, the estimated 2-year PFS was 81%, with a 2-year OS of 97%. Again, the main side-effect was reversible myelosuppression, which was less severe than after the previous chemotherapy (CHOP). Myeloablative radioimmunotherapy with subsequent reinfusion of autologous peripheral stem cells has been successfully applied in patients with refractory or relapsed FL. A single myeloablative dose of 131 I-tositumomab achieved an overall response of 93%, with a CR/CRu rate of 85% and estimated 5-year PFS and OS of 48% and 67%, respectively, in comparison with 29% and 53% after high-dose chemotherapy [31]. Importantly, the risk for secondary hematological neoplasias did not differ between the two treatment strategies and were

4 ii102 Figure 3. Time to treatment failure in follicular lymphoma: autologous stem cell transpantation (ASCT) versus interferon (IFN) after first-line CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. Patients with advanced-stage follicular lymphoma were randomized into a ASCT arm (n = 134) or IFN maintenance (n = 145) [32]. estimated to be 7.6% at 8 years (radioimmunotherapy) and 8.6% at 7 years (chemotherapy). Autologous stem cell transplantation (ASCT) ASCT in first remission In the last few years three large clinical trials have addressed this issue. In a multicenter phase III trial by the GLSG the effect of myeloablative radiochemotherapy followed by ASCT was evaluated in comparison with IFN-a maintenance (3 5 MIU weekly) after a CHOP-like induction [32]. Myeloablative consolidation consisted of total body irradiation (TBI) (12 Gy) and high-dose cyclophosphamide (2 60 mg/kg) followed by unpurged ASCT. ASCT consolidation achieved a significantly prolonged PFS (5-year PFS 64.7%) as compared with IFN-a maintenance (5-year PFS 33.3%) (P <0.0001; Figure 3). The Table 2. ASCT in first remission of advanced-stage follicular lymphoma superiority of ASCT was found in both the low- and intermediate-risk patient groups according to the IPI score, and especially in patients with PR after initial chemotherapy. Currently, with an overall 5-year survival of 84%, the median observation time is still too short to provide valid data on OS for the two study arms. Of note, myeloablative therapy was associated with only moderate increase of secondary hematological neoplasias [myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)] (5-year risk 3.8% versus 0%; P = 0.025), which was closely related to prior induction chemotherapy [33]. Thus, in the patients previously treated with CHOP, only 1.3% of AML/MDS have been observed after a 5-year follow-up. In a similar study, the French GOELAMS study group compared the impact of consolidating ASCT versus a extended combination therapy (CHVP and IFN-a) in patients with advanced FL and high tumor burden [34]. Again, the event-free survival rates at 5 years were in favor of the ASCT arm (60 versus 48; P = 0.050). This advantage of consolidating ASCT was mainly restricted to patients with a high-risk profile according to the FLIPI (>2). However, in contrast to the German study, seven patients died of secondary malignancies in the ASCT arm, resulting in a slightly lower 5-year survival rate in the ASCT arm. Similarly, a third randomized trial by the GELA study group evaluated myeloablative radiochemotherapy and ASCT after four courses of CHOP in comparison with an extended schedule of 12 courses of CHVP and IFN-a [35]. OS was significantly longer in the transplant arm (7-year OS 86% versus 74%; P = 0.05). In contrast, the estimated 7-year event-free survival was not statistically different (ASCT arm 45% versus conventional arm 36%; P = 0.5). However, when only patients with remissions of >6 months were evaluated (to avoid the imbalances of different induction duration), 7-year event-free survival was prolonged in the transplant arm (62% versus 44%, P = 0.01). In conclusion, two of the three studies demonstrated a significantly improved PFS after myeloablative consolidation (Table 2). However, the key question whether ASCT in first Author Induction Consolidation EFS OS Lenz et al. [32] ASCT Conventional ASCT Conventional ASCT Conventional ASCT Conventional CHOP/MCP (4 6 cycles) CHOP/MCP (6 8 cycles) TBI/Cyclo (n = 153) IFN-a (n = 154) 64.7% (5 years) 33.3% (5 years) (P <0.0001) Not available Not available Deconinck et al. [34] VCAP (2 3 cycles) CHVP/IFN-a (6 cycles) TBI/Cyclo (n = 86) CHVP + IFN-a (n = 80) 60% (5 years) 48% (5 years) (P <0.050) 78% (5 years) 84% (5 years) Sebban et al. [35] CHOP (4 cycles) CHVP/IFN-a (6 cycles) TBI/Cyclo (n = 192) CHVP+IFN-a (n = 209) 45% (7 years) 36% (7 years) (P=0.5) 86% (7 years) 74% (7 years) (P=0.05) ACST, autologous stem cell transplantation; EFS, event-free survivial; OS, overall survival; CHOP, cyclophosphamide, doxorubicin, vincristine and prednisone; MCP, mitoxantrone, chlorambucil and prednisone; VCAP, vindesine, cyclophosphamide, doxorubicin, prednisolone; CHVP, cyclophosphamide, doxorubicin, etoposide and prednisone; IFN-a, interferon-a; TBI, total body irradiation; Cyclo, cyclophosphamide.

5 remission prolongs OS remains open, with contradictory results of the two French trials and data of the GLSG trial still blinded. Additionally, most patients of these studies were treated with chemotherapy only. Thus, consolidating ASCT has to be reevaluated in comparison with combined immunochemotherapy, and so far cannot be generally considered as a standard first-line treatment outside of clinical trials. ASCT as salvage treatment In several phase II studies myeloablative therapy followed by ASCT prolonged disease-free survival in patients with recurrent FL, but only one trial evaluated high-dose consolidation in a prospectively randomized way [36]. In this trial, ASCT after an initial CHOP-like regimen resulted in a significantly improved PFS and OS in patients who received ASCT, but interpretation of data is limited because survival analysis was based on only 89 patients, with considerable imbalances between the patient subgroups. Similarly, this trial did not include combined immunochemotherapy induction, which has been demonstrated to be superior in relapsed FL [27]. Allogeneic transplantation Allogeneic transplantation with either conventional myeloablative or reduced intensity conditioning (RIC) remains the only curative treatment approach in patients with advanced FL. The latter approach has substantially reduced acute treatment-related morbidity, but longer follow-up demonstrated a high rate of chronic graft-versus-host disease (GvHD) and delayed infectious complications. The International Bone Marrow Transplant Registry retrospectively analyzed the treatment outcome in 176 patients with recurrent FL after (mostly TBI-based) conventional conditioning and human leukocyte antigen (HLA)-identical sibling donor transplantation [37]. Only 19% relapses were observed after 1 year and very few recurrences thereafter, but treatment-related mortality was 24% at 1 year and 30% at 5 years. In the last years, RIC has been increasingly performed because of its significantly lower acute treatment-related mortality. Khouri et al. [38] reported on HLA-identical donor allogeneic transplantation with RIC (fludarabine and cyclophosphamide) in 18 patients with recurrent FL; all patients achieved a CR. Acute GvHD was relatively low, but a cumulative incidence of 64% chronic GvHD was observed. The feasibility of this approach was also confirmed in another small phase II study emphasizing the curative potential of RIC even in chemorefractory patients [39]. Thus, non-myeloblative allogeneic transplantation may be an effective treatment option, especially in patients who fail after high-dose myelablative ASCT. References 1. Chiu BC, Weissenburger DD. An update of the epidemiology of non- Hodgkin s lymphoma. Clin Lymphoma 2003; 4: ii Horning SJ. Natural history of and therapy for the indolent non-hodgkin s lymphomas. Semin Oncol 1993; 20 (Suppl 5): Young RC, Longo DL, Glatstein E et al. The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol 1988; 25 (Suppl 2): 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 1997; 15: Ardeshna KM, Smith P, Norton A et al. 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 2003; 362: Solal-Celigny P, Roy P, Colombat P et al. Follicular Lymphoma International Prognostic Index. Blood 2004; 104: Montoto S, Lopez-Guillermo A, Altes A et al. Predictive value of Follicular Lymphoma International Prognostic Index (FLIPI) in patients with follicular lymphoma at first progression. Ann Oncol 2004; 15: Hoppe R, Kushlan P, Kaplan H 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 1981; 58: Nickenig C, Dreyling M, Schiegnitz E et al. CHOP improves response rates but not overall survival in follicular and mantle cell lymphoma (MCL) results of a randomized trail of the German Low Grade Lymphoma Study Group (GLSG). Annual Meeting of the American Society of Hematology, San Diego. Blood 2004; 104: 176a (Abstr 611). 10. Klasa RJ, Meyer RM, Shustik C et al. Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine and prednisone in patients with recurrent low-grade non-hodgkin s lymphoma previously treated with an alkylating agent or alkylatorcontaining regimen. J Clin Oncol 2002; 20: McLaughlin P, Hagemeister FB, Romaguera JE et al. Fludarabine, mitoxantrone and dexamethasone: an effective regimen for indolent lymphoma. J Clin Oncol 1996; 14: Bosch F, Perales M, Cobo F et al. Fludarabine, cyclophosphamide and mitoxantrone (FCM) therapy in resistant or relapsed chronic lymphocytic leukemia or follicular lymphoma. Blood 1997; 90: (Abstr 2360). 13. Seymour JF, Grigg AP, Szer J et al. Fludarabine and mitoxantrone: a highly effective and well-tolerated salvage therapy for low-grade lymphoproliferative disorders. Blood 1997; 90 (Suppl 1): 343a (Abstr 1530). 14. Lazzarino M, Orlandi E, Montillo M et al. Fludarabine, cyclophosphamide and dexamethasone (FluCyD) combination is effective in pretreated low-grade non-hodgkin s lymphoma. Ann Oncol 1999; 10: Santini G, Nati S, Spriano M et al. Fludarabine in combination with cyclophosphamide or with cyclophosphamide plus mitoxantrone for relapsed or refractory low-grade non-hodgkin s lymphoma. Haematologica 2001; 86: Weide R, Heymanns J, Gores A, Koppler H. Bendamustine mitoxantrone and rituximab (BMR): a new effective regimen for refractory or relapsed indolent lymphomas. Leuk Lymphoma 2002; 43: Cartron G, Watier H, Golay J, Solal-Celigny P. From the bench to the bedside: ways to improve rituximab efficacy. Blood 2004; 104:

6 ii Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 2003; 21: 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 1998; 16: Ghielmini M, Schmitz SF, Cogliatti SB et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly 4 schedule. Blood 2004; 103: 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 2002; 20: Czuczman MS, Weaver R, Alkuzweny B et al. Prolonged clinical and molecular remission in patients with low-grade or follicular non- Hodgkin s lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol 2004; 22: 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). Blood 2003; 102: 104a. 24. Marcus R, Imrie K, Belch A et al. CVP chemotherapy plus Rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105: Herold M, Pasold R, Srock S et al. Results of a prospective randomised open label phase III study comparing rituximab plus mitoxantrone, chlorambucile, prednisolone chemotherapy (R-MCP) versus MCP alone in untreated advanced indolent non-hodgkin s lymphoma (NHL) and mantle-cell-lymphoma (MCL). Blood 2004; 104: 584a. 26. Salles G, Foussard C, Nicolas M et al. Rituximab added to aifn + CHVP improves the outcome of follicular lymphoma patients with a high tumor burden: first analysis of the GELA-GOELAMS FL-2000 randomized trial in 359 Patients. Blood 2004; 104: 160a. 27. Forstpointner R, Dreyling M, Repp R et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2004; 104: Cheson BD. Radioimmunotherapy of non-hodgkin lymphomas. Blood 2003; 101: 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 2002; 20: 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 2003; 102: 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 2003; 102: Lenz G, Dreyling M, Schiegnitz E et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 2004; 104: Lenz G, Dreyling M, Schiegnitz E et al. Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 2004; 22: Deconinck E, Foussard C, Milpied N et al. High dose therapy followed by autologous purged stem cell transplantation and doxorubicin based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS. Blood 2005; Epub ahead of print. 35. Sebban C, Belanger C, Brousse N et al. Comparison of CHVP + interferon with CHOP followed by autologous stem cell transplantation with a TBI conditioning regimen in untreated patients with high tumor burden follicular lymphoma: results of the randomized GELF94 trial (G.E.L.A. study group). Blood 2003; 102: 354a. 36. 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 2003; 21: Van Besien K, Loberiza FR, Bajorunaite R et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 2003; 102: 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 treatment-related mortality. Blood 2001; 98: Tanimoto TE, Kusumi E, Hamaki T et al. High complete response rate after allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning regimens in advanced malignant lymphoma. Bone Marrow Transplant 2003; 32:

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