Non Transplant-Related Treatment Options in Follicular Lymphoma

Transcription

1 Biology of Blood and Marrow Transplantation 12:53-58 (2006) 2006 American Society for Blood and Marrow Transplantation /06/ $32.00/0 doi: /j.bbmt Non Transplant-Related Treatment Options in Follicular Lymphoma Arnold S. Freedman Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts Correspondence and reprint requests: Arnold S. Freedman, MD, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA ( KEY WORDS Follicular lymphoma INTRODUCTION BB&MT Follicular lymphoma (FL) is the second most common lymphoma in the United States and Western Europe, comprising approximately 20% of all non- Hodgkin lymphomas (NHLs) and up to 70% of the indolent lymphomas in Western countries. Although the natural history of this disease has not changed significantly in the past 3 decades, newer agents, specifically, antibody-based therapies, have changed the approach and may well alter the long-term outcome for these patients. Treatment options and the interpretation of clinical studies need to be within the context of prognostic factors. The current model used in FL is the Follicular Lymphoma International Prognostic Index, based on an international study of long-term survival in 4167 patients with FL diagnosed between 1985 and 1992 [1]. In this model, 5 adverse prognostic factors were identified: age 60 years; stage III or IV; hemoglobin 12 g/dl; number of involved nodal areas 4; and serum lactate dehydrogenase (LDH) greater than the upper limit of normal. With this model, 3 risk groups were identified low (0 risk factors or 1 risk factor), intermediate (2 risk factors), and high ( 3 risk factors) and the 10-year survivals for these risk groups are 71%, 51%, and 36%, respectively. It is important to note that this model predates the use of monoclonal antibody therapy, and the effect of these factors may therefore change. In 2005, there is evidence for the following concerning the treatment of FL: (1) early treatment in the absence of symptomatic disease or disease causing organ compromise does not affect survival; (2) combination chemotherapy does not affect survival; (3) currently there is no survival benefit of newer agents, including monoclonal antibodies (alone, with chemotherapy, or radiolabeled) or purine analogues; and (4) chemotherapy with rituximab or rituximab given as maintenance delays relapse. However, in a disease with a long natural history, newer approaches are likely to need long follow-up for a survival effect to be seen. THERAPY FOR EARLY-STAGE DISEASE Only 10% to 25% of patients have clinical stage I/II disease, and far less than 10% have pathologic stage I/II disease. Radiation therapy is the mainstay of treatment for patients with limited-stage FL grade I or II. The 10-year freedom from treatment failure in all 9 studies ranged from 41% to 49%. The 10-year overall survival (all causes) ranged from 43% to 79%, with a median survival of 11.9 to 15.3 years [2]. The role of combination chemotherapy in the management of early-stage FL is uncertain. At least 3 randomized studies conducted in the 1970s failed to demonstrate that combination chemotherapy regimens plus radiation therapy were superior to radiation therapy alone. A 1994 study randomized patients to receive either radiation therapy alone or radiation therapy plus chlorambucil, and there were no differences in freedom from recurrence or overall survival between the groups [3]. THERAPY OF PREVIOUSLY UNTREATED ADVANCED-STAGE DISEASE Close observation is still a reasonable option for asymptomatic patients with low-volume disease. A British National Lymphoma Investigation randomized study involving 309 patients with asymptomatic stage III or IV indolent NHL reported no differences 53

2 A. S. Freedman in overall survival or cause-specific survival between patients who were observed and those who received immediate treatment with chlorambucil [4]. The actuarial chance of not requiring chemotherapy at 10 years in the entire observation group was 19%, and it was 40% and 16% for those older or younger than 70 years, respectively. Conventional Chemotherapy Indolent lymphomas are very sensitive to both alkylating agents (eg, chlorambucil and cyclophosphamide) and combination chemotherapy; complete response (CR) rates range from 30% to 60% for previously untreated patients [5]. However, the median duration of CR with either a single alkylating agent (for example, cyclophosphamide) or combination chemotherapy (for example, cyclophosphamide, vincristine, and prednisone [CVP]) is only approximately 2.5 years. In an attempt to improve the relapse-free and overall survival in patients with FL, more aggressive combination chemotherapy regimens have been used, with CR rates of 35% to 70%, but the median relapsefree survival remains similar to that seen with CVP, in the range of 1.5 to 3 years. Cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-bleomycin was compared with cyclophosphamide alone in patients with FL grade I and II, and the CR rate and time to failure were not statistically different between the 2 arms for the entire patient population [6]. However, in the 46 patients with FL grade II, the failurefree and overall survival were better for combination chemotherapy. Still, because of problems of reproducibility of histologic interpretation of FL grade II and the limited number of patients in this study, the use of doxorubicin-containing regimens for patients with FL remains controversial. Combined-Modality Therapy Studies from the National Cancer Institute and Stanford have failed to demonstrate an improved relapse-free or overall survival for patients treated with CVP with or without total body irradiation or total lymphoid irradiation. The M.D. Anderson Cancer Center reported an 81% CR rate, a 75% 5-year survival, and a 52% 5-year relapse-free survival for patients with stage III FL treated with CHOP-bleomycin and involved-field radiotherapy [7]. Purine Analogues The purine analogues cladribine (2-chlorodeoxyadenosine) and fludarabine are active agents in FL. Fludarabine and cladribine have been effective agents when given as single agents in previously untreated and previously treated patients. In previously untreated patients with FL, the overall response rate to fludarabine was 65%, with a 37% CR; the median progression-free survival (PFS) was 13.6 months [8]. Similar results were obtained with cladribine. Fludarabine was compared with CVP in a randomized study of 381 patients with newly diagnosed advanced-stage FL. The overall response rates in the fludarabine and CVP arms were 68% (38% CR) and 50% (15% CR). Significant cytopenias were more frequent in the fludarabine group. The median time to progression in the fludarabine group was 21 months, versus 15 months in the CVP group. However, no differences in overall survival were detected [9]. Fludarabine has been combined with other chemotherapeutic agents in previously untreated patients with indolent lymphoma. In a phase II multicenter trial, the combination of cyclophosphamide, fludarabine, and filgrastim resulted in overall response rates of 92% in patients with previously untreated FL [10]. However, when this combination was brought to the intergroup setting, significant mortality from infection occurred, and the trial was closed early. The combination of fludarabine and mitoxantrone was tested in previously untreated patients with indolent lymphoma (FL and small lymphocytic lymphoma) [11]. Overall and CR rates were 91% and 43%, respectively, with 2-year PFS and overall survival rates of 63% and 93%, respectively. The addition of dexamethasone to fludarabine/mitoxantrone has been shown to be a highly effective regimen for patients with relapsed indolent lymphomas, with overall response and CR rates of 94% and 47%, respectively. The median failure-free survival was 14 months for all patients and 21 months for those who attained CR. Monoclonal Antibody Therapy Anti B-cell monoclonal antibody therapy has changed the treatment options for patients with FL. On the basis of the activity of rituximab as a single agent in patients with relapsed FL, several phase II trials have used rituximab initial therapy in patients with indolent lymphoma [12,13]. In 62 chemotherapy-naive patients, most of whom had stage III or IV disease, overall response rates at 6 weeks and at maximum response were 47% and 73%, with 7% and 37% CRs, respectively [12,14]. At a median follow-up of 30 months, the median PFS was 34 months. A second trial evaluated 50 patients with stage II to IV FL and a low tumor burden (no nodal or extranodal mass 7 cm, B symptoms, splenomegaly, pleural effusion, ascites, organ compression, increased serum LDH, or 2 -microglobulin) [13]. The overall response rate at 50 days was 73%, with 57% and 31% of informative patients negative by polymerase chain reaction (PCR) for bcl-2 rearrangement in peripheral blood and bone marrow, respectively. A recent trial by Witzig et al. [15] reported 37 54

3 Non Transplant-Related Treatment Options in Follicular Lymphoma patients with FL grade I treated with 4 weekly doses of rituximab, with an overall response rate of 72% and 36% CRs. The median time to progression was 2.2 years, and they noted that patients with increased LDH had a response rate of 33% and a median time to progression of only 6 months. The role of maintenance therapy with rituximab remains uncertain. A study of 62 patients, 38 with FL, evaluated a course of standard rituximab followed by 4 courses every 6 months [14]. The final response rate was 73%, with 37% CRs, and the median PFS was 34 months. This suggests that additional doses of rituximab increased the response rate and the duration of response. A randomized trial compared prolonged rituximab (375 mg/m 2 ) every 2 months 4 doses with no maintenance in patients whose disease was responding or stable after the standard 4 doses of rituximab [16]. A significant prolongation of event-free survival was observed with extended dosing. These studies demonstrate that rituximab is a very active agent, but its effect on survival has not been demonstrated to date. Rituximab Plus Chemotherapy Rituximab has been combined with CHOP chemotherapy, with encouraging results in patients with indolent lymphoma: overall response and CR rates were 100% and 63%, respectively [17]. The Southwest Oncology Group has conducted a study of rituximab after CHOP chemotherapy for the treatment of newly diagnosed FL [18]. The overall response rate was 72%, and rituximab converted 14 partial remissions to CRs. The 2-year PFS in this study was 76%. In a single-center open-label phase II trial in 40 patients, 27 of whom were treatment naive, the combination of fludarabine and rituximab achieved an overall response rate of 90% (CR rate, 80%) [19]. In the 16 subjects positive for t(14;18) at enrollment, molecular remission was attained in 88%. Serial PCR assays have remained negative for up to 4 years in those who attained molecular remission. At a median follow-up of 44 months, the median duration of response, time to progression, and overall survival had not been reached. An international multicenter randomized trial of 321 patients with previously untreated stage III/IV FL compared 8 cycles of CVP or 8 cycles of CVP plus rituximab [20]. Overall (81% versus 57%) and complete (41% versus 10%) response rates were higher in the CVP-rituximab treatment arm. At a median follow-up of 30 months, the median times to progression (32 versus 15 months) and treatment failure (27 versus 7 months) were significantly longer in the CVP-rituximab arm. However, no survival advantage for CVP-rituximab has been noted to date (89% versus 85% survival at 30 months). BB&MT Radioimmunoconjugates Two anti-cd20 radioimmunoconjugates have been approved for the treatment of indolent lymphomas. Kaminski et al. [21] reported that a single course of treatment with iodine 131 ( 131 I) tositumomab, given to 76 previously untreated patients with FL, had overall and CR rates of 95% and 75%, respectively, and 5-year overall survival and PFS of 89% and 59%, respectively. Five-year PFS was 77% for those who attained CR, whereas all patients who achieved partial remission had disease progression at a median time of 6 months. Of the 39 patients whose baseline bone marrows were PCR positive for t(14;18), 34 (87%) became PCR negative after B-cell recovery at 6 months. In a phase II study of CHOP followed by 131 I-tositumomab conducted by the Southwest Oncology Group in patients newly diagnosed with FL, the overall response rate was 80%, including 50% CRs [22]. The role of up-front use of 131 I-tositumomab in FL patients is currently being examined in a randomized trial comparing CHOP followed by rituximab with CHOP followed by 131 I-tositumomab. Interferon Prospective randomized trials have examined the use of interferon along with combination chemotherapy in patients with advanced-stage disease [23]. These studies have generally reported a significant improvement in PFS. Two trials that involved maintenance interferon alfa had a significant prolongation of survival. A phase III trial compared interferon alfa-2b with observation after induction therapy with aggressive combination chemotherapy for previously untreated patients with indolent NHL, and no significant difference in PFS or overall survival was found between the 2 groups [24]. Given the variability of results of the various trials, the expense and toxicity of treatment, and the lack of trials in which interferon was used along with rituximab and other newer treatment regimens, the use of interferon after intensive chemotherapy does not seem warranted. THERAPY OF RECURRENT FOLLICULAR NHL In general, only 20% to 25% of patients are disease free at 4 years after conventional chemotherapy in the prerituximab era. After relapse, these diseases continue to be sensitive to single alkylating agents and CVP, but the median relapse-free survival progressively decreases with each subsequent relapse. Purine analogues are very active agents in patients with relapsed and refractory disease. The overall response rate of previously treated patients with FL to fludarabine ranged from 48% to 100%, with a CR rate of 20%. A randomized trial has compared fludarabine with CVP in previously treated patients with FL. 55

4 A. S. Freedman Although the response rates (62% versus 52%) and 2-year overall survival (70% versus 75%) seemed similar, the 2-year PFS was significantly improved with fludarabine (32% versus 14%; P.03) [25]. The pivotal trial of the anti-cd20 monoclonal antibody rituximab in patients with relapsed or refractory follicular or low-grade lymphoma showed an overall response rate of 48% [26]. There were CRs in 6% of patients, and the subset of patients with FL had a response rate of 59%. The median time to progression in this study was 9 to 11 months. A phase II trial studied re-treatment with rituximab in 57 patients with relapsed, advanced, indolent lymphoma (small lymphocytic lymphoma and predominantly FL), all of whom had previously responded to treatment with this agent in 1 or more trials [27]. The overall response rate was 40%, with 11% CRs; the estimated median time to progression after treatment was 18 months. Rituximab has been combined with chemotherapy, with high response rates and longer remissions. CHOP plus rituximab has been reported in 9 patients with prior treatment, and 7 patients have either a CR or an unconfirmed CR, with a median PFS of 48 months [17]. Fludarabine and rituximab have been combined in a phase II trial of 40 patients, including 13 previously treated patients (most with FL). The overall response rate was 92% in these 13 patients, and 77% had a CR [19]. The German Low Grade Lymphoma Study Group has reported a randomized trial in patients with relapsed or refractory FL (and mantle cell lymphoma) [28]. Patients received 4 cycles of fludarabine, cyclophosphamide, and mitoxantrone (FCM) with or without rituximab. The overall and CR rates were higher for FCM-rituximab than FCM (79 versus 58% and 33 versus 13%). FCM-rituximab also significantly improved relapse-free survival. Ibritumomab tiuxetan is composed of the murine anti-cd20 monoclonal antibody ibritumomab covalently bonded to the linker chelator tiuxetan, radiolabeled with yttrium 90 for therapy and indium 111 for imaging, dosimetry, or both. In a phase III study, 143 patients with relapsed or refractory low-grade, follicular, or transformed CD20 lymphoma were randomized to receive either rituximab or ibritumomab tiuxetan [29]. The overall response rates to rituximab and ibritumomab tiuxetan were 56% and 80%, respectively (P.002). Interim results indicated that the response rates to the ibritumomab tiuxetan combination were similar in the chemorefractory (77%) and chemosensitive (81%) patients. In a study of rituximab-refractory patients, the overall response rate was 74%. The estimated median duration of response after ibritumomab tiuxetan therapy ( 7.7 months) was longer than that after prior rituximab therapy (4.0 months) and prior chemotherapy (6.5 months). Tositumomab is a murine anti-cd20 monoclonal antibody conjugated with radioactive 131 I tositumomab. In a study of 60 patients with previously treated or resistant low-grade or transformed lowgrade NHL, an overall response rate of 65% (20% CR) was observed [30]. The median duration of remission had not been reached by 47 months. In a phase III study comparing unlabeled tositumomab with 131 I tositumomab, 17% of patients responded to the unlabeled murine antibody, and 55% of patients receiving 131 I tositumomab responded [31]. Seventeen of 19 nonresponders in the unlabeled arm crossed over to 131 I tositumomab and subsequently responded. In a review of 995 patients treated with 131 I tositumomab, the incidence of treatment-related myelodysplastic syndrome or acute myelogenous leukemia was 3.5% [32]. Further follow-up is needed to define the overall risk of this disorder; however, patients with abnormal bone marrow cytogenetics or clonal hematopoiesis should probably avoid radioimmunotherapy. FUTURE DIRECTIONS Improving Monoclonal Antibody Therapy Augmenting antibody-dependent cell-mediated cytotoxicity may improve the response rates and response duration of single-agent rituximab. Several investigators have explored combination immunotherapy with rituximab and immunostimulants such as interleukin 2, interleukin 12, and interferon alfa [33]. These studies suggest such combinations are safe and may prolong PFS. Several other novel monoclonal antibodies with activity against B-cell lymphoma are being evaluated, including epratuzumab (anti-cd22) [34] and galiximab (anti-cd80) [35]. In early studies, these antibodies have demonstrated efficacy and tolerability in patients with relapsed FL. Clinical trials are ongoing to evaluate these antibodies as single agents and in combination with rituximab. Anti bcl-2 Therapy An obvious target in FL is the bcl-2 gene, which is overexpressed in 85% of patients with FL and t(14; 18). In phase I trials of bcl-2 antisense, a limited number of responses have been obtained, even in the presence of advanced or relapsed disease [36]. Several other small molecules that target BCL-2 are in earlyphase trials. Vaccines Several approaches of vaccination have been used in clinical trials of patients with FL, and the most frequent target is the idiotype. In phase II studies, anti-idiotype immune responses occurred after vaccination in approximately 50% of patients, and these patients had prolonged PFS compared with historical 56

5 Non Transplant-Related Treatment Options in Follicular Lymphoma controls [37]. Currently, there are 3 randomized trials evaluating the role of idiotype vaccination after chemotherapy or rituximab in patients with previously untreated FL. Ongoing and future studies in these areas may provide novel alternatives and complement conventional therapy. REFERENCES 1. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104: 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. 1996;14: Kelsey SM, Newland AC, Hudson GV, Jelliffe AM. A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-hodgkins lymphoma. Med Oncol. 1994;11: Ardeshna KM, Smith P, Norton A, et al. 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