J Clin Oncol 23: by American Society of Clinical Oncology INTRODUCTION

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1 VOLUME 23 NUMBER 33 NOVEMBER JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T New Treatment Options Have Changed the Survival of Patients With Follicular Lymphoma Richard I. Fisher, Michael LeBlanc, Oliver W. Press, David G. Maloney, Joseph M. Unger, and Thomas P. Miller From the James P. Wilmot Cancer Center, University of Rochester, Rochester, NY; Statistical Center, Southwest Oncology Group; Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA; and Cancer Center, University of Arizona, Tucson, AZ. Submitted June 17, 2005; accepted August 15, Supported in part by Public Health Service Cooperative Agreement grant Nos. CA38926, CA32102, CA20319, CA13612, and CA11083 awarded by the National Cancer Institute, US Department of Health and Human Services. Authors disclosures of potential conflicts of interest are found at the end of this article. Address reprint requests to Richard I. Fisher, MD, Director, James P. Wilmot Cancer Center, 601 Elmwood Ave, Box 704, Rochester, NY 14642; richard_fisher@urmc.rochester.edu by American Society of Clinical Oncology X/05/ /$20.00 DOI: /JCO A B S T R A C T Background The natural history of follicular lymphoma is believed not to have changed over the last 30 years. Median survivals have ranged from 7 to 10 years, and the disease is considered incurable. However, multiple new treatment options have been developed in the last decade, and their impact on survival of follicular lymphoma remains unknown. Patients and Methods In the current analysis, we identified all previously untreated, advanced-stage, follicular lymphoma patients treated with the following three sequential treatment approaches: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy nonspecific immunostimulants (Southwest Oncology Group [SWOG] 7426 and 7713: 1974 to 1983); prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide (ProMACE) plus mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) interferon (SWOG 8809: 1988 to 1994); and CHOP followed by monoclonal antibody (MoAb) therapy (SWOG 9800 and 9911: 1998 to 2000). We assessed the patients progression-free survival (PFS) and overall survival (OS). The MoAb trials included CHOP followed by rituximab (SWOG 9800) and CHOP followed by 131 I-tositumomab (SWOG 9911). Results The PFS curves for the CHOP and ProMACE-MOPP studies are overlapping, with 4-year PFS estimates of 46% and 48%, respectively. However, the PFS rate of the CHOP MoAb studies is significantly improved at 61% (P.005). The OS curves show improvement with each succeeding study. The 4-year estimate of OS is 69% for the CHOP regimens, 79% for the ProMACE-MOPP study, and 91% for the CHOP MoAb regimens (P.001). These conclusions were retained after adjusting for differences in prognostic factors between the study groups. Conclusion The results of this study suggest that OS for patients with follicular lymphoma has improved over time and that the choice of initial therapy may matter. J Clin Oncol 23: by American Society of Clinical Oncology INTRODUCTION During the last 30 years, the Lymphoma Committee of the Southwest Oncology Group (SWOG) has conducted a series of randomized clinical trials in previously untreated patients with advanced-stage, indolent non-hodgkin s lymphoma. Patients enrolled onto these trials were all treated with anthracycline-based combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) with or without nonspecific immunotherapy. The initial results of these studies have been previously published. 1,2 Recently, the development of monoclonal antibodies (MoAbs) has revolutionized the treatment of patients with follicular lymphoma. 8447

2 Fisher et al Since 1998, the SWOG Lymphoma Committee has conducted a series of sequential, national, phase II trials incorporating the concept of rapid cytoreduction with anthracycline-based combination chemotherapy followed immediately by treatment with an MoAb or radioimmunotherapy. The early treatment results from these trials have seemed extremely promising. 3,4 Therefore, this analysis was performed to assess the potential long-term impact of these treatment options on the progression-free survival (PFS) and overall survival (OS) of untreated patients with follicular lymphoma. PATIENTS AND METHODS We identified all advanced-stage (bulky II, III, or IV) patients with an excisional biopsy establishing the diagnosis of follicular lymphoma (grades 1, 2, or 3) who were initially treated with one of the following three sequential treatment approaches: CHOP chemotherapy nonspecific immunostimulants (SWOG 7426 and 7713: 1974 to 1983) 1 ; prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide (ProMACE) plus mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) interferon (SWOG 8809: 1988 to 1994) 2 ; and CHOP followed by MoAb therapy (SWOG 9800 and 9911: 1998 to 2000). We assessed the PFS and OS of these patients. The MoAb trials included CHOP followed by rituximab (SWOG 9800) 3 and CHOP followed by 131 I-tositumomab (SWOG 9911). 4 Prognostic factor data were collected prospectively at registration. 2 tests were used to assess differences in distributions of prognostic factors between the three treatment groups. OS and PFS were calculated from the date of registration until death (OS) or until disease progression or death (PFS). All eligible patients entering each of previously defined clinical trials are included in the analyses. Patient data were censored at the last contact date. OS and PFS were estimated using the Kaplan-Meier method, 5 and CIs were calculated. Analyses were based on the Cox regression model, 6 both adjusting and not adjusting for the International Prognostic Index (IPI) 7 factors (age, lactate dehydrogenase, stage, extranodal disease, and performance status). To adjust for the IPI, a stratified proportional hazards model was used. In an additional analysis, we adjusted for all IPI factors and the additional prognostic factors of bone marrow involvement and B symptoms in a multivariable Cox regression model. Twosided P values are reported. RESULTS A total of 960 patients who met the previously defined eligibility criteria were identified for this analysis. Three hundred fifty-six patients were treated with CHOP chemotherapy nonspecific immunostimulants (CHOP-bleomycin versus CHOP plus bacillus Calmette-Guerin, SWOG 7426; and CHOP levamisole bacillus Calmette-Guerin, SWOG 7713: 1974 to 1983); 425 patients were treated with ProMACE-MOPP interferon (SWOG 8809: 1988 to 1994); and 179 patients were treated with CHOP followed by MoAb therapy (SWOG 9800 and 9911: 1998 to 2000). In the tables and figures, these three groups will be referred to as CHOP, ProMACE, and CHOP MoAb. The patient characteristics for each group are listed in Table 1. The median ages were 55 years for the CHOP regimens, 48 years for the ProMACE-MOPP regimen, and 52 years for the CHOP MoAb regimens. The majority of the patients in each study had grade 1 or 2 histology. The percentage of patients with grade 3 histology was 12% on the CHOP regimens, 0% on the ProMACE-MOPP study (patients with grade 3 histology were excluded through Working Formulation A to C eligibility criteria in this particular study), and 12% on the CHOP MoAb regimens. Similarly, the vast majority of all patients had stage III or IV disease. Only 7% of patients on the CHOP MoAb studies had bulky stage II disease, with 0% bulky stage II disease in the CHOP and ProMACE studies. Of various known single prognostic factors, approximately 25% of all patients had elevated lactate dehydrogenase more than the international upper limit of normal, 29% had B symptoms, 14% to 19% had more than one extranodal site, and essentially all patients had excellent performance status of less than 2 (Table 1). Bone marrow involvement varied from 47% to 68% of patients. When these patients were categorized according to Table 1. Patient Characteristics at Entry by Regimen Characteristic CHOP (n 356) % of Patients ProMACE (n 425) CHOP MoAb (n 179) Age, years Median Range Male Follicular histology Grade Grade Grade Stage II bulky III IV LDH IULN B symptoms Extra nodal sites Performance status Bone marrow involvement IPI risk Low Low-intermediate High-intermediate High Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; ProMACE, prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide; MoAb, monoclonal antibody; LDH, lactate dehydrogenase; IULN, institutional upper limit of normal; IPI, International Prognostic Index. P JOURNAL OF CLINICAL ONCOLOGY

3 New Treatment Options in Follicular Lymphoma the IPI, 7 the majority of patients had low or low-intermediate risk. The percentage of patients with high-intermediate or high risk varied from 19% on for the CHOP regimens, 10% for the ProMACE study, and 8% for the CHOP MoAb regimens. The distributions of several known prognostically important factors (ie, bone marrow involvement, stage, and resulting IPI scores) were statistically different between studies; therefore, outcome analyses were adjusted as described earlier. Data were not available in the older studies to calculate the newly described follicular lymphoma IPI because this index uses a new method for defining and counting nodal sites that cannot be reconstructed from the older databases. 8 The PFS rates of the three groups are listed in Table 2 and shown in Figure 1. The curves for the CHOP and ProMACE studies are essentially overlapping, with 4-year PFS estimates of 46% and 48%, respectively. However, the PFS estimate of the CHOP MoAb studies is significantly improved at 61% (P.005). This difference is retained after adjusting for differences in IPI distribution (P.007). As a further analysis to correct for any imbalance in the prognostic factors, we adjusted for all IPI factors and the additional prognostic factors of bone marrow involvement and B symptoms in a multivariable Cox regression model (P.01). The OS rates of the three groups are also listed in Table 2 and shown in Figure 2. In contrast with the PFS, the OS improved significantly over each succeeding study. Thus, the 4-year estimates of OS are 69% for the CHOP regimens, 79% for the ProMACE study, and 91% for the CHOP MoAb regimens (P.001). This trend is retained after adjusting for differences in the IPI distribution (P.001). DISCUSSION There is a general consensus that the natural history of advanced stages of low-grade or indolent lymphoma has not changed for the last 30 years. For example, Horning 9 reported the results of sequential treatment studies conducted at Stanford University from 1960 to Median survival times have ranged from 7 to 10 years, and the OS for each group of studies was overlapping. Indolent lymphoma is generally considered incurable because no plateau in the survival curve has been demonstrable. Patients with advanced stages of indolent non-hodgkin s lymphoma have been treated for many years with various approaches, including deferred initial therapy (watch and wait), singleagent alkylating agents, radiation therapy, combination chemotherapy, and autologous stem-cell transplantation. Unfortunately, it has been impossible to demonstrate that the long-term prognosis for these patients has significantly changed with any these treatment options. For example, the use of anthracycline-based chemotherapy, which is curative for almost half of all patients with advanced-stage, diffuse, large-cell lymphoma, results in the same median survival time of 7 to 10 years as seen after single-agent chemotherapy. 1 Some randomized studies have suggested improved survival for follicular lymphoma patients treated with combination chemotherapy plus interferon, 10,11 whereas other large randomized trials have failed to show any patient benefit. 2 A recently published meta-analysis concluded that high doses of interferon given in the context of relatively intensive initial chemotherapy prolonged remission duration and survival in patients with follicular lymphoma. 12 However, in the United States, the toxicity of interferon has been thought to outweigh any clinical benefit, and interferon is rarely used. Thus, during the last 30 years, many investigators concluded that, because the initial treatment strategy did not affect the overall outcome as judged by OS, treatment intent was purely palliative. Although the Working Formulation classification of indolent included a heterogeneous group of small roundcell lymphomas, the majority of cases were follicular lymphomas. 13 Because of this heterogeneity in the Working Formulation, the Revised European-American Lymphoma and WHO classifications 14,15 were developed; the term follicular lymphoma continues to represent the majority of the indolent-behaving, non-hodgkin s lymphomas and is the focus of this report. In the late 1990s, the SWOG Lymphoma Committee initiated a series of large, national, phase II trials aimed at Table 2. SWOG Treatment Results: Follicular Lymphoma No. of 4-Year PFS 4-Year OS Treatment Patients % 95% CI % 95% CI CHOP regimens to to 74 ProMACE-MOPP to to 83 CHOP MoAb to to 95 P Abbreviations: SWOG, Southwest Oncology Group; PFS, progression-free survival; OS, overall survival; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; ProMACE-MOPP, prednisone methotrexate, doxorubicin, cyclophosphamide, and etoposide mechlorethamine, vincristine, procarbazine, and prednisone; MoAb, monoclonal antibody

4 Fisher et al Fig 1. Progression-free survival according to treatment program. CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; MoAb, monoclonal antibody; ProMACE, prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide. changing the natural history of patients with untreated, advanced-stage follicular lymphoma. The hypothesis was that the addition of treatment with an MoAb after cytoreductive chemotherapy would prolong the failure-free survival compared with chemotherapy alone. Initially, patients were treated with six cycles of CHOP chemotherapy. CHOP was selected because of the belief that it achieved more complete tumor shrinkage in a short period of time compared with chlorambucil or cyclophosphamide, vincristine, and prednisone (CVP). In SWOG 9800, 89 untreated follicular lymphoma patients who achieved either a complete or partial remission after six cycles of CHOP chemotherapy received four weekly doses of rituximab 375 mg/m 2 ;in SWOG 9911, the 90 complete or partial responders were subsequently treated with 131 I-tositumomab radioimmunotherapy according to the usual method of administration. 16 As noted previously, the results of these two studies were extremely promising. 3,4 Marcus et al 17 reported that CVP chemotherapy plus rituximab improved time to treatment failure compared with CVP alone as first-line treatment for advanced follicular lymphoma. Excellent results were also reported by Czuczman et al 18 with a slightly different combination of CHOP plus rituximab. These results prompted the current analysis to assess the outcome of patients entered onto SWOG therapeutic trials over the last 30 years and to test the current paradigm that treatment does not affect survival and should, therefore, be palliative in intent. Patients in the three treatment groups were generally well balanced according to known prognostic factors. PFS is a function of the result of initial therapy; it did not differ between the older CHOP- and ProMACE-based studies. However, there was a significant improvement with the recent CHOP MoAb studies. The 4-year estimate for PFS was improved by 13% to 15% compared with the older treatment results. Although there were observed differences in IPI groups and bone marrow involvement between the treatment groups, the improvement in PFS remained after adjusting for these factors in a multivariable Cox model (P.01). OS is a function of not only the initial therapy but also all subsequent treatments. In the case of OS, there was a Fig 2. Overall survival according to treatment program. CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; MoAb, monoclonal antibody; ProMACE, prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide JOURNAL OF CLINICAL ONCOLOGY

5 New Treatment Options in Follicular Lymphoma sequential improvement from a 4-year estimate of 69% for the CHOP studies to 79% for the ProMACE trial to 91% for the CHOP MoAb studies (P.001). Again, the significant improvement was retained after adjusting for IPI risk groups (P.0001). The improvement in OS for the CHOP MoAb studies is consistent with the observed improvement in PFS for this group. It is worth noting that there were 44 follicular grade 3 patients on the early CHOP studies and 20 on the CHOP MoAb studies. There were none on the ProMACE study because eligibility was limited to patients with low-grade Working Formulation A, B, and C only. Although the numbers are obviously quite small, there was still a significant improvement in PFS and OS for grade 3 patients treated with CHOP MoAb versus CHOP alone (P.04 and P.03, respectively). Likewise, exclusion of patients with follicular grade 3 disease from this overall analysis does not significantly change the results (data not shown). During the last 30 years, patients with follicular lymphoma have been entered onto the SWOG lymphoma trials based on the physician s determination of their need for treatment. One might legitimately question whether some of the improved survival seen with the later trials could be attributed to selection of patients earlier in the natural history of their disease for these more recent trials (ie, lead-time bias). Although this concept is difficult to prove or disprove, an analysis of the time between the initial diagnosis and date of registration demonstrates that interval to be longer in more recent studies (data not shown). Obviously, the improvement in OS on the ProMACE study is difficult to attribute to the initial therapy in the absence of improvement in PFS. The reason for this improvement in OS cannot be conclusively determined but might be related to better supportive care or the availability of MoAb-based secondary treatments for some of these patients. Because the PFS and OS with CHOP MoAb are superior to PFS and OS achieved with ProMACE and more clearly related to the initial treatment regimen, we do not advocate treatment with the ProMACE regimen. Finally, although any conclusions between nonrandomized groups may be subject to differences in observed and unobserved prognostic factors, we believe our conclusions regarding the improvement in PFS with the CHOP MoAb studies and the changes in OS over time are supported because the three treatment groups are relatively balanced with respect to most known prognostic factors and our conclusions with respect to PFS and OS are retained after adjusting for any differences in IPI levels, bone marrow involvement, and B symptoms. In summary, OS has improved significantly for untreated, advanced-stage patients with follicular lymphoma treated on SWOG Lymphoma Committee protocols from 1974 to Mortality in the first 4 years has been reduced by 70%. These results suggest that OS for patients with follicular lymphoma has improved over time and that the choice of initial therapy may matter. In our studies, treatment with CHOP combination chemotherapy followed by an MoAb seems to be the best option. To differentiate between the benefit provided by CHOP followed by rituximab versus CHOP followed by 131 I-tositumomab radioimmunotherapy, the Lymphoma Committees of SWOG and the Cancer and Leukemia Group B are currently conducting a randomized comparison of these two promising, new treatments (SWOG 0016) in untreated patients with advanced-stage follicular lymphoma. Authors Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Richard I. Fisher Genentech (A); Genentech (A); Genentech (C) GSK (A) GSK (A) Oliver W. Press Genentech (A); (A) GSK (C) David G. Maloney Thomas P. Miller (A); Genentech (A) (A); Genentech (A) (A); Genentech (A); GSK (A) (C) Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

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