Originally published as JCO Early Release 10.1200/JCO.2006.05.8198 on August 8 2006

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Phase II Trial of CHOP Chemotherapy Followed by Tositumomab/Iodine I-131 Tositumomab for Previously Untreated Follicular Non-Hodgkin's Lymphoma: Five-Year Follow-Up of Southwest Oncology Group Protocol S9911

Oliver W. Press, Joseph M. Unger, Rita M. Braziel, David G. Maloney, Thomas P. Miller, Michael LeBlanc, Richard I. Fisher

From the Fred Hutchinson Cancer Research Center; Southwest Oncology Group Statistical Center, Seattle, WA; Oregon Health Sciences University, Portland, OR; Arizona Cancer Center, University of Arizona, Tucson, AZ; and the James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY

Address reprint requests to Southwest Oncology Group (S9911), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: pubs{at}swog.org

	ABSTRACT

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Purpose Advanced follicular lymphoma (FL) is incurable with conventional chemotherapy and radiotherapy, and optimal front-line management is controversial. This study was performed to determine the efficacy of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy followed by tositumomab/iodine I-131 tositumomab.

Patients and Methods From 1999 to 2000, the Southwest Oncology Group (SWOG) conducted a phase II trial (S9911) to test a novel new regimen consisting of six cycles of CHOP chemotherapy followed 4 to 8 weeks later by tositumomab/iodine I-131 tositumomab in 90 eligible patients with previously untreated, advanced-stage FL.

Results The overall response rate was 91%, including a 69% complete remission (CR) rate. After a median follow-up time of 5.1 years, the estimated 5-year overall survival (OS) rate was 87%, and the progression-free survival (PFS) rate was 67%. The 5-year estimates of OS and PFS were each 23% better (absolute difference) than the corresponding figures for patients treated on previous SWOG protocols with CHOP alone. An analysis according to the Follicular Lymphoma International Prognostic Index showed that 21% of patients had high-risk features, 44% had intermediate-risk features, and 34% had low-risk features. High-risk patients had worse OS than lower risk patients (P = .05), but differences in PFS were not statistically significant (P = .21). Serial monitoring of the t(14;18) translocation in bone marrow by polymerase chain reaction demonstrated that 32 of 38 informative patients obtained molecular CRs, including seven patients (18%) after CHOP and 24 additional patients (63%) after tositumomab/iodine I-131 tositumomab. (The timing of conversion of one patient was unclear.)

Conclusion A prospective, phase III, randomized Intergroup Trial is currently underway comparing the efficacy of the promising CHOP + tositumomab/iodine I-131 tositumomab regimen with the efficacy of CHOP + rituximab.

	INTRODUCTION

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Follicular lymphoma (FL) affects approximately 15,000 Americans annually and is the second most common type of non-Hodgkin's lymphoma in the United States. FL usually progresses slowly but inexorably, with a median survival time of 7 to 10 years after diagnosis.^1-3 A Follicular Lymphoma International Prognostic Index (FLIPI) based on five clinical parameters has recently been delineated that is capable of stratifying patients treated with conventional therapies into low-, intermediate-, and high-risk subgroups with median survival times of 10, 7, and 5 years, respectively.⁴ Despite initial responsiveness to multiple treatments, there is currently no convincing evidence that any conventional therapy is curative for patients with advanced FL. Experts differ greatly in their opinions regarding optimal front-line management of patients with FL, resulting in a diverse menu of treatment recommendations including watchful waiting; chlorambucil; rituximab; cyclophosphamide, vincristine, and prednisone (CVP); fludarabine-based regimens; and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Recent randomized studies have convincingly demonstrated that the addition of rituximab to CVP, CHOP, and fludarabine-based regimens improves the overall response rates, complete remission (CR) rates, and event-free survival compared with the same regimens administered without rituximab.^5-7 Whether such combined immunochemotherapy regimens also improve overall survival (OS) of FL patients is controversial, although recent evidence suggests that this may be the case.^6,8,9

In the past few years, radiolabeled anti-CD20 antibodies have been introduced to improve the efficacy of antibody therapy for B-cell lymphomas. Studies with tositumomab/iodine I-131 tositumomab (Bexxar; GlaxoSmithKline, Philadelphia, PA) and yttrium-90 ibritumomab tiuxetan (Zevalin; Biogen Idec, Cambridge, MA) have demonstrated their safety and efficacy, with multiple trials demonstrating overall response rates of 50% to 80% and CR rates of 20% to 40% in patients with relapsed or refractory FL.^10-16 Both products are now approved by the Food and Drug Administration for treatment of patients with relapsed, refractory, or transformed FL, but their role in front-line therapy is uncertain.

In May 1999, the Southwest Oncology Group (SWOG) opened a phase II study (S9911) of multimodality therapy using six cycles of CHOP chemotherapy followed by consolidation with tositumomab/iodine I-131 tositumomab for patients with previously untreated advanced FL to determine whether administering this novel combination was feasible, safe, and effective. An initial report detailing the toxicities, response rates, and 2-year progression-free survival (PFS) has been previously published.¹⁷ We now report more mature safety and efficacy results with a median follow-up time of 5.1 years. Furthermore, we present here, for the first time, outcome according to FLIPI prognostic analysis, molecular remission rates after CHOP and after tositumomab/iodine I-131 tositumomab determined by serial polymerase chain reaction (PCR) for the t(14;18) translocation in bone marrow, and a comparison of the results of S9911 with SWOG's historical CHOP studies in FL.

	PATIENTS AND METHODS

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Eligibility
Patients with biopsy-proven, CD20-positive, untreated FL of any grade (1, 2, or 3) were eligible if they were over the age of 18 years, had bidimensionally measurable bulky stage II, stage III, or stage IV disease, a SWOG performance status of 0 to 2, a pretreatment granulocyte count 1,500 cells/µL, and a platelet count 100,000/µL. All diagnostic biopsies were reviewed centrally by expert pathologists of the SWOG. Exclusion criteria are defined in the initial publication.¹⁷ All patients signed a written informed consent in accordance with institutional and federal guidelines.

FLIPI Risk Stratification
The FLIPI was not defined at the time this study was conducted, but we reviewed the flow sheets and case report forms for all 90 eligible patients between October 2005 and December 2005 to assign FLIPI scores according to the published criteria.⁴

Protocol Treatment
Patients were treated with standard CHOP chemotherapy every 21 days for six cycles.¹⁷ Patients achieving at least an unconfirmed partial response (PR)¹⁸ after six cycles of CHOP chemotherapy were eligible for consolidation with tositumomab/iodine I-131 tositumomab using the standard regimen developed by Kaminski et al.^10,19 Thyroid protection was provided with Lugol's solution.¹⁷ Full details of the treatment regimen and dose modification guidelines are available in the initial publication. Human antimouse antibody testing was not performed in this study.

Assessment of Clinical Responses
Data were centrally reviewed, and clinical responses (PR, unconfirmed CR [CRu], or CR) were assigned by the SWOG statistical center according to the criteria of an international workshop.¹⁸ Remission status was recorded 4 weeks after the sixth cycle of CHOP (just before tositumomab/iodine I-131 tositumomab); then 8 weeks, 6 months, and 12 months after tositumomab/iodine I-131 tositumomab; at least annually thereafter; and whenever patients developed symptoms or signs of lymphoma by performing a medical history, physical examination, CBC with leukocyte differential, platelet count, abdominal and pelvic computed tomography (CT), chest radiograph or CT scan, and bone marrow aspiration and biopsy. Bone marrow cytogenetic studies were not required. Patients were removed from protocol treatment if they experienced progression of disease or unacceptable toxicity or declined protocol therapy.

Assessment of Molecular Responses
Patients were asked to undergo serial bone marrow aspirations at study entry, 4 weeks after the sixth cycle of CHOP (just before tositumomab/iodine I-131 tositumomab), and then 8 weeks, 6 months, and 12 months after tositumomab/iodine I-131 tositumomab for PCR testing. The mononuclear cell fraction was isolated from marrow aspirates by Ficoll-Hypaque sedimentation and cryopreserved for subsequent batch analysis using a double nested PCR assay to detect the major breakpoint region and the minor cluster region of the BCL2 gene using the method of Gribben.^20,21 Samples were initially analyzed by fragment size using ethidium bromide gel electrophoresis of the PCR product and then transferred to nitrocellulose membranes for confirmation of the identity of the BCL2 translocation by Southern blotting. The adequacy of samples was demonstrated using beta-globin as a positive control housekeeping gene. Patients were considered to have attained a molecular remission if their marrow sample at study entry contained a detectable t(14;18) translocation that became undetectable after protocol treatment.

Statistical Considerations
The study was designed to enroll 80 eligible patients, which was a number sufficient to estimate the 2-year PFS rate (given complete follow-up) to within ± 11% (95% CI). Previous SWOG studies have shown a 2-year PFS rate of approximately 65% in this patient group. This design gives 86% power to detect a 15% difference in 2-year PFS. Eighty patients were also sufficient to estimate the best response rate to CHOP to within ± 11% (95% CI) and the probability of any toxicity to within 11%. Any adverse event occurring with at least 5% probability was likely to be seen at least once (98% chance). OS and PFS curves were plotted by the Kaplan-Meier method.²² PFS was defined as the time from registration to the first observation of progressive disease or death as a result of any cause. Analyses of survival differences by category were performed using Cox regression.²³

	RESULTS

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Patient Characteristics
The characteristics of the patients entered onto this study have been published previously.¹⁷ One hundred two patients were registered between May 15, 1999, and June 1, 2000, and 90 of these patients were eligible. Seven patients were ineligible as a result of insufficient submission of prestudy information, three patients did not have FL, one patient had the wrong stage, and one patient had a prior history of lymphoma. The median age of patients on the trial was 50 years (range, 23 to 84 years); 61% were male, 27% presented with "B" symptoms, 23% had bulky adenopathy ( 10 cm), 4% had stage II disease, 33% had stage III disease, and 63% had stage IV disease. Central pathologic review confirmed that 60%, 29%, and 11% of patients had grade 1, 2, and 3 FL, respectively.

Acute Toxicities
An updated analysis of acute toxicity data revealed only minor differences from the initial report (Table 1). There were no treatment-related deaths. One patient refused therapy after registration and was not assessable for CHOP toxicity. Of 89 patients assessable for CHOP toxicity, 35 patients (39%) experienced, at worst, grade 4 toxicity and 31 patients (35%) experienced, at worst, grade 3 events during chemotherapy. Three patients were not assessable for antibody therapy toxicity, one because of patient refusal and two others because of lack of follow-up data submission. Of 82 patients assessable for toxicities after tositumomab/iodine I-131 tositumomab, 10 (12%) experienced, at worst, grade 4 toxicity and 28 patients (34%) experienced, at worst, grade 3 events after tositumomab/iodine I-131 tositumomab.

Clinical Responses
Of the 90 eligible patients, six (7%) had insufficient documentation to assess response, 62 (69%) achieved CRs (CR or CRu), 20 (22%) achieved a PR, and two (2%) had stable disease. If response analysis is limited to the 84 patients for whom sufficient documentation is available to assess response, 98% had objective remissions, including 74% with CR (CR or CRu) and 24% with PR. Therapy with tositumomab/iodine I-131 tositumomab seemed to substantially improve the CR rate (from 39% after six cycles of CHOP to 69% after tositumomab/iodine I-131 tositumomab).

Assessment of Molecular Responses
Patients were asked to undergo five serial bone marrow aspirations for PCR (at study entry; at completion of six cycles of CHOP but before tositumomab/iodine I-131 tositumomab; and then 8 weeks, 6 months, and 12 months after tositumomab/iodine I-131 tositumomab). Of the 90 eligible patients, 25 patients lacked detectable levels of the t(14;18) translocation by PCR at study entry, either because their tumor did not express the translocation or because the marrow was uninvolved with disease. Of the remaining 65 patients, 27 patients did not have both baseline and serial bone marrow testing (as a result of patient or physician refusal), leaving 38 patients with informative marrow specimens. Of these 38 informative patients, 32 (84%) became PCR negative after protocol therapy. Seven patients (18%) converted to PCR negative after CHOP, and an additional 24 patients (63%) converted after tositumomab/iodine I-131 tositumomab. One patient (3%) converted to PCR negative, but attribution of PCR conversion to a particular phase of treatment was not possible because the marrow aspirate between CHOP and tositumomab/iodine I-131 tositumomab was missing. One of the 24 patients who converted to PCR negativity after tositumomab/iodine I-131 tositumomab subsequently reverted to being PCR positive on a later marrow sample.

PFS and OS
With a median follow-up time of 5.1 years, 31 of 90 eligible patients haven experienced progression or died, yielding an estimated 5-year PFS rate of 67% (Fig 1). Twelve eligible patients (13%) have died, 10 after a diagnosis of progressive lymphoma. One of the other two patients died of apparent myocardial infarction unrelated to treatment, and the other patient died of colon cancer. None of these deaths were considered related to the treatment administered on this protocol. The 5-year estimate of OS was 87% (Fig 1). Significant differences were not observed in either PFS or OS according to PCR status (data not shown), although power to detect differences was low.

View larger version (6K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Progression-free and overall survival of 90 eligible patients with bulky stage II to stage IV follicular non-Hodgkin's lymphoma treated with six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy followed by tositumomab/iodine I-131 tositumomab. The 5-year estimate of overall survival is 87%, and the 5-year estimate of progression-free survival is 67%.

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Progression-free survival of 90 eligible patients with bulky stage II to stage IV follicular non-Hodgkin's lymphoma treated with six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy followed by tositumomab/iodine I-131 tositumomab, stratified by Follicular Lymphoma International Prognostic Index category (low risk, 31 patients; intermediate risk, 40 patients; and high risk, 19 patients).

View larger version (7K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Overall survival of 90 eligible patients with bulky stage II to stage IV follicular non-Hodgkin's lymphoma treated with six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy followed by tositumomab/iodine I-131 tositumomab, stratified by Follicular Lymphoma International Prognostic Index category (low risk, 31 patients; intermediate risk, 40 patients; and high risk, 19 patients).

View larger version (6K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Comparison of the progression-free survival (PFS) of 90 patients with bulky stage II to stage IV follicular non-Hodgkin's lymphoma treated with six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy followed by tositumomab/iodine I-131 tositumomab (radioimmunotherapy [RIT]) with the PFS of 356 similar patients treated on previous Southwest Oncology Group studies of CHOP without anti-CD20 antibodies (historical CHOP). Five-year estimates of PFS for each regimen are shown.

View larger version (6K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Comparison of the overall survival (OS) of 90 patients with stage II to IV follicular non-Hodgkin's lymphoma treated with six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy followed by tositumomab/iodine I-131 tositumomab (radioimmunotherapy [RIT]) on the current trial (S9911) with the OS of 356 similar patients treated on previous studies with CHOP without anti-CD20 antibodies (historical CHOP). Five-year estimates of OS with each regimen are shown.

	DISCUSSION

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The paucity of serious late toxicities in this trial is also encouraging. Delayed mild cytopenias were reported in only a small minority of patients, suggesting that bone marrow stem-cell reserve was preserved. Furthermore, the reported incidence of hypothyroidism was only 9%. Although these figures may underestimate the true rates of these events, the concordance between the rate of hypothyroidism reported on this trial (9%) and the rates published from other studies using the same dose of tositumomab/iodine I-131 tositumomab¹⁰ suggests that the data are reliable. The low incidences of MDS (1%) and AML (0%) after 5.1 years of follow-up are particularly reassuring because many investigators consider these sequelae to represent the greatest risks of radioimmunotherapy (RIT). The low incidence of MDS/AML after upfront RIT is supported by two other trials that have observed no cases of MDS/AML among 111 patients treated with tositumomab/iodine I-131 tositumomab as initial therapy.^25,26 Second solid tumors were also uncommon in this study, with only four cancers reported in three patients (3%), which approximates the expected rate of solid tumor formation in the general population in this age group.²⁷

In recent years, the efficacy and safety of RIT for relapsed, refractory, and transformed FL have been convincingly demonstrated for both tositumomab/iodine I-131 tositumomab and for yttrium-90 ibritumomab tiuxetan. However, the role of RIT in first-line therapy remains undefined. However, five trials using radiolabeled antibodies as front-line treatment of indolent non-Hodgkin's lymphoma have been recently reported, and all are extremely encouraging. Trials using tositumomab/iodine I-131 tositumomab alone²⁵ or after CVP,²⁸ fludarabine,²⁶ or CHOP chemotherapy¹⁷ and a preliminary report of yttrium-90 ibritumomab tiuxetan after three cycles of rituximab + CHOP²⁹ have reported overall response rates ranging from 90% to 100% and CR rates of 60% to 90%. Many of the remissions have persisted for more than 5 years, and toxicities have been manageable. Our study is notable for being the largest of the five reported trials (90 patients), has the longest follow-up time (5.1 years) and the highest reported 5-year PFS rate (67%), and is the only study to include grade 3 FL patients and to be conducted through a major cooperative group. Diagnostic biopsies from all eligible patients were centrally reviewed by expert hematopathologists on the SWOG trial to confirm the diagnosis of FL and the histologic grade. Furthermore, responses and remission durations were centrally assessed by the SWOG Statistical Center, not by investigators, to assure maximal objectivity. PCR assays were performed by an expert in molecular diagnostics at a central laboratory to assure standardized, uniform methodology.

The PFS and OS rates observed in this trial are the best ever observed in a study of FL conducted by the SWOG and represent a 23% improvement over historical experience for each parameter. Furthermore, the survival rates observed for the intermediate- and high-risk FLIPI subgroups appear substantially better than those predicted from previous publications.⁴ However, we recognize that such historical comparisons may be misleading because recent reports suggest better survival of FL patients in recent years, which has been attributed to improvements in supportive care, the availability of new agents (eg, maintenance rituximab),^30,31 and better management of comorbid illnesses.^8,9 It is also possible that these apparent differences might be a result of differences in patient characteristics or protocol eligibility criteria between the studies. Furthermore, it is conceivable that progression rates might have been impacted if more frequent monitoring with CT scans had been mandated by the protocol. Therefore, it is essential that new regimens, such as CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab, be compared with other regimens in rigorous, randomized, phase III trials before conclusions are reached about relative efficacy. Thus, we encourage FL patients and their physicians to participate in the ongoing Intergroup Trial S0016 being conducted jointly by SWOG, Cancer and Leukemia Group B (S0016), the Eastern Cooperative Oncology Group, and the Clinical Trial Support Unit, rather than to adopt this regimen based on favorable phase II results and historical comparisons. The randomized trial compares six cycles of CHOP administered concurrently with rituximab³² with the CHOP plus tositumomab/iodine I-131 tositumomab regimen described in this article. At the time of submission of this article, approximately 340 of the 500 planned patients had been enrolled.

	Authors' Disclosures of Potential Conflicts of Interest

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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 Oliver W. Press Genentech (A); Biogen Idec (A); GlaxoSmithKline (A) Genentech (A) David G. Maloney Biogen Idec (A); Genentech (A) Biogen Idec (A); Genentech (A) Genentech (B) Richard I. Fisher GlaxoSmithKline (A) GlaxoSmithKline (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Oliver W. Press, Joseph M. Unger, Rita M. Braziel, David G. Maloney, Thomas P. Miller, Michael LeBlanc, Richard I. Fisher Provision of study materials or patients: Oliver W. Press, Thomas P. Miller, Richard I. Fisher Collection and assembly of data: Oliver W. Press, Joseph M. Unger, Rita M. Braziel, Thomas P. Miller, Michael LeBlanc Data analysis and interpretation: Oliver W. Press, Joseph M. Unger, Rita M. Braziel, David G. Maloney, Thomas P. Miller, Michael LeBlanc, Richard I. Fisher Manuscript writing: Oliver W. Press, Joseph M. Unger, Rita M. Braziel, David G. Maloney, Thomas P. Miller, Richard I. Fisher Final approval of manuscript: Oliver W. Press, Joseph M. Unger, Thomas P. Miller, Michael LeBlanc, Richard I. Fisher

 

	ACKNOWLEDGMENTS

 
We thank Scott Kurruk, Jill Loveland, Michelle Ward, and the Operations and Statistical Offices of the Southwest Oncology Group for their administrative assistance with the conduct of this trial and the preparation of this manuscript. In addition, we acknowledge the generous support of GlaxoSmithKline Inc, who provided tositumomab and iodine I-131 tositumomab for this trial and a research grant covering the Nuclear Medicine costs.

	NOTES

 
published online ahead of print at www.jco.org on August 7, 2006.

Supported in part by the following Public Health Service Cooperative Agreement Grants awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA46113, CA46282, CA20319, CA13612, CA11083, CA35261, CA35128, CA35192, CA37981, CA45377, CA67575, CA58861, CA35090, CA63844, CA35176, CA35996, CA46368, CA04919, CA46441, CA12644, CA58686, CA63850, CA35119, CA35431, CA58348, CA35281, CA76132, CA12213, CA76447, CA45560. Also supported in part by GlaxoSmithKline Inc.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted February 3, 2006; accepted June 30, 2006.

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