Phase II Trial of Short-Course CHOP-RFollowed by Y-ibritumomab Tiuxetan and Extended Rituximab in Previously Untreated Follicular Lymphoma

Purpose: Radioimmunotherapy has been approved for relapsed follicular lymphoma (FL), including rituximab-refractory FL. This study was designed to determine the CR rate with shortcourse chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) followed by 90-Y ibritumomab tiuxetan (RIT) with extended rituximab as first-line treatment. Experimental Design:BetweenMarch 2004 and February 2007, 60 patients with stage II to IV symptomatic or bulky FL from a single institution supported by a large community network entered this phase II trial. Patients received CHOP-R for three treatment cycles before RIT followed by four additional weekly treatments with rituximab. Response was determined using fusion [ F] fluorodeoxyglucose-positron emission tomography (PET)-computed tomography (CT) imaging. Results: Of the 60 patients entering this trial, 55 patients completed all protocol therapy. The median follow up was 19.7 months (range, 0.26-35.9 months). For intent-to-treat analysis, the complete response (CR) rate after CHOP-R, as assessed by CTand PET imaging, was 40% and 46%, respectively. After RIT, the CR rate improved, as assessed by CTand PET imaging, to 82% and 89%, respectively. Ten patients have progressed, including eight from best response of CR. Seven of 18 patients who were PET positive after CHOP-R progressed compared with 3 of 37 patients who were PET negative (P = 0.010). Conclusions: In patients with previously untreated, symptomatic or bulky FL, short-course chemoimmunotherapy and consolidation RITand extended rituximab resulted in a high CR rate. Failure to achieve an early PETCR after CHOP-R indicated high risk of relapse. After three decades with little advance in the outcome for patients with follicular lymphoma (FL), the addition of the anti-CD20 chimeric monoclonal antibody, rituximab, dramatically changed the overall response rates (ORR) and may be affecting survival (1). As a single agent, rituximab was shown in a nonrandomized pivotal trial of 166 patients with relapsed low-grade lymphoma to have an ORR of 48% and a complete response (CR) of 6% (2). Lacking significant myelosuppression, investigators immediately recognized that rituximab was an ideal agent to combine with chemotherapy. Phase II studies combining chemotherapy with rituximab in relapsed and previously untreated patients with FL showed impressive ORR and CR rates of 90% to 100% and 50% to 70%, respectively (3, 4). Subsequently, two large randomized trials confirmed the benefit of combining chemotherapy with immunotherapy with CR rates of 41% and 20% compared with 10% and 17% with chemotherapy alone, significantly longer duration of response, and possibly, a survival advantage (5, 6). Radioimmunotherapy is a promising new therapy demonstrating complete and partial responses in chemotherapy and rituximab refractory patients. As early as 1996, a phase II study using single agent 131-iodine (I) tositumomab (Bexxar; GlaxoSmithKline), in previously untreated patients with FL, resulted in an ORR of 95% and a CR rate of 75% (7). In 2002, 90yttrium(Y) ibritumomab tiuxetan (RIT; Zevalin; Biogen Idec) was approved by the Food and Drug Administration for the treatment of relapsed and refractory low-grade FL. RIT received approval based on ORR of 73% to 83% and CR rates of 15% to 51% depending upon the previous number and type of prior therapies (8, 9). Several small studies have reported Cancer Therapy: Clinical Authors’Affiliations: Departments of Medicine, Pathology, and Radiology, Clinical Research Services, University of Pittsburgh Medical Center Cancer Centers, Department of Biostatistics, Graduate School of Public Health, NSABP and University of Pittsburgh Cancer Institute, and Oncology-Hematology Associates, Pittsburgh, Pennsylvania Received 4/11/08; revised 5/28/08; accepted 6/29/08. Grant support:BiogenIdec Pharmaceuticals andNational Cancer Institute CCSG/ IRAT P30 CA 047904. The trial is registered at http://www.clinicaltrials.gov (identifier: NCT00177554.) The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Samuel A. Jacobs, Department of Medicine, University of Pittsburgh Medical Center Cancer Centers, 5150 Centre Avenue, Suite 510, University of Pittsburgh Medical Center Cancer Pavilion, Pittsburgh, PA 15232. Phone: 412-235-1278; Fax: 412-623-4655; E-mail: [email protected]. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-0529 www.aacrjournals.org Clin Cancer Res 2008;14(21) November1, 2008 7088 Research. on April 13, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from sequencing chemotherapy with or without rituximab followed by radioimmunotherapy as first-line therapy. The ORRs were 90% to 100% and CR rates ranging from 69% to 86% (10–15). Based on these developments, we designed a phase II trial to take advantage of the exquisite sensitivity of FL to RIT and to decrease the amount of exposure to cytotoxic drugs. We reduced the number of cycles of standard dose cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) from 6 to 3 and followed with RIT and extended rituximab. The primary end points were safety and efficacy. Fusion [ F] fluorodeoxyglucose-positron emission tomography (PET)-computed tomography (CT) imaging was used to determine CR. Materials andMethods Patients. This phase II, nonrandomized study, was carried out at a single institution supported by a large community oncology network. Radioimmunotherapy was administered at the central academic hub, the Hillman Cancer Center, but over half the patients received chemoimmunotherapy and follow-up at community offices. Between March 2004 through February 2007, 60 patients were enrolled. Eligibility criteria were as follows: FL grade of 1, 2, and 3 by WHO criteria; age of z18 y; no prior chemotherapy or monoclonal antibody therapy; prior radiation therapy was allowed if <25% of active bone marrow was exposed; Ann Arbor stages of II to IV with either symptomatic or bulky disease (>5 cm); performance status of 0 to 2; and measurable disease. A baseline MUGA scan within the institutional reference range was required. Patients with known HIV-related lymphoma were excluded. All patients signed a written informed consent approved by the University of Pittsburgh Institutional Review Board. Each patient received a FLIPI score based on age, stage, hemoglobin level, number of nodal sites of disease, and serum lactate dehydrogenase level and was classified as either asymptomatic, symptomatic, or with B symptoms. The largest cross-sectional diameter of a nodal mass was recorded as either <5 cm, from 5 to 10 cm, or >10 cm. A baseline PET-CT scan was recorded as either positive or negative for fluorodeoxyglucose uptake. Drug administration. CHOP-R was administered at 21-d intervals. Rituximab 375 mg/m2 i.v was given on day 1 of each cycle. Standard Eastern Cooperative Oncology Group doses of CHOP were used (16). Doses were not modified, but use of growth factor and/or prophylactic antibiotics was allowed. For an absolute neutrophile count of <1,500/mm or a platelet count of <100,000/mm on day 1 of subsequent cycles, chemotherapy was delayed 1 wk. A 2-wk delay was allowed for neutropenic fever. After three cycles of CHOP-R, patients were restaged with fusion PET-CT scan and bone marrow biopsy before receiving the RIT regimen. To proceed with RIT, bone marrow recovery was required as evidenced by an absolute neutrophile count of z1,500/mm, a platelet of z100,000/mm, bone marrow cellularity of z15%, and lymphoma infiltration of <25%. The details of RIT have been described elsewhere (17). Within 1 to 2 wk of receiving RIT, patients began an additional 4-wk course of rituximab 375 mg/m on days 1, 8, 15, and 22. Clinical response criteria. Disease response and progression were determined by physical examination and fusion PET-CT scan done before therapy, 3 to 4 wk after 3 cycles of CHOP-R, at 12 wk postRIT therapy to minimize posttherapy inflammatory changes (18, 19), and thereafter at 6-mo intervals. Bone marrow biopsy was done at baseline, after 3 cycles of CHOP-R, at 12 wk post-RIT therapy if either of the prior biopsies were positive. A CR included the following: resolution of all palpable peripheral adenopathy, a normocellular bone marrow without evidence of lymphomatous infiltration by histology or flow cytometry, the CT portion of the PET-CT scan meeting the international working group criteria, or the PET portion read visually as negative (18, 20). Partial response, stable disease, and progressive disease were determined by international working group criteria (20). Assessment of molecular response. Quantitative PCR was done as described (21) using FAM-labeled forward primers directed toward BCL2 mbr or mcr sequences and a reverse consensus primer for the IgH joining region. Copies of t(14;18)-positive DNA were calculated from standard curves of serially diluted plasmids containing inserts of either mbr or mcr BCL2/IgH joining region translocation regions from t(14;18)-positive patients. Because this aspect of the study required potentially serial bone marrows, participation was optional. Toxicity. Adverse events were summarized for all patients who began any study therapy using the Common Toxicity Criteria of the National Cancer Institute version 3.0. All serious adverse events were discussed at a monthly disease center meeting. Serious adverse events that were either related, possibly or probably related to study treatment, but unexpected, were reported to the Institutional Review Board. Statistical analysis. Follow-up time was computed using KaplanMeier with reverse censoring for deaths (22). We compared CR rates by disease characteristics with Fisher’s exact tests. Progression-free survival (PFS) was calculated as the time from the start of treatment to the date of lymphoma progression or death from any cause. Overall survival (OS) was computed as the time from the start of treatment to death from any cause. PFS and OS were computed based on all patients with follow-up information. Statistical analyses were done with S-Plus version 7.0 (Insightful Corp.).