- © 2009 by American Society of Clinical Oncology
Phase II Study of Yttrium-90–Ibritumomab Tiuxetan in Patients With Relapsed or Refractory Mantle Cell Lymphoma
- Michael Wang,
- Yasuhiro Oki,
- Barbara Pro,
- Jorge Enrique Romaguera,
- Maria Alma Rodriguez,
- Felipe Samaniego,
- Peter McLaughlin,
- Frederick Hagemeister,
- Sattva Neelapu,
- Amanda Copeland,
- Barry I. Samuels,
- Evelyne M. Loyer,
- Yuan Ji and
- Anas Younes
- From the Departments of Lymphoma, Myeloma, and Diagnostic Imaging and Division of Quantitative Science, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
- Corresponding author: Anas Younes, MD, Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429, Houston, TX 77030; e-mail: ayounes{at}mdanderson.org.
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Presented in part at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Atlanta, GA.
Abstract
Purpose This phase II trial evaluated the safety and efficacy of yttrium-90 (90Y)–ibritumomab tiuxetan in patients with relapsed or refractory mantle cell lymphoma (MCL).
Patients and Methods Patients with relapsed or refractory MCL were eligible for the study if they had adequate major organ function and performance status. Those with CNS disease, pleural effusion, circulating lymphoma cells ≥ 5,000/μL, or history of stem-cell transplant were ineligible. Patients with a platelet count ≥ 150,000/μL received a dose of 0.4 mCi/kg of 90Y–ibritumomab tiuxetan, whereas those with a platelet count less than 150,000/μL received a dose of 0.3 mCi/kg.
Results Thirty-four patients with a median age of 68 years (range, 52 to 79 years) received the therapeutic dose. The patients had received a median of three prior treatment regimens (range, one to six treatment regimens), including those that contained rituximab (n = 32) and bortezomib (n = 7). Of the 32 patients with measurable disease, 10 (31%) achieved complete or partial remission. After a median follow-up of 22 months (range, 2 to 72+ months), an intent-to-treat analysis revealed a median event-free survival (EFS) duration of 6 months and an overall survival duration of 21 months. The median EFS for those who achieved partial or complete remission was 28 months, while it was 3 months for those whose disease did not respond (P < .0001); it was 9 months for patients whose tumor measured less than 5 cm in the largest diameter before treatment and 3 months for those whose tumor measured ≥ 5 cm (P = .015).
Conclusion The single-agent activity of 90Y–ibritumomab tiuxetan and its favorable safety profile warrant its further development for the treatment of MCL.
INTRODUCTION
Mantle cell lymphoma (MCL) is a relatively rare type of B-cell non-Hodgkin's lymphoma (NHL) that accounts for approximately 5% of NHL cases in North America. The majority of patients with MCL present with advanced stage disease requiring systemic therapy; therefore, experience with external radiation therapy remains limited to the rare early-stage presentations and to palliation of relapsed disease.1,2 While a variety of systemic combination chemotherapy regimens have been reported to produce high response rates, they remain noncurative: the durations of event-free survival (EFS) and overall survival (OS) remain short.3–6
Because the disease is disseminated in more than 90% of patients, we evaluated the potential therapeutic value of systemic radiation therapy delivered by the radioimmunotherapy (RIT) approach. While RIT has been shown to be effective for the treatment of relapsed indolent and transformed large B-cell lymphomas,7–10 the clinical efficacy of this treatment modality in MCL is not well established. In this phase II clinical trial, we evaluated the safety and efficacy of a single standard dose of yttrium-90 (90Y)–ibritumomab tiuxetan in patients with relapsed or refractory MCL.
PATIENTS AND METHODS
Patients
Patients were required to have histologically confirmed relapsed or refractory MCL with less than 25% bone marrow involvement with lymphoma, age ≥ 18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and adequate bone marrow (absolute neutrophil count ≥ 1,500/μL, platelets ≥ 100,000/μL), liver, and kidney function. Patients were excluded if they had undergone prior stem-cell transplantation or RIT, or if they had a history of CNS lymphoma, human immunodeficiency virus infection, pleural effusion, human antimouse antibody reactivity, or circulating lymphoma cell count ≥ 5,000/μL. All patients were required to sign a written informed consent approved by the institutional review board in accordance with the Declaration of Helsinki.
Study Design and Treatment
This phase II, open-label, single-arm, single-center study was designed to assess the safety and efficacy of ibritumomab tiuxetan RIT in patients with advanced relapsed or refractory MCL and was approved by the institutional review board. The components of the ibritumomab tiuxetan treatment regimen are described in detail elsewhere.11,12
Patients initially received one course of rituximab (250 mg/m2) and immediately thereafter an intravenous injection of an imaging dose of indium-111 (111In)–ibritumomab tiuxetan (5 mCi [185 MBq]; 1.6 mg). One week later, patients with favorable imaging results received a second infusion of rituximab (250 mg/m2) and a therapeutic intravenous injection of 90Y–ibritumomab tiuxetan at a dose based on body weight and platelet count. Patients with a pretreatment platelet count ≥ 150,000/μL received a dose of 0.4 mCi 90Y/kg (maximum dose 32 mCi), whereas those with a platelet count of 100,000 to 150,000/μL received 0.3 mCi 90Y/kg.
Assessment
Duration of EFS was calculated from the date of registration onto the study to the date of documented relapse, disease progression, or death from any cause. Duration of OS was calculated from the date of registration onto the study to the date of death from any cause. Tumor assessments were performed on all target lesions identified by computed tomographic scans (neck, thorax, abdomen, and pelvis) at baseline, every 3 months for 1 year, every 4 months during year 2, every 6 months during years 3 to 5, and yearly thereafter. Changes in the sum of the products of the largest perpendicular diameters of measurable lesions were used to establish partial remission (PR) and complete remission (CR) as defined by the International Workshop Response Criteria, which do not incorporate positron emission tomography findings.13 Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria version 3.
Statistical Analysis
The primary end point of the study was the overall response (CR + PR) rate, and the secondary end points were EFS, OS, and toxicities. The study used a MiniMax two-stage design, in which 18 patients were recruited in the first stage. If five or more responses were observed in the first stage, an additional 15 patients were recruited in the second stage. The two-stage design was based on α = .05, power = 0.8, undesirable response rate = 20%, and desirable response rate = 40%. Statistical analyses for patients' characteristics, response rates, and adverse events were descriptive. Analysis of EFS and OS was performed on an intent-to-treat basis and was calculated by the Kaplan-Meier method.14 Comparison between curves was performed by using a two-sided log-rank test (significance level of α = .05).
RESULTS
Patient Characteristics
Thirty-five eligible patients were enrolled between April 2002 and June 2006. Thirty-four of these patients received the therapeutic 90Y–ibritumomab tiuxetan dose and were evaluable for treatment toxicity. One patient withdrew consent after receiving the imaging dose. Patients entering the study had been treated previously with a median of three therapeutic regimens (range, one to six treatment regimens). Twenty-two patients had been previously treated with fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyperCVAD) alternating with methotrexate+cytarabine,15 seven with bortezomib,16 and 32 with rituximab. Sixty-three percent of the patients had low-risk features according to the MCL International Prognostic Index (MIPI).17 Patient characteristics are summarized in Table 1.
Patient Characteristics
Efficacy
Thirty-two patients had bidimensionally measurable disease before starting study therapy. Of these, 21 patients (67%) had tumor reductions ranging between 14% and 85% after therapy (Fig 1). Ten (31%) of the 32 patients with measurable disease achieved a major response (five CR and five PR), while 11 patients had stable disease. In 10 of the patients with at least one tumor measuring ≥ 5 cm in diameter, a response to therapy was seen in one (10%). In contrast, nine (41%) of the 22 patients with a tumor size of less than 5 cm achieved a major response (Fig 1). Furthermore, patients who had received one or two prior regimens (n = 16) had a higher response rate than those who had received at least three prior regimens (44% v 19%, respectively). Similarly, there was a trend for a higher response rate among patients who did not receive hyperCVAD than among those who did (50% v 23%, respectively). Among the four patients who received a dose of 0.3 mCi 90Y/kg, one achieved a CR and the others had progressive disease.
Waterfall chart demonstrating change in tumor measurements for 31 patients with measurable tumor at baseline who received the therapeutic dose of yttrium-90–ibritumomab tiuxetan. Patients with tumor measuring less than 5 cm in largest diameter (blue bars) had a higher response rate than those with tumor measuring ≥ 5 cm in largest diameter (gold bars).
The median observation period was 22 months for the entire group (range, 2 to 72+ months) and 34+ months for patients who are alive at the time of this report (range 30+ to 72+ months). On the basis of intent-to-treat analysis, the median OS duration was 21 months and the median EFS duration was 6 months (Fig 2). As shown in Figure 3, the median EFS duration was longer for patients who achieved PR or CR than for those who did not (28 v 3 months; P < .0001), for those with a tumor measuring less than 5 cm than for those with larger tumors (9 v 3 months; P = .015), and for those who had relapsed disease from prior CR than for those who did not achieve a CR after their last regimen (11 v 3 months; P = .0005). Conversely, the number of prior treatment regimens, prior exposure to the hyperCVAD regimen, age, MIPI score, and IPI score had no influence on EFS duration (Fig 3, and data not shown).
Event-free survival (EFS) and overall survival (OS) durations based on intent-to-treat analysis of all 35 registered patients.
Event-free survival (EFS) duration according to clinical parameters. (A) EFS for patients with partial remission (PR) and complete remission (CR) patient groups combined. (B) EFS for patients with tumor size measured at its largest diameter. (C) EFS for patients who received one or two prior treatment regimens or more than two prior treatment regimens. (D) EFS for patients who received prior treatment with or had no prior treatment with fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyperCVAD). (E) EFS for patients who had refractory mantle cell lymphoma (MCL) or had relapsed from CR. (F) EFS for patients according to their MCL international prognostic index (MIPI).
Safety
Toxicity was similar to what has been reported with the same dose and schedule of 90Y–ibritumomab tiuxetan in other types of lymphoma and was primarily hematologic, transient, and reversible.8,18 The most common nonhematologic toxic effects were grade 1 and included fatigue (50%), nausea (40%), chills (37%), and diarrhea (15%). Grade 3/4 thrombocytopenia was observed in 24% of the patients, with a median time to nadir platelet count of 41 days. Grade 3/4 neutropenia was observed in 32%, with a median time to nadir neutrophil count of 48 days. One patient developed neutropenic fever, and three developed grade 1/2 nonneutropenic fever. Two patients developed myelodysplastic syndrome (MDS) 20 and 48 months after receiving therapy and remained alive 33 and 72 months, respectively, after study entry.
DISCUSSION
In the past few years, little progress has been made in the management of MCL, and the search for new active agents is ongoing.17 Here, we report the results of what, to the best of our knowledge, is the first completed clinical trial using single-agent RIT in patients with relapsed MCL. In this study, we demonstrate that 90Y–ibritumomab tiuxetan yielded a 32% response rate in 35 heavily pretreated patients with MCL, of whom 91% had previously received rituximab, 68% the hyperCVAD regimen, and 20% bortezomib. This single-agent activity compares favorably with that of other single agents when used in patients who had previously received rituximab, with remarkable similarity to bortezomib- and temsirolimus-induced remission rates and progression-free survival duration (Table 2). Furthermore, 90Y–ibritumomab tiuxetan therapy offers the advantage that the treatment can be completed within 1 to 2 weeks, while bortezomib and temsirolimus require protracted treatment duration. In addition, 90Y–ibritumomab tiuxetan has fewer adverse effects than these agents. The single-agent activity of 90Y–ibritumomab tiuxetan in this study is similar to that in a smaller European study that was recently presented.22
Activity of Selected Single Agents in Relapsed or Refractory MCL
The response rate and progression-free survival duration achieved with 90Y–ibritumomab tiuxetan in this study is promising and is typical of other single agents used in similar patient populations (Table 2). It is possible, however, that these results may be improved when RIT is used in rituximab-naïve and/or previously untreated patients with low tumor burden. To test this hypothesis, Zelenetz et al23 examined the single-agent activity of tositumomab in patients with newly diagnosed MCL (rituximab- and chemotherapy-naïve) and reported an overall response rate of 86%, confirming the radiosensitive nature of this disease. In our study, patients with tumors measuring less than 5 cm in their largest diameter had a higher response rate and longer EFS than those who had a larger tumor. Thus, it seems logical to use cytoreductive chemotherapy to decrease the tumor burden before administering RIT. To test this strategy, Smith et al24 treated patients with newly diagnosed MCL with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy followed by 90Y–ibritumomab tiuxetan consolidation, with promising early results.
The safety of RIT that includes 90Y–ibritumomab tiuxetan is now well documented. In our study, the observed toxicity was similar to what has been described when 90Y–ibritumomab tiuxetan was used to treat other types of B-cell lymphoma. Both 90Y–ibritumomab tiuxetan and tositumomab have been reported to induce secondary MDS and acute myelogenous leukemia. In a study of 746 patients with NHL treated with 90Y–ibritumomab tiuxetan in registration and compassionate-use trials, Czuczman et al25 reported that 19 patients (2.5%) developed MDS or acute myelogenous leukemia a median of 1.9 years (range, 0.4 to 6.3 years) after receiving RIT. In our study, two patients (5.7%) developed MDS 20 and 48 months, respectively, after completing therapy with 90Y–ibritumomab tiuxetan, both of whom had previously received intensive therapy with the hyperCVAD regimen and who were older than age 65 years at the time of study entry. These patients remained alive 33 and 72 months from study registration. Finally, it is important to note that, although the median EFS duration in this study was 6 months, many patients were able to tolerate subsequent therapy, contributing to the median OS duration of 21 months.26
In summary, 90Y–ibritumomab tiuxetan has promising activity as a single agent in relapsed MCL, especially in patients with a small-volume disease and those who have previously achieved CR with their last therapy. Further investigation of regimens that include 90Y–ibritumomab tiuxetan after induction therapy in newly diagnosed patients with MCL is warranted.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. 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.
Employment or Leadership Position: None Consultant or Advisory Role: Peter McLaughlin, Eli Lilly (C), Biogen Idec (C), Genentech (C), Millennium Pharmaceuticals (C); Anas Younes, Amgen (C), Gloucester Pharmaceuticals (C), Seattle Genetics (C), Millenium Pharmaceuticals (C) Stock Ownership: None Honoraria: Michael Wang, Celgene, Millennium Pharmaceuticals; Peter McLaughlin, Millennium Pharmaceuticals, Genentech, Eli Lilly, Bayer Pharmaceuticals; Frederick Hagemeister, Biogen Idec, Millenium Pharmaceuticals, Genentech, Cephalon, Amgen; Anas Younes, Biogen Idec, Genentech, Seattle Genetics, MethylGene, Pharmion, sanofi-aventis, Xencor, Amgen Research Funding: Michael Wang, Celgene, Millennium Pharmaceuticals, Proteolix, Novartis; Barbara Pro, Gloucester Pharmaceuticals, Allos Therapeutics, Merck, Ortho Biotech; Jorge Enrique Romaguera, Celgene, Wyeth, Millennium Pharmaceuticals; Maria Alma Rodriguez, Ortho Biotech, Amgen, Biogen Idec; Peter McLaughlin, Bayer Pharmaceuticals, Millennium Pharmaceuticals, Genentech, OSI Pharmaceuticals; Frederick Hagemeister, Novartis; Anas Younes, Genentech, sanofi-aventis, Tanox, Xencor, S*Bio, Seattle Genetics, Novartis, Nereus Pharmaceuticals Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Anas Younes
Administrative support: Anas Younes
Provision of study materials or patients: Michael Wang, Yasuhiro Oki, Barbara Pro, Maria Alma Rodriguez, Felipe Samaniego, Peter McLaughlin, Sattva Neelapu, Anas Younes
Collection and assembly of data: Michael Wang, Yasuhiro Oki, Amanda Copeland, Barry I. Samuels, Evelyne M. Loyer, Anas Younes
Data analysis and interpretation: Michael Wang, Yasuhiro Oki, Yuan Ji, Anas Younes
Manuscript writing: Michael Wang, Yasuhiro Oki, Anas Younes
Final approval of manuscript: Michael Wang, Yasuhiro Oki, Jorge Enrique Romaguera, Sattva Neelapu, Barry I. Samuels, Anas Younes
Footnotes
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Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Clinical trial information can be found for the following: NCT00038623.
- Received January 10, 2009.
- Accepted May 21, 2009.
