Originally published as JCO Early Release 10.1200/JCO.2007.11.9248 on November 19 2007

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Phase II Trial of a Transplantation Regimen of Yttrium-90 Ibritumomab Tiuxetan and High-Dose Chemotherapy in Patients With Non-Hodgkin's Lymphoma

Amrita Krishnan, Auayporn Nademanee, Henry C. Fung, Andrew A. Raubitschek, Arturo Molina, Dave Yamauchi, Roberto Rodriguez, Ricardo T. Spielberger, Peter Falk, Joycelynne M. Palmer, Stephen J. Forman

From the Division of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte; Oncology Research and Development, Biogen Idec, San Diego, CA; and Section of Hematology and Stem Cell Transplantation, Rush University Medical Center, Chicago, IL

Corresponding author: Amrita Krishnan, MD, Division of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd, Duarte, CA 91010; e-mail: akrishnan{at}coh.org

	ABSTRACT

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Purpose This phase II trial evaluated the safety and efficacy of combining yttrium-90 (⁹⁰Y) ibritumomab tiuxetan with high-dose carmustine, cytarabine, etoposide, and melphalan (BEAM) and autologous stem-cell transplantation in patients with non-Hodgkin's lymphoma who were considered ineligible for total-body irradiation because of older age or prior radiotherapy.

Patients and Methods Between May 2002 and January 2006, 14 days before autologous stem-cell transplantation, 41 patients with non-Hodgkin's lymphoma received standard-dose ⁹⁰Y ibritumomab tiuxetan (14.8 MBq/kg [0.4 mCi/kg]) followed by high-dose BEAM.

Results The median age was 60 years (range, 19 to 78 years), and the median number of previous therapies was two (range, one to six). Disease histologies were diffuse large B-cell (n = 20), mantle cell (n = 13), follicular (n = 4), and transformed lymphoma (n = 4). With a median follow-up of 18.4 months (range, 5.5 to 53.3 months) the estimated 2-year overall and progression-free survival were 88.9% (95% CI, 75.3% to 95.2%) and 69.8% (95% CI, 56.4% to 79.7%). The median time to WBC engraftment was 11 days (range, 9 to 26 days) and time to platelet engraftment was 12 days (range, 3 to 107 days). Adverse events were similar to those seen historically with high-dose BEAM alone, and included grade 3 or 4 pulmonary toxicity in 10 patients.

Conclusion Adding ⁹⁰Y ibritumomab tiuxetan to high-dose BEAM with autologous stem-cell transplantation is feasible and has a toxicity and tolerability profile similar to that observed with BEAM alone. Rates of progression-free survival seen in these patients are promising and warrant additional study.

	INTRODUCTION

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Monoclonal antibody therapy with rituximab has improved treatment options for patients with indolent and aggressive non-Hodgkin's lymphoma (NHL).¹ However, relapse still remains a common cause of treatment failure.^2-5 High-dose chemotherapy (HDC) followed by autologous stem-cell transplantation (ASCT) induces long-term disease control in approximately 20% to 50% of patients with relapsed or refractory aggressive lymphoma.^6-9 A randomized study of HDC combined with ASCT versus conventional salvage chemotherapy for patients with chemotherapy-sensitive relapsed lymphoma demonstrated superior 5-year event-free survival in HDC (46% v 12%; P = .001).¹⁰

The role of HDC in the treatment of indolent lymphoma and mantle-cell lymphoma (MCL) is less defined. Conventional chemotherapy for indolent lymphoma has high response rates but is not curative, and median durations of first complete responses (CRs) range from 12 to 36 months.^11,12 Relapsed indolent lymphoma may respond to salvage therapy, but the durations of the remissions decrease progressively.¹³ HDC with ASCT has been shown to increase progression-free survival (PFS) in patients with relapsed low-grade NHL^14-16; however, the curative potential of ASCT in these patients is unclear. ASCT has been used as front-line consolidation and salvage treatment for patients with MCL, but the optimal conditioning regimen has not been determined.^17-20 A randomized trial by the European MCL Network showed that consolidation with myeloablative radiochemotherapy followed by ASCT after induction produced an improvement in median PFS compared with interferon alfa maintenance in patients with first CR in MCL (39 v 17 months; P = .011).²⁰

No preparative regimens before ASCT have been shown to be clearly superior. Phase II studies of fractionated total-body irradiation (FTBI) with HDC showed high response rates in patients with lymphoid malignancies.^21,22 Another trial showed the probability of relapse was lower in patients treated with FTBI than in those treated with HDC alone (41% v 67% at 5 years; P = .002).⁷ However, FTBI is generally not recommended for patients older than 60 years or for those treated with previous radiotherapy.

Investigators have incorporated iodine-131 (¹³¹I) tositumomab and yttrium-90 (⁹⁰Y) ibritumomab tiuxetan radioimmunotherapy into transplantation-conditioning regimens.^23-25 The radioimmunoconjugate ⁹⁰Y ibritumomab tiuxetan, which delivers low-dose β radiation to tumor cells, is produced by the high-affinity chelation of ⁹⁰Y to ibritumomab, a murine monoclonal antibody to CD20. Registration trials have shown that single-agent ⁹⁰Y ibritumomab tiuxetan produces long-term responses in 37% of patients with relapsed or refractory indolent NHL.²⁶ Schilder et al have found no differences in efficacy or safety between older ( 70 years) and younger patients (< 60 years).²⁷

In this phase II trial, we evaluated the safety and efficacy of standard-dose ⁹⁰Y ibritumomab tiuxetan with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) in patients with refractory, relapsed, or poor-risk NHL who were ineligible for FTBI because of age or prior radiation. We postulated that adding ⁹⁰Y ibritumomab tiuxetan might reduce the relapse rates without increasing toxicity, thereby improving PFS and overall survival (OS) in these patients.

	PATIENTS AND METHODS

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Patients
Patients with chronologic age older than 18 years and physiologic age 75 years (Karnofsky performance status > 80% and satisfactory functional testing) were eligible for the study. Patients had histologically confirmed CD20⁺ refractory or protocol-defined eligible follicular lymphoma, poor-risk MCL, diffuse large B-cell lymphoma (DLBCL), or transformed lymphoma. Poor risk was defined as DLBCL or MCL that required two different induction regimens to achieve either CR or partial response (PR), or DLBCL that had high- or high-intermediate–risk features per the age-adjusted International Prognostic Index (IPI) at diagnosis. Patients with relapsed DLBCL, MCL, or clinically aggressive follicular lymphoma were also eligible. All patients with follicular lymphoma had previously received a rituximab- and anthracycline-containing regimen; three patients had follicular grade 3 lymphoma. A patient with follicular grade 2 lymphoma presented with symptomatic bulky disease and pleural effusions, and was considered to be eligible in first relapse. All transformed lymphomas, defined as follicular lymphoma transformed to diffuse large-cell lymphoma, were considered poor risk. Organ function eligibility criteria were forced expiratory volume in 1 second 65% of predicted or diffusing capacity of lung for carbon monoxide 50% of predicted, cardiac ejection fraction 50% by echocardiography or multiple-gated acquisition scan, serum creatinine level 132 µmol/L (1.5 mg/dL) or a creatinine clearance 50 mL/min, and serum bilirubin 26 µmol/L (1.5 mg/dL). Patients were excluded if they had HIV, active or chronic hepatitis B or hepatitis C infection, previous treatment with radioimmunotherapy, previous irradiation more than 10 Gy to the liver or lung, human antimouse antibody (HAMA) positivity, more than 10% lymphomatous involvement in the bone marrow, or abnormal bone marrow cytogenetics before stem-cell collection. No baseline hematologic parameters were required. Patients were required to have a collection of 2 x 10⁶ CD34⁺ cells/kg. All patients provided written informed consent in accordance with the City of Hope Comprehensive Cancer Center (Duarte, CA) Institutional Review Board.

Treatment
Peripheral-blood progenitor cells were mobilized with filgrastim with or without chemotherapy before study enrollment. On day –21, patients were given an infusion of rituximab 250 mg/m² followed by indium-111 (¹¹¹In) ibritumomab tiuxetan 185 MBq (5 mCi; Fig 1). Imaging studies, but not dosimetry, were performed at 2, 24, 48, and 72 hours to determine the biodistribution of the ¹¹¹In-labeled antibody.²⁸ On day –14, patients were given rituximab 250 mg/m² followed by ⁹⁰Y ibritumomab tiuxetan 14.8 MBq/kg (0.4 mCi/kg) in an outpatient setting. The ⁹⁰Y dose was capped at 40 mCi, with no dose adjustments for neutropenia or thrombocytopenia. One week later, patients were admitted to a high-efficiency particulate air–filtered room for BEAM (carmustine 150 mg/m² on days –7 and –6, etoposide 100 mg/m² and cytarabine 100 mg/m² twice a day on days –5 through –2, and melphalan 140 mg/m² on day –1). Autologous stem cells were reinfused on day 0 according to institution practice.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Treatment schema. 111In, indium-111; 99Y, yttrium-99.

Adverse Events
Adverse events were assessed and graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. Patients were tested for HAMA positivity before and after ASCT. Cardiac echocardiography was performed at day +180 and at 1 year post-transplantation.

Follow-Up Staging
Patients were required to undergo formal disease assessment within 42 days before transplantation, and again at days 30, 100, and 180 post-transplantation. After day +180, disease assessments were performed every 6 months for 3 years and then annually. Restaging consisted of computed tomography of the chest, abdomen, and pelvis; CBCs; and metabolic profiles. Bone marrow biopsies were repeated at day +100 and then annually in patients with marrow involvement. Positron emission tomography (PET) scans were performed before transplantation and at 1 year post-transplantation. Disease response was defined in relation to the disease status at study entry. CR was defined as the complete disappearance of measurable disease and disease-related symptoms, and no new lesions. PR was defined as 50% reduction in tumor size (the sum of the products of perpendicular diameters of measurable lesions), with no disease progression or new lesions. Progressive disease (PD) was defined as more than 25% increase in the size of measurable lesions from the smallest size observed, worsening of assessable disease, new lesions, or reappearance of previously observed lesions. Stable disease was defined as disease that did not meet the criteria for CR, PR, or PD.

Study End Points and Statistical Analysis
Results were analyzed as of November 2006. Primary end points were OS and PFS. Secondary end points included safety and long-term complications. Demographic and disease characteristics were summarized for all patients using descriptive statistics. Survival estimates were calculated based on the product-limit method, and 95% CIs were calculated using the log transformation with Greenwood's variance estimate. The day of stem-cell infusion was counted as day 0. Factors possibly associated with OS and PFS were examined by univariate Cox regression analysis. The assumption of proportionality of the hazard ratio was tested for each variable; variables were disease stage at diagnosis (I-II v III-IV), marrow involvement at diagnosis, number of prior regimens (< two v two), and disease status at transplantation (first or second CR v > two CRs v induction failure). The risk ratio was calculated for each variable, along with the 95% confidence limits. Multivariable analyses were not performed due to the small number of patients.

	RESULTS

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Patient Characteristics
Between May 2002 and January 2006, 60 patients were enrolled; following additional screening, 41 patients received the full protocol of imaging and therapy. Nineteen patients did not receive full treatment for the following reasons: HAMA responses before any therapy (n = 6); bacterial sepsis precluding transplantation (n = 2); CD20^– disease (n = 1); an altered biodistribution of ¹¹¹In (n = 1); poor stem-cell collection (n = 3); physician-ordered switch to another protocol (n = 1); PD after stem-cell collection (n = 1); and patient withdrawal from the study (n = 4). Although all patients were accessioned to the protocol per Institutional Review Board guidelines, only data from patients who received full protocol therapy were included in the analysis.

The median age of these patients was 59.6 years (range, 19.8 to 78.9 years). Twenty-two patients had a positive PET at study entry. Disease histologies were DLBCL (n = 20), MCL (n = 13), grade 2 or 3 follicular lymphoma (n = 4), and transformed lymphoma (n = 4). Disease status and other characteristics are listed in Table 1. The median tumor bulk before transplantation was 3.1 cm. Of the 10 patients who underwent transplantation in first CR, six had MCL, three had DLBCL, and one had transformed lymphoma. Fourteen patients had an available IPI score at NHL diagnosis. In this subset, nine patients were considered high-intermediate risk or high risk by the age-adjusted score. At ASCT, 10 patients had an IPI score of 0, 18 had a score of 1, and 13 had a score of 2. Twenty-nine patients had chemotherapy-sensitive disease. The four patients who received imaging without ⁹⁰Y treatment were not included in the analysis but did receive ASCT with different regimens; two died within the first year of transplantation, and two remain alive without disease at 1 and 4 years, respectively.

Toxicity and Mortality
Transplantation-related mortality at 100 days was 0%. Grade 3 or 4 mucositis occurred in 21 patients. Pulmonary adverse events included grade 3 pneumonitis in three patients who responded to corticosteroids. Other adverse events included grade 3 hypoxia (n = 8) due to stem-cell infusion in seven patients and mucositis in one patient; sepsis-related grade 4 acute respiratory distress syndrome (n = 1); grade 1 or 2 aminotransferase elevation (n = 14); grade 3 aminotransferase elevation (n = 5); and sepsis-related grade 4 hyperbilirubinemia (n = 1). There were no significant declines in ejection fraction on cardiac echocardiography. An asymptomatic decline in diffusion capacity (from 70% to 50%) was observed in one patient at day +180 (Table A1). No patient became HAMA-positive after therapy, although six patients were HAMA positive before imaging.

Response to Therapy
Thirty-five of the 41 patients were alive at the time of analysis; 27 were in remission. With a median follow-up of 18.4 months (range, 5.5 to 53.3 months), the Kaplan-Meier estimated 2-year OS and PFS were 88.9% (95% CI, 75.3% to 95.2%) and 69.8% (95% CI, 56.4% to 79.7%; Fig 2). PFS was not stratified by IPI score because of patient numbers. The 2-year PFS in PET-positive and -negative patients was 45% v 85% (P = .006; Fig 3). Univariate analyses of risk factors previously outlined reveal only disease status at transplantation significantly influenced PFS (P = .008).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall and progression-free survival in all patients (N = 41).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Progression-free survival in patients with positive positron emission tomography (PET; n = 22) and negative PET (n = 19) at baseline.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Overall survival by disease histology.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Progression-free survival by disease histology.

	DISCUSSION

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Other investigators have combined radioimmunotherapy and high-dose BEAM, with safety results similar to those from this study. Winter et al³¹ combined escalating doses of ⁹⁰Y ibritumomab tiuxetan with high-dose BEAM in 44 patients with relapsed or refractory NHL; 57% had DLBCL. Two dose-limiting toxicities occurred at doses calculated to deliver 17 Gy to the critical organs: septic emboli to the lung and grade 4 stomatitis leading to pneumonia and sepsis. At a median follow-up of 21 months, OS and PFS at 3 years were estimated at 52% and 37%, respectively. Vose et al²⁴ evaluated escalating doses of ¹³¹I tositumomab with high-dose BEAM in a phase I study in 23 patients with relapsed or refractory NHL. The adverse events were similar to those expected with BEAM alone, with fever and neutropenia occurring in more than 90% of patients. The median mucositis score, however, was slightly higher than that in historical controls treated with BEAM alone. The overall response rate was 65%; at a median follow-up of 38 months, 3-year OS and event-free survival were estimated at 55% and 39%, respectively.

The addition of radioimmunotherapy does not seem to add to the toxicity of the BEAM conditioning regimen; however, a randomized trial would be required for definitive comparison. Similarly, the therapeutic benefit of using radioimmunotherapy with HDC is unproven. A retrospective analysis that compared the efficacy of high-dose ¹³¹I tositumomab with that of conventional HDC followed by ASCT in patients with relapsed follicular NHL found that the OS at 5 years (67% v 53%) and PFS (48% v 29%) were higher with high-dose radioimmunotherapy.³² In addition, the estimated 3-year PFS (61%) in a study of ¹³¹I tositumomab with high-dose etoposide and cyclophosphamide followed by ASCT in relapsed or refractory MCL compares favorably with outcomes for traditional transplantation regimens.¹⁷ A similar conditioning regimen using high-dose ⁹⁰Y ibritumomab tiuxetan in patients with poor risk or relapsed NHL was associated with an estimated 2-year OS and PFS of 92% and 78%, respectively.²⁵

⁹⁰Y ibritumomab tiuxetan was chosen for this trial because it can be delivered in an outpatient setting without dosimetry. We found that ⁹⁰Y ibritumomab tiuxetan plus high-dose BEAM may have benefit in older patients; the median age of the patients in this trial was considerably older than that in other trials of radioimmunotherapy and high-dose BEAM.^24,31 The regimen was well tolerated, toxicity remained low, and the transplantation-related mortality of 0% compares favorably to that with high-dose BEAM.²⁹ Although this was not a randomized trial, the estimated 2-year PFS (68%) in patients with DLBCL is promising in relation to historical results (48%) observed with BEAM alone at the City of Hope Comprehensive Cancer Center.³³

After this study, the IPI index for DLBCL patients receiving cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus rituximab was revised and no longer identifies a subset of patients with less than 50% chance of survival.³⁴ In light of this, future studies should concentrate on patients who experienced relapse or a more-defined subset of patients in first CR.

Combining ⁹⁰Y ibritumomab tiuxetan with high-dose BEAM before ASCT is feasible, with no evidence of increased toxicity. The high rates of PFS, especially in patients with DLBCL, are also encouraging. Additional study of this regimen in different lymphomas will better define its efficacy.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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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: Arturo Molina, Biogen Idec (C) Consultant or Advisory Role: None Stock Ownership: Arturo Molina, Biogen Idec Honoraria: Henry C. Fung, Biogen Idec; Andrew A. Raubitschek, Biogen Idec Research Funding: Henry C. Fung, Biogen Idec; Andrew A. Raubitschek, Biogen Idec; Amrita Krishnan, Biogen Idec Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Amrita Krishnan, Auayporn Nademanee, Henry C. Fung, Andrew A. Raubitschek, Arturo Molina, Dave Yamauchi, Peter Falk, Stephen J. Forman

Financial support: Arturo Molina, Stephen J. Forman

Administrative support: Henry C. Fung, Andrew A. Raubitschek, Stephen J. Forman

Provision of study materials or patients: Henry C. Fung, Arturo Molina, Roberto Rodriguez, Ricardo T. Spielberger, Peter Falk, Stephen J. Forman, Amrita Krishnan

Collection and assembly of data: Henry C. Fung, Andrew A. Raubitschek, Arturo Molina, Peter Falk, Joycelynne M. Palmer, Amrita Krishnan

Data analysis and interpretation: Amrita Krishnan, Henry C. Fung, Andrew A. Raubitschek, Arturo Molina, Dave Yamauchi, Peter Falk, Joycelynne M. Palmer

Manuscript writing: Amrita Krishnan, Auayporn Nademanee, Henry C. Fung, Andrew A. Raubitschek, Arturo Molina, Peter Falk, Joycelynne M. Palmer, Stephen J. Forman

Final approval of manuscript: Amrita Krishnan, Auayporn Nademanee, Henry C. Fung, Andrew A. Raubitschek, Arturo Molina, Dave Yamauchi, Ricardo T. Spielberger, Peter Falk, Stephen J. Forman

	Appendix

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	NOTES

 
published online ahead of print at www.jco.org on November 19, 2007.

Supported by Grant No. M01 RR0043 of the General Clinical Research Center, Cancer Center Support Grant No. P30CA3357, and Hematopoietic Cell Transplantation for Hematologic Malignancies Grant No. P01 CA030206.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

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

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Submitted March 28, 2007; accepted September 27, 2007.

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