Full-Dose Y Ibritumomab Tiuxetan Therapy Is Safe in Patients with PriorMyeloablative Chemotherapy

Purpose: Targeted radioimmunotherapy with yttrium-90 (Y)^ labeled ibritumomab tiuxetan (Zevalin, IDEC-Biogen, SanDiego, CA) has shown significant activity in the treatment of relapsed or refractoryCD20+non ^Hodgkin’s lymphoma. Eligibility criteriaused inphase I trials, andadopted in phase II and III trials, excluded patients with prior myeloablative therapy.We treated eight patients with Y ibritumomab tiuxetan who had prior autologous stem cell transplant, but met all other treatment criteria. Experimental Design: Eight patients with CD20+ non ^ Hodgkin’s lymphoma had extensive prior therapy including myeloablative chemotherapy but did not receive total body irradiation. Each had bone marrow cellularity of >15%, platelet count of >100,000/mm, and one had documented lymphomatous bone marrow involvement of <25%. The standard course of 0.3 to 0.4 mCi/kg of Y ibritumomab tiuxetan was administered to patients at full dose. 18-Flourodeoxyglucose positron emission tomography/computed tomography scans were done at pretreatment and f12 weeks after treatment to assess patient response. Maximum toxicities were monitored and classified according to the CommonTerminology Criteria forAdverse Events (ver. 3.0). Results: Toxicities observed included grade 4 thrombocytopenia in three of eight evaluable patients and grade 4 neutropenia in one of eight evaluable patients. One patient had a neutropenic fever; allpatientswere off bloodproduct support12weekspost-zevalin. Complete response by 18-flouro-deoxyglucose positron emission tomography/computed tomography imaging occurred in one of seven evaluable patients and one patient treated as consolidation had no evidence of disease. Conclusion: Our experience suggests that Y ibritumomab tiuxetan treatment is safe for use in patients with prior myeloablative therapy when the general inclusion criteria are fulfilled. In this small series, the response rates, however, are limited. Nevertheless, Y ibritumomab tiuxetan treatment may provide clinical benefit in carefully selected extensively pretreated patients. Yttrium-90 ibritumomab tiuxetan was approved by the Food and Drug Administration on February 12, 2002, and was the first radioimmunotherapy approved for use in the U.S. (1). It was indicated for patients with relapsed or refractory low-grade, follicular, or transformed B cell non– Hodgkin’s lymphoma. Witzig et al. have extensively evaluated the safety of this therapy in a multicenter review of 349 patients (2). The primary associated toxicities were acute and reversible cytopenias. In the trials leading to Food and Drug Administration approval of Y ibritumomab tiuxetan, participation was restricted to patients with ‘‘adequate’’ bone marrow reserves, defined as >15% cellularity, <25% lymphomatous involvement in the bone marrow, and no history of myeloablative therapy. The result of such limitations has been a relative contraindication of the drug for patients who, although possessing all other qualifying criteria, have previously failed high-dose chemotherapy followed by an autologous stem cell transplant (HDC-ASCT). As far as we have been able to determine from the literature, no study has evaluated the results of treating post-HDC-ASCT patients with Y ibritumomab tiuxetan. Given the late position of HDC-ASCT in the typical treatment arm of a low-grade lymphoma patient, these patients have few options for further treatment. A novel therapy such as radioimmunotherapy with a unique mechanism of action might offer significant palliation to this group of heavily pretreated patients. In previous reports, post-HDC-ASCT patients have been observed to respond to immunotherapy. McLaughlin et al. (3) treated 23 patients with low-grade follicular lymphoma who had relapsed after high-dose chemotherapy with ASCT with rituximab and reported an overall response rate of 78%. In another study, Kaminski et al. treated patients with low-grade and transformed B cell lymphoma who had prior ASCT with www.aacrjournals.org Clin Cancer Res 2005;11(19 Suppl) October1, 2005 7146s Clinical Studies Authors’ Affiliations: University of Pittsburgh Cancer Institute and Department of Radiology, Nuclear Medicine Division, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Presented at the Tenth Conference on Cancer Therapy with Antibodies and Immunoconjugates, October 21-23, 2004, Princeton, New Jersey. Requests for reprints: Samuel A. Jacobs, University of Pittsburgh Medical Center, Cancer Pavilion, Suite 510, 5150 Center Avenue, Pittsburgh, PA 15232. Phone: 412-235-1278; Fax: 412-623-4655. F2005 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-1004-0003 Cancer Research. on January 20, 2018. © 2005 American Association for clincancerres.aacrjournals.org Downloaded from I-tositumomab (Bexxar, Corixa Corp, South San Francisco, CA and GlaxoSmithKline, Philadelphia, PA; refs. 4, 5). He observed moderate, reversible myelosuppression and noted that supportive intervention was seldom required, even in postASCT patients, although in this latter group, the maximum dose of I-tositumomab was only 60% of the standard dose. Seven of 14 patients responded, with 5 patients achieving a complete response. As a result, we hypothesized that given the similarities in toxicity between the I-tositumomab and Y ibritumomab tiuxetan treatments, we should be able to safely treat post-HDC-ASCT patients with Y ibritumomab tiuxetan. Materials andMethods Patients . Eight patients were identified for this study between April 2002 and May 2004. Eligibility criteria included a diagnosis of relapsed or refractory CD20+ non–Hodgkin’s lymphoma, and at least three prior regimens of treatment, in seven of the eight patients, the most recent regimen was HDC-ASCT. Time from HDC-ASCT to treatment with Y ibritumomab ranged from 4 to 62 months With the exception of the lack of prior myeloablative chemotherapy, all other standard criteria for Y ibritumomab were required, including baseline platelet count of >100,000/mm, bone marrow cellularity >15%, and lymphomatous involvement in the bone marrow of <25%. Patients who had prior total body irradiation were excluded. All patients gave written informed consent at the time of study entry. The patient characteristics are shown in Table 1. The median age was 52 years with a range from 36 to 75. The number of prior radiation or chemotherapy regimens ranged from three to seven, with a median of four. Seven of the eight patients had lymphoma-free bone marrow at the time of treatment, and the remaining patient had lymphomatous involvement in the bone marrow of <25%. All patients were refractory to rituximab. Eastern Cooperative Oncology Group performance status was <2 in all patients and five patients had B symptoms. Lactate dehydrogenase was elevated in three of seven patients and at least one bulky mass of >5 cm was present in six of eight patients. Toxicity was evaluated using the National Cancer Institute’s Common Toxicity Criteria (version 3.0). In this group of patients, pegfilgastim was initiated at a leukocyte count of 2,000/mm and platelet support was initiated once the platelet count decreased to 20,000/mm. In patients developing grade 4 neutropenia or thrombocytopenia, the duration was measured from the first day of laboratory evidence of grade 4 toxicity until the last value of grade 4 toxicity without further support. Y Ibritumomab tiuxetan therapy. Patients identified for this study were administered the standard regimen of Y ibritumomab tiuxetan. On day 1, patients were given an initial infusion of 250 mg/m of rituximab followed within 4 hours by an imaging dose of 5 mCi (170-200/mbg) In-labeled ibritumomab tiuxetan. Patients were then evaluated after 24 and 48 (72) hours by whole-body gamma camera imaging to ensure acceptable biodistribution. The therapeutic regimen was given on day 8. Rituximab was once again infused at 250 mg/m and followed by 0.3 to 0.4 mCi/kg of Y ibritumomab tiuxetan. Dosing of the Y radionuclide was based on standard criteria, patients with platelet counts of >150,000/mm received a dose at 0.4 mCi/kg, and patients with platelets <150,000/mm but >100,000/mm received a dose of 0.3 mCi/kg. The only exception to this protocol was in the case of the first patient treated, who despite adequate platelet count, was administered 0.3 mCi/kg Y as a precaution. In no case was a total dose of >32 mCi Y administered. 18-Flouro-deoxyglucose positron emission tomography/computed tomography imaging. Response to the ibritumomab tiuxetan regimen was evaluated by use of homologous scans by computed tomography (CT) and 18-flouro-deoxyglucose positron emission tomography (PET). Patients were scanned at baseline and again at 12 weeks posttreatment. A partial response was defined as shrinkage of the lymphomatous area by at least 50% over the 12-week period, and a complete response was defined as elimination of abnormal 18-flouro-deoxyglucose-PET uptake and associated structures on CT. As previously published, a complete response by such analysis is predictive of a favorable clinical course (6–8).