Bortezomib May Be Safely Combined with Y-90 Ibritumomab Tiuxetan In Patients with Relapsed/Refractory Follicular or Transformed Non-Hodgkin Lymphoma: A Phase I Trial of Combined Induction Therapy and Bortezomib Consolidation

Preclinical studies suggest that bortezomib, through inhibition of NF-kB activation, may act as a radiosensitizer and enhance the effects of radioimmunotherapy.

This phase I trial was designed to determine the maximum tolerated dose (MTD) of weekly bortezomib induction combined with Y-90-ibritumomab tiuxetan in patients 18 years or older with relapsed/refractory follicular or transformed non-Hodgkin lymphoma. In addition, we assessed the tolerability of weekly bortezomib consolidation following induction therapy. Cohorts consisting of three patients each were treated with bortezomib induction at doses of 1.0, 1.3, or 1.6 mg/m² on days 1, 8, 15, and 22, rituximab 250 mg/m² on days 8 and 15, and Y-90 ibritumomab tiuxetan 0.4 mCi/kg on day 15. Consolidation, consisting of bortezomib 1.6 mg/m² weekly on days 1, 8, and 15 of three 28 day cycles, was initiated on day 71 after recovery of the platelet count to 100,000/uL and ANC> 1,000/uL. At least three patients per cohort were followed for 7 weeks or had recovery of blood counts without dose-limiting toxicities (DLTs) before dose escalation was allowed. MTD was defined as the dose previous to that in which two patients had DLTs. To be evaluable, patients were required to have received at least two doses of bortezomib and the Y-90-ibritumomab tiuxetan therapeutic dose. Response was assessed by CT scanning following induction therapy and PET/CT and diagnostic CT scans after completion of consolidation.

Nine patients with a median age of 55 (range: 29–71) were treated with bortezomib combined with Y-90-ibritumomab tiuxetan. Eight patients had FL and one had evidence of a transformation to diffuse, large B-cell lymphoma. All had a performance status of 0 or 1, and all had been previously treated with rituximab either as a single agent or in combination with chemotherapy. All but one had received prior chemotherapy [R-CHOP (n=7), chlorambucil (n=1), or R-CVP (n=2)], and three had received radiotherapy. Only one had bone marrow involvement. The median number of prior therapies was one (range: 1–3). Grade 3 or 4 toxicities were observed in all but one of the patients and as expected, all but one of these toxicities were hematologic (leukopenia, lymphopenia, neutropenia, and/or thrombocytopenia). One patient had grade 3 cardiotoxicity characterized by palpitations and shortness of breath on day 15 of her first consolidation, with PVC's noted on subsequent EKG. Though uncommon, cardiotoxicity has been reported in association with bortezomib in the form of systolic heart failure, arrhythmias, and angina. It should be noted that this patient was previously treated with an anthracycline as have the majority of patients reported to have experienced cardiotoxicity in association with bortezomib. A DLT of grade 4 thrombocytopenia lasting more than ten days was observed in two of three patients treated with bortezomib at 1.6 mg/m². One of these two patients was the only one to receive .3 mCi/kg rather than .4 mCi/kg of the radioisotope because of thrombocytopenia on the day of treatment. Thus, the MTD of bortezomib was 1.3 mg/m². All patients are alive, and the median followup for those patients who have not progressed is 6.5 months (range: 3 – 15 mo.). All but one patient responded to therapy (4 CR/CRu, 4PR, 1 SD). The four complete responders remain in remission at 3.0, 5.0, 5.0 and 15.0 months. All of the partial responders have progressed (3.5, 3.5, 11.5, and 17.5 months), as has the patient with stable disease (5.0 months).

The MTD for weekly bortezomib combined with Y-90 ibritumomab tiuxetan induction therapy is 1.3 mg/m². Consolidation with bortezomib at 1.6 mg/m² was well tolerated in this group of relapsed/refractory follicular and transformed non-Hodgkin lymphoma patients. Nearly all patients responded. A phase II trial at the MTD is underway to better define the toxicity and effectiveness of this regimen in patients with relapsed/refractory FL.

Evens:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrm: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ziopharm: Membership on an entity's Board of Directors or advisory committees; Lilly: Research Funding; Ortho- Biotec: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Gordon:Cure Tech, Ltd: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Inc: Research Funding; Genentech: Speakers Bureau; Millenium: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees. Winter:Millenium: Consultancy, Research Funding; Pfizer/Wyeth: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Spectrum: Honoraria.