Phase 1 Study of Radiosensitization Using Bortezomib in Patients with Relapsed Non-Hodgkin's Lymphoma Receiving Radioimmunotherapy

Radioimmunotherapy (RIT) is effective treatment for relapsed and refractory indolent lymphomas. Results in aggressive lymphomas such as diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) have been less impressive, with lower response rates and short duration of response. We hypothesized that administration of the proteasome inhibitor bortezomib as a radiosensitizer in patients receiving RIT would be tolerable and potentially improve efficacy in both aggressive and indolent lymphomas.

We performed a Phase 1 dose escalation study to evaluate the maximum tolerated dose (MTD) of bortezomib in combination with ¹³¹I-tositumomab. The study underwent review and was approved by each institution's Institutional Review Board. Dose escalation proceeded using a Time to Event-Continuous Reassessment Model (TiTE-CRM). Patients with relapsed or refractory DLBCL, MCL or indolent B cell non-Hodgkin's lymphoma were eligible if they had not undergone prior stem cell transplant, organ function was preserved, and bone marrow involvement by lymphoma was less than 25% of the intertrabecular space. Neutrophil count at least 1500/uL and platelet count at least 150 × 10³/uL were required. A dosimetric dose of ¹³¹I-tositumomab was administered on day 1, followed by three whole body gamma camera scans for purposes of dose calculation and evaluation of biodistribution. After an initial cohort received a reduced whole-body dose of 50 cGy ¹³¹I-tositumomab, patients received RIT at the standard dose of 75 cGy on day 8. Patients were treated with escalating doses of bortezomib (0.3 to 1.2 mg/m²) on days 6, 10, 13, 16 and 20. Dose limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematologic toxicity, or grade 4 hematologic toxicity.

The study has completed enrollment, with 25 patients having received study treatment. These include 8 patients with DLBCL, 5 with MCL, 11 with follicular lymphoma (FL), and one with marginal zone lymphoma (MZL). Median age is 68 (range 40–81). Median number of prior therapies is 2 (range 1–4), and all but one had received prior rituximab. Twenty-three patients are evaluable for response, while two patients have not yet undergone restaging. Twenty-four patients are evaluable for the primary endpoint of MTD. One treated patient was not evaluable for toxicity due to early progression of disease and need for further therapy prior to the end of the observation period. Of 24 patients evaluable, 4 experienced DLT (Table), all at dose level 5 (1.2 mg/m²). These events included grade 3 hyponatremia, herpes zoster, and grade 4 thrombocytopenia. Grade 3 hematologic toxicities included two patients with leukopenia, three with neutropenia, one with anemia, and five with thrombocytopenia. Dose level 4 (0.9 mg/m² bortezomib, 75 cGy ¹³¹I-tositumomab) was well tolerated, and this dose was identified as the MTD. Fourteen of 23 (61%) patients evaluable for response have responded, including 3/8 with DLBCL, 3/5 with MCL, and 8/9 with FL. Ten patients have achieved complete remission, including one patient with DLBCL, one with MCL, and 8 with FL. At median follow up of 8 months, median progression free survival is 6 months, and seven patients (50% of responders) remain in remission at 2 to 28 months.

Bortezomib can be safely administered in combination with ¹³¹I-tositumomab. Responses were seen in a majority of patients, including those with aggressive histology. The MTD has been defined as 0.9 mg/m² bortezomib plus 75 cGy ¹³¹I-tositumomab. This strategy of radiosensitization using bortezomib shows promise, and efficacy should be further evaluated in a Phase 2 trial.

Off Label Use: Azacitidine is approved for use in MDS. Discussion here is off label. Leonard:Glaxo SmithKline: Consultancy, Honoraria. Martin:Cephalon: Consultancy; Celgene: Consultancy; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lebovic:Genentech: Speakers Bureau. Coleman:Celgene Corp: Speakers Bureau. Kaminski:GlaxoSmithKline: Patents & Royalties, Research Funding.