The proteasome inhibitor bortezomib has been successfully used to treat patients with multiple myeloma and non-Hodgkin lymphoma.1-3 We have recently reported that bortezomib can induce cell cycle arrest and apoptosis in a variety of Hodgkin lymphoma (HL)-derived cell lines in vitro.4 Furthermore, bortezomib potentiated the activity of chemotherapy and agonistic antibodies to the TRAIL death receptors.5 Based on these preclinical data, we initiated a pilot study of bortezomib in patients with relapsed and refractory classical HL.
Patients were enrolled in the study if they had relapsed classical HL with a bidimensionally measurable disease, had received a minimum of 2 prior treatment regimens (including stem cell transplantation), and had adequate pretreatment bone marrow, hepatic, and renal functions. Patients were excluded if they had a history of human immunodeficiency virus infection or central nervous system involvement with HL. Patients were treated with 1.3 mg/m2 bortezomib intravenously on days 1, 4, 8, and 11 of 21-day cycles. Treatment was delayed if the platelet count on the first day of each cycle was less than 30 × 109/L (30 000/μL). After 3 cycles of bortezomib, patients were evaluated for treatment response. If there was no evidence of disease progression, patients were allowed to receive a maximum of 6 cycles.
Fourteen patients were enrolled in the study (Table 1). All patients were heavily pretreated and were refractory to their last therapy. Patients received a median number of 4 prior treatment regimens, and 13 (93%) patients were previously treated with autologous stem cell transplantation. The median pretreatment platelet count was 126 × 109/L (126 000/μL) (range, 66 × 109/L-339 × 109/L [66 000-339 000/μL]). All patients received at least one cycle of bortezomib (range, 1-6 cycles) and were evaluable for treatment toxicity and response. Treatment was well tolerated, with the majority of toxic effects of grades 1 and 2. Two patients had grade 3 dyspnea, and one patient had grade 3 neutropenic fever. Thrombocytopenia was the most common hematologic toxicity, which frequently caused delays in therapy. Nadir platelet counts below 30 × 109/L (30 000/μL) were observed in 29% of the patients during the first cycle and in 67% during the third cycle. Nadir absolute neutrophil counts below 1.0 × 109/L (1000/μL) were observed in 10% of the patients during cycle 1 and in 17% during cycle 3. One patient had a partial remission and 2 had minor responses. The patient who achieved a partial response was a 39-year-old woman who had received 9 prior treatment regimens, including stem cell transplantation (Table 1). She was also receiving concomitant low-dose prednisone for pain management. She had an extensive pulmonary, splenic, and nodal disease and had a dramatic response within 8 weeks of therapy, but her disease progressed shortly after discontinuation of bortezomib therapy.
Our data demonstrate that in these heavily pretreated patients with treatment refractory relapsed classical HL, bortezomib has minimal single-agent activity. Future studies should evaluate bortezomib in less heavily pretreated patients, preferably whose disease responded to their last treatment modality. Furthermore, bortezomib-based combination therapy should also be investigated in patients with relapsed classical HL to determine whether bortezomib may potentiate the activity of chemotherapy in vivo.
