Abstract
The proteasome inhibitor bortezomib has demonstrated clinical activity in patients with multiple myeloma and different types of non-Hodgkin’s lymphoma. Its activity in patients with Hodgkin’s disease (HD) is unknown. We have recently reported that bortezomib had a significant activity against HD-derived cell lines in vitro (Zheng et al, Clin Cancer Res 2004), In four HD-derived cell lines, bortezomib induced cell cycle arrest and apoptosis in a dose and time dependent manner, irrespective of IkB gene mutations. Furthermore, bortezomib enhanced the activity of chemotherapy and TRAIL in these cell lines. Based on these encouraging preclinical results, we initiated a pilot study of single agent bortezomib in patients with relapsed classical HD. Eligibility: (1) relapsed classical HD with a measurable disease (2) At least 2 prior treatment regimens; (3) Patients with prior autologous stem cell transplant (ASCT) are eligible (4) platelet counts > 50,000/uL and ANC counts of > 1,500/uL (5) no HIV infection, or CNS involvement with HD, (6) bilirubin < 2mg/dL and creatinine < 2.5 mg/dL. Patients were treated with 1.3 mg/m2 bortezomib intravenously on days 1, 4, 8, 11 of 21-day cycles in an outpatient setting. Treatment was delayed if the Platelet counts on the day of therapy was < 30,000/mm3. After 3 cycles of bortezomib therapy patients were evaluated for treatment response. If there was no evidence of disease progression after 3 cycles of therapy, patients were allowed to receive a maximum of 6 cycles. To date, 11 patients are enrolled (6 men and 5 women), with a median age of 28 years (range: 21 to 68 years). All patients were heavily pretreated, with a median number of 5 prior treatment regimens (range 2 to 7 regimens), and all patients have previously failed ASCT. The median pretreatment platelet count was 126, 000/uL (range 66,000 – 339,000/uL). All patients received at least one dose of bortezomib and are evaluable for treatment toxicity. Treatment was reasonably well tolerated with the majority of toxic effects were of grade 1 and 2. Two patients had grade 3 dyspnea and one patient had grade 3 neutropenic fever. Progressive thrombocytopenia was the most common hematologic toxicity, which frequently caused delays in therapy. Nadir platelet count below 30,000/uL was observed in 3/11 patients during the first cycle, in 4/10 during the second cycle, and in 4/6 during the third cycle. Nadir ANC below 1000/uL was observed in 1/11 pts during cycle 1, in 2/10 during cycle 2, and in 1/6 during cycle 3. Eight patients completed the planned 3 cycles and are evaluable for treatment response. One patient achieved a partial remission and one had a minimal response. Our preliminary data demonstrate encouraging clinical activity of bortezomib in this heavily pretreated patients with classical HD, and warrants studying bortezomib in less heavily pretreated patients either as a single agent or in combination with chemotherapy.
