Safety and Efficacy of Bortezomib Plus ICE (BICE) for the Treatment of Relapsed/Refractory Classical Hodgkin’s Lymphoma.

Background: The proteasome inhibitor bortezomib is an established treatment for multiple myeloma, and has been shown to have clinical activity in non-Hodgkin’s lymphoma. We previously have shown in Hodgkin’s lymphoma (HL) cell lines that bortezomib induces cell cycle arrest and apoptosis (Zheng, B et al, Clin Cancer Rsch 2004). Although bortezomib had no significant single agent activity in heavily pretreated patients with relapsed Hodgkin’s lymphoma (Younes, A et al, Blood 2004), preclinical experiments suggested that bortezomib may synergize with chemotherapy. To test this hypothesis, we initiated a phase I study combining bortezomib with ICE chemotherapy in patients with relapsed/refractory HL.

Methods: Eligibility:

1. Relapsed/refractory classical HL,

2. Prior treatment with anthracycline-containing regimen,

3. Only 1 prior chemotherapy regimen,

4. No prior stem cell transplant.

Regimen: Ifosfamide 5 gm/m2 plus Mesna D1, Carboplatin with target AUC of 5 mg/mL/min D1, Etoposide 100 mg/m2/day D1-D3, Bortezomib on D1 and D4. Dose levels for bortezomib are 0 = 1.0 mg/m2, 1 = 1.3 mg/m2, and 2 = 1.5 mg/m2. Neulasta is given on D5. Cycles are repeated on D14 if platelet count is ≥100,000/mm3 and ANC is ≥1,000/mm3. After 3 cycles patient’s treatment response is evaluated by CTs and PET/CT. Hematologic DLT is defined as grade 4 thrombocytopenia or neutropenia lasting greater than 2 weeks.

Results: Median age is 34 (range 21–39). 10 out of 12 planned patients have enrolled to date (6 patients with relapsed HL, 4 patients with primary refractory HL) with 3 at dose level 0, 3 at dose level 1, and 4 at dose level 2. 10 patients are evaluable for toxicity and 5 patients are evaluable for response (5 patients too early to determine response). 4/5 patients in CR and 1/5 patients with PD. 3/4 patients in CR have undergone autologous stem cell transplant (ASCT) with 4th patient in final preparation for ASCT. The patient with PD had primary refractory disease in the bone marrow and continues to have PD through 2 further chemotherapy regimens. Treatment is well tolerated with no DLTs noted. Reversible grade 3/4 thrombocytopenia is the most common toxicity and is both dose level and cumulative dose dependent. Nadir platelet counts of <25,000/mm3 have occurred in 0/3 patients treated at dose level 0, 3/3 patients treated at dose level 2, and 1/4 patients treated at dose level 2 although these 4 patients have only completed 1 of 3 planned cycles of treatment to date. Median day for retreatment for cycle 2 was D20 (range 15–25) and for cycle 3 was D22 (range 15–23). There have been no toxicities of peripheral neuropathy, febrile neutropenia, or infection reported.

Conclusions: Our preliminary data suggest favorable clinical activity and tolerability of bortezomib plus ICE chemotherapy in patients with relapsed/refractory Hodgkin’s lymphoma. These promising results support further evaluation of this combination as salvage treatment for Hodgkin’s lymphoma, ideally in a randomized phase II study, in patients being planned for an autologous stem cell transplant.