Bortezomib Is Not Active in Patients with Relapsed Hodgkin’s Lymphoma: Results of a Prematurely Closed Phase II Study.

Background: Hodgkin’s and Reed-Sternberg cells are known to be resistant to apoptosis due to over-expression of Nuclear Factor kappa-B (NF-κB). Bortezomib increases intracellular levels of Inhibitor of Nuclear Factor kappa-B (I-κB) which inhibits activation of NF-κB. Laboratory studies indicate that bortezomib has a strong antiproliferative activity in Hodgkin’s lymphoma derived cell lines. We aimed to investigate the activity of bortezomib given in combination with dexamethasone in patients with relapsed Hodgkin’s lymphoma (HL).

Methods: This was a multicenter, two-stage phase II study. Patients (pts.) with relapsed HL received 1.3 mg/m² bortezomib plus 20 mg dexamethasone on days 1, 4, 8, and 11 of a 3-weekly cycle for up to 8 cycles. Response and toxicity were evaluated using standard criteria (Cheson 1999, Lister 1989; NCI-CTC v3.0). Circulating proteasome concentration was measured using sandwich enzyme-linked immunosorbent assay. Sample size was calculated according to Simon’s optimal design with 12 pts in the first stage and 25 thereafter. At least one response in the first 12 pts was required to proceed to the second stage.

Results: As pre-specified in the protocol twelve pts were entered in the first stage and are assessable for response. All pts were heavily pre-treated with a median of 3 prior therapies and all but one had received high-dose chemotherapy. Two pts prematurely discontinued the study treatment due to toxicities after 2 and 3 cycles respectively. Both had stable disease at their final evaluation. All of the other 10 pts had progressive disease. Nine of these prematurely discontinued the study treatment due to insufficient response after a median of 2 cycles (range: 2–5 cycles) and only 1 received all 8 cycles. Since no response was observed in the first 12 pts, the study was stopped after the first stage. Eleven patients were assessable for toxicity as of August 2006. Two of these experienced no toxicity > °I. The other 9 patients experienced at least 1 episode of a ≥ °II toxicity requiring some dose modifications, treatment delays, or discontinuation and 4 of these experienced °IV toxicity. Reported toxicities included thrombocytopenia (°II: 1 pat; °III: 1 pat; IV: 2 pat); lymphopenia (°III: 1 pat); febrile neutropenia (°IV: 1 pat); infection (°II: 2 pat); herpes zoster (°III: 1 pat); pain (°II: 2 pat); loss of appetite (°IV: 1 pat); cough (°III: 1 pat); epistaxis (°III: 1 pat); paralytic ileus (°IV: 1 pat); diarrhea (°III: 1 pat); and sleep disturbance (°III: 2 pat). Details on treatment administration and proteasome concentration will be presented as well as results of a meta-analysis of all available phase II studies of bortezomib in HL.

Interpretation: Bortezomib in combination with dexamethasone is not active in heavily-pretreated patients with relapsed Hodgkin’s lymphoma. Furthermore, this treatment regimen possesses severe toxicities in heavily pre-treated Hodgkin’s patients. The use of bortezomib combined with dexamethasone is therefore discouraging in heavily pre-treated patients with HL. Further studies may only be justified with other combinations or less heavily pretreated patients.