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.

Table 1.

Summary of bortezomib clinical activity in 14 patients with relapsed classical Hodgkin lymphoma


Patient no.

Age, y

Sex

No. of prior treatment regimens

Prior stem cell transplantation

No. of bortezomib cycles received

Best response to bortezomib therapy
1   68   Male   4   Yes   3   Progression  
2   47   Male   6   Yes   3   Progression  
3   42   Male   5   Yes   3   Progression  
4   39   Female   9   Yes   6   PR  
5   37   Female   2   Yes   2   Progression  
6   32   Female   2   Yes   3   Progression  
7   31   Male   5   Yes   6   MR  
8   30   Female   7   Yes   6   MR  
9   28   Male   3   Yes   1   Progression  
10   28   Male   2   Yes   3   Progression  
11   25   Female   2   Yes   3   Progression  
12   23   Male   2   No   2   Progression  
13   21   Male   5   Yes   1   Progression  
14
 
21
 
Male
 
3
 
Yes
 
3
 
Progression
 

Patient no.

Age, y

Sex

No. of prior treatment regimens

Prior stem cell transplantation

No. of bortezomib cycles received

Best response to bortezomib therapy
1   68   Male   4   Yes   3   Progression  
2   47   Male   6   Yes   3   Progression  
3   42   Male   5   Yes   3   Progression  
4   39   Female   9   Yes   6   PR  
5   37   Female   2   Yes   2   Progression  
6   32   Female   2   Yes   3   Progression  
7   31   Male   5   Yes   6   MR  
8   30   Female   7   Yes   6   MR  
9   28   Male   3   Yes   1   Progression  
10   28   Male   2   Yes   3   Progression  
11   25   Female   2   Yes   3   Progression  
12   23   Male   2   No   2   Progression  
13   21   Male   5   Yes   1   Progression  
14
 
21
 
Male
 
3
 
Yes
 
3
 
Progression
 

All patients were refractory to last therapy.

PR indicates partial response; MR, minor response.

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.

1
Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma.
N Engl J Med
.
2003
;
348
:
2609
-2617.
2
Goy A, Younes A, McLaughlin P, et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma.
J Clin Oncol
.
2005
;
23
:
667
-675.
3
O'Connor OA, Wright J, Moskowitz C, et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma.
J Clin Oncol
.
2005
;
23
:
676
-684.
4
Zheng B, Georgakis GV, Li Y, et al. Induction of cell cycle arrest and apoptosis by the proteasome inhibitor PS-341 in Hodgkin disease cell lines is independent of inhibitor of nuclear factor-kappaB mutations or activation of the CD30, CD40, and RANK receptors.
Clin Cancer Res
.
2004
;
10
:
3207
-3215.
5
Georgakis GV, Li Y, Humphreys R, et al. Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death.
Br J Haematol
.
2005
;
130
:
501
-510.