Weekly Temsirolimus and Bortezomib For Relapsed Or Refractory B-Cell Non-Hodgkin Lymphoma: A Wisconsin Oncology Network Phase II Study

Proteosome inhibitors and mammalian target of rapamycin (mTOR) inhibitors are each known to have activity for various B-cell malignancies, and affect distinct cellular pathways. Preclinical data show synergy between bortezomib and various mTOR inhibitors, supporting this combination in non-Hodgkin lymphoma (NHL). We conducted a phase II trial of temsirolimus and bortezomib in relapsed and refractory B-cell NHL, using a weekly dosing scheme that was previously tested in multiple myeloma (Ghobrial et al, Lancet Oncology, 2011; 263-272).

Wisconsin Oncology Network study HO10407 is a single-arm phase II study of IV bortezomib and temsirolimus for patients with relapsed and refractory B-cell NHL. A 35 day cycle was employed with bortezomib given at 1.6 mg/m2 and temsirolimus given at 25 mg IV weekly on days 1, 8, 15, and 22. Initially temsirolimus was also given on day 29 but, due to a high rate of thrombocytopenia, after the first 14 patients were enrolled the protocol was amended and the day 29 temsirolimus dose was removed. Patients were enrolled from 10 sites within the Wisconsin Oncology Network. The primary endpoints were overall response rate (ORR) and progression-free survival (PFS). The secondary endpoints were to determine safety, tolerability, complete response (CR) rate, duration of response (DOR), and overall survival (OS).

Forty patients were enrolled between February 2011 and May 2013; however one patient withdrew consent immediately after enrollment and was never treated. We are therefore reporting results for 39 patients. The median age was 68, with 72% male. NHL subtypes consisted of diffuse large B-cell lymphoma (DLBCL, n=17), follicular lymphoma (FL, n=10), mantle cell lymphoma (MCL, n=7), small lymphocytic lymphoma (SLL, n=3), and marginal zone lymphoma (MZL, n=2). Patients received a median of 4 prior therapies (range 1 to 11). Three patients were previously treated with bortezomib, one of whom was refractory to a prior bortezomib-containing regimen. As of July, 24, 2013, two patients remained on protocol therapy. The median number of cycles given was 3. Out of 39 patients, CR was achieved in 3 patients (7.7% (95% CI: 1.6% - 21%)), partial response (PR) in 9 patients (23% (95% CI: 11% - 39%)), and stable disease in 9 patients (23% (95% CI: 11% - 39%)). The ORR was therefore 12/39 (31% (95% CI: 17-48%)). Among responders, the DOR ranged from 1.7 to 13.8 months, with a median DOR of 8.5 months (95% CI: 2.9-11.5). The median PFS was 4.7 months (95% CI: 2.1-7.8). The ORR for DLBCL was 18% (3/17, with 2 CR), for FL was 50% (5/10, with no CR), and for MCL was 57% (4/7, with 1 CR). In one patient, protocol therapy led to a partial response which served as a bridge to allogeneic stem cell transplantation. Grade 3/4 adverse events were experienced by 69% of patients. The grade 3/4 adverse events that occurred in at least 10% of patients were anemia (13%), lymphopenia (15%), neutropenia (23%), thrombocytopenia (38%), and gastrointestinal toxicities (15%).

In this phase II study, the combination of temsirolimus and bortezomib demonstrated activity in a group of heavily pre-treated patients. In some patients dramatic responses were seen, including two DLBCL patients who achieved complete remission after having previously progressed following autologous hematopoietic cell transplantation. Toxicities were manageable and treatment was delivered on an outpatient basis. Further studies with this combination or other proteosome inhibitor + mTOR inhibitor combinations are warranted in specific subtypes of NHL.

Fenske:Spectrum Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy. Off Label Use: Use of the combination of bortezomib and temsirolimus for relpased and refractory B-cell non-Hodgkin lymphoma. Ahuja:Bayer healthcare pharmaceuticals: Consultancy. Kahl:Millennium: Consultancy.