Is There a Role for Bortezomib Combinations in the Management of Patients With Follicular Lymphoma?
Authors: Gilles Salles
Journal: Journal of Clinical Oncology (2011)

Follicular lymphoma is the second most frequent lymphoma subtype occurring in North America and Europe, and like other lymphoma entities, it has its own biologic characteristics and natural history. Lymphoma cells overexpressing BCL2 are resistant to apoptosis and establish intimate relationships with their microenvironment. Patients often present with limited symptoms at the time of diagnosis or even at subsequent progressions. Therapeutic strategies may consist of watchful waiting, radiation therapy, and rituximab as a single agent or with chemotherapy, the latter option being widely used in patients in need of therapy. A vast majority of patients respond to induction therapy and may receive rituximab maintenance to delay lymphoma recurrence, which usually occurs after several years, the disease still being considered incurable (except eventually with allogeneic transplantation). Multiple efficient second-line treatments are available, but new therapeutic options are needed, especially in those patients who develop resistance to standard therapy or experience histologic transformation. Because overall survival has been markedly prolonged over the last decade, cumulative or long-term treatment toxicities have become important to consider to preserve patient quality of life and avoid therapy-related death. Proteasome inhibitors such as bortezomib have a wide spectrum of demonstrated activity against cancer cells, including nuclear factor B inhibition and modulation as well as proand antiapoptotic pathway and cell-cycle modification. Preclinical data have been generated in the investigation of the mechanisms of action of bortezomib in lymphoma cell lines, mainly in mantle-cell and diffuse large B-cell lymphoma cell lines. Whether this information is relevant in the context of follicular lymphoma biology—more difficult to explore in the absence of a dedicated preclinical model—remains to be determined. In multiple phase II studies performed in follicular lymphoma, bortezomib as a single agent seemed to show variable activity. The overall response rate ranged from 16% to 41%, with few complete remissions (CRs). Biweekly schedules eventually seemed to be associated with higher response rates; however, this did not translate into significant prolonged progression-free survival (PFS). It has also been suggested that bortezomib, in addition to its direct activity, may potentiate the cytotoxicity of chemotherapy drugs. These data (as well as the clinical activity of bortezomib observed in other lymphoma subtypes) have prompted further investigation of different regimens combining bortezomib with rituximab and chemotherapy in patients with follicular lymphoma. In Journal of Clinical Oncology, two such studies are reported. The VERTICAL (VELCADE in Relapsed or Refractory Follicular Lymphoma) study evaluated bortezomib plus bendamustine and rituximab (B-R) in 73 patients with relapsed or refractory follicular lymphoma. Four weekly infusions of bortezomib at 1.6 mg/m were administered with each cycle of B-R (every 35 days) for a total of five cycles. The population treated was quite heterogeneous, but approximately half of the patients were refractory to their last treatment. Most patients received the five planned cycles, but one third needed bortezomib or bendamustine dose reduction. Approximately 75% of patients experienced adverse events of grade 3 or higher (essentially hematologic), leading to discontinuation of treatment in 22%. The toxicity pattern was consistent with the known toxicity profile of bendamustine and bortezomib, and adverse effects seemed predictable and reversible, according to the investigators. Peripheral neuropathy occurred in 44% of patients (grade 3 in 11%) and resolved in about half of the patients, but quality of life related to these symptoms (or others) was not assessed during the study. The primary end point was ambitious and defined as an increase in CR rate to 75% as compared with that obtained with B-R alone (54% in rituximab pretreated but not refractory patients). This end point was not met, with only 53% of patients achieving CR. The presence of rituximab-refractory patients in the VERTICAL study and the use of 2007 International Working Group response criteria (as opposed to the B-R study that used 1999 response criteria, without positron emission tomography) eventually precluded a direct comparison of these CR rates. But the estimated median response duration (12 months) and median PFS (15 months) do not seem to have improved as compared with results achieved with B-R alone (21 months response duration and 23 months PFS, respectively). Another study combining bortezomib with B-R, using a different schedule (biweekly) and dose (1.3 mg/m) of bortezomib, was also recently reported, with only 16 patients with follicular lymphoma; again the primary end point was not met, and results regarding efficacy and toxicity were essentially comparable. The third study, conducted by the National Cancer Institute of Canada, enrolled 95 previously untreated patients with follicular lymphoma and evaluated bortezomib in combination with rituximab and cyclophosphamide, vincristine, and prednisone (R-CVP). Bortezomib was administered at a dose of 1.3 mg/m on days 1 and 8 of each R-CVP cycle for eight cycles. The investigators should be acknowledged for the detailed safety assessments performed, including a careful examination of neurologic toxicity. This regimen was well tolerated, allowing dose intensity of all compounds in more than 90% of patients. Although most patients developed neuropathy, it was usually grade 1 or 2, and the six patients with grade 3 neuropathy experienced a resolution of symptoms within 2 months after treatment completion. However, again, the primary objective—an increase of CR/CR unconfirmed rate from 41% (observed in the original R-CVP study) to 56%—was not met. The observed CR/CR unconfirmed rate with bortezomib plus R-CVP was only 51%, which does not seem to differ from that observed in 272 patients receiving R-CVP in the PRIMA (Primary Rituximab and Maintenance) study (53%). What lessons can be drawn from these studies? First, combinations of bortezomib with R-CVP or B-R are feasible, although the short-term toxicities encountered with the latter combination (including peripheral Editorials