Bortezomib, Rituximab, and Dexamethasone for Relapsed Mantle Cell Lymphoma

Abstract & Commentary

By Andrew S. Artz, MD, MS, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.

Synopsis: Preclinical data suggest bortezomib and rituximab have synergy for mantle cell lymphoma (MCL). The authors studied bortezomib, rituximab, and dexamethasone in relapsed and refractory MCL using 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 with rituximab on day 1 and 40 mg of dexamethasone on days 1-4. Among 16 patients enrolled, 81% achieved a response for an overall survival (OS) of 12.1 months and progression-free survival (PFS) of 38.6 months. Seven (43.8%) reached complete response for whom median PFS and OS have not been reached. Grade 3 toxicity included thrombocytopenia (37.5%), fatigue (18.8%), and peripheral neuropathy (12.5%). This combination has considerable activity in relapsed MCL and those reaching complete remission (CR) have prolonged disease control.

Source: Lamm W, et al. Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma. Haematologica 2011;96:1008-1014.

Mantle cell lymphoma is an uncommon B-cell non-Hodgkin's lymphoma for which historical survival with cytotoxic chemotherapy alone (e.g., CHOP) has been poor. Prognosis can be stratified with the mantle cell index or follicular lymphoma international prognostic index (FLIPI).1 Half of the patients fall into the high-risk FLIPI category for which 5-year survival is only 8%. Intensive therapy incorporating rituximab and high-dose chemotherapy followed by autologous stem cell rescue appears to enhance survival.2 Still, many patients relapse and many other patients have health limitations or advanced age that precludes high-dose chemotherapy approaches.3

Bortezomib, a proteasome inhibitor, has been approved by the FDA for relapsed myeloma and relapsed MCL. Inhibition of transcription factor nuclear factor kappa–B (NF-ΚB) is a downstream consequence from proteasome inhibition and may reverse chemoresistance.4 Preclinical data suggest bortezomib, rituximab, and dexamethasone may be a synergistic combination for MCL.5 Thus, investigators explored the combination for bortezomib, rituximab, and dexamethasone (BORID) for relapsed MCL.

Inclusion criteria for this single-center Phase 2 study required patients to have relapsed MCL after at least one line of conventional chemotherapy. Bortezomib was given at 1.3 mg/m2 on days 1, 4, 8, and 11 every 21 days. Rituximab at 375 mg/m2 was administered on day 1 and oral dexamethasone at 40 mg on days 1 through 4 of each cycle. The median age of the 16 patients enrolled was 69 years. All patients had failed at least CHOP-based chemotherapy, 88% had received rituximab, and 33% had received a prior autologous transplant. Patients received a median of 4.4 cycles enabling an overall response in 13 of 16 (81%). Seven (43.8%) of these reached CR of whom six underwent PET scanning, which confirmed absence of metabolic activity in all. For five of seven reaching CR, the response has been maintained for more than 48 months.

The median PFS and OS were 12.1 months and 38.7 months. As expected, those who achieved a CR had substantially prolonged PFS and OS relative to those reaching only a partial remission (PR). The most common serious hematologic toxicity was grade 3 thrombocytopenia in 6 (37%). Other grade 3 and 4 toxicities included fatigue (18.8%), peripheral neuropathy (12.5%), and hypnonatremia (12.5%). Common grade 1 and 2 toxicities were infections (43.8%), peripheral neuropathy (43.8%), fatigue (25%), diarrhea (25%), and skin toxicity (18.8%).

Commentary

This study showed a high overall response rate of 81% to bortezomib, rituximab, and dexamethasone for relapsed and/or refractory MCL in a single-center study of 16 patients. The overall rate of CR was 43.8%. Prior data suggest a CR rate of 8% to bortezomib alone and only partial responses to rituximab monotherapy.4,6 Therefore, the CR rate appears promising. The longer PFS and OS for those achieving CR is expected; the observation that five of seven patients achieving CR maintained response after 48 months provides additional support for this being a highly active regimen. Other trials have also shown high response rates to bortezomib combinations for MCL.7 As a consequence, bortezomib is now being studied in upfront trials for MCL.

The toxicities of the regimen were expected for a bortezomib-based regimen and primarily consisted of thrombocytopenia, fatigue, and neuropathy. A recent trial of bortezomib and rituximab for follicular and MCL reported 52% with grade 3 neurotoxicity but the bortezomib dose was higher at 1.5 mg/m2.8

The limitations are as expected from a small Phase 2 trial. As relapsed MCL is not common, any single-center study will be limited by small sample size. Of note, only one-third underwent an autologous transplant. The median age was 69 years and it is likely that some of the candidates for this trial could have proceeded to autologous transplant if not allogeneic transplant. One cannot confidently establish the true response rate or toxicity profile in a small Phase 2 study.

In summary, bortezomib, rituximab, and dexamethasone is an active combination for relapsed or refractory MCL. Bortezomib-based combination therapy continues to be explored at relapse and as initial therapy.

References

1. Moller MB, et al. Mantle cell lymphoma: Prognostic capacity of the Follicular Lymphoma International Prognostic Index. Br J Haematol 2006;133:43-49.

2. Dreyling M, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: Results of a prospective randomized trial of the European MCL Network. Blood 2005;105:2677-2684.

3. Andersen NS, et al. Primary treatment with autologous stem cell transplantation in mantle cell lymphoma: Outcome related to remission pretransplant. Eur J Haematol 2003;71:73-80.

4. Fisher RI, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006;24:4867-4874.

5. Wang M, et al. Bortezomib is synergistic with rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo. Leukemia 2008;22:179-185.

6. Ghielmini M, et al. Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: A study of the Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol 2005;23:705-711.

7. Barr PM, et al. Phase I trial of fludarabine, bortezomib and rituximab for relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma. Br J Haematol 2009;147:89-96.

8. Baiocchi RA, et al. Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. Cancer 2010 Dec 14. [Epub ahead of print].