Sequential Chemotherapy Followed by High Dose Therapy and Autologous Stem Cell Rescue for Mantle Cell Lymphoma: Impact of MIB-1 on Outcome

Introduction: Optimal management of mantle cell lymphoma (MCL) remains undefined. However, recent data support the conclusion that upfront consolidation with high dose therapy with autologous stem cell rescue (HDT/ASCR) can improve the PFS (Dreyling, et al., 2005; Geisler, et al., 2008) and possibly OS (Geisler, et al. 2008). Based on gene expression profiling data, the proliferation signature has emerged as a critical determinant of prognosis in MCL (Rosenwald, et al., 2003). Immunohistochemical assessment of proliferation as estimated by MIB-1 (Ki-67) staining has been shown to predict outcome in patients with MCL treated with chemotherapy or immunochemotherapy. With conventional chemotherapy, the reported MIB-1 staining cutoff associated with poor prognosis reportedly varies from 10–30%. Since 1994 we have treated patients (pts) with MCL with sequential chemotherapy followed by HDT/ASCR. The current analysis is a retrospective review of our treatment program focused on the impact of upfront consolidation with HDT/ASCR on the prognostic significance of proliferation as measured by MIB-1 immunohistochemistry.

Methods: Seventy-nine patients underwent upfront consolidation with HDT/ASCR for MCL. Fifty-two patients had evaluation of proliferation by MIB-1 immunohistochemistry. MIB-1 expression was estimated visually and assigned a percentage. Patients were binned into quintiles of MIB-1 expression: 0–20% (n=32, 61.5%); 21–40% (n=5, 9.6%); 41–60% (n=5, 9.6%); 61–80% (n=5, 9.6%); and 81–100% (n=5, 9.6%). Outcomes were analyzed by the method of Kaplan-Meier and comparisons were by log-rank.

Results: The EFS and OS at 5 years was 65.1% and 61.4% respectively for the subset of patients with available MIB-1 staining (n=52); the outcomes for the entire group (n=79) did not differ from the subset. Outcomes (PFS, OS) were evaluated by MIB-1 quintile with successive cutoff values of 20%, 40%, 60% and 80%. MIB-1 cutoff values of 40% or less were not predictive of outcome. However, when the cutoff was 60% or 80%, both the PFS and OS were significantly worse for the high proliferation group. Nineteen percent of patients had a proliferation fraction of greater than 60%. For patients with MIB-1 staining of >60% the PFS was 4.2 years and was not reached for the group with staining ≤60% (p=0.004). Similarly, overall survival was significantly different, (p=0.031).

Conclusions: These findings suggest that upfront consolidation with HDT/ASCR can partially overcome the adverse impact of proliferation on outcome and the adverse outcomes are seen in a subgroup of approximately 20% of patients with MIB-1 staining of greater than 60%.