Ki67 and PIM1 expression in aggressively treated mantle cell lymphoma (MCL): A Cancer and Leukemia Group B (CALGB) 59909 correlative science study.

8560 Background: Gene expression profiling has suggested that the proliferation signature is an important predictor of outcome in MCL. Retrospective studies have suggested that the proliferative index, measured by mitoses or Ki67, is an important prognostic indicator. This has not been validated in a US cooperative group setting or in the context of aggressive therapy. We assessed Ki67 and PIM1 (a cell cycle-related gene upregulated in blastoid MCL) expression in a prospective phase 2 cooperative group study. METHODS: CALGB 59909 examined the efficacy of aggressive chemotherapy followed by autologous stem cell transplantation (ASCT) in untreated MCL patients less than 70 years of age. Cases with available material were studied for Ki67 and PIM1 expression by immunohistochemistry. Ki67 was quantitated by image analysis (IA Ki67) and manually as # positive cells/1000x hpf (Ki67-count). PIM1 staining was scored semi-quantitatively (0-3+). Progression-free survival (PFS) and disease-free survival (DFS) were the clinical endpoints. 52 cases had evaluable IA Ki67 data, 49 cases had Ki67-count data, and 50 had data for PIM1. All patients received ASCT. The IA cases form the basis for this study. RESULTS: For the 52 IA Ki67 cases, the median age was 56 (range 37-68 yrs.) and male:female ratio was 3.7. The median IA Ki67 was 27.7% (0.01-84.0). Ki67-count correlated with IA Ki67 (R=0.79, P<.0001). As a continuous variable, IA Ki67 was associated with shorter PFS (P=.013) and DFS (P=.007). PIM1 was expressed in 72% of cases. PIM1 greater than 1+ was marginally associated with PFS (P=.033) and DFS (P=.043). Bivariate Cox models showed IA Ki67 and PIM1 to be independent of clinical factors such as age, stage and international prognostic index. CONCLUSIONS: CALGB 59909 met its primary endpoint, suggesting ASCT may be a reasonable first-line treatment in MCL. In this prospective, aggressively treated study group, proliferation remained a prognostic factor. PIM1 expression may also predict poor outcome. These data support routine measurement of Ki67 as a practical marker for risk stratification in MCL, and provide rationale for study of PIM1 in MCL. No significant financial relationships to disclose.

Duke Scholars

Author Sin-Ho Jung Biostatistics & Bioinformatics, Division of Integrative Geno ...