DLBCL: Two Gene Score (TGS) & International Prognostic Index (IPI)

*ECOG: Eastern Cooperative Oncology Group scale, in which 0 indicates that the patient has no symptoms, 1 indicates the patient has symptoms but is ambulatory, and 2 indicates the patient is bedridden less than half the day, 3 indicates the patient is bedridden half the day or longer, and 4 indicates the patient is chronically bedridden and requires assistance with the activities of daily living.

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Background: Several gene expression signatures are predictive of prognosis in diffuse large B cell lymphoma (DLBCL), but the lack of practical methods for a genome scale analysis has limited their translation to clinical practice.

Methods: To construct a predictor amenable to rapid testing on routinely obtained diagnostic clinical specimens, we studied genes associated with survival in DLBCL, by testing and validating risk scoring models with survival associations in multiple therapeutic eras.

Results: We verified LMO2 expression as a robust, independent robust univariate predictor of survival and of cell of origin classification of DLBCL. We examined bivariate models combining expression of LMO2 with other genes and identified TNFRSF9, a tumor microenvironment gene with independent prognostic influence in 3 previously described cohorts comprising 545 patients. A combined model termed the 'two gene score' (TGS) integrating both LMO2 and TNFRSF9 expression was independent of 'cell of origin' classification, 'stromal signatures', International Prognostic Index (IPI), and added to the predictive power of IPI. A composite model including the IPi (TGS-IPI) was also validated in multiple independent patient cohorts. Using routinely obtained formalin fixed and paraffin embedded diagnostic specimens from an additional independent cohort of 147 patients, we developed a simple assay validating the clinical utility of this 2-gene model, as well as a composite model integrating it with IPI. Three risk groups (Low, Intermediate, and High Risk, each capturing roughly a third of patients) could be stratified based on predefined thresholds of the TGS-IPI. Patients in the corresponding groups had estimated 3-year progression free survival rates of 98%, 69%, and 39%; the overall survival rates for these groups were 98% 73%, and 47%, respectively (P<0.00001).

Conclusion: Measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL. This simple test can be used to select patients of different risk groups for clinical trials.

Citations

The original IPI was developed by Shipp et al. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. NEJM 329:987-994. (1993)