Confirmation of the Mantle Cell Lymphoma International Prognostic Index (MIPI) in An Independent Prospective Patient Cohort.

The Mantle Cell Lymphoma (MCL) International Prognostic Index (MIPI) has been recently developed as first prognostic index especially designed for patients with advanced stage MCL (Hoster et al., Blood 2008). The MIPI is based on four easily available prognostic factors (age, ECOG performance status, leukocyte count, and LDH). It was internally validated using a bootstrap strategy, and several authors reported its validity on larger patient cohorts (Salek et al., ASH 2008, Geisler et al., EHA 2009). We evaluated the prognostic relevance of the MIPI using the pooled data of two currently recruiting randomized trials (MCL Younger and MCL Elderly) of the European MCL Network (Dreyling et al., ASH 2007).

Outcome parameters were primarily overall survival (OS) and secondarily time to treatment failure (TTF). Kaplan-Meier curves according to the MIPI prognostic groups were compared by means of the log rank test and univariate Cox regression. We checked the value of the MIPI prognostic factors within multiple Cox regression. We also evaluated the simplified MIPI and exploratively included patients with stage II into the analyses. Since randomization is ongoing, all analyses were blinded for treatment arms.

Currently, 606 patients with advanced stage MCL were evaluable, 317 in MCL Younger and 289 in MCL Elderly. Median age was 63 years (range 32 – 87), 6% had an ECOG performance status > 1, median LDH/ULN ratio was 0.95 (0.29 – 12.2), and median leukocyte count 7,600/μl (1,075/μl – 396,000/μl). The MIPI classified 220 patients (36%) into the low risk (LR), 187 (31%) into the intermediate risk (IR) and 199 (33%) into the high risk (HR) group. With a median follow-up of 19 months and 116 events, the probability for OS at 24 months was 91%, 77%, and 58% for LR, IR, and HR (medians not reached in LR, IR vs. 28 months in HR patients, p < 0.0001), corresponding to a hazard ratio of 2.7 for IR vs. LR (95% CI, 1.5 – 4.9, p = 0.001) and 2.6 for HR vs. IR (95% CI, 1.7 – 4.0, p < 0.0001). The four MIPI prognostic factors were independently prognostic for OS (p < 0.0001 each). In MCL Younger, the distribution to LR, IR, and HR groups was 61%, 23%, and 16%, as compared to 9%, 40%, and 51% in MCL Elderly, the difference reflecting the strong prognostic impact of age. According to preliminary subgroup analyses, 2-years OS rates were 92%, 76%, and 58% (p < 0.0001) in MCL Younger, and 85%, 78%, and 58% (p < 0.0001) in MCL Elderly. The MIPI also separated LR, IR, and HR group with respect to TTF, with medians of 49, 36, and 20 months (p < 0.0001) and a hazard ratio of 2.2 for IR vs. LR (95% CI, 1.4 – 3.4, p = 0.0004) and 2.0 for HR vs. IR (95% CI, 1.4 – 2.8, p = 0.0001). The simplified MIPI classified 36%, 32%, and 33% to LR, IR, and HR groups with high concordance to the MIPI (weighted kappa 0.82). Two-years OS rates were 90%, 79%, 58% for LR, IR, HR according to the simplified MIPI (p < 0.0001) with a hazard ratio of 2.4 for IR vs. LR (95% CI, 1.3 – 4.2, p = 0.003) and 2.5 for HR vs. IR (95% CI, 1.7 – 3.8, p < 0.0001). Inclusion of 32 patients with stage II MCL did not essentially change the results.

We could confirm the prognostic relevance of the MIPI in a large independent patient cohort treated within current randomized trials. Therefore, the MIPI may be used for risk stratification in future clinical trials, for the comparative interpretation of the results of different trials, for the evaluation of new biological prognostic factors, and may finally lead to risk-adapted treatment decisions in advanced stage MCL.

Hoster:Roche: travel support. Trneny:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Unterhalt:Roche: travel support.