Effect of Prognostic Risk Classification on Temsirolimus Efficacy and Safety Outcomes in Patients with Relapsed/Refractory Mantle Cell Lymphoma

The simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) has been shown to be a good predictor of patient survival (Blood 2008;111:558–65; Blood 2010;115:1530–1533). This post hoc study analyzed data from a randomized, phase III clinical trial investigating temsirolimus (TEM) in relapsed/refractory mantle cell lymphoma (MCL) in which TEM 175/75 (175 mg for first 3 weeks then 75 mg weekly) demonstrated significantly longer progression-free survival (PFS) vs investigator's choice of therapy (INV; 4.8 vs 1.9 months, respectively; hazard ratio [HR]=0.44; P=.0009; J Clin Oncol 2009;27:3822–9). Patients receiving TEM 175/25 (175 mg for first 3 weeks then 25 mg weekly) also had longer PFS vs INV, but this difference was not significant (3.4 vs 1.9 months; respectively; HR=0.65; P=.06). During the trial, baseline prognostic risk classification was not recorded; thus, patients were retrospectively assigned baseline prognostic scores, and outcomes were analyzed according to risk category.

All patients (N=162) were classified as low, intermediate, or high risk using the simplified MIPI. The MIPI scores were based on 4 independent prognostic markers: age, Eastern Cooperative Oncology Group (ECOG) performance status, lactate dehydrogenase level, and white blood cell count. Median PFS and overall survival (OS) were calculated using Kaplan-Meier estimates, and treatment effect was assessed using log-rank statistics. P values of ≤.05 indicated significance of the treatment effect between the 2 treatment groups. As the phase III study was not powered to analyze patients according to MIPI risk categorization, statistical analyses shown are for explanatory purposes.

Distribution was relatively even across MIPI risk categories (55 patients low, 59 patients intermediate, 48 patients high). MIPI distributions in the 2 TEM arms were: 175/75 (n=54: 28% low, 43% intermediate, 30% high); 175/25 (n=54: 28% low, 33% intermediate, 39% high). Relative to the TEM arms, the INV arm (n=54) had a higher proportion of low-risk patients (46% low; 33% intermediate; 20% high). TEM 175/75 resulted in significant improvement in median PFS (independent assessment) vs INV in high-risk patients (P=.003) (Table); trends toward improvement were observed for intermediate-risk and low-risk patients (P=.06 in each group). By investigator assessment, TEM 175/75 improved median PFS vs INV by 7.9 months in the low-risk category (P=.0007) and by 2.8 months (P=.06) and 1.1 month (P=.001) in the intermediate-risk and high-risk categories, respectively. A trend toward longer OS was observed in the low-risk patients treated with TEM 175/75 vs INV (P=.0502).

In the low-risk category, maintenance of stable disease or better response was achieved in more patients receiving TEM 175/75 (9/15 [60%]) vs INV (5/25 [20%]); objective responses were observed in 5 patients with TEM 175/75 and in no patients with INV. Patients in the low-risk category treated with TEM 175/75 received a longer duration of therapy vs INV (30.7 vs 9.0 wk, respectively). Across the duration of treatment, the average frequency of delay was once per 5.6 wk with TEM 175/75 vs once per 6.4 wk with INV. TEM was generally well tolerated. Grade 3/4 anemia, thrombocytopenia, and infection also were analyzed by patient risk category. In both the TEM 175/75 and INV groups, the selected grade 3/4 events occurred more commonly in high-risk than low-risk patients. In the low-risk category, a higher incidence of grade 3/4 thrombocytopenia and anemia was observed with TEM 175/75 vs INV.

Retrospective risk analysis of patients according to the simplified MIPI demonstrated that TEM 175/75 was effective across patient risk categories. The greatest benefit trend was observed in low-risk patients. In this study of relapsed/refractory MCL patients, MIPI was a good predictor of survival outcome.

Hess:Pfizer: Consultancy, Honoraria, Research Funding. Off Label Use: Torisel is licensed for treatment of relapsed and/or refractory mantle cell lymphoma and renal cell carcinoma in Europe. Torisel is licensed in the US for renal cell carcinoma. Kang:Pfizer: Employment. Moran:Pfizer: Employment.