Long-term analysis of the RiBVD phase II trial reveals the unfavorable impact of TP53 mutations and hypoalbuminemia in older adults with mantle cell lymphoma; for the LYSA group

Abstract

Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (rituximab, bendamustine, velcade and dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients over the age of 65. We have now re-examined the classic prognostic factors, adding an assessment of TP53 mutation status. Patients (N=74; median age 73 years) were treated with the RiBVD combination. Median progression-free survival (mPFS) was 79 months and median overall survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level (Alb) 3.6 g/dL were independently associated with a shorter mPFS. A hazard ratio (HR) of 3.16 (1.3-9.9, P=0.014) was obtained for TP53mt versus TP53 wild-type (wt), and 3.6 (1.39-9.5, P=0.009) for Alb <3.6 g/dL versus Alb ≥3.6 g/dL. In terms of mOS, multivariate analysis identified three PF: TP53mt (HR: 5.9 [1.77-19.5, P=0.004]), Alb <3.6 g/dL (HR: 5.2 [1.46- 18.5, P=0.011]), and ECOG=2 (HR: 3.7 [1.31-10.6, P=0.014]). Finally, a score combining TP53 status and Alb distinguished three populations based on the presence of 0, 1, or 2 PF. For these populations, mPFS was 7.8 years, 28 months, and 2.5 months, respectively. Our prolonged follow-up confirmed the efficacy of the RiBVD regimen, comparing it favorably to other regimens. TP53mt and hypoalbuminemia emerge as strong PF that can be easily integrated into prognostic scores for older adult patients with MCL.

Figure 1.

Outcomes for the whole population. Kaplan-Meier estimator of (A) progression-free survival and (B) overall survival for the whole population. Median follow-up was 115 months for surviving patients (N=37, 50%).

Figure 2.

Multivariate analysis identifies albumin level and TP53 status as independent prognostic factors. Hazard ratios determined from multivariate Cox models of (A) progression-free survival (PFS) and (B) overall survival (OS). Only statistically significant factors, as identified by univariate analysis, were tested. Kaplan-Meier estimators for PFS (C-E) and OS (D-F), with patients classed depending on (C and D) albumin level or (E and F) TP53 status. alb: albumin; ECOG: Eastern Cooperative Oncology Group; LDH: lactate dehydrogenase; mt: mutated; N: number; wt: wild-type.

Figure 3.

A composite score integrating albumin level and TP53 status is highly predictive for outcomes. Kaplan-Meier estimators for (A) progression-free survival and (B) overall survival. Patients were segregated using a composite score integrating albumin level (<3.6 g/dL or ≥3.6 g/dL) and TP53 status (mutated [mt] vs. wild-type [wt]) as prognostic factors (PF).