Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group

Abstract

Clinical outcome of mantle cell lymphoma (MCL) is highly heterogeneous. Tumor cell proliferation as assessed by the Ki-67 index has been shown to yield prognostic information on MCL in many studies using heterogeneously treated patient cohorts. The prognostic value of the Ki-67 index in patients treated with anti-CD20 therapy has not been studied so far. We analyzed the Ki-67 index at primary diagnosis in 249 advanced-stage MCL patients treated within randomized trials. Ki-67 showed high prognostic relevance for overall survival (relative risk 1.27 for 10% higher Ki-67, P < .001), also independently from clinical prognostic factors. The 3 groups with different Ki-67 index of less than 10%, 10% to less than 30%, and 30% or more showed significantly different overall survival in patients treated with CHOP (P ‫؍‬ .001) as well as in patients treated with CHOP in combination with anti-CD20 therapy (R-CHOP, P ‫؍‬ .013). Thus, the Ki-67 index remains an important prognostic marker in the era of anti-CD20 therapy. The European MCL study is registered at www. IntroductionMantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (B-NHL) with a median overall survival (OS) of the patients of 3 to 5 years. 1 Clinical outcome of this disease is highly heterogeneous. 2 Since MCL patients often present at an advanced age and treatment strategies differ in terms of their potential side effects, several attempts have been made to identify high-and low-risk patients for a risk-adapted therapy. [2][3][4][5] In contrast to many other B-NHLs, increased proliferation of the tumor cells has been shown to be distinctly correlated with shorter survival in MCL. Thus, the proliferation index as assessed by the percentage of Ki-67 positive cells represents an important prognostic marker in several studies. 2,6,7 However, the studies published so far aiming at the prognostic value of Ki-67 analyzed patients with heterogeneous therapeutic regimens that were not treated within prospective randomized trials. 2,6,7 The addition of anti-CD20 (rituximab) to the chemotherapy protocols improved the outcome and might have changed the risk-factor profile of diffuse large B-cell lymphomas (DLBCL). Thus, BCL2 expression, a marker for unfavorable outcome in DLBCL, might lose its predictive value in DLBCL patients treated with rituximab. 8 The introduction of rituximab into the treatment protocols for MCL has improved the outcome substantially. 9 However, to date it is uncertain, whether proliferation can predict outcome in MCL treated with rituximab. We studied the tumor-cell proliferation rate in 249 newly diagnosed patients with advanced-stage MCL treated within the randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group (GLSG; a list of the members of the study group is available as Document S1 on the Blood website; see the Supplemental Materials link at the top of the online article). Methods PatientsLocal ethics committees of the participating centers approved the study protocol, and written infor...

Increased tumor cell proliferation in mantle cell lymphoma is associated with elevated insulin-like growth factor 2 mRNA-binding protein 3 expression

“…26 The rate of tumor cell proliferation has been established as a key biological feature of clinical aggressiveness in mantle cell lymphoma, and several genetic events occurring during the progression of the disease appear to enhance proliferation leading to decreased survival times. 1 Despite the strong statistical association in our cohort between IGF2BP3 protein expression and an increased Ki-67 index of the tumor cells, the major prognostic marker for survival in previous studies, 22,23 IGF2BP3 expression itself did not correlate with clinical outcome in our analysis reinforcing the idea that the quantitative measurement of tumor cell proliferation in mantle cell lymphoma serves as an integrator of various unfavorable molecular events. 6 Our finding that IGF2BP3 protein expression is significantly increased in the mantle cell lymphoma subset with elevated tumor cell proliferation adds to the notion that increased IGF signaling in mantle cell lymphoma might contribute additional growth stimuli that enhance the proliferative capacity.…”

“…Given that increased proliferation of the tumor cells has been shown to be associated with inferior outcome in mantle cell lymphoma patients in several studies, 6,22,23 we next attempted to correlate IGF2BP3 expression with morphological features of the tumors, the genetic status of 7p and clinical survival in a larger series of 106 mantle cell lymphoma cases. As already observed in the pilot series, IGF2BP3 protein expression was heterogeneous, and higher expression was strongly associated with increased proliferation measured by the Ki-67 index (Po0.0001, Figure 3b).…”

Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma

“…It needs to be pointed out that these treatment results were obtained in a predomi-BORID in relapsed MCL haematologica | 2011; 96 (7) 1011 (Table 1). This is reflected by a median of three prior lines of therapy, risk scores (IPI, MIPI) 28 suggesting intermediate and high risk in the majority of patients, as well as a high proliferative activity 31 (Ki-67 index >30% in 9 of the 13 patients tested). The observed efficacy of this treatment combination clearly exceeds the activity of each single agent in the BORID regimen.…”

High-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting in mantle cell lymphoma: a 10-year update of the R-HDS regimen

“…In particular, our data (10-year OS, 68% for intermediate/ high-risk group, 76% for low-risk group; EFS, 34 and 57%, respectively) compare favorably with long-term reports from other groups who have used immunotherapy in association with dose-intense chemotherapy 6 (hyper-CVAD; 5-year OS, 65%; EFS, 48%), even though a stratification based on MIPI score would have helped in the comparison of the results; in addition, they are in agreement with data obtained after a shorter (6-year) follow-up with a similar chemoimmunotherapy strategy. 7 A direct comparison with data obtained in conventionally treated patients, as those reported recently by Determan et al, 8 is impossible for the short follow-up of these patients.…”