Key Points• The intensified standard-ofcare regimens for younger patients with MCL do not overcome the deleterious effects of TP53 mutations.• MCLs with TP53 mutations should be considered for alternative frontline treatment.Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%), were significantly associated with inferior outcomes (together with MIPI, MIPI-c, blastoid morphology, and Ki67 > 30%); however, in multivariate analyses, only TP53 mutations (HR, 6.2; P < .0001) retained prognostic impact for overall survival (OS), whereas TP53 mutations (HR, 6.9; P < .0001) and MIPI-c high-risk (HR, 2.6; P 5 .003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome, with a median OS of 1.8 years, and 50% relapsed at 1.0 years, compared to a median OS of 12.7 years for TP53-unmutated cases (P < .0001). TP53 mutations were significantly associated with Ki67 > 30%, blastoid morphology, MIPI high-risk, and inferior responses to both induction-and high-dose chemotherapy. In conclusion, we show that TP53 mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab, and autologous stem-cell transplant (ASCT). We suggest patients with MCL should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents. (Blood. 2017;130(17):1903-1910
SummaryMantle cell lymphoma (MCL) is a heterogenic non-Hodgkin lymphoma entity, with a median survival of about 5 years. In 2008 we reported the early -based on the median observation time of 4 years -results of the Nordic Lymphoma Group MCL2 study of frontline intensive induction immunochemotherapy and autologous stem cell transplantation (ASCT), with more than 60% event-free survival at 5 years, and no subsequent relapses reported. Here we present an update after a median observation time of 6·5 years. The overall results are still excellent, with median overall survival and response duration longer than 10 years, and a median eventfree survival of 7·4 years. However, six patients have now progressed later than 5 years after end of treatment. The international MCL Prognostic Index (MIPI) and Ki-67-expression were the only independent prognostic factors. Subdivided by the MIPI-Biological Index (MIPI + Ki-67, MIPI-B), more than 70% of patients with low-intermediate MIPI-B were alive at 10 years, but only 23% of the patients with high MIPI-B. These results, although highly encouraging regarding the majority of the patients, underline the need of a risk-adapted treatment strategy for MCL. The study was registered at www.isrctn.org as ISRCTN 87866680.
In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first-line regimens containing cytarabine, rituximab and consolidation with high-dose-therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15-year updated results of the Nordic MCL2 study after a median follow-up of 11·4 years: For all patients on an intent-to-treat basis, the median overall and progression-free survival was 12·7 and 8·5 years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI-B) and the MIPI-B including mIR-18b expression (MIPI-B-miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12 years, we still see an excess disease-related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL.
The IPI may not be an optimal tool for outcome prediction in MCL, and a better prognostic index may be obtained by including Ki-67 expression and possibly the histological subtype in the index.
Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, where survival has been remarkably improved by use of protocols including high dose cytarabine, rituximab and autologous stem cell transplantation, such as the Nordic MCL2/3 protocols. In 2008, a MCL international prognostic index (MIPI) was created to enable stratification of the clinical diverse MCL patients into three risk groups. So far, use of the MIPI in clinical routine has been limited, as it has been shown that it inadequately separates low and intermediate risk group patients. To improve outcome and minimize treatment-related morbidity, additional parameters need to be evaluated to enable risk-adapted treatment selection. We have investigated the individual prognostic role of the MIPI and molecular markers including SOX11, TP53 (p53), MKI67 (Ki-67) and CCND1 (cyclin D1). Furthermore, we explored the possibility of creating an improved prognostic tool by combining the MIPI with information on molecular markers. SOX11 was shown to significantly add prognostic information to the MIPI, but in multivariate analysis TP53 was the only significant independent molecular marker. Based on these findings, we propose that TP53 and SOX11 should routinely be assessed and that a combined TP53/MIPI score may be used to guide treatment decisions.
Y-ibritumomab-tiuxetan (Zevalin) to the highdose regimen. One hundred sixty untreated, stage II-IV mantle cell lymphoma patients <66 years received rituximab (R)-maxi-CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) alternating with R-high-dose cytarabine (6 cycles total), followed by high-dose BEAM/C (bis-chloroethylnitrosourea, etoposide, cytarabine, and melphalan or cyclophosphamide) and autologous stem cell transplantation from 2005 to 2009. Zevalin (0.4 mCi/kg) was given to responders not in CR before transplant. Overall response rate pretransplant was 97%. The outcome did not differ from that of the historic control: the MCL2 trial with similar treatment except for Zevalin. Overall survival (OS), eventfree survival (EFS), and progression-free survival (PFS) at 4 years were 78%, 62%, and 71%, respectively. For responding non-CR patients who received Zevalin, duration of response was shorter than for the CR group. Inferior PFS, EFS, and OS were predicted by positron emission tomography (PET) positivity pretransplant and detectable minimal residual disease (MRD) after transplant. In conclusion, positive PET and MRD were strong predictors of outcome. Intensification with Zevalin may be too late to improve the outcome of patients not in CR before transplant. This trial was registered at www.clinicaltrials.gov as
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