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On 17th August, in Blood, Christian W. Eskelund from Rigshospitalet, Copenhagen, Denmark, and colleagues published findings on common genomic alterations in Mantle Cell Lymphoma (MCL) and how they impact prognosis in two, large Nordic trials: MCL2 and MCL3 (NCT00514475).
Patients were aged 66 years or less, had stage II-IV disease, and were considered fit for Autologous Stem Cell Transplant (ASCT). The regimen used in the MCL2 and MCL3 trials included induction of alternating R-maxi-CHOP and R-high-dose-cytarabine, subsequently followed with BEAM or BEAC high-dose chemotherapy and ASCT. Overall, 320 patients were enrolled onto the two trials; one patient withdrew from the MCL2 trial because of a change in diagnosis.
Overall, the authors stated that “TP53-mutated MCL represents a phenotypically distinct and highly aggressive disease entity”. Patients who harbor mutated TP53 have poor responses to high-dose regimens that include rituximab, cytarabine, and ASCT. The authors recommend stratifying patients by TP53 mutational status and should be studied separately in clinical trials that aim to explore novel targeted agents.
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 MCL patients 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<0.0001) retained prognostic impact for overall survival (OS), while TP53 mutations (HR=6.9, p<0.0001) and MIPI-c high-risk (HR=2.6, p=0.003) 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 not reached (NR) and 12.7 years, respectively, for TP53-unmutated cases, p<0.0001). 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 that MCL patients should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents.
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