CDKN2A and TP53 deletions predict adverse outcome in younger mantle cell lymphoma patients, independent of treatment and MIPI
A partir d'échantillons tumoraux prélevés sur 135 patients atteints d'un lymphome à cellules du manteau (âge médian : 56 ans), cette étude met en évidence une association entre la présence de délétions des gènes CDKN2A et TP53 et un pronostic défavorable, indépendamment de la statégie thérapeutique utilisée
CDKN2A and TP53 deletions remain of bad prognostic value in younger MCL patients treated according to the current standard of care.
CDKN2A and TP53 deletions have independent deleterious effects. It should be considered for treatment decisions in addition to MIPI and Ki-67 index.
We revisited the prognostic value of frequently detected somatic gene copy number alterations (CNAs) in mantle cell lymphoma (MCL) patients younger than 66 years treated first-line with immuno-chemotherapy and autologous stem cell transplantation (ASCT), with or without high-dose cytarabine, in the randomized European MCL Younger trial. DNA extracted from tumor material of 135 patients (median age 56 years) was analyzed by multiplex ligation-dependent probe amplification (MLPA) and/or quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF). As expected, MYC (18%) was the more frequent gain, whereas RB1 (26%), ATM (25%), CDKN2A (p16) (25%) and TP53 (22%) were the more frequently deleted. Whether adjusted for MCL International Prognostic Index (MIPI) or not, deletions of RB1, CDKN2A (p16), TP53, and CDKN1B (p27) were associated with shorter overall survival (OS), similarly in both treatment arms, whereas CNAs in MYC, ATM, CDK2, CDK4, and MDM2 had no prognostic value. Additive effects were seen for CDKN2A (p16) (HR 2.3, p=0.007, adjusted for MIPI) and TP53 deletions (2.4, p=0.007), reflected in a dismal outcome with simultaneous deletions (median OS 1.8 years) compared to single deletions (4.3 and 5.1 years), or without these deletions (7 years), again similarly in both treatment arms. The additive prognostic effects of CDKN2A (p16) and TP53 deletions were shown to be independent of the Ki-67 index. Despite immuno-chemotherapy, high-dose cytarabine, and ASCT, younger MCL patients with deletions of CDKN2A (p16) and TP53 show an unfavorable prognosis and are candidates for alternative therapeutic strategies. The European MCL Younger trial is registered to www.clinicaltrials.gov as NCT00209222.
Blood , résumé, 2014