Prognostic impact of TP53 mutation in newly diagnosed diffuse large B‐cell lymphoma patients treated in the FIL‐DLCL04 trial

Abstract

The prognostic role of TP53 disruption has been established in diffuse large B-cell lymphoma (DLBCL). Aim of this analysis was to correlate TP53 mutations by Sanger sequencing, cell of origin (COO) profile by Lym-ph2Cx panel on the NanoString platform and MYC, BCL2 and BCL6 overexpression or re-arrangements by immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH), with outcome in DLBCL patients enrolled into the FIL-DLCL04 trial (NCT00499018). One hundred and twenty-five DLBCL patients with tumour block available were analyzed. TP53 was mutated in 11/125 (9%) cases; 60/125 patients received highdose chemoimmunotherapy up-front, as for the randomization arm; COO was reported in 88 patients: 48 germinal centre B-cell like, 25 activated Bcell like and 17 unclassified; 26 patients were double expressors in IHC and 11 double hit in FISH. After a median follow-up of 72 months, five-year failure-free survival (FFS) for TP53 mutated versus wild-type was 24% and 72%, and five-year overall survival (OS) was 34% and 83%, respectively. Adjusted hazard ratio (HR) was 2Á28 [95% confidence interval (CI) 0Á89-5Á86, p = 0Á086] and 4Á05 (95% CI 1Á37-11Á97, p = 0Á011) for FFS and OS, respectively. In this series of young DLBCL patients, TP53 gene mutation identified a poor prognosis subgroup, regardless of treatment and other biological markers.

Clonally unrelated Richter syndrome are truly de novo diffuse large B‐cell lymphomas with a mutational profile reminiscent of clonally related Richter syndrome

“…Besides documenting the truly de novo origin of clonally unrelated RS, our data show a certain degree of commonality between the pathogenetic lesions of clonally unrelated and clonally related RS, including a high frequency of TP53 disruption. Importantly, TP53 disruption predisposes to failure of R‐CHOP‐like chemoimmunotherapy regimens 25 in de novo DLBCL without a history of CLL 25 . The molecular pattern of clonally unrelated RS identified in this study might deserve consideration when designing future treatment algorithms of RS.…”

“…Importantly, TP53 disruption predisposes to failure of R-CHOP-like chemoimmunotherapy regimens 25 in de novo DLBCL without a history of CLL. 25 The molecular pattern of clonally unrelated RS identified in this study might deserve consideration when designing future treatment algorithms of RS. For clonally related RS, expert opinions propose transplant consolidation after the achievement of first remission in transplant-eligible patients.…”

Role of estrogen receptor signaling pathway-related genes in diffuse large B-cell lymphoma and identification of key targets via integrated bioinformatics analysis and experimental validation

“…Chiappella et al also noted that in young patients with intermediate-and highrisk DLBCL, TP53 disruption due to genetic mutations identified a subgroup of patients with an abysmal prognosis. DLBCL cases with TP53 mutations have lower response rates to chemoimmunotherapy and lower survival rates for FFS and OS compared with patients with TP53 WT (66). Currently, there is a lack of effective treatment for patients with TP53 mutations in clinical practice, and the disease development can be appropriately delayed through targeted drug therapy.…”

Safety and Efficacy of Humanized Versus Murinized CD19 and CD22 CAR T-Cell Cocktail Therapy for Refractory/Relapsed B-Cell Lymphoma

“…In our previous study analyzing 254 B-ALL patients, compared to the TP53 wild-type group, patients with TP53 mutations had lower CR rates, resulting in significantly poorer OS and LFS, despite receiving CD19 CAR-T cell therapy [ 37 ]. In a multicenter, randomized, phase 3 trial, 5-year OS rates were 81% and 33% in wild type and TP53 mutation type cases, respectively, and the 5-year PFS rates were 73% and 19% respectively [ 38 , 39 ]. The standard salvage chemotherapy with subsequent HDT/ASCT still cannot overcome the poor prognosis conferred by the presence of a TP53 mutation.…”