Prognostic impact of TP53 mutation in newly diagnosed diffuse large B-cell lymphoma patients treated in the FIL-DLCL04 trial
Correction(s) for this article
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Corrigendum
- Volume 197Issue 6British Journal of Haematology
- pages: 803-803
- First Published online: June 13, 2022
Corresponding Author
Annalisa Chiappella
Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
Correspondence: Annalisa Chiappella, Division of Hematology and Stem Cell Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, via Giacomo Venezian 1, Milano 20133, Italy.
E-mail: [email protected]
Search for more papers by this authorFary Diop
Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
Search for more papers by this authorClaudio Agostinelli
Pathology Unit, Università degli Studi di Bologna, Bologna, Italy
Search for more papers by this authorMattia Novo
Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Torino, Italy
Search for more papers by this authorLuca Nassi
Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
Search for more papers by this authorAndrea Evangelista
Unit of Clinical Epidemiology and CPO, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorGiovannino Ciccone
Unit of Clinical Epidemiology and CPO, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorAlice Di Rocco
Department of Traslational and Precision Medicine, Università La Sapienza, Roma, Italy
Search for more papers by this authorMaurizio Martelli
Department of Traslational and Precision Medicine, Università La Sapienza, Roma, Italy
Search for more papers by this authorFederica Melle
Haematopathology Division, IRCCS, Istituto Europeo di Oncologia, IEO, Milano, Italy
Search for more papers by this authorRiccardo Moia
Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
Search for more papers by this authorGiovanna Motta
Haematopathology Division, IRCCS, Istituto Europeo di Oncologia, IEO, Milano, Italy
Search for more papers by this authorSimona Righi
Pathology Unit, Università degli Studi di Bologna, Bologna, Italy
Search for more papers by this authorElisa Santambrogio
Hematology Unit, Santa Croce e Carle Hospital, Cuneo, Italy
Search for more papers by this authorAlessandra Tucci
Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
Search for more papers by this authorMonica Balzarotti
IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
Search for more papers by this authorMarco Ladetto
Hematology, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
Search for more papers by this authorStefano A. Pileri
Haematopathology Division, IRCCS, Istituto Europeo di Oncologia, IEO, Milano, Italy
Search for more papers by this authorGianluca Gaidano
Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
Search for more papers by this authorUmberto Vitolo
Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Torino, Italy
Search for more papers by this authorFondazione Italiana Linfomi (FIL)
Search for more papers by this authorCorresponding Author
Annalisa Chiappella
Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
Correspondence: Annalisa Chiappella, Division of Hematology and Stem Cell Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, via Giacomo Venezian 1, Milano 20133, Italy.
E-mail: [email protected]
Search for more papers by this authorFary Diop
Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
Search for more papers by this authorClaudio Agostinelli
Pathology Unit, Università degli Studi di Bologna, Bologna, Italy
Search for more papers by this authorMattia Novo
Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Torino, Italy
Search for more papers by this authorLuca Nassi
Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
Search for more papers by this authorAndrea Evangelista
Unit of Clinical Epidemiology and CPO, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorGiovannino Ciccone
Unit of Clinical Epidemiology and CPO, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorAlice Di Rocco
Department of Traslational and Precision Medicine, Università La Sapienza, Roma, Italy
Search for more papers by this authorMaurizio Martelli
Department of Traslational and Precision Medicine, Università La Sapienza, Roma, Italy
Search for more papers by this authorFederica Melle
Haematopathology Division, IRCCS, Istituto Europeo di Oncologia, IEO, Milano, Italy
Search for more papers by this authorRiccardo Moia
Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
Search for more papers by this authorGiovanna Motta
Haematopathology Division, IRCCS, Istituto Europeo di Oncologia, IEO, Milano, Italy
Search for more papers by this authorSimona Righi
Pathology Unit, Università degli Studi di Bologna, Bologna, Italy
Search for more papers by this authorElisa Santambrogio
Hematology Unit, Santa Croce e Carle Hospital, Cuneo, Italy
Search for more papers by this authorAlessandra Tucci
Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
Search for more papers by this authorMonica Balzarotti
IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
Search for more papers by this authorMarco Ladetto
Hematology, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
Search for more papers by this authorStefano A. Pileri
Haematopathology Division, IRCCS, Istituto Europeo di Oncologia, IEO, Milano, Italy
Search for more papers by this authorGianluca Gaidano
Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
Search for more papers by this authorUmberto Vitolo
Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Torino, Italy
Search for more papers by this authorFondazione Italiana Linfomi (FIL)
Search for more papers by this author†Annalisa Chiappella and Fary Diop contributed equally.
‡Umberto Vitolo and Gianluca Gaidano contributed equally.
Summary
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 Lymph2Cx 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 high-dose chemoimmunotherapy up-front, as for the randomization arm; COO was reported in 88 patients: 48 germinal centre B-cell like, 25 activated B-cell 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 2·28 [95% confidence interval (CI) 0·89–5·86, p = 0·086] and 4·05 (95% CI 1·37–11·97, p = 0·011) 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.
Conflicts of interests
AC: advisory boards: Celgene-BMS, Clinigen, Gilead-Sciences, Janssen, Roche, Takeda; honoraria for lectures: AstraZeneca, Celgene-BMS, Clinigen, Gilead-Sciences, Incyte, Janssen, Novartis, Roche, Takeda. LN: advisory boards: Takeda, Janssen, Merck. MM: advisory boards: Roche, Celgene, Janssen, Sandoz, Novartis, Gilead; honoraria for lectures: Roche, Celgene, Janssen, Sandoz, Novartis, Gilead. MB: advisory boards: Celgene, Janssen, Roche; honoraria for lectures: Celgene, Roche. ML: invitation to scientific meetings, institutional research support and contracts: AbbVie, Acerta, Amgen, Archigen, ADC Therapeutics, BeiGene Celgene, Gilead, J&J, Jazz, Roche, Sandoz, Takeda. UV: advisory board: Celgene, Janssen, Gilead, Juno Therapeutics, Genmab, Bayer, Novartis; honoraria for lectures: Celgene, Gilead, Roche, Abbvie, Janssen. GG: advisory board: Janssen, Abbvie, AstraZeneca, Sunesys; speaker's bureau: Janssen, Abbvie; SAP: advisory board: Takeda and NanoString; honoraria for lecture: Roche. The other authors declare they have no conflicts of interest.
Supporting Information
| Filename | Description |
|---|---|
| bjh17971-sup-0001-Supinfo.docxWord 2007 document , 47.5 KB |
Table SI. TP53 primers for coding exons from 2 to 11. Table SII. Characteristics of TP53 mutated patients. |
| bjh17971-sup-0002-FigureS1.pdfPDF document, 267.2 KB | Fig S1. Failure free survival and overall survival by mutational status availability. Kaplan-Meier estimates of failure free survival (A) and overall survival (B) of patients with available DNA included in the present molecular study (dashed line) and of patients without available DNA not included in the present molecular study (solid line). The Log-rank statistics P values are indicated adjacent curves. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010; 116(12): 2040–5.
- 2Ziepert M, Hasenclever D, Kuhnt E, Glass B, Schmitz N, Pfreundschuh M, et al. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol. 2010; 28(14): 2373–80.
- 3Chiappella A, Martelli M, Angelucci E, Brusamolino E, Evangelista A, Carella AM, et al. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol. 2017; 18(8): 1076–88.
- 4Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, et al. Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med. 2013; 369(18): 1681–90.
- 5Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, et al. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002–1). Lancet Oncol. 2012; 13(12): 1250–9.
- 6Cortelazzo S, Tarella C, Gianni AM, Ladetto M, Barbui AM, Rossi A, et al. Randomized trial comparing R-CHOP versus high-dose sequential chemotherapy in high-risk patients with diffuse large B-cell lymphomas. J Clin Oncol. 2016; 34(33): 4015–22.
- 7Le Gouill S, Milpied NJ, Lamy T, Delwail V, Gressin R, Guyotat D, et al. First-line rituximab (R) high-dose therapy (R-HDT) versus R-CHOP14 for young adults with diffuse large B-cell lymphoma: preliminary results of the GOELAMS 075 prospective multicenter randomized trial. J Clin Oncol. 2011; 29(15_suppl): 8003.
- 8Lenz G, Wright GW, Emre NCT, Kohlhammer H, Dave SS, Davis RE, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A. 2008; 105(36): 13520–5.
- 9Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th Edition. Lyon: IARC Press; 2017. https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-Haematopoietic-And-Lymphoid-Tissues-2017
- 10Cheung K-JJ, Horsman DE, Gascoyne RD. The significance of TP53 in lymphoid malignancies: mutation prevalence, regulation, prognostic impact and potential as a therapeutic target. Br J Haematol. 2009; 146(3): 257–69.
- 11Halldórsdóttir AM, Lundin A, Murray F, Mansouri L, Knuutila S, Sundström C, et al. Impact of TP53 mutation and 17p deletion in mantle cell lymphoma. Leukemia. 2011; 25(12): 1904–8.
- 12Nordström L, Sernbo S, Eden P, Grønbæk K, Kolstad A, Räty R, et al. SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma—a Nordic Lymphoma Group study. Br J Haematol. 2014; 166(1): 98–108.
- 13Lo Coco F, Gaidano G, Louie DC, Offit K, Chaganti RS, Dalla-Favera R, et al. p53 mutations are associated with histologic transformation of follicular lymphoma. Blood. 1993; 82(8): 2289–95.
- 14O'Shea D, O'Riain C, Taylor C, Waters R, Carlotti E, MacDougall F, et al. The presence of TP53 mutation at diagnosis of follicular lymphoma identifies a high-risk group of patients with shortened time to disease progression and poorer overall survival. Blood. 2008; 112(8): 3126–9.
- 15Leroy K, Haioun C, Lepage E, Le Métayer N, Berger F, Labouyrie E, et al. p53 gene mutations are associated with poor survival in low and low-intermediate risk diffuse large B-cell lymphomas. Ann Oncol. 2002; 13(7): 1108–15.
- 16Young KH, Weisenburger DD, Dave BJ, Smith L, Sanger W, Iqbal J, et al. Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAILreceptor-2, predict for poor survival in diffuse large B-cell lymphoma. Blood. 2007; 110(13): 4396–405.
- 17Zainuddin N, Berglund M, Wanders A, Ren ZP, Amini RM, Lindell M, et al. TP53 mutations predict for poor survival in de novo diffuse large B-cell lymphoma of germinal center subtype. Leuk Res. 2009; 33(1): 60–6.
- 18Xu-Monette ZY, Wu L, Visco C, Tai YC, Tzankov A, Liu W-M, et al. Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study. Blood. 2012; 120(19): 3986–96.
- 19Zenz T, Kreuz M, Fuge M, Klapper W, Horn H, Staiger AM, et al. TP53 mutation and survival in aggressive B cell lymphoma. Int J Cancer. 2017; 141(7): 1381–8.
- 20Young KH, Leroy K, Møller MB, Colleoni GWB, Sánchez-Beato M, Kerbauy FR, et al. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study. Blood. 2008; 112(8): 3088–98.
- 21Scott DW, Wright GW, Williams PM, Lih C-J, Walsh W, Jaffe ES, et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood. 2014; 123(8): 1214–7.
- 22Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Döhner K, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014; 123(21): 3247–54.
- 23Dodero A, Guidetti A, Marino F, Tucci A, Barretta F, Re A, et al. Dose-Adjusted Epoch and Rituximab for the treatment of double expressor and double hit diffuse large B-cell lymphoma: impact of TP53 mutations on clinical outcome. Haematologica. 2020. https://doi.org/10.3324/haematol.2021.278638
10.3324/haematol.2021.278638 Google Scholar
- 24Yemelyanova A, Vang R, Kshirsagar M, Lu D, Marks MA, Shih IM, et al. Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis. Mod Pathol. 2011; 24(9): 1248–53.
- 25Lepelley P, Preudhomme C, Vanrumbeke M, Quesnel B, Cosson A, Fenaux P. Detection of p53 mutations in hematological malignancies: comparison between immunocytochemistry and DNA analysis. Leukemia. 1994; 8(8): 1342–9.
- 26Zenz T, Kröber A, Scherer K, Häbe S, Bühler A, Benner A, et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood. 2008; 112(8): 3322–9.
- 27Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, et al. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019; 37(15): 1285–95.
- 28Nowakowski G, Chiappella A, Witzig TE, Spina M Gascoyne R, Zhang L, et al. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021; 39(12): 1317–28.
- 29Zelenetz AD, Salles G, Mason KD, Casulo C, Le Gouill S, Sehn LH, et al. Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial. Blood. 2019; 133(18): 1964–76.
- 30Morschhauser F, Feugier P, Flinn IW, Gasiorowski R, Greil R, Illés Á, et al. A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma. Blood. 2021; 137(5): 600–9.
- 31Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018; 24(5): 679–90.
- 32Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018; 378(15): 1396–407.
- 33Ciavarella S, Vegliante MC, Fabbri M, De Summa S, Melle F, Motta G, et al. Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue. Ann Oncol. 2018; 29(12): 2363–70.
- 34Derenzini E, Agostinelli C, Rossi A, Rossi M, Scellato F, Melle F, et al. Genomic alterations of ribosomal protein genes in diffuse large B cell lymphoma. Br J Haematol. 2019; 185(2): 330–4.
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