Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study

H A Poirel, M S Cairo, N A Heerema, J Swansbury, A Aupérin, E Launay, W G Sanger, P Talley, S L Perkins, M Raphaël, K McCarthy, R Sposto, M Gerrard, A Bernheim, C Patte, FAB/LMB 96 International Study Committee, H Avet-Loiseau, L Baranger, C Barin, C Bastard, A Bernheim, M F Berthéas, C Bilhou-Nabera, C Borie, E Caillet-Bauchu, A M Capdano, M A Collonge-Rame, P Cornillet, J Couturier, N Dastugue, A Daudignon, N Gachard, M J Grégoire, P Heimann, C Henry, J L Laï, D Leroux, M Lessard, I Luquet, C H M Mellink, N Nadal, M P Pagès, D Penther, B Perissel, S Raynaud, P Talman, S Taviaux, I Tigaud, J Van den Akker, J Beigel, P Benn, E Cantu, K Carlson, L Cooley, A Dawson, V G Dev, G Dewald, T Drumheller, J Fink, I Gadi, J Hanna, A Glassman, K Harrison, N Heerema, J Higgins, R Higgins, B Hirsch, D Horsman, D Kalousek, P Koduru, R Lebo, X Li, R E Magenis, K McFadden, L McGavron, L McMorrow, A Murch, K Opheim, D Panzar, L Pasztor, A Pettigrew, C Philips, K Rao, P N Rao, D Rouston, W Sanger, K L Satya-Prakash, S Schwartz, G S Sekhon, G Shaw, S Shekter-Levin, N Spinner, W Stanley, P Storto, M Thangavelu, K Theil, G Vance, D VanDyke, T Zadeh, K Andrews, M Booth, N Bown, T Davies, E Grace, M Griffiths, P Howard, D Hughes, H Kempski, D Lillington, G Lowther, K Martin, P Roberts, F Ross, J Sadler, R Stallings, D Stevenson, J Swansbury, P Talley, N Telford, H Walker, H A Poirel, M S Cairo, N A Heerema, J Swansbury, A Aupérin, E Launay, W G Sanger, P Talley, S L Perkins, M Raphaël, K McCarthy, R Sposto, M Gerrard, A Bernheim, C Patte, FAB/LMB 96 International Study Committee, H Avet-Loiseau, L Baranger, C Barin, C Bastard, A Bernheim, M F Berthéas, C Bilhou-Nabera, C Borie, E Caillet-Bauchu, A M Capdano, M A Collonge-Rame, P Cornillet, J Couturier, N Dastugue, A Daudignon, N Gachard, M J Grégoire, P Heimann, C Henry, J L Laï, D Leroux, M Lessard, I Luquet, C H M Mellink, N Nadal, M P Pagès, D Penther, B Perissel, S Raynaud, P Talman, S Taviaux, I Tigaud, J Van den Akker, J Beigel, P Benn, E Cantu, K Carlson, L Cooley, A Dawson, V G Dev, G Dewald, T Drumheller, J Fink, I Gadi, J Hanna, A Glassman, K Harrison, N Heerema, J Higgins, R Higgins, B Hirsch, D Horsman, D Kalousek, P Koduru, R Lebo, X Li, R E Magenis, K McFadden, L McGavron, L McMorrow, A Murch, K Opheim, D Panzar, L Pasztor, A Pettigrew, C Philips, K Rao, P N Rao, D Rouston, W Sanger, K L Satya-Prakash, S Schwartz, G S Sekhon, G Shaw, S Shekter-Levin, N Spinner, W Stanley, P Storto, M Thangavelu, K Theil, G Vance, D VanDyke, T Zadeh, K Andrews, M Booth, N Bown, T Davies, E Grace, M Griffiths, P Howard, D Hughes, H Kempski, D Lillington, G Lowther, K Martin, P Roberts, F Ross, J Sadler, R Stallings, D Stevenson, J Swansbury, P Talley, N Telford, H Walker

Abstract

Clinical studies showed that advanced stage, high LDH, poor response to reduction therapy and combined bone marrow and central nervous system disease are significantly associated with a decreased event-free survival (EFS) in pediatric mature B-cell non-Hodgkin's lymphoma (B-NHL) treated on FAB/LMB96. Although rearranged MYC/8q24 (R8q24) is characteristic of Burkitt lymphoma (BL), little information is available on other cytogenetic abnormalities and their prognostic importance. We performed an international review of 238 abnormal karyotypes in childhood mature B-NHL treated on FAB/LMB96: 76% BL, 8% Burkitt-like lymphoma, 13% diffuse large B-cell lymphoma (DLBCL). The main BL R8q24-associated chromosomal aberrations were +1q (29%), +7q and del(13q) (14% each). The DLBCL appeared heterogeneous and more complex. Incidence of R8q24 (34%) was higher than reported in adult DLBCL. The prognostic value of cytogenetic abnormalities on EFS was studied by Cox model controlling for the known risk factors: R8q24, +7q and del(13q) were independently associated with a significant inferior EFS (hazard ratio: 6.1 (P=0.030), 2.5 (P=0.015) and 4.0 (P=0.0003), respectively). The adverse prognosis of R8q24 was observed only in DLBCL, whereas del(13q) and +7q had a similar effect in DLBCL and BL. These results emphasize the significant biological heterogeneity and the development of cytogenetic risk-adapted therapy in childhood mature B-NHL.

Figures

Figure 1. Distribution of cytogenetic abnormalities in…
Figure 1. Distribution of cytogenetic abnormalities in FAB/LMB 96 Study stratified by histological subtypes Burkitt Lymphoma (BL), Burkitt Like Lymphoma (BLL) and Diffuse Large B-Cell Lymphoma (DLBCL)
R8q24, dup(1q), del(6q), der(11q), +12, ploidy and complexity are helpful in the discrimination between BL and DLBCL. BLL exhibit an intermediary pattern.
Figure 2. Probability of EFS by Kaplan-Meier…
Figure 2. Probability of EFS by Kaplan-Meier method in children with B-NHL treated on FAB/LMB 96 on the whole population (N=238)
Figure 2A: EFS with and without rearranged 8q24 cytogenetic abnormality Figure 2B: EFS with and without del(13q) cytogenetic abnormality Figure 2C: EFS with and without +7q cytogenetic abnormality Figure 2D: EFS with and without a complex karyotype (>3 cytogenetic abnormalities)
Figure 3. Probability of EFS by Kaplen-Meier…
Figure 3. Probability of EFS by Kaplen-Meier method in children with B-NHL treated on FAB/LMB 96 according to the main morphologic entities BL (N=182) and DLBCL (N=30)
Figure 3A: EFS with and without rearranged 8q24 cytogenetic abnormality Figure 3B: EFS with and without del(13q) cytogenetic abnormality Figure 3C: EFS with and without +7q cytogenetic abnormality Figure 3D: EFS with and without a complex karyotype (>3 cytogenetic abnormalities) While del(13q), +7q and the complexity altered the prognosis of BL and DLBCL in the same proportion, the adverse effect of R8q24 is only detected in DLBCL.

References

    1. Patte C, Auperin A, Gerrard M, Michon J, Pinkerson CR, Sposto R, et al. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin’s lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood. 2007;109:2773–2780.
    1. Cairo MS, Gerrard M, Sposto R, Auperin A, Pinkerson CR, Michon J, et al. Results of a randomized international study of high risk central nervous system B-non-Hodgkin’s lymphoma and B-acute lymphoblastic leukemia in children and adolescents. Blood. 2007;109:2736–2743.
    1. Gerrard M, Cairo MS, Weston C, Auperin A, Pinkerton R, Lambilliote A, et al. Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell Non-Hodgkin’s Lymphoma: Results of the FAB/LMB 96 International Study. Br J Haematol. 2008;141:840–7.
    1. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84:1361–1392.
    1. Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. Pathology & genetics of tumours of haematopoietic and lymphoid tissues. Lyon: IARCPress; 2001. World Health Organization Classification of tumors; pp. 181–184.
    1. Lenoir GM, Preud’homme JL, Bernheim A, Berger R. Correlation between immunoglobulin light chain expression and variant translocation in Burkitt’s lymphoma. Nature. 1982;298:474–476.
    1. Battey J, Moulding C, Taub R, Murphy W, Stewart T, Potter H, et al. The human c-myc oncogene: structural consequences of translocation into the IgH locus in Burkitt lymphoma. Cell. 1983;34:779–787.
    1. Zech L, Haglund U, Nilsson K, Klein G. Characteristic chromosomal abnormalities in biopsies and lymphoid-cell lines from patients with Burkitt and non-Burkitt lymphomas. Int J Cancer. 1976;17:47–56.
    1. Bernheim A, Berger R, Lenoir G. Cytogenetic studies on African Burkitt’s lymphoma cell lines: t(8;14), t(2;8) and t(8;22) translocations. Cancer Genet Cytogenet. 1981;3:307–315.
    1. Blum KA, Lozanski G, Byrd JC. Adult Burkitt leukemia and lymphoma. Blood. 2004;104:3009–3020.
    1. Wilda M, Bruch J, Harder L, Rawer D, Reiter A, Borkhardt A, et al. Inactivation of the ARF-MDM-2-p53 pathway in sporadic Burkitt’s lymphoma in children. Leukemia. 2004;18:584–588.
    1. Lindstrom MS, Wiman KG. Role of genetic and epigenetic changes in Burkitt lymphoma. Semin Cancer Biol. 2002;12:381–387.
    1. Berger R, Bernheim A. Cytogenetics of Burkitt’s lymphoma-leukaemia: a review. IARC Sci Publ. 1985;60:65–80.
    1. Berger R, Le Coniat M, Derre J, Vecchione D. Secondary nonrandom chromosomal abnormalities of band 13q34 in Burkitt lymphoma-leukemia. Genes Chromosomes Cancer. 1989;1:115–118.
    1. Lai JL, Fenaux P, Zandecki M, Nelken B, Huart JJ, Deminatti M. Cytogenetic studies in 30 patients with Burkitt’s lymphoma or L3 acute lymphoblastic leukemia with special reference to additional chromosome abnormalities. Ann Genet. 1989;32:26–32.
    1. Kornblau SM, Goodacre A, Cabanillas F. Chromosomal abnormalities in adult non-endemic Burkitt’s lymphoma and leukemia: 22 new reports and a review of 148 cases from the literature. Hematol Oncol. 1991;9:63–78.
    1. Johansson B, Mertens F, Mitelman F. Cytogenetic evolution patterns in non-Hodgkin’s lymphoma. Blood. 1995;86:3905–3914.
    1. Berger R, Bernheim A. Is there a functional equivalence between abnormalities of the long arm of chromosome 1 and the presence of Epstein-Barr virus in continuous lines of Burkitt’s lymphoma? C R Acad Sci III. 1984;298:143–145.
    1. Knutsen T. Cytogenetic changes in the progression of lymphoma. Leuk Lymphoma. 1998;31:1–19.
    1. Garcia JL, Hernandez JM, Gutierrez NC, Flores T, Gonzalez D, Calasanz MJ, et al. Abnormalities on 1q and 7q are associated with poor outcome in sporadic Burkitt’s lymphoma. A cytogenetic and comparative genomic hybridization study. Leukemia. 2003;17:2016–2024.
    1. Lones MA, Sanger WG, Le Beau MM, Heerema NA, Sposto R, Perkins SL, et al. Children’s Cancer Group Study CCG-E08. Chromosome abnormalities may correlate with prognosis in Burkitt/Burkitt-like lymphomas of children and adolescents: a report from Children’s Cancer Group Study CCG-E08. J Pediatr Hematol Oncol. 2004;26:169–178.
    1. Heerema NA, Bernheim A, Lim MS, Look AT, Pasqualucci L, Raetz E, et al. Pediatr Blood Cancer; State of the Art and Future Needs in Cytogenetic/Molecular Genetics/Arrays in childhood lymphoma: Summary report of workshop at the First International Symposium on childhood and adolescent non-Hodgkin lymphoma; April 9, 2003; New York City, NY. 2005. pp. 616–622.
    1. Dave BJ, Weisenburger DD, Higgins CM, Pickering DL, Hess MM, Chan WC, et al. Cytogenetics and fluorescence in situ hybridization studies of diffuse large B-cell lymphoma in children and young adults. Cancer Genet Cytogenet. 2004;153:115–121.
    1. Patte C, Auperin A, Michon J, Behrendt H, Leverger G, Frappaz D, et al. The Société Française d’Oncologie Pédiatrique LMB89 protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood. 2001;97:3370–3379.
    1. Lones MA, Auperin A, Raphael M, McCarthy K, Perkins SL, MacLennan KA, et al. Mature B-cell lymphoma/leukemia in children and adolescents: intergroup pathologist consensus with the revised European-American lymphoma classification. Ann Oncol. 2000;11:47–51.
    1. Shaffer LG, Tommerup N, editors. An International System for Human Cytogenetic Nomenclature. Recommendations of the International Standing Committee on Human Cytogenetic Nomenclature. Basel: S Karger; 2005.
    1. Reiter A, Schrappe M, Tiemann M, Ludwig WD, Yakisan E, Zimmermann M, et al. Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: a report of the Berlin-Frankfurt-Munster Group trial NHL-BFM 90. Blood. 1999;94:3294–3306.
    1. Barin C, Valtat C, Briault S, Bremont JL, Petit A, Lejars O, et al. Structural rearrangements of chromosome 13 as additional abnormalities in Burkitt lymphoma and type 3 acute lymphoblastic leukemia. Cancer Genet Cytogenet. 1992;60:206–209.
    1. Ogden CA, Pound JD, Batth BK, Owens S, Johannessen I, Wood K, et al. Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: implications for Burkitt’s lymphoma. J Immunol. 2005;174:3015–3023.
    1. Calin GA, Liu CG, Sevignani C, Ferracin M, Felli N, Dumitru CD, et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci U S A. 2004;101:11755–11760.
    1. Hummel M, Bentink S, Berger H, Klapper W, Wessendorf S, Barth TF, et al. Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe. A biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling. N Engl J Med. 2006;354:2419–2430.
    1. Dave SS, Fu K, Wright GW, Lam LT, Kluin P, Boerma EJ, et al. Lymphoma/Leukemia Molecular Profiling Project. Molecular diagnosis of Burkitt’s lymphoma. N Engl J Med. 2006;354:2431–2442.
    1. Kawasaki C, Ohshim K, Suzumiya J, Kanda M, Tsuchiya T, Tamura K, et al. Rearrangements of bcl-1, bcl-2, bcl-6, and c-myc in diffuse large B-cell lymphomas. Leuk Lymphoma. 2001;42:1099–1106.
    1. Akasaka T, Akasaka H, Ueda C, Kanda M, Tsuchiya T, Tamura K, et al. Molecular and clinical features of non-Burkitt’s, diffuse large-cell lymphoma of B-cell type associated with the c-MYC/immunoglobulin heavy-chain fusion gene. J Clin Oncol. 2000;18:510–518.
    1. Miles R, Raphael M, McCarthy K, Wotherspoon A, Lones M, Cairo M, et al. Diffuse large B-cell lymphomas in pediatric patients demonstrate a marked predominance of germinal center cell phenotype. Ann Oncol. 2005;16:v 61. abstract.
    1. Oschlies I, Klapper W, Zimmermann M, Krams M, Wacker HH, Burkhardt B, et al. Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Munster) Multicenter Trial. Blood. 2006;107:4047–4052.
    1. Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large B-cell lymphoma. N Engl J Med. 2002;346:1937–1947.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe