With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern; a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern; and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively (p < 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments.

2nd Department of Pediatrics Semmelweis University 1094 Budapest Hungary

Central European Institute of Technology Masaryk University 60200 Brno Czech Republic

Centre Oscar Lambret Department of Biostatistics 59020 Lille cedex France

Clinical Research Centre National Hospital Organization Nagoya Medical Center Nagoya 460 0001 Japan

Department of Bone Marrow Transplantation Children Oncology and Hematology Wroclaw Medical University 50 367 Wroclaw Poland

Department of Paediatric Haematology Oncology and Palliative Care Cambridge University Hospitals NHS Foundation Trust Addenbrooke's Hospital Cambridge CB2 0QQ UK

Department of Pathological Anatomy San Bortolo Hospital 36100 Vicenza Italy

Department of Pathology Institut Universitaire du Cancer Toulouse Oncopole France Université Toulouse 3 Paul Sabatier UMR1037 CRCT F 31000 Toulouse France

Department of Pathology University of Cambridge Cambridge CB2 1QP UK

Department of Pediatric Haematology and Oncology Sahlgrenska University Hospital 41685 Gothenburg Sweden

Department of Pediatric Hematology and Oncology Justus Liebig University Giessen 35390 Giessen Germany

Department of Pediatric Hematology and Oncology St Anna Children's Hospital Medical University of Vienna 1090 Vienna Austria

Department of Pediatric Hematology and Oncology University Hospital Muenster D 48149 Muenster Germany

Department of Pediatric Hematology and Oncology University Hospitals Leuven 3000 Leuven Belgium

Department of Pediatrics and Adolescents Oncology Gustave Roussy 94800 Villejuif France

Department of Pediatrics Obstetrics and Gynaecology University of Valencia 46010 Valencia Spain

Division of Pathology Saitama Children's Medical Center Saitama 330 0081 Japan

Institute of Pathology Hematopathology University Hospital Schleswig Holstein D 24105 Kiel Germany

Istituto di Ricerca Pediatrica Città della Speranza 35127 Padua Italy

Maternal and Child Health Department Padua University 35128 Padua Italy

Pediatric Hematology Oncology and Stem Cell Transplant Division Padua University Hospital 35128 Padua Italy

Princess Máxima Center for Pediatric Oncology 3584 CS Utrecht The Netherlands

University Medical Center Hospital Hamburg Eppendorf Pediatric Hematology and Oncology 20246 Hamburg Germany

Zobrazit více v PubMed

Burkhardt B., Zimmermann M., Oschlies I., Niggli F., Mann G., Parwaresch R., Riehm H., Schrappe M., Reiter A., The BFM Group The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br. J. Haematol. 2005;131:39–49. doi: 10.1111/j.1365-2141.2005.05735.x. PubMed DOI

Delsol G. The 2008 WHO lymphoma classification. Ann. Pathol. 2008;28:S20–S24. doi: 10.1016/j.annpat.2008.09.002. PubMed DOI

Le Deley M.C., Reiter A., Williams D., Delsol G., Oschlies I., McCarthy K., Zimmermann M., Brugières L. Prognostic factors in childhood anaplastic large cell lymphoma: Results of a large European intergroup study. Blood. 2008;111:1560–1566. doi: 10.1182/blood-2007-07-100958. PubMed DOI

Brugières L., Le Deley M.C., Rosolen A., Williams D., Horibe K., Wrobel G., Mann G., Zsiros J., Uyttebroeck A., Marky I., et al. Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: Results of a randomized trial of the EICNHL. Group J. Clin. Oncol. 2009;27:897–903. doi: 10.1200/JCO.2008.18.1487. PubMed DOI

Le Deley M.C., Rosolen A., Williams D.M., Horibe K., Wrobel G., Attarbaschi A., Zsiros J., Uyttebroeck A., Marky I.M., Lamant L., et al. Vinblastine in children and adolescents with high-risk anaplastic large-cell lymphoma: Results of the randomized ALCL99-vinblastine trial. J. Clin. Oncol. 2010;28:3987–3993. doi: 10.1200/JCO.2010.28.5999. PubMed DOI

Brugières L., Deley M.C., Pacquement H., Meguerian-Bedoyan Z., Terrier-Lacombe M.J., Robert A., Pondarré C., Leverger G., Devalck C., Rodary C., et al. CD30(+) anaplastic large-cell lymphoma in children: Analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood. 1998;92:3591–3598. PubMed

Alexander S., Kraveka J.M., Weitzman S., Lowe E., Smith L., Lynch J.C., Chang M., Kinney M.C., Perkins S.L., Laver J., et al. Advanced stage anaplastic large cell lymphoma in children and adolescents: Results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: A report from the children’s oncology group. Pediatr. Blood Cancer. 2014;61:2236–2242. doi: 10.1002/pbc.25187. PubMed DOI PMC

Lowe E.J., Sposto R., Perkins S.L., Gross T.G., Finlay J., Zwick D., Abromowitch M. Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: Final results of Children’s Cancer Group Study 5941. Pediatr. Blood Cancer. 2009;52:335–339. doi: 10.1002/pbc.21817. PubMed DOI PMC

Seidemann K., Tiemann M., Schrappe M., Yakisan E., Simonitsch I., Janka-Schaub G., Dorffel W., Zimmermann M., Mann G., Gadner H., et al. Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood. 2001;15:3699–3706. doi: 10.1182/blood.V97.12.3699. PubMed DOI

Williams D.M., Hobson R., Imeson J., Gerrard M., McCarthy K., Pinkerton C.R. Anaplastic large cell lymphoma in childhood: Analysis of 72 patients treated on The United Kingdom Children’s Cancer Study Group chemotherapy regimens. Br. J. Haematol. 2002;117:812–820. doi: 10.1046/j.1365-2141.2002.03482.x. PubMed DOI

Rosolen A., Pillon M., Garaventa A., Burnelli R., d’Amore E.S., Giuliano M., Comis M., Cesaro S., Tettoni K., Moleti M.L., et al. Anaplastic large cell lymphoma treated with a leukemia-like therapy: Report of the Italian Association of Pediatric Hematology and Oncology (AIEOP) LNH-92 protocol. Cancer. 2005;104:2133–2140. doi: 10.1002/cncr.21438. PubMed DOI

Lamant L., McCarthy K., d’Amore E., Klapper W., Nakagawa A., Fraga M., Maldyk J., Simonitsch-Klupp I., Oschlies I., Delsol G., et al. Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: Results of the ALCL99 study. J. Clin. Oncol. 2011;29:4669–4676. doi: 10.1200/JCO.2011.36.5411. PubMed DOI

Mussolin L., Pillon M., d’Amore E.S., Santoro N., Lombardi A., Fagioli F., Zanesco L., Rosolen A. Prevalence and clinical implications of bone marrow involvement in pediatric anaplastic large cell lymphoma. Leukemia. 2005;19:1643–1647. doi: 10.1038/sj.leu.2403888. PubMed DOI

Damm-Welk C., Busch K., Burkhardt B., Schieferstein J., Viehmann S., Oschlies I., Klapper W., Zimmermann M., Harbott J., Reiter A., et al. Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK-positive anaplastic large-cell lymphoma. Blood. 2007;110:670–677. doi: 10.1182/blood-2007-02-066852. PubMed DOI

Ait-Tahar K., Damm-Welk C., Burkhardt B., Zimmermann M., Klapper W., Reiter A., Pulford K., Woessmann W. Correlation of the autoantibody response to the ALK oncoantigen in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with tumor dissemination and relapse risk. Blood. 2010;115:3314–3319. doi: 10.1182/blood-2009-11-251892. PubMed DOI

Mussolin L., Damm-Welk C., Pillon M., Zimmermann M., Franceschetto G., Pulford K., Reiter A., Rosolen A., Woessmann W. Use of minimal disseminated disease and immunity to NPM-ALK antigen to stratify ALK-positive ALCL patients with different prognosis. Leukemia. 2013;27:416–422. doi: 10.1038/leu.2012.205. PubMed DOI

Carbone P.P., Kaplan H.S., Musshoff K., Smithers D.W., Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res. 1971;31:1860–1861. PubMed

Murphy S.B. Classification, staging and end results of treatment of childhood non-Hodgkin’s lymphomas: Dissimilarities from lymphomas in adults. Semin. Oncol. 1980;7:332–339. PubMed

Del Baldo G., Abbas R., Woessmann W., Horibe K., Pillon M., Burke A., Beishuizen A., Rigaud C., Le Deley M.C., Lamant L., et al. Neuro-meningeal relapse in anaplastic large-cell lymphoma: Incidence, risk factors and prognosis—A report from the European intergroup for childhood non-Hodgkin lymphoma. Br. J. Haematol. 2020 doi: 10.1111/bjh.16755. PubMed DOI

Kaplan E.L., Meier P. Nonparametric estimation from incomplete observation. J. Am. Stat. Assoc. 1958;53:457–481. doi: 10.1080/01621459.1958.10501452. DOI

Cox D.R. Regression models and life tables. J. R. Stat. Soc. 1972;34:187–220. doi: 10.1111/j.2517-6161.1972.tb00899.x. DOI

Damm-Welk C., Mussolin L., Zimmermann M., Pillon M., Klapper W., Oschlies I., D’Amore E.S.G., Reiter A., Woessmann W., Rosolen A. Early Assessment of Minimal Residual Disease Identifies Patients at Very High Relapse Risk in NPM-ALK-positive Anaplastic Large-Cell Lymphoma. Blood. 2014;123:334–337. doi: 10.1182/blood-2013-09-526202. PubMed DOI

Larose H., Burke G.A.A., Lowe E.J., Turner S.D. From bench to bedside: The past, present and future of therapy for systemic paediatric ALCL, ALK. Br. J. Haematol. 2019;185:1043–1054. doi: 10.1111/bjh.15763. PubMed DOI

Turner S.D., Lamant L., Kenner L., Brugières L. Anaplastic large cell lymphoma in paediatric and young adult patients. Br. J. Haematol. 2016;173:560–572. doi: 10.1111/bjh.13958. PubMed DOI

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