Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma

Eva Landmann, Birgit Burkhardt, Martin Zimmermann, Ulrike Meyer, Wilhelm Woessmann, Wolfram Klapper, Grazyna Wrobel, Angelo Rosolen, Marta Pillon, Gabriele Escherich, Andishe Attarbaschi, Auke Beishuizen, Karin Mellgren, Robert Wynn, Richard Ratei, Adriana Plesa, Martin Schrappe, Alfred Reiter, Christophe Bergeron, Catherine Patte, Yves Bertrand, Eva Landmann, Birgit Burkhardt, Martin Zimmermann, Ulrike Meyer, Wilhelm Woessmann, Wolfram Klapper, Grazyna Wrobel, Angelo Rosolen, Marta Pillon, Gabriele Escherich, Andishe Attarbaschi, Auke Beishuizen, Karin Mellgren, Robert Wynn, Richard Ratei, Adriana Plesa, Martin Schrappe, Alfred Reiter, Christophe Bergeron, Catherine Patte, Yves Bertrand

Abstract

In the European Intergroup EURO-LB02 trial, children and adolescents with lymphoblastic lymphoma underwent the non-Hodgkin lymphoma Berlin-Frankfurt-Münster protocol without prophylactic cranial radiotherapy. The primary aims of this trial were to test whether replacing prednisone with dexamethasone during induction increases event-free survival in the subgroups with T-cell lymphoblastic lymphoma and whether therapy duration could be reduced from 24 to 18 months (factorial design, randomizations). These questions could not be answered due to premature closure of the trial. Here we report on the secondary aims of the trial: whether the results of the NHL-BFM90 study could be reproduced and evaluation of disease features and prognostic factors. Three hundred and nineteen patients (66 with precursor B-cell lymphoblastic lymphoma, 233 with T-cell lymphoblastic lymphoma, 12 with mixed phenotype, 8 not classifiable) were enrolled. In induction, 215 patients received prednisone and 104 patients received dexamethasone. The median follow-up was 6.8 years (range, 3.0-10.3). The 5-year event-free survival was 82±2% [12 toxic deaths, 5 secondary malignancies, 43 non-response/relapse (central nervous system n=9; all received prednisone during induction)]. The event-free survival rate was 80±5% for patients with precursor B-cell lymphoblastic lymphoma, 82±3% for those with T-cell lymphoblastic lymphoma, and 100% for patients with a mixed phenotype. During induction, significantly more grade III/IV toxicities were observed in patients receiving dexamethasone, resulting in significant treatment delays. The number of toxic deaths did not differ significantly. The only variable associated with outcome was performance status at diagnosis. The 90% event-free survival rate for patients with T-cell lymphoblastic lymphoma shown in study NHL-BFM90 was not replicated, mainly due to more toxic deaths and central nervous system relapses. Dexamethasone in induction may prevent central nervous system relapse more effectively than prednisone but produces a higher burden of toxicity. (#NCT00275106).

Copyright© 2017 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Consort flow diagram and flow chart of the EURO-LB02 trial. (A) CONSORT flow diagram. *In 11 patients, the diagnosis of T-LBL was subsequently revised (precursor B-cell LBL, n=1; biphenotypic/bilineal LBL, n=5; T-NHL not further classified, n=3; undifferentiated lymphoma, n=2). Six of these patients were randomized. (B) Flow chart of the EURO-LB02 trial. Patients with precurcor B-cell-LBL received the standard arm. *Resulting in a total therapy duration of 18 or 24 months.
Figure 2.
Figure 2.
The 5-year event-free survival (EFS, from diagnosis) of protocol patients with T-cell, precursor B-cell and biphenotypic lymphoblastic lymphoma. EFS: event-free survival SE: standard error. The median time to an event was 0.9 and 2.3 years (P=0.21) in patients suffering from T-LBL and pB-LBL, respectively.

References

    1. Abromowitch M, Sposto R, Perkins S, et al. Shortened intensified multi-agent chemotherapy and non-cross resistant maintenance therapy for advanced lymphoblastic lymphoma in children and adolescents: report from the Children’s Oncology Group. Br J Haematol. 2008;143(2):261–267.
    1. Amylon MD, Shuster J, Pullen J, et al. Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study. Leukemia. 1999;13(3):335–342.
    1. Burkhardt B, Woessmann W, Zimmermann M, et al. Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol. 2006;24(3):491–499.
    1. Pillon M, Piglione M, Garaventa A, et al. Long-term results of AIEOP LNH-92 protocol for the treatment of pediatric lymphoblastic lymphoma: a report of the Italian Association of Pediatric Hematology and Oncology. Pediatr Blood Cancer. 2009;53(6):953–959.
    1. Reiter A, Schrappe M, Ludwig WD, et al. Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood. 2000;95(2):416–421.
    1. Sandlund JT, Pui CH, Zhou Y, et al. Effective treatment of advanced-stage childhood lymphoblastic lymphoma without prophylactic cranial irradiation: results of St Jude NHL13 study. Leukemia. 2009;23(6):1127–1130.
    1. Uyttebroeck A, Suciu S, Laureys G, et al. Treatment of childhood T-cell lymphoblastic lymphoma according to the strategy for acute lymphoblastic leukaemia, without radiotherapy: long term results of the EORTC CLG 58881 trial. Eur J Cancer. 2008;44(6):840–846.
    1. Burkhardt B, Reiter A, Landmann E, et al. Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma: a report from the Berlin-Frankfurt-Muenster group. J Clin Oncol. 2009;27(20):3363–3369.
    1. Bonn BR, Huge A, Rohde M, et al. Whole exome sequencing hints at a unique mutational profile of paediatric T-cell lymphoblastic lymphoma. Br J Haematol. 2015;168(2):308–13.
    1. Burkhardt B, Moericke A, Klapper W, et al. Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact. Leuk Lymphoma. 2008;49(3):451–461.
    1. Feng H, Stachura DL, White RM, et al. T-lymphoblastic lymphoma cells express high levels of BCL2, S1P1, and ICAM1, leading to a blockade of tumor cell intravasation. Cancer Cell. 2010;18(4):353–366.
    1. Minard-Colin V, Brugieres L, Reiter A, et al. Non-Hodgkin lymphoma in children and adolescents: progress through effective collaboration, current knowledge, and challenges ahead. J Clin Oncol. 2015;33(27): 2963–2974.
    1. Conter V, Bartram CR, Valsecchi MG, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 2010;115(16):3206–3214.
    1. Schrappe M, Valsecchi MG, Bartram CR, et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011;118(8): 2077–2084.
    1. Reiter A, Schrappe M, Tiemann 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(10):3294–3306.
    1. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. Wiley, New York, 1980.
    1. Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16(3):1141–1154.
    1. Cox DR. Regression models and life-tables. J R Stat Soc B. 1972;34(2):187–220.
    1. Common Toxicity Criteria V 2, 1999. NC.
    1. De Moerloose B, Suciu S, Bertrand Y, et al. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood. 2010;116(1):36–44.
    1. Hurwitz CA, Silverman LB, Schorin MA, et al. Substituting dexamethasone for prednisone complicates remission induction in children with acute lymphoblastic leukemia. Cancer. 2000;88(8):1964–1969.
    1. Igarashi S, Manabe A, Ohara A, et al. No advantage of dexamethasone over prednisolone for the outcome of standard- and intermediate-risk childhood acute lymphoblastic leukemia in the Tokyo Children’s Cancer Study Group L95-14 protocol. J Clin Oncol. 2005;23(27):6489–6498.
    1. Vrooman LM, Stevenson KE, Supko JG, et al. Postinduction dexamethasone and individualized dosing of Escherichia coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study–Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol. 2013;31(9):1202–1210.
    1. Moricke A, Zimmermann M, Valsecchi MG, et al. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016;127(17):2101–2112.
    1. Termuhlen AM, Smith LM, Perkins SL, et al. Disseminated lymphoblastic lymphoma in children and adolescents: results of the COG A5971 trial: a report from the Children’s Oncology Group. Br J Haematol. 2013;162(6):792–801.
    1. Bergeron C, Coze C, Segura C, et al. Treatment of childhood T-cell lymphoblastic lymphoma-long-term results of the SFOP LMT96 trial. Pediatr Blood Cancer. 2015;62(12):2150–2156.
    1. Schrappe M, Zimmermann M, Moricke A, et al. Dexamethasone in induction can eliminate one third of all relapses in childhood acute lymphoblastic leukemia (ALL): results of an international randomized trial in 3655 patients (Trial AIEOP-BFM ALL 2000). ASH Annual Meeting Abstracts. 2008;112(11):7.
    1. Bostrom BC, Sensel MR, Sather HN, et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group. Blood. 2003;101(10):3809–3817.
    1. Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO. Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol. 2005;129(6):734–745.
    1. Ito C, Evans WE, McNinch L, et al. Comparative cytotoxicity of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. J Clin Oncol. 1996;14(8):2370–2376.
    1. Kaspers GJ, Veerman AJ, Popp-Snijders C, et al. Comparison of the antileukemic activity in vitro of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. Med Pediatr Oncol. 1996;27(2):114–121.
    1. Balis FM, Lester CM, Chrousos GP, Heideman RL, Poplack DG. Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia. J Clin Oncol. 1987;5(2):202–207.
    1. Larsen EC, Devidas M, Chen S, et al. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children’s Oncology Group study AALL0232. J Clin Oncol. 2016;34(20):2380–2388.
    1. Tubergen DG, Gilchrist GS, O’Brien RT, et al. Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial. J Clin Oncol. 1993;11(3):527–537.
    1. Termuhlen AM, Smith LM, Perkins SL, et al. Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children’s Oncology Group trial A5971: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2012;59(7):1229–1233.
    1. Oschlies I, Burkhardt B, Chassagne-Clement C, et al. Diagnosis and immunophenotype of 188 pediatric lymphoblastic lymphomas treated within a randomized prospective trial: experiences and preliminary recommendations from the European childhood lymphoma pathology panel. Am J Surg Pathol. 2011;35(6):836–844.
    1. Gerr H, Zimmermann M, Schrappe M, et al. Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations. Br J Haematol. 2010;149(1):84–92.
    1. Bonn BR, Rohde M, Zimmermann M, et al. Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood. 2013;121(16):3153–3160.
    1. Callens C, Baleydier F, Lengline E, et al. Clinical impact of NOTCH1 and/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma. J Clin Oncol. 2012;30(16):1966–1973.
    1. Burkhardt B, Bruch J, Zimmermann M, et al. Loss of heterozygosity on chromosome 6q14-q24 is associated with poor outcome in children and adolescents with T-cell lymphoblastic lymphoma. Leukemia. 2006;20(8): 1422–1429.
    1. Coustan-Smith E, Sandlund JT, Perkins SL, et al. Minimal disseminated disease in childhood T-cell lymphoblastic lymphoma: a report from the Children’s Oncology Group. J Clin Oncol. 2009;27(21):3533–3539.
    1. Mussolin L, Buldini B, Lovisa F, et al. Detection and role of minimal disseminated disease in children with lymphoblastic lymphoma: the AIEOP experience. Pediatr Blood Cancer. 2015;62(11):1906–1913.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe