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Proposal of a genetic classifier for risk group stratification in pediatric T-cell lymphoblastic lymphoma reveals differences from adult T-cell lymphoblastic leukemia

Leukemia volume 30, pages 970–973 (2016)Cite this article

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T-cell lymphoblastic lymphoma (T-LBL) represents the second most common subtype of non-Hodgkin’s lymphoma (NHL) in children and adolescents. Current chemotherapy protocols reach event-free survival probabilities (pEFS) of 75–85%,1 and are associated with relevant late effects2, 3 and treatment-related death rates of ∼4%.4 Although reduction of treatment-associated toxicities therefore remains an important aim, poor probabilities of survival in relapsed LBL of 10–15%5 leave no room for treatment de-escalation in frontline protocols. For pediatric acute lymphoblastic leukemia (ALL), risk assessment and treatment stratification have allowed safe treatment de-escalation for low-risk patients and intensification for high-risk patients.6 Limitations in numbers of newly diagnosed patients have impeded evaluation and validation of potential markers for pediatric LBL.

Molecular genetic markers are promising candidates for risk stratification because they represent underlying biological characteristics of the subgroups, and their analyses can be standardized, which is essential for cooperative clinical trials. Recent retrospective molecular studies in T-LBL have shown association of outcome with loss of heterozygosity at chromosome 6q (LOH6q), biallelic T-cell receptor-γ deletions and with FBXW7 and NOTCH1 mutations.1, 7, 8 Here we present the prognostic relevance of mutations in the genes NRAS and KRAS, which have been found highly relevant in T-ALL,9 and in the PTEN gene, which we have recently identified in pediatric T-LBL by whole-exome sequencing.10 We also screened for mutations in PIK3R1 and PIK3CA that, similar to PTEN mutations, can lead to hyperactivated phosphatidylinositol 3-kinase (PI3K)–AKT signaling.11 We analyzed a previously described cohort of 114 pediatric T-LBL patients who have been treated uniformly according to the NHL-BFM (Berlin–Frankfurt–Muenster group) regimen for LBL.1 We then combined these data and results on the prognostic relevance of NOTCH1 mutations and LOH6q published earlier to define a prognostic classifier for risk group stratification in pediatric T-LBL, with the aim of identifying high pEFS patients, for whom therapy reduction might be possible, and patients with poor survival, who might benefit from experimental therapy.

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References

  1. Bonn BR, Rohde M, Zimmermann M, Krieger D, Oschlies I, Niggli F et al. Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood 2013; 121: 3153–3160.

    Article  CAS  Google Scholar 

  2. Wachowski O, Zimmermann M, Burkhardt B, Determann O, Meyer U, Kaatsch P et al. Secondary neoplasms subsequent to Berlin-Frankfurt-Muenster (BFM) therapy of Non-Hodgkin lymphoma of childhood: significantly higher risk for patients with lymphoblastic lymphoma compared to other NHL-subtypes. Blood 2005; 106: 11 (abstract 232).

    Article  Google Scholar 

  3. Landmann E, Burkhardt B, Zimmermann M, Niggli F, Mann G, Reiter A . Osteonecrosis in children with Non-Hodgkin Lymphoma (NHL). Haematol Meet Rep 2009; 3: 87 (abstract 148).

    Google Scholar 

  4. Reiter A, Burkhardt B, Zıimmermann M, Landmann E, Meyer U, Klapper W et al. Results of the European intergroup trial EURO-LB02 on lymphoblastic lymphoma (LBL) in children/adolescents. Br J Haematol 2012; 159: 38 (abstract 69).

    Google Scholar 

  5. Burkhardt B, Reiter A, Landmann E, Lang P, Lassay L, Dickerhoff R 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: 3363–3369.

    Article  Google Scholar 

  6. Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grumayer R, Moricke A 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: 2077–2084.

    Article  CAS  Google Scholar 

  7. Callens C, Baleydier F, Lengline E, Ben Abdelali R, Petit A, Villarese P 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: 1966–1973.

    Article  CAS  Google Scholar 

  8. Burkhardt B, Bruch J, Zimmermann M, Strauch K, Parwaresch R, Ludwig WD 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: 1422–1429.

    Article  CAS  Google Scholar 

  9. Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, Lambert J, Beldjord K, Lengliné E et al. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. J Clin Oncol 2013; 31: 4333–4342.

    Article  CAS  Google Scholar 

  10. Bonn BR, Huge A, Rohde M, Oschlies I, Klapper W, Voss R et al. Whole exome sequencing hints at a unique mutational profile of paediatric T-cell lymphoblastic lymphoma. Br J Haematol 2014; 168: 308–313.

    Article  Google Scholar 

  11. Palomero T, Dominguez M, Ferrando AA . The role of the PTEN/AKT pathway in NOTCH1-induced leukemia. Cell Cycle 2008; 7: 965–970.

    Article  CAS  Google Scholar 

  12. Zuurbier L, Petricoin R, Emanuel F, Vuerhard MJ, Calvert V, Kooi C et al. The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia. Haematologica 2012; 97: 1405–1413.

    Article  CAS  Google Scholar 

  13. Barata JT . The impact of PTEN regulation by CK2 on PI3K-dependent signaling and leukemia cell survival. Adv Enzyme Regul 2011; 51: 37–49.

    Article  CAS  Google Scholar 

  14. Perentesis JP, Bhatia S, Boyle E, Shao Y, Shu XO, Steinbuch M et al. RAS oncogene mutations and outcome of therapy for childhood acute lymphoblastic leukemia. Leukemia 2004; 18: 685–692.

    Article  CAS  Google Scholar 

  15. Bandapalli OR, Zimmermann M, Kox C, Stanulla M, Schrappe M, Ludwig WD et al. NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia. Haematologica 2013; 98: 928–936.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Gabriele Buck (cytomorphology), Bettina Paul and Ulrike Meyer (data management) for their expert work. We also thank Felix Niggli and all other physicians, radiologists, nurses and data managers in the participating centers of the NHL-BFM group who cared for the children and supplied data. This work was supported by ‘Löwenkinder–Verein zur Unterstützung krebskranker Kinder e.V.–Dr Elisabeth Deimann-Veenker, Viersen, Germany’ and ‘Hilfe für das krebs-und schwerstkranke Kind e.V.–Marita Neumann, Paderborn, Germany’. WK und IO are supported by the ‘Kinderkrebsinitiative Buchholz, Holm-Seppensen, Germany’. STB received support from ‘Kinderkrebshilfe Münster e.V., Münster, Germany’.

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Author notes

  1. S T Balbach, O Makarova and B R Bonn: These authors contributed equally to this work.

Authors and Affiliations

  1. Pediatric Hematology and Oncology, University Children’s Hospital, Münster, Germany

    S T Balbach, O Makarova, B R Bonn, C Rössig & B Burkhardt

  2. Pediatric Hematology and Oncology, Medical School Hannover, Hannover, Germany

    M Zimmermann

  3. Pediatric Hematology and Oncology, Justus Liebig University, Giessen, Germany

    M Rohde

  4. Pathology, Hematopathology Section and Lymph Node Registry, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

    I Oschlies & W Klapper

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  1. S T Balbach
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  2. O Makarova
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Correspondence to B Burkhardt.

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Balbach, S., Makarova, O., Bonn, B. et al. Proposal of a genetic classifier for risk group stratification in pediatric T-cell lymphoblastic lymphoma reveals differences from adult T-cell lymphoblastic leukemia. Leukemia 30, 970–973 (2016). https://doi.org/10.1038/leu.2015.203

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