Download PDF
Klin Padiatr 2014; 226(06/07): 338-343
DOI: 10.1055/s-0034-1387795
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Minimal Residual Disease–based Treatment is Adequate for Relapse-prone Childhood Acute Lymphoblastic Leukemia with an intrachromosomal amplification of chromosome 21: The experience of the ALL-BFM 2000 trial

Eine auf der minimalen Resterkrankung basierende Risikostratifizierung ist adäquat zur Behandlung von Kindern mit akuter lymphoblastischer Leukämie und einer intrachromosomalen Amplifikation am Chromosom 21: Erfahrungen aus der ALL-BFM 2000 Studie
A. Attarbaschi
1   Department of pediatric Hematology and Oncology, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
,
R. Panzer-Grümayer
2   Children’s Cancer Research Institute (CCRI), Vienna, Austria
,
G. Mann
1   Department of pediatric Hematology and Oncology, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
,
A. Möricke
3   Department of Pediatric Hematology and Oncology, Children’s University Hospital, University Hospital Schleswig-Holstein, Campus Kiel, Germany
,
M. König
2   Children’s Cancer Research Institute (CCRI), Vienna, Austria
,
A. Mecklenbräuker
2   Children’s Cancer Research Institute (CCRI), Vienna, Austria
,
A. Teigler-Schlegel
4   Department of Pediatric Hematology and Oncology, Oncogenetic Laboratory, Justus-Liebig-University, Giessen, Germany
,
J. Bradtke
5   Institute of Pathology, Justus-Liebig-University, Giessen, Germany
,
J. Harbott
4   Department of Pediatric Hematology and Oncology, Oncogenetic Laboratory, Justus-Liebig-University, Giessen, Germany
,
G. Göhring
6   Institute of Cell and Molecular Pathology, Medical School of Hannover, Hannover, Germany
,
M. Stanulla
7   Department of Pediatric Hematology and Oncology, Medical School of Hannover, Hannover, Germany
,
M. Schrappe
3   Department of Pediatric Hematology and Oncology, Children’s University Hospital, University Hospital Schleswig-Holstein, Campus Kiel, Germany
,
M. Zimmermann
7   Department of Pediatric Hematology and Oncology, Medical School of Hannover, Hannover, Germany
,
O. A. Haas
1   Department of pediatric Hematology and Oncology, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
2   Children’s Cancer Research Institute (CCRI), Vienna, Austria
,
on behalf of the Austrian and German ALL-BFM (Berlin-Frankfurt-Münster) Study Group › Author Affiliations
Further Information

Publication History

Publication Date:
28 November 2014 (online)

Also available at
    Permissions and Reprints

Abstract

Background: Recently, the UK CCLG and COG reported that an intrachromosomal amplification of chromosome 21 (iAMP21) in acute lymphoblastic leukemia (ALL) loses its adverse prognostic impact with intensified therapy.

Patient and Methods: We evaluated the prognosis of iAMP21 among patients from the ALL-BFM (Berlin-Frankfurt-Münster) 2000 trial with 46 of 2 637 (2%) patients iAMP21+.

Results: 8-year event-free-survival (EFS, 64±8% vs. 81±1%, p=0.0026) and cumulative incidence of relapse (CIR, 29±8% vs. 14±1%, p=0.008) of the iAMP21 cases were significantly worse compared with non-iAMP21 patients. Within the MRD low-risk group, iAMP21 cases (n=14) had an inferior 8-year EFS (76±12% vs. 92±1%, p=0.0081), but no increased CIR (10±10% vs. 6±1%, p=0.624). Within the MRD intermediate-risk group, iAMP21 cases (n=27) had a worse 8-year EFS (56±11% vs. 78±2%, p=0.0077) and CIR (44±11% vs. 20±2%, p=0.003) with 6/10 relapses occurring after 2 years.

Conclusions: Conclusively, we believe that there is no necessity for enrolling all iAMP21 patients into the high-risk arm of ongoing ALL-BFM trials because MRD low-risk patients have a moderate relapse risk under current therapy. Whether the increased relapse risk in MRD intermediate-risk patients can be avoided by late treatment intensification remains to be answered by the AIEOP-BFM ALL 2009 trial randomly using protracted pegylated L-asparaginase during delayed intensification and early maintenance.

Zusammenfassung

Hintergrund: In 2 rezenten Publikationen der UK CCLG und der COG ist gezeigt worden, dass die intrachromosomale Amplifikation am Chromosom 21 (iAMP21) ihre ungünstige Prognose mit einer intensivierten Therapie verliert.

Patients und Methoden: Wir evaluierten die Prognose von iAMP21 innerhalb einer Kohorte von 2 637 Patienten aus der ALL-BFM (Berlin-Frankfurt-Münster) 2000 Studie, wobei 46 Patienten (2%) iAMP21+ waren.

Ergebnisse: Das 8-Jahres Ereignisfreie Überleben (EFS) (64±8% vs. 81±1%, p=0.0026) und die kumulative Inzidenz an Rezidiven (29±8% vs. 14±1%, p=0.008) der iAMP21 Patienten waren signifikant schlechter im Vergleich zu den non-iAMP21 Patienten. Innerhalb der MRD Low-risk Gruppe (n=14) hatten iAMP21 Patienten eine ungünstigere 8-Jahres EFS Rate (76±12% vs. 92±1%, p=0.0081), aber keine erhöhte Rezidivinzidenz (10±10% vs. 6±1%, p=0.624). Innerhalb der MRD Intermediate-risk Gruppe (n=27) hatten iAMP21 Patienten eine ungünstigere 8-Jahres EFS Rate (56±11% vs. 78±2%, p=0.0077) und erhöhte Rezidivinzidenz (44±11% vs. 20±2%, p=0.003), wobei 6 von 10 Rezidiven nach 2 Jahren zu beobachten waren.

Schlussfolgerungen: Schlussfolgernd glauben wir, dass derzeit kein Anlass besteht, sämtliche iAMP21 Patienten in den Hochrisikoarm laufendender ALL-BFM Studien einzuschließen, da MRD Low-risk Patienten mit der derzeitigen Therapie nur ein moderates Rezidivrisiko haben. Ob sich das erhöhte Rezidivrisiko der MRD Intermediate-risk Patienten mittels einer späten Therapieintensivierung vermeiden lässt, wird sich vielleicht innerhalb der AIEOP-BFM ALL 2009 zeigen können, in welcher pegylierte L-Asparaginase protrahiert während der späten Intensivierung und frühen Dauertherapie randomisiert verwendet wird.

Key words

iAMP21 - minimal residual disease - relapse - prognosis

Schlüsselwörter

iAMP21 - minimale Resterkrankung - Rezidiv - Prognose

Supplementary Material

 

  • References

  • 1 Attarbaschi A, Mann G, Konig M et al. Incidence and relevance of secondary chromosome abnormalities in childhood TEL/AML1+ acute lymphoblastic leukemia: an interphase FISH analysis. Leukemia 2004; 18: 1611-1616
    CrossrefPubMedSearch in Google Scholar
  • 2 Attarbaschi A, Mann G, Panzer-Grumayer R et al. Minimal residual disease values discriminate between low and high relapse risk in children with B-cell precursor acute lymphoblastic leukemia and an intrachromosomal amplification of chromosome 21: the Austrian and German acute lymphoblastic leukemia Berlin-Frankfurt-Munster (ALL-BFM) trials. J Clin Oncol 2008; 26: 3046-3050
    CrossrefPubMedSearch in Google Scholar
  • 3 Attarbaschi A, Morak M, Cario G et al. Treatment outcome of CRLF2-rearranged childhood acute lymphoblastic leukaemia: a comparative analysis of the AIEOP-BFM and UK NCRI-CCLG study groups. Br J Haematol 2012; 158: 772-777
    CrossrefPubMedSearch in Google Scholar
  • 4 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: 3206-3214
    CrossrefPubMedSearch in Google Scholar
  • 5 Dorge P, Meissner B, Zimmermann M et al. IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica 2013; 98: 428-432
    CrossrefPubMedSearch in Google Scholar
  • 6 Flohr T, Schrauder A, Cazzaniga G et al. Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia 2008; 22: 771-782
    CrossrefPubMedSearch in Google Scholar
  • 7 Harewood L, Robinson H, Harris R et al. Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases. Leukemia 2003; 17: 547-553
    CrossrefPubMedSearch in Google Scholar
  • 8 Harrison CJ, Moorman AV, Schwab C et al. An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome. Leukemia. 2013
    PubMedSearch in Google Scholar
  • 9 Heerema NA, Carroll AJ, Devidas M et al. Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk children’s oncology group studies: a report from the children’s oncology group. J Clin Oncol 2013; 31: 3397-3402
    CrossrefPubMedSearch in Google Scholar
  • 10 Mitchell C, Payne J, Wade R et al. The impact of risk stratification by early bone-marrow response in childhood lymphoblastic leukaemia: results from the United Kingdom Medical Research Council trial ALL97 and ALL97/99. Br J Haematol 2009; 146: 424-436
    CrossrefPubMedSearch in Google Scholar
  • 11 Mitchell CD, Richards SM, Kinsey SE et al. 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: 734-745
    CrossrefPubMedSearch in Google Scholar
  • 12 Moorman AV, Richards SM, Robinson HM et al. Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). Blood 2007; 109: 2327-2330
    CrossrefPubMedSearch in Google Scholar
  • 13 Moorman AV, Robinson H, Schwab C et al. Risk-directed treatment intensification significantly reduces the risk of relapse among children and adolescents with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21: a comparison of the MRC ALL97/99 and UKALL2003 trials. J Clin Oncol 2013; 31: 3389-3396
    CrossrefPubMedSearch in Google Scholar
  • 14 Nachman JB, Sather HN, Sensel MG et al. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 1998; 338: 1663-1671
    CrossrefPubMedSearch in Google Scholar
  • 15 Pichler H, Reismuller B, Steiner M et al. The inferior prognosis of adolescents with acute lymphoblastic leukaemia (ALL) is caused by a higher rate of treatment-related mortality and not an increased relapse rate--a population-based analysis of 25 years of the Austrian ALL-BFM (Berlin-Frankfurt-Munster) Study Group. Br J Haematol 2013; 161: 556-565
    CrossrefPubMedSearch in Google Scholar
  • 16 Prucker C, Attarbaschi A, Peters C et al. Induction death and treatment-related mortality in first remission of children with acute lymphoblastic leukemia: a population-based analysis of the Austrian Berlin-Frankfurt-Munster study group. Leukemia 2009; 23: 1264-1269
    CrossrefPubMedSearch in Google Scholar
  • 17 Robinson HM, Harrison CJ, Moorman AV et al. Intrachromosomal amplification of chromosome 21 (iAMP21) may arise from a breakage-fusion-bridge cycle. Genes Chromosomes Cancer 2007; 46: 318-326
    CrossrefPubMedSearch in Google Scholar
  • 18 Seibel NL, Steinherz PG, Sather HN et al. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood 2008; 111: 2548-2555
    CrossrefPubMedSearch in Google Scholar
  • 19 van der Does-van den Berg A, Bartram CR, Basso G et al. Minimal requirements for the diagnosis, classification, and evaluation of the treatment of childhood acute lymphoblastic leukemia (ALL) in the “BFM Family” Cooperative Group. Med Pediatr Oncol 1992; 20: 497-505
    CrossrefPubMedSearch in Google Scholar
  • 20 van Dongen JJ, Seriu T, Panzer-Grumayer ER et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998; 352: 1731-1738
    CrossrefPubMedSearch in Google Scholar