Key Treatment Questions in Childhood Acute Lymphoblastic Leukemia: Results in 5 Consecutive Trials Performed by the ALL-BFM Study Group From 1981 to 2000

M. Schrappe; A. Möricke; A. Reiter; G. Henze; K. Welte; H. Gadner; W.-D. Ludwig; J. Ritter; J. Harbott; G. Mann; T. Klingebiel; B. Gruhn; C. Niemeyer; B. Kremens; F. Niggli; K.-M. Debatin; R. Ratei; M. Stanulla; R. Beier; G. Cario; A. Schrauder; M. Zimmermann

doi:10.1055/s-0033-1337966

Klin Padiatr 2013; 225(S 01): S62-S72
DOI: 10.1055/s-0033-1337966

Zum 80. Geburtstag von Prof. Riehm

Key Treatment Questions in Childhood Acute Lymphoblastic Leukemia: Results in 5 Consecutive Trials Performed by the ALL-BFM Study Group From 1981 to 2000

Kernfragen der Behandlung von akuten lymphoblastischen Leukämien im Kindesalter: Ergebnisse aus 5 konsekutiven Studien der ALL-BFM-Studiengruppe von 1981 bis 2000

M. Schrappe

¹Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany

,

A. Möricke

¹Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany

,

A. Reiter

²Department of Pediatric Hematology and Oncology, University Children’s Hospital, Giessen, Germany

,

G. Henze

³Department of Pediatric Hematology and Oncology, Charité, Humboldt University, Berlin, Germany

,

K. Welte

⁴Department of Pediatric Hematology and Oncology, Medizinische Hochschule, Hannover, Germany

,

H. Gadner

⁵Department of Pediatrics, St. Anna Kinderspital, Vienna, Austria

,

W.-D. Ludwig

⁶Department. of Hematology, Oncology, and Tumor Immunology, Robert-Rössle-Clinic, HELIOS Medical Center Berlin-Buch, Germany

,

J. Ritter

⁷Department of Pediatric Hematology and Oncology, University Children’s Hospital, Münster, Germany

,

J. Harbott

⁸Oncogenetic Laboratory, University Children’s Hospital, Giessen, Germany

,

G. Mann

⁵Department of Pediatrics, St. Anna Kinderspital, Vienna, Austria

,

T. Klingebiel

⁹Department of Pediatric Hematology and Oncology, University Children’s Hospital, Frankfurt, Germany

,

B. Gruhn

¹⁰Department of Pediatric Hematology and Oncology, University Children’s Hospital, Jena, Germany

,

C. Niemeyer

¹¹Department of Pediatric Hematology and Oncology, University Children’s Hospital, Freiburg, Germany

,

B. Kremens

¹²Department of Pediatric Hematology and Oncology, University Children’s Hospital, Essen, Germany

,

F. Niggli

¹³Department of Pediatric Hematology and Oncology, University Children’s Hospital, Zürich, Switzerland

,

K.-M. Debatin

¹⁴Department of Pediatric Hematology and Oncology, University Children’s Hospital, Ulm, Germany

,

R. Ratei

⁶Department. of Hematology, Oncology, and Tumor Immunology, Robert-Rössle-Clinic, HELIOS Medical Center Berlin-Buch, Germany

,

M. Stanulla

¹Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany

,

R. Beier

⁴Department of Pediatric Hematology and Oncology, Medizinische Hochschule, Hannover, Germany

,

G. Cario

¹Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany

,

A. Schrauder

¹Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany

,

M. Zimmermann

⁴Department of Pediatric Hematology and Oncology, Medizinische Hochschule, Hannover, Germany

› Institutsangaben

Abstract

Between 1981 and 2000, 6 609 children (<18 years of age) were treated in 5 consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria, and Switzerland. Probability of 10-year event-free survival (survival) improved from 65% (77%) in study ALL-BFM 81–78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: 1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk ALL patients and eliminated in non-high-risk non-T-ALL patients, if it was replaced by high-dose and intrathecal methotrexate; 2) omission of delayed reintensification severely impaired outcome of low-risk patients; 3) 6 months less maintenance therapy caused an increase in systemic relapses; 4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; 5) condensed induction therapy resulted in a significant improvement of outcome; 6) the daunorubicin dose in induction could be safely reduced in low-risk patients; 7) intensification of consolidation/reintensification treatment led to considerable improvement of outcome in high-risk patients.

Zusammenfassung

In den Jahren von 1981–2000 wurden 6 609 Kinder mit ALL unter 18 Jahren in 5 aufeinander folgenden klinischen Studien der Berlin-Frankfurt-Münster (BFM) Gruppe in bis zu 82 Kliniken in Deutschland, Österreich und der Schweiz behandelt. Die 10 Jahres-Wahrscheinlichkeit des ereignisfreien Überlebens (bzw. Gesamtüberlebens) verbesserte sich von 65% (77%) in Studie ALL-BFM 81 auf 78% (85%) in Studie ALL-BFM 95. Neben der Reduktion der Rezidive fokussierten die Studien durch einen risikoadaptierten Ansatz vor allem auf eine Senkung der akuten und späten Toxizität. Die wichtigsten Ergebnisse dieser Studien waren folgende: 1) Die präventive Schädelbestrahlung konnte bei T-ALL und Hochrisiko-ALL in der Dosis auf 12 Gy reduziert werden und bei allen anderen Patienten sogar eliminiert werden; 2) die Reinduktionstherapie ist selbst bei Niedrigrisiko ALL unverzichtbar; 3) eine um 6 Monate verkürzte Erhaltungstherapie führt zu einem Anstieg von systemischen Rezidiven; 4) das verzögerte Ansprechen auf eine 7-tägige Prednisonvorphase ist ein ungünstiger Prognosefaktor; 5) eine „kondensierte“, also dosisintensivierte Induktionstherapie führt zu einem signifikant besseren Therapieergebnis; 6) die Daunorubicin Dosis konnte bei Niedrigrisiko Patienten sicher gesenkt werden; 7) mit einer Intensivierung der Konsolidierungselemente ließ sich bei Hochrisikopatienten ein erheblich besseres Therapieergebnis erreichen.

Key words

acute lymphoblastic leukemia - ALL - long-term follow-up - prognostic factors

Schlüsselwörter

akute lymphoblastische Leukämie - ALL - Prognosefaktoren - Langzeitergebnisse

Volltext

Referenzen

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