Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study

Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study

1. Martin Schrappe1,*,
2. Maria Grazia Valsecchi2,*,
3. Claus R. Bartram3,
4. André Schrauder1,
5. Renate Panzer-Grümayer4,
6. Anja Möricke1,
7. Rosanna Parasole5,
8. Martin Zimmermann6,
9. Michael Dworzak4,
10. Barbara Buldini7,
11. Alfred Reiter8,
12. Giuseppe Basso7,
13. Thomas Klingebiel9,
14. Chiara Messina7,
15. Richard Ratei10,
16. Giovanni Cazzaniga11,
17. Rolf Koehler3,
18. Franco Locatelli12,
19. Beat W. Schäfer13,
20. Maurizio Aricò14,
21. Karl Welte6,
22. Jacques J.M. van Dongen15,
23. Helmut Gadner4,
24. Andrea Biondi11,16,†, and
25. Valentino Conter16,17,†

+ Author Affiliations

1. ¹Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany;
2. ²Medical Statistics Unit, Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy;
3. ³Institute of Human Genetics, Ruprecht-Karls University, Heidelberg, Germany;
4. ⁴Children's Cancer Research Institute and St Anna Kinderspital, Wien, Austria;
5. ⁵Department of Pediatrics Hemato-Oncology, Ospedale Pausillipon, Napoli, Italy;
6. ⁶Department of Pediatric Hematology and Oncology, Medical School Hannover, Hannover, Germany;
7. ⁷Pediatric Hemato-Oncology, Department of Pediatrics “Salus Pueri,” University of Padova, Padova, Italy;
8. ⁸Pediatric Hematology and Oncology, University Hospital Giessen, Giessen, Germany;
9. ⁹Pediatric Hematology and Oncology, University Hospital, Frankfurt, Germany;
10. ¹⁰Hematology/Oncology, Robert-Rössle-Klinik at the HELIOS Klinikum, Charité, Berlin, Germany;
11. ¹¹Centro M. Tettamanti, Clinica Pediatrica Università Milano-Bicocca, Monza, Italy;
12. ¹²Department of Pediatric Hemato-Oncology, Ospedale Bambin Gesù, Rome, University of Pavia, Pavia, Italy;
13. ¹³Pediatric Oncology, University Children's Hospital Zürich, Zürich, Switzerland;
14. ¹⁴Department of Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer, Firenze, Italy;
15. ¹⁵Department.of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands;
16. ¹⁶Department of Pediatrics, University of Milano-Bicocca, Ospedale S. Gerardo, Monza, Italy; and
17. ¹⁷Department of Pediatrics, Ospedali Riuniti, Bergamo, Italy

 

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Abstract

The prognostic value of MRD in large series of childhood T-ALL has not yet been established. Trial AIEOP-BFM-ALL 2000 introduced standardized quantitative assessment of MRD for stratification, based on immunoglobulin and TCR gene rearrangements as polymerase chain reaction targets: Patients were considered MRD standard risk (MRD-SR) if MRD was negative at day 33 (time point 1 [TP1]) and day 78 (TP2), analyzed by at least 2 sensitive markers; MRD intermediate risk (MRD-IR) if positive either at day 33 or 78 and < 10⁻³ at day 78; and MRD high risk (MRD-HR) if ≥ 10⁻³ at day 78. A total of 464 patients with T-ALL were stratified by MRD: 16% of them were MRD-SR, 63% MRD-IR, and 21% MRD-HR. Their 7-year event-free-survival (SE) was 91.1% (3.5%), 80.6% (2.3%), and 49.8% (5.1%) (P < .001), respectively. Negativity of MRD at TP1 was the most favorable prognostic factor. An excellent outcome was also obtained in 32% of patients turning MRD negative only at TP2, indicating that early (TP1) MRD levels were irrelevant if MRD at TP2 was negative (48% of all patients). MRD ≥ 10⁻³ at TP2 constitutes the most important predictive factor for relapse in childhood T-ALL. The study is registered at http://www.clinicaltrials.gov/; “Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia,” protocol identification #NCT00430118 for BFM and #NCT00613457 for AIEOP.

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Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study