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135 Daunorubicin or Not During the Induction Treatment of Childhood Standard-Risk B-Cell Precursor Acute Lymphoblastic Leukemia (SR-BCP-ALL): The Randomized Fralle 2000-A ProtocolClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemia - Therapy, excluding Transplantation: Clinical Trials
Sunday, December 9, 2012: 5:00 PM
A103, Level 1, Building A (Georgia World Congress Center)

Andre Baruchel, MD1,2, Arnaud Petit3*, Thierry Leblanc4*, Gérard Michel5*, Yves Perel, MD, PhD6*, Francoise Mechinaud, MD7*, Virginie Gandemer8, Claudine Schmitt, MD9*, Pascale Schneider10*, Benoit Brethon, MD11*, Anne Auvrignon12*, Caroline Thomas, M.D.13*, Geneviève Margueritte14*, Christiane Vermylen, MD, PhD15, Odile Lejars, MD16*, Isabelle Pellier17*, Claire Berger, MD18*, Gérard Couillault19*, Catherine Paillard20*, Christian Berthou, MD21*, Christophe Piguet, MD22*, Brigitte Pautard, MD23*, Jean Soulier, MD, PhD24, Nathalie Grardel25*, Kheira Beldjord26*, Marie-Francoise Auclerc27*, Elizabeth Macintyre, MD, PhD28, Jean-Michel Cayuela, PhD29*, Sylvie Chevret30* and Guy Leverger, MD31*

1Department of Pediatric Hematology, Robert Debré Hospital, AP-HP, Paris, France
2UFR de Médecine, University Paris-Diderot, Paris, France
3hopital Trousseau, hematologie et oncologie pediatrique, Paris, France
4Dept. of Pediatric Hematology, Robert Debré hospital, APHP, Paris, France
5Service de Pédiatre et Hématologie Pédiatrique, Hôpital de la Timone Enfants, Marseille, France
6Pediatric Hematology Unit, CHU Bordeaux, Bordeaux, France
7Pediatric Oncology Unit, University Hospital, Nantes, France
8CHU-Hopital Sud, Department of Pediatric Hematology/Oncology, Rennes, France
9Pediatric Hematology Oncology, CHU de Nancy, Vandoeuvre, France
10Immuno-Hématologie Pédiatrique, CHU, Rouen, France
11Pediatric Hematology, Hopital Robert Debre APHP, Paris, France
12Pediatric Oncology, Hopital Trousseau, Paris, France
13Hematology Dpt., CHU de Nantes, Nantes, France
14CHU Montpellier pédiatrie, Montpellier, France
15Dept. of Pediatric Hematology, Cliniques Universitaires Saint Luc, 1200 Brussels, Belgium
16Pediatric Oncology, CHU, TOURS
17Centre Hospitalier Universitaire Angers, Angers, France
18Pediatric Oncology, CHU, Saint-Etienne, France
19Immuno-Hématologie-Oncologie Pédiatrique, CHU, Dijon, France
20CHU Estaing, Centre de cancérologie et thérapie cellulaire pédiatrique INSERM CIC501, Clermont-ferrand, France
21Hematology, Brest University Hospital, Brest, France
22Pediatric Hemato-Oncology, CHU Limoges, Limoges, France
23Pediatric Hematology/Oncology, Univ. Hospital Amiens, Amiens, France
24Hematology laboratory, Saint-Louis Hospital, Paris, France
25CHRU Lille, Université Lille, Lille, France
26Hematology Laboratory, CHU Saint-Louis, PARIS, France
27centre hayem-Hopital Saint louis, Paris, France
28Hôpital Necker-Enfants Malades, AP-HP and University Paris 5 CNRS UMR8147, Paris, France
29Laboratoire Central d'Hematologie, Hopital Saint-Louis, Paris, France
30Biostatistics, Hôpital Saint-Louis, AP-HP, Université Paris 7, Paris, France
31Pediatric Haematology and Oncology Unit, Hopital Trousseau, Paris, France

From December 2000 to June 2010, 1201 children with SR-BCP-ALL (age: 1-9 years, WBC<50 G/L, CNS-, no MLL rearrangement, no BCR-ABL, no Down syndrome) were included in the FRALLE 2000-A multicenter protocol. At a MFU of 60 months, 1195 patients are evaluable. An ETV6-RUNX1 fusion transcript was documented in 28% of the pts (329 out of 1173 evaluable pts). Induction regimen: prednisone prephase +IT MTX, dexamethasone (DEX) 6 mg/m2/d, vincristine (VCR), native E.coli L-asparaginase ASPA: 6000 IU/m2 x 9 infusions). Response was assessed at D8 (blood, good if < 1000 blasts/mm3), D21 (bone marrow morphology, good if less than 5% blasts, so-called M1) and end of induction D35 (bone marrow morphology and DNA-based PCR for Ig/TCR rearrangements MRD). A D21 M1 marrow was observed in 1132 pts (94.7%). Out of these, 1128 pts were randomized to receive daunorubicin (DNR; 40 mg/m2 at D22 and D29) [560 DNR(+) pts] or not [568 DNR(-) pts]. Pts with D21 M2/M3 marrow (n= 61; 5%) were not randomized and received two infusions of DNR. Two pts died before D21. Pts with D21 M1 marrow (A1 group) received after induction a 12 week-consolidation based on VCR, DEX, mercaptopurine (6-MP) and oral methotrexate (MTX), followed by a 1st delayed intensification (reduced “Protocol II”, including a total of 75 mg/m2 of doxorubicin), an interphase therapy (VCR, DEX, 6-MP, MTX), and a triple drug only-2nd delayed intensification (DI°2) (VCR, MTX 100 mg/m2, ASPA 20000 IU/m2; 4 cycles). A 24-month maintenance was then applied, including 12 VCR-DEX pulses the first year. A total of 18 intrathecal injections of MTX was given. Only the rare patients with D21 M3 marrow and/or EOI MRD level ≥1% (n= 47, 4%)(A3 group) received an intensified treatment after CR with 3 block-consolidation, intensified interphase with 6 cycles of MTX 5 g/m2  and a second DI (“reduced protocol II”). No pt received CNS irradiation.


1. Overall efficacy:  no leukemic induction failure was observed; 4 induction deaths (0.3%) occurred leading to a 99.7% CR rate. Only 30 out 1097 evaluable pts (2.7%) had a decisional EOI MRD ≥ 1%. Eighty-two relapses have been observed (BM: 47, CNS+: 24, BM+CNS: 9, testis: 2). For the whole population 5-year EFS is 91.5% (95%CI: 89.8-93.3), 5-year OS is 97.4% (95%CI: 96.4-98.4). 5-yr EFS and OS for the A1 and A3 groups are 93.1% vs. 61.2% (p<0.0001), and 98.3% vs. 84.2% respectively (p<0.0001). Five-year DFS of the 30 pts with MRD ≥1% is 58.8% (95%CI: 41.7-82.8). Five-year EFS of the children with ETV6-RUNX1 fusion transcript is 96.6% (95%CI: 94.4-98.8).

2. Overall toxicity: 5 non leukemic deaths have been observed after CR (0.4%). Other main toxicities were attributable to ASPA (CNS thrombosis: 1.5%, grade 3-4 pancreatitis: 0.8%, allergic reaction-all grades- during DI °2: 70%). Six cases of secondary neoplasms were observed (AML: 5 pts, astrocytoma: 1 pt).

3. Randomization: 5y EFS and OS from randomization was 92.9% and 97.2% for D21 M1 pts DNR(+) versus 93.3% and 98.2% for D21 M1 DNR(-) pts (p= 0.89 and p= 0.85, respectively). Interestingly EOI MRD levels in the two arms were not different at the sensitivity cut-off of 10-2 (p=0.93) or 10-3(p= 0.74).

4. Prognostic factors: for the whole population, age < 6 years, WBC < 20.000/mm3, ETV6-RUNX1 positivity, as well as D21 marrow M1 and EOI MRD levels of 10-2 and 10-3 were all associated to EFS in univariate analysis. In multivariate analysis remain only WBC < 20.000/mm3 (p=.001), ETV6-RUNX1 positivity (p=.02), EOI MRD levels ≤ 10-3 (p=1.4x10-5). Considering only randomized pts (D21M1 pts) age <6 (p=.004), WBC < 20.000/mm3 (p=.04), ETV6-RUNX1 positivity (p=.01), EOI MRD levels ≤ 10-3(p=.002) remain as independent prognostic factors in multivariate analysis.


Very good results were obtained with this VCR-DEX-ASPA oriented protocol. SR-BCP ALL pts which represents around 55 % of all children with ALL can be cured with a modest dose of anthracyclin (75 mg/m2). A further decrease in therapy based on the identified prognostic factors could be proposed. Intensification of the chemotherapy for the rare SR pts with a very high MRD has salvaged half of these pts but the addition of new drugs and/or HSCT is now to be evaluated.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH