Page 18 - Haematologica May 2022

Ferrata Storti Foundation
Haematologica 2022 Volume 107(5):1026-1033
Clofarabine increases the eradication of minimal residual disease of primary B-precursor acute lymphoblastic leukemia compared to high-dose cytarabine without improvement of outcome. Results from the randomized clinical trial 08-09 of the Cooperative Acute Lymphoblastic Leukemia Study Group.
Gabriele Escherich,1 Udo zur Stadt,1 Arndt Borkhardt,2 Dagmar Dilloo,3 Jörg Faber,4 Tobias Feuchtinger,5 Thomas Imschweiler,6 Norbert Jorch,7 Arnulf Pekrun,8 Irene Schmid,5 Franziska Schramm,1 Michael Spohn,9,10 Martin Zimmermann11 and Martin A Horstmann1,9
1Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg- Eppendorf, Hamburg; 2Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty Duesseldorf, Duesseldorf; 3Department of Pediatric Hematology/Oncology, University Hospital Bonn, Bonn; 4Department of Pediatric Hematology/Oncology, University Hospital Mainz, Mainz; 5Dr. Von Hauner Children's Hospital, Ludwig Maximilian University, Munich; 6Department of Pediatric Hematology and Oncology, Helios Hospital, Krefeld; 7Department of Pediatric Hematology and Oncology, Protestant Hospital of Bethel Foundation, Bielefeld; 8Department of Pediatric Hematology and Oncology, Hospital Bremen-Mitte, Bremen; 9Research Institute Children’s Cancer Center Hamburg, Hamburg; 10Bioinformatics Core Unit, University Medical Center Hamburg, Hamburg and 11Department of Pediatric Hematology and Oncology, Medical School Hannover, Hannover, Germany
ABSTRACT
Novel treatment strategies are needed to improve cure for all chil- dren with acute lymphoblastic leukemia (ALL). To this end, we investigated the therapeutic potential of clofarabine in primary ALL in trial CoALL 08-09 (clinicaltrials gov. identifier: NCT01228331). The primary study objective was the minimal residual disease (MRD)- based comparative assessment of cytotoxic efficacies of clofarabine 5x40 mg/m2 versus high-dose cytarabine (HIDAC) 4x3g/m2, both in combina- tion with PEG-ASP 2,500 IU/m2 as randomized intervention in early con- solidation. The secondary objective was an outcome analysis focused on treatment arm dependence and MRD after randomized intervention. In B-cell precursor (BCP)-ALL, eradication of MRD was more profound after clofarabine compared to cytarabine, with 93 versus 79 of 143 ran- domized patients per arm reaching MRD-negativity (c2 test P=0.03, left- sided P [Fisher’s exact test]=0.04). MRD status of BCP-ALL after random- ized intervention maintained its prognostic relevance, with a significant impact on event-free survival (EFS) and relapse rate. However, no differ- ence in outcome regarding EFS and overall survival (OS) between ran- domized courses was observed (5-year EFS: clofarabine 85.7, SE=4.1 vs. HIDAC 84.8, SE=4.7 [P=0.96]; OS: 95.7, SE=1.9 vs. 92.2, SE=3.2 [P=0.59]), independent of covariates or overall risk strata. Severe toxici- ties between randomized and subsequent treatment elements were also without significant difference. In conclusion, clofarabine/PEG-ASP is effective and safe, but greater cytotoxic efficacy of clofarabine compared to HIDAC did not translate into improved outcomes indicating a lack of surrogacy of post-intervention MRD at the trial level as opposed to the patient level, which hampers a broader implementation of this regimen in the frontline treatment of ALL.
Acute Lymphoblastic Leukemia
Correspondence:
GABRIELE ESCHERICH
escherich@uke.de
MARTIN A. HORSTMANN
horstmann@uke.de
Received: June 1, 2021. Accepted: July 16, 2021. Pre-published: August 5, 2021.
https://doi.org/10.3324/haematol.2021.279357 ©2022 Ferrata Storti Foundation
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