A Treatment Protocol with Imatinib and Intensive Chemotherapy for Pediatric Philadelphia Positive Acute Lymphoblastic Leukemia: A Single-Arm, Intergroup Study (Esphall 2010)

Abstract

Background. EsPhALL2004 study showed a 10% advantage in DFS for short, discontinuous use of imatinib after induction in Ph ALL patients receiving BFM therapy and HSCT. Other contemporary studies showed an advantage from continuous protracted exposure to imatinib challenging the indications to transplant. Methods. Patients aged 1-17 years were enrolled in EsPhALL2010 trial and received imatinib 300/mg/m2 continuously from day 15 of induction, during chemotherapy. MRD was measured by IG/TR. Eligibility to HSCT depended on early morphological response and MRD. Imatinib was recommended throughout the first year after transplant. Findings. 155 evaluable patients were registered between 2010-2014. 151 (97%) achieved CR1 after induction and 4 after consolidation phase IB. 59 patients (38%) underwent HSCT in CR1. The 5-year EFS and OS were 57·0 (SE 4·1) and 71.8 (SE 3·8), respectively. The 5-year cumulative incidence of relapse was 26·9% (SE 3·7, 8 relapses in 59 transplanted patients and 32 relapses in 96 patients who received chemotherapy). In patients MRD negative at end of IB, there were no relapses in those transplanted (N=17) and 9 relapses in those (N=30) treated with chemotherapy. In patients with positive MRD at end of IB, 5 relapses each occurred in 15 transplanted and 12 not transplanted patients. WBC count at diagnosis ≥100x109/L was associated with a poor prognosis (HR 3·47, 95% CI 1·74-6·89, p=0·0004). Interpretation. Imatinib given since day 15 of induction markedly improved CR rates to 97% from 78% in EsPhALL2004. Though HSCT rates were significantly lower (38% versus 81%), outcomes were similar in the two studies: 5-year EFS and survival were 57·0% and 71·8% versus 60·3% and 71·6%, respectively. WBC ≥100x109/L was the most relevant independent prognostic factor. Funding. Projet Hospitalier de Recherche Clinique-Cancer and Novartis (France); Bloodwise and CRUK (UK). Wellcome-DBT Margdarshi fellowship (VS). MH CZ- DRO, 00064203 (Czech Republic). AIRC 5‰, Ref. 21147 (AB). AIRC2013, ID 14634 (MGV). Conflict of interest statements. No conflicts of interest have been declared by the authors. Ethics approval statement: EsPhALL2010 is a prospective, single arm trial derived from an amendment of the EsPhALL2004 protocol (EudraCT No. 2004-001647-30) which was approved by the ethics committee of each participating institution in ten national study groups (AIEOP, BFM-G/CH, COALL, French ALL-group, NOPHO, MRC, DCOG, CPH, PINDA, and HKPHOSG).