Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study

Abstract

SummaryBackgroundTrials of imatinib have provided evidence of activity in adults with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (ALL), but the drug's role when given with multidrug chemotherapy to children is unknown. This study assesses the safety and efficacy of oral imatinib in association with a Berlin–Frankfurt–Munster intensive chemotherapy regimen and allogeneic stem-cell transplantation for paediatric patients with Philadelphia-chromosome-positive ALL.MethodsPatients aged 1–18 years recruited to national trials of front-line treatment for ALL were eligible if they had t(9;22)(q34;q11). Patients with abnormal renal or hepatic function, or an active systemic infection, were ineligible. Patients were enrolled by ten study groups between 2004 and 2009, and were classified as good risk or poor risk according to early response to induction treatment. Good-risk patients were randomly assigned by a web-based system with permuted blocks (size four) to receive post-induction imatinib with chemotherapy or chemotherapy only in a 1:1 ratio, while all poor-risk patients received post-induction imatinib with chemotherapy. Patients were stratified by study group. The chemotherapy regimen was modelled on a Berlin–Frankfurt–Munster high-risk backbone; all received four post-induction blocks of chemotherapy after which they became eligible for stem-cell transplantation. The primary endpoints were disease-free survival at 4 years in the good-risk group and event-free survival at 4 years in the poor-risk group, analysed by intention to treat and a secondary analysis of patients as treated. The trial is registered with EudraCT (2004-001647-30) and ClinicalTrials.gov, number NCT00287105.FindingsBetween Jan 1, 2004, and Dec 31, 2009, we screened 229 patients and enrolled 178: 108 were good risk and 70 poor risk. 46 good-risk patients were assigned to receive imatinib and 44 to receive no imatinib. Median follow-up was 3·1 years (IQR 2·0–4·6). 4-year disease-free survival was 72·9% (95% CI 56·1–84·1) in the good-risk, imatinib group versus 61·7% (45·0–74·7) in the good-risk, no imatinib group (p=0·24). The hazard ratio (HR) for failure, adjusted for minimal residual disease, was 0·63 (0·28–1·41; p=0·26). The as-treated analysis showed 4-year disease-free survival was 75·2% (61·0–84·9) for good-risk patients receiving imatinib and 55·9% (36·1–71·7) for those who did not receive imatinib (p=0·06). 4-year event-free survival for poor-risk patients was 53·5% (40·4–65·0). Serious adverse events were much the same in the good-risk groups, with infections caused by myelosuppression the most common. 16 patients in the good-risk imatinib group versus ten in the good-risk, no imatinib group (p=0·64), and 24 in the poor-risk group, had a serious adverse event.InterpretationOur results suggests that imatinib in conjunction with intensive chemotherapy is well tolerated and might be beneficial for treatment of children with Philadelphia-chromosome-positive ALL.FundingProjet Hospitalier de Recherche Clinique-Cancer (France)...

Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

“…38,39 Subsequently, several studies explored the efficacy of incorporating imatinib into frontline chemotherapy regimens. 15,16,19,[40][41][42][43][44] In one of the first clinical trials combining imatinib with chemotherapy (the hyperCVAD regimen), we reported a complete remission rate of 100% in patients treated with active disease and a 2-year DFS rate of 85%. 17 There were no unexpected toxicities from the addition of imatinib mesylate to the regimen and the outcomes were superior to historical outcomes with chemotherapy alone.…”

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis

“…14 For infants and patients with bcr-abl rearrangement after 2005, indications of HSCT were as described in the INTERFANT and ESPHALL trials. 15,16 Patients with relapsed ALL were treated according to the risk stratification of BFM relapses protocols. 17 For AML patients in CR1, HSCT was recommended for all patients with monosomy 5 or 7, translocation t(6,9) and mixed lineage leukemia rearrangement, except for translocation t(9,11) with related or unrelated donors, and was performed in other cases with matched sibling donors (MSDs) only, except for patients with translocation t (8,21).…”

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

“…103 The paradigm for precision medicine in leukemia is the use of ABLclass TKIs in chronic myeloid leukemia and combination therapy with TKIs and chemotherapy in Ph1 ALL. 104,105 Although important questions remain in Ph1 ALL (including the optimal TKI, the optimal chemotherapy backbone, the length of TKI therapy, the role of allogeneic hematopoietic stem cell transplantation in first remission, and the role of TKIs after hematopoietic stem cell transplantation), any patient diagnosed with Ph1 ALL in the United States or western Europe will receive a TKI as part of therapy. There is consequently enthusiasm to extend TKI therapy to Ph-like ALL, but it is critical to determine whether kinase-activating alterations are similar drivers to BCR-ABL1; that is, to show that they arise early in disease development, that they are present in all subclones at all stages of disease, and that the leukemia is dependent upon continued activity of the mutant kinase.…”