Long-term follow up of pediatric Philadelphia positive acute lymphoblastic leukemia treated with the EsPhALL2004 study: high white blood cell count at diagnosis is the strongest prognostic factor

Approximately 3-5% of children with acute lymphoblastic leukemia (ALL) present with Philadelphia chromosome (Ph). In the pre-tyrosine kinase inhibitors (TKIs) era, Ph ALL was associated with a poor prognosis. The outcome improved with the use of TKIs. Results of the EsPhALL2004 study (EudraCT 2004-001647-30 and clinicaltrials.gov identifier 00287105) with the use of imatinib mesylate were published with a median follow-up time of 3.1 years; we now report on long-term outcomes and the impact of prognostic factors in this study. This update shows that event-free survival (EFS) is stable after about 4 years, and that white blood cell (WBC) count at diagnosis is the most relevant prognostic factor, in a setting where the large majority of patients receives imatinib and hematopoietic stem cell transplantation (HSCT). Between January 2004 and December 2009, 160 Ph ALL patients were enrolled in the EsPhALL2004 study in the centers of 10 national study groups. Any subject aged 1-17 years, recruited into national frontline trials for ALL, who showed evidence of t(9;22)(q34;q11) translocation was eligible for the study. Ninety patients were defined as good risk (GR; prednisone good response at day 8, or ≤25% bone marrow [BM] blast cells at day 15, or <5% BM blast cells at day 21, and in complete remission (CR) at the end of induction and were randomized to receive (N=46) or not (N=44) imatinib. The remaining 70 poor risk (PR) patients were all given imatinib. Thus, 128 patients overall were given intermittent imatinib, for a total of 10 weeks if transplanted or 18 weeks if treated with chemotherapy only. In total, 130/160 patients underwent HSCT, and some received imatinib postHSCT according to local guidelines. EFS was calculated as the time from diagnosis to first failure, including resistance, relapse, death or second malignant neoplasm (SMN). Disease-free survival (DFS) in GR patients was defined as the time from randomization until relapse, death or SMN, whichever occurred first. Overall survival (OS) considered death as event. Observation periods were censored at the date of last contact when no event was observed. The final follow up was on June 30, 2014. DFS analysis in GR patients was done by intention to treat; a secondary analysis was done of patients as treated. EFS, DFS and OS curves were estimated according to Kaplan-Meier (with Greenwood standard error) and compared with the log-rank test. KaplanMeier plots for comparison of HSCT with chemotherapy alone were adjusted to account for the waiting time to transplantation. To deal with lack of proportional hazards, univariate comparison was performed at predefined time points based on log-log transformation. The impact of age and WBC count on EFS was analyzed with a Cox model, stratified by risk group (GR and PR). The cumulative incidence of relapse (CIR) and death (CID) were estimated adjusting for competing risks of other events and compared with the Gray test. All tests were two sided. All analyses were performed with SAS software (version 9.2).