Longer follow-up confirms major improvement in outcome in children and adolescents with Philadelphia chromosome acute lymphoblastic leukaemia treated with continuous imatinib and haematopoietic stem cell transplantation. Results from the Spanish Cooperati

We have previously reported in this journal the major improvement in early outcome in children and adolescents with Philadelphia chromosome acute lymphoblastic leukaemia (Ph+ ALL) treated according to the Spanish Cooperative Paediatric Haematology-Oncology (SHOP) protocol SHOP/ALL-2005 (Rives et al, 2011). We present here an update of this series with longer follow-up (median follow-up of 65 months for the patients of the imatinib cohort). In this protocol, patients received continuous intermediate-dose imatinib (260 mg/m2) from day 15 of induction in combination with intensive chemotherapy, followed by haematopoietic stem cell transplantation (HSCT) from a matched related or unrelated donor. The results of the imatinib cohort (16 patients) were compared to our historical series of patients who received similar treatment but without imatinib (n = 27). In spite of the low number of patients, the difference in outcome was so considerable that it reached statistical significance (3-year event-free survival (EFS) of 78·7% in the imatinib cohort versus 29·6% in the pre-imatinib cohort, P = 0·01). In the imatinib cohort, only three events occurred: one relapse after HSCT and two toxic deaths (one before and the other after HSCT). As patients with Ph+ALL may suffer from late relapses, longer follow-up was needed to ascertain if this improved early outcome was translated into a long-term improvement. Currently, with a median follow-up of 65 months for the patients of the imatinib cohort, no new events have occurred. Fourteen patients are alive, 13 in continuous complete molecular remission and one patient in second complete molecular remission. All patients but one, who died before transplant, underwent HSCT in first complete remission. Only three patients received imatinib post-transplant: one after salvage chemotherapy for haematological relapse, one as a treatment for severe chronic cutaneous graft-versus-host disease and another patient prophylactically after HSCT without evidence of molecular relapse. At 5 years, EFS was 81·3% and 29·6% for the imatinib and pre-imatinib cohorts respectively (P = 0·0035) and overall survival (OS) was 87·5% and 30·8% for the imatinib and pre-imatinib cohorts respectively (P = 0·0017) (Figs 1 and 2). The long-term outcome of paediatric Ph+ALL patients treated with continuous imatinib has not yet been published. In historical controls, in the pre-imatinib era, a 4-year follow-up was deemed necessary to evaluate the efficacy of new treatments for Ph+ALL because most relapses occurred in this time frame (Aricò et al, 2010). In the recently published European Intergroup Study on Post-Induction Treatment with Imatinib followed by HSCT in childhood Ph+ALL (EsPhALL), all the relapses occurred during the first 3 years (Biondi et al, 2012). Thus, we believe that the 5-year EFS and OS reported in the present series of patients may probably be close to their long-term outcome. The American Children's Oncology Group (COG) had previously reported 45 Ph+ALL patients treated with continuous imatinib after remission induction (cohort 5), followed by HSCT only if a matched sibling donor was available (Schultz et al, 2009). The results in their cohort of patients also showed an impressive improvement in early outcome (3-year EFS of 80%). Noteably, these results were achieved even in patients treated with chemotherapy only, without transplantation. Longer follow-up of this series is needed to confirm that patients treated with chemotherapy do not suffer from late relapses. In the adult setting, a clear benefit of HSCT in PhALL+ patients treated with imatinib only emerged with longer follow-up (Thomas, 2012). In the EsPhALL study (Biondi et al, 2012), which included a large series of patients (n = 178), the impact of adding imatinib to chemotherapy compared favourably to historical controls, with better 4-year disease-free survival [61·9% in the EsPhALL study versus 42·3% in the historical cohort (Aricò et al, 2010)]. The improvement in the outcome of these patients, although statistically significant, was inferior to the results achieved with the COG and the SHOP protocols, probably due to the less intensive and intermittent use of imatinib. In addition, good risk patients were randomized to receive or not imatinib. Following the publication of the COG results (Schultz et al, 2009), the EsPhALL protocol was amended in December 2009 in which imatinib was to be given in all patients (good and poor risk patients) in a continuous fashion. The results of this amendment will be of great interest to confirm the major improvement obtained when imatinib or another tyrosine-kinase inhibitor (TKI) is added in a continuous manner early in induction in paediatric patients with Ph+ALL in a larger series of patients. An unresolved question in paediatric Ph+ALL is whether the use of TKI following HSCT should be used prophylactically or pre-emptively (triggered by minimal residual disease) to prevent relapses. Twelve out of 15 patients of the SHOP series who underwent HSCT did not receive imatinib post-HSCT and remain in complete molecular remission. Three patients received imatinib post-HSCT, one after relapse, one prophylactically and one as part of the treatment of severe cutaneous graft-versus-host disease. Although our series of patients is too small to answer this question, it may suggest that prophylactic treatment with imatinib after HSCT might not be necessary. The pre-emptive versus prophylactic use of imatinib after HSCT in the adult setting is not yet clear (Nishiwaki et al, 2010; Ribera et al, 2010) and is currently being addressed in a randomized study conducted by the German Multicentre ALL group, GMALL (Pfeifer et al, 2011). In conclusion, the results of our series of paediatric Ph+ALL patients treated with continuous imatinib concurrently with intensive chemotherapy and followed by HSCT, indicate that major improvement in outcome is maintained with a longer follow-up, with 5-year EFS and OS of 81·3% and 87·5%, respectively. SR was the principal investigator and takes primary responsibility for the paper. SR, JE, PG, AV, MJM, JLV, RF, MM, FL, RL, JU, AF and IB recruited the patients. SR and MC participated in the statistical analysis and SR wrote the paper. The authors report no potential conflicts of interest.