Impact of age, leukocyte count and day 21-bone marrow response to chemotherapy on the long-term outcome of children with philadelphia chromosome-positive acute lymphoblastic leukemia in the pre-imatinib era: results of the FRALLE 93 study

Abstract

BackgroundWe explored the heterogeneity of philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL) in a study of the effect of early features on prognosis in children. Here we report the long-term results of the FRALLE 93 study conducted in the era before the use of tyrosine kinase inhibitors.MethodsBetween 1993 and 1999, 36 children with Ph1-ALL were enrolled into the FRALLE 93 protocol. After conventional four-drug induction, children were stratified by availability of an HLA-matched sibling.ResultsComplete remission (CR) was observed in 26 children (72%), of which 13 underwent allogeneic bone marrow transplantation (BMT). Thirty-one children were good responders to prednisone, defined on day 8, and 21 were good responders to chemotherapy, defined by day-21 bone marrow (M1). Overall five-year disease-free survival (DFS) was 42 ± 9.7%. Based on multivariate analysis, two groups showed marked differences in five-year outcome: children with age<10, leukocyte count <100,000/mm3 and day-21 M1 marrow had a more favorable prognosis (14 pts: 100% CR, event free survival [EFS]: 57%, overall survival [OS]: 79%), than the high-risk group (22 patients: 55% CR, EFS: 18%, OS: 27%) (p < 0.005). We also observed a non statistically significant difference (p = 0.14) in outcome between these groups for transplanted patients (5-year DFS: 83 ± 14% and 33 ± 15%, respectively).ConclusionAge, leukocyte count and early response to treatment defined by the D21 bone marrow response provide an accurate model for outcome prediction. The combination of available tools such as minimal residual disease assessment with determination of these simple factors could be useful for refining indications for BMT in the current era of tyrosine-kinase inhibitor-based therapy.

Validation of the ‘French Acute Lymphoblastic Leukaemia Study Group FRALLE prognostic index’ for paediatric Philadelphia‐chromosome acute lymphoblastic leukaemia

“…From February 1994 to March 2005, 27 patients were treated with intensive chemotherapy and HSCT from a matched related or unrelated donor (Rives et al, 2011). The disease outcome in our patients was heterogeneous, depending on clinical features at diagnosis and early response to treatment, in line with other series of children with Ph+ALL (Ribeiro et al, 1997;Schrappe et al, 1998;Aricó et al, 2000Aricó et al, , 2010Roy et al, 2005;Gandemer et al, 2009).…”

“…This prognostic index included two presenting features (age < 10 years and white blood cell [WBC] count <100 · 10 9 /l) and early response (less than 5% of blasts in bone marrow on day 21 of induction treatment) for good risk. One third of their patients belonged to the good-risk group and had a 5-year event-free survival (EFS) of 79% (Gandemer et al, 2009). In order to test this prognostic index in an independent cohort of patients we analysed the impact of the FRALLE index in our series of paediatric Ph+ ALL patients.…”

Intermediate dose of imatinib in combination with chemotherapy followed by allogeneic stem cell transplantation improves early outcome in paediatric Philadelphia chromosome‐positive acute lymphoblastic leukaemia (ALL): results of the Spanish Cooperative Group SHOP studies ALL‐94, ALL‐99 and ALL‐2005

“…Patients with Ph+ ALL treated with pre‐imatinib SHOP protocols (ALL/SHOP‐94 and ALL/SHOP‐99) had a similar outcome to those reported in other contemporary protocols from collaborative cooperative groups (Roy et al , 2005; Gandemer et al , 2009; Aricó et al , 2010). The disease outcome in these patients was heterogeneous, depending on the clinical features at diagnosis and early response to treatment, in line with other series of children with Ph+ ALL (Ribeiro et al , 1997; Schrappe et al , 1998; Aricó et al , 2000, 2010; Roy et al , 2005; Gandemer et al , 2009). The median age of this series of patients was slightly younger than that of other paediatric Ph+ ALL and this may have impact on outcome as older age is a known risk factor in this subtype of ALL.…”

“…Philadelphia positive ALL (Ph+ ALL) is a subtype of very high risk ALL in which allogeneic haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) is considered the standard treatment (Aricó et al , 2000, 2010; Satwani et al , 2007). Despite this intensive treatment, relapses prior to and after HSCT are frequent and only 30–50% of these children can be cured with this approach (Schrappe et al , 1998; Aricó et al , 2000; Roy et al , 2005; Gandemer et al , 2009).…”

“…Second generation TKI and minimal residual disease (MRD) determination to guide treatment are now being tested to further improve outcome in these patients (Cazzaniga et al , 2002; Pane et al , 2005; Yanada et al , 2008; Lee et al , 2009; Castillo et al , 2010; Ravandi et al , 2010a,b). Studies focusing on Ph+ ALL in children are scarce due to its rarity (only 3–5% of childhood ALL) (Schrappe et al , 1998; Aricó et al , 2000, 2010; Heerema et al , 2004; Roy et al , 2005; Bhojwani et al , 2009; Gandemer et al , 2009; Schultz et al , 2009) and additional information on indications, dosage, tolerability and efficacy of imatinib in combination with chemotherapy is needed (Barr, 2010). Phase I studies with imatinib as a sole agent in refractory and relapsed Ph+ ALL were promising with a good toxicity profile (Champagne et al , 2004).…”