Impact of therapy in a cohort of unselected children with Down Syndrome‐associated Acute Lymphoblastic Leukaemia

Down syndrome (DS) children account for approximately 3% of children with acute lymphoblastic leukaemia (ALL) and 5–8% of children with acute myeloid leukaemia (AML) (Maloney et al, 2010). Most reports indicate that DS-ALL patients fare worse than their nonDS counterparts (Buitenkamp et al, 2014). We describe therapy for ALL in 92 unselected children with DS registered in the French Leukaemia Registry between 1990 and 2008. DS patients were allocated to either a reduced-dose chemotherapy regimen (RD) or a standard dose (SD) on a case-by-case basis. RD was defined as an omission of anthracyclines, dose reduction of high dose methotrexate (HD-MTX), >25% dose reduction of all drugs, switch to the lowest risk group treatment, or treatment according to FRALLE 2000A1 specific recommendations for DS ALL. Early response was evaluated at day 8 as either prednisone good response (PGR) (<1 9 10/l circulating blasts) or poor response (PPR) (≥1 9 10/l circulating blasts). Induction death (ID) was defined as death within 42 days following diagnosis. Treatment-related mortality (TRM) was death occurring ≥42 days after diagnosis in patients in remission, unrelated to refractory or progressive disease. Ninety-two children from 30 institutions were registered; 53 cases were diagnosed between 1990 and 1999 (Table I). The male/female ratio was 0 8 (42/50). The median age at diagnosis was 5 2 years [interquartile range (IQR) 25–75 (3 17–9 44)]. No central nervous system (CNS) involvement was observed. Immunophenotype analysis according to the European Group for the Immunological classification of Leukaemias (EGIL) recommendations showed predominance of B-II (73 9%), B-III (14 1%). ETV6/RUNX1 transcript was identified in 5 cases of t(12;21) and in five additional patients; nine patients presented hyperdiploidy above 50 chromosomes. No DS patient showed BCR-ABL1 or AFF1-KMT2A aberrations. 82/84 (97 6%) evaluable patients were PGR and two were PPR. 88/92 (95 9%) achieved complete remission (CR) after induction. ID rate was 3 3%. Toxic deaths were due to congenital heart disease (n = 2) and multi-organ failure (n = 1). Six children died in first CR (CR1) due to MTX toxicity (n = 2) or infectious disease (n = 4). 26 1% of children relapsed at a median time of 29 months [IQR 25–75 (19–42)], of whom three have been cured. Fifty-one patients were given SD therapy and 37 were given RD therapy. There was no difference between these groups with respect to antecedents, sex, median age at diagnosis, CNS status, white blood cell count (WBC) or immunophenotype. Moreover, there was no significant difference in terms of relapse rate, ID and TRM. According to the period of treatment (before or after 2000), the combined proportion of events due to ID and TRM was not statistically different (5 7% (3/53) and 17 9% (7/39) respectively). Similarly, the relapse rate wasn’t significantly for the two time periods (before 2000, 32 1%; after 2000, 15 4%. In this cohort, 34 grade 3–4 infections were recorded during induction and 66 during post-induction therapy. No chronic cardiac failure was evidenced with a cumulative doxorubicin-equivalent dose of 175 mg/m2 (75–220) and a 5 6year median follow-up. Transient diabetes mellitus (DM) occurred in 18/77 (23 4%) evaluable patients and 13 required insulin therapy, mostly during the induction phase with a significantly different incidence in patients treated with dexamethasone [8/22 (36 4%)] versus those treated with prednisone [10/62 (16 1%)] (P < 0 05). 139 courses of HD-MTX (1 5–8 g/m2) were given in 39 patients, 12 of them (30 9%) had a grade 3/4 mucositis and 4 had a severe cutaneous toxicity. Event-free survival (EFS) and overall survival (OS) at five years were 64 1% and 73 6% respectively (Fig. 1). Univariate analysis showed that gender, age, leucocyte count, National Cancer Institute classification, bulky disease, immunophenotyping and cytogenetics had no significant impact. With an intention-to-treat analysis at five years, OS and EFS were not statistically different between RD and SD (70 3% vs. 75% and 64 3% vs. 66% respectively). However risk of relapse in patients with hyperploidy or ETV6/RUNX1 abnormalities was lower than that of the remaining patients (10 5% vs. 30 5%; P = 0 05). This study confirms previously reported characteristics of DS-ALL children, including a slightly higher age at diagnosis (Buitenkamp et al, 2014), female predominance, no infant leukaemia or T-ALL (Garcia-Bernal et al, 2010; Whitlock et al, 2005) and dismal outcome (Whitlock, 2006; Xavier & Taub, 2010; Buitenkamp et al, 2012). With a 64 1% EFS rate, the prognosis of ALL in our experience and in other series (Patrick et al, 2014) remains significantly worse than in non-DS children, due to an increased risk of relapse (26 4% relapse rate) and increased lethal toxicity (3 4% ID rate and 6 8% death rate in CR1). correspondence