TEL/AML1 Rearrangement Is Rare in Children with Acute Lymphoblastic Leukemia (ALL) and Down Syndrome (DS). Presenting Features and Treatment Outcome in the Experience of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP).
Authors: Arico Maurizio , Ziino Ottavio , Valsecchi Maria Grazia , Cazzaniga Giovanni , Rizzari Carmelo , Barisone Elena , Biondi Andrea , Casale Fiorina , Locatelli Franco , Nigro Luca Lo , Luciani Matteo , Messina Chiara , Micalizzi Concetta , Parasole Rosanna , Pession Andrea , Santoro Nicola , Testi Anna Maria , Silvestri Daniela , Basso Giuseppe , Masera Giuseppe , Conter Valentino ,   for the AIEOP
Published: October 2019

Abstract
We compared the clinical and biologic features and treatment results of patients with DS-ALL (n=120, 1.9%), compared to those without DS (n=6237), enrolled in the AIEOP trials between 1988 and October 2004. DS patients had significantly more often the following characteristics: female gender (55.0% vs 44.9%, p=0.027), age 10 years or older (28.3 vs 17.7%, p=0.014), high risk by NCI criteria (41.7 vs. 33%, p=0.045); on the contrary significantly less often they belonged to high-risk group according to current stratification (10.8 vs. 20.3%, p=0.017) or had T-lineage immunophenotype (0.8 vs 11.8%, p=<0.001); the distribution of WBC count was not different (p=0.32) except for a mild reduction of cases with very high count (>100K/mm3: 6.6 vs. 10.8%). TEL/AML1 rearrangement was found in only 1 of 44 tested (2.2%). Of the 120 DS patients, 5 died during induction (4.2 vs 1.2% in non-DS), 1 was resistant (0.8 vs 1.4%). Leukemia relapse occurred in 31.6% of DS patients, compared with 24.9% of non-DS: bone marrow 22.5 vs 15.5%, CNS isolated 4.2 vs 3.6%, testis 0.8 vs 1.6%, BM combined 3.3 vs. 3.6%, other site 0.8 vs 0.6%. Death in complete remission occurred in 4.2 vs 2.0%. No second malignancy was reported. Overall, 59.2% of DS patients remained in first remission, compared with 70.2% of non-DS patients. This translated into a probability of EFS (SE) at 10 years of 56.2% (4.8) versus 67.7% (0.6) and a survival of 60.8% (5.0) versus 77.2% (0.6). 57 DS patients were diagnosed <1995: their EFS was 48.3% (6.7) versus 62.1% (0.9) in non-DS; their overall survival was 49% (6.8) versus 71.9% (0.8). For the 63 patients diagnosed ≥1995 EFS was 61.9% (7.5) versus 73.3% (1.1) in non-DS; their overall survival was 76.5% (5.9) versus 84.5% (0.7). According to NCI criteria, DS patients at standard risk had an EFS of 60.2% (6.2) vs 73.4% (0.7); in the 50 patients at high risk EFS was 50.7% (7.5) vs 56.2% (1.2). The presenting features of ALL in children with DS are significantly different from their non-DS counterparts: the usual excess of males is not reproduced, their WBC is less frequently very high, patients are are often older and never younger than 1 year, TEL/AML1 rearrangement as well as T-immunophenotype are very rare or exceptional. Treatment of DS-ALL remains complicated by inherent risk of infectious death not only during induction, while resistance is unusual. Leukemia relapse in the marrow remains the main cause of failure. Although the outcome has been traditionally inferior to that of non-DS patients, modern treatment and support and a more confident approach currently allow to rescue over 75% of such patients.