Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children's Cancer Group study

Abstract

We assessed the outcome of children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) receiving contemporary risk-based therapy by evaluating clinical and biologic features and outcome of children with ALL, with or without DS, enrolled in Children's Cancer Group (CCG) protocols between 1983 and 1995. Comparison of characteristics of children with ALL with (ALL-DS; n ‫؍‬ 179) or without (ALL-NDS; n ‫؍‬ 8268) DS showed no differences in initial white blood cell (WBC) count, central nervous system disease, and risk group. Children with ALL-DS did not present with unfavorable translocations and were older than 1 year of age at diagnosis with ALL. Eventfree (56% vs 74%; P < .001) and diseasefree (55% vs 73%; P < .001) survival at 10 years was significantly lower in the standard-risk ALL-DS population compared with ALL-NDS, but not in high-risk ALL-DS population (event-free survival, 62% vs 59%; P ‫؍‬ .9; disease-free survival, 64% vs 59%; P ‫؍‬ .9), and these differences persisted regardless of treatment era (early era [1983][1984][1985][1986][1987][1988][1989] vs recent era [1989][1990][1991][1992][1993][1994][1995]

Outcome and toxicity of chemotherapy for acute lymphoblastic leukemia in children with down syndrome

“…We found that EFS was significantly lower in the DS ALL group than in matched controls and that the difference was most marked in patients with high-risk ALL and those treated during the earlier era, which included the majority of DS cases (14 of 16) with high-risk ALL. Similarly, Whitlock et al noted the most significant improvements of survival for children with ALL and DS particularly in the high-risk group during the most recent treatment era [18].…”

“…Although adverse prognostic features of ALL in children without DS, such as infant leukemia, T cell phenotype, CNS involvement and high-risk cytogenetic abnormalities are underrepresented in children with DS and ALL [6,8,18,19], the OS rate for the latter group, particularly after standard risk ALL, remains inferior [5,6,18]. We found that EFS was significantly lower in the DS ALL group than in matched controls and that the difference was most marked in patients with high-risk ALL and those treated during the earlier era, which included the majority of DS cases (14 of 16) with high-risk ALL.…”

Frequency and prognostic implications of JAK 1-3 aberrations in Down syndrome acute lymphoblastic and myeloid leukemia

“…Furthermore, the prognosis of DS ALL patients is at best similar and often inferior to that of non-DS ALL patients. 4 Janus kinases (JAK) belong to a family of intracellular nonreceptor protein tyrosine kinases that transduce cytokinemediated signals through the STAT family of transcription factors. JAK has an important role in regulating the processes of cell proliferation, differentiation and apoptosis in response to growth factors.…”

“…2 The acquired genetic aberrations in T-ALL include chromosomal translocations (frequently involving TCR) as well as gene rearrangements and mutations resulting in abnormal expression of genes such as NOTCH1, TAL1, HOX11, HOX11L2, LMO1 and LMO2. 4 Acquired NOTCH1 mutations are present in B50% of T-ALL cases. 5 NOTCH1 signaling is crucial for several steps in T-cell differentiation and also acts on proliferation and survival of these cells.…”

“…Therefore, the mutational activation of this gene is an important factor in T-ALL pathogenesis. 4 In one case of T-ALL, NOTCH1 mutation was pre-natal and preceded SIL-TAL fusion, 6 suggesting that it might, at least in some cases, be an early and initiating genetic lesion. Animal models reveal that NOTCH1 mutations can initiate T-cell leukemia 7 or arise as secondary, genetic lesions.…”