Clinical Relevance of Genetic Alterations in Acute Lymphoblastic Leukemia in Children with Down syndrome

__Abstract__ Hematopoiesis encompasses the process by which mature peripheral blood cells are generated by differentiation of hematopoietic stem cells (HSC) in the bone marrow (BM). The daughter cells of HSC’s, progenitor cells, can each commit to the myeloid or lymphoid differentiation pathways that lead to the production of one or more specific types of mature blood cells. These cells are then released in the peripheral blood. The myeloid lineage generates platelets, erythrocytes, granulocytes (basophils, neutrophils and eosinophils) and monocytes, whereas the lymphoid lineage differentiates into T and B-lymphocytes

Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with down syndrome and acute lymphoblastic leukemia

Background Children with Down syndrome have an increased risk of developing acute lymphoblastic leukemia and a poor tolerance of methotrexate. This latter problem is assumed to be caused by a higher cellular sensitivity of tissues in children with Down syndrome. However, whether differences in pharmacokinetics play a role is unknown. Design and Methods.We compared methotrexate-induced toxicity and pharmacokinetics in a retrospective case-control study between patients with acute lymphoblastic leukemia who did or did not have Down syndrome. Population pharmacokinetic models were fitted to data from all individuals simultaneously using non-linear mixed effect modeling. Results. Overall, 468 courses of methotrexate (1-5 g/m2) were given to 44 acute lymphoblastic leukemia patients with Down syndrome and to 87 acute lymphoblastic leukemia patients without Down syndrome. Grade 3-4 gastrointestinal toxicity was significantly more frequent in the children with Down syndrome than in those without (25.5% versus 3.9%; P=0.001). The occurrence of grade 3-4 gastrointestinal toxicity was not related to plasma methotrexate area under the curve. Methotrexate clearance was 5% lower in the acute lymphoblastic leukemia patients with Down syndrome (P=0.001); however, this small difference is probably clinically not relevant, because no significant differences in methotrexate plasma levels were detected at 24 and 48 hours. Conclusions We did not find evidence of differences in the pharmacokinetics of methotrexate between patients with and without Down syndrome which could explain the higher frequency of gastrointestinal toxicity and the greater need for methotrexate dose reductions in patients with Down syndrome. Hence, these problems are most likely explained by differential pharmacodynamic effects in the tissues between children with and without Down syndrome. Although the number of patients was limited to draw conclusions, we feel that it may be safe in children with Down syndrome to start with intermediate dosages of methotrexate (1-3 g/m2) and monitor the patients carefully

Acute lymphoblastic leukemia in children with Down syndrome: A retrospective analysis from the Ponte di Legno study group

Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt- Münster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% ± 2% vs 15% ± 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% ± 1% vs 2.0% ± <1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% ± 2% vs 81% ± 2%, P < .0001) and overall survival (74% ± 2% vs 89% ± 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 3 109/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DSALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups. (Blood. 2014; 123(1):70-77)