Acute Leukemias in Children with Down Syndrome

Zwaan, C. Michel; Reinhardt, Dirk; Vyas, Paresh

doi:10.1016/j.hoc.2009.11.009

Cited by 43 publications

(27 citation statements)

References 75 publications

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“…Infants with Down syndrome frequently have leukocytosis, neutrophilia, differential shift to the left, and immature forms (blasts) in the blood (myeloproliferative disorder) during the postnatal period [1,6]. In most cases, this change is transient (referred to as transient myeloproliferative disorder); however, some develop acute leukemia.…”

Section: Discussionmentioning

confidence: 99%

Hyperleukocytosis in Newborn: A Diagnosis of Concern

Parvez

Mathew

2013

Indian J Hematol Blood Transfus

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Section: Discussionmentioning

confidence: 99%

Hyperleukocytosis in Newborn: A Diagnosis of Concern

Parvez

Mathew

2013

Indian J Hematol Blood Transfus

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“…16,30 Another plausible explanation for the observed methotrexate toxicity in DS patients could be a gene dosage effect for enzymes found on chromosome 21. 30,31 In particular, the reduced folate carrier gene (RFC), which is responsible for methotrexate transport over the cell-membrane, is localized on chromosome 21q22. 15,32 However, at higher concentrations passive diffusion of methotrexate across the cell-membrane may also occur.…”

Section: Discussionmentioning

confidence: 99%

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

Buitenkamp¹,

Mathôt²,

Haas³

et al. 2010

Haematologica

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BackgroundChildren 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 MethodsWe compared methotrexate-induced toxicity and pharmacokinetics in a retrospective casecontrol 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. ResultsOverall, 468 courses of methotrexate (1-5 g/m 2 ) 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. ConclusionsWe 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/m 2 ) and monitor the patients carefully.Key words: metrotrexate pharmacokinetics, Down syndrome, acute lymphoblastic leukemia, methotrexate.Citation: Buitenkamp TD, Mathôt RAA, de Haas V, Pieters R, and Zwaan CM. Methotrexateinduced side effects are not due to differences in pharmacokinetics in children with Down's syndrome and acute lymphoblastic leukemia. Haematologica 2010;95:01106-1113. doi:10.3324/haematol.2009

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“…Based upon the data described above, a multistep model of leukemogenesis of myeloid leukemias in children with DS has been proposed (Ahmed et al, 2004;Gurbuxani et al, 2004;Cantor, 2005;Hitzler & Zipursky, 2005;Hitzler, 2007;Roy et al, 2009;Zwaan et al, 2010) (Fig. 6).…”

Section: Multistep Model Of Myeloid Leukemogenesis In Children With Dsmentioning

confidence: 99%

“…The genes RUNX1 (alternatively called AML1), BACH1, ETS2 and ERG, all of which are located on chromosome 21 and are associated with megakaryopoiesis, have been suggested to be the candidate genes involved in leukemogenesis of TL and AMKL-DS (Ahmed et al, 2004;Gurbuxani et al, 2004;Cantor, 2005;Hitzler & Zipursky, 2005;Osato & Ito, 2005;Hitzler, 2007;Roy et al, 2009;Zwaan et al, 2010). Translocations and point mutations of RUNX1, leading to loss of function or haploinsufficiency (namely, reduced expression) of RUNX1, have been detected in a variety of human leukemias and are thought to be involved in leukemogenesis .…”

Section: Multistep Model Of Myeloid Leukemogenesis In Children With Dsmentioning

confidence: 99%

Unique Myeloid Leukemias in Young Children with Down Syndrome: Cell Origin, Association with Hematopoietic Microenvironment and Leukemogenesis

Miyauchi¹

2011

Prenatal Diagnosis and Screening for Down Syndrome

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Acute Leukemias in Children with Down Syndrome

Cited by 43 publications

References 75 publications

Hyperleukocytosis in Newborn: A Diagnosis of Concern

Hyperleukocytosis in Newborn: A Diagnosis of Concern

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

Unique Myeloid Leukemias in Young Children with Down Syndrome: Cell Origin, Association with Hematopoietic Microenvironment and Leukemogenesis

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