| Disease |
Acute lymphoblastic leukemia (ALL) associated with Down syndrome (ALL-DS), is predominantly a B lymphoblastic leukemia, with only very rare cases of mature B cell ALL ( Burkitt leukemia) and T-cell ALL. |
| Epidemiology | Trisomy 21 has an incidence of approximately 1 in 700 live births. The frequency of acute lymphoblastic leukemia in Down syndrome (ALL-DS) is estimated at 1 in 300 (Lange, 2000). The incidence of ALL-DS <5 years of age is 40.7 times greater than that in individuals without Down syndrome of the same age; in addition, there remains an increased risk of ALL-DS compared to those without Down syndrome up to the age of 30 years (Hasle et al., 2000). However, unlike those without Down syndrome, ALL -DS usually does not present in patients <1 year of age. |
| Clinics | Other than the lack of presentation in children <1 year of age, ALL-DS has similar clinical features to ALL in children without Down syndrome, including age, sex, presenting white blood cell count, and NCI risk group (Maloney et al., 2010). Some studies identify similar rates of mediastinal masses and central nervous system involvement at diagnosis in those with ALL-DS and those with ALL without Down syndrome, but other studies identified decreased CNS disease and mediastinal masses in those with ALL-DS (Maloney, 2011). |
| Cytology | Blasts are characterized as small to medium in size with high nuclear-to-cytoplasmic ratios, round to irregular nuclei, smooth chromatin, and scant deeply basophilic agranular cytoplasm. |
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| Figure 1: Bone marrow aspirate smears reveal increased blasts which are small to medium in size with high nuclear-to-cytoplasmic ratios, round to irregular nuclei, smooth chromatin, and scant basophilic agranular cytoplasm. Some background maturing myeloid cells are also present in this case. |
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| Pathology | The blasts of ALL-DS usually have an immature B cell phenotype, expressing CD19, CD10, and CD79a. |
| Cytogenetics | The cytogenetics of ALL-DS differs from the cytogenetics in those with ALL not associated with Down syndrome. The children with ALL-DS have a decreased frequency of favorable cytogenetics including high hyperdiploidy, trisomies of chromosomes 4, 10, and 17, and the t(12;21) translocation compared to children without Down syndrome (Maloney et al., 2010; Bruwier and Chantrain, 2012); these ALL-DS children also have a decreased frequency of unfavorable translocations such as t(9;22) and 11q23 (MLL) rearrangements. Overall, these common B-ALL gene rearrangements, which occur at a rate of approximately 60% in non-Down syndrome patients, only occur at a rate of approximately 20% in ALL-DS. Instead, ALL-DS is more likely to have a normal karyotype (with the exception of the constitutional trisomy 21). In those without normal karyotypes, DS-ALL are more likely to be low hyperdiploid, with common acquired changes including +X and/or del(9p) (Forestier et al., 2008; Lundin et al., 2014).
Approximately 50-60% of ALL-DS have been found to have CRLF2 gene rearrangements by FISH or RT-PCR (Mullighan et al., 2009; Hertzberg et al., 2010). The most common rearrangement is a deletion in the pseudoautosomal region 1 (PAR1) of Xp22.33/Yp11 resulting in a fusion between the first noncoding exon on P2RY8 with the entire coding region of CRLF2 ( del(X)(p22.33p22.33)/del(Y)(p11p11)) (Mullighan et al., 2009). Less commonly, CRLF2 rearrangements with IGH (immunoglobulin heavy chain locus) are identified (t(X;14)(p22;q32)/t(Y;14)(p11;q32)). These fusions result in overexpression of CRLF2. Overexpression of CRFL2 has not been found to be correlated with outcome. |
| Genes | JAK2 activating mutations have been found in approximately 20% of ALL-DS, with the most common mutations occurring at or around amino acid R683 in the pseudokinase domain (Bercovich et al., 2008; Kearney et al., 2009; Gaikwad et al., 2009); however, other JAK2 mutations have been identified in ALL-DS, as have mutation in other JAK genes including JAK1 (Mullighan et al., 2009). These JAK2 mutations are found predominantly in those with CRLF2 gene rearrangements. JAK2 mutation status has not been found to correlate with outcome. The JAK2 mutations are thought to act in concert with the CRFL2 gene rearrangements, resulting in cytokine-independent growth and leukemogenesis (Mullighan et al., 2009).
In addition to mutations in the JAK-STAT pathway, mutations in the RAS/receptor tyrosine kinase (RTK) pathway genes such as KRAS and NRAS have been identified at a rate of approximately 35%; these mutations are mutually exclusive of the JAK2 mutations (Nikolaev et al., 2014). However, similar to the JAK2 mutations, the RAS pathway mutations often occur in the setting of CRLF2 rearrangements. Nikolaev et al. (2014) also identified mutations in cohesion complex genes, epigenetic modifiers/remodellers of DNA or chromatin, classical tumor suppressor genes, and lymphoid differentiation factors/markers.
Activating mutations in CRLF2 can also occur, again usually in the setting of CRLF2 gene rearrangements (Hertzberg et al., 2010).
Deletions in IKZF1 are also often found in DS-ALL, estimated at 24-35% (Hertzberg et al., 2010; Buitenkamp et al., 2012), as are deletions in the PAX5 gene (12-22%) (Kearney et al., 2009; Lundin et al., 2012; Buitenkamp et al., 2012). Patients with an IKZF1 deletion or a PAX5 deletion have decreased overall survival compared to those without these deletions (Buitenkamp et al., 2012). |
| Treatment | ALL-DS is treated similarly to ALL in those without Down syndrome. However, some additional modifications and supportive care guidelines are often employed in their treatment, including the use of discontinuous dexamethasone during delayed intensification and adding leucovorin rescue after intrathecal methotrexate (Maloney, 2011). Down syndrome patients have increased susceptibility to methotrexate, with higher rates of mucositis, gastrointestinal toxicity, and hepatotoxicity. Some trials have decreased the methotrexate dosage, increasing the dose only if tolerated. Additionally, Down syndrome patient have a higher risk of hyperglycemia after corticosteroids and asparaginase therapy due to alterations in glucose metabolism. |
| Prognosis | In some studies, children with ALL-DS have been found to have poorer outcomes than children with ALL without Down syndrome, sometimes demonstrating increased induction failures, higher relapse rates, and increased therapy-related mortality. The poorer outcomes are thought to be due, at least in part, to increased sensitivity to methotrexate side effects, and increased susceptibility to infection. The latter susceptibilities are thought to be enhanced by the inherent immunodeficiencies of Down syndrome. However, more recently, with appropriate prognostic group identification based upon favorable and unfavorable cytogenetic features, ALL-DS has been found to have comparable outcomes to ALL not associated with Down syndrome (Maloney et al., 2010; Maloney, 2011). In addition, Buitenkamp et al., 2014 found favorable prognostic factors to include diagnosis < 6 years of age and a WBC <10 x 109/L.
In those who relapse, ALL-DS has a lower event-free survival and lower overall survival compared to those with ALL without Down syndrome, usually due to induction deaths and treatment-related mortality (Meyr et al., 2013). These relapses usually occur late (more than 6 months after completion of therapy) (Meyr et al., 2013; Buitenkamp et al., 2014).
In those who undergo a hematopoietic cell transplant (HCT), post-transplant relapse often occurs, with a probability of 54% within 3 years in one cohort, with an overall survival at 3 years of 29% (Hitzler et al., 2014). |
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