Down syndrome is a genetic disorder caused by trisomy 21 and is associated with an increased risk of certain leukemias. Transient abnormal myelopoiesis (TAM) occurs in 10% of newborns with Down syndrome and involves increased peripheral blood blasts. It typically resolves spontaneously within 3 months. Acute myeloid leukemia (AML) develops in 20-30% of children with a history of TAM and usually occurs 1-3 years later. AML in Down syndrome most commonly involves megakaryoblasts and is associated with mutations in the GATA1 gene. While chemotherapy is needed to treat AML, reduced intensity protocols can be used due to greater toxicity risks in Down syndrome patients.

1. DOWN SYNDROME
RELATED
LEUKEMIAS

2. Introduction
A genetic disorder involving an extra copy of chromosome 21
(trisomy 21) that is d/t :
1. Improper separation of chromosome 21 (non-disjunction)
95%
2. Translocation : no. of chromosomes in each cell remains 46
but there is an extra copy of Ch 21 that attaches itself on Ch 14.
4%
3. Mosaicism when there are 2 types of cells in body i.e. one with
normal no. of chromosome 21 & one with 3 copies of ch 21. 1%

4. ■ Incidence 1 in 1000 - 1100 live births worldwide.
■ Symptoms include intellectual disabilities, distinct facial
features, developmental delay, congenital heart diseases,
alzheimers disease, GI malformations , poor immune system &
leukemias.

5. DS related leukemias
■ TAMTransient abnormal myelopoiesis
■ MDS (prior to leukemia)
■ AML : 20% childhood leukemia, 40% DS leukemia
■ ALL : 80% childhood leukemia, 60% DS leukemia

7. Transient abnormal myelopoeisis
■ A disorder of DS newborns that presents with clinical and morphologic
findings indistinguishable from AML.
■ Characterized by increased peripheral blood blasts, usually
megakaryoblasts, with or without clinical symptoms.
■ Underlying genetics demonstrate somatic mutations in
the GATA1 gene.
■ majority of newborns are asymptomatic, with spontaneous resolution
by 2-3 months (median 54 days), although some develop severe
disease.
■ Most of the antenatal cases die before birth with fetal hydrops
■ The cell of origin is fetal liver hematopoietic stem cell/progenitor cell.

8. EPIDEMIOLOGY
■ It occurs in approximately 10% of DS newborns.

10. Clinical features
■ Median presentation within 3 – 7 days of birth
■ Male : female ratio of 1.2-1.5 : 1
■ Thrombocytopenia is common. (thrombocytosis may be seen)
■ There may be marked leucocytosis and % of in BM may exceed
the BM.
■ Hb & ANC usually within normal limits.
■ most common clinical symptom is hepatomegaly, which is a
result of megakaryoblast infiltration and/or hepatic fibrosis (
PDGF &TGF-β by megakaryoblasts)
■ Splenomegaly, exudative effusions maybe present.
■ In utero presentations include hydrops fetalis and anemia.

11. MORPHOLOGYAND
IMMUNOPHENOTYPE
■ Are similar to those of blasts in most cases of DS AML.
■ In most cases blasts are positive for
CD34,CD56,CD117,CD13,CD33,CD7,CD4,CD41,CD42,TPO-R,IL-
3R,CD36,CD61,CD71 and are
■ negative for MPO,CD15,CD14AND Glycophorin a.

12. Peripheral blood smear reveals increased blasts which are medium to large in size with smooth chromatin, prominent
nucleoli (sometimes multiple) and basophilic cytoplasm. Some of these blasts may demonstrate cytoplasmic blebs.
Giant platelets may often be seen.

13. ■ Usually a BM exam does not need to be performed as the
peripheral blood blast count is equal to or exceeds the bone
marrow blast percentage.
■ If performed, the bone marrow may demonstrate variable
numbers of megakaryocytes, including frequent dysplastic
forms such as micromegakaryocytes.
■ Variable numbers of blasts may be present, in one study
ranging from 0-87%, with a mean of 26% (Massey et al., 2006).
Dyserythropoiesis may be seen in up to 25% of patients
(Massey et al., 2006).
■ Liver biopsies may demonstrate fibrosis with sinusoidal
infiltration by megakaryoblasts (Massey et al., 2006).

14. BM biopsy : increased blasts characterized as large cells with round to irregular nuclear
contours, prominent nuclei, and mild amounts of cytoplasm. Background maturing
erythroid and myeloid precursors are identified.

17. CYTOGENETICS
■ Cytogenetics on PB mostly demonstrates trisomy 21.
■ about 20% of affected infants have additional cytogenetic
aberrations including MLL gene rearrangements and complex
karyotypes.

18. Genes
■ TAM is characterized by somatic mutations in the transcription
factor gene GATA1 on chromosome Xp11.23.These mutations
are predominantly within exon 2 (97%), with the remaining in
exon 3.1.
■ GATA1 mutations result in N-terminal truncating mutations
leading to a shortened GATA1 protein, GATA1s.

19. • GATA1 protein is a transcription factor which regulates megakaryocytes and
erythroid differentiation.
• Location : Xp11.23.

20. ACUTE MYELOID LEUKEMIA & MDS
Individuals with DS have a 50 fold increase in incidence of acute
leukemia during the first 5 yrs of life compared to non- DS
individuals.
AML in DS is usually an acute megakaryoblastic leukemia(AMKL-
M7) ,accounting for 50% of acute leukemia in DS individuals
beyond the neonatal period.

21. ■ There are no biological differences in DS individuals between
MDS andAML,therefore a comparable diagnostic
differentiation is not relevant and would have no prognostic or
therapeutic consequences.

22. EPIDEMIOLOGY
■ Majority of children with DS having myeloid leukemia are
under 5 yrs of life.
■ DS children account for 20% of all paediatric patients with
AML/MDS .
■ Myeloid leukemia of DS occurs in 20-30% of children with a
prior history ofTAM and leukemia usually occurs 1-3 yrs after
TAM.

23. SITES OF INVOLVEMENT
■ Blood & BM are principle sites of involvement.
■ Extramedullary involvement of liver & spleen is almost always
present.

24. Clinical Features
■ Disorder mainly manifests in first 3 yrs of life.
■ It may occur after remission period fromTAM or as overt
progression ofTAM without remission period.
■ Clinical course in children with <20% blast cells in BM appear to
be indolent & presents initially with a period of
thrombocytopenia with or without leukopenia & anemia & low
or absent blasts.
■ Preleukemic phase comparable to refractory cytopenia of
childhood generally preceeds MDS with excess blasts or overt
leukemia.
■ In 70% of patients, MDS precedes acute leukemia,
■ Hepatosplenomegaly may be present.
■ AML-DS cases are less likely to have lymphadenopathy & CNS
blast involvement

25. Morphology
■ Peripheral blood and bone marrow blasts in ML-DS are similar
to those inTAM, both morphologically and
immunophenotypically.
■ The bone marrow aspirate may be hemodilute and/or
aparticulate due to marrow fibrosis hampering aspiration.
■ During the myelodysplastic syndrome phase, dysplastic
changes of megakaryocytes and erythroid cells may also be
identified along with low levels of blasts in the bone marrow.

26. Morphology
In preleukemic phase the disease has features of RCC,lacking
significant inc of blasts.
Erythroid cells are macrocytic.
Dysplastic features may be more pronounced.
In c/o AML,blasts and occasionally erythroid precursors are usually
present in peripheral blood.
Erythrocytes often show considerable anisopoikilocytosis.

27. ■ Platelet count is usually low and giant platelets may be
observed.
■ In BM aspirate ,morphology of leukemic blasts show particular
features with round to slightly irregular nuclei and a moderate
amount of basophilic cytoplasm.
■ Cytoplasmic blebs may be present also.
■ Cytoplasm of a variable numb of blasts contains coarse
granules ,that are generally MPO negative.

28. ■ Erythroid precursors often show megaloblastic changes as well
as dysplastic forms,including bi-or tri nucleated cells and
nuclear fragments.
■ BM core may show dense network of reticulin fibres making
aspiration difficult.
■ Maturing cells of neutrophil lineage are dec usually.

29. Increased blasts may be identified on a bm aspirate if it does contain particles.These blasts are
characterized as medium to large sized cells with round to irregular nuclear contours, smooth
chromatin, prominent nucleoli (sometimes multiple), and basophilic cytoplasm often with cytoplasmic
blebs. Rare blasts may demonstrate cytoplasmic granules such as the blast in the bottom center.
Dysplastic megakaryocytes may also be identified such as the small megakaryocyte at the top center.

30. In the BM biopsy obtained from the same patient demonstrates
increased blasts with prominent nucleoli in a background of maturing
erythroid and myeloid precursors.

31. BM trephine biopsy demonstrates :
marked fibrosis, as demonstrated by the bottom panel stained for reticulin.The core biopsy can demonstrate
a marked increase in atypical and dysplastic megakaryocytes, many of which are blasts.The inset panel
demonstrates CD117 immunohistochemical staining of the megakaryoblasts.

32. IMMUNOPHENOTYPE
■ Mostly blasts are positive for
CD117,CD13,CD33,CD7,CD4,CD42,TPO-R,IL-
3R,CD36,CD41,CD61,CD71,and
■ negative for MPO ,CD15,CD14 and glycophorin.
■ Antibodies to CD41 and CD61 may be present.

33. Cytogenetics
■ In addition to trisomy 21, somatic mutations of gene encoding
transcription factor GATA1 are pathognomonic of
TAM,AML/MDS of DS.
■ Recurrent genetic abnormalities such as t(8;21), t(15;17),
and inv(16) are underrepresented in this cohort compared to
those without DS.
■ t(1;22) often found in infant megakaryoblastic leukemia is only
rarely found in AML-DS
■ Trisomy 8 is a common cytogenetic abnormality in myeloid
leukemia of DS in 13-36% of patients.
■ Loss of chromosome 5 &/or loss of chromosome 7 material is
present in 23% of cases

34. Treatment
■ UnlikeTAM, ML-DS does require chemotherapy to achieve
complete remission (CR).
■ However, compared to non-Down syndrome pediatric acute
leukemia, they can be treated with reduced intensity
chemotherapy protocols without stem cell transplantation.
■ Reduced chemotherapy intensity is encouraged due to high
rates of treatment toxicity in DS children.

35. Prognostic factors
■ Clinical outcome for young children with DS & AML with GATA1
is associated with better response to chemotherapy and is
favourable prognosis compared to non-DS childrenAML.
■ However, ML-DS children are still at high risk for treatment-
related deaths, often due to infection.
■ WBC count >20K/uL & age >3 years are independent predictors
for poor event-free survival

36. Acute lymphoblastic leukemia
(ALL)
■ The risk of developing acute lymphoblastic leukemia (ALL) is
approximately 10 to 20 times higher in DS compared with
children without DS and accounts for 1 to 3 percent of all
patients with ALL.The clinical presentation is similar to that in
children without DS.

37. ■ A report comparingALL in children with and without DS, the
following findings were noted at presentation
■ Leukocyte count and leukemic cell mass were similar
■ Age distribution and immunophenotype Clinically were
indistinguishable
■ Mediastinal mass (1.6 versus 8.9 percent) and CNS leukemia (0
versus 2.7 percent) were less common in DS, both favorable
prognostic sign.

38. ■ LessT-cell leukemia or translocation of (9;22) or t(4;11) were
seen in DS, both unfavorable prognostic signs
■ Cytogenetic differences occurred, including less hyperdiploidy
in DS, an unfavorable prognostic sign

39. ■ B-precursor ALL is the most common type of leukemia among
patients with Down syndrome (DS).Children with DS who
develop ALL are usually younger than 10 years of age and often
respond to chemotherapy as well as do children without DS.
However, children with DS are more likely to experience severe
toxicity with standard chemotherapy regimens, particularly
those requiring methotrexate, and often require reduced doses
of chemotherapy.

40. ■ Because children with DS have a higher incidence of treatment-
related toxicity, their survival rate is generally inferior to that of
children without DS .
The most common genetic abnormality seen in ALL that develops
in children with DS is the overexpression of CRLF2 and JAK2
mutations .Although JAK2 mutations and CRLF2
overexpression have clearly been associated with poor
prognosis in patients with non-DSALL, the prognostic
significance of these molecular changes in DS-ALL remains
unclear.

41. ■ Immunophenotype is typical for B-cell precursor ALL.
■ Blasts are positive for CD10,CD19,CD79a.

42. Treatment of leukemia in ds
■ Leukemia of patients with DS are often treated suboptimally
and many patients don’t receive cytoreductiveT/T at all.
■ Their several physical abnormalities including potentially life
threatening cardiac and intestinal malformations alongwith
mental retardation and associated psychosocial issues as well
as inc chemotherapy related toxicity make the use of standard
chemotherapy difficult for the physician

43. ■ Fibroblasts and lymphocytes of DS individuals have increased
chromosomal sensitivity to mutagenic agents and abnormal
DNA repair.
■ Patients are therefore disposed to more severe toxicity of
irradiation or alkylating agents.
■ Despite these obstacles ,modern intensive schedules including
methotrexate have been used.
■ With improved supportive careT/T is acceptably tolerated.

44. Thank you