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Cancer in Down Syndrome : Focus on Disorders of Infancy

Cancer in Down Syndrome : Focus on Disorders of Infancy. James A. Whitlock, M.D. Division Head, Hematology/Oncology Women’s Auxiliary Millennium Chair in Haematology/Oncology The Hospital for Sick Children Professor of Paediatrics, University of Toronto. Disclosures.

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Cancer in Down Syndrome : Focus on Disorders of Infancy

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  1. Cancer in Down Syndrome : Focus on Disorders of Infancy James A. Whitlock, M.D. Division Head, Hematology/Oncology Women’s Auxiliary Millennium Chair in Haematology/Oncology The Hospital for Sick Children Professor of Paediatrics, University of Toronto

  2. Disclosures • No Relevant Potential Conflicts of Interest • Non-relevant Disclosures: • Current consultant: • EUSA Pharmaceuticals • Hanna Biosciences • Research funding: • Glaxo-Smith-Kline • I will discuss many off-label uses of drugs

  3. Objectives of my Presentation • Be familiar with: • hematologic aspects of DS in neonatal period • Differential diagnosis of cancers in DS in infancy • This talk has been truncated for the purposes of focusing on a neonatal specific topic by Dr Phillip Gordon (with the author’s permission)

  4. Summary of my Presentation:Individuals with DS… • are 10-20 times more likely to develop leukemia than those without DS, and less likely to develop solid tumors • have a 1 in 10 risk of transient myeloproliferative disorder (TMD), a form of self-limited leukemia, during infancy • have better outcomes for childhood AML than non-DS children, despite less intensive treatment • have similar outcomes for childhood ALL as non-DS children, despite more severe toxicities, after accounting for differing biologic features

  5. Down Syndrome is caused by Trisomy 21 1866: Langdon Down describes the clinical features of Down syndrome 1959: Jerome Lejeune describes trisomy 21 in association with DS

  6. Leukemias are more common in Down Syndrome 1845: Rudolph Virchow, the “Father of Pathology,” describes leukemia (“white blood”) 1957: Krivit & Good recognize association of DS & leukemia

  7. Leukemias are more common in Down Syndrome • Incidence of leukemia in DS is 1 in 200-300 • 10-20 fold higher incidence than in non-DS subjects • Myeloid leukemias are overrepresented in DS: • Ratio of ALL : AML • non-DS: 4:1 • DS: 1:1 • 46-fold excess incidence of myeloid diseases in DS • This increased risk does not extend into adulthood Robison, J Peds 105:235, 1984; Gurbuxani, Blood 103:399,2004

  8. Solid tumors are less common in Down Syndrome • Incidence of solid tumors in DS is 50% lower than expected vs. non-DS population • Lower incidence of solid tumors (except for testicular cancers) occurs in both children and adults with DS Hasle, Lancet 355:165, 2000; Yang, Lancet 359:1019, 2002

  9. Why are solid tumors less common in DS? • Tumors establish a blood supply by secreting pro- angiogenic factors (VEGF, etc) • Endostatin is an endogenously occurring inhibitor of angiogenesis whose gene maps to chromosome 21 • Increased endostatin levels may protect against cancer (-> therapeutic applications?) • DS subjects have significantly higher serum levels of endostatin than controls (39 vs 20 ng/mL; p<0.0001) • Thus, increased serum endostatin levels may protect against development of solid tumors in DS subjects Zorick, Eur J Hum Genet 9:811, 2001

  10. Why are solid tumors less common in DS? • Ts65Dn mice, trisomic for ~100 Hsa21 gene orthologues, recapitulate DS. • Mice carrying the ApcMinmutation recapitulate familial adenomatouspolyposis (FAP), predisposing them to intestinal tumors. • Crossing of these 2 strains leads to a significant reduction in size and incidence of intestinal tumors. Sussan et al , Nature 451:73, 2008

  11. Multiple Types of Leukemia Are Increased in DS • Acute lymphoblastic leukemia (ALL) • Acute myeloid leukemia (AML) • Transient myeloproliferative disorder (TMD) (also transient leukemia or TL) Gurbuxani et al, Blood 103:399, 2004

  12. Multiple Types of Leukemia Are Increased in DS • Acute lymphoblastic leukemia (ALL) • Acute myeloid leukemia (AML) • Transient myeloproliferative disorder (TMD) (also transient leukemia or TL) Gurbuxani et al, Blood 103:399, 2004

  13. Case Presentation #1 • Hx: 32 week EGA female infant born by C-S • Known DS due to elevated maternal AFP • Day 2: WBC 30,000 (1% blasts) • Day 3: WBC 50,000 (8% blasts) • Peripheral blood flow cytometry: AML • Management: aggressive observation • Day 15: WBC 20,000 (2% blasts) • Day 55: normal CBC

  14. Transient Myeloproliferative Disorder is Unique to DS • What is TMD? • accumulation of immature blasts in peripheral blood, liver and BM of DS infants • usually presents by 3 weeks of age • typically spontaneously regresses by 2-3 months • at least 10% of DS infants have TMD; many mildly affected patients likely go undetected Lange, BJH 110:512, 2000; Gurbuxani, Blood 103:399, 2004

  15. Hematologic Abnormalities are Common in DS Neonates • In 157 DS infants < 1 wk old with CBCs: • neutrophilia 80% • thrombocytopenia < 50K 6% • polycythemia 33% • peripheral blasts 6% • anemia, thrombocytosis, or neutropenia <1% each Henry et al, Am J Med Genet 143A:42, 2007

  16. Is TMD really leukemia? YES 1. TMD blasts are morphologically indistinguishable from acute megakaryocytic leukemia (AMKL) 2. TMD blasts are clonal 3. TMD blasts can have acquired cytogenetic alterations NO 1. TMD blasts often spontaneously regress without treatment Lange, BJH 110:512, 2000; Gurbuxani, Blood 103:399, 2004

  17. Complications of TMD • Hepatic dysfunction due to infiltration by blasts • Hepatic fibrosis • Hyperleukocytosis(markedly high WBC count) • Respiratory insufficiency due to hyperleukocytosis or hepatic enlargement • Renal failure due to infiltration of blasts • Hydropsfetalis Lange, BJH 110:512, 2000

  18. Management of TMD • Goals of management of TMD: • address complications • minimize therapy-related toxicities • Management strategies: • hyperleukocytosis: exchange transfusion or leukopheresis • hepatic dysfunction: low-dose chemotherapy (Ara-C) Lange, BJH 110:512, 2000

  19. Natural History of TMD in DS: POG 9481 • Eligibility criteria: • trisomy 21 < 3 mo age with blasts in PB, BM or liver • Results (n = 48): • average age at diagnosis: 7 days • 74% had trisomy 21 as sole cytogenetic abnormality • 89% spontaneously cleared blasts • 74% normalized blood counts • 17% suffered early death: • risk factors: high WBC, hepatic dysfunction • 19% subsequently developed AMKL @ mean age 20 mo. • risk factor: additional cytogenetic abnormalities Massey et al, Blood 107:4606, 2006

  20. Genetic Etiology of Myeloid Diseases in Down Syndrome • GATA1: a transcription factor which regulates control of normal hematopoesis • mutations in GATA1 found exclusively in TMD, DS-AMKL www.einstein.yu.edu/GRAFLAB/graffactors.html; Wechsler et al, Nat Genet 32:148, 2002

  21. Genetic Etiology of AML in Down Syndrome • GATA1 mutations found in 2 / 21 (10%) neonatal blood spots from randomly selected healthy DS newborns • Proposed model for GATA1 in DS leukemogenesis: 2nd mutation 2nd mutation + 2nd mutation Vyas, Hemtol J, 4:210a, 2003; Vyas, Early Child Devel, 82:767,2006

  22. Acute Myeloid Leukemia in Down Syndrome • ~30% of TMD patients develop AML within 3 yrs; most of these are AMKL • ~50% of AML in DS is AMKL (vs. <5% in non-DS) • most AML in DS children < 4 years is AMKL • most AML in DS children > 4 years is not AMKL Crispino, Ped Blood Cancer 44:40, 2005; Hasle et al, Leukemia 22:1428, 2008

  23. Age Influences Prognosis in DS-AML: CCG-2891 Gamis et al , JCO 21:3415, 2003

  24. Children with DS-AML have Favorable Outcomes with Standard Therapy: POG 8498 • 4-yr EFS: 100% vs 28% Ravindranath et al, Blood 80:2210, 1992

  25. Children with DS-AML Maintain Excellent Outcomes with Reduced Intensity Therapy: COG A5971 • 3-yr EFS: 79% (A5971) vs. 77% (2891) Courtesy of Alan Gamis, MD

  26. Summary: Myeloid Disease in DS • Children with DS have a ~50-fold increase in myeloid diseases compared to non-DS children • Transient Myeloproliferative Disorder (TMD): • occurs in 10% of children with DS • most cases spontaneously resolve • high WBC or hepatic dysfunction predict a poor outcome • predisposes to later development of AMKL (30%) • is due to an acquired mutation in GATA1 • Acute Megakaryocytic Leukemia: • is the most common AML subtype in DS • occurs primarily in patients < 4 years of age • has an excellent outcome with reduced therapy in DS • DS-AML in pts > 4 yrs behaves more like NDS-AML

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