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Evidence-Based Oncology, January 2019, Volume 25, Issue 1

Updates from the annual ASH meeting, December 2018.

ASH-EHA Joint Symposium Dives Deep Into the Leukemia—Down Syndrome Connection

Surabhi Dangi-Garimella, PhD

Although several associations between constitutional syndromes, such as Down syndrome (DS), and predisposition to cancers have been recognized, recommendations for surveillance or clear association between the two are lacking. Speakers at a joint symposium between the American Society of Hematology (ASH) and the European Hematology Association (EHA), held December 2, 2018, during the 60th ASH Annual Meeting & Exposition in San Diego, California, highlighted the current understanding of cancer surveillance screening, as well as translational studies that target pathways in these and related hematologic malignancies.

Between 5% and 30% of children with DS are born with transient leukemia of DS (TL-DS), also called transient myelop- roliferative disorder.1 Mutations in the transcription factor gene GATA1, in conjunction with trisomy 21 (T21), are key drivers of this myeloproliferative disorder. Research has shown that TL-DS may lead to early death in 15% to 23% of cases; survivors may develop acute myeloid leukemia (AML) of DS in the first 4 years of their life. Although guidelines for management of TL-DS were recently developed in the United Kingdom,2 much remains to be discovered.

The first presentation during the joint session, “Leukemia in Down Syndrome: Why Does It Happen and Why Is It Important?” was by Irene Roberts, MD, MRC Molecular Haematology Unit and Paediatrics, MRC Weatherall Institute of Molecular Medicine, Oxford, United Kingdom.

There is increased susceptibility to leukemia in DS—both myeloid and lymphoid leukemias are common—and young children are especially susceptible, Roberts said. “The incidence ratio for AML is 12 in adults and 114 in children. On the other hand, the incidence of acute lymphoblastic leukemia is 13 in adults and 27 in children less than 4 years of age,” Roberts told the audience. The incidence is negligible in solid tumors.

For her talk, Roberts focused on AML. Myeloid leukemia of DS (ML-DS) originates in fetal life and presents before the child is 4 years. “It is preceded by a stage called transient abnormal myelopoiesis, or TAM,” Roberts explained. Development of TAM and ML-DS both require trisomy 21 and acquired GATA1 mutations.

Neonatal preleukemia, she said, results from the N-terminal truncation of GATA1 protein, called GATA1s, in T21 cells. Additional mutations cause ML-DS in persisting mutant GATA1 cells and result in ML-DS before age 4.

What is the importance and relevance of leukemia in DS? Roberts listed several characteristics of this phenomenon, based on what is known in the literature combined with her laboratory’s findings:

  • It provides a model of the natural history of leukemia within a defined time window
  • It provides insight into GATA1 function
  • T21 leads to adapting to aneuploidy, gene dosage, and T21 in non-DS leukemias
  • Constitutional syndromes with malignant potential are managed to implement research findings in the clinic
  • There are policy and societal issues associated with this phenomenon beyond the leukemia itself

Neonates with higher blasts and clinical TAM had more severe disease, as determined by using hepatomegaly, effusions, and splenomegaly. Disease severity was determined based on infiltration of tissue into mutant blast cells and fibrosis.

Roberts said that GATA1 mutations in DS neonates predict for translation of GATA1s, which is the N-terminal truncated protein. It can lead to abnormal platelet production in DS neonates. Other characteristics of TAM are giant platelets and megakaryocyte fragments.

A significant finding is that GATA1 mutations likely develop late in the second trimester or early in the third trimester of fetal development. The progression of TAM to ML-DS has several driver mutations, but the 2 most frequent mutations are in Cohesin and CTCF.

Roberts summed her findings by delineating clinical implications of the leukemia—DS relationship. “Children at high risk of developing myeloid leukemia within 4 years can be identified

at birth based on the percentage of blasts and also by GATA1 mutation analysis,” she said. This would also provide insight into those children who are at a low or no risk of developing myeloid leukemia, based on their blast count.

“A close liaison among hematologists, pediatricians, and neonatologists for guideline development would be important,” which she highlighted has recently been done in the United Kingdom.2

Presenting the developments in the United States was John D. Crispino, PhD, MBA, Division of Hematology and Oncology, Northwestern University, Chicago, Illinois.

GATA1, a zinc finger-binding transcription factor, is important for megakaryopoiesis, Crispino said, with N-terminal mutants leading to congenital dyserythropoietic anemia, congenital thrombocytopenia, and congenital erythropoietic porphyria. The GATA1s mutation can result in transient abnormal myelo- poiesis, ML-DS, congenital hypoplastic anemia, and Diamond Blackfan anemia. The importance of GATA1 in erythropoiesis is underscored by the fact that GATA1-deficient mice die of anemia, Crispino said.

Crispino’s laboratory conducted high-throughput studies in vitro to identify small molecule drugs that could target the GATA1 deficiency in cells and to query if these drugs had disease-altering activity. Subsequent studies evaluated small molecule drugs that could force polyploidization in megakaryocytes and their maturation. This eventually led to the identification of Aurora kinase, which regulates cell cycle and proliferation, as a potential target, the inhibition of which can induce polyploidy and differentiation in megakaryocytic leukemia cells. Additionally, “the Aurora kinase inhibitor, alisertib, also caused a delayed differentiation-associated apoptosis,” Crispino said.

In mouse studies, primary human megakaryocyte leukemia cells are placed in mice, which were then treated with 2 cycles of alisertib and bone marrow was assayed at 27 days. The drug reduced immature human megakaryocytes in the mice and upregulated the mature megakaryocytes. The study also found alisertib to have a survival effect.

Crispino’s group then treated a myeloproliferative neoplasms—AML cell line with alisertib and found that it increased both polyploidization and GATA1 protein expression. When mice injected with these cells were subsequently injected with 3 cycles of alisertib, the infiltrated mice had a high platelet count and transient increase in hemoglobin and hematocrit.

Because these studies identified Aurora kinase A as a therapeutic target in myelofibrosis, further studies are now evaluating the drug in the clinic.

“Can this strategy be used in the treatment of other GATA1 deficiency syndromes?” Crispino asked. This question remains unanswered.


  1. Roberts I, Alford K, Hall G, Juban G, et al; Oxford-Imperial Down Syndrome Cohort Study Group. GATA1‐mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. Blood. 2013;122(24):3908-3917. doi: 10.1182/blood-2013-07-515148.
  2. Tunstall O, Bhatnagar N, James B; British Society for Haematology. Guide- lines for the investigation and management of Transient Leukaemia of Down Syndrome. Br J Haematol. 2018;182(2):200-211. doi: 10.1111/bjh.15390.

NCI Director Highlights a Year of Progress in Hematology, Outlines Areas of Focus Going Forward

Jaime Rosenberg

"Now more than a year into the job, I’ve heard from a lot of stakeholders. I’ve heard from doctors and scientists, patients and advocates, and one clear fact from all those conversations is this: it is a great time to be a cancer scientist and a cancer doctor in the United States,” said Norman Sharpless, MD, director of the National Cancer Institute (NCI), as he addressed a crowd at the 60th American Society of Hematology Annual Meeting & Exposition held December 1-4, 2018, in San Diego, California.

Sharpless highlighted numerous recent advancements in the care of hematologic malignancies, including moxetumomab pasudotox-tdfk, a new treatment for hairy cell leukemia, which hasn’t had a new treatment option in 20 years, as well as the 2 chimeric antigen receptor T-cell therapies approved in the last year: tisagenlecleucel and axicabtagene ciloleucel.

He also brought attention to 2 NCI-supported trials of both younger and older patients with chronic lymphocytic leukemia that identified a chemotherapy-free approach using rituximab and ibrutinib rather than drugs like bendamustine and fludarabine for these patients. “This is really important because we now have a relatively gentle regimen that works really well for these patients,” he said.

Sharpless called the past year an “extraordinary period” for acute myeloid leukemia, which came after decades of limited progress. In the last year and a half, the FDA has approved 8 new drugs for the disease, including 2 isocitrate dehydrogenase inhibitors, 2 Flt-3 inhibitors, and venetoclax.

Advancements like these are a result of detailed, elegant basic science, according to Sharpless. “There’s this great basic science that’s developing in hematologic cancers, and these scientific developments are translating into meaningful therapies for patients,” he said.

However, despite this progress, many will rightly say it’s not enough, said Sharpless, with many of these new therapies being only moderately effective and sometimes not curative. He called these therapies singles and doubles, noting that we still need home runs.

Following a listening tour to hear from stake- holders across the hematologic landscape, Sharpless identified areas that, while they are not new concepts, we need to sharpen our focus on in the next few years. He outlined 4 focus areas:

  • Workforce development: Supporting the cancer research enterprise by focusing on the workforce cancer investigators
  • Basic science: Reaffirming the NCI’s commitment to basic science to drive novel approaches and technologies
  • Big data: Increasing data aggregation and interpretation to speed work across the cancer enterprise
  • Clinical trials: Fully realizing the power of clinical trials through innovative design, administration, and analyses