Transient Leukemia-Associated Pericardial Tamponade in a Neonate with Down Syndrome

Abstract Background: Transient leukemia (TL) occurs in 30% of newborns with Down syndrome (DS) and typically resolves spontaneously. Approximately 20% of infants with TL go on to develop acute myeloid leukemia of DS (DS-AML) within the first four years of life. The blasts of both TL and DS-AML harbor somatic mutations of GATA1 . The objective of this study was to identify additional genetic events, which associated with the progression of TL to DS-AML. Methods: Leukemic blasts of TL, DS-AML and normal T lymphocytes were sorted from blood and bone marrow samples of five patients who successively developed both disorders. In addition, blasts of one patient with subsequent relapse of DS-AML were analyzed. Mutational spectrum and gene expression and were determined by exome sequencing and RNASeq (Illumina HiSeq2000). The presence of mutations, which were identified with this approach in DS-AML blasts, was examined by droplet digital PCR in TL blasts (BioRad QX200). Results: Blasts of TL overall harbored fewer mutations than those of DS-AML. Mutations of cohesin and RAS pathway genes were identified in a subset of DS-AML but not TL. In the patient who developed a relapse, different cohesin gene mutations were detected at initial diagnosis of AML and relapse; a minor clone present at initial diagnosis of AML emerged as the predominant clone at relapse. Concordant somatic GATA1 mutations were present in both TL and DS-AML blasts derived from the same patient. In contrast, other genetic events, which were detected in DS-AML blasts by exome sequencing, were confirmed to be absent in TL (by droplet digital PCR). The majority of differentially expressed genes showed higher expression levels in blasts of TL compared to DS-AML. They included genes encoding chemokines and related to IL1 and TGFb signaling. Conclusions: The pathogenic sequence starting with TL and culminating in AML is uniquely initiated in children with DS by somatic mutation of GATA1. In contrast, the events associated with the transformation of TL to DS-AML resemble progression factors also found in non-DS AML. These progression events were not detectable even in minor subclones of TL suggesting they are acquired after the onset of TL. This research was supported by funding from the Canadian Cancer Society Research Institute and Ontario Institute for Cancer Research. Disclosures No relevant conflicts of interest to declare.

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Treatment and prognostic impact of transient leukemia in neonates with Down syndrome

Blood ◽

10.1182/blood-2007-10-118810 ◽

2008 ◽

Vol 111 (6) ◽

pp. 2991-2998 ◽

Cited By ~ 140

Author(s):

Jan-Henning Klusmann ◽

Ursula Creutzig ◽

Martin Zimmermann ◽

Michael Dworzak ◽

Norbert Jorch ◽

...

Keyword(s):

Multivariate Analysis ◽

Down Syndrome ◽

Early Death ◽

Spontaneous Remission ◽

Prognostic Impact ◽

Free Survival ◽

Transient Leukemia ◽

Treatment Data ◽

History Of ◽

Wbc Count

Abstract Approximately 10% of the neonates with Down syndrome (DS) exhibit a unique transient leukemia (TL). Though TL resolves spontaneously in most patients, early death and development of myeloid leukemia (ML-DS) may occur. Prognostic factors as well as treatment indication are currently uncertain. To resolve that issue, we prospectively collected clinical, biologic, and treatment data of 146 patients with TL. The 5-year overall survival (OS) and event-free survival (EFS) were 85% plus or minus 3% and 63% plus or minus 4%, respectively. Multivariate analysis revealed a correlation between high white blood cell (WBC) count, ascites, preterm delivery, bleeding diatheses, failure of spontaneous remission, and the occurrence of early death. Treatment with cytarabine (0.5-1.5 mg/kg) was administered to 28 patients with high WBC count, thrombocytopenia, or liver dysfunction. The therapy had a beneficial effect on the outcome of those children with risk factors for early death (5-year EFS, 52% ± 12% vs 28% ± 11% [no treatment]; P = .02). Multivariate analysis demonstrated its favorable prognostic impact. A total of 29 (23%) patients with TL subsequently developed ML-DS. Patients with ML-DS with a history of TL had a significantly better 5-year EFS (91% ± 5%) than those without documented TL (70% ± 4%), primarily due to a lower relapse rate. A history of TL may therefore define a lower-risk ML-DS subgroup. This study was registered at www.clinicaltrials.gov as no. NCT 00111345.

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The myeloproliferative reaction in a child with down syndrome: Cytological and chromosomal evidence for a transient leukemia

American Journal of Hematology ◽

10.1002/ajh.2830110411 ◽

1981 ◽

Vol 11 (4) ◽

pp. 417-423 ◽

Cited By ~ 43

Author(s):

Kenneth H. Lazarus ◽

Nyla A. Heerema ◽

Catherine G. Palmer ◽

Robert L. Baehner

Keyword(s):

Down Syndrome ◽

Transient Leukemia

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GATA1 as a new target to detect minimal residual disease in both transient leukemia and megakaryoblastic leukemia of Down syndrome

Leukemia Research ◽

10.1016/j.leukres.2005.04.007 ◽

2005 ◽

Vol 29 (11) ◽

pp. 1353-1356 ◽

Cited By ~ 19

Author(s):

Sharon R. Pine ◽

Qianxu Guo ◽

Changhong Yin ◽

Somasundaram Jayabose ◽

Oya Levendoglu-Tugal ◽

...

Keyword(s):

Down Syndrome ◽

Minimal Residual Disease ◽

Residual Disease ◽

Megakaryoblastic Leukemia ◽

Transient Leukemia ◽

Minimal Residual

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MicroRNA-155-5p Plays a Critical Role in Transient Leukemia of Down Syndrome by Targeting Tumor Necrosis Factor Receptor Superfamily Members

Cellular Physiology and Biochemistry ◽

10.33594/000000283 ◽

2020 ◽

Vol 54 (5) ◽

pp. 994-1012

Keyword(s):

Down Syndrome ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Critical Role ◽

Tumor Necrosis Factor Receptor ◽

Transient Leukemia ◽

Necrosis Factor

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Transient leukaemia of Down syndrome in a neonate: case report

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20194615 ◽

2019 ◽

Vol 6 (6) ◽

pp. 2712

Author(s):

Baraturam Bhaisara, ◽

Charusheela Korday ◽

Minal Wade ◽

Chandra Kiran Chunchu ◽

Priyanka Modi ◽

...

Keyword(s):

Down Syndrome ◽

Myeloid Leukemia ◽

Spontaneous Remission ◽

Myeloproliferative Disorder ◽

Mutant Clone ◽

Children With Down Syndrome ◽

Transient Abnormal Myelopoiesis ◽

Oncogenic Mutations ◽

Transient Leukemia ◽

Mutant Cells

Transient leukemia of Down syndrome(TL-DS) or transient myeloproliferative disorder (TMD) or transient abnormal myelopoiesis (TAM) is a hematologic abnormality characterized by an uncontrolled proliferation of myeloblasts in peripheral blood and bone marrow which characteristically affects newborns and babies with Down syndrome. Children with Down syndrome (Trisomy 21) have a unique predisposition to develop myeloid leukemia of Down syndrome(ML-DS). In majority of cases of TL-DS, the GATA1 mutant clone goes into spontaneous remission without the need for chemotherapy. However, 10-20 % of neonates with TL-DS and silent TL-DS subsequently develop ML-DS in the first 5 years of life due to additional oncogenic mutations acquired by the persistent GATA1 mutant cells. We present here, one such case of Down syndrome with TL-DS in a neonate.

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Relapsed acute megakaryoblastic leukemia in Down syndrome (AMKL-DS) may be cured with chemotherapy alone, without stem cell transplantation (HSCT)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.17543 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 17543-17543

Author(s):

S. Jayabose ◽

C. Sandoval ◽

O. Levendoglu-Tugal ◽

M. F. Ozkaynak

Keyword(s):

Down Syndrome ◽

Good Health ◽

Lung Lesion ◽

High Dose ◽

Unrelated Donor ◽

Intensive Chemotherapy ◽

Megakaryoblastic Leukemia ◽

Transient Leukemia ◽

High Dose Cytarabine ◽

Disease Free

17543 Background: Children with recurrent AMKL -DS have an extremely poor prognosis without HSCT. Methods: We report a case of a relapsed AMKL-DS cured with intensive chemotherapy alone, without HSCT. Results: A 19 month old boy with Down syndrome, who had transient leukemia as a newborn, developed AMKL-DS (GATA1 positive) and was treated with four cycles of CI-TAD: continuous infusion of cytarabine and daunorubicin, and oral thioguanine for four days, and intrathecal cytarabine; followed by two cycles of high dose cytarabine plus L-Asparaginase; and three weekly doses of intrathecal cytarabine. Although he achieved remission at the completion of first cycle of the induction chemotherapy, he relapsed within 6 weeks after the completion of therapy. He then received the following chemotherapy over the next six months: Cycle 1 and 2. High dose Ara-C ( 33. 3 mg/kg q 12 hours x 8 doses) on days 0 to 3 plus mitoxantrone 0. 4 mg/kg/day x 4 on days 3 to 6 Cycle 3. High dose Ara-C 33. 3 mg/kg q 12 hours x 8 doses Cycle 4 and 5 (FLAG): Fludarabine 0. 8 mg/kg/day x 4 plus Ara-C 67 mg/kg/d x 4 and G-CSF 10 mcg/kg/day x 4 all on days 0 to 3. He achieved complete remission after the 1st cycle of chemotherapy, and underwent further cycles of chemotherapy while waiting for HSCT from an unrelated donor. But after the 5th cycle of chemotherapy, he developed a pulmonary lesion of fungal etiology for which he received three months of therapy with liposomal amphotericin. Because of a persistent lung lesion on imaging, he was considered ineligible for HSCT, and no further therapy was given. His bone marrow aspirate after the 3rd cycle of therapy was negative for GATA1. He has been disease-free for 59 months after the completion of his last cycle of chemotherapy, and he is currently in good health without any evidence of pulmonary or cardiac dysfunction. Conclusions: Intensive chemotherapy alone, without HSCT, may be curative for relapsed AMKL- DS. No significant financial relationships to disclose.

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