Sensitive detection of GATA1 mutations using complementary DNA‐based analysis for transient abnormal myelopoiesis associated with the Down syndrome

2021 ◽  
Author(s):  
Shumpei Mizuta ◽  
Noriko Yamane ◽  
Saya Mononobe ◽  
Asami Watanabe ◽  
Ritsuko Kitamura ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Sensitive Detection ◽  
Complementary Dna ◽  
Transient Abnormal Myelopoiesis

Clinical features of 35 Down syndrome patients with transient abnormal myelopoiesis at a single institution

2021 ◽  
Author(s):  
Genki Yamato ◽  
Myoung-ja Park ◽  
Manabu Sotomatsu ◽  
Taeko Kaburagi ◽  
Kenichi Maruyama ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Clinical Features ◽  
Single Institution ◽  
Transient Abnormal Myelopoiesis

scholarly journals Predictive factors for the development of leukemia in patients with transient abnormal myelopoiesis and Down syndrome

Leukemia ◽  
2021 ◽  
Author(s):  
Genki Yamato ◽  
Takao Deguchi ◽  
Kiminori Terui ◽  
Tsutomu Toki ◽  
Tomoyuki Watanabe ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Predictive Factors ◽  
Transient Abnormal Myelopoiesis

Mirror syndrome associated with fetal transient abnormal myelopoiesis in Down syndrome

2015 ◽  
Vol 65 (8) ◽  
pp. 443-445 ◽  
Author(s):  
Yoshinari Kobayashi ◽  
Takekazu Miyoshi ◽  
Taka-aki Matsuyama ◽  
Jun Miyauchi ◽  
Toshiyuki Miyashita ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Transient Abnormal Myelopoiesis

scholarly journals Predictive Factors of the Development of Leukemia in Patients with Transient Abnormal Myelopoiesis and Down Syndrome: The Jccg Study JPLSG TAM-10

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3833-3833 ◽  
Author(s):  
Genki Yamato ◽  
Hideki Muramatsu ◽  
Tomoyuki Watanabe ◽  
Takao Deguchi ◽  
Shotaro Iwamoto ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Blood Transfusion ◽  
Steroid Therapy ◽  
Early Death ◽  
Therapeutic Interventions ◽  
Systemic Steroid ◽  
Transient Abnormal Myelopoiesis ◽  
Systemic Steroid Therapy ◽  
Leukemia Development ◽  
Wbc Count

Introduction: Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells that harbor somatic GATA1 gene mutation. Although most patients show spontaneously resolution without therapeutic interventions, approximately 20% of TAM cases result in early deaths within 9 months and 20% of survivors develop acute megakaryoblastic leukemia (AMKL) within 4 years. Although the risk factors associated with early deaths are known, the definite clinical predictive indicators of AMKL onset in patients with TAM remain unclear. Therefore, we analyzed 167 TAM patients with DS enrolled in the TAM-10 prospective observational study conducted by the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) to determine the clinical characteristics of TAM and predictive factors of leukemia development. Patients and Methods: Between May 2011 and February 2014, 167 neonates (89 boys and 78 girls) diagnosed with TAM were prospectively registered in the TAM-10 study. Somatic GATA1 gene mutations were confirmed in 163 (98%) patients using Sanger and/or next-generation sequencing. Minimal residual disease using flow cytometry (FCM-MRD; cut-off level, ≥0.1%) was monitored at 1 (n = 133) and 3 months (n = 104). Results: Median (range) gestational age, birth body weight, white blood cell (WBC) count, and percentage of blasts at diagnosis were 37 (29-40) weeks, 2,612 (1,066-3714) g, 38.3 (2.4-478.7) × 109 cells/L, and 37% (0.5%-95.5%), respectively. Systemic edema and organ hemorrhage was observed in 31/167 (19%) and 14/167 (8%) patients, respectively; 68/167 (41%) patients received some therapeutic interventions, including low-dose cytarabine (LDCA; n = 52), exchange blood transfusion (n = 20), and systemic steroid therapy (n = 31). Early death (<9 months of age) occurred in 22/167 (13%) patients. In multivariate analysis, early death was significantly associated with a high WBC count [≥100 × 109 cells/L; HR (95% CI) = 5.329 (2.194-12.945), P < 0.001] and systemic edema [HR (95% CI) = 8.073 (3.130-20.823), P < 0.001]. Subgroup analysis in patients with such high WBC count (n = 36) showed that LDCA therapy significantly improved survival [1-year OS (95% CI) = 78.3% (55.4-90.3; n = 23) vs. 38.5% (14.1-62.8; n = 13); P = 0.009]. Among 145/167 patients without early death, 28 (19%) developed AMKL. FCM-MRD positivity at 1 month [positive, n = 107; negative, n = 26; cumulative incidence ratio (CIR) (95% CI) = 25.2% (17.3-33.9%) vs 3.8% (0.3%-16.8%), P = 0.022] and 3 months (positive, n = 20; negative, n = 84; CIR (95% CI), 45.0% (22.3%-65.4%) vs. 16.0% (9.0%-24.8%), P = 0.002] was significantly associated with leukemia development. However, other clinical covariates, including sex, birth weight, gestational age, WBC count, blast percentage, and GATA1 gene mutational types, could not predict AMKL development. Considering their severe clinical conditions, 13/31 (42%) patients who received systemic steroid therapy died before AMKL development; interestingly, none of the remaining 18 patients developed AMKL but they showed significantly lower CIR than those who did not receive this therapy [CIR (95% CI), 0% vs. 19.4% (10.9%-29.6%), P = 0.010]. Other therapeutic interventions, including LDCA and exchange blood transfusion, were not associated with AMKL development. Conclusion: FCM-MRD positivity at 1 month and 3 months might be a useful marker to predict leukemia development in patients with TAM. Although LDCA therapy significantly decreased the rate of early deaths, it did not suppress leukemia development. Interestingly, systemic steroid therapy might suppress leukemia development. These results pave the way to design clinical trials for developing MRD-directed leukemia prevention therapy for patients with TAM. Disclosures No relevant conflicts of interest to declare.

scholarly journals Investigating the Link Between Trisomy 21 and Acquired Mutations in the GATA1 Gene

The Physician ◽  
2019 ◽  
Vol 6 (1) ◽  
pp. c9
Author(s):  
Triya Chakravorty ◽  
Irene Roberts
Keyword(s):  
Down Syndrome ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Trisomy 21 ◽  
Children With Down Syndrome ◽  
Transient Abnormal Myelopoiesis ◽  
Increased Risk ◽  
Leukaemic Cells ◽  
Acute Myeloid

Children with Down syndrome (DS) due to trisomy 21 (T21) are at an increased risk of developing the neonatal preleukaemic disorder transient abnormal myelopoiesis (TAM), which may transform into childhood acute myeloid leukaemia (ML-DS). Leukaemic cells in TAM and ML-DS have acquired mutations in the GATA1 gene. Although it is clear that acquired mutations in GATA1 are necessary for the development of TAM and ML-DS, questions remain concerning the mechanisms of disease.

A Case of Novel GATA-1 Mutation–positive Transient Abnormal Myelopoiesis With Life-threatening Complications in a Neonate With Down Syndrome

2019 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Ritesh R. Sah ◽  
Somosri Ray ◽  
Prateek Bhatia ◽  
Shashi K. Dhir ◽  
Sidharth Totadri ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Transient Abnormal Myelopoiesis ◽  
Life Threatening

scholarly journals Cytokine Profiles in Pericardial Effusion in a Down Syndrome Infant with Transient Abnormal Myelopoiesis

2017 ◽  
Vol 241 (2) ◽  
pp. 149-153
Author(s):  
Yoshihiko Shitara ◽  
Naoto Takahashi ◽  
Yoshinori Aoki ◽  
Motohiro Kato ◽  
Riki Nishimura ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Pericardial Effusion ◽  
Cytokine Profiles ◽  
Transient Abnormal Myelopoiesis

scholarly journals Fetal Liver Stromal Cells Support Blast Growth in Transient Abnormal Myelopoiesis in Down Syndrome Through GM-CSF

2014 ◽  
Vol 115 (6) ◽  
pp. 1176-1186 ◽  
Author(s):  
Jun Miyauchi ◽  
Hiroyuki Kawaguchi
Keyword(s):  
Down Syndrome ◽  
Stromal Cells ◽  
Fetal Liver ◽  
Gm Csf ◽  
Transient Abnormal Myelopoiesis

Prospective Study of 168 Infants with Transient Abnormal Myelopoiesis with Down Syndrome: Japan Pediatric Leukemia/Lymphoma Study Group, TAM-10 Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1311-1311 ◽  
Author(s):  
Hideki Muramatsu ◽  
Tomoyuki Watanabe ◽  
Daisuke Hasegawa ◽  
Park Myoung-ja ◽  
Shotaro Iwamoto ◽  
...  
Keyword(s):  
Risk Factors ◽  
Down Syndrome ◽  
Gestational Age ◽  
Early Death ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Factors Associated ◽  
Transient Abnormal Myelopoiesis ◽  
Lymphoma Study Group ◽  
Wbc Count

Abstract Introduction: Transient abnormal myelopoiesis (TAM) occurs in approximately 10% of infants with Down syndrome (DS). Although most patients achieve spontaneous remission, some develop severe organ failure and die in their infancy. Previous studies have identified several risk factors associated with early death in such cases, including a high white blood cell (WBC) count, early gestational age, and ascites (Massey GV, 2006; Muramatsu H, 2008; Klusmann JH, 2008). Although chemotherapy with low-dose cytosine arabinoside (LDCA) has been applied for severe cases, its side effect profile has not been fully demonstrated in an adequate number of patients. Here we prospectively analyzed 168 infants with DS who were diagnosed with TAM, including 52 patients treated with LDCA. We assessed the efficacy and safety of LDCA therapy in these cases. Patient and Methods: Between May 2011 and February 2014, 168 infants (90 boys and 78 girls) were diagnosed with TAM and prospectively registered in the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) TAM-10 study. GATA1 gene mutations were identified in all except 7 patients who had a very low blast percentage. The median (range) of WBC count was 38.6 (2.4-478.7) × 109 cells/L, and the median (range) of gestational age was 37 (29-40) weeks. Thirty one (18%) patients developed anasarca at diagnosis, and 23 (14%) patients developed acute megakaryocytic leukemia. Results: The overall survival (OS) rate and the event-free survival (EFS) rate at 1 year from diagnosis [95% confidential interval (CI)] were 86.3% (80.1-90.7), and 80.2% (73.2-85.5), respectively. Univariate analysis identified the following covariates as risk factors associated with early death (<9 months): early gestational age [<37 weeks; hazard ratio (HR; 95% CI) = 4.482 (1.826-10.997), p = 0.001], parenchymal bleeding [HR (95% CI) = 5.746 (2.241-14.734), p < 0.001], anasarca [HR (95% CI) = 13.344 (5.419-32.860), p < 0.001], and high WBC count [ ≥100 × 109 cells/L; HR (95% CI) = 8.013 (3.354-19.144), p < 0.001]. The multivariate Cox hazard model identified anasarca and a high WBC count (≥100 × 109 cells/L) as independent risk factors for early death. With regard to the 52 patients who received LDCA therapy, only anasarca remained an independent risk factor for early death. Subgroup analysis in patients with a high WBC count (≥100 × 109 cells/L; n = 36) showed that LDCA therapy significantly improved survival [1-year OS (95% CI) = 78.3% (55.4-90.3; n = 23) vs. 38.5% (14.1-62.8; n = 13); p = 0.009]. In contrast, the survival rate of patients with anasarca (n = 31) did not improve on receiving LDCA therapy [1-year OS (95% CI) = 58.3% (27.0-80.1; n = 12) vs. 47.4% (24.4-67.3; n = 19); p = 0.525]. The most common side effect of LDCA was neutropenia (grade 3-4 = 59%), and one patient died due to tumor lysis syndrome. Conclusion: This prospective study confirmed that a high WBC count and anasarca are risk factors for early death in patients with DS who were diagnosed with TAM. Although LDCA therapy could significantly improve the survival rate in patients with a high WBC count, it failed to change the prognosis of patients with anasarca. A new treatment modality is required for most severe TAM patients with anasarca at diagnosis. Disclosures No relevant conflicts of interest to declare.

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