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.

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 Retrospective Analysis of the Treatment Outcome in Myeloid Leukemia of Down Syndrome in Polish Pediatric Leukemia and Lymphoma Study Group From 2005 to 2019

2020 ◽  
Vol 8 ◽  
Author(s):  
Malgorzata Czogala ◽  
Katarzyna Pawinska-Wasikowska ◽  
Teofila Ksiazek ◽  
Barbara Sikorska-Fic ◽  
Michal Matysiak ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Treatment Outcome ◽  
Retrospective Analysis ◽  
Myeloid Leukemia ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Lymphoma Study Group

scholarly journals Risk-Oriented Therapy for Myeloid Leukemia of Down Syndrome: A Nationwide Prospective Study By the Japanese Pediatric Leukemia / Lymphoma Study Group (JPLSG)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3668-3668
Author(s):  
Takashi Taga ◽  
Tomoyuki Watanabe ◽  
Kazuko Kudo ◽  
Daisuke Tomizawa ◽  
Kiminori Terui ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Dose Reduction ◽  
Induction Therapy ◽  
Cytotoxic Agents ◽  
Age At Diagnosis ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Monosomy 7 ◽  
Female Ratio ◽  
Lymphoma Study Group

Abstract Introduction: Asmyeloid leukemia in Down syndrome patients (ML-DS) is known to have higher sensitivity against cytotoxic agents, children with ML-DS are treated with less intensive ML-DS-oriented protocol in recent clinical studies. On the basis of results of previous Japanese trials for ML-DS, we have evaluated an efficacy of the risk-oriented therapy in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-D05 study. Patients and Methods: Between January 2008 and December 2010, seventy-four patients with newly diagnosed ML-DS from 122 hospitals in Japan were enrolled in this study. All patients received induction chemotherapy consisted of pirarubicin (25 mg/m2/d for 2 days), cytarabine (100 mg/m2/d for 7 days), and etoposide (150 mg/m2/d for 3 days). Patients who achieved complete remission (CR) after initial induction therapy were stratified to the Standard Risk (SR) and received four courses of reduced dose intensification therapy. Patients who did not achieve CR were stratified to the High Risk (HR) and received intensfied therapy consisted of continuous and high-dose cytarabine. Prophylaxis for CNS leukemia was not included throughout the therapy. Results: Out of 74 patients registered in this study, two patients were excluded (one because of uncontrolled cardiac failure, another of non-Down syndrome), and 72 were eligible and were evaluated. Male/Female ratio was 40/32. The median age at diagnosis was 19 months (range, 10 months and 17 years old). Median follow-up period was 3.64 years (range, 0.05 -5.96 years. One patient died of sepsis during initial induction therapy. Sixty-nine patients were stratified to SR and 2 patients to HR. Both of the two HR patients achieved CR but one relapsed. No therapy-related death was observed during intensification therapy. The 3-year event free and overall survival rate was 83.3% ± 4.4% and 87.5% ± 3.9 %, respectively. Age at diagnosis less than 2 years old was significant favorable prognostic factor for relapse (p=0.009). Sex, history of TAM, and chromosomal abnormalities (Normal karyotype or monosomy 7) did not influence the risk of relapse. Conclusion: This study succeeded the previous Japanese strategy with very low-intensive chemotherapy regimen for ML-DS, and despite the dose reduction of chemotherapeutic agents compared to the previous studies, the overall outcome was good and further dose reduction might be possible for specific subgroups. However, considering that most relapse occurred in the SR group defined by morphological treatment response and that relapsed cases are rarely salvageable, more accurate method for identification of the poor prognostic subgroup is needed. This trial is registered with UMIN Clinical Trials Registry (UMIN-CTR, URL: http://www.umin.ac.jp/ctr/index.htm), number UMIN000000989. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Efficacy of Low-Dose Cytosine Arabinoside Therapy for Patients of Down Syndrome with Transient Abnormal Myelopoiesis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 977-977
Author(s):  
Takahiro Kanzawa ◽  
Kyogo Suzuki ◽  
Hirotoshi Sakaguchi ◽  
Nao Yoshida ◽  
Koji Kato
Keyword(s):  
Down Syndrome ◽  
Pericardial Effusion ◽  
Liver Fibrosis ◽  
Liver Failure ◽  
Clinical Outcomes ◽  
Gestational Age ◽  
Low Dose ◽  
Transient Abnormal Myelopoiesis ◽  
Wbc Count ◽  
Peak Value

Abstract <Introduction> Transient abnormal myelopoiesis (TAM) occurs in about 10% of neonates with Down syndrome. While TAM is generally considered as self-limiting disease, substantial number of patients suffer from serious complications including liver fibrosis or pericardial effusion and eventually leads to fatal clinical outcomes. Low-dose cytosine arabinoside (CA) therapy has been reported to be effective for clinical symptoms of TAM patients, but it is still controversial as to which patient should be treated. We have retrospectively reviewed the clinical outcomes of TAM patients in our institution to confirm the efficacy as well as the safety of low-dose CA therapy by comparing the clinical outcomes before and after introduction of CA. <Patients> Before introduction of CA, we have experienced 20 TAM patients of 13 male and 7 female between September 1992 and November 2008. The median gestational age of those was 37w4d (range, 31w5d - 39w2d) , median peak value of white blood cell (WBC) count was 48×109/L (range, 19.8 - 399×109/L), and median peak direct bilirubin(DB) level was 0.9 mg/dL (range, 0.1 - 18.4 mg/dL), respectively. Sixteen of twenty patients (80%) had various complications including dyspnea, hepatosplenomegaly, pericardial effusion, and ascites. Since 2009, we have introduced low dose CA (0.4 - 1.0mg/kg/day) for those with high WBC count (>100×109/L) until WBC count decrease to 10×109/L . Three patients received chemotherapy, but one patient with high WBC count did not, because consent was not obtained. The median gestational age of those was 36w4d (range, 33w6d - 39w2d) , median peak value of WBC count was 106×109/L (range, 101 - 267×109/L), and median peak DB level was 1.95mg/dL (range, 1.0 - 11.0 mg/dL), respectively. All of them had various complications including dyspnea, hepatosplenomegaly, pericardial effusion, liver fibrosis and ascites. <Results> Before introduction of low dose CA therapy, five of six patients (83%) with high WBC count (>100×109/L) died of liver failure(4 of 5 patients) or AML, and one of 14 patients (7%) with low WBC count (<100×109/L) died of pneumonia at the age of eight without any relation to TAM. After introduction of CA, all three patients who received chemotherapy are alive without serious complications related to TAM or chemotherapy. Their blast cells in the peripheral blood disappeared promptly and liver dysfunction as well as biomarker of liver fibrosis is getting normalized. One patient who did not receive chemotherapy died of liver failure in spite of supportive care. <Conclusion> It is suggested that low dose CA therapy is safely conducted and is effective to improve the clinical outcomes of TAM patients with high WBC count. Prospective analysis is mandatory to confirm our findings by multi-institutional basis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Post-Induction Minimal Residual Disease Measured By Flow Cytometry and Deep Sequencing of Mutant GATA1 Are Both Significant Prognostic Factors for Children with Myeloid Leukemia and Down Syndrome: A Nationwide Prospective Study of the Japanese Pediatric Leukemia/Lymphoma Study Group

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3848-3848 ◽  
Author(s):  
Takashi Taga ◽  
Shiro Tanaka ◽  
Kiminori Terui ◽  
Shotaro Iwamoto ◽  
Hidefumi Hiramatsu ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Prognostic Factors ◽  
Deep Sequencing ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Lymphoma Study Group ◽  
Minimal Residual

Background: Myeloid leukemia in Down syndrome (ML-DS) is associated with good response to chemotherapy thus results in a favorable outcome. However, relapsed and refractory cases are rarely salvageable, regardless of receiving hematopoietic stem cell transplantation. Several factors such as certain chromosomal abnormalities and age at diagnosis are somewhat prognostic, but no universal prognostic factor has been found to date. In order to identify a subgroup with high risk of treatment failure, the role of minimal residual disease (MRD) with three methods were explored in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) trial AML-D11. Procedure: AML-D11 is a nationwide single-arm clinical trial for children (4 months to 17 years old) with ML-DS. All patients received an identical chemotherapy to the previous AML-D05 study (Taga T. Pediatr Blood Cancer 2016). MRD was evaluated at two time points, one after the induction therapy and another at the end of whole chemotherapy, using 3 different methods; flow cytometric MRD (FCM-MRD), deep sequencing MRD of mutant GATA1 (GATA1-MRD) and PCR MRD of WT1 mRNA expression (WT1-MRD). WT1-MRD was measured in both bone marrow (BM) and peripheral blood (PB) samples, while FCM- and GATA1-MRD were measured only in BM samples. Results: A total of 78 patients were eligible and followed-up with a median of 47.6 months (range, 8 to 68.8 months). Seventy-six patients were stratified to the standard risk (SR) and one patient to the high risk (HR) group by morphological response. One patient died of sepsis during initial induction therapy. Three-year event-free survival (EFS) and overall survival (OS) rates were 87.2% (95%CI, 77.5 to 92.9%) and 89.7% (95%CI, 80.5 to 94.7%), respectively. FCM-MRD and GATA1-MRD after initial induction therapy were positive in 5/65 and 7/59 patients, respectively, which were both significantly prognostic (Fig.1). Prognostic significance of WT1-MRD could not be evaluated due to a limited number of collected samples. Conclusions: MRD detections by FCM and targeted deep sequencing of GATA1 after initial induction therapy are both significant prognostic factors for predicting relapse. Risk stratification using FCM-MRD is currently incorporated in the on-going Japan Children's Cancer Group ML-DS trial (AML-D16; jrct.niph.go.jp, jRCTs041190047). Figure 1 Disclosures No relevant conflicts of interest to declare.

Leukostasis in Children and Adolescents with Chronic Myeloid Leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group

2015 ◽  
Vol 63 (3) ◽  
pp. 406-411 ◽  
Author(s):  
Hidemitsu Kurosawa ◽  
Akihiko Tanizawa ◽  
Chikako Tono ◽  
Akihiro Watanabe ◽  
Haruko Shima ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Children And Adolescents ◽  
Myeloid Leukemia ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Lymphoma Study Group

Risk factors associated with reported bruxism among children and adolescents with Down Syndrome

CRANIO® ◽  
2018 ◽  
Vol 38 (6) ◽  
pp. 365-369 ◽  
Author(s):  
Natália Cristina Ruy Carneiro ◽  
Isabela de Castro Souza ◽  
Tahyná Duda Deps Almeida ◽  
Júnia Maria Cheib Serra-Negra ◽  
Isabela Almeida Pordeus ◽  
...  
Keyword(s):  
Risk Factors ◽  
Down Syndrome ◽  
Children And Adolescents ◽  
Factors Associated

Infectious complications in children treated for hodgkin and non-hodgkin lymphomas in polish pediatric leukemia/lymphoma study group: incidence, epidemiology and etiology

2018 ◽  
Vol 60 (1) ◽  
pp. 124-132 ◽  
Author(s):  
Olga Zajac-Spychala ◽  
Jacek Wachowiak ◽  
Anna Szmydki-Baran ◽  
Lukasz Hutnik ◽  
Malgorzata Salamonowicz ◽  
...  
Keyword(s):  
Infectious Complications ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Lymphoma Study Group

Interventions for metabolic problems in people with schizophrenia

2017 ◽  
Author(s):  
David J. Castle ◽  
Peter F. Buckley ◽  
Fiona P. Gaughran
Keyword(s):  
Risk Factors ◽  
Metabolic Syndrome ◽  
Physical Health ◽  
Early Death ◽  
Effective Communication ◽  
Self Management ◽  
Antipsychotic Medications ◽  
Factors Associated ◽  
The Metabolic Syndrome ◽  
Comprehensive Framework

To address the risk factors associated with early death in people with schizophrenia, a comprehensive framework is required. This is required to address individuals, systems, and the community. A number of specific frameworks are available to provide better physical health treatments for people with schizophrenia. The most effective of these embrace elements of self-management and self-efficacy. The engagement of patients, carers, and clinicians requires concerted work and effective communication. Peer workers can play a particular role. Various medications can also be used to address specific aspects of the metabolic syndrome in particular, and care should be taken to try to choose (where feasible) antipsychotic medications with the lowest possible risk of metabolic syndrome.

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