Low-Dose Cytosine Arabinoside Therapy for Neonates with Down Syndrome (DS) and Transient Leukemia (TL).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1074-1074
Author(s):  
Hideki Muramatsu ◽  
Yasuhide Hayashi ◽  
Machiko Kawamura ◽  
Seiji Kojima ◽  
Miharu Yabe ◽  
...  
Keyword(s):  
Overall Survival ◽  
Down Syndrome ◽  
Clinical Outcome ◽  
Cytosine Arabinoside ◽  
Peripheral Blood ◽  
Low Dose ◽  
Early Death ◽  
Transient Leukemia ◽  
Blast Cells ◽  
Wbc Count

Abstract Abstract 1074 Introduction: Transient leukemia (TL), which is also referred to as transient myeloproliferative disorder or transient abnormal myelopoiesis, occurs in approximately 10% of infants with Down syndrome (DS). This disorder is characterized by the appearance of blast cells with megakaryoblastic and/or erythroblastic characteristics in the peripheral blood. While most TL patients have a favorable clinical course and the blast cells disappear spontaneously, vital organ failure and early death occurs in some patients. In this group of patients, liver failure with hepatic fibrosis and cardiopulmonary failure are the major causes of death. Recently, low-dose cytosine arabinoside (Ara-C) therapy has been reported to be effective for improving the clinical outcome in TL patients with severe liver or cardiopulmonary disease. However, because the disease resolves spontaneously in most instances, it is not generally recommended that all patients receive antileukemic therapy. It is unknown whether the survival rate of certain TL patients could be improved by low-dose Ara-C. This study was conducted to clarify the safety and efficacy of low-dose Ara-C therapy for TL patients with DS. Patients and Methods: A retrospective questionnaire survey of patients diagnosed with DS between 2003 and 2009 was conducted to identify all DS neonates with TL. The eligibility criteria for the analysis were infants with DS who were younger than 3 months and had circulating blast cells in the peripheral blood. A total of 153 patients (81 male, 72 female) were identified. Results: Thirty-four of the 153 patients (22%) died. Early death occurred in 31 of 153 patients (20%); the median age at death was 47 days (range, 9–241 days). The covariates that were significantly correlated with early death were examined further. On univariate analysis, the following covariates were identified: early estimated gestational age, WBC ≥ 100 × 109/L, severe bleeding, and anasarca. On multivariate analysis, it was confirmed that WBC ≥ 100 × 109/L and anasarca were independent risk factors for early death. Twenty of the 121 patients (16.5%) who survived for more than 9 months after birth subsequently developed acute myeloid leukemia at a median age of 16 months (range, 3–45 months). All 21 patients were diagnosed as having acute megakaryoblastic leukemia (AMKL) and received low intensity chemotherapy specific for AMKL in DS patients. Eighteen of 21 (86%) patients achieved a complete remission, and they are alive and well; whereas 3 patients who had refractory or relapsed leukemia died. Twenty-eight of the 153 patients (18%) received low-dose Ara-C therapy. The median dose and duration of Ara-C were 0.95 mg/kg/day (range, 0.4–3.1 mg/kg/day) and 7 days (range, 2–15 days), respectively. The median duration of neutropenia (<0.5 × 109/L) was 0 days (range, 0–14 days). All patients recovered from myelosuppression and safely accomplished the treatment, except in 1 patient who had received 11 days of Ara-C treatment and died of prolonged neutropenia-induced sepsis. Sixteen of 28 (57%) patients were started to receive Ara-C within 10 days after diagnosis, whereas 12 patients received Ara-C later. While the median WBC count of early treated patients was significantly higher than that of other patients (133.5 × 109/L; range, 16.0–356.9 □L 109/L vs 31.9 × 109/L; range, 4.4–341.5 × 109/L.; p < 0.001), the probability of 1-year overall survival of patients who received low-dose Ara-C within 10 days after the initial diagnosis of TL was similar to that of patients who received Ara-C later or who did not receive Ara-C (69.4 ± 12.9%; n = 16 vs. 79.7 ± 3.5%; n = 137; p = 0.614). By subgroup analysis of patients with WBC ≥ 100 × 109/L, the probability of 1-year overall survival of patients who received early Ara-C treatment was significantly higher than that of others (66.1 ± 13.9%; n = 13 vs. 33.3 ± 8.6%; n = 30; p = 0.035). Conclusion: In summary, we found that low-dose Ara-C therapy for patients with TL and DS has a tolerable toxicity profile, and early intervention with this therapy could improve the clinical outcome of patients whose WBC count exceeds 100 × 109/L. We plan to confirm the efficacy of low dose Ara-C treatment in a prospective clinical trial for high-risk patients with DS and TL. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 2991-2998 ◽  
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.

A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4606-4613 ◽  
Author(s):  
Gita V. Massey ◽  
Alvin Zipursky ◽  
Myron N. Chang ◽  
John J. Doyle ◽  
Suhail Nasim ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Natural History ◽  
Trisomy 21 ◽  
Subsequent Development ◽  
Early Death ◽  
Spontaneous Remission ◽  
Disease Recurrence ◽  
Megakaryoblastic Leukemia ◽  
Transient Leukemia ◽  
Blast Cells

AbstractA unique transient leukemia (TL) has been described in newborns with Down syndrome (DS; or trisomy 21 mosaics). This leukemia has a high incidence of spontaneous remission; however, early death and subsequent development of acute megakaryoblastic leukemia (AMKL) have been reported. We prospectively evaluated 48 infants with DS and TL to determine the natural history and biologic characteristics of this disease, identify the clinical characteristics associated with early death or subsequent leukemia, and assess the incidence of subsequent leukemia. Blast cells associated with TL in DS infants exhibited FAB M7 morphology and phenotype. Most infants (74%) had trisomy 21 (or mosaicism) as the only cytogenetic abnormality in the blast cells. Most children were able to spontaneously clear peripheral blasts (89%), normalize blood counts (74%), and maintain a complete remission (64%). Early death occurred in 17% of infants and was significantly correlated with higher white blood cell count at diagnosis (P < .001), increased bilirubin and liver enzymes (P < .005), and a failure to normalize the blood count (P = .001). Recurrence of leukemia occurred in 19% of infants at a mean of 20 months. Development of leukemia was significantly correlated with karyotypic abnormalities in addition to trisomy 21 (P = .037). Ongoing collaborative clinical studies are needed to determine the optimal role of chemotherapy for infants at risk for increased mortality or disease recurrence and to further the knowledge of the unique biologic features of this TL.

GATA1 Mutants Lacking Rb-Binding Motif Observed in Transient Abnormal Myelopoiesis in Down Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1491-1491
Author(s):  
Tsutomu Toki ◽  
Eri Kobayashi ◽  
Rika Kanezaki ◽  
RuNan Wang ◽  
Kiminori Terui ◽  
...  
Keyword(s):  
Amino Acids ◽  
Down Syndrome ◽  
Peripheral Blood ◽  
Early Death ◽  
Nucleotide Deletion ◽  
Transient Abnormal Myelopoiesis ◽  
Id Proteins ◽  
Blast Cells

Abstract Abstract 1491 Five to ten percent of neonates with Down syndrome (DS) develop transient abnormal myelopoiesis (TAM), which is characterized by a rapid growth of abnormal blast cells with the erythroid/megakaryocytic phenotype. In most cases, it resolves spontaneously within three months. However, 20 to 30% of patients develop acute megakaryocytic leukemia referred to as myeloid leukemia of DS (ML-DS) within four years. Blast cells in most of TAM and ML-DS patients have mutations in exon 2 of the gene encoding transcription factor GATA1, which is essential for the normal development of erythroid and megakaryocytic cells. These mutations lead to expression of a truncated GATA1 protein lacking the N-terminal 83 amino acids (GATA1s). However, the molecular mechanism whereby GATA1s contributes to the genesis of TAM and ML-DS remains elusive. From 2003 to 2010, we screened GATA1 mutations in clinical samples obtained from 106 patients with TAM upon request from referring hospitals. We performed direct sequencing analysis using cDNA prepared form total RNA extracted from white blood cells in peripheral blood and genomic DNA. Acquired GATA1 mutations were detected in a total of 99 (93.4%) patients among them. Most of these mutations were coding GATA1s. However, the mutations coding GATA1 mutants with internal deletion of 43 and 15 amino acids were detected in five and one patients, and we referred to them as GATA-ID type-1 and GATA1-ID type-2, respectively. Sequences of exon 3 were discrepant with that expected from the corresponding cDNA sequence. Instead, a 2-nucleotide insertion, a 2-nucleotide deletion and a 7-nucleotide deletion with a single-nucleotide substitution were detected in exon 3 of the GATA1 gene in the GATA1-ID type-1 patients, and a 21-nucleotide deletion encompassing the boundary of intron 2 and exon 3 was found in the GATA-ID type-2 patient. These findings suggest that the mutations in exon 3 lead to expression of alternative splicing forms of mRNA encoding GATA1-ID. To investigate the role of GATA1-ID on the pathogenesis of TAM and ML-DS, we next expressed GATA1-ID by retrovirus in a ML-DS cell line, KPAM1, or primary GATA1-deficient fetal megakaryocytic progenitors. Expectedly, the cell growth was markedly reduced upon transduction with full-length GATA1-expression retrovirus. However, ectopic expression of GATA1-ID type-1 and type-2 failed to restrict the proliferation of cells as similar as expression of GATAs. Interestingly, all these patients had high white blood cell counts in the peripheral blood at diagnosis. Furthermore, three patients developed liver fibrosis and two had effusion. All these factors are significantly associated with early death. Three patients were treated with low dose of Ara-C. However, early death occurred in three patients. In this study we found that GATA1-ID proteins are created by somatic mutations in DS patients and contribute to the generation of TAM phenotypes. Our newly identified GATA1-ID mutants have highlighted a much narrower set of sequences responsible for the pathogenesis of than was previously suggested. The missing region identified by the GATA1-ID proteins contains a consensus motif (LxCxE, amino acids 81–85) essential for the interaction with pRB protein and this motif is also lost in GATA1s. Our results suggested the lack of Rb-GATA1 interaction as the most likely pathogenesis for onset of TAM. Disclosures: No relevant conflicts of interest to declare.

GATA1 mutations Outside the Blast Cell Population in Transient Leukemia of Down Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2562-2562
Author(s):  
Jian Chen ◽  
Agnieszka Wendorff ◽  
Yue Li ◽  
Johann K. Hitzler
Keyword(s):  
Down Syndrome ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Cell Clone ◽  
Blast Cell ◽  
Cell Populations ◽  
Wild Type ◽  
Blood Samples ◽  
Transient Leukemia ◽  
Blast Cells

Abstract Abstract 2562 Background. Transient leukemia (TL), a disorder of fetal hematopoiesis, occurs in approximately 10% of infants with Down syndrome and in one fifth of cases is followed by the development of acute myeloid leukemia. The diagnosis of TL is based on the detection of a spontaneously resolving population of blasts in the peripheral blood of newborns with DS and, more recently, the detection of clone-specific somatic mutations of the hematopoietic transcription factor GATA1. The alternative terms for this condition, transient myeloproliferative disorder (TMD) and transient abnormal myelopoiesis (TAM), reflect the observation that the peripheral blood of affected infants frequently shows an expansion of immature granulocytic precursor cells at various stages of development as well as nucleated erythroid precursors in addition to a population of blast cells. We hypothesized that the immature myeloid precursor cells observed in TL arise from the same hematopoietic cell clone that is defined by the specific GATA1 mutation found in TL blasts. Methods. Cryopreserved mononuclear cells from peripheral blood samples of three male infants with TL of Down syndrome were stained at a density of 106 cells/100ul with the following antibodies: CD45-Alexa Flour 700, CD61-PE, CD11b-PE-Cy5, CD235a-PE-Cy7, CD3-APC, CD34-APC-Cy7, CD15-Pacific Blue. In addition, aliquots of these cell populations were fixed, permeabilized and stained with for intracellular myeloperoxidase (MPO-FITC). Fractions of cells corresponding to different hematopoietic lineages were prepared by fluorescence activated cell sorting (FACSAriaII, BD Biosciences, San Jose, CA) both as bulk populations and single cells (sorted into 96-well plates). Morphology of sorted cell populations was determined by Giemsa staining. Lineage-specific hematopoietic colonies were cultured from primary mononuclear cell samples in a standard CFC assay. DNA of sorted bulk and single cell populations as well as individual lineage-specific hematopoietic colonies was used to detect GATA1 mutations in exon 2 by PCR, restriction enzyme analysis or sequencing of PCR products, or nested PCR. The location of the GATA1 gene on the X chromosome and the use of samples derived from males meant that wild type GATA1 alleles were not derived from TL cells. Results. Primary TL blood samples could be fractionated in a blast cell (CD45+CD34+and/or CD61+), erythroid (CD45-CD235a+), immature myeloid (CD45+CD15+MPO+) and lymphoid (CD45+CD3+) cell population. Cell morphology was consistent with this sorting strategy. The cell fraction designed to enrich TL blasts in all cases showed the presence of cells harboring only the mutant GATA1 allele indicating a high degree of purity of the blast fraction. As expected, the lymphoid cell populations contained in the CD3+ fractions exclusively harbored wild type alleles. Similarly, both sorted erythroid cell populations and individual erythroid colonies (Bfu-E) derived from unsorted input cells harbored only wild type GATA1 alleles. In contrast, CD15+ and/or MPO+ myeloid cell fractions consistently showed the presence of both mutant and wild type GATA1 alleles. Quantification by single cell PCR is in progress. Conclusion. Somatic GATA1 mutations which result in the translation of a N-terminally truncated mutant protein (GATA1s), are pathognomonic for TL and myeloid leukemia of Down syndrome. Published data do not determine if the cell clone harboring GATA1 mutations in TL extends beyond the population of blast cells and megakaryocytic lineage. We confirmed the presence of GATA1 mutations in TL blasts and their expected absence from lymphoid cell populations. The absence of mutations from cells of erythroid lineage suggests that the altered GATA1 function induced by mutations found in TL is incompatible with erythroid differentiation. The detection of clone-specific GATA1 mutations in myeloid cells expressing MPO was unexpected and raises the possibility that either the progenitor cells giving rise to TL blasts or the blasts themselves retain myeloid lineage differentiation potential. The finding lends support to definitions of TL and myeloid leukemia in Down syndrome that are based on the specific mutational and cellular mechanism and transcend a megakaryoblastic blast phenotype. 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.

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.

Recommendations for Diagnosis and Treatment of Children with Transient Abnormal Myelopoiesis (TAM) and Myeloid Leukemia in Down Syndrome (ML-DS)

2021 ◽  
Author(s):  
Sina Al-Kershi ◽  
Richard Golnik ◽  
Marius Flasinski ◽  
Katharina Waack ◽  
Mareike Rasche ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Early Death ◽  
Spontaneous Remission ◽  
Therapeutic Strategies ◽  
Treatment Protocols ◽  
Transient Abnormal Myelopoiesis ◽  
Cure Rates ◽  
Low Dose Cytarabine

AbstractChildren with Down syndrome are at a high risk of developing transient abnormal myelopoiesis (TAM; synonym: TMD) or myeloid leukemia (ML-DS). While most patients with TAM are asymptomatic and go into spontaneous remission without a need for therapy, around 20% of patients die within the first six months due to TAM-related complications. Another 20–30% of patients progress from TAM to ML-DS. ML-DS patients are particularly vulnerable to therapy-associated toxicity, but the prognosis of relapsed ML-DS is extremely poor – thus, ML-DS therapy schemata must strive for a balance between appropriate efficacy (to avoid relapses) and treatment-related toxicity. This guideline presents diagnostic and therapeutic strategies for TAM and ML-DS based on the experience and results of previous clinical studies from the BFM working group, which have helped reduce the risk of early death in symptomatic TAM patients using low-dose cytarabine, and which have achieved excellent cure rates for ML-DS using intensity-reduced treatment protocols.

Four Different Presentations of Transient Myeloproliferative Disorder.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4966-4966
Author(s):  
Nataly Apollonsky ◽  
Mark P. Atlas ◽  
Banu Aygun
Keyword(s):  
Bone Marrow ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Low Dose ◽  
Normal Karyotype ◽  
Full Term ◽  
Cd 34 ◽  
Hla Dr ◽  
Buccal Smear ◽  
Wbc Count

Abstract Transient myeloproliferative disorder (TMD) develops in 10 % of the newborns with Down syndrome and resolves spontaneously by 2 – 3 month of life. It can also occur in a newborn with normal karyotype and trisomy 21 restricted to the abnormal clone in the bone marrow. We report 4 cases with TMD, who were diagnosed and followed in our institution between 2001–2005. Two newborns had normal germline karyotype but trisomy 21 in the bone marrow and two newborns had Down syndrome. Case 1: Full term phenotypically normal newborn presented with hepatosplenomegaly. WBC was 50,000/mm3 with 48% blasts. Bone marrow showed 84% blasts that were CD10, CD19, CD20, partial CD34, partial HLA-DR positive. Skin biopsy revealed normal karyotype 46 XY, but cytogenetics of bone marrow showed that 8/20 cells had 48 XY, +21, +22. Patient’s counts improved by second month of life. At 7 months of age, he developed pancytopenia and bilateral temporal swelling with bony involvement. BMA showed AML (CD13+ and CD33+). He was treated with chemotherapy following CCG-2981. Currently he is 4 years old and in remission. Case 2: Full term phenotypically normal newborn presented with thrombocytopenia. WBC count was 20,000/mm3 with 5% blasts. Bone marrow aspiration showed 26% blasts that expressed CD33, CD13, CD4, Cd117, Cd56, partial HLA-DR and partial CD34. Cytogenetics of the blood was normal, however bone marrow revealed 47, XY, +21. His CBC normalized during the second month of life. Currently he is 4 years old and doing well. Case 3: Full term phenotypically normal newborn presented with respiratory distress, organomegaly and WBC: 115,000/mm3 with 60% blasts. Immunophenotype demonstrated expression of CD 45 with two populations; one CD33+, CD34 + and the other CD61+, CD42+. The karyotype of the blood and buccal smear revealed 47,XY, +21. Patient was treated with low dose ARA-C due to critical condition and WBC decreased to 20,000/mm3. During the next weeks he developed multiorgan failure (cardiorespiratory, renal and hepatic). Despite all measures he expired on Day 21 of life. Case 4: Full term baby with Down syndrome was diagnosed with AV canal and Tetralogy of Fallot during the prenatal period. Initial WBC count was 36,000/mm3 with 65% blasts. Immunophenotype was positive for CD33, CD34, CD4, CD117, partial HLA DR, partial CD13, partial CD56. The karyotype of the blood and buccal smear both revealed trisomy 21. Her clinical course was complicated by cardiac surgery, sepsis with persistent thrombocytopenia. Currently she is 6 months old with a normal CBC. Conclusion: TMD can have many variable presentations and outcomes ranging from spontaneous remission to leukemia to death. Any newborn with TMD should have cytogenetic studies and be followed up closely for development of leukemia. Clinical characteristics of newborns with TMD Patient Initial WBC/Blast % Karyotype Cytogenetics (bone marrow) Treatment Immunophenotype Outcome CCR: continous clinical remission, y: year, mo: months 1 50.000/ 48% 46 XY (skin biopsy) 48 XY, +21, +22 CCG 2981 CD 10, CD 19, CD 20, CD 34 partial, HLA DR. At leukemia CD13 and CD 34 CCR, alive (4 y) 2 20.000/26% 46 XY(peripheral blood) 47 XY, +21 supportive Low dose ARA CD 33, CD 13, CD 4, CD 7, CD 56, CD 34 partial, HLA DR partial CCR, alive (4 y) expired 3 115.000/ 60% 47 XY, +21 (buccal smear) 47 XY, +21 C x 5 days CD 33, CD 34, CD 61, CD 42 CD 33, CD 34, CD 4, CD 117, CD 56 Day 21 CCR, alive 4 36.000/65% 47 XX, +21 (buccal smear) 47 XX, +21 supportive partial, HLA DR partial, CD 13 partial. (6mo)

A Retrospective Analysis of 70 Cases of Transient Leukemia (TL) in Neonates with Down Syndrome (DS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4864-4864 ◽  
Author(s):  
Hideki Muramatsu ◽  
Nobuhiro Watanabe ◽  
Kimikazu Matsumoto ◽  
Tomohiko Nakamura ◽  
Junichi Mimaya ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Prognostic Factors ◽  
Gestational Age ◽  
Apgar Score ◽  
Univariate Analysis ◽  
Case Series ◽  
Early Death ◽  
Direct Bilirubin ◽  
Prospective Clinical Study ◽  
Transient Leukemia

Abstract Transient Leukemia (TL) occurs in approximately 10% of infants with Down syndrome(DS). Most of cases achieve spontaneous remission, but there are severe, potentially lethal cases which manifest hepatic fibrosis or cardiopulmonary failure. COG reported the incidence of 17% early death in 48 TL cases in DS, but no other large case series reported till now. We retrospectively analyzed Japanese 70 cases of TL in DS to identify the prognostic factors associated with early death. From 1992 to 2006, 46 boys and 24 girls were treated in 14 Japanese institutes. 16 cases (22.9%) were dead in their early life, and 12cases (17.1%) developed AMKL. One patient died with relapsed AMKL, so the overall survival rate was 75.7%. Univariate analysis showed that mechanical ventilation (p=0.001), pulmonary hypertension (p=0.0105), low birth weight (p=0.0063), early gestational age (p=0.0016), low Apgar score at 1min (p=0.0003), low Apgar score at 5min (p=0.0057), high WBC count (p=0.0006), elevated aspartate aminotransferase(AST) (p=0.0004) and elevated direct bilirubin (p&lt;0.0001) are associated with early death of TL in DS. Multivariate proportional hazard model identified gestational age (p=0.0266; RR 0.708) and elevated direct bilirubin (p=0.0487; RR 1.076) as independent prognostic factors. Prospective clinical study is needed to find the optimal therapeutic approach to save neonates with TL who have these poor prognostic factors.

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