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.

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.

Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 48-49
Author(s):  
Samantha Ferrari ◽  
Chiara Pagani ◽  
Mariella D'Adda ◽  
Nicola Bianchetti ◽  
Annamaria Pelizzari ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
High Risk ◽  
Board Of Directors ◽  
Advisory Board ◽  
Advisory Committees ◽  
Risk Status ◽  
History Of ◽  
Wbc Count

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=&lt;0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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.

Prognostic Implications of the IDH1 synonymous SNP rs11554137 In Pediatric and Adult AML: a Children's Oncology Group and Southwest Oncology Group Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2737-2737
Author(s):  
Phoenix A. Ho ◽  
Todd A. Alonzo ◽  
Kenneth J. Kopecky ◽  
Kristen L. Miller ◽  
Julia Kuhn ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Expression Profiling ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Wild Type ◽  
Bone Marrow Blast ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
Pediatric Aml

Abstract Abstract 2737 Synonymous SNPs may directly impact gene function through various translational or post-translational mechanisms. Further, such “silent” SNPs in the mutational hotspots of AML-associated genes have recently been reported to carry prognostic impact. We aimed to determine the prevalence, clinical associations, and prognostic significance of a known SNP in exon 4 of IDH1, near the location of the frequently-mutated R132 codon. Diagnostic marrow specimens from 253 pediatric AML patients (treated on the COG trial AAML03P1) and 274 adult AML patients (treated on SWOG trials S9031, S9333, or S9500) were analyzed for the presence of SNP rs11554137 via direct sequencing. In the pediatric cohort (median age 9.8 years), SNP rs11554137 was present in 27 of 253 (10.7%) patients. SNP+ pediatric patients did not differ significantly from wild-type patients in terms of sex, racial distribution (African American patients accounted for 23% of SNP+ patients vs. 14% of wild-type patients, P=0.24), bone marrow blast percentage, or age distribution, except in patients aged 0–2 years, who accounted for 44% of SNP+ patients vs. 23% of wild- type patients (P=0.013). Recurrent cytogenetic abnormalities occurred with similar frequencies in both the SNP+ and wild-type pediatric populations, as did FLT3/ITD, NPMc, and CEBPA mutations. Miscellaneous cytogenetic abnormalities accounted for 33% of SNP+ patients vs. 14% of wild-type patients, P=0.033. IDH1 SNP status had no prognostic impact on survival in the pediatric cohort, as SNP+ and wild-type patients had similar rates of five-year overall survival (OS, 76% vs. 63%, P=0.50), disease-free survival (DFS, 48% vs. 53%, P=0.97), and relapse rate (RR, 39% vs. 39%, P=0.94). In the adult cohort (median age 63 years), the IDH1 SNP was present in 30 of 274 (10.9%) patients. A slight female predominance for the SNP (63% vs. 37%, P=0.052) occurred among adult patients. The SNP was more prevalent in African American patients, who accounted for 30% of the SNP+ patients vs. 7% of wild-type patients, P=0.0046. SNP+ patients also had somewhat higher diagnostic bone marrow blast percentages (medians 80% vs. 70%, P=0.025). The normal karyotype subset accounted for similar proportions of SNP+ vs. wild-type patients (42% vs. 46%, P=0.83). Notably, SNP rs11554137 was not present in adult core-binding factor AML. Miscellaneous cytogenetic abnormalities were significantly more common in SNP+ patients (46% vs. 22%, P=0.022). SNP status was not significantly associated with FLT3/ITD status when all adult patients were considered (P=0.14). However, within the normal karyotype subset, FLT3/ITD was present in 90% of SNP+ patients vs. 59% of wild-type patients (P=0.0053). SNP+ patients had somewhat poorer 5 year OS (10% vs. 18%, hazard ratio [HR]=1.17) though this difference was not statistically significant (P=0.44). Among the 142 patients who achieved complete remission (CR), however, 5-year relapse-free survival (RFS) was significantly worse for SNP+ patients (0% vs. 25%, HR = 2.89, P=0.0014). Of the 14 SNP+ patients who achieved CR, 13 relapsed and the 14th patient died of sepsis in remission after 61 days. In multivariate analysis, after adjusting for the effects of age and cytogenetic group, SNP rs11554137 retained an independent prognostic effect (P=0.0062) regarding RFS. Notably, when FLT3/ITD status is included in multivariate analysis, SNP positivity loses independent prognostic significance (HR=1.72, P=0.18). Genome-wide expression profiling was performed on 134 pediatric AML specimens in whom IDH1 SNP status was known. By comparing SNP+ patients with wild-type patients, we derived a distinct gene-expression signature for patients with SNP rs11554137. Among the most upregulated probe sets in the SNP+ cohort were those representing PEX6 and NFYA, both of which interact with the TGF-beta/SMAD signaling network; the retinoid × receptor beta gene RXRB; and the FER gene, a tyrosine kinase critical to FLT3 signaling. The IDH1 SNP rs11554137 is present in approximately 11% of pediatric and adult AML patients, and gene expression profiling data suggests that leukemia in SNP+ patients may have unique biologic features. The SNP was an independent predictor of decreased RFS in adult AML in univariate analysis, but not in multivariate analysis when adjusting for FLT3/ITD status. 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.

scholarly journals Survival after Curative Resection for Stage I Colorectal Mucinous Adenocarcinoma

2020 ◽  
Author(s):  
Liang Huang ◽  
Shuangling Luo ◽  
Sicong Lai ◽  
Yonghua Cai ◽  
Zhanzhen Liu ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Mucinous Adenocarcinoma ◽  
Disease Free Survival ◽  
Stage I ◽  
Prognostic Impact ◽  
Clinicopathologic Characteristics ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Free Survival ◽  
Disease Free

Abstract Background : The prognostic value of the mucinous adenocarcinoma histotype on the early stages especially for stage I colorectal cancer (CRC) is still unclear. This study determined the clinicopathologic characteristics and long-term outcome of stage I colorectal mucinous adenocarcinomas (MAC).Methods : Among the total of 503 patients with stage I CRC (56 having MAC and 447 having non-MAC) who underwent radical resection, the correlation between clinicopathological factors and MAC was analyzed. Multivariate analysis was performed to determine whether mucinous histotype itself was an independent prognostic impact in stage I patients.Results : MACs were observed more frequently located in the colon than rectum ( p =0.046), more frequently displayed the microsatellite instability (MSI) phenotype ( p =0.023) and had a greater frequency of T2 stage ( p =0.001). The rate of recurrence was 13.5% and the cancer-specific mortality was 4.3% among all stage I CRC patients. There was no difference in disease-free survival and overall survival between MACs and non-MACs. On multivariate analysis, older age ( p =0.030), rectal cancer ( p =0.025), lymphovascular invasion (LVI) ( p <0.001), and microsatellite stability (MSS) phenotypes ( p =0.023) were independently associated to poor survival of stage I CRC. A high carcinoembryonic antigen (CEA) level ( p =0.031), LVI ( p =0.002) and MSS phenotypes ( p =0.012) were independently related to short disease-free survival of stage I CRC.Conclusions : Compared with non-MAC, MAC patients had more T2 patients and more MSI phenotypes in stage I CRC at presentation, but the mucinous histology is not a significant predictor of recurrence and prognosis in stage I CRC.

scholarly journals Transient leukaemia of Down syndrome in a neonate: case report

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. 

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.

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