OBJECTIVETo enrich our national database with data of rare diseases by analyzing molecular diagnosis and hematopoietic stem cell transplantation (HSCT) in children with inherited bone marrow failure syndromes (IBMFS).

METHODNext-generation sequencing (NGS)-based genetic diagnosis panel was applied for the clinical diagnosis and management of IBMFS. Retrospective analysis was performed on clinical and genetic data of 17 consecutive children who received HSCT over a long time interval (November. 2005-June 2015).

RESULTThree patients were diagnosed only by clinical manifestation before 2012. After that NGS-based genetic diagnosis panel was used to identify IBMFS-related genes in 12/14.IBMFS patients (except two Diamond-Blackfan anemia (DBA) patients). Two Fanconi anemia (FA) patients were confirmed to be new variations through family-genotype-analysis and 3 families accepted prenatal diagnosis to avoid birth of affected fetuses. Seventeen IBMFS patients (10 FA,5 DBA and 2 dyskeratosis congenital (DKC)) were treated with HSCT from matched sibling donors (n=2), matched unrelated donors (n=8) or mismatched unrelated donors (n=7). The source of stem cells for transplantation included peripheral blood (n=12) and cord blood (n=5). With regard to the conditioning regimens, FA and DKC patients received fludarabine-based reduced intensity conditioning, while DBA patients received classical busulfan-based myeloablative conditioning. Median age at the time of HSCT was 36 months (7-156 months). The number of infused mononuclear cells and CD34⁺ cells was (10.6 ± 6.7) × 10⁸ and (5.9 ± 7.0) × 10⁶ per kilogram of recipient body weight, respectively. The median number of days to neutrophil recovery was 13 days after HSCT (range: 10-19 days). Platelet recovery was faster in the PBSCT group than in the CBT group ((16.3 ± 6.0) days vs. (30.0 ± 17.1) days,t=-2.487,P=0.026). During a median follow-up of 17 months (range: 2-114 months), except one FA patient who was transplanted with HLA-matched unrelated cord blood (CB) died from pneumonia and heart failure because of engraftment failure, other 16 children are alive after the successful HSCT. The failure-free survival rate of the patients three years after HSCT was 94%.

CONCLUSIONNGS-based molecular diagnosis technology and effective HSCT have significantly facilitated the treatment of children with IBMFS in our country, and our national database about this rare disease is to be further exploited.

Anemia, Aplastic ; Anemia, Diamond-Blackfan ; therapy ; Bone Marrow Diseases ; Child ; Dyskeratosis Congenita ; therapy ; Fanconi Anemia ; therapy ; Fetal Blood ; Hematopoietic Stem Cell Transplantation ; Hemoglobinuria, Paroxysmal ; diagnosis ; genetics ; therapy ; Humans ; Retrospective Studies ; Siblings ; Survival Rate ; Transplantation Conditioning ; Unrelated Donors ; Vidarabine ; analogs & derivatives ; therapeutic use

OBJECTIVE: To investigate the efficacy and safely of DAC and CAG/HAG preexcitation chemotherapy regimens for the treatment of patients with MDS-RAEB (refractory anemia with excess blasts, RAEB). METHODS: The clinical data of 86 MDS-RAEB patients were analyzed retrospectively from February 2014 to February 2018. According to therapeutic regimem, the 86 patients were divided into 2 groups: group A (41 patients) with DAC preexcitation chemotherapy regimen, and group B (45 patients) with CAG/HAG preexcitation chemotherapy regimen; and the disease control effect, effective treatment course, median survival time and incidence of adverse reactions were compared between these 2 groups. RESULTS: The CR rate and ORR rate were not significantly different between these 2 groups (P＞0.05). The mCR rate in group A was significantly higher than that in group B (P＜0.05). The numbers of cases obtained therapeutic efficacy at 2 rd and 3 rd conrse in group A significantly more than those in group B (P＜0.05), but the number of cases obtained efficacy at 1 st course in group B was significantly higher than that in group A (P＜0.05). The median OS time was not significanly different between 2 groups (P＞0.05). The duration of neutrophils deficiency in group A was significantly shorter than that in group B (P＜0.05). The transfusion volume of red blood cells and platelets in group A was significantly less than that of group B (P＜0.05). The incidence of neutropenia, anemia and thrombocytopenia of III-IV grade at different treatment courses of group A were significantly lower than that in group B (P＜0.05). The incidence of infection of III-IV grade in group A at 3rd treatment course was significantly lower than that in group B (P＜0.05). CONCLUSION Preexcitation chemotherapy regimens of DAC and CAG/HAG for the treatment of MDS-RAEB possess the same effects for disease control; application of DAC regimen can efficiently reduce the risk of adverse reaction, but CAG/HAG regimen can be helpful to accelerate the effective process of treatment.
Anemia, Refractory ; Anemia, Refractory, with Excess of Blasts ; drug therapy ; Humans ; Myelodysplastic Syndromes ; drug therapy ; Retrospective Studies ; Treatment Outcome

BACKGROUND: The myelodysplastic syndromes (MDS) in childhood is considered to be very rare and the nature of this disease in childhood is very different from that in adults. We analyzed the hematologic findings of childhood myelodysplastic syndrome. METHODS: The retrospective study was performed with the confirmed patients who were admitted to the Department of Pediatrics, Asan Medical Center (AMC) from June 1989 till May 1999, to analyze the hematologic findings. Sixteen children with a primary myelodysplastic syndrome (MDS) were presented to AMC during a 10 year period. RESULTS: Morphological assessment of the peripheral blood and the bone marrow showed nine patients (56%) had refractory anemia (RA), two patients (13%) had RA with excess blasts (RAEB), five patients (31%) had RAEB in transformation (RAEB-t). Five children with juvenile chronic myelogenous leukemia were diagnosed over the same period. Age distribution showed the predilection between 6~10 years and male : female ratio was 1 : 1. Inperipheralblood, pancytopenia was found in seven cases (44%) and leukocytosis in four cases (25%). The bone marrow findings showed hypercellularity in 54%, hypocellularity in 8% and variable cellularity in 15% and myelofibrosis was observed in 23%. Various dyspoietic changes of erythrocytes, leuko- cytes and platelets in peripheral blood and three cell lines in bone marrow were observed and trilineage dysplasia was observed in 62% of MDS, and 56% of RA. The four cases (25%) of RAEB and RAEB-t have transformed to acute myelogenous leukemia. CONCLUSION: In our study, the MDS in childhood seemed to be characterized by higher incidence of RA. Compared with the adult MDS, trilineage dysplasia in RA was frequently seen, but, no significant differences of dyspoietic features between adults and childhood were observed.
Adult ; Age Distribution ; Anemia, Refractory ; Anemia, Refractory, with Excess of Blasts ; Bone Marrow ; Cell Line ; Child ; Chungcheongnam-do ; Erythrocytes ; Female ; Humans ; Incidence ; Leukemia, Myeloid, Acute ; Leukemia, Myelomonocytic, Juvenile ; Leukocytosis ; Male ; Myelodysplastic Syndromes* ; Pancytopenia ; Pediatrics ; Primary Myelofibrosis ; Retrospective Studies

OBJECTIVE: To evaluate the clinical efficacy of low dose combined chemotherapy（LDCC） for patients with relapsed and refractory aplastic anemia-paroxysmal nocturnal hemoglobinuria（AA-PNH） syndrome, and to analyze the advantages of LDCC in the treatment of AA-PNH syndrome. METHODS: The clinical characteristics and the curative effect of LDCC in 9 patients with relapsed and refractory AA-PNH syndrome were retrospectively analyzed. Five patients were treated with MP therapy［melphalan 2 mg/(m·d); prednisone 0.5 mg/(kg·d)］, and the other 4 patients were treated with HA therapy(HHT 2 mg/d iv drip, for 5 days; Ara-C 100 mg/d iv drip, for 5 days). The changes of PNH clone, dosage of corticosteroid, hemolysis and the relapse of disease, hematological parameters and adverse reactions were compared before and after therapy. All patients were treated for 1-2 courses. RESULTS: Seven out of 9 patients responded well, the dosage of corticosteroid and the bilirubin concentration decreased significantly and anemia was relieved in 7 patients (P<0.05). One patient relapsed in one year. PNH clone of 3 patients turned negative. Five patients did not rely on blood transfusion in 1 year. There was no bone marrow failure to be found in all patients. CONCLUSION The LDCC has better efficacy and safety in the treatment of patients with AA-PNH syndrome, moreover, the patients is more tolerant to LDCC, thus the LDCC may be a selection for treatment of patients with relapsed and refractory AA-PNH syndrome.
Anemia, Aplastic ; Anemia, Refractory ; Hemoglobinuria, Paroxysmal ; Hemolysis ; Humans ; Retrospective Studies

BACKGROUND: Myelodysplastic syndrome (MDS) is a disorder of the hematopoietic pluripotent stem cell. The treatment modality and its prognosis were based on the FAB classification. But, because there is a variation of the clinical course, we evaluated the clinical characteristics and prognostic factors of MDS with score system. METHOD: We analyzed age, FAB classification, symptoms, peripheral blood and bone marrow findings of MDS patients for evaluation of clinical course and prognosis. RESULTS: 1) Age & Sex : Male to female ratio was 19:11, and age distribution was mainly over 5th decade (77%). 2) Subtype : The most common subtype was RAEB (43%), followed by RA (23%), RAEBT (17%), CMML (10%), and RARS (6.7%). 3) Initial symptom : The most common symptom was exertional dyspnea, followed by general weakness, headache, dizziness, and febrile sensation. 4) Peripheral blood : Anemia (<10g/dL) was noted in 90%, leukopenia (<2.5x109/L) in 36.6%, and thrombocytopenia (<100x109/L) in 73.3%. 5) Bone marrow finding : Hypocellularity was noted in 23%, normocellularity in 13%, hypercellularity in 63%. Bone marrow fibrosis was noted in 1 case of CMML. 6) Duration of mean follow-up period was 12.3 months and mean survival rate was 17.4 months. 7) The score of Sanz and Gattermann in the patient with RAEB and RAEBT were significantly higher than those of the patients with RA and RARS. Transformation to AML was seen in 5 cases with group C of Gattermann score. 8) With anabolic steroid therapy in 10 cases of RA & RARS, 2 cases were clinically improved, and with low dose Ara-C therapy in 5 cases, one case in RARS and another in RAEB were completely remitted but the latter converted to AML after 16 months. CONCLUSION: The patients with RA and RARS have longer survival rate than the patients with other types of MDS. The score system of Bournemouth, Sanz and Gattermann were useful in evaluating the prognosis of MDS, being Gattermann score more valuable than those of Bournmouth and Sanz to predict the prognosis of MDS.
Age Distribution ; Anemia ; Anemia, Refractory, with Excess of Blasts ; Bone Marrow ; Classification ; Cytarabine ; Dizziness ; Dyspnea ; Female ; Follow-Up Studies ; Headache ; Humans ; Leukopenia ; Male ; Myelodysplastic Syndromes* ; Pluripotent Stem Cells ; Primary Myelofibrosis ; Prognosis ; Sensation ; Survival Rate ; Thrombocytopenia

PURPOSE: This study was undertaken to investigate the clinical characteristics and prognostic predictors of myelodysplastic syndrome (MDS) in childhood. Method: The characteristics and laboratory findings of 20 patients seen at Asan Medical Center for the past 10 years from September 1989 to August 1998 were reviewed retrospectively with regard to the new International Prognostic Scoring System (IPSS) proposed by International MDS Risk Analysis Workshop. RESULTS: 1) In 20 children with MDS we studied, there was no age or sex predilection unique to the subgroups of MDS. 2) 19 cases (95%) out of the 20 had pallor at the time of diagnosis. Other major clinical findings were bleeding tendency in 11 (55%), fever in 8 (40%), hepatosplenomegaly in 8 (40%), and lymphadenopathy in 3 (15%). 3) The hemoglobin level was less than 10 g/dL in all cases and absolute neutrophil count (ANC) was decreased in 11 cases, thrombocytopenia in 15 cases. Pancytopenia was noted in 8 cases (40%). 4) Of the 20 cases, 9 had refractory anemia (RA), 3 refractory anemia with excess blasts (RAEB), 3 refractory anemia with excess blasts in transformation (RAEBIT), and 5 juvenile chronic myelogenous leukemia (JCML). 5) All RA patients were Intermediate (INT)-1 risk group, and all RAEB children were INT-2 risk group. The 3 cases of RAEBIT fell into INT-1, INT-2, and high risk group. Three cases of JCML were INT-1 group, and 2 cases INT-2 group. 6) Seven cases out of 13 INT-1 group had mean survival of 20.2 month (6~57 month), but only 1 out of 6 INT-2 survived. One case of high risk group succumbed to disease 50 months after diagnosis. CONCLUSION: These results showed that there was no age or sex predilection for the specific subgroup of childhood MDS. All the FAB subtypes of the childhood MDS except RA subgroup had poor survival. In this study, we found the IPSS seemed to be a prognostic predictor in childhood MDS but more cases are needed to confirm the validity of IPSS.
Anemia, Refractory ; Anemia, Refractory, with Excess of Blasts ; Child ; Chungcheongnam-do ; Diagnosis ; Education ; Fever ; Hemorrhage ; Humans ; Leukemia, Myelomonocytic, Juvenile ; Lymphatic Diseases ; Myelodysplastic Syndromes* ; Neutrophils ; Pallor ; Pancytopenia ; Prognosis ; Retrospective Studies ; Thrombocytopenia

BACKGROUND: Myelodysplastic syndrome (MDS) is a preleukemic condition that transforms into acute myeloid leukemia. However, the genetic events underlying this transformation remain poorly understood. Aberrant DNA methylation may play a causative role in the disease and its prognosis. Thus, we compared the DNA methylation profiles in refractory anemia with excess blast (RAEB) to those in refractory cytopenia with multilineage dysplasia (RCMD). METHODS: Bone marrow samples were collected from 20 patients with primary MDS (9 with RAEB and 11 with RCMD), and peripheral blood samples were collected from 4 healthy controls. These samples were assessed using a commercial whole genome-wide methylation assay. Methylation-specific polymerase chain reaction (PCR) was used to detect the methylation of candidate gene promoters in RAEB and RCMD. RESULTS: Microarray data revealed significant hypermethylation in 69 genes within RAEB but not RCMD. Candidate genes were mapped to 5 different networks, and network 1 had the highest score due to its involvement in gene expression, cancer, and cell cycle. Five genes (GSTM5, BIK, CENPH, RERG, and ANGPTL2) were associated with malignant disease progression. Among them, the methylated promoter pairs of GSTM5 (55.5% and 20%), BIK (20% and 0%), and ANGPTL2 (44.4% and 10%) were observed more frequently in RAEB. CONCLUSION: DNA methylation of GSTM5, BIK, and ANGPTL2 may induce epigenetic silencing and contribute to the increasing blasts and resulting MDS progression; however, the functions of these genes were not determined. Further study focusing on epigenetic silencing using various detection modalities is required.
Anemia, Refractory ; Anemia, Refractory, with Excess of Blasts ; Bone Marrow ; Cell Cycle ; Disease Progression ; DNA Methylation ; Epigenomics ; Gene Expression ; Humans ; Leukemia, Myeloid, Acute ; Methylation ; Myelodysplastic Syndromes ; Polymerase Chain Reaction ; Prognosis

BACKGROUND: Several studies about myelodysplastic syndromes (MDS) have demonstrated that patients with high score of erythrocytic and total dysplasia showed a significantly lower degree of acute myeloid leukemia (AML) development. We analyzed correlation between bone marrow dysplasia and peripheral blood indices, and estimated the value of peripheral blood indices substituted for bone marrow examination to predict the progress of MDS to AML. METHODS: RBC count, MCV, RDW, WBC count, platelet count, MPV, and PDW were measured by Coulter Counter STKS (USA). We calculated the granulation score (G-score), percentage of peudo-pelger polymorphs (PPP) in the peripheral blood film, and examined the dysplasia in bone marrow aspirates. The reticulocyte survival study was performed with the venous blood collected in CPDA-1 under sterile conditions which was incubated immediately after collection at 37degrees C. RESULTS: G-score was inversly correlated with granulocytic and total dysplasia, but highly scored PPP showed a significantly lower degree granulocytic and total dysplasia. Reticulocyte survival curves showed variable pattern according to degree of erythrocytic and total dysplasia. Patients with a high degree of erythrocytic and total dysplasia showed significant difference compared with normal control group. MPV was increased in accordance with increase in megakaryocytic and total dysplasia. A lower score for erythrocytic and total dysplasia was observed in RAEB-t than in RA and RAEB. CONCLUSIONS: It is suggested that G-score, PPP, and MPV in peripheral blood as well as reticulocyte survival curve may be good markers for bone marrow dysplasia, and erythrocytic and total dysplasia in RAEB-t is lower than in RA and RAEB. Therefore, peripheral blood indices can be used to predict the progress of MDS to AML
Anemia, Refractory, with Excess of Blasts ; Bone Marrow Examination ; Bone Marrow* ; Humans ; Leukemia, Myeloid, Acute ; Myelodysplastic Syndromes* ; Platelet Count ; Reticulocytes

OBJECTIVETo explore the efficiency and side-effects of the combination of cyclosporine A (CsA) and thalidomide in patients with myelodysplastic syndromes (MDS).

METHODSA total of thirty-seven patients with MDS-RCMD or-RAEB-I were treated with CsA in combination with thalidomide. The initial CsA dose of 3 mg×kg(-1)×d(-1) was administered, all patients had their CsA blood concentration concurrently monitored until it reached and maintained between 100 and 200 µg/L. The initial dose of thalidomide was 50 mg/d, with increasing dose of 50 mg every week until the maximum of 200 mg/d. The hematological response was assessed according to the modified criteria of the International Working Group, and adverse events were graded with the Common Toxicity Criteria (v3.0) of the National Cancer Institute. The response duration and overall survival of the patients were also observed.

RESULTS19/37 cases (51.4%) achieved hematologic improvement (HI)-erythroid response (HI-E), 9/29 cases (31.0%) HI-platelet response (HI-P) and 7/33 cases (21.2%) HI-neutrophil response (HI-N). 15 of 32 transfusion-dependent patients (46.9%) achieved transfusion independence. The median response duration of HI-E, HI-P and HI-N were 88 (4 - 88) weeks, 78 (8 - 84(+)) weeks and 78 (10 - 84(+)) weeks respectively. The median overall survival was 52 months on a 29 (4 - 103) months median follow-up. Some patients developed grades I-II hepatic or nephritic impairment, constipation, lethargy, dizziness, edema, rashes or numbness, and all were tolerable and reversible. No grade III or severer adverse events were observed.

CONCLUSIONCsA in combination with thalidomide appears to be effective mainly in inducing HI-E and relatively well-tolerated for the treatment of patients with MDS.

Anemia, Refractory, with Excess of Blasts ; drug therapy ; Cyclosporine ; therapeutic use ; Humans ; Myelodysplastic Syndromes ; drug therapy ; Thalidomide ; therapeutic use ; Treatment Outcome

BACKGROUND: Acquired idiopathic sideroblastic anemia (AISA) is a heterogeneous condition. Most instances, involving only the erythroid line, are benign disease with a longer survival and a low propensity for evolution into acute leukemia. A subset of patients have severe clinical course and evidence of other cell line involvement at presentation, may develop the emergence of blast cells and evolution into acute leukemia. In an attempt to identify the natural history and the risk factors for the development of acute leukemia, the clinical, hematological and outcome data were studied in the patients with AISA. METHODS: We reviewed retrospectively the medical records of 15 patients of AISA treated at the Catholic University of Taegu-Hyosung and Kyungpook National University Hospital from March 1989 to December 1995. RESULTS: The median age at diagnosis was 41 years and the male to female ratio was 8 : 7. On bone marrow examination, erythroid abnormalities were prominent in all cases, 5 patients also showed involvement of the granulocytic and/or megakaryocytic cell lines (AISA with myelodysplastic features, AISA-M). The median follow-up duration was 32 months. Transfusion dependence occurred in 11 of 16 cases. Progression towards refractory anemia with excess of blasts or acute leukemia (M2) was observed in two patients with AISA-M after follow-up period of 16 months and 24 months, respectively. Infections and hemorrhages were causes of death in 3 patients with AISA-M but not in patients with dyserythropoiesis only (AISA-erythroid, AISA-E). CONCLUSIONS: Most patients with AISA have a relatively benign course with prolonged survival after the onset of anemia. Patients with features of dysgranulopoiesis and/or dysmegakaryopoiesis in addition to dyserythropoiesis at presentation were increased risk of transformation to refractory anemia with excess of blasts or acute leukemia and shorter surtival. But further study of larger numbers of patients and longer follow-up may be warranted.
Anemia ; Anemia, Refractory, with Excess of Blasts ; Anemia, Sideroblastic* ; Bone Marrow Examination ; Cause of Death ; Cell Line ; Diagnosis ; Female ; Follow-Up Studies ; Gyeongsangbuk-do ; Hemorrhage ; Humans ; Leukemia ; Male ; Medical Records ; Natural History ; Retrospective Studies ; Risk Factors