Myelodysplastic syndrome is a group of diseases characterized by abnormal clonal proliferation of hematopoietic cells and pancytopenia with dysplasia. The pathogenesis of MDS includes factors of chromosome aberrations, gene mutations, immune abnormalities, environmental changes, and so on. Now it is commonly accepted that MDS is a multistep process disorder involving more etiologic alterations. Recently more and more investigations indicate that the abnormality of cellular immunity is one of important reasons related to MDS. Some proofs about the abnormal activation of T-cell and the abnormal expressions of cytokines in different stages of immune response in MDS have been documented, meanwhile, numerous clinical studies on immune therapy in MDS provide a great number of evidences to disclose its immune abnormalities.
Cytokines ; blood ; Humans ; Immunosuppressive Agents ; therapeutic use ; Lymphocyte Activation ; Myelodysplastic Syndromes ; drug therapy ; immunology ; Signal Transduction ; T-Lymphocytes ; immunology

OBJECTIVETo summarize the clinical features of cytopenia with bone marrow hypoplasia in 100 children and to investigate an effective treatment regimen for myelodysplastic syndrome (MDS) in children.

METHODSA retrospective analysis was performed on the clinical data of 100 children non-randomly selected from Japan and China who were diagnosed with cytopenia with bone marrow hypoplasia between 2006 and 2011. The data of patients from China were subjected to prognostic analysis.

RESULTSThere was no significant difference in the proportion of MDS cases and acquired aplastic anemia (AA) cases between the Japanese and Chinese children. Of the 100 patients, there were 29 cases of acquired AA, 58 cases of refractory cytopenia of childhood (RCC) and 13 cases of refractory cytopenia with multilineage dysplasia (RCMD). There were significant differences in reticulocyte absolute value in peripheral blood and degree of bone marrow proliferation among the three patient groups (P<0.05). The patients from China were followed up for 16-70 months (median, 41 months). After being treated with cyclosporine (CsA) combined with stanozolol, the patients with AA had response rates of 25% and 75%, the patients with RCC had response rates of 47.1% and 82.4%, and the patients with RCMD had response rates of 60% and 60% respectively at 3 and 6 months after treatment.

CONCLUSIONSThere are significant differences in reticulocyte absolute value in peripheral blood and degree of bone marrow proliferation among patients with RCC, RCMD and acquired AA. CsA combined with stanozolol has a good therapeutic efficacy in the treatment of acquired AA and hypoplastic MDS in children, but studies of more cases and a longer follow-up duration are needed.

Adolescent ; Anemia, Aplastic ; blood ; drug therapy ; pathology ; Bone Marrow ; pathology ; Child ; Child, Preschool ; Cyclosporine ; therapeutic use ; Female ; Follow-Up Studies ; Hematopoietic Stem Cell Transplantation ; Humans ; Infant ; Male ; Myelodysplastic Syndromes ; blood ; drug therapy ; pathology ; Pancytopenia ; blood ; drug therapy ; pathology

The study was aimed to explore clinical result of cyclosporin A (CsA) and androgens for treatment of myelodysplastic syndrome (MDS) with refractory anemia. Four cases of MDS-RA were treated with CsA and androgens, while the changes of blood counts, bone marrow and chromosome were observed. The results showed that substantial hematological response was observed in all four patients, that their anemia improved and all transfusion-dependent patients achieved transfusion independence. In conclusion, CsA and Adr therapy was well tolerated. CsA and Adr therapy offer an alternative treatment of MDS with RA. The mechanisms of the benifical effect from this therapy remain the subject of an ongoing study.
Adolescent ; Adult ; Aged ; Androgens ; therapeutic use ; Blood Cell Count ; Cyclosporine ; therapeutic use ; Drug Therapy, Combination ; Female ; Hemoglobins ; analysis ; Humans ; Immunosuppressive Agents ; therapeutic use ; Male ; Middle Aged ; Myelodysplastic Syndromes ; blood ; drug therapy ; Treatment Outcome

This study was aimed to investigate the changes of erythropoietin (EPO), hemoglobin(Hb) and recombinant EPO (rEPO) levels in MDS patients receiving iron chelation therapy, and to explore the relationship between EPO and serum ferritin(SF). A total of 172 MDS patients and 30 healthy controls were studied. The levels of SF, EPO, serum iron (SI), total iron binding capacity (TIBC), C-reaction protein (CRP) and Hb were measured respectively, the level of SF was adjusted according to the changes of CRP. Among them, there were 34 cases of low-risk (SF>1 000 mg/L) receiving deferoxamine therapy, whose changes of SF, EPO, SI, TIBC, Hb levels were detected and compared before and after treatment. Besides, the difference in the incidence of EPO resistance in iron overload group and non-iron overload group was assessed before and after therapy, and 58 cases of low-risk and EPO<1 000 U/L MDS patients were given rEPO therapy. The results showed that the level of EPO in non-iron overload group was higher than that in the normal control group (997.44 ± 473.48 vs 467.27 ± 238.49, P < 0.05). Obviously, the level of EPO in iron overload group was higher than that in non-iron overload group and control group (3257.59 ± 697.19 vs 997.44 ± 473.48, P = 0.012, 3257.59 ± 697.19 vs 467.27 ± 238.49, P = 0.002). Otherwise, the incidence of EPO resistance in iron overload group was higher than that in non-iron overload group (18/35 vs 2/23, P = 0.001), and the level of EPO and SF was positively related to each other in iron overload group (r = 0.310,P = 0.036). After receiving iron chelation therapy, the levels of SF, SI, TIBC and EPO in iron overload group were significantly lower than that before therapy (3942.38 ± 641.82 vs 2266.35 ± 367.31, P = 0.028;48.61 ± 10.65 vs 28.52 ± 12.61, P = 0.034;59.84 ± 12.62 vs 33.76 ± 15.43, P = 0.045;3808.01 ± 750.22 vs 1954.78 ± 473.18, P = 0.042). Moreover, the level of Hb increased (35 ± 18 vs 57 ± 21, P = 0.046) and the EPO resistance in some patients was decreased. It is concluded that iron chelation therapy can improve the efficacy of EPO to alleviate EPO resistance in patients wtih anemic MDS, decrease the pathological level of EPO, enhance Hb levels and reduce the dependency on blood transfusion.
Adult ; Aged ; C-Reactive Protein ; metabolism ; Case-Control Studies ; Chelation Therapy ; Erythropoietin ; blood ; Female ; Ferritins ; blood ; Hemoglobins ; metabolism ; Humans ; Iron ; metabolism ; Iron Overload ; Male ; Middle Aged ; Myelodysplastic Syndromes ; drug therapy ; metabolism ; Recombinant Proteins ; therapeutic use

This study was aimed to detect the methylation status of FHIT gene promoter region in the DNA from plasma of patients with myelodysplastic syndrome (MDS), and to investigate the demethylating effect of decitabine. Methylation-specific PCR method was used to detect the methylation status of FHIT gene promoter region in the DNA from plasma of 4 patients with MDS before and after treatment with decitabine plus semis CAG therapy (among them, 1 case of newly diagnosed MDS, 3 cases progressed into acute leukemia). The results indicated that 3 cases were found to have an increased methylation in the promoter region. After treatment with decitabine plus semis CAG, increased methylation was reversed in 2 cases. In 4 cases, 2 cases displayed clinical response. It is concluded that FHIT gene hypermethylation is associated with MDS pathogenesis. Decitabine has demethylating effect on the FHIT gene hypermethylation of plasma from MDS patients. Detecting the methylation status of FHIT gene in DNA from plasma may play a role in MDS auxiliary diagnosis or prognosis.
Acid Anhydride Hydrolases ; genetics ; Adult ; Aged ; Azacitidine ; analogs & derivatives ; therapeutic use ; DNA ; blood ; DNA Methylation ; Female ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes ; blood ; drug therapy ; Neoplasm Proteins ; genetics ; Promoter Regions, Genetic

OBJECTIVETo investigate the long- term outcome of cyclosporin A (CsA) combined with thalidomide regime for Chinese patients with IPSS low/intermediate- 1 myelodysplastic syndromes (MDS) without del（5q）and the predictive variables which could impact the response to the therapy.

METHODSSeventy-six MDS patients who were treated with these drugs at a single institute in China were retrospectively analyzed. The polymorphism of cereblon gene, rs1672753, was detected in patients of this cohort by PCR and direct sequencing.

RESULTSA total of 53% of patients showed hematological improvement（HI）to the therapy. Thirty-one patients（31/73, 43%）achieved erythrocyte response（HI-E）; 15 patients（15/50, 30%）achieved neutrophil response（HI-N); 18 patients（18/58, 31%）achieved platelet response（HI-P). Twenty-seven of the 50 patients（46%）who were dependent on red blood cell transfusion achieved HI- E and became independent of transfusion. The median duration of response among the responders was 22 months (range, 1- 131 + months). Bone marrow blasts ≤2% was the only factor associated with longer response duration in univariate analysis （P=0.010）. There was no significant difference between the two groups of celeblon gene rs1672753 polymorphism either on the response rate or the response duration. The median survival of 67 patients without stem cell transplantation was 82 months. In multivariate analyses, factors significantly correlated with survival were IPSS-R（HR=3.461, 95%CI 1.126-10.639, P=0.030), age ≥ 60 y（HR=4.120, 95%CI 1.070-15.867, P=0.040）and HI-N（HR=7.733, 95%CI 1.007-59.396, P=0.049).

CONCLUSIONCsA combined with thalidomide regime could improve the anemia symptom in low/int-1 risk MDS patients without del（5q）. The predictive value of cereblon gene polymorphism, rs1672753, could not be verified in this study.

Anemia ; Blood Platelets ; Blood Transfusion ; Bone Marrow ; China ; Cyclosporine ; therapeutic use ; Erythrocytes ; Humans ; Myelodysplastic Syndromes ; classification ; drug therapy ; Neutrophils ; Peptide Hydrolases ; metabolism ; Remission Induction ; Retrospective Studies ; Thalidomide ; therapeutic use ; Treatment Outcome

We have reviewed the medical records of 4 pregnant patients with concomitant acute leukemia at our institution in conjunction with determining the delivery process in order to reduce complications associated with the delivery. Of the 4 patients, three cases were diagnosed as acute leukemia and the other as myelodysplastic syndrome. One experienced an incomplete abortion at gestational age of 10 weeks, after remission induction chemotherapy. The remaining three patients made delivery at full term by Cesarean section. Our observation indicated that Cesarean delivery was advisable for these three patients. Most of the patients had thrombocytopenia or anemia. Before the Cesarean section or dilatation or evacuation, transfusion was undertaken to prevent hemorrhage or severe anemia. In the cases of refractoriness to blood transfusion, a greater amount was transfused. After Cesarean section, some complications were reported such as fever, delayed wound repair, and vaginal bleeding. Based on the our observations, we are of the opinion that pregnant women with acute leukemia or myelodysplastic syndrome can be managed even in those cases where the state of leukemia is not in complete remission or chemotherapy-induced cytopenia is. And the proper measures are timely undertaken to prevent complications associated with delivery.
Abortion, Incomplete ; Anemia ; Blood Transfusion ; Cesarean Section ; Dilatation ; Drug Therapy ; Female ; Fever ; Gestational Age ; Hemorrhage ; Humans ; Leukemia* ; Medical Records ; Myelodysplastic Syndromes ; Pregnancy* ; Pregnant Women ; Remission Induction ; Thrombocytopenia ; Uterine Hemorrhage ; Wounds and Injuries

BACKGROUND: High risk myelodysplastic syndrome has various clinical courses and refractoriness to various therapies. It is important to analyze clinical characteristics and therapeutic responses in high risk myelodysplastic syndrome. METHODS: Sixty nine cases of primary high risk myelodysplastic syndrome at diagnosis were enrolled in this study at Kyungpook National University Hospital and Taegu Hyosung- Catholic University Hospital from January 1987 to June 1996. We have investigated the clinical characteristics and therapeutic outcomes after low dose cytarabine chemotherapy. RESULTS: 1) The median age of the patients was 48 years. Male to female ratio was 2.1:1. The each numbers of RAEB, CMML and RAEB-T patients were 38, 11 and 20, respectively. 2) The most common chief complaint was dyspnea on exertion. General weakness, fever and dizziness were also observed. The most common physical finding was pallor. 3) The peripheral blood findings showed anemia in 65 cases (94.2%), thrombocytopenia in 64 cases (92.8%), leukopenia in 32 cases (46.4%) and pancytopenia in 26 cases (37.7%). 4) Twenty two cases transformed to acute myelogenous leukemia during the follow-up periods. Chemotherapy was done in 18 cases among 22 cases of transformed acute myelogenous leukemia. Complete remission was achieved in 3 cases (16.7%), partial remission in 4 cases (22.2%) and no response in 11 cases (61.1%). 5) Forty seven cases were treated by low dose cytarabine chemotherapy. Complete response was achieved in 11 cases (23.4%), partial response in 13 cases (27.7%) and no response in 23 cases (48.9%). Median duration of complete response was 12 weeks. 6) We made score system, which based on Sanz score and Gattermann score, according to age, hemoglobin, platelet and bone marrow blast. Overall survival was higher in group A (score< or = 5) than group B (score> or = 6). Complete response of low dose cytarabine chemotherapy was higher in group A than group B but overall survival according to low dose cytarabine chemotherapy was not different in group A and group B. CONCLUSION: Low dose cytarabine chemotherapy was not effective in survival benefit. Score system according to prognostic factors was important to predict therapeutic response and prognosis. In the future, more intensive therapeutic plan and analysis of prognostic factors should be considered.
Anemia ; Anemia, Refractory, with Excess of Blasts ; Blood Platelets ; Bone Marrow ; Cytarabine* ; Daegu ; Diagnosis ; Dizziness ; Drug Therapy ; Dyspnea ; Female ; Fever ; Follow-Up Studies ; Gyeongsangbuk-do ; Humans ; Leukemia, Myeloid, Acute ; Leukopenia ; Male ; Myelodysplastic Syndromes* ; Pallor ; Pancytopenia ; Prognosis ; Thrombocytopenia

This study was aimed to examine whether a combination of all-trans retinoic acid (ATRA), 1, 25-dihydroxyvitamin D(3) and androgen possesses the therapeutic value for the MDS-refractory anemia (MDS-RA), and to analyze the mechanisms in detail. 62 cases receiving a scheme of combination of ATRA, 1, 25-dihydroxyvitamin D(3) and androgen (group A) were monitored. The remaining 33 cases (group B) were provided with vitamin supplementation, chalybeate drugs, and one or two of the combination. Bone marrow aspiration and biopsy were performed for collecting the specimens at the baseline and afterwards. The conditions of the patients were monitored by means of weekly complete blood counts and the monthly examination, including toxicity test, physical examination, electrocardiography, and biochemistry panel. The results showed that after treating for 8 weeks in group A, 4 out of 62 patients showed complete remission and 12 patients showed partial remission according to the defined response criteria, and 43 patients (69.35%) showed hematological improvement (HI). The further treatment for 16 out of 62 patients (25.81%), 13 failures (10 deaths, 2 RAEB and 1 RAEB-T) and 3 transformations (M(2), M(3), M(5)) with a median survival interval of 26.25 months, were observed and interrupted for some reasons. However, partial remission was observed only in 3 patients in group B, and HI amounted to 51.51%. Furthermore, the disease progression was observed in 12 out of 33 patients (36.36%) with a median survival interval of 16 months, 9 failures (including 6 deaths, 2 RAEB and 1 RAEB-T) and 3 transformations (M(2), M(3), M(4)). The overall ratios of survival for 3 and 5 years in group A, which received the combination, reached to 69.24% and 53.72% respectively, in comparison with 52.23% and 31.34% in the patients of group B (log-rank, P = 0.016). The following requirements, if were met, would be significant for prognosis: the combination regiment, no transformation, children, no complication, female, 90-120 g/L of hemoglobin concentration, normal cellular bone marrow and uni-cytopenias (P < 0.05). Moreover, Cox regression showed that therapy, transformation and age are all the independent factors (P < 0.05). It is concluded that the combination of above mentioned 3 drugs may be effective and safe treatment for the patients with MDS-RA. Its relevant mechanisms can be involved in the combination, that elicits a wide range of pharmacological effects, such as differentiation, anti-tumor-promotion, anti-apoptosis, anti-angiogenesis, anti-cachexia and immunoregulation.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Androgens ; administration & dosage ; therapeutic use ; Anemia, Refractory ; blood ; drug therapy ; Blood Cell Count ; Calcitriol ; administration & dosage ; therapeutic use ; Child ; Child, Preschool ; Drug Therapy, Combination ; Female ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes ; blood ; drug therapy ; Retrospective Studies ; Survival Analysis ; Time Factors ; Treatment Outcome ; Tretinoin ; administration & dosage ; therapeutic use

Loss of bone mass is usually detected after bone marrow transplantation (BMT) during the early post-transplant period. However, little is known about the long-term effects of BMT on bone metabolism. We have prospectively investigated 11 patients undergoing BMT. Bone mineral density (BMD) was measured before BMT, and 1, 2, and 3 yr after BMT. Serum markers of bone turnover were serially measured before BMT and 1, 2, 3, 4, and 12 weeks, 6 months, and 1 yr after BMT. The mean change in the lumbar spine (L2-4) BMD, calculated as the percent change from the baseline to the level at 1, 2, and 3 yr was -4.7% (NS), -1.1% (NS), and +6.4% (p<0.05), respectively. The mean change in the total proximal femur BMD from the baseline to the level at 1, 2, and 3 yr was -8.5% (p<0.01), -8.7% (p<0.05) and -5.6% (p<0.05), respectively. In summary, there was little decline in lumbar BMD at 1 yr following BMT and gradual recovery until 3 yr. In contrast, femoral BMD decreased much more than the lumbar area at 1 yr and did not recover until 3 yr. The mechanism of skeletal site-selective differences in the changes of BMD needs to be elucidated.
Adult ; Age Factors ; Anemia, Aplastic/therapy ; *Bone Density ; Bone Marrow Transplantation ; Bone and Bones/drug effects/*metabolism/radiation effects ; Collagen/blood ; Collagen Type I ; Cyclophosphamide/therapeutic use ; Estradiol/blood ; Follicle Stimulating Hormone/blood ; Humans ; Leukemia/therapy ; Luteinizing Hormone/blood ; Middle Aged ; Myelodysplastic Syndromes/therapy ; Peptides/blood ; Prospective Studies ; Time Factors