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Refractory Anemia (refractory + anemia)
Selected AbstractsThe soluble transferrin receptor in dysplastic erythropoiesis in myelodysplastic syndromeEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2007Georgia Metzgeroth Abstract Objectives:,In individuals without iron deficiency, the soluble transferrin receptor (sTfR) directly reflects the erythropoietic activity. This study investigated sTfR concentrations in ineffective, dysplastic erythropoiesis in myelodysplastic syndrome (MDS). Methods:,To exclude influences of other myeloid cells on sTfR, only patients with refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS) and 5q, syndrome were included. sTfR was measured nephelometrically (normal range 0.81,1.75 mg/L). Results:,Thirty-four untreated MDS patients (RA = 14, RARS = 10, 5q, syndrome = 10) were enrolled and analysed. The mean sTfR value of all MDS patients (1.30 ± 0.8 mg/L, range 0.2,3.8) did not differ from our control group. In 5q, syndrome, the mean sTfR concentration (0.80 ± 0.5 mg/L) was significantly lower than in RA (1.32 ± 0.4 mg/L, P = 0.02) and RARS (1.75 ± 1.1 mg/L, P = 0.03). Subdividing MDS according to their amount of erythroid mass in bone marrow a significant difference of sTfR between patients with decreased (0.70 ± 0.4 mg/L), normal (1.32 ± 0.4 mg/L) and increased (2.06 ± 0.9 mg/L) erythropoiesis was observed. MDS patients with sTfR values below the reference range of 0.81 mg/L required transfusions in 90% of cases and showed higher erythropoietin levels compared to MDS patients with sTfR levels ,0.81 mg/L (P = 0.01). There was a good agreement between sTfR and the amount of polychromatic erythroblasts observed (r = 0.68, P < 0.001). Conclusion:,In conclusion, the serum concentration of sTfR reflects erythropoietic activity in MDS, but it is in particular determined by the degree of erythroid maturation and the severity of ineffective erythropoiesis. Low sTfR values in MDS are associated with a reduced, poorly differentiated erythropoiesis and requirement of blood transfusions. [source] Different pathophysiological mechanisms of intramitochondrial iron accumulation in acquired and congenital sideroblastic anemia caused by mitochondrial DNA deletionEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2006Thomas Matthes Abstract:, Sideroblastic anemias (SA) are characterized by iron accumulation in the mitochondria of erythroblasts. Although we have evidence of mitochondrial gene alterations in sporadic congenital cases, the origin of acquired forms [refractory anemia with ring sideroblasts (RARS)], is still largely unknown. Here, we report the analysis of respiratory chain function in a patient with a large mitochondrial deletion and in patients with RARS. A young boy with SA showed symptoms typical of a mitochondrial disease with metabolic acidosis, muscle weakness and cerebral involvement. His bone marrow DNA was analyzed for the presence of mitochondrial deletions. We found a new mitochondrial (mt)DNA deletion spanning 3614 bp and including all the mt genes encoding complex IV, plus ATPase 6 and 8, and several transfer (t)RNAs. All tissues analyzed (liver, skeletal muscle, brain, pancreas) showed a heteroplasmic distribution of this mutant DNA. Bone marrow homogenates were obtained from five patients with RARS and from three patients with normal bone marrow and respiratory chain function assayed by spectrophotometric analysis. Cytochrome c oxidase (CCO) activity was greatly reduced in the patient's bone marrow. In contrast, CCO activity and global respiratory chain function were conserved in patients with RARS. We conclude that deficient CCO activity secondary to mtDNA deletions is related to intramitochondrial iron accumulation, as in our patient or in those with Pearson's syndrome, whereas other mechanisms, e.g. nuclear DNA mutations, have to be proposed to be involved in the acquired forms of SA. [source] Lichenoid nail changes as sole external manifestation of graft vs. host diseaseINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 1 2002Sara Isabel Palencia MD A 56-year-old-man who had refractory anemia with an excess of blasts underwent an allogeneic peripheral blood stem cell transplantation (PBSCT) from his brother after preparation with melphalan and fludarabin. He received GvHD (graft-vs.-host disease) prophylaxis with cyclosporine from day ,1 at a daily dose of 5 mg/kg of body weight. The daily dosage was tapered gradually from day +20. On post-PBSCT day 68 he developed acute cutaneous GvHD grade 3 and acute gastrointestinal GvHD grade 2,3, which was resolved with a daily dose of 1 mg/kg of body weight of prednisone. The patient was discharged in good clinical condition and without signs of GvHD, and he started tapering his immunosuppressive treatment. By day 160 he developed oral lichen planus-like changes, with several reticulate white lesions on the oral mucosa. A biopsy specimen was microscopically consistent with lichenoid GvHD (Fig. 1). By day 150 after PBSCT, when he was being treated with CsA 100 mg once daily and prednisone 10 mg once daily, his fingernails started to grow abnormally and gradually became dystrophic and painful. Two months later his toenails became similarly affected. Although affecting all finger and toe nails, the lesions were especially important in both thumbs. Physical examination revealed multiple findings on his nails (Fig. 2): thickening, fragility, onycholysis, longitudinal striations, and even pterygium. The micological cultures were negative. A biopsy specimen showed an sparse papillary dermis lymphoid infiltrate with focal exocytosis and presence of isolated multiple necrotic keratinocytes (Fig. 3). These findings were interpreted as a lichenoid GvHD with oral and nail involvement. The patient did not have other associated cutaneous lesions. He did not develop signs or symptoms consistent with hepatic GvHD. In May 2000 thalidomide was added to the immunosuppressive therapy, at a daily dose from 100 to 300 mg according to tolerance (constipation, sedation, ,). The lesions on the oral mucous showed a substantial improvement, but the nail changes remained more or less stable. Thalidomide was discontinued after 7 months because the patient displayed numbness and tingling in the hands and feet consistent with a peripheral neuropathy. Twenty days later he stopped taking thalidomide and the oral lichenoid lesions worsened, resulting in difficulty in eating. He also developed periungueal erythema, swelling and intense pain after minimal trauma. The daily dose of prednisone increased to 20,30 mg with moderate improvement. However, the dose could not be increased because of the secondary immunosuppressive effects. Twenty-three months post-PBSCT the patient remains with intense oral and nail lichenoid lesions. Figure Figure 1 . Oral mucosa with a lichenoid hiperplasia and a band-like lymphoid infiltrate. Note the basal lymphocytosis with isolated necrotic keratinocytes Figure 2. Lichenoid graft-vs.-host disease showing marked nail involvement with a ridge in the midline Figure 3. Panoramic view of the nail epithelium. Dermal lymphocytes with basal exocytosis and apoptotic keratinocytes (arrow) are evident [source] Wilms' tumor 1 message and protein expression in bone marrow failure syndrome and acute leukemiaPATHOLOGY INTERNATIONAL, Issue 10 2007Takashi Iwasaki Wilms' tumor 1 (WT1) is a useful marker for the diagnosis of acute leukemia and myelodysplastic syndromes (MDS). In the current study quantitative reverse transcription,polymerase chain reaction and immunostaining were used simultaneously to examine the relationship between WT1 RNA and protein level and also to evaluate WT1 as a tool to differentiate aplastic anemia (AA) and MDS refractory anemia (RA). Three types of WT1 messages (total, exon 5(+) and KTS(+)) and WT1 immunostaining of these diseases were analyzed. An increase of all three WT1 messages in high-grade MDS and acute leukemia was observed as compared with the normal control, whereas there was no significant difference in WT1 message between AA and RA, suggesting that WT1 message is not a good tool to discriminate AA and RA. No significant difference was observed between normal and RA, except for exon 5 message. Three WT1 message levels had a significant correlation, suggesting that the total WT1 message is sufficient for clinical practice. Positive immunostaining of WT1 was observed only in the portion of acute leukemia and overt leukemia (OL) transformed from MDS with a high WT1 message level, suggesting the relatively high detection threshold of WT1 protein with the immunostaining method. [source] A Phase II intra-patient dose-escalation trial of weight-based darbepoetin alfa with or without granulocyte-colony stimulating factor in myelodysplastic syndromes,AMERICAN JOURNAL OF HEMATOLOGY, Issue 1 2009Jason Gotlib This Phase II study evaluated darbepoetin alfa (DA) in 24 patients with predominantly low or intermediate-1 risk myelodysplastic syndrome (MDS). Intra-patient dose escalation of DA was undertaken in three 6-week dose cohorts until a major erythroid response was achieved: 4.5 mcg/kg/week, 9 mcg/kg/week, and 9 mcg/kg/week plus granulocyte-colony stimulating factor (G-CSF) 2.5 mcg/kg twice weekly. Patients with refractory anemia with ringed sideroblasts (RARS) commenced DA at 9 mcg/kg/week. The weight-based dosing regimen translated into a median starting DA dose of 390 mcg/week. Erythroid responses were observed in 16/24 patients (67%; 12 major and 4 minor), with a median response duration of 11 months in major responders. Addition of G-CSF generated a major erythroid response in 7/15 patients (47%) who suboptimally responded to DA alone. DA was well tolerated, except for worsening of baseline mild hypertension and renal insufficiency in one patient with diabetes. IPSS score <0.5 and RBC transfusions <2 units/month increased the probability of an erythroid response. A minority of subjects (12%) developed low-level non-neutralizing anti-DA antibodies. Our data indicate that weekly weight-based dosing of DA, with the addition of G-CSF in selected individuals, can be an effective erythropoietic option in a high proportion of lower-risk MDS patients. Am. J. Hematol, 2009. © 2008 Wiley-Liss, Inc. [source] Transcriptosome and serum cytokine profiling of an atypical case of myelodysplastic syndrome with progression to acute myelogenous leukemiaAMERICAN JOURNAL OF HEMATOLOGY, Issue 10 2006Daruka Mahadevan Abstract A Native American-Indian female presenting with anemia and thrombocytosis was diagnosed with myelodysplastic syndrome (MDS, refractory anemia). Over the course of 5 years she developed cytopenias and periods of leukocytosis with normal bone marrow (BM) blast counts, features of an unclassifiable MDS/MPS syndrome. The patient ultimately progressed to acute myelogenous leukemia (AML, FAB M2) and had a normal karyotype throughout her course. The episodes of leukocytosis were associated with infectious complications. Transformation to AML was characterized by a BM blast percentage of 49%. Peripheral blood and BM samples were obtained for serum protein analysis and gene expression profiling (GEP) to elucidate her disease process. An ELISA assay of the serum analyzed ,80 cytokines, which demonstrated that hepatocyte growth factor/scatter factor and insulin-like growth factor binding protein 1 were markedly elevated compared to normal. GEP demonstrated a unique "tumor molecular profile," which included overexpression of oncogenes (HOXA9, N-MYC, KOC1), proliferative genes (PAWR, DLG5, AKR1C3), invasion/metastatic genes (FN1, N-CAM-1, ITGB5), pro-angiogenesis genes (c-Kit), and down regulation of tumor suppressor genes (SUI1, BARD1) and anti-apoptotic genes (PGLYRP, SERPINB2, MPO). Hence, a biomics approach has provided insight into elucidating disease mechanisms, molecular prognostic factors, and discovery of novel targets for therapeutic intervention. Am. J. Hematol., 2006. © 2006 Wiley-Liss, Inc. [source] Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acidCANCER, Issue 1 2005Chiara Pilatrino M.D. Abstract BACKGROUND The authors investigated the efficacy and safety of the histone deacetylase inhibitors valproic acid (VPA) and all-trans retinoic acid (ATRA) as differentiation agents in a cohort of older, poor-risk patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). METHODS Twenty older patients with recurrent or refractory AML or MDS were treated in a Phase II protocol with sequential VPA and ATRA therapy. VPA was started at a dose of 10 mg/kg per day and then escalated to achieve the serum concentration of 45,100 ,g/mL. ATRA was added at 45 mg/square meters (sm) per day when VPA reached the target serum concentration. Only patients treated continuously for , 2 months were considered evaluable. RESULTS Hematologic improvement, according to World Health Organization criteria, was observed in 6 of 20 patients enrolled in the protocol but in 6 of 11 considered evaluable. In five patients, a major platelet response was observed, achieving platelet transfusion independence. Three of these five patients also exhibited a minor erythroid response. A sixth patient showed both a minor erythroid response and a platelet response. The median duration of response was 189 days (range, 63,550 days). No significant reduction in the blast count was observed. Grade 3 neurocortical toxicity was observed in four patients. Severe bone pain was experienced by 4 patients (2 Grade 4 and 2 Grade 3) and was associated with an increase in the peripheral blast cell count. Treatment with ATRA did not modify the response observed with VPA alone. CONCLUSIONS Differentiation therapy with VPA was of clinical benefit in approximately 30% of elderly patients with AML and MDS of the refractory anemia with excess of blast type with unfavorable prognostic features. A striking platelet transfusion independence lasting several months may be obtained in some patients, reducing the burden of palliative care and improving the quality of life. Cancer 2005;. © 2005 American Cancer Society. [source] Effects of cyclosporine on hematopoietic and immune functions in patients with hypoplastic myelodysplasiaCANCER, Issue 9 2002In vitro, in vivo studies Abstract BACKGROUND Immunosuppression may benefit some patients with hypoplastic myelodysplasia (HMDS) and refractory anemia (RA), but its mechanism of action is still obscure. METHODS Using flow cytometry, we studied Fas-receptor (Fas-R), Fas-ligand (Fas-L), and interferon-, (IFN-,) expression in CD34+ cells and lymphocytes obtained from 11 HMDS and 20 RA patients. In colony assays and long-term cultures, the effects of Fas triggering, IFN-, blockade, or cyclosporine(CsA) on the growth of hematopoietic progenitors (colony-forming cells [CFC]) were determined. The effects of CsA at daily doses of 1,3 mg/kg for at least 3 months in HMDS patients were also studied. RESULTS In basal conditions, committed and immature progenitor cells were found decreased in myelodysplastic (MDS) patients. No significant differences between HMDS and RA patients were detected. IFN-,,expressing CD4+ cells were significantly increased in HMDS patients, whereas intracytoplasmic Fas-L expression was only borderline elevated in CD3+ MDS cells. Increased numbers of CD34+ cells expressing Fas-R were found in HMDS and RA patients. CFC and secondary CFC showed higher susceptibility to Fas-L,mediated inhibition and the blockade of IFN-, improved marrow primary, but not secondary, CFC growth. CsA added in vitro to patient's lymphocytes significantly decreased the number of IFN-,,expressing CD4+ cells, but not Fas-L production. These effects were associated with increased colony formation. Similar to IFN-,blockade, production of secondary CFC was not enhanced by CsA. Administration of CsA to patients resulted in prolonged partial hematologic improvement in 8 of 11 HMDS patients. CONCLUSIONS Increased frequency of IFN-, producing CD4+ cells supports the involvement of lymphocyte-mediated suppression of hematopoiesis in the development of cytopenia in MDS patients. The ability of CsA to decrease in vitro IFN-, production may improve hematopoietic function, explaining the beneficial effect of this agent in HMDS patients. Cancer 2002;95:1911,22. © 2002 American Cancer Society. DOI 10.1002/cncr.10915 [source] Absence of p16 and p27 gene rearrangements and mutations in de novo myelodysplastic syndromesEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2005Sotirios G. Papageorgiou Abstract:, Myelodysplastic syndromes (MDS) represent a group of clonal hematopoietic disorders characterized by dyshemopoiesis and frequent evolution to acute leukemia. Tumor suppressor gene inactivation may be involved in MDS pathogenesis. The two families of cyclin-dependent kinase inhibitors (CDKIs) (INK4 family of p15, p16, p18 and p19 and CIP/KIP family of p21, p27 and p57) that negatively regulate cell cycle progression are known tumor suppressor genes. To determine whether genetic alterations of p16 and p27 genes play an important role in MDS pathogenesis, we examined DNA from 51 patients classified as 17 refractory anemias (RA), four refractory anemias with ringed sideroblasts (RARS), 19 refractory anemias with an excess of blasts (RAEB), 5 refractory anemias with excess of blasts in transformation (RAEB-t) and 6 chronic myelomonocytic leukemias (CMML). Southern blot analysis detected no homozygous deletions of p16 and p27. Polymerase chain reaction,single-strand conformation polymorphism (PCR,SSCP) and sequencing did not reveal point mutations for both genes with the exception of two allelic polymorphisms, namely a C , G transition at 447 bp of p16exon3 and a T , A transition at 791 bp of p27exon1 genes. Our results suggest that mutations of p16 and p27 genes resulting in abnormal p16 and p27 proteins do not represent a mechanism of gene inactivation involved in the pathogenesis of MDS. [source] | ||||||||||