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Introduction: This retrospective study aimed to compare a range of conditioning regimens in children with severe aplastic anemia (SAA) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the Seventh Medical Center of PLA General Hospital between January 2008 and June 2017. Methods: Patients were categorized into the Bu (Bu + Flu + Cy + ATG-F regimen) and control (Flu + Cy + ATG-F) groups, with a median follow-up time after HSCT of 3.5 (range, 3.1–6.2) and 3.7 (3.2–5.9) years in the Bu and control groups, respectively. Results: No differences were observed between the two groups regarding the median time of peripheral blood neutrophil and platelet engraftment (p = 0.538 and p = 0.491); the 28-day engraftment rates of neutrophils were similar (p = 0.199), although higher for platelets with Bu (p = 0.044). Additionally, graft failure was 0% and 20.0% in the Bu and control groups, respectively (p = 0.004). In both groups, the incidence of grades III–IV (or grades II–IV) acute graft-versus-host disease (GVHD) and chronic GVHD was not significantly different (p > 0.05). Moreover, the 3-year overall survival and failure-free survival did not show significant differences (p = 0.670 and p = 0.908). Discussion: In children with SAA undergoing allo-HSCT, conditioning regimen with Bu + Flu + Cy + ATG-F is capable of enhancing the myeloablation effect, promoting donor hematopoietic stem cell engraftment, and reducing the graft failure rate. Furthermore, it does not increase the incidence of complications, including GVHD. [ABSTRACT FROM AUTHOR]

Introduction: Complement C5 inhibitor eculizumab is the first approved treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder caused by uncontrolled terminal complement activation. Approximately 50% of patients with aplastic anemia (AA) have PNH cells. Limited data are available for patients with AA-PNH taking concomitant immunosuppressive therapy (IST) and eculizumab. Methods: Data from the International PNH Registry (NCT01374360) were used to evaluate the safety and effectiveness of eculizumab and IST in patients taking IST followed by concomitant eculizumab (IST + c-Ecu) or eculizumab followed by concomitant IST (Ecu + c-IST). Results: As of January 1, 2018, 181 Registry-enrolled patients were included in the eculizumab effectiveness analyses (n = 138, IST + c-Ecu; n = 43, Ecu + c-IST); 87 additional patients received IST alone. Reductions from baseline with eculizumab were observed in the least squares mean lactate dehydrogenase ratio (IST + c-Ecu, −3.4; Ecu + c-IST, −3.5); thrombotic event incidence rates were similar between groups (IST + c-Ecu, 1.3; Ecu + c-IST, 0.7). Red blood cell transfusion rate ratios decreased from baseline for IST + c-Ecu (0.7) and increased for Ecu + c-IST (1.2); there were none for IST alone. Hematological parameters generally improved for IST + c-Ecu and IST alone, and changed minimally or worsened for Ecu + c-IST. Safety signals were generally consistent with those previously described for the respective therapies. Discussion/conclusion: Although some intergroup differences were seen, concomitant eculizumab and IST were safe and effective regardless of treatment sequence. [ABSTRACT FROM AUTHOR]

Kabuki syndrome (KS) is a rare congenital disorder commonly complicated by humoral immunodeficiency. Patients with KS present with mutation in the histone-lysine N-methyltransferase 2D (KMT2D) gene. Although various KMT2D mutations are often identified in lymphoma and leukemia, those encountered in aplastic anemia (AA) are limited. Herein, we present the case of a 45-year-old Japanese man who developed severe pancytopenia and hypogammaglobulinemia. He did not present with any evident malformations, intellectual disability, or detectable levels of autoantibodies. However, B-cell development was impaired. Therefore, a diagnosis of very severe AA due to a hypoplastic marrow, which did not respond to granulocyte colony-stimulating factor, was made. The patient received umbilical cord blood transplantation but died from a Pseudomonas infection before neutrophil engraftment. Trio whole-exome sequencing revealed a novel missense heterozygous mutation c.15959G >A (p.R5320H) in exon 50 of the KMT2D gene. Moreover, Sanger sequencing of peripheral blood and bone marrow mononuclear cells and a skin biopsy specimen obtained from this patient identified this heterozygous mutation, suggesting that de novo mutation associated with KS occurred in the early embryonic development. Our case showed a novel association between KS mutation and adult-onset AA. [ABSTRACT FROM AUTHOR]

Objectives: PNH clones, also aptly called "escape clones," are evidence of acquired immune-mediated bone marrow failure and have a high prevalence in patients with aplastic anemia (AA). Several studies have reported contradictory results regarding the impact of PNH clones on AA patients with immunosuppression treatment, and PNH clones have not been confirmed as positive predictors of response in the AA guidelines of the British Society for Standards in Haematology. Methods: We performed a meta-analysis to address this issue by searching for articles in PubMed, EMBASE, The Coch-rane Library, Web of Science, and ClinicalTrials.gov, and for abstracts from the annual meetings of the American Society of Hematology and the European Hematology Association. We included 1,236 participants from 11 cohort-controlled studies. Our primary outcome was the 6-month hematologic response with a secondary outcome of the mortality rate within 3 months. Results: A better response rate was observed in the PNH+ group than in the PNH– group (odds ratio [OR] 2.85; 95% confidence interval [CI] 2.17–3.75; p < 0.00001), and further subgroup analysis strengthened the outcome, with minor heterogeneity in non-Asian countries. In contrast, the early mortality was not significantly different between the PNH+ and PNH– groups (OR 0.54; 95% CI 0.26–1.10; p = 0.09). Conclusions: The meta-analysis suggested an evidence-based role for PNH clones in predicting a better response in AA patients with immunosuppression. [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate the effect of stem cell source and dose on the survival of various donor subgroups, such as matched sibling donor (MSDs) and alternative donors (ADs), upon bone marrow (BM) or peripheral blood stem cell (PBSC) infusion in aplastic anemia (AA). Methods: We retrospectively investigated the effects of stem cell source and dose on allogeneic hematopoietic stem cell transplantation (alloHSCT) in AA. Results: A total of 267 patients were included in this analysis. The BM-treated group showed an association with low incidence of any-grade acute graft versus host disease (GvHD) (p < 0.001). A higher stem cell dose was related with a low incidence of extensive chronic GvHD in MSDs (p = 0.025). Multivariate analysis for overall survival (OS) revealed that only age at alloHSCT <31 years (p = 0.010) and prior platelet transfusion <86 U (p = 0.046) in MSDs and higher stem cell dose (hazard ratio = 2.596, p = 0.045) in ADs were favorable prognostic factors. Conclusion: PBSCs could be preferred in AD because high stem cell dose may be easily achieved to improve the OS at the expense of acute GvHD. However, BM stem cells are preferred in MSDs. [ABSTRACT FROM AUTHOR]

Recent studies have indicated that Sirt1 plays critical roles in the suppression of inflammation, T cell activation, and differentiation of hematopoietic progenitor cells. Severe aplastic anemia (SAA) is an immune-mediated disease that is characterized by elevated cytotoxic lymphocytes and type 1 cytokines. As a negative effector cytokine, interferon gamma (IFNγ) takes part in aplastic anemia through its inhibitory effect on hematopoiesis. In this study, we investigated the role of Sirt1 in the regulation of IFNγ in patients with SAA. A significant decrease in relative SIRT1 (p< 0.05) and increase in IFNG (p< 0.05) expression levels was observed in the sorted CD8+T cells of SAA patients compared to the controls. There was a significant negative correlation (r = –0.53, p < 0.05) between SIRT1 and IFNG expression in SAA patients. SRT3025, a Sirt1 activator, was shown to significantly reduce IFNγ (p < 0.01) and elevate Sirt1 (p < 0.05) expression in the CD8+T cells of SAA patients, and also showed a therapeutic role in an aplastic anemia mouse model. In conclusion, the defective Sirt1 may be correlated to the abnormal IFNγ expression in SAA patients, and activation of Sirt1 signaling may help improve the inflammatory status of SAA. [ABSTRACT FROM AUTHOR]

Aplastic anemia (AA) is a hematologic disease characterized by pancytopenia and hypocellular bone marrow, potentially leading to chronic anemia, hemorrhage, and infection. The China Aplastic Anemia Committee and British Committee for Standards in Haematology guidelines recommend hematopoietic stem-cell transplantation (HSCT) or immunosuppressive therapy (IST) comprising antithymocyte globulin (ATG) with cyclosporine (CsA) as initial treatment for AA patients. With limited epidemiological data on the clinical management of AA in Asia, a prospective cohort registry study involving 22 AA treatment centers in China was conducted to describe the disease characteristics of newly diagnosed AA patients and investigate real-world treatment patterns and patient outcomes. Of 340 AA patients, 72.9, 12.6, and 3.5% were receiving IST, traditional Chinese medicine, and HSCT, respectively, at baseline; only 22.2% of IST-treated patients received guideline-recommended ATG with CsA initially. Almost all patients received supportive care (95.6%) as blood transfusion (97.8%), antibiotics (63.7%), and/or hematopoietic growth factors (58.2%). Overall, 64.8% achieved a partial or complete response, and 0.9% experienced relapse. No new safety concerns were identified; serious adverse events were largely unrelated to the treatment regimen. These results demonstrate the need to identify and minimize treatment barriers to standardize and align AA management in China with treatment guideline recommendations and further improve patient outcomes. [ABSTRACT FROM AUTHOR]

Objectives: This meta-analysis aimed to evaluate the risk of clonal evolution of granulocyte colony-stimulating factor (G-CSF) in acquired aplastic anemia (AA), and whether the use of G-CSF increases the occurrence of secondary malignant neoplasms, mainly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) or paroxysmal nocturnal hemoglobinuria (PNH). Methods: Data were gathered from randomized controlled trials (RCTs) to evaluate the effect of G-CSF versus no G-CSF at the risk of developing the clonal complications of acquired AA. Electronic searches in PubMed, Embase, and the Cochrane Library were performed to identify studies up to 1 January 2017. Only RCTs performed on patients who were randomly assigned to receive G-CSF or not to receive G-CSF were included. Results: Four relevant trials that met the inclusion criteria were identified. In a pooled analysis, the G-CSF groups of AA patients were not associated with a statistically significant higher occurrence of secondary malignant neoplasm, mainly MDS and AML (relative risk [RR] 0.86; 95% confidence interval [CI] 0.34–2.19; 4 trials). No significant heterogeneity was found (p = 0.67, I2 = 0%). There was no statistically significant higher occurrence of PNH in the G-CSF groups with AA (RR 1.17; 95% CI 0.51–2.71; 4 trials) and no significant heterogeneity was found (p = 0.42, I2 = 0%). Conclusions: G-CSF for patients with AA is not associated with a higher occurrence of secondary malignant neoplasm, mainly MDS/AML, or PNH. [ABSTRACT FROM AUTHOR]

Acquired amegakaryocytic thrombocytopenia (AAT), a rare entity characterized by severe thrombocytopenia and the absence of megakaryocytes in the bone marrow, may mimic or precede the diagnosis of aplastic anemia (AA). Here, we describe a patient who presented with apparent Epstein-Barr virus (EBV)-associated immune thrombocytopenia resistant to several lines of therapies, which was in fact a form of AAT with some features of AA. He eventually responded to therapy with eltrombopag, cyclosporine A (CSA), and antithymocyte globulin (ATG) and recovered completely. EBV infection is known to cause a variety of benign and malignant hematologic disorders, including bone marrow failure. However, to the best of our knowledge, this is the first case report of EBV-associated AAT. Treatment options for AAT are still not well defined, and even response to eltrombopag together with CSA and ATG does not always imply successful therapy. The natural history of EBV infection may well be sufficient to explain unexpected eventual recovery. [ABSTRACT FROM AUTHOR]

Background: This study focuses on the iron overload (IOL) of patients with transfused aplastic anemia (AA) or a low/intermediate-1 risk of myelodysplastic syndrome (MDS). Methods: Ninety-two AA or MDS patients with IOL were prospectively recruited. Clinical data were collected every 6 months, and organ magnetic resonance imaging T2* values were collected annually. Patients with IOL were chelated. Results: Serum ferritin was correlated with liver T2* and pancreatic T2* in the AA and MDS groups. Transfusion amounts were correlated with serum ferritin values, liver T2*, and pancreatic T2* in the AA group. At the 6-month and 1-year evaluations, patients with sufficient chelation experienced significant decreases in serum ferritin, and those with decreased serum ferritin experienced an obvious increase in hemoglobin. At their 1-year-follow-up, patients with adequate chelation showed significant increases in hepatic T2*, cardiac T2*, and left ventricular ejection fraction (LVEF). Patients with decreased serum ferritin (including those without chelation) experienced an increase in hemoglobin, hepatic T2*, cardiac T2*, and LVEF. Conclusion: The transfusion amount was more reliable at predicting IOL in patients with AA than in those with MDS. Adequate iron chelation can decrease serum ferritin levels and may improve hepatic T2*, cardiac T2*, and LVEF levels. A decrease in serum ferritin, even in the absence of chelation, may also benefit patients. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) is a currently emerging serious complication in immunosuppressed patients, especially in allogeneic transplant recipients. Several fatal cases of EBV-LPD have been reported in aplastic anemia (AA) patients receiving immunosuppressive therapy (IST) with antithymocyte globulin (ATG) plus cyclosporine A (CsA), but no appropriate prophylactic or therapeutic strategy has been established. Herein, we describe a 29-year-old man whose EBV-LPD was successfully treated with rituximab. He received IST with ATG plus CsA for hepatitis-associated AA. EBV-DNA in plasma, which was not detectable before IST, gradually increased after IST initiation. A high fever and systemic lymphadenopathy developed 31 days after IST initiation. An EBV-DNA titer of 5.7 × 105 copies/ μl was detected, and a diagnosis of EBV-LPD was made. Although discontinuation of IST was not effective, a single dose of rituximab on day 33 resolved the clinical symptoms and completely eliminated EBV-DNA. Even after restarting CsA administration, no elevation of EBV-DNA was observed, and his complete blood cell count had fully recovered 1 year after IST. This case suggests that this treatment strategy for EBV-LPD with EBV-DNA monitoring and rituximab administration, which has been recommended in allogeneic transplant recipients, may also be useful in the context of AA patients receiving IST. [ABSTRACT FROM AUTHOR]

We performed a study on allogeneic hematopoietic cell transplantation (alloHCT) from an HLA-haplo-identical familial donor (haploFD) using a busulfan-fludarabine-antithymocyte globulin conditioning regimen for severe aplastic anemia (sAA) and hypoplastic myelodysplastic syndrome. For the comparison between a haploFD and an alternative donor (AD; matched unrelated or partially matched donor) for sAA in adults, we collected haploFD data retrospectively and prospectively. Forty-eight AD cases were selected for the comparison with 16 haploFD cases. All transplantation outcomes except for extensive chronic graft versus host disease (GvHD) were similar. The frequencies of hepatic sinusoi- dal obstruction syndrome (p = 1.000), acute GvHD (p = 0.769), grade 3/4 acute GvHD (p = 0.258), chronic GvHD (p = 0.173), extensive chronic GvHD (p = 0.099), primary neutrophil engraftment failure (p = 1.000), secondary graft failure (p = 1.000) and platelet engraftment failure (p = 0.505) were similar. Time to neutrophil engraftment was faster in haploFD (p = 0.003), while the cumulative incidence of platelet engraftment was similar (p = 0.505). Overall survival was also similar between AD and haploFD (p = 0.730). In conclusion, alloHCT from haploFD in sAA was comparable with alloHCT from AD, but extensive chronic GvHD seemed frequent in haploFD. Therefore alloHCT from haploFD could be an alternative approach for alloHCT from AD in adult sAA. [ABSTRACT FROM AUTHOR]

Iron overload in transfusion-dependent patients with rare anemias can be managed with chelation therapy. This study evaluated deferasirox efficacy and safety in patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemias. A 1-year, open-label, multicenter, single-arm, phase II trial was performed with deferasirox (10-40 mg/kg/day, based on transfusion frequency and therapeutic goals), including an optional 1-year extension. The primary end point was a change in liver iron concentration (LIC) after 1 year. Secondary end points included changes in efficacy and safety parameters (including ophthalmologic assessments) overall as well as in a Japanese subpopulation. Overall, 102 patients (42 with MDS, 29 with AA and 31 with other rare anemias) were enrolled; 57 continued into the extension. Mean absolute change in LIC was -10.9 mg Fe/g dry weight (d.w.) after 1 year (baseline: 24.5 mg Fe/g d.w.) and -13.5 mg Fe/g d.w. after 2 years. The most common drug-related adverse event was increased serum creatinine (23.5%), predominantly in MDS patients. Four patients had suspected drug-related ophthalmologic abnormalities. Outcomes in Japanese patients were generally consistent with the overall population. Results confirm deferasirox efficacy in patients with rare anemias, including a Japanese subpopulation. The safety profile was consistent with previous studies and ophthalmologic parameters generally agreed with baseline values (EUDRACT 2006-003337-32). © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Clinical and experimental evidence suggests an immune-mediated pathophysiology in subjects with lower-risk myelodysplastic syndromes (MDS) in whom immunosuppressive therapy may be effective. The novel immunosuppressive strategy of cyclosporine A (CsA) alternately combined with levamisole (LMS; CsA + LMS regimen) can dramatically improve the response rate and survival in aplastic anemia from those of our previous study. Herein, we retrospectively analyzed the data of 89 lower-risk MDS patients who received the CsA + LMS regimen. A total of 63 patients (70.8%) achieved either complete remission or hematological improvement at 4 months. Overall, 51, 41 and 19 patients had erythroid, platelet and neutrophil responses, respectively. Following the CsA + LMS regimen, 6 patients progressed to more advanced MDS at a median interval of 5 months (range, 3-42 months). The estimated 24-month progression-free survival was 82.2% (95% CI, 72.84-91.56) for all patients. Within the median follow-up of 18.5 months (range, 7.0-61.0), 6 patients died. In conclusion, the CsA + LMS regimen alleviated cytopenias and improved survival and freedom from evolution, suggesting that it could be reserved as an alternative choice for lower-risk MDS. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease, especially in children. To characterize the clinical presentations and survival, we performed a retrospective analysis of pediatric patients. Methods: We reviewed 55 pediatric patients with PNH referred to our hospital from January 1990 through June 2012 to assess clinical presentations, survival, and differences among subcategories. Results: The overall survival 10 years after diagnosis estimated via the Kaplan-Meier method was 77.6%. The cohort of patients was divided into subcategories of classic PNH, PNH/aplastic anemia (AA), and subclinical PNH (PNH-sc)/AA based on the recently proposed PNH working clinical classification. We found that patients with classic PNH and PNH/AA had larger PNH clones and many more parameters of hemolysis, but patients with PNH-sc/AA had smaller PNH clones, fewer parameters of hemolysis, and a higher rate of bone marrow failure. Our results revealed a high rate of bone marrow failure and a low rate of hemoglobinuria at presentation. Furthermore, thrombotic events were not observed in our patients, which is significantly different from the rate seen in Caucasian patients. Additionally, pediatric patients with PNH may develop bone marrow cytogenetic abnormalities. Conclusion: This study provides insight into Chinese pediatric PNH patients and may aid in setting up individualized therapeutic regimens. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Adolescent and young adult patient presentations of aplastic anemia require a particular perspective on both diagnosis and treatment. This unique age group necessitates a thorough diagnostic evaluation to ensure the etiology, acquired or inherited, is sufficiently determined. The treatment options include human leukocyte antigen-identical sibling hematopoietic cell transplantation or immunosuppressive therapy, and both require attention to the specific medical and social needs of these adolescents and young adults. Longitudinal surveillance throughout life for the development of late complications of the disease and treatment is mandatory. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Eltrombopag is a thrombopoietin receptor agonist frequently used to manage immune thrombocytopenia and aplastic anemia. At the high doses used for aplastic anemia, but not the doses used for immune thrombocytopenia, eltrombopag can cause reddish-brown discoloration of plasma, which can interfere with bilirubin measurement and cause false clinical alarm. This case report and clinical image describes a patient with aplastic anemia managed with eltrombopag who developed reddish-brown plasma initially concerning for possible hemolysis or rhabdomyolysis. [ABSTRACT FROM AUTHOR]

Iron overload due to regular transfusions of packed red cells can cause multiple organ damage. Iron chelation therapy (ICT) is important in patients with aplastic anemia (AA) who require blood transfusions as supportive management. With the introduction of the oral iron chelator deferasirox, ICT has become more widely available and feasible. We studied 4 adult AA patients who had transfusion-induced iron overload and showed hematological improvement after ICT with oral deferasirox. Following deferasirox treatment, hemoglobin increased and serum ferritin levels decreased, and the patients subsequently became transfusion independent. Our experience raises the possibility of the potential benefit of ICT on hematopoiesis. Further long-term studies in larger patient cohorts are needed to clarify the effect of the restoration of hematopoiesis after iron chelation therapy. [ABSTRACT FROM AUTHOR]

Background/Aims: Antibodies against carbonic anhydrase (CA) have been detected in patients with an aplastic anemia (AA)-like syndrome after autologous stem cell transplantation. Methods: We analyzed sera of 53 bona fide AA patients before and after treatment with anti-thymocyte globulin (ATG) or bone marrow transplantation for the presence of anti-CA antibodies. Results: Anti-CA antibodies were detected in 20 patients (38%) and were associated with older age at diagnosis of AA. Antibody-positive patients showed poor response to ATG treatment (complete response 14%) and inferior long-term survival (36% at 10 years), when compared to antibody-negative patients (complete response and 10-year survival both 64%). Two thirds of patients with antibodies at diagnosis of AA became antibody negative after treatment with ATG. Clearance of the antibody did not appear to be associated with hematological improvement. Conclusion: Antibodies against CA are detected frequently at diagnosis of AA, and their presence identifies a subset of patients with poor response to immunosuppressive treatment. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

To investigate the correlations between polymorphisms of human leukocyte antigen (HLA)-A, HLA-B and HLA-DRB1 alleles and childhood susceptibility to aplastic anemia (AA), 80 children with AA were investigated. Among the 80 children, 74 had severe AA (SAA). Blood samples were collected from 109 healthy children as the controls. High-resolution genotyping of HLA-A, HLA-B and HLA-DRB1 alleles was conducted using polymerase chain reaction amplification with sequence-specific primers and polymerase chain reaction amplification with sequence-based typing. The expression frequencies of HLA-B*48:01 and DRB1*09:01 were significantly higher and the frequencies of HLA-B*51:01, DRB1*03:01 and DRB1*11:01 were significantly lower in the AA group compared with those in the control group. In addition, the frequencies of HLA-B*48:01 and DRB1*09:01 were significantly higher and the frequencies of HLA-B*51:01, DRB1*03:01 and DRB1*11:01 were significantly lower in the SAA group compared with those in the control group. HLA-B*48:01 and DRB1*09:01 were correlated with childhood AA, and thus they may be susceptibility genes for childhood SAA. HLA-B*51:01, DRB1*03:01 and DRB1*11:01 are expressed at low levels in children with AA. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Lymphoproliferative disorders (LPDs) are generally caused by uncontrolled B-cell proliferation induced by the Epstein-Barr virus (EBV) in the setting of impaired EBV-specific T-cell immunity, particularly when there is pharmacological immunosuppression including antithymocyte globulin. We herein present an unusual case of EBV associated with LPD (EBV-LPD) in which LPD occurred 3 weeks after the use of rabbit antithymocyte globulin administered for severe hepatitis-associated aplastic anemia; the patient died of fulminant leukemic lymphoma 5 days after the onset. We also review the pertinent literature on EBV-LPD after immunosuppressive therapy and document the efficacy of EBV viral load monitoring and the need for preemptive therapy. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The clinical and biological spectrum of paroxysmal nocturnal hemoglobinuria (PNH) is variable, ranging from classical hemolytic forms to PNH associated with aplastic anemia or other bone marrow (BM) failure syndromes. We report a previously undescribed case of PNH occurring after autologous stem cell transplantation (ASCT) in a patient affected by relapsing non-Hodgkin's lymphoma. The intensive chemotherapy and the ASCT resulted in a contraction of the effective hematopoietic stem cell (HSC) pool and a derangement of the immune system. The delayed engraftment and the BM hypoplasia represented a favorable environment for the expansion of the pathological clone. This case is paradigmatic even for the unexpected trend of the PNH clone during treatment with the terminal complement inhibitor eculizumab; in fact, the clone reduced until undergoing unexpected extinction, i.e. the recovery of normal hematopoiesis. Eculizumab seems not to play a direct role in HSC kinetics; the clinical remission probably occurred because the environmental conditions that led to the expansion of the PNH clone were transient and disappeared. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

No abstract available Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Antibody (Ab)-mediated pure red cell aplasia (PRCA) is a rare but important side effect in patients with chronic kidney disease who receive recombinant human erythropoietin (rhEPO). Ab-mediated PRCA was first reported in the 1990s, and the incidence subsequently increased and reached a peak in 2001. After improvements in rhEPO products and the administration route, the incidence was reduced by 90%, and now Ab-mediated PRCA only develops in a limited number of patients who receive rhEPO subcutaneously for a long period. We describe here the clinical course of one such rare patient with Ab-mediated PRCA. The patient was a 70-year-old man with chronic renal failure secondary to diabetic nephropathy. He had not received rhEPO therapy before the initiation of hemodialysis. He started hemodialysis and began to receive rhEPO therapy intravenously. Three months later, his hemoglobin level started declining and he became transfusion dependent. A diagnosis of Ab-mediated PRCA was made by bone marrow examination and detection of anti-EPO Abs. He was successfully treated with cyclosporine and became independent of blood transfusions. This case is a reminder that vigilance is required regarding the development of Ab-mediated PRCA upon rhEPO therapy, regardless of the administration route. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

No abstract available Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aplastic anemia is a rare bone marrow failure disorder. Allogeneic hematopoietic cell transplantation (alloHCT) and immunosuppressive therapy (IST) are the main therapeutic modalities currently used to treat patients with aplastic anemia. Systematic reviews and meta-analyses of randomized controlled trials (RCTs) are regarded as the highest level of evidence and as such aid practitioners in solving clinical questions. The objective of this review is to assess the base of evidence for the common practice and the current guidelines for the management of aplastic anemia. It focuses on data obtained from systematic reviews and meta-analyses of RCTs conducted in this field. Specifically, it focuses on four major therapeutic questions: the roles of alloHCT, IST, hematopoietic growth factors and supportive care. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To evaluate the treatment efficacy and tolerance of anti-human T lymphocyte porcine immunoglobulin (p-ALG) plus cyclosporine A (CsA) in acquired severe aplastic anemia (SAA). Method: Forty-eight SAA patients [31 males and 17 females; 17 with very SAA (VSAA)] were treated with p-ALG plus CsA and were analyzed retrospectively according to early mortality, response rate and quality, survival rate, toxicity, and complications. They were stratified further by gender, age, disease severity, interval from diagnosis to treatment, and preexisting infections. Result: The median age was 28 years (range 13-64). The interval from diagnosis to treatment was 45 days. The median neutrophil count was 0.178 × 109/l. The overall response was 83.3% (54.2% complete and 29.2% partial) with a 90-day median time (range 23-380), and 10.4% died of infection within 30 days. The 1.5-year survival was 87.5%. vSAA patients had less response, a higher early mortality, and less survival (64.7, 29.4, 51.8%) compared to SAA patients (93.5, 0, and 100%, respectively; p < 0.05). Groups with different age, gender, intervals between diagnosis and treatment, and preexisting infections had the same response. Mild toxicities were observed. Conclusion: p-ALG plus CsA is a reliable and well-tolerated treatment for SAA, and it has the great advantage of a much lower cost compared to horse/rabbit ATG. VSAA was a poor predictive factor for the response rate. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Aplastic anemia (AA) is rarely described after a diagnosis of autoimmune disease (aID). Aims: To assess the prevalence of prior aID in patients with AA recorded in the registry of the European Group for Blood and Marrow Transplantation (EBMT) and to evaluate treatment and outcome. Methods: 1,251 AA patients from 18 EBMT centers were assessed. Results: Fifty patients (4%) were eligible: 22 males and 28 females with a median age of 46 years at the diagnosis of aID and of 51 years at the diagnosis of AA. Information on the treatment of AA was available in 49 patients: 38 received only immunosuppressive therapy (IST), 8 patients underwent hematopoietic stem cell transplantation (HSCT) - 6 as first-line therapy and 2 after failure of IST - whilst 3 patients had a spontaneous recovery. After a median follow-up of 3.19 years, 32 patients were alive, including 7 of the 8 patients who underwent HSCT. Only 6 of 32 patients who were alive at the last follow-up were receiving IST for AA. Conclusions: Most cases of AA following aID benefitted from IST or HSCT if a matched donor was available. Further prospective investigation is needed to assess the effects of IST on the outcome of underlying aID. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A 61-year-old Japanese man was referred to our hospital in 2002 due to severe pancytopenia. Bone marrow and peripheral blood findings indicated he had severe aplastic anemia (AA). A whole-body CT scan and Ga scintigraphy revealed no abnormal findings. Antithymocyte globulin and cyclosporine A (CyA) were administered and he got transfusion independently. In September 2004, he complained of abdominal fullness and a skin eruption in the lower abdomen. An abdominal CT revealed a spleen mass and lymphoadenopathy of the pancreas head. Splenectomy was done, and he was diagnosed with a diffuse large B cell lymphoma (DLBCL) of the spleen and skin. His karyotype was associated with t(14; 18). CyA was stopped, all lesions disappeared, and then his AA relapsed. In January 2007, antithymocyte globulin/CyA was readministered. In May 2007, he complained of acute swelling in his right thigh. A biopsy from the tumor revealed DLBCL. CyA was stopped again, yet the lymphoma did not regress. He was given R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisolone), followed by 5 cycles of R-VP (rituximab, vincristine, prednisolone) and radiation therapy, resulting in a partial remission. We report DLBCL after immunosuppressive therapy for AA. Although this is a rare complication, it should be considered before beginning immunosuppressive therapy. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Immunosuppression is the therapeutic alternative for patients with aplastic anemia who are ineligible for allogeneic transplant. We aimed to assess the benefit of the combination of antithymocyte globulin (ATG) and cyclosporine (CsA). Methods: We performed a systematic review and meta-analysis of all randomized controlled trials that compared ATG and CsA to ATG alone as first-line treatment for patients with severe and nonsevere aplastic anemia. The Cochrane Library, Medline, conference proceedings and references were searched until 2008. Relative risks (RR) with 95% confidence intervals (CIs) were estimated for each trial and pooled. Results: Our search yielded 4 trials. For patients with severe aplastic anemia, there was a significant reduction in mortality in the ATG and CsA arm, which began at 3 months (RR = 0.50, 95% CI 0.29–0.85) and was maintained over a long follow-up of 5 years (RR = 0.58, 95 % CI 0.36–0.93). Conversely, in patients with nonsevere aplastic anemia, there was no difference in mortality. Conclusions: The combination of both drugs should be considered the gold standard only for patients with severe aplastic anemia. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article describes the case of a 9-year old girl with refractory severe aplastic anemia who was treated with haploidentical adipose tissue-derived mesenchymal stem cells to enhance the insufficient number of autologous peripheral blood hematopoietic progenitor cells for engraftment. The patient manifested reactions to the horse anti-thymocyte globulin and cyclosporine which she received for treatment. The patient experienced relapse, had a drop in her blood count and had a bone marrow biopsy.

Natural killer T (NKT) cells play an important role in the regulation of immune responses in a broad range of diseases, including autoimmune disorders, infectious diseases and cancer. So far, few studies have evaluated the roles of NKT cells in the pathogenesis of aplastic anemia (AA), an autoimmune disease. In this study, we investigated the quantitative and qualitative changes in NKT cells in bone marrow (BM) mononuclear cells of AA patients in response to in vitro stimulation with α-galactosylceramide. Compared to healthy controls, BM from AA patients had reduced fraction of NKT cells, which possessed a decreased potential to expand in vitro in response to α-galactosylceramide stimulation, producing more IFNγ+ NKT1 cells. In the presence of rhG-CSF, the expansion capacity of NKT cells stimulated by α-galactosylceramide was significantly reduced in both AA and control groups, with the majority of the activated NKT cells expressing intracellular IL-4, and the fractions of IFNγ+ NKT cells were significantly reduced. In summary, our results indicate that polarization of NKT cells towards the NKT2 subpopulation occurs after co-stimulation with α-galactosylceramide and rhG-CSF in AA. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Over the last 7 years we have seen more than 200 severe aplastic anemia patients at this centre. Three of them developed an unusual complication in the form of thymic hemorrhage. Following this complication, all 3 patients recovered partially from their aplastic anemia, without any need for further immunosuppression. These cases show possible ways to manipulate the thymus gland as a management strategy for this disease. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We report on a 22-year-old female who developed aplastic anemia after administration of phenobarbital for 6 years. Being refractory to steroid and anti-lymphocyte serum, the patient received allogeneic stem cell transplantation, achieving complete remission. We discuss here the potential mechanisms by which phenobarbital and other anti-epileptic drugs can cause aplastic anemia and review the literature for previous case reports and epidemiological studies. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

One of the major changes suggested by the World Health Organization (WHO) classification with respect to the French-American-British (FAB) proposal for myelodysplastic syndromes (MDS) was to lower the bone marrow (BM) blast count from 30 to 20%, thus eliminating the refractory anaemia with excess of blasts in transformation (RAEB-t) category. However, a general consensus has not been reached, and several authors still retain RAEB-t as an MDS sub-entity. We re-evaluated our series of 74 patients classified as RAEB-t according to the FAB criteria by stratifying them into two subsets: patients with at least 5% peripheral blast (PB) cells but with BM blasts <20% (group I) and patients with BM blastosis between 20 and 30% and PBs <5% (group II). We found differences among the two groups regarding sex, haematological parameters at presentation (white blood cell and neutrophil counts, haemoglobin level) and frequency of infectious episodes during the course of disease. We did not find differences as to the frequency of acute myeloid leukaemia transformation, but a significant difference was evidenced as to survival (9.3 vs. 16 months in group I vs. group II, respectively; p = 0.02). Furthermore, at our institution, we compared the RAEB-t group I patients who, based on >5% PBs, should be included in the RAEB-II category according to the WHO criteria, with a group of 98 patients who were diagnosed as RAEB-II according to the WHO criteria. The findings showed that the aggregation of these two subsets appeared inappropriate, because patients of the two groups showed different clinical features and rates of acute transformation. In conclusion, the RAEB-t entity according to the FAB criteria, although including heterogeneous clinical patient subsets, should more likely be considered as an advanced stage of MDS, rather than a true acute myeloid leukaemia. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Immunologic abnormalities have been described in patients with Hodgkin lymphoma, including autoimmune hemolytic anemia and immune thrombocytopenic purpura. The concurrent diagnoses of Hodgkin lymphoma and acquired aplastic anemia, however, is extremely rare. We report a 56-year-old Japanese female patient with severe aplastic anemia and increased large granular lymphocytes prior to the recurrence of Hodgkin lymphoma. After being in remission for 10 years from Hodgkin lymphoma, she developed progressive pancytopenia. The large granular lymphocytes (expressed CD3+ CD8+ TCRαβ+) had a polyclonal distribution, the serum-soluble FasL concentration was significantly elevated, and bone marrow biopsy showed severely hypocellular bone marrow without infiltration of abnormal lymphocytes. No lymphadenopathy was observed that would suggest a relapse of Hodgkin lymphoma. A diagnosis of aplastic anemia was made, and treatment with corticosteroids and cyclosporine was initiated. Two months later, she suddenly developed celiac and mediastinal lymphadenopathy. She underwent one cycle of chemotherapy before she died of progressive pancytopenia. Autopsy revealed the recurrence of Hodgkin lymphoma, nodular sclerosis in the lymph nodes and markedly hypocellular bone marrow. Although autoimmune disorders are described in Hodgkin lymphoma, our case shows a rare instance of a patient who had aplastic anemia as the first manifestation of a relapse of Hodgkin lymphoma. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A transient aplastic crisis (TAC) is a well-known complication in all types of chronic hemolytic anemia but only 2 cases of such an event were described in congenital dyserythropoietic anemias (CDAs). Here, we report a third case, and by retrospective chart review of 78 cases we found evidence of TAC in 8 further patients with CDA II, with serological evidence of previous human parvovirus B19 (B19V) infection in all but one. Although B19V infection results in TAC in only a minority of patients with CDA, physicians responsible for these patients should be aware of such a potentially life-threatening complication. Testing for B19V-specific IgG is recommended in patients with CDA to estimate the risk of a possible future aplastic crisis. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The etiology of acquired aplastic anemia (AA) in most patients remains unclear. It is believed that patients with a reduced ability to detoxify environmental toxins are at increased risk of developing AA. Cytochrome P450 (CYP450) and glutathione S transferase (GST) are the major phase I and phase II xenobiotic-metabolizing enzymes. We analyzed the impact of the polymorphisms in CYP4501A1 and GSTM1 and GSTT1 genes on the susceptibility and disease severity in 200 patients with AA and compared the frequency with the normal population. There was a significantly increased frequency of the CYP1A1m4 allele in AA patients compared with normal controls (odds ratio = 3.01; 95% confidence interval 1.76–5.17; p = 0.00001). None of the other CYP1A1 genotypes or the GST genotypes were significantly different between AA patients and controls. Altered metabolism of benzo(a)pyrene due to the polymorphism in the CYP1A1 gene might be an etiologic factor in the increased incidence of AA in these patients. The CYP1A1m4 allele may play a role in determining the risk of AA in India. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Presents information on deviations of colony growth from normal growth in cell cultures. Possible causes of grossly reduced colony growth including severe aplastic anemia; Sources of error of strongly increased colony growth; Background on erythroid and myeloid ratio.

Presents differential diagnosis of cytopenic disorders. Guidelines from culture observation to diagnosis; Background on aplastic anemia; Information on myelodysplastic syndrome.

Telomeres represent the nucleoprotein tails of chromosomes that get shortened with each cell division. When the telomere length reaches a critical point, cell senescence and death occur. Telomerase is a reverse transcriptase that counteracts telomere loss by adding telomeric sequences. In patients with acquired aplastic anemia, the mean telomere length (TRF) of peripheral blood leukocytes is generally short when compared to normal controls, without it being clear whether a relationship between TRF and disease severity exists. Additionally, increased telomerase activity (TA) is found in the bone marrow mononuclear cell population (MNCs) of aplastic anemia patients, especially in the chronic form of the disease. Fanconi anemia (FA) patients generally demonstrate increased TA and short telomeres in peripheral blood MNCs, a fact attributed to the high turnover of hematopoietic progenitor cells in combination with direct breakages at telomeric sequences. Furthermore, a strong correlation has been shown between TRF and the severity of aplastic anemia, but not with FA evolution towards myelodysplastic syndrome or acute myeloblastic leukemia. In respect of dyskeratosis congenita (DC), a disease of either X-linked or autosomal dominant/recessive inheritance which is characterized by premature ageing of highly regenerative tissues, studies have been carried out in order to elucidate whether the X-linked DC is caused by a defect in ribosomal RNA processing and/ or telomere maintenance. Finally, the direct genetic link established between DC pathogenesis and short telomeres may lead to the development of new therapeutic protocols for diseases characterized by short telomere length and subsequent genomic instability. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS), especially refractory anemia (RA) are very heterogeneous diseases regarding their morphological, biological and clinical features. One important clinical problem is the difficulty of diagnosis. Soluble transferrin receptors (sTfRs) reflect the erythropoietic activity in the bone marrow (BM). To establish whether determination of serum sTfR could be useful for the differential diagnosis between RA and aplastic anemia (AA), we measured the serum sTfR concentrations, BM cellularity and BM erythroblast percentages in 14 untreated AA and 7 untreated RA patients. The serum sTfR levels of the RA patients (820.1 ± 402.8 ng/ml) were significantly higher than those of the AA patients (491.1 ± 195.2 ng/ml; p = 0.0207). However, the serum sTfR values of RA and AA patients also overlapped. A new index, the 'sTfR-E index' [the ratio of serum sTfR level (ng/ml) to BM cellularity (%) x BM erythroblasts (%)] is proposed, which is expected to reflect the number of transferrin receptors (TfR) on the cell membrane per BM erythroblast. The sTfR-E index values of the 7 RA patients (0.395 ± 0.234) were significantly lower than those of the 14 AA patients (2.669 B 1.633; p = 0.0003). The sTfR-E index values of AA and RA patients overlapped only marginally. In conclusion, the sTfR-E index may be a useful new diagnostic tool to distinguish between AA and RA patients. [ABSTRACT FROM AUTHOR]

In México, only few patients can afford adequate treatment for aplastic anemia. In a single institution 61 individuals with severe aplastic anemia (SAA) were identified; of these, 33 were followed for at least 3 months, 26 could be treated with immunosuppression (IS), 20 with antithymocyte globulin and cyclosporin A (ATG + CyA) and 6 with CyA, whereas 7 individuals were given only anabolic androgens. In the patients treated with IS a complete remission was achieved in 12 and a partial remission in 6, the overall response rate being 69%. The 5,729-day overall survival (SV) was 54%; it was superior for the patients who received both ATG and CyA (58 vs. 50%). These data contrast with those of the patients who were given only androgens: 14% SV at 5,510 days. Within the group of patients who received IS, one developed acute myelogenous leukemia, another paroxysmal nocturnal hemoglobinuria and another a primary Sjögren’s syndrome-associated low-grade, B cell, non-Hodgkin’s lymphoma. Two individuals who received IS were allografted from HLA-identical siblings and survived 70 and 413 days after the allograft. On the other hand, we also found that, for several reasons, mainly economic ones, only 41% of individuals with SAA finally benefited from the best immunosuppressive therapeutic approach. IS was a good therapeutic choice for some patients with SAA, clearly better than androgen treatment. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]