ArticleLiterature Review

Guidelines for the diagnosis and management of aplastic anaemia. British Committee for Standards in Haematology

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... Aplastic anemia is a bone marrow failure disease characterized by severe deficiencies in peripheral-blood platelets, white cells, and red cells [1]. Aplastic anemia is acquired in 80-85% of the cases, and the majority of the acquired cases (75%) are idiopathic [2]. Aplastic anemia can affect people at any age, regardless of race or gender [3,4]. ...
... Aplastic anemia can affect people at any age, regardless of race or gender [3,4]. One to two new cases per million per year have been reported in Europe and North America [2,5,6]. ...
... SAA is defined by having two of the following three conditions present: absolute neutrophil count (ANC) less than 500 cells/μL, reticulocyte count less than 20,000/μL, and platelet count less than 20,000/μL. Patients with SAA are at risk for life-threatening infections and bleeding [2]. ...
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This study assessed treatment patterns and healthcare resource utilization (HRU) of patients with severe aplastic anemia (SAA) with insufficient response to immunosuppressive therapy (IST). A retrospective chart review was conducted at Dana-Farber Cancer Institute (DFCI), United States, and Hôpital Saint-Louis (HSL), France. Eligible patients were ≥ 18 years old, diagnosed with acquired SAA between January 1, 2006, and July 31, 2016, had insufficient response to IST, and had ≥ 12 months of follow-up post-diagnosis. Overall survival (OS) was estimated using the Kaplan-Meier method. Among the 40 patients, mean age at diagnosis was 44 years and 53% were women. Median follow-up time after SAA diagnosis was 48.3 months. Ninety-five percent of patients received antithymocyte globulin (ATG) as primary therapy prior to hematopoietic stem cell transplant (HSCT). Most common secondary SAA therapies prior to HSCT were eltrombopag (28%) and androgens (15%). Seventy-five percent of patients received HSCT. Prior to HSCT, patients received an average of 2.7 red blood cell (RBC) and 3.3 platelet transfusions per month; patients had 0.9 hospitalizations, 0.4 emergency room visits, and 12.8 office visits per year. Five-year OS was 75%, with infection as the primary cause of death. Additionally, this study provides information on the subgroup of patients receiving eltrombopag which was the most common secondary therapy. This study quantified transfusion and HRU burden associated with SAA and demonstrated high 5-year survival in a recently treated cohort.
... It is defined as pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrates, marrow fibrosis or dysplastic changes. To diagnose AA a hematologist must exclude other causes of pancytopenia [1][2][3]. ...
... The majority (70-80%) of AA cases are idiopathic [1][2][3]. The incidence of AA is 2-3 per million per year in Europe, but higher in East Asia. ...
Article
Aplastic anemia (AA) is a type of anemia that is caused by an intrinsic defect of hematopoietic progenitors or an extrinsic immune mediated destruction of stem cells. Patients commonly presented with pancytopenia, particularly leukopenia that renders patient susceptible to various infections. COVID-19 is one of these infections that could be life threatening and highly contagious. Infection with COVID-19 is expected in a patient who developed fever, respiratory manifestations, leukopenia and lymphopenia together with history suggestive of exposure to infection. Furthermore COVID-19 was found associated with thrombocytopenia, agranulocytosis and monocytopenia in severe cases. Thus the relationship between COVID-19 infection and AA would be a vicious circle as both cause leukopenia and lymphopenia. This study aimed to break this circle, through proposing risk stratification of vulnerability to COVID-19 in AA patients who were admitted in our institution in the period from Mar. 2018 to Mar. 2020 followed by a strict preventive plan tailored for each risk group. 79% of AA patients were at high risk of acquiring COVID-19 infection if exposed. This group of patients have to be targeted with more aggressive preventive plan than normal healthy persons. In conclusion this study proposed next step in combating COVID-19 infection through mass survey of high risk people then application of specific precautions to them, perhaps they could be candidate for future vaccine or prophylactic treatment.
... The trial was conducted from July 2016 to December 2018 with inclusion criteria as follows: (1) SAA and very severe aplastic anaemia (VSAA) patients diagnosed according to Camitta's criteria [11] without sex or age limitations; (2) patients with newly diagnosed SAA and VSAA did not receive ATG or CSA for more than 6 months within 1 year; ...
... Haematopoietic recover y was def ined as an ANC ≥ 0.5 × 10 9 /L for 3 days, Hb ≥ 60 g/L for 7 days without red blood cell transfusion and platelet count ≥ 20 × 10 9 /L for 1 week with no platelet transfusion. The CR and PR rates were evaluated after 3, 6 and 12 months of treatment according to the 2009 Guidelines for the Diagnosis and Management of Aplastic Anaemia [11]. Recurrence was defined as a decrease in routine blood indices from the original pretreatment levels of patients with therapeutic responses and efficacy lasting for at least 3 months or the recurrence of blood product dependence. ...
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Immunosuppressive therapy (IST) is an effective treatment regimen for severe aplastic anaemia (SAA) patients without HLA-identical donors. This study further compared the outcomes between IST and IIST-UCB in SAA on the basis of research shown that IST combined with umbilical cord blood infusion (IIST-UCB) treated effectively. A total of 123 patients from 11 hospitals in China were enrolled. Sixty-nine patients in IIST-UCB group were treated with ATG + CsA + CTX combined with cord blood, while 54 patients in IST group with ATG + CsA. The overall remission rates (ORRs), complete remission (CR) rates and partial response (PR) rates of IIST-UCB group and IST group at 3 months were 69.67% vs 51.85% ( P = .045), 21.74% vs 3.7% ( P = .004) and 47.83% vs 48.15% ( P = .972), respectively. After 6 months of treatment, they were 76.81% vs 57.41% ( P = .022), 37.68% vs 11.11% ( P = .001) and 39.13% vs 46.30% ( P = .425), respectively. After 1 year of treatment, they were 85.51% vs 61.11% ( P = .002), 59.42% vs 25.93% ( P = .000) and 26.09% vs 35.19% ( P = .275), respectively. The ORRs and CR rates of IIST-UCB group were both significantly higher than IST group after 3 months, 6 months and 1 year of treatment. The neutrophil granulocyte, platelet and haemoglobin recovery times of IIST-UCB group were significantly shorter than IST group. Compared with standard IST, IIST-UCB as an effective therapy for SAA patients without HLA-identical donors accelerated the haematopoietic reconstitution, resulting in higher early CR rates.
... In those who switched to subsequent therapy, the responses were reassessed to evaluate the efficacy of the second-line treatment. Criteria for responses were based on the British Committee for Standard Haematology (BCSH) guideline [12,17]. Briefly, the response criteria were as follows: complete response (CR): normal hemoglobin (Hb) for age and gender with ANC ≥ 1.5 × 10 9 /L and platelet ≥ 150 × 10 9 /L; partial response (PR): transfusion independence and no longer met the criteria for severe disease, and no response (NR): not achieving CR/PR. ...
... Cox regressions were used to estimate hazard ratios among given subgroup stratifications. Treatment responses to immunosuppressive therapy were pre-defined as previously described criteria [17]. The statistical analyses were performed using SAS 9.4. ...
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The incidence and outcomes of aplastic anemia (AA) in Asia remain limited. This study aimed to explore the incidence and outcomes of patients with adult AA across the country of Thailand. This is a prospective multi-center nationwide population-based observational study of AA patients aged at least 15 years old, diagnosed from August 2014 to July 2016, with a longitudinal follow-up period over 2 years. There were 348 newly diagnosed adult AA patients during the enrollment period, giving an annual incidence of 4.6 per million. The incidence of severe (SAA) and very severe aplastic anemia (VSAA) (3.8 per million) was higher than non-severe AA (NSAA, 0.8 per million). The peak incidence was observed in the patients aged from 80 to 89 years old (14.4 per million). The 2-year overall survival (OS) in NSAA, SAA, and VSAA were 65.5%, 49.3%, and 20.1%, respectively ( P < 0.001). With regard to the response to immunosuppressive therapy, the overall response rate (ORR) in SAA/VSAA treated with rabbit anti-thymocyte globulin with/without cyclosporin A (rATG ± CsA) were significantly superior to those treated with CsA alone, or anabolic steroids (44.4% vs 36.4% and 31.2%, respectively, P < 0.001). The 2-year OS in SAA/VSAA treated with rATG ± CsA, CsA, and anabolic steroids were 54.8%, 54.5%, and 37.6% ( P = 0.037), respectively. The incidence of adult AA in Thailand is higher than those in Western countries, and the peak incidence is in the elderly. rATG ± CsA provided a better response than anabolic steroids, translating to the superior survival in SAA/VSAA treated with rATG ± CsA.
... AA severity was defined according to the guidelines published by Marsh et al. [10]. Neutrophil and platelet engraftment were defined as an absolute neutrophil count (ANC) of >500/µL on 3 consecutive days and a platelet count of >20000/µL without transfusion support on 3 consecutive days, respectively. ...
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Objective: Although inhibition of complement system at different steps is a promising therapy modality in PNH (paroxysmal paroxysmal nocturnal hemoglobinuria) patients, allogeneic hematopoetic stem cell transplantation (HCT) is still the only curative therapy especially for patients with intractable hemolysis or bone marrow failure. The aim of this study is to evaluate the outcomes of allogeneic HCT in PNH patients with or without aplastic anemia ( PNH-AA). Material and methods: 35 PNH / PNH-AA patients who were treated with allegeneic HCT in ten transplantation centers in Turkey were retrospectively analyzed. Results: 16 (45.7 %) and 19 (54.3 %) patients were diagnosed as classical PNH and PNH / AA respectively. The median age of the patients was 32 ( 18-51) 2-year overall survival (OS) and GVHD-free, failure-free survival (GFFS) was 81.2 % and 78.1 % , respectively. 2 year OS in classical PNH and PNH /AA was 81.3 % and % 79.9 (p =0,87), respectively and 2 year GFFS in PNH and PNH/AA was 79% and 76% (0,977) without statistical significance. OS and GFFS rates did not differ between transplantations with matched sibling donor (MSD) and matched unrelated donor (MUD), neither. Conclusion: Allo HCT with MSD or MUD is a good option in selected patients with classical PNH and PNH / AA. Especially, patients with debilitating and refractory hemolysis and patients with bone marrow failure might form the excellent group for allo - HCT.
... ATG doses and regimens are empiric and have not been established based on scientific evidence. According to the UK treatment guideline, rabbit ATG as a first-line treatment should be dosed at 3Á75 mg/kg/day for five consecutive days (Marsh et al, 2009). However, each research centre uses different doses. ...
Article
The treatment of choice for patients with severe aplastic anaemia (SAA) includes immunosuppressive therapy (IST) with anti‐thymocyte globulin (ATG) and ciclosporin A. However, the optimal dose for rabbit ATG has yet to be established. We herein report the first prospective, randomized, multicentre study comparing two doses of rabbit ATG in patients with SAA. Patients with SAA who required initial IST in Japan (n = 89), China (n = 85) and Korea (n = 48) were enrolled between May 2012 and October 2017. A 1:1 block randomization was employed for two doses of rabbit ATG. In total, 222 patients were randomized, with 112 patients receiving 2·5 mg/kg and 110 receiving 3·5 mg/kg of rabbit ATG for 5 days. The primary endpoint was the haematological response at day 180. After 6 months, no significant difference in response rates was observed between the 2·5 and 3·5 mg/kg groups (49% vs. 48%, P = 0·894). Overall survival at 3 years was similar between the two groups [85% (95% confidence interval [CI], 76%−91%) vs. 91% (95% CI, 82%−96%); P = 0·107]. The current study revealed no significant differences in the efficacy and safety between the 2·5 and 3·5 mg/kg doses of rabbit ATG in patients with SAA. Trial registration: UMIN000011134.
... Adverse events were graded based on the Common Terminology Criteria for Adverse Events (CTCAE). Complete remission (CR) and partial remission (PR) were defined according to previous literature [17]: briefly, (1) CR: normal hemoglobin (HGB), neutrophil (ANC) > 1.5 × 10 9 /L, platelet (PLT) > 100 × 10 9 /L; (2) PR: (A) free from blood transfusion (previously blood transfusion dependent); (B) at least one lineage restored to normal or twice increased compared with the baseline; (C) HGB increased > 30 g/L (< 60 g/L before treatment), ANC increased > 0.5 × 10 9 /L (less than 0.5 × 109/L before treatment), PLT increased > 20 × 10 9 /L (less than 20 × 10 9 /L before treatment) compared with the baseline. No response (NR) was defined as not having any of the above responses. ...
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Eltrombopag has shown a promising effect on patients with refractory/relapsed aplastic anemia (AA). However, data in Asian patients are limited due to the short launching time. Data from relapsed/refractory AA patients treated with eltrombopag in Peking Union Medical College Hospital from December 2017 to May 2019 were analyzed retrospectively. Totally 41 patients including 37 non-severe AA and 4 severe AA were analyzed with a median age of 47 (13~81) years old. The dosage of eltrombopag varies from 25 mg every other day (qod) to 100 mg every day (qd) (median 75 mg qd) with the duration of 13 (3~23) months. The overall response rates were 51.2%, 58.5%, and 55.2% at 3-month, 6-month, and 1-year follow-up. Seventy-five percent of patients achieved the best response below the dosage of 75 mg qd at 3 (1-6) months. Two patients stopped eltrombopag after achieving complete remission and remained stable. Two patients relapsed and evolved to myelodysplastic syndrome. Adverse events included gastrointestinal discomfort, hepatic toxicity, and skin reactions, which were mild and controllable. Eltrombopag is effective for Chinese relapsed/refractory AA patients with a relatively lower dose and acceptable side effects.
... Efficacy was evaluated according to international guidelines. [2] Patients were followed up for at least 1 year. ...
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With the emergence of COVID-19 pandemic, health care for many non-COVID illnesses has inadvertently slid back. For most patients with life-threatening illnesses, the directive from the Ministry of Health and Family Welfare to continue the treatment for essential health services has come as a relief. However, for certain life-threatening illnesses such as aplastic anemia, the situation has been grim. We discuss the poor outcome of 2 children followed up at our center for aplastic anemia and analyze the reasons for the same.
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Background: The effects of long noncoding RNAs (lncRNAs) and their related messenger RNAs (mRNAs) remain unknown in children with acquired aplastic anemia (AA). The aim of this study is to screen key lncRNAs and mRNAs and investigate their potential roles in the pathology of acquired AA in children. Methods: RNA sequencing was performed to identify differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between blood samples of acquired AA children and healthy controls. cis-regulation, trans-regulation, competing endogenous (Ce) regulation networks of DElncRNAs and DEmRNAs were constructed. A literature search was performed to identify immune- or hematopoietic-related DElncRNA-DEmRNA pairs, and qPCR was conducted to validate the expression of the immune- or hematopoietic-related DElncRNA and DEmRNA. Results: 60 DElncRNAs and 364 DEmRNAs were identified. 13 DElncRNAs were predicted to have 15 cis-regulated target DEmRNAs, 16 DElncRNAs might have 28 trans-regulated DEmRNAs, and 2 DElncRNAs might have 9 Ce-regulated DEmRNAs. After literature screen and qPCR validation, 6 immune- or hematopoietic-related DElncRNA-DEmRNA pairs in the networks above were identified as key RNAs in the pathology of acquired AA. Conclusion: This study revealed key lncRNAs in children with acquired AA and proposed their potential functions by predicting their target mRNAs, which lay the foundation for future study of potential effects of lncRNAs in children with acquired AA.
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The COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplant conditioning. The effect on transplant outcomes in non-malignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the US during 2013-2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received non-cryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (HR 2.26, 95% CI 1.17 – 4.35, p=0.01) and of 1-year overall mortality (HR 3.13, 95% CI 1.60 – 6.11, p=0.0008) after transplantation of cryopreserved compared to non-cryopreserved grafts with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match). Acute and chronic GVHD did not differ between groups. Adjusted probabilities of 1-year survival were 73% (95% 60 – 84) and 91% (95% CI 86 – 94) with cryopreserved and non-cryopreserved grafts, respectively. These data support the use of non-cryopreserved grafts, when possible, for severe aplastic anemia.
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Aplastic anemia (AA) is a serious hematological disorder, which is solely cured by hematopoietic stem cell transplantation (HSCT). Haploidentical HSCT is an emerging modality with encouraging outcomes in several blood conditions. The present study aims to comprehensively assess the feasibility and safety of haploidentical HSCT in patients with severe and very severe AA. It is a systematic review and meta-analysis of studies related to haploidentical stem cell transplantation in idiopathic AA investigating rates of successful engraftment, acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), transplant-related mortality (TRM), and posttransplantation viral infections (including cytomegalovirus [CMV]) in patients with AA. The effects of reduced-intensity conditioning (RIC) and nonmyeloablative conditioning (NMA), as well as various GvHD prophylaxis regimens on these outcomes were evaluated. In total 15 studies were identified, (577 patients, 58.9% males), successful engraftment was observed in 97.3% of patients (95% CI, 95.9–98.7) while grades II–IV aGvHD and cGvHD were reported in 26.6% and 25.0%, respectively. The pooled incidence of TRM was 6.7% per year (95% CI, 4.0–9.4). RIC regimens were associated with higher proportions of successful engraftment (97.7% vs 91.7%, P = 0.03) and aGvHD (29.5% vs 18.7%, P = 0.008) when compared with NMA regimens with no differences in cGvHD or mortality incidence. When compared with methotrexate-containing regimens and other regimens, posttransplant cyclophosphamide-containing regimens reduced the rates of aGvHD (28.6%, 27.8%, and 12.8%, respectively, P = 0.02), CMV viremia (55.7%, 38.6%, and 10.4%, respectively, P < 0.001), and CMV disease in initially viremic patients (2.1%, 33.0%, and 0%, respectively, P < 0.001). We have concluded that Haploidentical HSCT was associated with promising outcomes in terms of successful engraftment and reduced complications. Future prospective trials are needed to identify the preferred conditioning regimen, GvHD prophylaxis, and graft source in the setting of haploidentical transplant for AA.
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Aplastic anemia (AA) is an immune-mediated disorder in which hematopoietic stem and progenitor cells are targeted by a number of cellular and molecular pathways. This case control study aims to investigate the association of interleukin-1beta (IL-1β) gene polymorphisms, (IL-1β-31, IL-1β-511 and IL-1β-3954) and their plasma levels with acquired AA. Genotyping was done by Restricted Fragment Length Polymorphism (PCR–RFLP) method and IL-1β plasma levels were evaluated in peripheral blood using ELISA. Increased level of IL-1β was reported to be significant in cases as compared to controls. The susceptibility of developing AA was higher in the cases for IL-1β-3954 genotype. IL-1β-511 genotype showed significant association with the severity groups of AA. No significant association was noticed in responder versus non-responder group. Plasma level of IL-1β gene was found to be significantly higher in severe and very-severe group of AA versus control group. Our findings suggest that IL-1β gene and its genotypes might be involved in the pathophysiology of AA and play a central role in the etiopathogenesis of AA.
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There is no standard or widely effective treatment of patients with moderate aplastic anemia (MAA) or hypo-productive uni-lineage cytopenias (UC). Eltrombopag (EPAG), a small molecule thrombopoietin mimetic, has previously been shown to result in durable multi-lineage hematologic responses with low toxicity in patients with refractory severe aplastic anemia (SAA). Its safety and efficacy in MAA are unknown. This prospective phase 2 study enrolled previously untreated and treated MAA and UC patients with clinically relevant cytopenias. EPAG was administered at doses escalating from 50 to 300 mg/d. Hematologic responses were assessed at 16 to 20 weeks. Responding patients were continued on EPAG until reaching defined robust or stable blood counts. EPAG was reinstituted for relapse. Thirty-four patients were enrolled between 2012 and 2017, including 31 with MAA and 3 with UC. Seventeen patients responded in at least 1 eligible lineage by the primary end point. A striking improvement in anemia was observed in a patient with Diamond-Blackfan anemia. EPAG was well tolerated, and it was discontinued for robust or stable blood counts in 12 of 17 patients after a median of 8 months. A majority required re-initiation of EPAG for declining counts, and all regained response. Two of 34 patients developed non–chromosome 7 bone marrow cytogenetic abnormalities while taking EPAG, without dysplasia or increased blasts. Somatic mutation allele frequencies in cancer genes did not increase overall on EPAG. EPAG is a well-tolerated oral treatment of cytopenias in patients with MAA/UC. This trial was registered at www.clinicaltrials.gov as #NCT01328587.
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Acquired aplastic anemia (AA) is a rare hematological disease characterized by bone marrow hypocellularity and varying degrees of pancytopenia. Immunosuppressive therapy (IST) is currently one of the first-line treatments for AA; however, unresponsiveness remains a major concern. Although previous studies have suggested several common risk factors for unresponsiveness, there are currently no widely accepted predictors. Therefore, a meta-analysis of clinical trials including information on factors associated with unresponsiveness of AA to IST was performed in the present study. The PubMed, Embase and Cochrane Library databases were searched for clinical studies on AA evaluating the association between risk factors and unresponsiveness to IST. After the factors were defined from the selected studies, the association between these factors and unresponsiveness to IST was analyzed using Review Manager software. A total of 10 studies comprising 1,820 cases were included in the present meta-analysis. The following factors were identified as predictors of unresponsiveness: Age (≥60 years), sex, absolute neutrophil count, severity of the disease, paroxysmal nocturnal hemoglobinuria clone, human leukocyte antigen (HLA)-DR2 and cytogenetic abnormalities (CAs). Among these factors, only age (≥60 years) [odds ratio (OR)=1.65], HLA-DR2 negativity (OR=2.72) and CAs (OR=1.93) exhibited a statistically significant association with unresponsiveness to IST (P=0.006, P=0.04 and P=0.01, respectively). In conclusion, the present meta-analysis revealed that age ≥60 years, HLA-DR2 negativity and CAs are risk factors for unresponsiveness to IST. This result may enable clinicians to select an effective therapeutic scheme for patients with AA and even provide novel clues to the pathogenesis of AA.
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Thymus neoplasms are frequently related to paraneoplastic autoimmune manifestations. Its most common associations are myasthenia gravis and pure red cell aplasia. Aplastic anemia has been increasingly documented as an initial presentation of thymoma. Nevertheless, its development after successful surgical resection of thymoma is a rare condition. We report a case of a 53-year-old man with severe aplastic anemia preceded by amegakaryocytic thrombocytopenia three years after thymectomy with no signs of disease recurrence. He underwent immunosuppressive therapy with cyclosporine 5 mg/kg/day and prednisone 2 mg/kg/day for six weeks. Considering the availability of a compatible donor, allogeneic stem cell transplantation was carried out. However, the patient died 11 days after transplant. A literature review was conducted, and another ten cases of aplastic anemia, diagnosed three months to four years after thymectomy, were identified. These cases suggest persistence of peripheral self-reactive T lymphocytes even years after tumor definitive treatment.
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Background: This study aimed to assess the outcome of stem cell transplantation (SCT), including overall survival (OS), failure-free survival (FFS) and graft-versus-host disease (GvHD)-free/failure-free survival (GFFS), and to analyze prognostic factors in children with aplastic anemia (AA). Methods: From 1991 to 2018, 43 allogeneic SCT recipients were enrolled in the study to investigate the demographic characteristics, survival outcomes and prognostic factors. Results: With the median follow-up of 7.1 years, the estimated 10-year OS, FFS, GFFS were 86.0%, 60.5%, and 51.2%, respectively. Matched related donors (MRD, n = 28) showed better 10-year OS than unrelated donors (n = 15) (96.4% vs. 66.7%; P = 0.006). Engraftment failure was seen in 13 patients (30.2%). Donor-type aplasia was seen in 13.8% (4/29) after fludarabine (Flu)-based conditioning (Flu-group), while in 42.6% (6/14) after cyclophosphamide (Cy)-based regimen (Cy-group) (P = 0.035). Six patients died. The 10-year OS in Cy-group was 92.9% (n = 14, all MRD), while that of Flu-group was 82.1% (n = 29; P = 0.367). But Flu-group tended to have better FFS and GFFS than Cy-group, although Flu-group had less MRDs (41.4% vs. 100%; P = 0.019), and higher proportion of previous immunosuppressive treatment (IST; 62% vs. 21.4%, P = 0.012). In MRD transplants, OS was similar between Flu-group (100%, n = 14) and Cy-group (92.9%, n = 14), while FFS (100.0% vs. 42.9%; P = 0.001) and GFFS (85.7% vs. 35.7%; P = 0.006) were significantly better in Flu-group. Stem cell sources, irradiation in the conditioning, and method of GvHD prophylaxis did not significantly influence the outcome. Conclusion: This study reviewed SCT outcomes for pediatric AA with changes of transplant strategies over the last 25 years. The FFS and GFFS were higher in Flu-group than in Cy-group, especially in matched related transplantation. Graft failure including donor-type aplasia remains troublesome even with Flu-based conditioning. Further refinement of transplant strategies to ensure better quality-of-life should be pursued.
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Objective To investigate the expression of lymphocyte activation gene 3(LAG3) on CD8+T effector cells (Teffs), CD4+ Teffs and regulatory T cells (Tregs) in patients with severe aplastic anemia (SAA).Methods We detected the expression of LAG3 on CD8+ Teffs, CD4+ Teffs and Tregs in SAA patients and healthy controls (HC) by flow cytometry, and analyzed its correlation with the immune status and severity of the disease. ELISA was used to detect soluble LAG3(sLAG3).ResultsThe expression of LAG3 on CD8+ Teffs, CD4+ Teffs and Tregs in untreated SAA patients were significantly lower than those in HC group (P < 0.05). After IST, the LAG3 expression of target cells increased to a level even higher than that in HC group (P < 0.05). LAG3 on T cell subsets was closely related to immune status and severity of the disease. The concentration of sLAG3 in these groups showed similar trends. LAG3 was not a prognostic factor of response.Conclusion The decreased expression of LAG3 on CD8+ Teffs, CD4+ Teffs and Tregs may be involved in the pathogenesis of SAA. LAG3 intervention may have therapeutic potential in treating SAA.
Article
Immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine A (CsA) is currently the standard treatment for patients with severe aplastic anemia (SAA) who have no suitable donor or are ineligible for allogeneic stem cell transplantation. However, the delayed hematopoietic recovery, which accounts for most early deaths, remains a key problem. Thus, we designed an IST protocol with fludarabine, rabbit ATG, and CsA followed by unrelated cord blood (UCB) infusion to study whether hematopoiesis could be accelerated. Nineteen patients were enrolled in this study. The median neutrophil recovery time was 22 days and the treatment-related mortality within 3 months was 5.3%. The median platelet recovery time was 180 days. Six patients had transient or sustained UCB engraftment and the median platelet recovery time of these patients was significantly shorter than those who had no UCB engraftment (46 days vs 206 days, p = 0.006). The cumulative incidence of response rate at 12 months was up to 88.7% with CR rate of 72.2%. The overall survival at 2 years and 5 years was 94.7% and 78.9%, respectively. These results suggest that UCB infusion may play an important role in accelerating hematopoietic recovery in this protocol.
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Hepatitis-associated aplastic anemia (HAAA) is a variant of acquired aplastic anemia and characterized by bone marrow failure that follows the development of acute hepatitis. We herein report a rare case of HAAA with rapid progression of liver fibrosis due to repeated hepatitis. A pathological examination of liver specimens revealed liver fibrosis progression over a short period. Immunosuppressive therapy with cyclosporine effectively cured both the pancytopenia and hepatitis. Our case suggests that the pathological examination of the liver tissue is useful for determining a treatment plan and that immunosuppressive therapy is a promising treatment for both aplastic anemia and persistent hepatitis.
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Objective: The aim of this study was to analyze T-lymphocyte subsets and Th1/Th2 cytokines in convalescent patients with Epstein–Barr virus (EBV)-associated aplastic anemia (AA). Methods: Sixty AA patients were enrolled, who were in remission following immunosuppressive therapy, including 34 EBV-negative cases and 26 EBV-positive cases. Their complete blood count (CBC), T-lymphocyte subsets, Th1/Th2 cytokines were analyzed. The correlation between EBV-DNA and T-lymphocyte subsets was evaluated, as well as the relationship between EBV-DNA and Th1/Th2 cytokines. The presence of EBV-DNA in peripheral blood mononuclear cells (PBMCs) was also assessed in 60 normal controls. Results: EBV-DNA was detected in 26/60 (43.33%) patients and 21/60 (35.00%) controls. EBV-DNA copy number in AA patients was higher than in controls (Z = −2.138, P = 0.033). The percentage of CD3⁺CD4⁺ T-lymphocytes and the ratio of CD4⁺/CD8⁺ T-lymphocytes in the EBV-negative group were higher than in the EBV-positive group (P = 0.001 and 0.001, respectively). EBV was positively correlated with CD3⁺CD8⁺ T-lymphocyte percentages (Pearson R: 0.496, P = 0.009). Moreover, EBV was positively correlated with IL-10 and IFN-γ levels (Pearson R: 0.559, P = 0.002 and Pearson R: 0.621, P = 0.001, respectively). Conclusions: EBV-DNA copy number in AA patients was higher than in normal controls. Both AA and EBV infection may cause changes in the levels of T-lymphocyte subsets. We recommend monitoring the changes in the immune function and EBV infection simultaneously in AA patients, especially following immunosuppressive therapy.
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Background: Severe aplastic anemia (SAA) is a rare autoimmune condition resulting in low blood cell counts across lineages. Immunosuppressive therapy (IST) has demonstrated low response, toxicity, and risk of transformation. In a Phase I/II trial, the addition of eltrombopag to first-line IST increased response rates relative to an IST-only historical cohort. Methods: A model was developed to estimate the budget impact of treating SAA with eltrombopag-based therapy from a US private healthcare system perspective. A simulated cohort of newly diagnosed SAA patients based on the total US population received 6 months of IST ± eltrombopag and were followed for 1 year, with mutually exclusive patient cohorts entering in years 1, 2, and 3. The model assessed the budget impact of first-year treatment for each cohort without considering subsequent years. At 6 months, responders in either arm received maintenance therapy (low-dose cyclosporine), and non-responders received 6 months of second-line eltrombopag monotherapy. Costs considered included first-line, maintenance, and second-line therapy, administration, routine care, mortality, and adverse events (AEs). All cost data were reported in 2018 US dollars. Results: The annual incidence of aplastic anemia was 0.000234%, with 83.8% of cases assumed to be SAA. Based on trial data, 94% of patients receiving eltrombopag and IST responded versus 66% of patients receiving IST, with a 0.3% reduction in the annual risk of mortality for the eltrombopag + IST group. Use of first-line eltrombopag in a model SAA population based on the total US population increased overall costs by $50 million over 3 years. First-line drug costs accounted for an increase of $69 million, while improved response produced $19 million in secondary therapy cost savings. Sensitivity analyses confirmed the robustness of the analysis. Conclusion: High response rates combined with reduced rescue medication use and mortality in patients treated with eltrombopag and IST mediated higher medication costs.
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BACKGROUND Graft rejection and graft versus host disease (GvHD) have impeded the success of hematopoietic cell transplantation for severe aplastic anemia (SAA) patients. There is no sufficient data to identify the outcomes of peripheral blood stem cell transplantation (PBSCT) in SAA patients, especially for adult SAA patients. The aim of this study was to evaluate the outcomes of adult SAA patients undergoing PBSCT with the FCA regimen. The FCA regimen includes fludarabine, cyclophosphamide, and anti-thymocyte globulin (ATG). MATERIAL AND METHODS We report our experience with 46 adult SAA patients who underwent PBSCT with the FCA regimen. Thirty SAA patients who received only cyclophosphamide and ATG (CA) regimen were used as controls. Complications and survival outcomes were evaluated and compared. RESULTS There was a significantly higher percentage of patients who achieved >95% donor chimerism by day 30 in the FCA group. The 5-year event-free survival (EFS) rate in the FCA group was higher than that in the CA group (95.4% versus 73.3%). In addition, the 5-year rejection rate (RR) in the FCA group was lower than that in the CA group (4.6% versus 23.6%). A multivariable model identified the FCA regimen as an independent factor affecting EFS and RR. However, GvHD and serious infection did not differ between the 2 groups. For patients with an unrelated donor, the FCA regimen had a higher EFS and a lower RR than the CA regimen. CONCLUSIONS The FCA regimen for PBSCT in adult SAA patients compared favorably to the CA regimen. It can improve EFS and reduce graft rejection, especially for unrelated donor PBSCT.
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The pathogenesis of aplastic anemia (AA) in children is not clear. This study was conducted to investigate the changes in the proportion and function of regulatory T cells (Tregs) in pediatric AA. The proportion of Tregs, mRNA levels of transcription factors, and concentrations of cytokines were measured by flow cytometry, reverse transcription-PCR, and enzyme-linked immunosorbent assay, respectively. Tregs were co-cultured with effector T cells (Teff) to evaluate the function of Tregs. The proportion of Tregs after immunosuppressive therapy (IST) in pediatric AA was monitored dynamically. Compared to the control, the proportions of Tregs in peripheral blood and bone marrow lymphocytes of the untreated AA group were lower (1.31% ± 0.73% vs. 3.16% ± 0.92%, 1.49% ± 0.81% vs. 3.06% ± 0.82%, respectively, p < 0.001). The mRNA levels of FOXP3 and STAT3 in the AA group were lower (p = 0.014; p < 0.001). However, the mRNA levels of T-BET did not significantly differ between groups. The concentration of interferon-γ and interleukin-17 in the AA group were higher (p = 0.004; p = 0.003), whereas the concentration of TGF-β decreased (p = 0.044). The immunosuppressive function of Tregs was impaired in the AA group. After IST, the proportion of Tregs was significantly lower than that in the control. The proportion of Tregs at the time of diagnosis in the nonresponsive group was lower than that in the responsive group, but the difference was not significant. Treg levels were significantly decreased and were functionally impaired at the time of diagnosis of pediatric AA. However, there was no significant change in Tregs at the resolution of AA.
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Immunosuppressive therapy (IST), consisting of anti thymocyte globulin and cyclosporine, is the standard of care for elderly patients and in younger patients without matched donor for stem cell transplant. In this retrospective study of 60 patients, most had non severe AA (51.6%) followed by very severe AA (26.7%) and severe AA (21.7%). The response rate at 6 months was 68.3% (complete response-3.3% and partial response-65%). Of the 45 who completed 12 months follow up, RR was 54.7% (CR-7.5%, PR-47.2 %). Eight patients died during the study period. Also, Indian data on IST is briefly reviewed.
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The normal red blood cell count is kept by the balance between erythrocyte production and erythrocyte destruction. The regulation of progenitor cells to the erythroid lineage and their maturation are controlled by growth factors, cytokines and, very important, by the bone marrow microenvironment signaling directing nuclear transcription factors and gene expression. Erythropoietin is an obligate growth factor for the erythropoiesis and is required for the proliferation, differentiation, and survival of erythropoietic progenitor cells. GATA1 and GATA2 are transcription factors with key roles in gene regulation during erythropoiesis.
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The underlying mechanisms and clinical significance of ineffective erythropoiesis in myelodysplastic syndromes (MDS) remain to be fully defined. We conducted the ex vivo erythroid differentiation of megakaryocytic-erythroid progenitors (MEPs) from MDS patients and discovered that patient-derived erythroblasts exhibit precocity and premature aging phenotypes, partially by inducing the pro-aging genes, like ERCC1. Absolute reticulocyte count (ARC) was chosen as a biomarker to evaluate the severity of ineffective erythropoiesis in 776 MDS patients. We found that patients with severe ineffective erythropoiesis displaying lower ARC (<20 × 10⁹/L), were more likely to harbor complex karyotypes and high-risk somatic mutations (p < 0.05). Lower ARCs are associated with shorter overall survival (OS) in univariate analysis (p < 0.001) and remain significant in multivariable analysis. Regardless of patients of lower-risk who received immunosuppressive therapy or higher-risk who received decitabine treatment, patients with lower ARC had shorter OS (p < 0.001). Whereas no difference in OS was found between patients receiving allo-hematopoietic stem cell transplantations (Allo-HSCT) (p = 0.525). Our study revealed that ineffective erythropoiesis in MDS may be partially caused by premature aging and apoptosis during erythroid differentiation. MDS patients with severe ineffective erythropoiesis have significant shorter OS treated with immunosuppressive or hypo-methylating agents, but may benefit from Allo-HSCT.
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Aplastic anemia results from bone marrow failure caused by an autoimmune abnormality, but the pathogenesis of severe aplastic anemia (SAA) is not well characterized. To identify potential metabolic markers of SAA and to further elucidate the pathogenetic mechanisms of SAA, we performed a metabolomic study of plasma samples and characterized the intestinal microbiota of patients with SAA and healthy controls. Patients with SAA had more Enterobacteriales and Lactobacillales, but fewer Bacteroidales, Clostridiales, and Erysipelotrichales than healthy controls. At the species level, the abundances of Escherichia coli and others including Clostridium citroniae were higher, whereas those of Prevotella copri , Roseburia faecis , and Ruminococcus bromii were lower. Eight metabolites showed significantly different plasma concentrations in the SAA and healthy control groups. Coumaric acid, L -phenylalanine, and sulfate were present at higher concentrations in the SAA group; whereas L -glutamic γ-semialdehyde, theobromine, 3a, 7a-dihydroxy-5b-cholestane, γ-δ-dioxovaleric acid, and (12Z)-9, 10-dihydroxyoctadec-12-enoic acid were present at lower concentrations. In conclusion, patients with SAA show abnormalities in both their plasma metabolomes and intestinal microbial compositions. These differences might reflect the molecular mechanisms involved in the defective immunity that characterizes SAA.
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For over two decades, the EBMT has updated recommendations on indications for haematopoietic cell transplantation (HCT) practice based on clinical and scientific developments in the field. This is the eighth special EBMT report on the indications for HCT for haematological diseases, solid tumours and immune disorders. Our aim is to provide general guidance on HCT indications according to prevailing clinical practice in EBMT countries and centres. In order to inform patient decisions, these recommendations must be considered in conjunction with the risk of the disease, risk of HCT procedure and non-transplant strategies, including evolving cellular therapies. HCT techniques are constantly evolving and we make no specific recommendations, but encourage harmonisation of practice, where possible, to ensure experience across indications can be meaningfully aggregated via registry outputs. We also recommend working according to JACIE accreditation standards to maintain quality in clinical and laboratory components of practice, including benchmarking of survival outcomes. Since the last edition, the COVID-19 pandemic has affected clinical decision making and activity across indications. Although the full impact of the pandemic is yet to be determined, we recommend that decision making across indications is delivered with ongoing reference to EBMT and national COVID-19 guidance, in accordance with current local conditions.
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Cofilin‐1 interacts with actin to regulate cell movement. The importance of cofilin‐1 in immunity has been established, and its involvement in a number of autoimmune diseases has been confirmed. However, its role in severe aplastic anaemia (SAA) remains elusive. Thus, the aim of the current study was to investigate the role of cofilin‐1 in patients with SAA. Flow cytometry, Western blotting and real‐time quantitative reverse transcription‐polymerase chain reaction were performed to detect the mRNA and protein expression of cofilin‐1 in myeloid dendritic cells (mDCs) from patients with SAA. The expression of cofilin‐1 was then suppressed via siRNA, and its effects on mDCs and downstream effector T‐cell function were evaluated. Cofilin‐1 expression was higher in mDCs from patients with SAA and correlated with routine blood and immune indexes. Moreover, cofilin‐1 knockdown in mDCs from patients with SAA reduced their phagocytic capacity, migration capacity, and CD86 expression through F‐actin remodelling, downregulating the stimulatory capacity of mDCs on CD4+ and CD8+ T lymphocytes. Collectively, these findings indicate that cofilin‐1 participates in the hyperfunction of mDCs in patients with SAA and that the downregulation of cofilin‐1 in mDCs from patients with SAA could be a novel treatment approach for SAA.
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In acquired aplastic anemia (AAA) exogenous antigen initiates the obliteration of hematopoietic stem cells (HSc) instigating excessive secretion of antihematopoietic cytokines. Cytogenetic abnormalities (CAs) are infrequent in AAA. This study emphasized CA and the level of Interleukin-2 in bone marrow plasma (BMP) and peripheral blood plasma (PBP) of the selfsame acquired aplastic anemia patients in West Bengal. Essential ethical permissions from the concerned institutional authority were duly taken. After BM aspiration and biopsy, 100 AA patients (3–85 years) were taken. Plasma samples were isolated from 52 AAA patients and 10 controls. Giemsa trypsin giemsa banding followed karyotyping was done according to ISCN 2013. The magnitude of IL-2 was estimated by ELISA. Five (9.61%) cases showed CA. The extent of IL-2 was significantly elevated in patients with CA to without CA (PBP: 55.81 ± 18.79 vs. 33.28 ± 9.46; BMP: 135.79 ± 39.13 vs. 67.58 ± 35.81) and controls (PBP: 55.81 ± 18.79 vs. 1.99 ± 1.25; BMP: 135.79 ± 39.13 vs. 3.12 ± 1.82). The p values (F test) were found to be <0.00001. Hence, a high level of IL-2 may suggest the evolution of CA.
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Introduction: We aimed to investigate the balance between the mRNA levels of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in CD8+ T cells of patients with severe aplastic anemia (SAA). Methods: Twenty untreated SAA patients, 18 remission SAA patients (R-SAA), and 22 normal controls were evaluated. The mRNA expression levels of HATs, HDACs, and IFNG in CD8+ T cells were measured by real-time quantitative reverse transcription polymerase chain reaction. Results: Histone acetylase EP300 and CREBBP mRNA levels were significantly elevated in CD8+ T cells of SAA patients compared with the normal controls (both p < 0.05). No significant differences were observed in HDAC1 and HDAC7 mRNA between SAA patients and the normal controls. There was an obvious positive correlation between IFNG and EP300 (r = 0.5126, p < 0.01), and CREBBP (r = 0.4663, p < 0.05), respectively, in SAA and R-SAA patients. In addition, EP300 and CREBBP mRNA levels were clearly correlated with clinical parameters of peripheral blood and bone marrow in those patients. Conclusion: Our findings suggest that EP300 and CREBBP are increased in CD8+ T cells of SAA patients and are correlated with disease severity. The imbalances in HATs and HDACs may play a role in activating CD8+ T cells to promote the immune pathogenesis of SAA.
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Introduction: Lymphocyte activation gene 3 (LAG3) is an inhibitory checkpoint protein expressed on activated T effector, T regulatory, and natural killer cells. The main function of LAG3 is the regulation of immune homeostasis. Several studies have suggested its role in malignant and autoimmune diseases. The objective of this study was to explore the association between LAG3 single-nucleotide polymorphisms (SNPs) and bone marrow failure diseases. Methods: Sixty-two patients newly diagnosed with bone marrow failure diseases in the Hematology Department of Tianjin Medical University General Hospital between January 2019 and December 2020 and 16 healthy controls were enrolled in this study. SNPs in LAG3 were investigated by performing Sanger sequencing, and the association of the detected SNPs with bone marrow failure diseases was analyzed. Results: Eleven SNPs were identified. Among them, the frequency of LAG3 rs1941928301 (C>T) was statistically different among the groups (P = 0.013). It was higher in the myelodysplastic syndrome (MDS) group than that in the severe aplastic anemia (SAA) group (P = 0.004) and that in the healthy control group (P = 0.009). Conclusions: LAG3 rs1941928301 (C>T) might be associated with a higher risk of MDS. The detected LAG3 SNPs have no apparent effect on susceptibility to SAA and immune-related pancytopenia (IRP).
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Background: A deeper understanding of the pathogenesis of severe aplastic anemia (SAA) is urgently warranted to achieve better therapeutic effects. The objective of this study was to investigate the phagocytosis of myeloid dendritic cell (mDC) in SAA patients. Methods: Myeloid dendritic cells were induced in vitro from bone marrow mononuclear cells from 26 SAA patients and 12 normal controls (HCs). The phagocytosis of mDCs was detected by flow cytometry using FITC-Dextran (40KD), and its correlation with the immune status and severity of the disease was analyzed. Results: The phagocytosis of mDC from untreated SAA patients was significantly stronger than that from complete remission group and HC group (p < 0.05). There was no statistical difference between the latter two groups (p > 0.05). The phagocytosis of mDC from SAA patients correlated positively with the concentration of interleukin (IL)-2 (r = 0.389, p < 0.05), and IL-4 (r = 0.556, p < 0.05), negatively with CD4+ /CD8+ ratio (r = -0.421, p < 0.05). It also had negative correlations with the level of hemoglobin (r = -0.393, p < 0.05), white blood cell (r = -0.436, p < 0.05), platelet (r = -0.431, p < 0.05), and reticulocyte (r = -0.447, p < 0.05). The phagocytosis of mDC does not correlate with the response to IST. Conclusions: The increased phagocytosis of mDC in untreated SAA patients may contribute to abnormal activation of T helper (Th) and subsequent cytotoxic T lymphocyte (CTL) activation in these patients. It may be involved in the immune pathogenesis of SAA.
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Background and Aims This study aimed at comparing the efficacy and safety of severe aplastic anemia (SAA) cases that had met the criteria for SAA at the time of diagnosis (group A) with SAA that had progressed from non-SAA (NSAA) (group B), both undergoing first-line immunosuppressive therapy (IST). Additionally, group B was compared with SAA that had progressed from NSAA and who had been treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) (group C). Methods We retrospectively compared 608 consecutive patients in group A (n = 232), group B (n = 229) and group C (n = 147) between June 2002 and December 2019. Six months after treatment, the rate of overall response and the fraction of patients who had achieved normal blood values, treatment-related mortality (TRM), secondary clonal disease, 5-year overall survival (OS) and failure-free survival (FFS) were indirectly compared between group A and group B, group B and group C. Results Six months after treatment, the rate of overall response and the fraction of patients who had achieved normal blood values in group A was higher than in group B (65.24% vs . 40.54%, P < 0.0001; 23.33% vs . 2.25%, P < 0.0001); the same was true for group C (92.50% vs . 2.25%, P < 0.0001). The rate of relapse in group B was higher than in group C ( P < 0.0001), but there were no differences in TRM and secondary clonal disease ( P > 0.05). There were no differences in estimated 5-year OS between groups A and B (83.8% ± 2.6% vs . 85.8% ± 2.6%, P = 0.837), or between B and C (85.8% ± 2.6% vs . 77.9% ± 3.4%, P = 0.051). The estimated 5-year FFS in groups A and C was higher than for group B (57.1% ± 3.3% vs . 39.7% ± 3.4%, P < 0.001; 76.7% ± 3.5% vs. 39.7% ± 3.4%, P < 0.0001). Conclusion These results indicate that IST is less effective in SAA progressing from non-SAA but allo-HSCT can improve outcomes.
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Objectives Hypocellular bone marrow (BM) disorders comprise heterogeneous entities associated with peripheral cytopenias and decreased production of hematopoietic cells in BM. This study was undertaken to analyze immunohistochemical expression of CD34, CD117, and p53 in morphologically diagnosed patients of hypocellular BM (aplastic anemia [AA], hypocellular myelodysplastic syndrome [h-MDS], and hypocellular acute myeloid leukemia [h-AML]). Materials and Methods BM specimens were obtained from patients presenting with pancytopenia/bicytopenia. On 30 patients diagnosed as hypocellular BM, immunohistochemistry (IHC) for CD34, CD117, and p53 was performed. Results BM cellularity was < 30% in all (100%) patients. Blast count was increased in h-MDS and h-AML. Features of dysplasia were noted in six (20%) patients. Out of these, three patients were diagnosed as h-MDS having bilineage/trilineage dysplasia, and the other three patients were of AA (11.5% patients) displaying only dyserythropoiesis. On IHC, percentage of BM CD34+ cells was increased in h-MDS+ h-AML (3.87 ± 0.86) as compared with AA (0.19 ± 0.15) and controls (0.81 ± 0.21), p = 0.01. Percentage of BM p53+ cells was also increased in h-MDS+ h-AML (2.9 ± 2.07) as compared with AA and controls, which did not show any p53+ cells, p = 0.0. No statistically significant difference was observed in the expression of CD117 in h-MDS+ h-AML (4.95 ± 3.40) compared with AA (4.49 ± 1.07), p = 0.99. Conclusion The study demonstrates the usefulness of CD34 and p53 immunoexpression as an important ancillary method in distinguishing various hypocellular BM disorders, especially h-MDS and AA. However, the role of CD117 remains unclear and needs to be evaluated further by larger studies.
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Objective: The aim of the present study is to evaluate the efficacy, complications, and contributing factors of immunosuppressive therapy (IST) response in children with acquired aplastic anemia (AA) and to explore optimal therapeutic methods for different clinical AA types. Methods: A total of 130 children diagnosed with acquired AA underwent IST in the Department of Pediatrics at Sun Yat-sen Memorial Hospital and the Department of Pediatrics at Seventh Affiliated Hospital, Sun Yat-sen University, between January 1, 2006, and July 15, 2020. The overall survival (OS), response rates, complications, and response predictors were analyzed. The response rates were compared according to clinical AA type. Results: All 130 children with AA were followed up with for a median of 50.6 months. Among the patients, 25 had non-severe AA (NSAA), 64 had severe AA (SAA), and 41 had very severe AA (VSAA). All patients initially received IST. In 13 patients, the IST failed; these patients received an allo-hematopoietic stem cell transplant as a salvage regimen. The OS rate was 90.3% ± 2.8%, and the response rates at 3, 6, 9, and 12 months were 34.19%, 39.32%, 49.57%, and 66.67%, respectively. The prolonged follow-up period might have led to higher response rates, especially in patients with SAA and VSAA. A multivariate logistic regression analysis of prognostic factors was conducted; the results showed that high red blood cell (RBC) and platelet (PLT) counts were associated with a high overall response rate and that the RBC count at diagnosis is a major contributing factor. Conclusion: With the use of rabbit anti-thymocyte globulin, proper cyclosporine management, and a prolonged IST follow-up period, a higher number of patients with acquired AA than normal achieved response. Proportionally, the number of patients who achieved remission within 12 months was higher in the SAA group (38.18%→63.64%) and VSAA group (28.95%→65.79%) than in the NSAA group (58.33%→75%). Higher RBC and PLT counts at diagnosis can predict a favorable outcome.
Article
The prognosis of patients with hypoplastic myelodysplastic syndrome (hMDS) after receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. This study aimed to evaluate the outcomes of patients with hMDS after allo-HSCT. Between September 2013 and October 2019, a total of 20 consecutive patients with hMDS and 1 patient with clonal cytopenia of undermined significance (CCUS) who underwent allo-HSCT, which included procedures with 9 matched sibling donors, 2 matched unrelated donors, 4 mismatched unrelated donors and 6 haploidentical donors, were enrolled in this study. The median time for myeloid engraftment was 11 days (range 9-17 days), and that for platelet engraftment was 10 days (range 7-17 days). The cumulative incidence (CI) of myeloid and platelet recovery was 95.2 ± 6.0% and 90.5 ± 7.3%, respectively. The CI rates were 40.0 ± 11.3% for grades II-III acute graft-versus-host disease (GVHD), 36.8 ± 11.5% for chronic GVHD and 23.8 ± 9.6% for nonrelapse mortality. No patients experienced relapse. Sixteen surviving patients were followed up for a median of 1113 days (range 110-2305 days), and the overall survival and relapse-free survival rates were both 72.7 ± 10.6%. This limited retrospective analysis suggests that patients with hMDS had a favorable survival after allo-HSCT.
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Background: Mixed chimerism (MC) frequently occurs in patients with severe aplastic anemia (SAA) after allogeneic hematological stem cell transplantation (allo-HSCT). Methods A retrospective study on 287 patients with SAA who underwent allo-HSCT between October 2012 and January 2020 was conducted to explore the outcomes, risk factors and treatment options for MC. Among 287 AA patients who excluded Fanconi anemia (FA), Congenital dyskeratosis (DKC), Paroxysmal nocturnal hemoglobinuria (PNH), etc.112 underwent matched sibling donor (MSD)-HSCT, 91 matched unrelated donor-HSCT and 84 haploidentical-HSCT. Patients were divided into the following 4 groups: group 1: Donor chimerism (DC); group 2: MC without cytopenia; group 3: MC with cytopenia; group 4: secondary graft failure (SGF). Results Compared with the other three groups, SGF predicted a poor prognosis of SAA (P< 0.001). In addition, SGF was associated with the early (within 3 months after transplantation) presence of MC and the high levels of MC. Uni- and multivariate logistic regression analysis showed that donor/recipient sex-mismatching and CTX + ATG regimen were high-risk factors for MC. Of note, in MC patients with cytopenia (group 3), the effective response rate reached 55% (6/11) following enhanced immunosuppression combined with cellular therapy, while only one of the four was effective who received enhanced immunosuppression alone. Conclusion SGF was associated with poor prognosis, early presence of MC and increased levels of recipient chimerism. The donor/recipient sex-mismatching and CTX + ATG regimen based MSD-HSCT were risk factors for MC. Cellular therapy could improve the effective response rate of patients with progressive MC.
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Severe aplastic anemia (SAA) is an acquired, T cell-driven bone marrow (BM) failure disease characterized by elevated interferon gamma (IFNγ), loss of hematopoietic stem cells (HSCs), and altered BM microenvironment, including dysfunctional macrophages (MΦs). T lymphocytes are therapeutic targets for treating SAA, however, the underlying mechanisms driving SAA development and how innate immune cells contribute to disease remain poorly understood. In a murine model of SAA, increased beta-chemokines correlated with disease and were partially dependent on IFNγ. IFNγ was required for increased expression of the chemokine receptor CCR5 on MΦs. CCR5 antagonism in murine SAA improved survival, correlating with increased platelets and significantly increased platelet-biased CD41hi HSCs. T cells are key drivers of disease, however, T cell-specific CCR5 expression and T cell-derived CCL5 were not necessary for disease. CCR5 antagonism reduced BM MΦs and diminished their expression of Tnf and Ccl5, correlating with reduced frequencies of IFNγ-secreting BM T cells. Mechanistically, CCR5 was intrinsically required for maintaining BM MΦs during SAA. Ccr5 expression was significantly increased in MΦs from aged mice and humans, relative to young counterparts. Our data identify CCR5 signaling as a key axis promoting the development of IFNγ-dependent BM failure, particularly relevant in aging where Ccr5 expression is elevated.
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Background and purpose: Eltrombopag (ELT) can be effective in the treatment of relapse/refractory aplastic anemia (AA) patients. Responses and adverse drug reactions (ADRs) differed greatly among individuals treated at the same dosage of ELT. Methods: Patients diagnosed with nonsevere aplastic anemia (NSAA) between January 2018 and January 2019 in Peking Union Medical Colleague Hospital who were refractory to immunosuppressive therapy were treated with ELT and followed up for at least 6 months. Plasma concentrations of ELT were detected by high-performance liquid chromatography-mass spectrometry after at least two months of ELT treatment and treatment at the same dosage for at least 2 weeks. The dose-concentration, concentration-response and concentration-ADR relationships were evaluated. Results: Among the 72 patients treated with ELT during the study period, 44 patients with complete data were enrolled. Six (13.6%) were males, and 38 were females (86.4%), with a median age of 54 years [interquartile range (IQR): 38.5–63]. At the time the ELT plasma concentration was detected, the median dosage of ELT was 75 (IQR 50–100) mg/d, the median time of total ELT exposure was 3 (IQR 2.0–6.0) months, and 37 (70.5%) patients had responded to ELT. The median concentration of ELT was 10.4 μg/ml (IQR 3.7–24.4 μg/ml). The concentration of ELT was positively correlated with the daily dose of ELT ( r = 0.68, p < 0.001). Multivariate logistic regression analysis showed that the risk of inefficacy of ELT at a concentration between 11.2 and 15.2 μg/ml was 0.028-fold (95% CI: 0.001–0.864; p = 0.041) of that at a concentration between 3.2 and 7.2 μg/ml. The cutoff value for the concentration of ELT showing efficacy was 12.50 μg/ml according to the receiver operation characteristic curve. A higher risk of ADR was related to a longer total exposure to ELT ( p = 0.012). Although the correlation was not significant, the odds ratio increased with the ELT concentration, suggesting that it was possible that an elevated risk of ADR was correlated with the ELT blood concentration. Conclusion: ELT is effective for the treatment of NSAA and has acceptable side effects. The plasma concentration of ELT was correlated with the dose and the effects of ELT.
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Objectives To investigate the relationship between immune status and paroxysmal nocturnal hemoglobinuria (PNH) clonal evolution of severe aplastic anemia (SAA) patients who received anti‐human thymocyte globulin (ATG) treatment. Methods The clinical data of 102 SAA patients who received ATG were collected and retrospectively analyzed. The remission rate, remission time, response rate, hematopoietic, and immune status were compared. Malignant clones were also observed. Results The remission rate of the group with PNH clones appeared after treatment was significantly higher than the group without PNH clones. The response rate at 12 months of the groups with PNH clones was significantly higher than the group without PNH clones. The recovery of Hb and Ret % of patients with PNH clones was earlier than the patients without PNH clones. The reduction of percentage of CD8⁺HLA‐DR⁺/CD8⁺ and Th1/Th2 ratio of patients with PNH clones was both earlier than the patients without PNH clones. Six patients developed myelodysplastic syndromes (MDS). Conclusion In SAA patients with PNH clones, the cytotoxic T‐cell function and Th1 cell number recovered more quickly and had better response to IST. A small number of SAA patients with or without PNH clones developed MDS malignant clones.
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A previous dose‐finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as a starting dose. In this Phase II/III, multicentre, open‐label study, romiplostim was administered subcutaneously at a fixed dose of 10 µg/kg once weekly for 4 weeks (weeks 1–4) followed by weekly doses (5, 10, 15 and 20 µg/kg) titrated by platelet response for up to 52 weeks (weeks 5–52). A total of 31 patients with AA who were refractory to immunosuppressive therapy (IST) and thrombocytopenia (platelet count of ≤30 × 10⁹/l) were enrolled. The primary efficacy endpoint of the proportion of patients achieving any haematological (platelet, neutrophil and erythrocyte) response at week 27 was 84% [95% confidence interval (CI) 66–95%]. Trilineage response was 39% (95% CI 22–58%) at week 53. The most common treatment‐related adverse events (AEs) were headache and muscle spasms (each 13%). All AEs were mild or moderate except for three patients with Grade 3 hepatic AEs; no AEs necessitated romiplostim discontinuation. Two patients developed cytogenetic abnormalities, of whom one returned to normal karyotype at last follow‐up. High‐dose romiplostim is effective and well tolerated in the treatment of patients with AA refractory to IST.
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The first-line treatment for severe aplastic anemia (SAA) patients is hematopoietic stem cell transplantation (HSCT), with full-matched related donors considered the most suitable. We report a case of SAA in which the patient successfully underwent HSCT from a donor with β-thalassemia minor. The patient in this case underwent HSCT from a human leukocyte antigen (HLA)-matched younger brother with β-thalassemia minor. A 7-year-old girl was referred to our facility following a 6-month history of easy bruising and pallor. Laboratory examinations showed pancytopenia and hypocellular bone marrow with cellularity of <5%. She was diagnosed with acquired SAA, and HLA typing of her family members was performed. Her younger brother was an HLA-matched sibling but had β-thalassemia minor. Since his hemoglobin levels were maintained at 10-11 d/dL, he was considered a suitable HSCT donor. The conditioning regimen included fludarabine, cyclophosphamide, and anti-thymocyte globulin. The CD34+ and CD3+ cell counts were 6.6 × 106/kg and 0.48 × 108/kg, respectively. White blood cell engraftment was evident on day +11. Regimen-associated toxicities, such as anorexia and enteritis, were mild; no infections occurred, and no symptoms of acute graft-versus-host disease (GVHD) were observed. The 30-day follow-up bone marrow examination revealed normocellular marrow with 80%-90% cellularity. Acute or chronic GVHD has not been reported, and good performance status has been observed throughout the 5 years after HSCT. β-thalassemia minor patients can be considered as bone marrow donors for SAA patients.
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Background: Aplastic anemia (AA), an unusual hematological disease, is characterized by hypoplasia of the bone marrow and failure to form blood cells of all three lineages resulting in pancytopenia. This study aimed to investigate TNF-α-308 and IFN-γ-874 gene polymorphisms and their respective plasma protein levels in patients with AA and healthy controls. Methods: Two hundred and forty individuals were included in this study; the case group comprised 120 AA patients, while 120 healthy individuals served as controls. Genotyping was performed using the PCR-restriction length fragment polymorphism method and TNF-α-308 and IFN-γ-874 plasma levels were evaluated using an ELISA kit. Results: There was a significantly higher prevalence of the IFN-γ-874 genotype in patients with AA than in healthy controls, while the TNF-α-308 genotype was associated with lower risk of developing AA. Furthermore, the levels of both TNF-α-308 and IFN-γ-874 were higher in the plasma of AA patients. Conclusion: Our findings suggest that the IFN-γ-874 genotype may be a greater risk factor in the causation of AA, whereas the TNF-α-308 genotype has a protective role in the North Indian population.
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Background: Paroxysmal nocturnal haemoglobinuria (PNH) clones in children are rare but commonly associated with aplastic anaemia (AA) and myelodysplasia. Objective: This study aimed to determine the prevalence of PNH clones in paediatric patients with idiopathic AA, identify differences in clinical and laboratory features and outcomes, and determine the impact of clone size on clinical presentation. Methods: Patients with confirmed idiopathic AA who were tested for PNH between September 2013 and January 2018 at the Inkosi Albert Luthuli Central Hospital, Durban, KwaZulu-Natal, South Africa, were included. PNH clones were detected in neutrophils and monocytes by flow cytometry using fluorescent aerolysin, CD24, CD66b and CD14. Results: Twenty-nine children with AA were identified and 11 were excluded. Ten patients (10/18, 55.6%) had PNH clones ranging from 0.11% to 24%. Compared to the PNH-negative group, these children were older (median: 10 years vs 4 years, p = 0.02) and had significantly lower total white cell counts (median 1.7 × 109/L vs 3.2 × 109/L; p = 0.04). There was no difference in median absolute neutrophil count or haemoglobin concentration. Four patients in each group received immunosuppressive therapy (IST). At six months, all four patients with PNH clones had responded, compared to one in the PNH-negative group. Conclusion: More than half of children with AA had a PNH clone. The size of the clone did not impact clinical severity; however, IST use may positively impact prognosis. We recommend early initiation of IST in patients with AA to avoid delays associated with human leukocyte antigen typing.
Article
Objective: To investigate the efficacy of haplotype hematopoietic stem cell transplantation in the treatment of acquired severe aplastic anemia (SAA) in children. Methods: The clinical characteristics of 59 pediatric patients with SAA, including 26 cases VSAA, 37males and 22 females, 47 cases typeⅠ and 12 cases typeⅡ, undrerwent haplo-HSCT in our hospital between December 1st, 2011 and December 1st, 2017 were retrospectively analyzed. Among 59 patients, 56 patients with a median age of 4.5 (1.2-14.8) years and median weight of 43 (12-80) kg underwent their first HSCT and 3 patients underwent their second HSCT. All patients received the following conditioning regimen: busulfan, cyclophosphamide, and rabbit ATG or Bu (-, CTX) , fludarabineand rabbit ATG. The prophylaxis of acute graft versus host disease (aGVHD) was cyclosporine (CsA) , MMF and methotrexate. All patients received bone marrow transfusion on day 01 and peripheral stem cell transfusion on day 02 from haploid donor. The median dose of donor mononuclear cell counts was 15.60 (7.74-21.04) ×108/kg of recipient weight and CD34+ cell counts was 4.86 (3.74-7.14) ×106/kg of recipient weight. Results: Neutrophils and platelets of all 59 children were implanted. The median implantation time of granulocytes and platelets were 13 (10-19) d, 19 (9-62) d, respectively. The incidence of grade Ⅰ-Ⅱ aGVHD was 45.76% (27 cases) and grade Ⅲ/Ⅳ 13.56% (8 cases) , The incidence of chronic GVHD was 8.47% (5 cases) , The incidences of CMV and EBV viremia were 59.32% (35 cases) and 28.81% (17 cases) , respectively. The median follow-up was 30 (8-80) months, 57 patients survived with disease free, 2 patients died of GVHD. Both of the estimated 5-year OS and DFS rates were (96.4±2.5) %. Conclusion: Haplo-HSCT could improve the outcomes of SAA children.
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Background and Methods Recent studies have shown that long-term survivors of acquired aplastic anemia may be at high risk for malignant diseases. We assessed the risk of cancer after aplastic anemia was treated with immunosuppression or bone marrow transplantation and sought to identify risk factors according to treatment. The study population consisted of 860 patients treated by immunosuppression and 748 patients who had received bone marrow transplants for the treatment of severe aplastic anemia. The risk of cancer was analyzed overall and according to treatment relative to the risk in the general population. In calculating relative risk, we excluded patients with myelodysplastic syndromes or acute leukemias arising less than 6 months after treatment, and solid cancers arising less than 12 months after treatment, because of a possible association with aplastic anemia itself rather than with the treatment received. Results Forty-two malignant conditions were reported in the 860 patients who received immunosuppressive therapy: 19 cases of myelodysplastic syndrome, 15 cases of acute leukemia, 1 case of non-Hodgkin's lymphoma, and 7 solid tumors. Nine were reported in the 748 patients who received bone marrow transplants: two cases of acute leukemia and seven solid tumors. After the exclusions listed above, the overall relative risk of cancer was 5.50 (P<0.001) as compared with that in the general European population; the risk was 5.15 (P<0.001) after immunosuppressive therapy and 6.67 (P<0.001) after transplantation. The 10-year cumulative incidence rate of cancer was 18.8 percent after immunosuppressive therapy and 3.1 percent after transplantation. The risk factors for myelodysplastic syndrome or acute leukemia after immunosuppressive therapy included the addition of androgens to the immunosuppressive treatment (relative risk = 0.28), older age (relative risk = 1.03), treatment in 1982 or later, as compared with 1981 or earlier (relative risk = 3.01), splenectomy (relative risk = 3.65), and treatment with multiple courses of immunosuppression (relative risk = 2.26). Risk factors for solid tumors after bone marrow transplantation were age (relative risk = 1.11 per year) and the use of radiation as a conditioning regimen before transplantation (relative risk = 9.56); such tumors occurred only in male patients. Conclusions Survivors of aplastic anemia are at high risk for subsequent malignant conditions. Myelodysplastic syndrome and acute leukemia tend to follow immunosuppressive therapy, whereas the incidence of solid tumors is similar after immunosuppression and after bone marrow transplantation.
Article
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Although the use of chloramphenicol eye drops is thought to cause aplastic anaemia,1 this side effect has not been studied critically. We examined the use of ocular chloramphenicol in two population based case-control studies conducted with the same methods.2,3
Article
Long-term survival after HLA-matched sibling transplants for SAA is 80–90% in patients <20 years at transplantation. Survival in older patients is lower. Herein, we report risk factors affecting hematopoietic recovery and long-term survival in older patients with SAA after HLA-matched sibling transplants. All transplantations occurred in 1991–2004. Before analysis of risk factors affecting survival we determined the ages at which survival rates differed significantly. Significant differences in survival rates were observed in the following age groups: <20 years (n=818), 20–40 years (n=618) and >40 years (n=127). Beyond 40 years, we were unable to find an age effect despite 44% of patients in this group being ≥50 years. Patients older than 40 years were more likely to have received >50 red blood cell transfusions, immunosuppressive therapy (65% vs. 50% in patients <40 years), have poor performance scores at transplantation, a longer waiting period to transplant (40% received transplants beyond 6 months from diagnosis compared to < 25% in the other groups) and more likely to receive peripheral blood grafts. Neutrophil recovery rates (day-28) did not differ in the three groups; 83%, 88% and 86% in patients aged <20 years, 20–40 years and >40 years, respectively. Recovery was more likely with peripheral blood transplants (odds ratio [OR] 1.96, p=0.022). Neutrophil recovery was lower with cyclophosphamide alone (OR 0.50, p=0.002) and fludarabine-containing conditioning regimens (OR 0.44, p=0.033). In contrast, age at transplantation was associated with platelet recovery (day- 100). Recovery was lowest in patients >40 years (89%) compared to 94% in patients <20 years (p<0.001) and 94% in patients 20–40 years (p=0.004). Platelet recovery was higher in patients with performance scores 90–100, OR 2.22, p<0.001, independent of age. As expected acute and chronic graft-versus-host disease (GVHD) risks were higher in those ≥20 years. We did not observe differences in acute (RR 1.42, p=0.089) and chronic GVHD (RR 1.21, p=0.354) risks between patients aged 20–40 years and >40 years. As shown in the Table below mortality risks increased with age. The 5-year probabilities of overall survival after adjusting for performance score, preparatory regimen, interval from diagnosis to transplantation, donor-recipient sex match and cytomegalovirus serostatus, factors affecting overall survival, were 81%, 72% and 53% in patients aged <20 years, 20–40 years and >40 years, respectively (p<0.001). Independent of age, mortality rates were higher in patients with poor performance score (RR 1.92, p<0.001), recipients of transplant preparatory regimens other than cyclophosphamide with or without anti-thymocyte globulin (RR 1.52, p=0.004), >6 months from diagnosis to transplantation (RR 1.50, p=0.001) and female recipients receiving grafts from male donors (RR 1.57, p=0.001). Mortality rates were lower when both donor and recipient were CMV sero-negative (RR 0.53, p<0.001). In conclusion, survival after transplantation in patients >40 years was significantly lower compared to younger patients. Longer interval from diagnosis to transplantation, higher numbers of pretransplant red blood cell transfusions and poor performance scores at transplantation may explain the inferior outcomes in patients >40 years. Use of peripheral blood grafts did not affect overall survival (p=0.169). The data suggest there is a need to improve survival in older patients; early referral for transplantation and improved supportive care may improve outcomes. Outcome Relative Risk P-value Overall mortality 20–40 years vs. <20 years 1.63 <0.001 >40 years vs. <20 years 3.25 <0.001 >40 years vs. 20–40 years 2.00 <0.001
Article
We report the results of the first prospective randomized multicenter study of immunosuppressive treatment in patients with previously untreated nonsevere aplastic anemia (AA) as defined by a neutrophil count of at least 0.5 × 109/L and transfusion dependence. Patients were randomized to receive cyclosporin (CSA) alone or the combination of horse antithymocyte globulin ([ATG] Lymphoglobuline; Merieux, Lyon, France) and CSA. The endpoint of the study was the hematologic response at 6 months. One hundred fifteen patients were randomized and assessable with a median follow-up period of 36 months; 61 received CSA and 54 ATG and CSA. In the CSA group, the percentage of complete and partial responders was 23% and 23%, respectively, for an overall response rate of 46%. A significantly higher overall response rate of 74% was found in the ATG and CSA group, with 57% complete and 17% partial responders (P = .02). Compared with CSA alone, the combination of ATG and CSA resulted in a significantly higher median hemoglobin level and platelet count at 6 months. Fewer patients required a second course of treatment before 6 months due to a nonresponse. In the CSA group, 15 of 61 (25%) patients required a course of ATG before 6 months because of disease progression, compared with only 3 of 54 (6%) in the ATG and CSA group. The survival probabilities for the two groups were comparable, 93% (CSA group) and 91% (ATG and CSA group), but at 180 days, the prevalence of patients surviving free of transfusions, which excluded patients requiring second treatment because of nonresponse, death, disease progression, or relapse, was 67% in the CSA group and 90% in the ATG and CSA group (P = .001). We conclude that the combination of ATG and CSA is superior to CSA alone in terms of the hematologic response, the quality of response, and early mortality, and a second course of immunosuppression is less frequently required.
Article
We reviewed the records and reevaluated 212 patients with aplastic anemia transplanted at the Fred Hutchinson Cancer Research Center (FHCRC) between 1970 and 1993 who survived ≥2 years and who have been followed for up to 26 years. Parameters analyzed included hematopoietic function, chronic graft-versus-host disease (GVHD), skin disease, cataracts, lung disease, skeletal problems, posttransplant malignancy, depression, pregnancy/fatherhood, and the return to work or school, as well as patient self-assessment of physical and psychosocial health, social interactions, memory and concentration, and overall severity of symptoms. Survival probabilities at 20 years were 89% for patients without (n = 125) and 69% for patients with chronic GVHD (n = 86) (the status was uncertain in 1 surviving patient). All patients had normal hematopoietic parameters. Skin problems occurred in 14%, cataracts in 12%, lung disease in 24%, and bone and joint problems in 18% of patients. Eleven patients (12%) developed a solid tumor malignancy and 19% of patients experienced depression. Chronic GVHD was the dominant risk factor for late complications. Seventeen patients died at 2.5 to 20.4 years posttransplant; 13 of these had chronic GVHD and related complications. At 2 years, 83% of patients had returned to school or work; the proportion increased to 90% by 20 years. At least half of the patients preserved or regained the ability to become pregnant or father children. Patients rated their quality of life as excellent and symptoms as minimal or mild. In conclusion, marrow transplantation in patients with aplastic anemia established long-term normal hematopoiesis. No new hematologic disorders occurred. The major cause of morbidity and mortality was chronic GVHD. However, the majority of patients who survived beyond 2 years returned to a fully functional life.
Article
The improved outcome of acquired aplastic anemia (AA) has revealed later complications, such as myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). We retrospectively analyzed 167 children with severe acquired AA. Eleven of 50 children treated with cyclosporin (CSA) and recombinant human granulocyte colony-stimulating factor (rhG-CSF ) developed MDS/AML; 8 of these were within 36 months of the diagnosis of AA, much earlier than previous reports. Six of the 11 children received rhG-CSF exceeding 10 μg/kg/d, and 9 received rhG-CSF therapy for over 1 year. Ten children showed monosomy 7 at diagnosis of MDS. All of the 11 children were administered both CSA and rhG-CSF. There was no development of MDS/AML among 41 children treated with either CSA or rhG-CSF or among 48 children who underwent bone marrow transplantation. A well-controlled clinical trial is warranted to determine whether therapeutic modalities affect the development of MDS/AML in children with severe acquired AA.
Article
Aplastic anemia (AA) is a rare, severe disease of mainly unknown origin. Numerous case history reports have incriminated drugs in the etiology of this disease. Because those reports were questionable, a case-control study was conducted in France between 1985 and 1988. Cases selected from the national register were eligible for inclusion when at least two blood lineages were depressed (hemoglobin < or = 10 g/100 mL and reticulocytes < or = 50 x 10(9)/L, granulocytes < or = 1.5 x 10(9)/L, platelets < or = 100 x 10(9)/L) and when the bone marrow biopsy was compatible with the disease. Using a standardized questionnaire, trained investigators interviewed one AA patient and two groups of controls (two hospitalized patients and one neighbor of the AA patient) matched for age, sex, and interviewer. One hundred forty- seven AA patients, 287 hospitalized controls, and 108 neighbors were interviewed. The occurrence of AA was analyzed by matched design with relation to medical history and drug use during the last 5 years, and specifically during the last year. Three times as many AA patients reported having suffered from clinical hepatitis during the last 6 months than either type of control. Similarly, a higher proportion of AA patients reported a history of chronic immune disorder, mainly rheumatoid arthritis (odds ratio of 6.8), and a previous use of gold salts and D-penicillamine in the 5 previous years (odds ratio of 4.9 for each drug). An excess of colchicine and allo/thiopurinol intake in the 5 previous years was observed among the AA patients (odds ratio equal to 4.1 and 3.6, respectively). These results for gold salts, D- penicillamine, and colchicine were confirmed when looking for drug use within the last year. A moderate risk was associated with acetaminophen or salicylate intake during the 5 previous years or during the last year (odds ratio between 1.8 and 2.0). The frequent use of salicylates within the last year was associated with a high risk of AA (odds ratio of 5.0). A high risk was also associated with indolic derivative intake but only when comparing AA patients to neighbor controls. No association could be evidenced with diclofenac intake, whatever the control group. Differences observed with recently published studies suggest that targeted studies on each category of drugs according to the treated pathologies should be initiated.
Article
One hundred and seventeen patients with severe aplastic anemia (SAA) were treated at our institution between 1976 and 1990 with antilymphocyte globulin (ALG) therapy. Seventy-nine (68%) are alive and probability of survival at 14 years, according to Kaplan and Meier, is 62% +/- 12%. Twenty-six patients developed a late clonal complication: 11 had a myelodysplastic syndrome (MDS) and 17 had paroxysmal nocturnal hemoglobinuria (PNH); two patients had both. The cumulative risk at 10 years is 42%. The development of MDS/PNH after SAA directly affects survival. The probability of being alive at 14 years is 81% +/- 10% for patients with stable disease and 36% +/- 13% for those with clonal evolution (P = .001). To look for predictive signs, we reevaluated peripheral blood and bone marrow cytomorphology at presentation, during regeneration, and in remission. We examined the peripheral blood values for hemoglobin, reticulocytes, granulocytes, thrombocytes, mean corpuscular volume (MCV), and fetal hemoglobin, as well as bone marrow for cellularity, erythropoiesis, myelopoiesis, and megakaryopoiesis. ALG therapy induces slow and incomplete recovery. Although in “remission,” ALG patients have lower hemoglobin values, higher reticulocyte counts, lower granulocyte and platelet values, and a higher MCV and fetal hemoglobin than normal controls. They retain a reduced number of megakaryocytes and a persistence of atypical monocytes in bone marrow morphology as stigmata of their disease. Patients with late clonal complications show distinct morphologic abnormalities: patients with PNH have higher MCVs, higher granulocyte and reticulocyte counts, and more dyserythropoiesis at diagnosis and a lower hemoglobin with an increased proportion of erythroblasts in the bone marrow in “remission.” Patients who later developed MDS are not different from the total patient population at diagnosis. After therapy, these patients are characterized by the presence of ring sideroblasts and atypical monocytes during regeneration and by a persistent increase in MCV, a higher fetal hemoglobin, lower granulocyte values, and megakaryocytic dysplasia during “remission.” Thus, routine morphologic follow-up examination of blood and bone marrow can discover patients at risk for late hematologic complications after ALG therapy.
Article
Despite androgens and intensive supportive care, satisfactory survival in severe aplastic anemia remains at 20% or less. Histocompatible bone marrow transplantation can restore normal hematopoiesis in approximately 40% of similarly severe individuals. Delay of transplantation for 3 wk after diagnosis allows time for proper evaluation and for many spontaneous recoveries. Further delay increases risks of fatal complications and decreases chances for successful transplantation while the incidence of spontaneous remission declines. When available, early histocompatible bone marrow transplantation may be the treatment of choice for severe aplastic anemia.
Article
One hundred consecutive patients with severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), 6-methylprednisolone (6Mpred), and granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 16 years (range, 1-72 years) and median neutrophil count was 0.2 × 109/L (range, 0-0.5 × 109/L). Trilineage hematologic recovery (at a median interval of 96 days from treatment) was seen in 77 patients (48 complete, 29 partial) after 1 (n = 50) or more courses of ALG (n = 27). Of the 23 nonresponders, 11 patients died at a median interval of 83 days (range, 16-1132 days), 6 were considered treatment failures and underwent transplantation, and 6 were pancytopenic. Cytogenetic abnormalities were seen in 11% of patients, clonal hematologic disease in 8%, and relapse of marrow aplasia in 9%. The actuarial survival at 5 years was 87% (median follow-up 1424 days): 76% versus 98% for patients with neutrophil counts less than versus greater than 0.2 × 109/L (P = .001) and 88% versus 87% for patients aged less than versus more than 16 years (P = .8). The actuarial probability of discontinuing CyA was 38%. Patients who did not achieve a white blood cell (WBC) count of 5 × 109/L during G-CSF treatment have a low probability of responding (37%) and a high mortality rate (42%). This update confirms a high probability for SAA patients of becoming transfusion independent and of surviving after treatment with ALG, CyA, 6Mpred, and G-CSF, with a significant effect of neutrophil counts on outcome. Problems still remain, such as absent or incomplete responses, clonal evolution, relapse of the original disease, and cyclosporine dependence. Early transplantation, also from alternative donors, may be warranted in patients with poor WBC response to G-CSF.
Article
Background: Bacterial infections are a major cause of illness and death in patients who are neutropenic after chemotherapy treatment for cancer. Trials have shown the efficacy of antibiotic prophylaxis in decreasing the incidence of bacterial infections but not in reducing mortality rates. Purpose: To evaluate whether antibiotic prophylaxis in neutropenic patients reduces mortality and incidence of infection and to assess related adverse events. Data sources: The Cochrane Cancer Network register of trials (2004), The Cochrane Library (Issue 4, 2004), EMBASE (1980-2004), MEDLINE (1966-2004), and references of identified studies. Study selection: Randomized, controlled trials comparing antibiotic prophylaxis with placebo or no intervention or another antibiotic in afebrile neutropenic patients. Data extraction: Two reviewers independently appraised the quality of trials and extracted data. Data synthesis: Ninety-five trials performed between 1973 and 2004 met inclusion criteria. Fifty-two trials addressed quinolone prophylaxis. Antibiotic prophylaxis significantly decreased the risk for death when compared with placebo or no treatment (relative risk, 0.67 [95% CI, 0.55 to 0.81]). All prophylactic antibiotics were associated with an increased risk for adverse events (relative risk, 1.69 [CI, 1.14 to 2.50]). Fluoroquinolone prophylaxis reduced the risk for all-cause mortality (relative risk, 0.52 [CI, 0.35 to 0.77]), as well as infection-related mortality, fever, clinically documented infections, and microbiologically documented infections. Fluoroquinolone prophylaxis increased the risk for harboring bacilli resistant to the specific drug after treatment and adverse events, but these results were not statistically significant (relative risks, 1.69 [CI, 0.73 to 3.92]) and 1.30 [CI, 0.61 to 2.76], respectively). Limitations: Most trials involved patients with hematologic cancer. Data on all-cause mortality were missing in 10 of 50 trials comparing prophylaxis with no prophylaxis. Effect estimates were larger in trials of unclear methodologic quality compared with trials of adequate methodologic quality. Conclusions: Antibiotic prophylaxis for neutropenic patients undergoing cytotoxic therapy reduces mortality. Mortality was substantially reduced when analysis was limited to fluoroquinolones. Antibiotic prophylaxis, preferably with a fluoroquinolone, should be considered for neutropenic patients.
Article
A serious complication of aplastic anemia (AA) is its evolution to clonal hematologic diseases such as myelodysplasia (MDS) and leukemia, which is usually associated with the appearance of a cytogenetic abnormality in bone marrow cells. We present here an analysis of a cohort of 30 patients with otherwise typical AA in whom clonal karyotypic evolution was observed during frequent periodic marrow examinations. The actuarial risk for this complication has been estimated in other studies at around 15% at 5 years. Conversion from normal to abnormal karyotype occurred at a constant rate after initial diagnosis, with about 50% of cases developing within the first 30 months. Transient chromosomal abnormalities were infrequent. Clinically, AA patients with clonal cytogenetic patterns were heterogenous; a variety of karyotypic defects with numerical and structural abnormalities of chromosome 7 accounted for 40% of all cases followed by trisomy 8, structural and numerical abnormalities of chromosome 13, deletion of Y chromosome, and complex cytogenetic abnormalities. Unlike in primary MDS, aberrancies of chromosome 5 and 20 were infrequent. The clinical course depended on the specific abnormal cytogenetic pattern. Most deaths related to leukemic transformation occurred in patients with abnormalities of chromosome 7 or complex cytogenetic alterations or both. Evolution of chromosome 7 abnormalities was seen most often in refractory patients who had failed to respond to therapy. In contrast, trisomy 8 developed in patients with good hematologic responses who often required chronic immunosuppression with cyclosporine A (CsA), and survival was excellent. Although AA patients with monosomy 7 showed a similar prognosis to those with primary MDS, trisomy 8 in AA appears to have a more favorable prognosis than in MDS.
Article
Background: Severe aplastic anemia is a life-threatening bone marrow failure disorder. High-dose cyclophosphamide therapy followed by allogeneic bone marrow transplantation cures the disease. However, it requires a suitable donor and carries the risk for graft-versus-host disease. A small pilot study demonstrated that high-dose cyclophosphamide therapy without bone marrow transplantation leads to durable, treatment-free complete remission. Objective: To confirm the safety and efficacy of high-dose cyclophosphamide therapy alone in patients with severe aplastic anemia. Design: Uncontrolled clinical trial. Setting: Three tertiary care hospitals. Patients: 19 patients with untreated severe aplastic anemia. Intervention: Cyclophosphamide, 50 mg/kg of body weight per day for 4 consecutive days. Measurements: Probability of response and overall survival were measured. Complete remission was defined as normal blood count for age and sex. Partial remission was defined as independence from transfusion and an absolute neutrophil count greater than 0.5 × 10 9 cells/L without growth factor support. Non-responders were patients who remained transfusion dependent or died. Relapse was defined as no longer meeting criteria for partial or complete remission. Results: The median time to an absolute neutrophil count of 0.5 × 10 9 cells/L was 49 days. The probability of survival was 84% (95% Cl, 59% to 95%) at 24 months. The probability of achieving treatment-free remission was 73% (Cl, 51% to 91%) at 24 months, and the probability of achieving complete remission was 65% (Cl, 39% to 89%) at 50 months. No responding patients have had relapse or have developed secondary clonal disorders. Conclusions: High-dose cyclophosphamide therapy without bone marrow transplantation produces durable treatment-free remission in severe aplastic anemia. This approach deserves further study in patients with severe aplastic anemia who are not suitable candidates for allogeneic bone marrow transplantation.
Article
Aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH) are rare hematologic diseases that often appear in the same patient. Patients with aplastic anemia have severe thrombocytopenia, neutropenia, and anemia accompanied by absent hematopoietic precursors in an “empty” bone marrow (1). In contrast, the classic evidence of PNH is the intermittent appearance of dark urine due to excretion of hemoglobin, the result of intravascular hemolysis (2). The knowledge that this peculiar form of erythrocyte destruction resulted from increased susceptibility of the PNH erythrocyte to complement led to the development of laboratory assays, such as the Ham and sugar hemolysis tests. Modern clinical studies have shown that patients with PNH experience serious morbidity and mortality, mainly from venous thromboses and, especially in younger patients, pancytopenia (3). On the basis of results of the Ham test in several patients, Lewis and Dacie (4) formalized the overlap between the two diseases as the aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome. With improved survival in aplastic anemia, many patients show laboratory and clinical evidence of PNH, often months or years after completion of successful immunosuppressive therapy (5–6).
Article
Recent progress in the treatment of aplastic anemia has dramatically changed the previously grim prognosis for these patients. Improvements in bone marrow transplantation and immunosuppression have increased the number of long-term survivors so that immediate survival is no longer the sole concern. Here, we review the major clinical studies and summarize recent analyses of risk factors for developing paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), acute leukemia, or solid tumor after treatment for aplastic anemia. We also examine biologic clues that may shed light on the interrelationship between aplastic anemia and clonal diseases.
Article
Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare and usually fatal syndrome. Clinical manifestations are fever, maculopapular skin rash, nausea, vomiting, diarrhea, hepatitis and pancytopenia owing to bone marrow hypoplasia. It can occur in recipients with severe immunosuppression and in immunocompetent recipients after transfusion of cellular components from HLA homozygous donor to recipients heterozygous for that HLA haplotype. The diagnosis is made by clinical manifestation and skin biopsy. Antithymocyte globulin and high dose systemic corticosteroids are both the most used therapy. The back of knowledge about this syndrome, the rapid evolution and the absence of treatment response are related to patients bad evolution. Gamma irradiation of blood products has been the mainstay of TA-GVHD prevention. Dose of 2500 cGy is required to completely inactivate T cells. Irradiation damage red cells membrane and the red celis units can not be storage for long time after irradiation. High potassium levels is the mainly change in red cells units. White cell-reduction filters do not prevent TA-GVHD and gamma irradiation does not prevent alloimmunization or blood reactions. Only cellular components like whole blood, red cells, platelets and granulocytes need be irradiated. Ali blood components should be irradiated to: first or second-degree relatives, patients need HLA-matched platelets, recipients of allogeneic or autologous bone marrow transplantation, patients with Hodgkin's disease, patients treated with purine analogue drugs, intrauterine transfusion, pre-term infants and when congenítal immunodeficiency states is suspected. It is recommended irrradiated blood to patients with neoplastic disease when they receive intensive chemotherapy.
Article
We are concerned about the inappropriate use of haemopoietic growth factors in patients with severe aplastic anaemia (SAA). The treatment of choice for this disorder is bone-marrow transplantation from an HLA-identical sibling donor if the patient is younger than 45 years, but it must be done soon after onset before the patient becomes sensitised by multiple red-cell and platelet transfusions. Other patients should receive immunosuppressive therapy with antithymocyte globulin alone or with cyclosporin or oxymetholone. Haemopoietic growth factors may have a role in stimulation of granulopoiesis after immunosuppressive therapy, but there is no evidence that they can correct the underlying stem-cell defect in SAA, and therefore no justification for their use alone in newly diagnosed SAA. Such treatment is harmful because it delays bone-marrow transplantation, or immunosuppressive therapy in older patients and those without suitable donors, thus reducing the chances of a successful outcome.
Article
One hundred consecutive patients with severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), g-methylprednisolone (6Mpred), and granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 16 years (range, 1-72 years) and median neutrophil count was 0.2 x 10(9)/L (range, 0-0.5 x 10(9)/L). Trilineage hematologic recovery (at a median interval of 96 days from treatment) was seen in 77 patients (48 complete, 29 partial) after 1 (n = 50) or more courses of ALG (n = 27), of the 23 nonresponders, 11 patients died at a median interval of 83 days (range, 16-1132 days), 6 were considered treatment failures and underwent transplantation, and 6 were pancytopenic. Cytogenetic abnormalities were seen in 11% of patients, clonal hematologic disease in 8%, and relapse of marrow aplasia in 9%, The actuarial survival at 5 years was 87% (median follow-up 1424 days): 76% Versus 98% for patients with neutrophil counts less than versus greater than 0.2 x 10(9)/L (P = .001) and 88% versus 87% for patients aged less than versus more than 16 years (P = .8). The actuarial probability of discontinuing CyA was 38%, Patients who did not achieve a white blood cell (WBC) count of 5 x 10(9)/L during G-CSF treatment have a low probability of responding (37%) and a high mortality rate (42%), This update con-firms a high probability for SAA patients of becoming transfusion independent and of surviving after treatment with ALG, CyA, 6Mpred, and G-CSF, with a significant effect of neutrophil counts on outcome, Problems still remain, such as absent or incomplete responses, clonal evolution, relapse of the original disease, and cyclosporine dependence. Early transplantation, also from alternative donors, may be warranted in patients with poor WBC response to G-CSF, (C) 2000 by The American Society of Hematology.
Article
An expanded cohort study of 74,828 benzene-exposed and 35,805 unexposed workers were followed during 1972 to 1987, based on a previous study in 12 cities in China. A small increase was observed in total cancer mortality among benzene-exposed compared with unexposed Workers (relative risk [RR] = 1-2). Statistically significant excesses were noted for leukemia (RR = 2.3), malignant lymphoma (RR = 4.5), and lung cancer (RR = 1.4). When risks were evaluated by leukemia subtype, only acute myelogenous leukemia was significantly elevated (RR = 3.1), although nonsignificant excesses were also noted for chronic myelogenous leukemia (RR = 2.6) and acute lymphocytic leukemia (RR = 2.3). A significant excess was also found for aplastic anemia. 19 refs., 5 tabs.
Article
This report defines four levels of care required for the management of adult patients with haematological malignancies and marrow failure (acute and chronic leukaemias, lymphomas, myelodysplastic and myeloproliferative disorders, myeloma and severe aplastic anaemia). The higher levels of care require increasing specialist expertise, staffing and resources. Staffing includes both the medical, nursing and scientific/laboratory professions and other support staff. Resources include ward provision, bed numbers, equipment, laboratory and radiotherapy facilities, pharmacy, support services and research. Blood transfusion services and their organisation are discussed separately. The guidelines indicate to providers and purchasers the issues to be considered in placing contracts for the care of these patients. A glossary of terms is provided for purchasers.
Article
About 30% of patients with severe aplastic anaemia (SAA) unresponsive to one course of immunosuppressive (IS) therapy with antithymocyte or antilymphocyte globulin can achieve complete or partial remission after a second IS treatment. Among various second-line treatments, rabbit ATG (r-ATG) could represent a safe and effective alternative to horse ALG (h-ALG). In a multicentre study, 30 patients with SAA (17 males and 13 females, median age 21 years, range 2–67) not responding to a first course with h-ALG plus cyclosporin (CyA) and granulocyte colony stimulating factor (G-CSF), were given a second course using r-ATG (3.5 mg/kg/d for 5 d), CyA (5 mg/kg orally from day 1 to 180) and G-CSF (5 μg/kg subcutaneously from day 1 to 90). The median interval between first and second treatment was 151 d (range 58–361 d). No relevant side-effects were observed, but one patient died early during treatment because of sepsis. Overall response, defined as transfusion independence, was achieved in 23/30 (77%) patients after a median time of 95 d (range 14–377). Nine patients (30%) achieved complete remission (neutrophils 2.0 × 109/l, haemoglobin 11 g/dl and platelets 100 × 109/l). The overall survival rate was 93% with a median follow-up of 914 d (range 121–2278). So far, no patient has relapsed. Female gender was significantly associated with a poorer likelihood to respond (P = 0.0006). These data suggest that r-ATG is a safe and effective alternative to h-ALG for SAA patients unresponsive to first-line IS treatment.
Article
Pretransplant blood transfusions from a dog leukocyte antigen (DLA)-identical canine Iittermate marrow donor will sensitize the recipient to non-DLA-linked polymorphic minor histocompatibility antigens, which uniformly results in graft rejection. We observed previously that 2000 cGy gamma-irradiation of marrow donor blood transfusions prevented this sensitization and subsequent marrow graft rejection. The purpose of the present study was to determine whether treatment of unrelated blood transfusions with gamma-irradiation would also prevent sensitization. conceivably sensitization to minor histocompatibility antigens might be more efficient or potent and thus more difficult to prevent when those antigens are seen in the context of disparity for DLA antigens. Furthermore, this model, in which sensitization to DLA-identical Iittermate marrow is caused by unrelated blood transfusions, is directly relevant to the clinical circumstances of human marrow transplantation. We assessed sensitization caused by unrelated blood transfusions by monitoring graft outcome in recipients transplanted with DLA-identical littermate marrow after conditioning with 920 cGy total body irradiation. Two thousand cGy gamma-irradiation of unrelated blood transfusions significantly reduced the incidence of transfusion-induced sensitization of recipients. There was successful marrow engraftment in 15 of 16 (94%, P<0.003) of these animals in contrast to the previous study in which only 7 of 16 (44%) animals engrafted after they were transfused with unmodified blood on the same schedule. These results suggest that blood transfusions for use in humans, especially for patients with aplastic anemia, should be gamma-irradiated in order to reduce the incidence of marrow graft rejection caused by sensitization to minor histocompatibility antigens.
Article
The incidence of aplastic anemia was estimated in a 4-year study conducted in Israel and seven areas in Europe. Strict definition criteria were used, and all data and bone marrow specimens were reviewed by a panel of experienced hematologists. Complete ascertainment of cases was attempted by establishing a telephone network including all relevant hospitals in the study areas. The incidence of aplastic anemia was estimated to be less than three per million per year, a figure lower than previously reported. The most likely explanation for the differences among studies is variation in diagnostic criteria, which might lead to an overestimation of the incidence in some previous studies.
Article
EDITOR,--We disagree with Marie Doona and J Bernard Walsh's conclusions and recommendations relating to chloramphenicol eye drops and aplastic anaemia.1 Many drugs have been implicated as causing aplastic anaemia, but for most the evidence is weak, and no in vitro tests are available to prove causation. Furthermore, an apparent association may not mean causality: the exposure may have been a response to the early features of aplastic anaemia itself.An association between use of chloramphenicol and the development of aplastic anaemia was predicted because of the drug's structure, and many reports appeared in …
Article
Ninety-one patients were studied serially for chimeric status following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA) or Fanconi Anaemia (FA). Short tandem repeat polymerase chain reaction (STR-PCR) was used to stratify patients into five groups: (A) complete donor chimeras (n = 39), (B) transient mixed chimeras (n = 15) (C) stable mixed chimeras (n = 18), (D) progressive mixed chimeras (n = 14) (E) recipient chimeras with early graft rejection (n = 5). As serial sampling was not possible in Group E, serial chimerism results for 86 patients were available for analysis. The following factors were analysed for association with chimeric status: age, sex match, donor type, aetiology of aplasia, source of stem cells, number of cells engrafted, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, occurrence of acute and chronic GvHD and survival. Progressive mixed chimeras (PMCs) were at high risk of late graft rejection (n = 10, P < 0·0001). Seven of these patients lost their graft during withdrawal of immunosuppressive therapy. STR-PCR indicated an inverse correlation between detection of recipient cells post-SCT and occurrence of acute GvHD (P = 0·008). PMC was a bad prognostic indicator of survival (P = 0·003). Monitoring of chimeric status during cyclosporin withdrawal may facilitate therapeutic intervention to prevent late graft rejection in patients transplanted for SAA.
Article
Summary 134 patients with acquired aplastic anaemia (AA) were given HALG 15 mg/kg/d for 5 d and methylprednisolone for 1 month, and randomized to receive (n= 69) or not (n= 65) oxymetholone 2 mg/kg/d p.o. daily for 4 months. Early mortality (<120 d) was comparable in the two arms 12/69 (17%) and 11/65 (17%), and correlated with the severity of the disease (39%, 10% and 6% respectively in patients with neutrophil counts (PMN) <0.2, 0.2–0.5, >0.