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This devastating disease is characterized by near-total to complete loss of the blood forming cells of the bone marrow. The result is more than just anemia, but severe reduction in the other blood components such as the white blood cells and platelets. The result is bleeding and infections in addition to the anemia. About 1000 new cases are diagnosed each year in the United States.

Aplastic anemia has been clearly linked to a variety of chemical or toxic exposure such as drugs, radiation, environmental toxins, and insecticides. Autoimmune and Infectious causes such as viruses have been implicated but in over half of all cases, the cause is idiopathic, or unknown.

Treatments included immunosuppressive agents such as Anti-Thymocyte Globulin (ATG) or bone marrow transplant. Additional therapies include cytokines (interleukin 3, monocyte colony stimulating factor, stem cell factor (SCF or C-kit ligand) and IL-6), granulocyte monocyte colony stimulating factor (GM-CSF), or erythropoietin (EPO).


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The impact of Asian descent on the incidence of acquired severe aplastic anaemia in children.

McCahon E, Tang K, Rogers PC, McBride ML, Schultz KR.

Oncology Department, The Children's Hospital, Westmead, New South Wales, Australia.

Br J Haematol. 2003 Apr;121(1):170-2. Abstract quote

Previous studies have suggested an increased incidence of acquired severe aplastic anaemia in Asian populations.

We evaluated the incidence of aplastic anaemia in people of Asian descent, using a well-defined paediatric (0-14 years) population in British Columbia, Canada to minimize environmental factors. The incidence in children of East/South-east Asian descent (6.9/million/year) and South Asian (East Indian) descent (7.3/million/year) was higher than for those of White/mixed ethnic descent (1.7/million/year). There appeared to be no contribution by environmental factors.

This study shows that Asian children have an increased incidence of severe aplastic anaemia possibly as a result of a genetic predisposition.


Aplastic anemia in Brazil: incidence and risk factors.

Maluf EM, Pasquini R, Eluf JN, Kelly J, Kaufman DW.

Bone Marrow Transplantation Center, Faculty of Medicine, Federal University of Parana, Curitiba, Brazil.

Am J Hematol. 2002 Dec;71(4):268-74. Abstract quote

This study is the first large-scale epidemiological investigation of acquired aplastic anemia (AAA) in South America. The objective was to estimate the incidence and to identify risk factors for AAA in Brazil.

A national case-control study was conducted to investigate the risk factors for the disease. One hundred twenty-five cases and 129 controls were included. Multiple logistic regression was used in the estimation of odds ratios (OR) to control confounding. The size of Brazil made it unfeasible to estimate the incidence of AAA in the whole country, and we limited the calculation to the state of Parana. The annual incidence of AAA in Parana was 2.4 cases/10(6) inhabitants. There was no positive association between chloramphenicol use and AAA (OR 0.4; 95% CI: 0.1-2.9). The OR of AAA associated with household pesticides that include organophosphates in their composition was 2.7 (1.0-8.4). The OR for the usage of unspecified thinner and/or acetone for at least 7 days was 3.0 (1.2-7.3).

Cases of AAA in Brazil seem to be associated with some factors traditionally related to this disease, such as certain solvents and the incidence is similar to what has been reported from Europe.



Prevalence of parvovirus B19 in liver tissue: no association with fulminant hepatitis or hepatitis-associated aplastic anemia.

Wong S, Young NS, Brown KE.

Virus Discovery Group, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

J Infect Dis. 2003 May 15;187(10):1581-6. Abstract quote

Parvovirus B19 has been proposed as the etiological agent of fulminant hepatitis (FH) or hepatitis-associated aplastic anemia (HAA).

We studied the prevalence of parvovirus B19 in liver-tissue samples from patients with FH and HAA and from control subjects. In the first study, parvovirus B19 DNA was detected by nested polymerase chain reaction (PCR) in 4 of 15 livers from patients with FH and in 3 of 22 livers from patients with nonviral hepatic disease. In a second confirmatory study, livers were tested for parvovirus B19 and its variant erythroviruses, V9 and A6. Tissues were also tested by reverse-transcriptase PCR for the presence of parvovirus B19 transcripts as a marker of viral replication.

There was no significant difference in the prevalence of parvovirus B19 DNA in livers from patients with FH or HAA, compared with liver-tissue samples from patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; parvovirus B19 transcripts were not detected.

There was a significant increase (P<.1) in the prevalence of variant erythrovirus sequences in livers of patients with HBV or HCV hepatitis, the reason for which is currently unknown.

Human parvovirus B19 in patients with aplastic anemia.

Mishra B, Malhotra P, Ratho RK, Singh MP, Varma S, Varma N.

Department of Virology, Post Graduate Institute of Medical Education & Research, Chandigarh, India.
Am J Hematol. 2005 Jun;79(2):166-7. Abstract quote  

Aplastic anemia is characterized by pancytopenia with hypoplastic bone marrow. Various factors including viral infections have been implicated as the precipitating factors. Human parvovirus B19 has been associated with red-cell aplasia, leukopenia, and thrombocytopenia.

The present study was carried out to determine the role of parvovirus B19 in aplastic anemia patients. Twenty-seven aplastic anemia patients and 20 healthy controls were tested for the presence of parvovirus B19 infection by detecting parvovirus B19-specific IgM by ELISA and viral DNA by PCR. Parvovirus B19 IgM and viral DNA were detected in significantly higher numbers of patients in comparison to the controls (40.7% vs. 5%, P < 0.01; 37% vs. 0%, P < 0.001, respectively). The presence of parvovirus DNA in aplastic anemia patients indicates active or recent infection.

However, more studies are needed to explore the mechanism of bone-marrow aplasia due to human parvovirus B19 infection.

Bone Marrow Samples From Patients With Aplastic Anemia Are Not Infected With Parvovirus B19 and Mycobacterium tuberculosis

Hui-Chi Hsu, MD
Yuan-Ming Lee, MS
Wei-Juin Su, MD
Chang-Yi Huang, MS
Ching-Fen Yang, MD
Chi-Kuan Ho, PhD
Chau-Hung Ho, MD
Sheng-Yuan Wang, MD
and Wu-Tse Liu, PhD

Am J Clin Pathol 2002;117:36-40 Abstract quote

The majority of patients with aplastic anemia (AA) have an idiopathic form of the disease. The aim of this study was to detect the presence of parvovirus B19 DNA and Mycobacterium tuberculosis (MTB) DNA by nested polymerase chain reaction (N-PCR) assays in the bone marrow biopsy samples from 30 patients with idiopathic AA. Serologic assays for parvovirus B19 were based on indirect antibody capture enzyme-linked immunosorbent assay.

Our results indicate that neither parvovirus B19 DNA nor MTB DNA could be demonstrated in any of the bone marrow samples by N-PCR. Moreover, IgM antibody against parvovirus B19 also was undetectable in the serum samples of 17 patients.

Thus, our results suggest that parvovirus B19 and MTB are not associated with AA and, consequently, do not have a role in the pathogenesis of this disease.


Pregnancy associated aplastic anemia: maternal and fetal outcome.

Deka D, Malhotra N, Sinha A, Banerjee N, Kashyap R, Roy KK.

Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India.

J Obstet Gynaecol Res. 2003 Apr;29(2):67-72. Abstract quote

AIM: To study the maternal and fetal outcome in cases of aplastic anemia associated with pregnancy.

METHOD: Retrospective analysis of seven cases of aplastic anemia diagnosed during pregnancy.

RESULT: Four patients had an overall successful pregnancy outcome. These were all cases of non-severe aplastic anemia. There was one case each of intrauterine and neonatal death in the severe aplastic anemia group. There was one maternal mortality.

CONCLUSION: Maternal and fetal outcome is poor in severe aplastic anemia.


Aplastic anemia complicating systemic lupus erythematosus--report of a case and review of the literature.

Pavithran K, Raji NL, Thomas M.

Department of Haematology, Medical College Hospital, Trivandrum-695011, India.

Rheumatol Int. 2002 Nov;22(6):253-5. Abstract quote

Aplastic anemia is a very unusual feature of systemic lupus erythematosus (SLE). A 32-year-old lady presented with generalized purpuric lesions and was diagnosed as having immune thrombocytopenic purpura.

Fourteen months later, she developed progressive pancytopenia, arthritis of small joints, and oral ulcers. Investigations confirmed SLE with aplastic anemia. High-dose methylprednisolone therapy had been unsuccessful in controlling the pancytopenia. She had a progressive course and died due to septicemia. Even though pancytopenia is common in SLE, a bone marrow examination should be done in all cases of persistent pancytopenia to exclude bone marrow aplasia.

This will help in tailoring the treatment with more aggressive immunosuppressants.


Very severe aplastic anemia appearing after thymectomy.

Park CY, Kim HJ, Kim YJ, Park YH, Lee JW, Min WS, Kim CC.

Catholic Hemopoietic Stem Cell Transplantation Center, Catholic University College of Medicine, Seoul, Korea.


Korean J Intern Med. 2003 Mar;18(1):61-3. Abstract quote

Aplastic anemia is a rare complication of thymoma and is extremely infrequent after thymectomy.

We present a case of a 60-year-old woman with very severe aplastic anemia appearing sixteen months after thymectomy for a thymoma. She underwent thymectomy for a thymoma in April 2000. Preoperative examination revealed no hematologic abnormality.

About sixteen months after the operation, she was readmitted because of pancytopenia with cough and fever. Bone marrow aspiration revealed a very severe hypoplasia in all the three cell lines with over 80% fatty tissue, and chest CT revealed no recurrence of thymoma. Her aplastic anemia had responded to cyclosporine A and granulocyte-colony stimulating factor (G-CSF).


Severe aplastic anemia associated with thymic carcinoma and partial recovery of hematopoiesis after thymectomy.

Koizumi K, Nakao S, Haseyama Y, Kato H, Ohi M, Motohara T, Endo T, Sawada K, Koike T.

Department of Internal Medicine, Federation of National Public Service Personnel Mutual Aid Association, Tonan Hospital, 060-0001, Sapporo, Hokkaido, Japan,

Ann Hematol. 2003 Jun;82(6):367-70. Abstract quote

Aplastic anemia has been a rare complication of thymic tumors documented in only a few cases.

We now report that a previously healthy, 72-year-old woman had a well-differentiated squamous cell thymic carcinoma and severe aplastic anemia, as detected on a simultaneous basis. After extirpation of the thymic carcinoma, hematological recovery was achieved.

While cyclosporine (CyA), prednisolone (PSL), and methenolone improved hematological data even more, a partial and stable remission has been sustained for 22 months. The patient's serum prior to the surgery had a suppressive effect on the formation of colonies of erythroid and nonerythroid colonies, as determined using the patient's bone marrow cells and compared with the patient's serum after the surgery and normal AB serum.

This case report concerns a patient in whom we observed simultaneous occurrence of a thymic tumor and a sever marrow aplasia for which we describe our therapeutic approach.


Severe aplastic anemia with autoimmune thyroiditis showing no hematological response to intensive immunosuppressive therapy.

Tomonari A, Tojo A, Iseki T, Ooi J, Hase H, Shirafuji N, Tani K, Asano S.

Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Japan.

Acta Haematol. 2003;109(2):90-4. Abstract quote

A 39-year-old woman with severe aplastic anemia (SAA) was transferred to our institution. She also had autoimmune thyroiditis with several positive autoantibodies. Clonal or oligoclonal T-cell proliferation was demonstrated by determining the size distribution of the complementarity-determining region 3 (CDR3) of T-cell receptor beta-chain (TCR-Vbeta) subfamilies in the patient's bone marrow and peripheral blood cells.

The results suggested that hematopoiesis was suppressed by immune-mediated mechanisms. Immunosuppressive therapy for SAA using cyclosporin A (CsA) alone or concurrent CsA and antithymocyte globulin (ATG) failed to induce a hematological response. The intensity of the autoantibodies, however, partially decreased during this period. In addition, the CD4/CD8 ratio was inverted after immunosuppressive therapy.

These observations indicate that, in a subset of SAA, immune-mediated hematopoietic suppression cannot be successfully treated by conventional immunosuppressive therapy, even though a substantial improvement in the underlying immunological changes can be achieved. Other therapies such as hematopoietic stem cell transplantation or more intensified repeated ATG therapy may be necessary for such patients.



Immune pathophysiology of aplastic anemia.

Maciejewski JP, Risitano A, Kook H, Zeng W, Chen G, Young NS.

Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic Foundation, OH, USA.


Int J Hematol. 2002 Aug;76 Suppl 1:207-14. Abstract quote

Aplastic anemia (AA) remains an elusive disease. Its pathophysiology is not only fascinating by the seemingly simple findings of cytopenia and marrow hypoplasia, but may also contain key information to the understanding of other fundamental processes such as stem cell regeneration, evolution, and immune control of clonal diseases.

Although measurements of blood counts provide an objective tool to assess the disease activity and response to the therapy, immune pathophysiology of AA, as inferred from the successes of immunosuppression, provides only few other clinical clues. Similarly, the current laboratory evidence remains mostly indirect. In spite of the recognition of immune pathways of hematopoietic inhibition and apoptosis in AA, the fundamental question about the nature of the antigen(s) inciting or maintaining the pathologic immune response that ultimately leads to bone marrow failure, remains open. However, recognition of the immune targets may aid in understanding not only the pathogenesis but also many of clinical associations and the late squelae of AA. For example, abnormal cells in AA and myelodysplastic syndrome (MDS) MDS may harbor inciting antigens but the immune response lacks selectivity. Clonal selection pressure may be a result of this process or alternatively, emergence of tolerance could lead to the establishment of abnormal hematopoiesis.

Clonal proliferation of large granular lymphocytosis could represent an example of an exaggerated response to an immunodominant hematopoietic antigen. In addition to the traditional functional or phenotypic analysis, pathologic immune response in AA can be studied on molecular level by identifying and quantitating T cell clones based on the presence of unique variable B-chain CDR3 sequences. Detection of clonal expansion is based on the observation that in infections and autoimmune conditions, the presence of antigenic drive will lead to the expansion and overrepresentation of T cell clones recognizing this antigen. However, simple analysis of clonal representation is not sufficient to resolve the complex nature of the immune repertoire in the context of genetic and clinical heterogeneity. Therefore, we analyzed VB and CDR3 repertoire in CD4 and CD8 cells, activated or effector cell subsets.

To distinguish truly expanded and likely immunodominant clones, we first studied VB distribution and cloned CDR3 sequences from expanded VB families. Identified clonotypic sequences can be used to design molecular tests to quantitate the strength of pathologic immune response. Clonotype sharing has been confirmed in patients with similar clinical features indicating presence of common antigens. In addition, quantitative analysis showed correlation with the therapy response.

Persistence and patterns of clonotypes may be helpful in the classification of immune-mediated marrow failure based on the immune characteristics and will allow inferences into the inciting pathways.


Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome.

Yamaguchi H, Baerlocher GM, Lansdorp PM, Chanock SJ, Nunez O, Sloand E, Young NS.

Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Blood. 2003 Apr 3 [Epub ahead of print]. Abstract quote

Mutations in the human telomerase RNA (TERC) occur in the autosomal dominant form of dyskeratosis congenita (DKC).
Because of the possibility that TERC mutations might underlie seemingly acquired forms of bone marrow failure, we examined blood samples from a large number of patients with aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplasia (MDS). Only three of a total of 210 cases showed heterozygous TERC mutations: both n305 (G-A) and n322 (G-A) were within the CR4-CR5 domain; n450 (G-A) was localized to the boxH/ACA domain.

However, the clinical characteristics of only one patient (with a mutation at n305 (G-A)) suggested DKC; her blood cells contained short telomeres and her sister also suffered from bone marrow failure. Another 21 patients with short telomeres did not show TERC mutations.

Our results suggest that cryptic DKC, at least secondary to mutations in the TERC gene, is an improbable diagnosis in patients with otherwise typical AA, PNH, and MDS.

Views on the pathophysiology of aplastic anaemia.

Gordon-Smith EC, Marsh JC, Gibson FM.

Department of Haematology, St George's Hospital Medical School, London, UK.


Int J Hematol. 2002 Aug;76 Suppl 2:163-6. Abstract quote

Aplastic anaemia seems to be predominantly a defect of the stem cell rather than the stroma, though abnormalities of the microenvironment may co-exist.

There is highly suggestive evidence that the stem cell is the target of an immune attack, though the main evidence remains the response to immunosuppression with antilymphocyte globulin and cyclosporin. The stem cell defect remains even after recovery of the peripheral blood counts and the AA marrow is a fertile environment for the emergence of abnormal clones, particularly PNH. However, it has recently become apparent that there is an overlap with the myelodysplastic syndromes and clones of monosomy 7 and trisomy 8 amongst others are not uncommon in aplastic anaemia. Recent work has suggested that the emergence of a clone of monosomy 7 cells carries a poor prognosis, whereas trisomy 8 has a good prognosis particularly in response to cyclosporin. However, the setting in which monosomy 7 arises may affect the phenotypic expression.

The immune targeting of stem cells may be associated with increased apoptosis in aplastic anaemia, in part mediated by fas expression, but not exclusively. Understanding the pathophysiology of AA should help to improve and perhaps target therapy.



Diamond-Blackfan anemia: report of 6 cases.

Manglani M, Lokeshwar MR, Sharma R.

Division of Pediatric Hematology-Oncology, Department of Pediatrics, L.T.M.M. College and General Hospital, Sion, Mumbai 400 050, India.

Indian Pediatr. 2003 Apr;40(4):355-8. Abstract quote

Diamond-Blackfan anemia is a rare congenital hypoplastic anemia.

We report 6 children diagnosed as Diamond-Blackfan anemia at our clinic. All had severe pallor at presentation, with mild hepatomegaly and just palpable spleen in one child. Thumb anomaly was present in one of them. All of them had macrocytic or normocytic anemia with reticulocytopenia, and bone marrow examination revealed marked erythroid hypoplasia.

All of them were treated with oral steroids with a good response.



Persistent remission after immunosuppressive therapy of hairy cell leukemia mimicking aplastic anemia: two case reports.

Sugimori C, Kaito K, Nakao S.

Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.

Int J Hematol. 2003 May;77(4):391-4. Abstract quote

Some patients with hairy cell leukemia (HCL) manifest pancytopenia and bone marrow hypoplasia without an apparent increase in atypical cells, so their disease resembles severe aplastic anemia at onset.

We treated 2 HCL patients, who were initially diagnosed with aplastic anemia, with antithymocyte globulin (ATG) in combination with cyclosporine or antilymphocyte globulin (ALG). Both patients obtained partial remission in response to the immunosuppressive therapy and did not need transfusion treatment for more than 3 years.

Sustained improvement of hematopoiesis in such B-cell malignancies after ATG/ ALG therapy suggests that the mechanisms underlying successful immunosuppressive therapy for aplastic anemia may involve B-cell suppression, inhibiting hematopoietic stem cells.



Donor-cell myelodysplastic syndrome developing 13 years after marrow grafting for aplastic anemia.

Haltrich I, Muller J, Szabo J, Kovacs G, Koos R, Poros A, Dobos M, Fekete G.

II Department of Pediatrics, Faculty of Medicine, Semmelweis University, H-1094 Budapest, Hungary.

Cancer Genet Cytogenet. 2003 Apr 15;142(2):124-8 Abstract quote

Donor-cell-derived hematopoietic malignancy is a rare event after bone marrow transplantation. Most cases in the literature occurred within the first year.

We present a rare case of a female patient who had a bone marrow transplant for severe aplastic anemia (SAA) at the age of two and a half years from her human leukocyte antigen-identical brother. She developed a myelodysplastic syndrome (refractory cytopenia with multilineage dysplasia) 12 years later. Initially, the malignant clone was of recipient origin, but within several months, progression to a clinically more aggressive refractory anemia with excess blasts (RAEB) was accompanied by the outgrowth of a new clone of donor origin. In this report we provide evidence proving that the patient's final malignant clone arose in donor cells: cytogenetic analysis of the marrow showed a male karyotype and a t(3;21)(q26;q21) in all 62 metaphases analyzed. Interphase fluorescence in situ hybridization showed that all identifiable cells contained the Y chromosome.

We conclude that donor-cell-derived hematopoietic malignancy after bone marrow transplantation can occur even after many years. We believe that the 13 years that elapsed between the transplant and the development of RAEB in our case represent the longest latency period in the literature.


Membranous nephropathy after allogeneic hematopoietic stem cell transplantation in a patient with aplastic anemia: a case report.

Kim KW, Yoon CH, Kay CS, Kim HJ, Suh KS, Kim SY, Park SY.

Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

J Korean Med Sci. 2003 Apr;18(2):287-9. Abstract quote

Nephrotic syndrome has been described as one of the clinical forms of chronic graft-versus-host disease (cGVHD), but a limited number of cases have been described.

We experienced a young female patient with nephrotic syndrome developed 22 months after allogeneic hematopoietic stem cell transplantation (HSCT) for severe aplastic anemia. She had been well after successful management for gut-limited cGVHD until she developed a clinical nephrotic syndrome with hypoalbuminemia of 2.0 g/dL and 24-hr urine protein of 6.88 g/dL. On physical examination and laboratory findings, there was no other evidence of cGVHD. Clinical and renal biopsy findings were consistent with cGVHD-related membranous nephropathy, and immunosuppressive agents with cyclosporine and prednisone were prescribed. After 3 month of treatment, the proteinuria decreased to normal range; and the patient from nephrotic syndrome nearly recovered.

We recommend cGVHD-related glomerulonephritis should be considered in all patients with hypoalbuminemia following allogeneic HSCT, even if there is no other evidence of clinical GVHD.


Haematopoietic stem cell transplantation to treat aplastic anaemia.

Jaime-Perez JC, Ruiz-Arguelles GJ, Gomez-Almaguer D.

Universidad Autonoma de Nuevo Leon Servicio de Hematologia, Hospital Universitario, Dr Jose E. Gonzalez, Edificio Dr Rodrigo Barragan, 2 piso., Avenida Madero y Gonzalitos, Monterrey, Nuevo Leon, C.P. 64460, Mexico.
Expert Opin Biol Ther. 2005 May;5(5):617-26. Abstract quote  

Aplastic anaemia (AA) consists of pancytopenia and empty bone marrow. Its incidence varies worldwide but predominates in developing countries. Diverse aetiologies are involved, with autoimmunity at the centre of the picture.

For the 70% of patients with the severe and very severe forms of AA and who lack a human leukocyte antigen (HLA)-matched sibling, immunosuppressive therapy (IST) is key in treating the disease, with a remission rate close to 70%, an 80-90% 5-year survival rate in responding patients and a relapse rate close to 10%.

For the 30% with a sibling donor available, haematopoietic stem cell transplant (HSCT) from bone marrow or peripheral blood has up to a 90% chance of cure, with a 5-10% graft rejection/failure rate. Patients who fail IST (25-30%) and lack a sibling donor can benefit from CD34(+)-enriched, partially T cell-depleted unrelated stem cell transplants, with a general survival rate up to 37%, the newest source of stem cells for this modality being cord blood. Non-myeloablative, irradiation-free conditioning regimens offer appreciable benefits, and new immunosuppressive agents, such as fludarabine and alemtuzumab, have been incorporated with promising preliminary results.

Graft-versus-host disease, graft failure and infections remain significant challenges in HSCT for which innovative treatment strategies are being developed at present.

The treatment of severe aplastic anemia: outcomes of bone marrow transplantation and immunosuppressive therapy in a single institution of Korea.

Kim I, Yoon SS, Park S, Kim BK, Kim NK.

Department of Internal Medicine, Seoul National University, College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, Korea.

J Korean Med Sci. 2003 Jun;18(3):365-71 Abstract quote

The present study represents an analysis of 96 patients with severe aplastic anemia (SAA) treated in Seoul National University Hospital, Seoul, Korea between 1990 and 1999.

Twenty-two patients were treated by allogeneic bone marrow transplantation (BMT) from HLA identical sibling donors and 74 by immunosuppressive therapy (IS) with antithymocyte globulin (ATG) or antilymphocyte globulin (ALG). There was no statistical difference between the two treatment groups in age, sex, disease duration, and previous transfusion amount. In the BMT group, grade II-IV acute graft versus host disease (GVHD) develeped in 10% and chronic GVHD occurred in 33% of patient. Only one patient died from complication of transplantation (veno-occlusive disease). Of 74 patients who received IS treatment, 45% achieved a complete or partial response. Twenty patients died among IS treatment group. Major causes of death were hemorrhage (40%) and infection (55%). In the BMT group, the 5-yr overall survival (OS) was 95% after a median follow-up of 42 months. In the IS group, the 5-yr OS was 70% after a median follow-up of 49 months (p=0.04).

In conclusion, the long-term survival rates of SAA in Koreans receiving BMT or IS were excellent compared with the Western data. Further evaluation on the prognosis of aplastic anemia in Asians should be done.

Bone marrow transplantation for patients with acquired severe aplastic anemia using cyclophosphamide and antithymocyte globulin: the experience from a single center.

Abdelkefi A, Othman TB, Ladeb S, Torjman L, Hsairi M, Abdeladhim AB.

1Centre National de Greffe de Moelle Osseuse (CNGMO), Tunis, Tunisia.

Hematol J. 2003;4(3):208-13. Abstract quote

Between 1998 and 2001, 31 (24 male, 7 female) patients with severe aplastic anemia (SAA) and a median age of 19 years (range, 4-39 years) received an allogeneic bone marrow transplantation.

Marrow donors were genotypically HLA-identical siblings in 30 cases and a monozygous twin in one case. The median time from diagnosis to bone marrow transplantation was 1 month (range, 0.5-5 months). Conditioning regimen consisted of cyclophosphamide (CY) combined with antithymocyte globulin (ATG), in all patients.

For graft-versus-host disease (GvHD) prophylaxis, all patients received methotrexate and cyclosporin. A total of 84% of patients had sustained grafts, whereas 16% rejected grafts between 3 and 20 months after transplantation. Of the five rejecting patients, three are alive with successful second engraftments and two died from infections. Acute grade II-IV GvHD was seen in only 11% of patients. A limited chronic GvHD was seen in one patient. With a median follow-up of 18 months (range, 5-42 months), survival rate was 86% and Karnofsky score was at least 90%.

This study confirms the high success rate of the CY/ATG regimen in SAA allografted from an HLA-identical sibling. Early and late graft failure remains a problem and may require modification of this regimen.

Successful allogeneic hematopoietic stem cell transplantation using triple agent immunosuppression in severe aplastic anemia patients.

Kim HJ, Park CY, Park YH, Kim YJ, Kim DW, Min WS, Kim CC.


Bone Marrow Transplant. 2003 Jan;31(2):79-86. Abstract quote

Graft rejection in patients with severe aplastic anemia (SAA) following allogeneic hematopoietic stem cell transplantation (HSCT) is strongly associated with a large number of prior transfusions and with prolonged disease duration before transplant.

We retrospectively analyzed the outcomes and the factor affecting these multitransfused SAA patients, who had received triple agent immunosuppression and high doses of stem cells to overcome rejection. In total, 113 patients with SAA who had a median 16 months (range 1-216) of disease duration were transplanted using HLA-matched sibling donors after conditioning with cyclophosphamide (CY), procarbazine (PCB), and ATG. Graft failure occurred in 16 of the eligible 113 patients, and with a median follow-up of 30 months (range, 1-80), probability of overall rejection was 15%. Specifically, the multitransfused patients who received high doses of stem cells with T-cell depletion showed the lowest rejection rate, 5.6%, compared with 30.3% in multitransfused patients with bone marrow stem cells alone (P=0.0310). Disease duration (P=0.0338) and the number of infused CD34+cells (P=0.0101) were associated with a high risk of graft rejection on multivariate analysis. ABO mismatch and the number of CD34+ cells were significant factors in the incidence of acute graft-versus-host-disease (GVHD). The incidence of chronic GVHD among patients with sustained engraftment was 13/109 (11.9%).

With the same follow-up period, probability of disease-free survival for the entire group of patients at 6 years was 89% and the only factor associated with long-term survival was rejection (P=0.0241). These results suggest that allogeneic HSCT conditioned with triple agent immunosuppression, and specifically with high-dose stem cell return is probably an effective treatment for successful engraftment in SAA patients with a high risk of rejection.

Long-term follow-up of allogeneic stem cell transplantation in patients with severe aplastic anemia after conditioning with cyclophosphamide plus antithymocyte globulin.

Kroger N, Zabelina T, Renges H, Kruger W, Kordes U, Rischewski J, Schrum J, Horstmann M, Ayuk F, Erttmann R, Kabisch H, Zander AR.

Department of Bone Marrow Transplantation, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.

Ann Hematol. 2002 Nov;81(11):627-31. Abstract quote

We investigated the efficacy of an antithymocyte globulin/cyclophosphamide preparative regimen prior to allogeneic stem cell transplantation from HLA-identical siblings in patients with severe aplastic anemia. Since 1990, 21 patients, 6 males and 15 females, with a median age of 25 years (range: 7-43) have been enrolled in the protocol consisting of 200 mg/kg cyclophosphamide and 90-120 mg/kg antithymocyte globulin (ATG, rabbit, Fresenius, Bad Homburg, Germany).

For further graft-versus-host disease (GVHD) prophylaxis all patients received cyclosporin A and a short course of methotrexate (MTX). Only one patient had a primary graft failure (5%). All other patients engrafted with a leukocyte count >1.0 x 10(9)/l and a platelet count >20 x 10(9)/l after a median of 19 (range: 11-28) and 26 days (range: 13-67), respectively. No late graft failure or relapse was observed. Two patients experienced mild acute GVHD grade I (10%), and one patient developed grade II GVHD (5%). No severe grade III/IV GVHD was observed; 17% of the patients developed limited chronic GVHD.

The treatment-related mortality was 14% and mainly due to fungal infection. After a median follow-up of 70 months (range: 2-139), the estimated overall and event-free survival at 10 years for all patients is 86% (95% confidence interval: 70-100%). We conclude that ATG plus cyclophosphamide is an effective conditioning regimen in patients with aplastic anemia undergoing stem cell transplantation with a low treatment-related mortality, resulting in an excellent outcome.


Long-term follow-up of patients with aplastic anemia and refractory anemia responding to combination therapy with recombinant human granulocyte colony-stimulating factor and erythropoietin.

Matsuda A, Kishimoto K, Yoshida K, Yagasaki F, Ito Y, Sakata T, Kawai N, Ino H, Hirashima K, Bessho M.

Int J Hematol. 2002 Oct;76(3):244-50. Abstract quote

In our previous study, approximately 60% of aplastic anemia (AA) and refractory anemia (RA) patients treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human erythropoietin (rhEpo) showed a multilineage response.

In this study, we analyzed the long-term follow-up of the multilineage responders (multi-R). In the follow-up analysis of 11 multi-R (6 AA and 5 RA), 10 patients (5 AA and 5 RA) were evaluable. The range of time from the start of treatment to the final contact was 50 to 125 months. Analysis of survival times revealed a significant difference between multi-R and non-multi-R among AA patients given this treatment (P = .016). One AA and 1 RA patient among the multi-R developed acute leukemia. Of 7 living multi-R, 3 AA and 2 RA patients did not need transfusion at final contact.

Four of them maintained the target hemoglobin concentration of more than 11 g/dL for quality-of-life benefit. The findings suggested that this result is an important advantage of this treatment.


Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction.

Gross M, Hanenberg H, Lobitz S, Friedl R, Herterich S, Dietrich R, Gruhn B, Schindler D, Hoehn H.

Department of Human Genetics, University of Wurzburg, Wurzburg, Germany.

Cytogenet Genome Res. 2002;98(2-3):126-35. Abstract quote

Fanconi anemia (FA) is a genetically and phenotypically heterogenous autosomal recessive disease associated with chromosomal instability and hypersensitivity to DNA crosslinkers. Prognosis is poor due to progressive bone marrow failure and increased risk of neoplasia, but revertant mosaicism may improve survival. Mechanisms of reversion include back mutation, intragenic crossover, gene conversion and compensating deletions/insertions.

We describe the types of reversions found in five mosaic FA patients who are compound heterozygotes for single base mutations in FANCA or FANCC. Intragenic crossover could be shown as the mechanism of self-correction in the FANCC patient. Restoration to wildtype via back mutation or gene conversion of either the paternal or maternal allele was observed in the FANCA patients. The sequence environments of these mutations/reversions were indicative of high mutability, and selective advantage of bone marrow precursor cells carrying a completely restored FANCA allele might explain the surprisingly uniform pattern of these reversions. We also describe a first example of in vitro phenotypic reversion via the emergence of a compensating missense mutation 15 amino acids downstream of the constitutional mutation, which explains the reversion to MMC resistance of the respective lymphoblastoid cell line.

With one exception, our mosaic patients showed improvement of their hematological status during a three- to six-year observation period, indicating a proliferative advantage of the reverted cell lineages. In patients with Fanconi anemia, genetic instability due to defective caretaker genes sharply increases the risk of neoplasia, but at the same time increases the chance for revertant mosaicism leading to improved bone marrow function.

Immunosuppressive therapy for aplastic anaemia in children: a more severe disease predicts better survival.

Fuehrer M, Rampf U, Baumann I, Faldum A, Niemeyer C, Janka-Schaub G, Friedrich W, Ebell W, Borkhardt A, Bender-Goetze C.

Children's University Hospital, Department of Hematology and Oncology, Ludwig-Maximilians University, Munich, Germany.

Blood. 2005 Jun 2; [Epub ahead of print] Abstract quote  

Severe acquired aplastic anaemia (SAA) is a life-threatening disease characterized by pancytopenia and hypoplastic bone marrow. Autologous T-lymphocytes are thought to cause bone marrow failure by immune-mediated excessive apoptosis of stem and progenitor cells. The disease is sub-classified into a severe (neutrophils >200/microl) and a very severe (< 200/microl) (vSAA) form.

We report the results of a prospective multicentre trial with a combined immunosuppressive regimen of cyclosporin A (CSA), anti-thymocyte-globulin (ATG) and, in cases with neutrophils < 500/microl, granulocyte colony-stimulating factor (G-CSF) for treatment of SAA in children. Children with vSAA showed a higher rate of complete response than children with SAA (68% vs. 45%; p = 0.009), as well as better survival (93% vs. 81%; p = 0.0266).

Thus, in children with SAA a more severe disease stage at diagnosis indicates a favourable outcome with immunosuppressive therapy.

Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia.

Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H; German Aplastic Anemia Study Group.

Department of Hematology/Oncology, Dr-Horst-Schmidt-Kliniken, Wiesbaden, Germany.

Blood. 2003 Feb 15;101(4):1236-42. Abstract quote

Immunosuppression with antithymocyte globulin, (methyl)prednisolone, and cyclosporin A is considered the treatment of choice for the patient with aplastic anemia without a donor for standard-risk stem cell transplantation. This consensus is supported by the results of several series, including a randomized German trial.

Here we report 11-year results of the latter trial. With stringent response criteria and 4 months as the time to evaluate responses, this analysis confirms the superiority of the cyclosporine regimen regarding the response rate in all patients treated (70% vs 41%, with or without cyclosporine; P =.015) and in patients with severe aplastic anemia (65% vs 31%; P =.011). Patients responded more rapidly after treatment with cyclosporine (median, 60 vs 82 days; P =.019). Most patients treated with cyclosporine needed only one course of immunosuppression, whereas many patients treated without cyclosporine required repeated immunosuppressive treatment.

Because of the efficacy of salvage treatment, overall survival was not different between the 2 treatment groups. However, failure-free survival favored the cyclosporine regimen (39% vs 24%; P =.04). The relapse rate, projected at 38% after 11.3 years, was similar between the 2 treatment groups. Remissions were cyclosporine dependent in 26% of the patients responding to a regimen that included cyclosporine. Clonal or malignant diseases developed in 25% of the patients.

These data demonstrate that antithymocyte globulin, methylprednisolone, and cyclosporin A are an effective regimen for the treatment of aplastic anemia. However, remissions are unstable, and secondary diseases are common. In contrast to the results of stem cell transplantation, most patients are not cured.

Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome.

Rosenfeld S, Follmann D, Nunez O, Young NS.

Hematology Branch, Bldg 10, National Heart, Lung, and Blood Institute, Bethesda, Md, USA.


JAMA. 2003 Mar 5;289(9):1130-5. Abstract quote

CONTEXT: In most patients, aplastic anemia results from T-cell-mediated immune destruction of bone marrow. Aplastic anemia can be effectively treated by stem cell transplantation or immunosuppression.

OBJECTIVE: To assess long-term outcomes after immunosuppressive therapy.

DESIGN, SETTING, AND PATIENTS: Cohort of 122 patients (31 were < or =18 years and 91 were >18 years) with severe aplastic anemia, as determined by bone marrow cellularity and blood cell count criteria, were enrolled in a single-arm interventional research protocol from 1991 to 1998 at a federal government research hospital.

INTERVENTIONS: A dose of 40 mg/kg per day of antithymocyte globulin administered for 4 days, 10 to 12 mg/kg per day of cyclosporine for 6 months (adjusted for blood levels), and a short course of corticosteroids (1 mg/d of methylprednisolone for about 2 weeks).

MAIN OUTCOME MEASURES: Survival, improvement of pancytopenia and transfusion-independence, relapse, and evolution to other hematologic diseases.

RESULTS: Response rates were 60% at 3 months after initiation of treatment, 61% at 6 months, and 58% at 1 year. The blood cell counts of patients who responded no longer satisfied severity criteria and they were transfusion-independent. Overall actuarial survival at 7 years was 55%. Survival was associated with early satisfaction of response criteria (86% vs 40% at 5 years; P<.001) and by blood counts at 3 months (reticulocyte count or platelet count of >50 x 10(3)/ microL predicted survival at 5 years of 90% [64/71] vs 42% [12/34] for patients with less robust recovery [P<.001 by log-rank test]). There were no deaths among responders more than 3 years after treatment. Relapse was common, but severe pancytopenia usually did not recur. Relapse did not influence survival. Thirteen patients showed evolution to other hematologic diseases, including monosomy 7.

CONCLUSIONS: Approximately half of patients with severe aplastic anemia treated with antithymocyte globulin and cyclosporine have durable recovery and excellent long-term survival. These outcomes were related to the quality of hematologic recovery.

Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party.

Marsh J, Schrezenmeier H, Marin P, Ilhan O, Ljungman P, McCann S, Socie G, Tichelli A, Passweg J, Hows J, Raghavachar A, Locasciulli A, Bacigalupo A.

Department of Haematology, St George's Hospital Medical School, London, UK.

Blood. 1999 Apr 1;93(7):2191-5. Abstract quote

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 x 10(9)/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.

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