Management Of Aplastic Anemia Research Articles

Interpretiation of guidelines for the diagnosis and management of aplastic anemia in China (2022)

Interpretiation of guidelines for the diagnosis and management of aplastic anemia in China (2022)

Guidelines for the diagnosis and management of aplastic anemia in China (2022)

Guidelines for the diagnosis and management of aplastic anemia in China (2022)

Management of Aplastic Anemia in Pregnancy: A Case Report

Aplastic anemia was first recognized by Ehrlich in 1888, although the pathogenesis of aplastic anemia has remained elusive. Aplastic anemia is a subtype of anemia characterized by pancytopenia and a hypocellular bone marrow which are the risk factor can be due to chemicals, drugs, infections, irradiation, leukemia, and inherited disorders. There is universal agreement that pregnancy complicated by aplastic anemia is a serious condition. The risk to the mother is mainly in the form of hemorrhage meanwhile the fetus may suffer from growth restriction and even intrauterine death. Most of the fetal complications are due to maternal anemia. We here present one cases of pregnancy complicated by aplastic anemia, which were seen within 3 months at our hospital. This high incidence is because the hospital is a top national care referral unit with good hematology and blood bank support.
 Keyword: aplastic anemia, pregnancy, pancytopenia
 Abstrak
 Anemia aplastik pertama kali dikenali oleh Ehrlich pada tahun 1888, walaupun patogenesis anemia aplastik masih sulit dipahami. Anemia aplastik adalah subtipe anemia yang ditandai dengan pansitopenia dan hiposeluler sumsum tulang yang merupakan faktor risiko yang dapat disebabkan oleh bahan kimia, obat-obatan, infeksi, iradiasi, leukemia, dan kelainan bawaan. Terdapat kesepakatan universal bahwa komplikasi kehamilan berupa anemia aplastik merupakan kondisi serius. Risiko kepada ibu hamil terutama dalam bentuk perdarahan sementara janin dapat mengalami hambatan dalam pertumbuhan dan bahkan kematian dalam kandungan. Sebagian besar komplikasi janin disebabkan oleh anemia pada maternal. Kami di sini menyajikan satu kasus komplikasi kehamilan berupa anemia aplastik, yang ditemukan dalam waktu 3 bulan di rumah sakit kami. Kejadian yang tinggi ini karena rumah sakit adalah unit rujukan perawatan nasional teratas dengan hematologi yang baik dan dukungan bank darah.

Clinical audit on management of aplastic anemia at hematology unit of Assiut University Children Hospital

Background Aplastic anemia (AA) is a rare bone marrow failure disorder with high mortality rate, which is characterized by peripheral blood pancytopenia, with a hypocellular bone marrow. Objective The aim was to evaluate the management of aplastic anemia in Assiut University Children Hospital, trying to find any defects and suggest methods of their correction. Patients and methods A retrospective cross-sectional study was done on 50 children having AA for a period of 1 year. Results Management of AA in Assiut University Children Hospital is compatible with the British Committee for Standards in Hematology guideline 2015 except for some defects such as using high dose of cyclosporine alone, due to no availability of antithymocyte globulin in definitive drug therapy. There is no availability of stem cell transplantation, although it is the only curative treatment. Conclusion Management of AA in Assiut University Children Hospital is compatible with British Committee for Standards in Hematology guideline (2015), but there are some defects owing to limited recourses.

Management of Aplastic Anaemia in a 15-year Old Boy with Down Syndrome in a Low Resource Setting

We present a case report of idiopathic aplastic anaemia (AA) in a 15-year old Sudanese boy with Down syndrome (47XY, 21+ in all metaphases). AA is rare in Down syndrome with 10 cases published in the literature.

Ambispective Observational Study to Evaluate the Incidence and Management of Aplastic Anemia in Spain

Ambispective Observational Study to Evaluate the Incidence and Management of Aplastic Anemia in Spain

Eltrombopag in the management of aplastic anaemia: real-world experience in a non-trial setting

ABSTRACTObjective: The thrombopoietin mimetic eltrombopag has been used in clinical trials for the frontline and salvage treatment of aplastic anaemia (AA). Eltrombopag was investigated in AA patients on a non-trial all-comer basis.Methods: Consecutive newly diagnosed and relapsed/refractory AA patients were treated with eltrombopag.Results: In a 4.5-year period, 20 consecutive AA patients (newly diagnosed, N = 10; relapsed/refractory, N = 10) at a median age of 47 (22–84) years were treated with eltrombopag. For newly diagnosed patients, the frontline use of eltrombopag (concomitant medications: anti-thymocyte globulin, ATG, and ciclosporin, N = 4; ciclosporin, N = 5; nil, N = 1) at a median maximum dose of 150 (50–300) mg/day led to an overall response rate (ORR) of 90% (trilineage: 60%; neutrophil: 20%; platelet: 10%). After a median follow-up of 47 (14–179) weeks, responses were maintained in all cases. In relapsed/refractory patients, eltrombopag at a median maximum dose of 150 (50–300) mg/day led to an ORR of 50% (trilineage: 40%; neutrophil: 10%), with responses maintained after a median follow-up of 115 (53–253) weeks. Adverse effects included reversible skin pigmentation (observed in all patients taking eltrombopag at ≥150 mg/day), dyspepsia, and liver function derangement.Conclusion: In a routine haematological practice, the use of eltrombopag in AA patients was feasible, safe, and associated with very favourable responses.

Role of Arsenic Trioxide in the Management of Aplastic Anemia.

Aplastic anemia is a common problem in the developing world with therapeutic challenges as most of the patients are non-affording to standard care owing to resource constraints. We present the results of an open label single arm, non-randomized, single center, prospective phase II trial of the compassionate use of arsenic trioxide in patients refractory to ATG or unable to afford the standard of care therapy. The study was prematurely terminated at eighth week due to non-response in 100% of patients and death in two patients. The results are contradictory to what is already published and needs validation in a multicentric setting.

Dysplastic Changes and Proliferation Index in Acquired Aplastic Anemia Are Not Associated with Progression to MDS/AML - a Study of Bone Marrow in Children and Adults

Acquired Aplastic Anemia (AAA) is a rare disease which progresses to MDS / AML in up to 15% of cases. When this happens, hematopathologists are asked whether the diagnosis of hypocellular Myelodisplastic Syndrome (h-MDS) would not have been confused morphologically with aplastic anemia.This study aims to identify morphological/immunophenotypical (M/I) findings that could predict this adverse prognosis in adults and children (<19y) diagnosed as AAA and verify if those criteria match with the ones described in literature in adult h-MDS (Bennett JM, Orazi A. Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach. Haematologica, 2009;94:264-9)¹ and, more recently, in pediatric MDS (Baumann I, Niemeyer CM, Bennett JM, et al. Childhood Myelodisplastic Syndrome. In: Swerdlow SH, Campo E, Harris NL, et al (Ed.). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Fourth Edition. Lyon: IARC Press, 2008:104-7)², contributing to the discussion of this "grey zone".We retrospectively analyzed 123 patients/bone marrow (BM) biopsies at the moment of AAA diagnosis at Clinical Hospital of São Paulo Medical School from 1993 to 2012. Diagnosis of AAA was carried out according to classical criteria (Marsh JCW. et al. Guidelines for the diagnosis and management of aplastic anaemia. British Journal of Haematology, 2009;147:43-70). Evolution to MDS or AML was considered in the presence of at least one of the findings: significant dysgranulopoiesis or dysmegakaryocytopoiesis, more than 15% ring sideroblasts, blasts in peripheral blood or more than 5% blasts in bone marrow smear and/or biopsy, or in the presence of monosomy or deletion of the long arm of chromosome 7 by cytogenetic analysis (FISH or karyotype) of the BM. All biopsies were submitted to morphological (see Table 1) and immunophenotypic (MPO, Glycophorin A, Factor VIII, CD34, CD117 and Ki-67) evaluation by two hematopathologists without previous knowledge nor about the evolution of the patients neither cytogenetic analysis results. Nominal qualitative variables were analyzed by using Fisher’s exact test to check significant disproportion between the groups. The ordinal qualitative variables were analyzed for differences between groups by Mann-Whitney test. The significance level was 5% (a = 0.05). The correlation between the overall cellularity values of the samples and their proliferative index was evaluated by nonparametric Spearman r test.Seventy three (59%) were male, median age 25,3 years (7 months to 76years), 42 belongs to the pediatric group and 81 to the adults group. Median follow-up was 5,1y (range, 1 month to 22,1 years). Twelve patients (9,7%) (6 in each group) progressed to MDS/AML.Evaluation of M/I parameters are presented in Table 1. Criteria described by Bennett and Orazi¹ suggestive of h-SMD evaluated in our study were marrow dysgranulopoiesis, marrow dysplasia of megakaryocytes and CD34-positive blast cells in the presence of at least one of the previous two. Criteria described by Baumann et al.² suggestive of childhood MDS evaluated in our study were marrow dysgranulopoiesis, clusters of at least 20 erythroid precursors (1), increased number of proerythroblasts (2), increased number of mitoses of the erythroid elements (3) (criteria counted if 1+2, 1+3 or 2+3 were observed) and marrow dysplasia of megakaryocytes.There was no statistically difference in M/I findings as well as the presence of Bennett and Orazi¹ criteria for MDS and Baumann et al.² criteria for childhood MDS among total population, adults and children who developed and did not develop MDS/AML. There was a statistically significant correlation between the overall cellularity values of the samples and their proliferative index.Adult and pediatric patients with AAA, including those that progress to MDS/AML, have similar M/I characteristics. Some changes described by Baumann for pediatric MDS are also found in pediatric and adults cases with AAA. In addition, the proliferative index may be increased in cases of AAA and this finding has no correlation with progression to MDS/AML. M/I changes in bone marrow biopsies in AAA have failed to identify a group at higher risk for progression to MDS/AML in our series. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Aplastic anemia.

Treatments of aplastic anemia are comprised of supportive therapy and aplastic anemia-specific therapy aimed at restoring hematopoiesis. Supportive therapies include transfusion, G-CSF, and the administration of iron chelation agents, as well as dealing specifically with individual symptoms. Aplastic anemia-specific treatments given with the aim of achieving hematopoietic recovery include immunosuppressive therapy, allogeneic hematopoietic stem cell transplantation, and anabolic hormone therapy. Although transplantation provides complete recovery of hematopoiesis (cure), there is a risk of death due to transplant-related complications. The most effective immunosuppressive therapy is a combination of anti-thymocyte globulin and cyclosporine. This treatment is also effective against the secondary, drug-induced and hepatitis-associated forms of aplastic anemia. In the management of aplastic anemia, a treatment is selected from among these options depending on the disease severity and the age of the individual case. The thrombopoietin receptor agonist eltrombopag appears to be effective and to provide tri-lineage recovery of hematopoiesis in some cases. Indications for its use are expected to expand in Japan.

Sweet spot for cyclophosphamide: a balancing act

Severe aplastic anaemia is a rare but life-threatening disorder for which allogeneic haemopoietic stem-cell transplant (HSCT) is a potential cure. In patients younger than 35 years and up to 50 years of age without substantial comorbidities with HLA-matched sibling donor, upfront HSCT is the recommended treatment. Healthy patients without a HLA-matched sibling donor are offered HSCT as a second-line treatment after failure of immunosuppressive therapy. 1 Marsh JC Ball SE Cavenagh J et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol. 2009; 147: 43-70 Crossref PubMed Scopus (419) Google Scholar Although 60–70% of patients respond to immunosuppressive therapy, blood counts return to normal only in a third of patients, and another third need long-term cyclosporin therapy and the risk of relapse of aplastic anaemia and clonal evolution to myelodysplastic syndromes occurs in a further third of patients. HSCT, however, offers an opportunity for longlasting haematological response and minimises the risk of relapse and reduces the likelihood of clonal evolution. Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1–2 dose de-escalation studyCyclophosphamide at 50 mg/kg and 100 mg/kg with TBI 2 Gy, fludarabine, and anti-thymocyte globulin results in effective conditioning and few early deaths after unrelated donor transplantation for severe aplastic anaemia. These doses of cyclophosphamide provide a framework for further regimen optimisation strategies. Full-Text PDF

The latest treatment advances of severe acquired aplastic anemia

Acquired aplastic anemia is a refractory blood disease for children, and severe acquired aplastic anemia can be a great threaten for life.China is a high incidengce area, children at a period during which this disease can mostly occur.In China, except some congenital aplastic anemia, most children who have this diease is acquired aplastic anemia.In 2009, the Britain society of hematology recommended Guidelines for the diagnosis and management of aplastic anaemia, which represented the latest diagnosis and treatment principle and mainstream view of the clinical methodology about aplastic anemia.They make it clear that the main treatment for the disease are allogeneic hemato-poietic stem cell transplantation(allo-HSCT) and immunosuppressive therapy(IST). This article collects the documents in recent 5 years, and provides a overview about the latest advance of the allo-HSCT and IST in the word. Key words: Acquired aplastic anemia; Allogeneic hematopoietic stem cell transplantation; Immunosuppressive therapy; Effectiveness

Treatment and hematopoietic SCT in aplastic anemia

This edition of the journal Bone Marrow Transplantation is the dedicated to the diagnosis and treatment of aplastic anemia, a disease that has had an important role in developing SCT and maybe even modern hematology. This was borne out of a project to design algorithms for the diagnosis and treatment of this disease, comprising different clinical issues such as different age groups and disease severity, as well as strategies arising from the unavailability of a specific type of donor. Aplastic anemia is an orphan disease with an incidence of 1–2 patients per million inhabitants per year, and given the different paths in the algorithms this breaks down into even smaller distinct sub-entities. Without wishing to stress the common place of personalized medicine, these distinct situations require individualized attention. Often, the approach to patient care has to differ, be it while caring for the child or the older person being diagnosed with aplastic anemia, according to severity of the disease and response to initial treatment as well as depending on the availability or not of a matched donor. Given the difficulty to study rare diseases, we also designed these algorithms with the intention to standardize treatment and to record treatment outcome. Diagnostic procedures need to be standardized; congenital disease has to be ruled out in the young, hypoplastic myelodysplastic syndrome in the older patient and procedures are discussed in the chapter on the diagnosis of acquired aplastic anemia. Outcome of patients with aplastic anemia has greatly improved over the past decades and to a large part this is due to progress in supportive care, given that our currently used immunosuppressive and transplant regimens were developed in the 1970s. This progress includes treatment of infectious complications and transfusional support, among others. In younger patients, the primary decision in treatment is to choose between transplantation versus immunosuppression. We have learned recently through a randomized trial conducted at the National Institutes of Health that not all antithymocyte globulin regimens are equal.1 Standards for immunosuppression are to be found in the chapter on front line immunosuppressive treatment as well as current standards on upfront BMT with a sibling donor. Older patients with a donor are recommended to be treated with immunosuppression, but patients failing this treatment are candidates for BMT using a reduced intensity regimen containing fludarabine. Patients without a sibling donor failing immunosuppressive treatment may have an unrelated donor search initiated and may undergo marrow transplantation from an unrelated donor. Transplant rates in Europe for aplastic anemia continue to increase2 and this is mostly due to the increased use of unrelated donors following publications showing that outcomes with unrelated donors were similar to outcomes with sibling donors. The average age of patients with aplastic anemia is ~16 years, that is, half the patients are children, but the disease can occur in all age groups. There is a specific chapter on the management of aplastic anemia in children and also on the management of aplastic anemia in the older adults. The issue is rounded up by particular chapters on second- and third-line treatment options, including cord blood transplantation, transplantation from mismatched family donors (that is, haploidentical donors) and experimental immunosuppressive regimens including Campath. These specific protocols are detailed here to incite treating physicians to manage these patients according to common treatment protocols and to report outcomes in order for us to progress toward improved outcomes for these patients. All these chapters have been written by members of the aplastic anemia working party of the European Group for Blood and Marrow Transplantation and the algorithms are the fruits of many discussions held during our biannual group meetings. We hope to provide a platform for the reader that may help him in all clinical situations that can be encountered with these patients. For this reason, the working title of this project had been ‘the complete treatment algorithm’.

Aplastic Anemia: Effectiveness and Safety of Treatment Profiles Depending On Age

AbstractAbstract 4407 Introduction:The treatment of acquired aplastic anemia (AA) is based on allogeneic hematopoietic cell transplantation (HCT) and immunosuppressive therapy (IST). The choice between immunosuppression or HCT is based on the availability of a sibling donor and on the patient's age. According to the PETHEMA group's guidelines for the diagnosis and management of aplastic anaemia, patients over 40 years old are not considered for HCT as first-line therapy, while there is no age limit for immunosuppressive treatment. The decision of whether to treat older patients is based on their performance status. Aims:To compare the safety and effectiveness of treatment profiles, mortality rates and causes of death in adults with AA depending on age (over or under 60 years old). Methods:We reviewed clinical histories of patients who have been treated for AA at our hospital over the last ten years (2002–2012). Patients were divided in to 2 groups: over 60 year olds and under 60 year olds. We collected data on age, sex, disease severity, treatment protocols and toxicities, type and duration of response to therapy, mortality and cause of death. Data source: clinical histories. Statistical desciption, non inferential because of the low level of patients. Results:We identified 15 patients in total, 7 over 60 and 8 under 60 years old. One of the over 60 year olds was excluded from the study due to incomplete follow-up. Of the 6 remaining over 60 year old patients all were female and they had a median age of 73 years (r, 63–87 years), while in the under 60 group, 50% of the patients were male with a median age of 30.5 years (r, 19–49 years).50% of the over 60 year olds had a Charlson Index score of 2 or more. The Charlson index in the under 60 year olds was 0, with the exception of 1 subject (11.1%) with a score of 2 (due to chronic lung and liver disease).We observed a higher rate of moderate AA in the under 60 year olds (62.5% vs 50%) and 1 case of severe AA and 2 cases of very severe AA in each group respectively.100% of over 60 year olds received treatment with ciclosporin (CsA) in combination with other immunosuppresant drugs (in 3 cases associated with antithymocyte-globulin (ATG) and corticosteroids). After a median follow-up of 300 days (r, 90–1044 days), only 1 patient of the 6 responded to therapy, obtaining a partial response (PR) which lasted 953 days.In the under 60 group 2 of the patients (25%) recieved an allogeneic HCT obtaining a complete response (CR) in both cases, which they maintain after a median follow-up of 1870 days (r, 1781–1960 days). The remaining 75% received treatment with IST. In this group we observed 2 CR, 3 PR and one non-responder. All responses are maintained after a median follow-up of 1038 days.Toxicities observed in the over 60s consisted of 3 cases of diabetes mellitus, 1 case of renal failure and 3 severe infections in three different patients, while 62.5% of the under 60s suffered from infectious complications.In the over 60 year old group we observed 3 cases of exitus (50%). At 15 months global survival was of 40% for non-responders, clearly inferior to the survival of the only responder. However in the under 60 year old group there was only 1 case of exitus corresponding to the non-responder and a global survival of 87.5% after a median follow-up of 1602 days (r, 643–3094). Conclusion:Treatment of AA in patients under 60 years old is effective and safe. The incidence of serious adverse events and mortality rates are low. Survival is superior in patients treated with HCT than in those treated with IST. Outcomes of IST are related to patient age. Response rates in over 60 year olds are low, although the higher survival rates in responders clearly support the indication of IST. Disclosures:No relevant conflicts of interest to declare.

Etiology and Survival of Aplastic Anemia: A Study Based on Clinical Investigation

Management of aplastic anemia is etiology driven, whether constitutional or acquired. Age, gender, and severity of disease also play crucial role in the survival of aplastic anemia. Since, inadequate data are available from India, the present study was conducted with the aim to evaluate the etiology and survival of aplastic anemia. Three hundred patients were enrolled between May 2007 and April 2010. Severity analysis and chromosomal breakage study was performed and patients were followed up to calculate the survival rate. Only 9.4% of the cases demonstrated the evidence of constitutional disease. Patients with acquired disease showed a significantly higher odd ratio for hepatitis. Overall survival was found to be independent of the gender and inherited etiology. Phenotype resembling to constitutional disease was present in only 22.22% (6/27) of patients. Similar ratio of the constitutional and acquired disease in both the age groups was observed. Irrespective of the age and phenotype, chromosomal breakage study should be mandatory for all patients with aplastic anemia. Hepatitis as a preceding event may be associated with the cause of aplastic anemia. Young age and less severe disease were strongly associated with better survival. Lack of tertiary care facility in the country, time lag between diagnosis and treatment, and unaffordability to abide the treatment cost could be the major contributory factors for poorer survival.

Diagnosis and Management of Aplastic Anemia

Aplastic anemia remains a diagnosis of exclusion. Our ability to reliably diagnose, and therefore exclude, a variety of inherited or acquired diseases with similar phenotypes has improved markedly. An efficient diagnostic plan is important because time from diagnosis to treatment is related to outcome regardless of the therapeutic option chosen. HSCT remains the mainstay of therapy for those with matched sibling donors, and results have improved even further in recent years. For those without a sibling donor, the high response and overall survival rates of combined immunosuppressive therapy (IST) have proven robust. Nonetheless, incomplete response, relapse, and progression to myelodysplasia/leukemia have more clearly emerged as significant long-term issues. Improvements in outcome of alternative donor transplantation and the use of established and novel immunosuppressive agents provide multiple alternatives for treating refractory or relapsed patients. Best practices in this regard are not yet clearly established and may vary by a variety of demographic and treatment-specific factors. Regardless of the type of therapeutic approach, patients require ongoing monitoring for occurrence of disease and/or therapy-related side effects.

Management of aplastic anemia in a woman during pregnancy: a case report

IntroductionAplastic anemia is a rare disease caused by destruction of pluripotent stem cells in bone marrow. During pregnancy it could be life-threatening for both mother and child. The only causal therapy for aplastic anemia is bone marrow transplantation, which is contraindicated during pregnancy because of potential embryo toxicity. Treatment options are erythrocytes and platelet transfusions and immunosuppressive therapy. There is, however, no agreement about the optimal supportive care and treatment regime for this disorder during pregnancy.Case PresentationA 26-year-old nulliparous Asian woman with an uneventful medical history was admitted to the hospital at 14 weeks' gestation because of excessive vomiting. Routine laboratory tests showed pancytopenia (Hb 3.5 mmol/L, leukocytes 3.5 *109/L, platelets 45 *109L). A bone marrow biopsy confirmed aplastic anemia. Methylprednisolon, cyclosporine A, packed cells and platelet transfusions were initiated. At 33 weeks she developed neutropenia (0.1 *109/L) for which oral colistin and tobramycin were given prophylactically. At 35 weeks labor was induced, during which she developed a fever of 38.2°C. She gave birth spontaneously to a healthy son weighing 2415 grams, who had no signs of pancytopenia. After delivery the blood count of the patient did not recover and did not respond to medication. Eighteen weeks after delivery she died of sepsis complicated by cerebral bleeding and infarction due to severe thrombocytopenia and neutropenia, despite optimal supportive treatment.ConclusionThis potential life-threatening disease has a relatively good prognosis for both mother and child after optimal treatment. Transfusion during pregnancy is the first choice treatment with recommended hemoglobin levels of >5.5 mmol/L and platelet counts of >20 *109/L. Cyclosporine A seems a reasonable alternative therapy with a reported success rate in non-pregnant patients of 70% when combined with antithymocyte globuline. Our patient died 18 weeks postpartum from cerebral bleeding and infarction due to severe thrombocytopenia despite intensive supportive treatment, methylprednisolon and cyclosporine A.

Guidelines for the diagnosis and management of aplastic anaemia

King’s College Hospital, St Mary’s Hospital, Barts and The London Hospital, London, Birmingham Children’s Hospital, Birmingham, Barts and The London School of Medicine and Dentistry, St George’s Hospital, London, Queen Elizabeth Hospital, King’s Lynn, Norfolk, Ashford Hospital, Middlesex, London, Patient representative, St Helier Hospital, Carshalton, Surrey, Royal Bournemouth Hospital, Dorset, Chesterfield Royal Hospital, Derbyshire, and Manchester Royal Infirmary, Manchester, UK.

Identification of a Subset of Aplastic Anemia Patients Highly Responsive to Danazol.

Treatment of patients refractory to immunosuppressive therapy is a major problem in the management of aplastic anemia (AA). Some patients who are ineligible for allogeneic stem cell transplantation have been successfully treated with anabolic steroids although little is known about the common characteristics of these patients. In order to characterize high responders to danazol, we retrospectively studied 44 AA (13 male and 31 female) patients who were treated with 300 mg of danazol daily for at least 3 months. All patients had been previously treated with ATG+CsA or CsA alone without appreciable effects before danazol therapy. Peripheral blood of these patients was examined for the presence of PNH-type cells and clonality in granulocytes using sensitive flow cytometry (Blood 100: 3897, 2002) and the improved HUMARA assay (Blood 102: 1211, 2003). 24 of 44 (55%) patients attained PR or CR according to the response criteria proposed by Camitta. All 3 lineage cells increased in the responders. The rate of response in female patients (21/31, 68%) was significantly higher than that (3/13, 23%) in male patients (P=0.0058). There was no difference in the response rate between older (>50 years) patients (75%) and younger (<50 years) patients (60%) in female patients, indicating that the effect of danazol is not affected by a female sex hormone. Increased PNH-type cells were detectable in 2 (8.3%) of 24 responders and in 6 (40%) of 15 non-responders. The HUMARA assay revealed presence of clonal granulocyte population in 13 (76%) of 17 responders and 2 (33%) of 6 non-responders, respectively. For a female patient without increased PNH type cells who has not responded to immunosuppressive therapy, the rate of response to danazol was 64%. Probability of 3-year survival in responders to danazol was 100% while that in non-responders to the therapy was 90%. Univariate analysis revealed that negativity for increased PNH-type cell and being female were significantly associated with good response to danazol. These findings indicate that danazol is a useful drug in the treatment of a subset of female AA patients characterized by refractoriness to conventional immunosuppressive therapy and absence of increased PNH-type cells. Given the high frequency of clonal hematopoiesis in responders to danazol, this anabolic steroid may stimulate expansion of a small number of stem cells that survived non-immune marrow insult.

Relapse and clonal disease in children with aplastic anemia (AA) after immunosuppressive therapy (IST): the SAA 94 experience. German/Austrian Pediatric Aplastic Anemia Working Group.

Since the introduction of combined immunosuppressive therapy (IST) into management of aplastic anemia (AA) in childhood response and probability of survival improved. In contrast to bone marrow transplantation (BMT), however, patients after IST are not considered cured as high rates of relapse and development of clonal disease demonstrate. From 11/93 to 9/97 114 children (65 m, 49 f; median age 9.5 y.) from 37 centers in Germany and Austria were registered in the SAA 94 study. 86 patients lacking a matched sibling donor received IST. Most of the patients suffered from very severe (VSAA: PMN < 200/microliter) or severe AA (SAA: PMN < 500/microliter). All patients were treated with combined IST consisting of ALG and Cyclosporin A (CSA). VSAA and SAA patients were additionally treated with G-CSF. Therapy response was evaluated at day 112, after 6, 12 and 18 months. 8/86 patients died, the probability of survival being 87% after 4 years. At d 112 61% of evaluable patients became independent of transfusions (IST response: CR + PR), 13% with normal blood counts (CR). After 6 months 33% showed CR. At 12 and 18 months response improved to 74% resp. 80%, 39% resp. 55% CR. The best response was achieved in the subgroup of VSAA with 90% (PR + CR) and 65% CR after 18 months. 4 patients developed AML 3-19 months after the beginning of IST. In 2/4 pts. an aberrant clone (-7; 5q-) could be detected retrospectively in BM at diagnosis of AA. 3 nonresponders developed chromosomal aberrations (+19; -7, +12; +8) after 4, 12 and 16 months without morphological signs of AML or MDS. Overall 11 relapses occurred at a median time of 12 months (range 5-27 months) after the beginning of IST. 2 of them relapsed under CSA therapy, 2 under tapering of CSA and 7 after cessation of CSA. 7 patients responded again to CSA monotherapy. Overall response rate is 77% with a probability of event free survival (EFS) of 54% after 4 years regarding all complications mentioned as events.