Original Article
Treatment of Aplastic Anemia with Antilymphocyte Globulin and Methylprednisolone with or without Cyclosporine
N Engl J Med 1991; 324:1297-1304May 9, 1991
- Abstract
- Abstract
Background and Methods.
Immunosuppression is the most effective treatment for patients with aplastic anemia, except for bone marrow transplantation. The best results are achieved with antilymphocyte globulin or cyclosporine. Patients have been treated successfully with a combination of both agents, but there has been no controlled evaluation of its efficacy. We conducted a randomized, multicenter trial in 84 patients not eligible for bone marrow transplantation, comparing treatment with antilymphocyte globulin and methylprednisolone (41 patients — control group) with antilymphocyte globulin, methylprednisolone, and cyclosporine (43 patients — the cyclosporine group).
Results.
At three months significantly more patients in the cyclosporine group had a complete or partial remission in response to treatment than did patients in the control group (65 percent vs. 39 percent, P<0.03); this difference was confirmed at six months (70 percent vs. 46 percent, P<0.05). The superior results of the regimen including cyclosporine were most evident in the patients with severe or very severe aplastic anemia, whose response rate at six months was 65 percent, as compared with 31 percent of such patients in the control group (P<0.02). Granulocyte and hemoglobin levels became normal in most patients who responded, but platelet counts continued to be subnormal in 61 percent of the patients. Ten of 52 patients with responses (3 in the cyclosporine group and 7 in the control group) relapsed 4 to 37 months after treatment. The actuarial survival of all patients at 41 months is 64 percent in the cyclosporine group and 58 percent in the control group (P = 0.16); among the patients with severe or very severe disease, survival is 80 percent and 44 percent, respectively (P = 0.077). Cyclosporine had substantial but reversible side effects.
Conclusions.
Immunosuppressive treatment of aplastic anemia with antilymphocyte globulin, methylprednisolone, and cyclosporine appears to be more effective than a regimen of antilymphocyte globulin and methylprednisolone without cyclosporine and may thus represent a treatment of choice for patients who are not eligible for bone marrow transplantation. (N Engl J Med 1991; 324:1297–304.)
Media in This Article
Figure 1
Kinetics of Response.Figure 2
Survival in All Patients and Patients with Severe Disease, Including Patients Who Received More Than One Course of Immunosuppression.Article Activity
- Article
THE prognosis in patients with aplastic anemia has improved substantially with the introduction of treatment with bone marrow transplantation and antilymphocyte serum. The long-term survival of patients with severe disease has increased from less than 25 percent in patients treated with androgens1 to 40 to 75 percent in those treated with antilymphocyte serum2 3 4 5 6 7 8 and to 60 to 80 percent in those treated with bone marrow transplantation.9 10 11 12
There has been much interest in the use of antilymphocyte serum, since allogeneic bone marrow transplantation is currently considered the treatment of choice only for young patients with severe aplastic anemia and a histocompatible sibling donor.13 The results of transplantation in patients more than 45 years old are poor,14 and protocols using matched unrelated donors still carry a considerable risk of treatment failure.15
Treatment with antilymphocyte or antithymocyte globulin (we use the term ``antilymphocyte globulin'' for all antilymphocyte serums) is based on the observation of Mathé et al. that some patients recovered autologous bone marrow function after undergoing conditioning with antilymphocyte globulin and allogeneic bone marrow transplantation.16 The effectiveness of antilymphocyte globulin has been confirmed in two randomized trials, which reported significantly improved rates of recovery and survival in patients as compared with controls.2 , 3
The mechanism of action of antilymphocyte globulin in aplastic anemia is unknown. In vitro, this agent promotes the growth and differentiation of hematopoietic cells17 and induces the release of growth factor from lymphocytes.18 19 20 21 22 It may interfere with T-cell—mediated bone marrow suppression.21 However, the in vitro characteristics and in vivo immunosuppressive capabilities of different antilymphocyte globulins do not correlate with their efficacy in the treatment of aplastic anemia.18 19 20
In 1984, cyclosporine was proposed as an alternative form of immunosuppressive treatment for this disease.22 After an encouraging pilot study,23 several centers in Germany cooperated in a prospective trial evaluating the use of cyclosporine in addition to antilymphocyte globulin and methylprednisolone for the treatment of aplastic anemia in patients not eligible for bone marrow transplantation. We report the results of that study.
Methods
Patients
Patients requiring treatment for aplastic anemia were eligible for this study unless they met all three of the following criteria for bone marrow transplantation: severe aplastic anemia, age of less than 20 years, and the availability of an HLA-identical sibling donor. Bone marrow transplantation was also offered to patients 20 to 45 years old for whom there was a bone marrow donor, if they had had one unsuccessful course of immunosuppressive therapy.
The diagnosis of acquired aplastic anemia was established according to published criteria.24 A negative standard sucrose and acidified serum lysis test was required to exclude paroxysmal nocturnal hemoglobinuria; in addition, the cells of 47 patients were analyzed with a sensitive serum lysis test that used anti–S protein antiserum,25 and were confirmed as having normal complement sensitivity. Chromosome-breakage studies to rule out Fanconi's anemia were performed in all children and in adults with clinical characteristics compatible with this diagnosis. All patients were evaluated for evidence of infection with hepatitis A and B viruses, cytomegalovirus, or Epstein–Barr virus.
Aplastic anemia was considered severe if it met the modified criteria of Camitta et al.1: hypocellular bone marrow, a granulocyte count below 0.5×109 per liter, a platelet count below 20×109 per liter, and a reticulocyte count below 20×109 per liter.2 It was considered very severe if it met the criteria for severe disease and the granulocyte count was below 0.2×109 per liter.13 Patients who did not meet the criteria for severe or very severe disease (those with so-called nonsevere disease) were eligible for treatment if their granulocyte count was below 0.5×109 per liter or their platelet count was below 20×109 per liter or if they were dependent on red-cell transfusions. There were no age restrictions. Patients were excluded from the study if they had a systemic infection that could not be controlled by antibiotics (four patients), if they had been treated with immunosuppressive agents (antilymphocyte globulin, cyclosporine, or corticosteroids in a dose of ≥5 mg per kilogram of body weight) within the previous three months (two patients), if they had liver or kidney disease of more than grade 1 or heart disease of more than grade 2 (six patients),26 or if they had bleeding that could not be controlled by platelet transfusions (one patient). No patient was excluded because of a systemic reaction to intradermal skin testing with antilymphocyte globulin.
Treatment Protocol
The treatment protocol was approved by the institutional review board of the University of Ulm. Written informed consent was obtained from all patients. Randomization was stratified on the basis of the severity of disease (severe and very severe vs. less severe) and its duration from diagnosis to treatment (≤4 vs. >4 months).2 Treatment assignment was randomized at the University of Ulm by means of random lists for the four strata. Patients were assigned to treatment with either horse antilymphocyte globulin (Lymphoglobulin, Institute Mérieux, Leimen, Germany) and methylprednisolone (Urbason, Hoechst, Frankfurt, Germany) —the control group — or cyclosporine (Sandimmune, Sandoz, Nuremberg, Germany) in addition to antilymphocyte globulin and methylprednisolone — the cyclosporine group.
Two lots of antilymphocyte globulin were used throughout the study (1056–A0366 in 38 patients and B0909 in 46 patients). Antilymphocyte globulin was infused over a period of 8 to 12 hours through a central venous line in a dose of 0.75 ml per kilogram per day for eight consecutive days (days 1 to 8). Methylprednisolone was given in a single oral or intravenous dose of 5 mg per kilogram per day on days 1 to 8 and in a dose of 1 mg per kilogram per day on days 9 to 14; the dose was then tapered until day 29. Cyclosporine was given orally twice a day, for a total dose of 12 mg per kilogram per day in adults and 500 mg per square meter of body-surface area in children. Doses were adjusted to achieve whole-blood trough cyclosporine levels of 500 to 800 ng per milliliter on radioimmunoassay27 during days 1 to 28 and levels of 200 to 500 μg per liter during follow-up, unless toxicity developed. If severe toxicity occurred, cyclosporine treatment was discontinued for one to four days and then continued at a lower dose level. Patients assigned to cyclosporine treatment received this drug for at least three months. If they did not respond within three months, treatment with cyclosporine was discontinued; if they had any response by three months, cyclosporine was continued until peripheral-blood cell counts became stable for one month (plateau) and then the dose was tapered over a one-month period.
Patients in the control group who had no response by the end of three months (and who were not eligible for bone marrow transplantation) or who had a relapse were offered the treatment given the cyclosporine group. Patients in the cyclosporine group who relapsed during cyclosporine treatment were treated with a higher dose of cyclosporine; a relapse after the discontinuation of cyclosporine was treated either with cyclosporine alone or with a second course of antilymphocyte globulin, methylprednisolone, and cyclosporine.
Supportive care was recommended in detail in the protocol in an effort to ensure comparable care in both groups. Patients were hospitalized without barrier nursing care during antilymphocyte globulin treatment and for about one week thereafter for care during the period of serum sickness. All patients received oral ofloxacin (200 mg twice a day) and amphotericin B (500 mg four times a day) for selective gut decontamination. Broad-spectrum antibiotics, including synthetic penicillins and aminoglycosides, were given if unexplained fever or documented infection occurred. Packed red cells were transfused if symptoms of anemia developed. Platelet counts were raised to 50×109 per liter during days 1 to 8 to counter the antiplatelet effect of antilymphocyte globulin and were maintained above 20×109 per liter thereafter. Platelets from random donors were used unless inadequate increments required the transfusion of platelets from HLA-matched single donors.
Evaluation of Response
Patients whose blood counts increased within three months after the start of treatment were considered to have responded. The quality of response was analyzed at three months and monthly thereafter, according to the following modified criteria of Champlin et al.2: (1) a complete remission was indicated by a hemoglobin level of ≥7.4 mmol per liter, a granulocyte count of ≥1.5×l09 per liter, and a platelet count of ≥100×109 per liter; (2) a partial remission was indicated by the absence of infections and of the need for transfusions and by sustained increases over base-line values of all cell lines (an increase in the reticulocyte count of at least 30×109 per liter, an increase in the granulocyte count of at least 0.5×109 per liter, and an increase in the platelet count of at least 30×109 per liter); and (3) the absence of remission was indicated by the absence of change or of death. Relapse was indicated by a decrease in any of the peripheral-blood cell counts to less than 50 percent of the median sustained count during remission or by a return of the counts to levels meeting the definition of severe aplastic anemia.
Evaluation of Toxicity
The toxicity of the regimens was evaluated for the first three weeks of study (short-term toxicity) and for the period from three weeks to three months (long-term toxicity) and graded according to the criteria of the World Health Organization.26
Statistical Analysis
All participating centers were required to complete standardized case-report forms. Data accumulated up to March 1990 were entered into a data base at the University of Ulm. Pretreatment and post-treatment data on the two treatment groups and the kinetics of response were compared by the Wilcoxon rank-sum test. Response rates were evaluated with Fisher's exact test. Survival was analyzed by the product—limit method,28 and treatment groups were compared by a log-rank test performed with the SAS package (SAS Institute, Cary, N.C.). All comparisons were made with two-tailed tests.
Results
Patients' Characteristics
From May 1986 to June 1989, 91 patients with aplastic anemia were entered in the study by 24 university medical centers and community hospitals in Germany. Seven patients were excluded from analysis because of leukemia diagnosed at the initial biopsy (one patient), treatment with cyclosporine despite assignment to the control group (one), treatment with a different brand of antilymphocyte globulin (two), and loss to follow-up (three).
The clinical characteristics of the two treatment groups were comparable (Table 1Table 1
Pretreatment Characteristics of the Study Groups.). The majority of the patients (71 percent) had severe or very severe aplastic anemia. Ten patients had a history of exposure to potentially myelosuppressive drugs or chemicals, such as nonsteroidal antiinflammatory drugs (seven patients), pesticides (two), and organic solvents (one). Three patients in the control group and four in the cyclosporine group had local infections. Thirteen patients in the control group and 14 in the cyclosporine group had been unsuccessfully treated with androgens or low doses of corticosteroids (or both) before entry; 1 patient in each treatment group had been treated for a relapse after treatment with antilymphocyte globulin (ATGAM, Upjohn, Kalamazoo, Mich.) more than six months before entry. There was no significant difference between the groups in the total doses of antilymphocyte globulin and methylprednisolone administered.Response to Treatment
The surviving patients in the control group have been followed for a median of 507 days (range, 184 to 1141) and those in the cyclosporine group for 516 days (range, 183 to 1295). By the end of three months, significantly more patients had responded to treatment with antilymphocyte globulin, methylprednisolone, and cyclosporine than to treatment with antilymphocyte globulin and methylprednisolone (65 percent vs. 39 percent, P<0.03) (Table 2Table 2
Response to Treatment with Antilymphocyte Globulin, Methylprednisolone, and Cyclosporine in Patients Who Could Be Evaluated 3, 6, and 12 Months after Initial Treatment.*). Subgroup analysis revealed that the difference in response rate was primarily due to the response in patients with severe disease (58 percent vs. 31 percent, P = 0.064); 4 of 8 patients with very severe disease in the cyclosporine group responded, as compared with 2 of 12 in the control group. Among the patients with ``nonsevere'' disease, the response rates of the treatment groups were not significantly different (83 percent vs. 67 percent). Both patients who had responded to antilymphocyte globulin before the study had a partial or complete remission again. The results in the patients less than 10 years of age constitute anecdotal evidence of treatment effect, because of the small numbers of patients: three children (2, 3, and 4 years old) treated without cyclosporine had no response, and one child (7 years old) given cyclosporine had a partial remission.The superior results of cyclosporine treatment were confirmed at six months (Table 2): in the cyclosporine group the results were again significantly better in all the patients (70 percent vs. 46 percent, P<0.05) and in those with severe disease, of whom 65 percent had at least a partial remission, as compared with 31 percent of patients with severe disease in the control group (P<0.02). At 12 months, the rate of remission in the cyclosporine group was still higher than in the control group, both for all patients (72 percent vs. 50 percent, P = 0.08) and for those with severe disease (67 percent vs. 38 percent, P = 0.059), but it was no longer significantly different. However, the results observed in the control group at 12 months were biased by the secondary treatment of patients who did not respond: four of six such patients had a partial remission after their treatment was changed to the regimen including cyclosporine.
The kinetics and quality of response were similar in both treatment groups: first responses were observed four weeks after the start of treatment, and the median time to remission during the first six months was 82 days in the control group and 60 days in the cyclosporine group (P = 0.6) (Fig. 1Figure 1
Kinetics of Response.). The proportion of patients with complete remissions at 12 months was higher in the cyclosporine group (Table 2), but the difference did not reach statistical significance (P = 0.17). Granulocyte counts rose above 1.5×109 per liter in 94 percent of all responders from both groups combined, and hemoglobin concentrations became normal in 65 percent (>7.4 mmol per liter in women and >8.7 mmol per liter in men), whereas platelet counts rose above 150×109 per liter in only 39 percent.Seventeen nonresponding patients who were alive three months after treatment and who were not treated according to the cyclosporine regimen (see above) had variable courses. Twelve of these 17 patients did not undergo a second course of treatment: they had a partial remission (3 in the control group and 1 in the cyclosporine group), survived with active disease (4 controls), or died (4 controls). Of the other 5 patients, 2 (control group) received cyclosporine alone because of sensitization to antilymphocyte globulin but did not respond, and 3 (cyclosporine group) were treated unsuccessfully with a different brand of antilymphocyte globulin (ATGAM [Upjohn] or Lymphoser Berna [Schweizer Serum und Impfinstitut, Bern, Switzerland]) and methenolone acetate (metenolone). None of the nonresponding patients underwent transplantation since none had an HLA-matched sibling donor; a search for matched unrelated donors for four patients was unsuccessful.
Relapse
Of the 52 patients with responses, 10 (19 percent) relapsed 4 to 37 months after treatment (Table 3Table 3
Response to Further Treatment.*). Except for one patient, whose treatment with cyclosporine had to be discontinued after five weeks because of liver toxicity (Patient 345), the relapses in the cyclosporine group occurred late and only after discontinuation of cyclosporine (Patients 149 and 197). Dependence of remission on cyclosporine was observed in three patients, whose blood counts decreased after reduction of the dose of cyclosporine and increased again after administration of a higher dose of the drug. Nine responding patients were still being treated with cyclosporine at the time of this analysis. The other patients in the cyclosporine group are in remission 2 weeks to 29 months (median, 7 months) after discontinuation of cyclosporine; they were treated with the agent for 5 to 18 months (median, 11).Seven patients who relapsed responded to a second course of immunosuppressive therapy (Table 3). Two patients in the control group were not treated again with antilymphocyte globulin because of sensitization to horse IgG. They did not respond to rabbit antilymphocyte globulin or to treatment with cyclosporine alone.
Survival
Survival analysis at two years revealed no significant difference in survival according to treatment assignment for the whole patient group or for those with severe disease (P = 0.14 and 0.16, respectively) (Fig. 2Figure 2
Survival in All Patients and Patients with Severe Disease, Including Patients Who Received More Than One Course of Immunosuppression.). Although analysis of survival to date (at 3 1/2 years) is limited by the small number of patients, it is interesting that among the patients with severe disease, the survival of those initially treated with antilymphocyte globulin, methylprednisolone, and cyclosporine may be better than the survival of those treated with antilymphocyte globulin and methylprednisolone only (80 percent vs. 44 percent, P = 0.077) (Fig. 2B).Four patients in the control group and three in the cyclosporine group died within three weeks after the start of treatment. Sixteen other patients died 37 to 1019 days after treatment, of complications of pancytopenia such as pneumonia (five patients), septic shock (four), and cerebral (six) or gastrointestinal hemorrhage (one). No death was considered to be attributable to the treatment itself.
Secondary Disease
Oligoblastic leukemia developed in one patient 15 months after initial presentation with aplastic bone marrow. Gastric cancer led to death in another patient nine months after treatment. Neither patient responded to treatment. We did not observe the clinical symptoms of paroxysmal nocturnal hemoglobinuria or a positive result on Ham's test in any patient during the time covered by this analysis.
Toxicity
Short-term toxicity was caused primarily by antilymphocyte globulin and methylprednisolone (Table 4Table 4
Toxicity of Immunosuppressive Treatment during the First Three Months of Observation.*). Fever and serum sickness occurred significantly less frequently in the cyclosporine group, whereas rash and urticaria occurred with a similar frequency in both groups. The most severe adverse effect was liver toxicity occurring early in treatment, which was significantly more frequent and more severe in the cyclosporine group: in the control group the maximal grade of hepatotoxicity was 2, whereas in the cyclosporine group the maximum was 3 in eight patients and 4 in four patients. There was no significant correlation between the grade of liver toxicity and the cyclosporine blood concentration. In two of the patients with grade 4 toxicity, cyclosporine treatment had to be discontinued when hepatic aminotransferase concentrations did not return to normal after the dose was reduced. The typical long-term toxicity of cyclosporine was observed three weeks to three months after treatment (Table 4). All long-term toxicity was grade 1 or 2; renal toxicity never exceeded grade 1. Mammary hyperplasia developed in one patient and did not resolve completely after discontinuation of cyclosporine. All other adverse effects were mitigated or eliminated by reducing the dose of cyclosporine. Aseptic necrosis of both humeral heads developed in one patient after repeated treatment with methylprednisolone for a total of about seven months. Of 13 patients given repeated treatment with antilymphocyte globulin or a different brand of this agent, 11 tolerated it well.Discussion
We conclude from this trial that patients with aplastic anemia responded better to a combination of cyclosporine, antilymphocyte globulin, and methylprednisolone than to a standard protocol of antilymphocyte globulin and methylprednisolone, and that the difference was most evident in patients with severe disease, whose response rate nearly doubled after the addition of cyclosporine.
The response rate was chosen as the chief variable to be evaluated since survival is strongly correlated with response.2 , 3 , 7 , 8 , 29 Although the survival of patients with severe disease was better in the cyclosporine group than in the control group, the difference was not statistically significant. The inability to translate the increased response rate into prolonged survival may seem surprising. However, our survival analysis did not reflect survival entirely as a result of the initial treatment, since this assessment included patients who did not respond and patients with relapses who responded to a second course of immunosuppression. The second course of treatment frequently included cyclosporine, but the response could have been due to repeated treatment with antilymphocyte globulin, since patients with aplastic anemia have been reported to respond to two sequential courses of the latter drug.4 , 7 Furthermore, retrospective analyses have shown that a plateau of survival may not be reached in patients with severe disease for many years after treatment7 , 29 and that there may never be a true plateau in view of the late development of clonal diseases.30 31 32 A longer observation period is thus required to assess survival.
Several details of the analysis deserve comment. First, although the response rate was higher in the patients treated with cyclosporine, the kinetics of response and the quality of remission were not significantly different from the pattern observed in patients responding to antilymphocyte globulin and methylprednisolone. Cyclosporine thus increased the proportion of patients with responses without significantly altering the level of improvement within 12 months. This study confirmed that many patients had incomplete responses29 , 33; thrombocytopenia was the most frequent persisting abnormality.
Relapse occurred in 19 percent of those responding — a rate similar to rates in previous studies after a comparable period of follow-up4 , 6 — and less frequently in patients given cyclosporine. Treatment with cyclosporine, however, may delay rather than prevent relapses, since relapse occurred in two patients after the drug was discontinued. The true relapse rate can be determined only after treatment has been discontinued in all patients.
Finally, although toxicity was worse in the patients treated with cyclosporine, almost all side effects were reversible, and some of the toxicity due to antilymphocyte globulin, such as fever and serum sickness, was in fact ameliorated by cyclosporine. It should be possible to reduce the dose of methylprednisolone used in the cyclosporine regimen, since it was given primarily to reduce the side effects of antilymphocyte globulin and not for its immunosuppressive properties.34 It would also be desirable to reduce the time of treatment with cyclosporine. This would not only reduce the cost of treatment but also mitigate potential long-term complications such as an increased incidence of neoplasms.35
The results of treatment with the combination of antilymphocyte globulin, methylprednisolone, and cyclosporine compare favorably with those reported by other groups of investigators using antilymphocyte globulin2 3 4 5 6 7 8 , 13 or cyclosporine alone.22 , 23 , 36 37 38 39 40 A recent study compared antilymphocyte globulin with cyclosporine in 82 patients with severe aplastic anemia and found comparable response rates and survival in the treatment groups.41 Preliminary experience with a combination regimen of antithymocyte globulin and cyclosporine very similar to that used in our study has confirmed the high response rate, particularly in patients with severe disease (Young NS: personal communication).
The results of our study must be viewed in the context of current alternative treatments of patients with aplastic anemia. We agree with recommendations derived from retrospective analyses13 that bone marrow transplantation from an HLA-identical sibling donor is the treatment of choice for patients less than 20 years of age who have very severe disease, since the morbidity of bone marrow transplantation has been substantially reduced, long-term survival is better when these patients are treated with transplantation rather than immunosuppression, and surviving patients can be considered cured of their disease. In patients in the intermediate age group (20 to 45 years old) who have severe or very severe disease, there is a need to identify factors that predict survival after immunosuppressive therapy.13 In our study, a pretreatment granulocyte count below 0.2×109 per liter was associated with a low response rate and short survival in all patients (data not shown). We advise that transplantation of bone marrow from a family donor be performed in these high-risk patients even if they are more than 20 years old; the use of unrelated-donor transplants in this group is currently under discussion.42 We treat all other patients 20 years old or older with antilymphocyte globulin, cyclosporine, and methylprednisolone.
We are indebted to the physicians of the cooperating centers for closely following the protocol and documenting the courses of their patients; to the staff of the hospitals who cared for the patients; to Prof. Dr. C. Mueller-Eckhardt (Giessen, Germany) for detailed testing for paroxysmal nocturnal hemoglobinuria; to Mrs. Schweickardt for help in data collection; to the members of the Department of Clinical Documentation of the University of Ulm, who did much of the statistical evaluation of the data; and to Institute Mérieux (Leimen, Germany) for supplying the lots of antilymphocyte globulin for this trial.
Source Information
Address reprint requests to Dr. Frickhofen at the Department of Medicine III, University of Ulm, P.O. Box 3880, D-7900 Ulm, Germany.
* For a list of the members of the German Aplastic Anemia Study Group, see the Appendix.
Appendix
The following cooperating centers are members of the German Aplastic Anemia Study Group: Abt. Hämatologie, Zentralklinikum Augsburg (G. Schlimok); Klinikum Charlottenburg, Berlin (H. Malchus); II. Innere Abteilung, Krankenhaus Neukölln, Berlin (A. Grüneisen); Abt. Hämatologie und Onkologie, Klinikum Steglitz, Freie Universität Berlin (E.D. Kreuser); Medizinische Klinik A, Universität Düsseldorf (M. Burk); Medizinische Klinik III, Erlangen (T. Harrer); Evang. Krankenhaus, Essen-Werden (W. Heit); Innere Klinik und Poliklinik, Westdeutsches Tumorzentrum, Essen (K. Höffken); Abt. Hämatologie, Universität Essen (P. Meusers); Universitätskinderklinik Essen (B. Stollman-Gibbels); Abt. Hämatologie, Universität Frankfurt (J.P. Kaltwasser and H. Vogt); Abt. Innere Medizin I, Universität Freiburg (F. Herrmann); Institut für Klinische immunologic und Transfusionsmedizin, Universität Giessen (A. Salama); Medizinische Klinik, Göttingen (R. Bätge); Hämatologische Abt., Allgemeines Krankenhaus St. Georg, Hamburg (R. Sonnen); Kinderklinik, Universitäts-Krankenhaus Eppendorf, Hamburg (G. Janka-Schaub); Medizinische Klinik, Universitäts-Krankenhaus Eppendorf, Hamburg (H.J. Weh); Abt. Hämatologie und Onkologie, Medizinische Hochschule Hannover (M. Freund); Innere Medizin I, Universitätskliniken des Saarlandes, Homburg (H.W. Pees); Abt. Hämatologie und Onkologie, Zentrum für Innere Medizin, Marburg (M. Maasberg); Medizinische Klinik A, Münster (P. Koch); 5. Medizinische Klinik Nürnberg (H. Wandt); Medizinische Universitätsklinik Tübingen, Abt. II (M.R. Clemens); Abt. Innere Medizin III, Klinik und Poliklinik der Universität, Ulm (N. Frickhofen, H. Schrezenmeier, A. Raghavachar, and H. Heimpel); and Krankenhaus Bethesda, Wuppertal (D. Böttcher).
- References
References
1
Camitta
Web of Science | Medline2
Champlin
Full Text | Web of Science | Medline3
Camitta
Web of Science | Medline4
Speck
Web of Science | Medline5
Hinterberger-Fischer
CrossRef | Web of Science | Medline6
Doney
Web of Science | Medline7
Marsh
Web of Science | Medline8
Young
Web of Science | Medline9
Storb
Web of Science | Medline10
McGlave
Web of Science | Medline11
Gluckman
Web of Science | Medline12
Locasciulli
Web of Science | Medline13
Bacigalupo
CrossRef | Web of Science | Medline14
Klingemann
Web of Science | Medline15
Hows
Web of Science | Medline16
Mathé
CrossRef | Web of Science | Medline17
Hunter
CrossRef | Web of Science | Medline18
Raefsky
Web of Science | Medline19
Kawano
CrossRef | Web of Science | Medline20
Taniguchi
CrossRef | Web of Science | Medline21
Zoumbos
Full Text | Web of Science | Medline22
Stryckmans
Full Text | Web of Science | Medline23
Frickhofen
CrossRef | Medline24
International Agranulocytosis and Aplastic Anemia Study
Web of Science | Medline25
Salama
CrossRef | Web of Science | Medline26
Miller
CrossRef | Web of Science | Medline27
Rogerson
CrossRef | Web of Science | Medline28
Kaplan
CrossRef | Web of Science29
de Planque
CrossRef | Web of Science | Medline30
Appelbaum
Web of Science | Medline31
Tichelli
CrossRef | Web of Science | Medline32
de Planque
CrossRef | Web of Science | Medline33
Speck B, Tichelli A, Gratwohl A, Nissen C. Treatment of severe aplastic anemia: a 12-year follow-up of patients after bone marrow transplantation or after therapy with antilymphocyte globulin. In: Shahidi NT, ed. Aplastic anemia and other bone marrow failure syndromes. New York: Springer, 1989:96–103.
34
Bacigalupo
CrossRef | Web of Science | Medline35
Penn
CrossRef | Web of Science | Medline36
Hinterberger-Fischer M
CrossRef | Web of Science | Medline37
Wisløff
Web of Science | Medline38
Porwit
CrossRef | Medline39
Tötterman
CrossRef | Web of Science | Medline40
Leonard
CrossRef | Web of Science | Medline41
Esperou
Medline42
Hows
CrossRef | Web of Science | Medline
- Citing Articles (120)
Citing Articles
1
David Gómez-Almaguer, Jose Carlos Jaime-Pérez, Guillermo J. Ruiz-Arguelles. (2012) Antibodies in the Treatment of Aplastic Anemia. Archivum Immunologiae et Therapiae Experimentalis
CrossRef2
Antonio M. Risitano. (2011) Immunosuppressive therapies in the management of acquired immune-mediated marrow failures. Current Opinion in Hematology1
CrossRef3
P. Scheinberg, O. Nunez, B. Weinstein, P. Scheinberg, C. O. Wu, N. S. Young. (2011) Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia. Blood
CrossRef4
Rebecca J. Deyell, Evan B. Shereck, Ruth A. Milner, Kirk R. Schultz. (2011) Immunosuppressive Therapy Without Hematopoietic Growth Factor Exposure in Pediatric Acquired Aplastic Anemia. Pediatric Hematology-Oncology 28:6, 469-478
CrossRef5
Scheinberg, Phillip, Nunez, Olga, Weinstein, Barbara, Scheinberg, Priscila, Biancotto, Angélique, Wu, Colin O., Young, Neal S., . (2011) Horse versus Rabbit Antithymocyte Globulin in Acquired Aplastic Anemia. New England Journal of Medicine 365:5, 430-438
Full Text6
Lucio Luzzatto, Giacomo Gianfaldoni, Rosario Notaro. (2011) Management of Paroxysmal Nocturnal Haemoglobinuria: a personal view. British Journal of Haematology 153:6, 709-720
CrossRef7
J. M. Valdez, P. Scheinberg, O. Nunez, C. O. Wu, N. S. Young, T. J. Walsh. (2011) Decreased Infection-Related Mortality and Improved Survival in Severe Aplastic Anemia in the Past Two Decades. Clinical Infectious Diseases 52:6, 726-735
CrossRef8
Michael A. Pulsipher, Neal S. Young, Jakub Tolar, Antonio M. Risitano, H. Joachim Deeg, Paolo Anderlini, Rodrigo Calado, Seiji Kojima, Mary Eapen, Richard Harris, Phillip Scheinberg, Sharon Savage, Jaroslaw P. Maciejewski, Ramon V. Tiu, Nancy DiFronzo, Mary M. Horowitz, Joseph H. Antin. (2011) Optimization of Therapy for Severe Aplastic Anemia Based on Clinical, Biologic, and Treatment Response Parameters: Conclusions of an International Working Group on Severe Aplastic Anemia Convened by the Blood and Marrow Transplant Clinical Trials Network, March 2010. Biology of Blood and Marrow Transplantation 17:3, 291-299
CrossRef9
Antonio M. Risitano. (2011) Immunosuppressive therapies in the management of immune-mediated marrow failures in adults: where we stand and where we are going. British Journal of Haematology 152:2, 127-140
CrossRef10
Philip Lanzkowsky. 2011. Bone Marrow Failure. , 123-167.
CrossRef11
R. P. de Latour, V. Visconte, T. Takaku, C. Wu, A. J. Erie, A. K. Sarcon, M. J. Desierto, P. Scheinberg, K. Keyvanfar, O. Nunez, J. Chen, N. S. Young. (2010) Th17 immune responses contribute to the pathophysiology of aplastic anemia. Blood 116:20, 4175-4184
CrossRef12
H Yagasaki, Y Takahashi, A Hama, K Kudo, N Nishio, H Muramatsu, M Tanaka, N Yoshida, K Matsumoto, N Watanabe, K Kato, K Horibe, S Kojima. (2010) Comparison of matched-sibling donor BMT and unrelated donor BMT in children and adolescent with acquired severe aplastic anemia. Bone Marrow Transplantation 45:10, 1508-1513
CrossRef13
Dario Sangiolo, Rainer Storb, H. Joachim Deeg, Mary E.D. Flowers, Paul J. Martin, Brenda M. Sandmaier, Hans-Peter Kiem, Richard A. Nash, Kris Doney, Wendy M. Leisenring, George Earl Georges. (2010) Outcome of Allogeneic Hematopoietic Cell Transplantation from HLA-Identical Siblings for Severe Aplastic Anemia in Patients Over 40 Years of Age. Biology of Blood and Marrow Transplantation 16:10, 1411-1418
CrossRef14
Tsutomu Shichishima, Kazuhiko Ikeda, Naoto Takahashi, Junichi Kameoka, Katsushi Tajima, Kazunori Murai, Yoshiko Tamai, Akiko Shichishima-Nakamura, Kazuko Akutsu, Hideyoshi Noji, Masatoshi Okamoto, Hideo Kimura, Hideo Harigae, Takashi Oyamada, Toyomi Kamesaki, Yasuchika Takeishi, Kenichi Sawada. (2010) Low concentration of serum haptoglobin has impact on understanding complex pathophysiology in patients with acquired bone marrow failure syndromes. International Journal of Hematology 91:4, 602-610
CrossRef15
R. A. Brodsky, A. R. Chen, D. Dorr, E. J. Fuchs, C. A. Huff, L. Luznik, B. D. Smith, W. H. Matsui, S. N. Goodman, R. F. Ambinder, R. J. Jones. (2010) High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up. Blood 115:11, 2136-2141
CrossRef16
Moo-Kon Song, Joo-Seop Chung, Young-Don Joo, Yang-Soo Kim, Sung-Hyun Kim, Young-Mi Seol, Ho-Jin Shin, Young-Jin Choi, Goon-Jae Cho. (2009) Is the early cyclosporine A level predictive of the outcome of immunosuppressive therapy in severe aplastic anemia?. European Journal of Haematology 83:1, 72-78
CrossRef17
Jessica M. Valdez, Phillip Scheinberg, Neal S. Young, Thomas J. Walsh. (2009) Infections in Patients With Aplastic Anemia. Seminars in Hematology 46:3, 269-276
CrossRef18
Nobuhiro Nishio, Hiroshi Yagasaki, Yoshiyuki Takahashi, Hideki Muramatsu, Asahito Hama, Nao Yoshida, Kazuko Kudo, Seiji Kojima. (2009) Natural history of transfusion-independent non-severe aplastic anemia in children. International Journal of Hematology 89:4, 409-413
CrossRef19
Ari Wiesen, Jonathan Wiesen, Sewanti Limaye, Neeraj Kaushik. (2009) Mesalazine-Induced Aplastic Anemia. The American Journal of Gastroenterology 104:4, 1063-1063
CrossRef20
Ryoji Kobayashi, Makoto Kaneda, Tomonobu Sato, Mizuho Ichikawa, Daisuke Suzuki, Tadashi Ariga. (2008) The Clinical Feature of Invasive Fungal Infection in Pediatric Patients With Hematologic and Malignant Diseases. Journal of Pediatric Hematology/Oncology 30:12, 886-890
CrossRef21
H. Bellaaj, C. Kallel, M. Elloumi, H. Rekik, O. Kassar, S. Hdiji, M. Medhaffar, T. Souissi. (2008) Évaluation d’un protocole thérapeutique prospectif des aplasies médullaires acquises non sévères de l’adulte dans le Sud tunisien. La Revue de Médecine Interne 29:12, 981-985
CrossRef22
Ronit Gurion, Anat Gafter-Gvili, Mical Paul, Liat Vidal, Isaac Ben-Bassat, Moshe Yeshurun, Ofer Shpilberg, Pia Raanani, Ronit Gurion. 2008. Hematopoietic Growth Factors in the Treatment of Acquired Aplastic Anemia. .
CrossRef23
Karen K. Ballen, Roberta J. King, Pintip Chitphakdithai, Charles D. Bolan, Edward Agura, Robert J. Hartzman, Nancy A. Kernan. (2008) The National Marrow Donor Program 20 Years of Unrelated Donor Hematopoietic Cell Transplantation. Biology of Blood and Marrow Transplantation 14:9, 2-7
CrossRef24
Neal S Young, Phillip Scheinberg, Rodrigo T Calado. (2008) Aplastic anemia. Current Opinion in Internal Medicine 7:4, 338-344
CrossRef25
Mamiko Hattori, Teruhiko Terasawa, Keitaro Tsushita, Makoto Utsumi, Fumio Kawano, Hidehiko Saito, Masanori Shimoyama, Haruhiko Ohashi. (2008) The status of antithymocyte globulin therapy for adult patients in Japan: retrospective analysis of a nationwide survey. International Journal of Hematology 87:1, 48-55
CrossRef26
Bunchoo Pongtanakul, Prabodh Kumar Das, Karen Charpentier, Yigal Dror. (2008) Outcome of children with aplastic anemia treated with immunosuppressive therapy. Pediatric Blood & Cancer 50:1, 52-57
CrossRef27
Nedim Hadžić, Susan Height, Sarah Ball, Mohamed Rela, Nigel D. Heaton, Paul Veys, Giorgina Mieli-Vergani. (2008) Evolution in the management of acute liver failure-associated aplastic anaemia in children: A single centre experience. Journal of Hepatology 48:1, 68-73
CrossRef28
Benjamin Leader, Quentin J. Baca, David E. Golan. (2008) Protein therapeutics: a summary and pharmacological classification. Nature Reviews Drug Discovery 7:1, 21-39
CrossRef29
Sule Unal, Mualla Çetin, Betül Tavil, Neslihan Çalışkan, Sevgi Yetgin, Duygu Uçkan. (2007) Favorable outcome with allogeneic hematopoietic stem cell transplantation in pediatric acquired aplastic anemia patients. Pediatric Transplantation 11:7, 788-791
CrossRef30
M. Teramura, A. Kimura, S. Iwase, Y. Yonemura, S. Nakao, A. Urabe, M. Omine, H. Mizoguchi. (2007) Treatment of severe aplastic anemia with antithymocyte globulin and cyclosporin A with or without G-CSF in adults: a multicenter randomized study in Japan. Blood 110:6, 1756-1761
CrossRef31
Günçağ Dinçol, Melih Aktan, Reyhan Diz-Küçükkaya, Selim Yavuz, Meliha Nalçacı, Şükrü Öztürk, Şükrü Palanduz, Öner Doğan, Mehmet Ağan. (2007) Treatment of acquired severe aplastic anemia with antilymphocyte globulin, cyclosporin A, methyprednisolone, and granulocyte colony-stimulating factor. American Journal of Hematology 82:9, 783-786
CrossRef32
Deepti Bulchandani, Jagdish Nachnani, Robert Belt, Stuart Hinton. (2007) Acquired pure megakaryocytic aplasia: Report of a single case treated with mycophenolate mofetil. American Journal of Hematology 82:7, 650-651
CrossRef33
Rosa Sanchez, Philip Rosenthal, Robert Goldsby. (2007) Immunotherapy for severe aplastic anemia following orthotopic liver transplantation in children. Pediatric Blood & Cancer 49:1, 93-98
CrossRef34
Philippe Armand, Joseph H. Antin. (2007) Allogeneic Stem Cell Transplantation for Aplastic Anemia. Biology of Blood and Marrow Transplantation 13:5, 505-516
CrossRef35
Monika Führer, Jürgen Durner, Günter Brünnler, Heiko Götte, Cornelia Deppner, Christine Bender-Götze, Ekkehard Albert. (2007) HLA association is different in children and adults with severe acquired aplastic anemia. Pediatric Blood & Cancer 48:2, 186-191
CrossRef36
Yizhou Zheng, Yongze Liu, Yulin Chu. (2006) Immunosuppressive therapy for acquired severe aplastic anemia (SAA): A prospective comparison of four different regimens. Experimental Hematology 34:7, 826-831
CrossRef37
Phillip Scheinberg, Olga Nunez, Colin Wu, Neal S. Young. (2006) Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil. British Journal of Haematology 133:6, 606-611
CrossRef38
M Okamoto, T Shichishima, H Noji, K Ikeda, A Nakamura, K Akutsu, Y Maruyama. (2006) High frequency of several PIG-A mutations in patients with aplastic anemia and myelodysplastic syndrome. Leukemia 20:4, 627-634
CrossRef39
Wolfgang Füreder, Maria-Theresa Krauth, Wolfgang R. Sperr, Karoline Sonneck, Ingrid Simonitsch-Klupp, Leonhard Müllauer, Michael Willmann, Hans-Peter Horny, Peter Valent. (2006) Evaluation of Angiogenesis and Vascular Endothelial Growth Factor Expression in the Bone Marrow of Patients with Aplastic Anemia. The American Journal of Pathology 168:1, 123-130
CrossRef40
2006. Immunoglobulins. , 1719-1730.
CrossRef41
Kenji Tajika. (2006) Aplastic Anemia; Current Findings of its Pathophysiology and Treatment. Nihon Ika Daigaku Igakkai Zasshi 2:3, 138-144
CrossRef42
Peter Kurre, F. Leonard Johnson, H. Joachim Deeg. (2005) Diagnosis and treatment of children with aplastic anemia. Pediatric Blood & Cancer 45:6, 770-780
CrossRef43
Albert N. Békássy, Anna Locasciulli, Judith C.W. Marsh, Gerard Socié, Monika Fuehrer, Jakob Passweg. (2005) Immunosuppression with ALG and CsA is first line treatment in children with SAA lacking an HLA identical sibling. Pediatric Blood & Cancer 45:3, 359-360
CrossRef44
Wenji Piao, Jens Grosse, Andreas Czwalinna, Philipp Ivanyi, Arnold Ganser, Anke Franzke. (2005) Antigen-recognition sites of micromanipulated T cells in patients with acquired aplastic anemia. Experimental Hematology 33:7, 804-810
CrossRef45
Robert A Brodsky, Richard J Jones. (2005) Aplastic anaemia. The Lancet 365:9471, 1647-1656
CrossRef46
J-H Lee, S-J Choi, J-H Lee, Y-S Lee, M Seol, S-G Ryu, J-S Lee, W-K Kim, K-H Lee. (2005) Non-total body irradiation containing preparative regimen in alternative donor bone marrow transplantation for severe aplastic anemia. Bone Marrow Transplantation 35:8, 755-761
CrossRef47
J Starý, F Locatelli, C M Niemeyer. (2005) Stem cell transplantation for aplastic anemia and myelodysplastic syndrome. Bone Marrow Transplantation 35, S13-S16
CrossRef48
Romaine Viollier, Jakob Passweg, Michael Gregor, Genevi
ve Favre, Thomas K
CrossRef49
Scott C. Howard, Paula E. Naidu, X. Joan Hu, Michael R. Jeng, Carlos Rodriguez-Galindo, Martha D. Rieman, Winfred C. Wang. (2004) Natural history of moderate aplastic anemia in children. Pediatric Blood & Cancer 43:5, 545-551
CrossRef50
Robert A Brodsky, Allen R Chen, Isadore Brodsky, Richard J Jones. (2004) High-dose cyclophosphamide as salvage therapy for severe aplastic anemia. Experimental Hematology 32:5, 435-440
CrossRef51
M.-S. Dai, W.-Y. Kao, R.-Y. Shyu, T.-Y. Chao. (2004) Restoration of immunity and reactivation of hepatitis B virus after immunosuppressive therapy in a patient with severe aplastic anaemia. Journal of Viral Hepatitis 11:3, 283-285
CrossRef52
Myung-Ju Ahn, Jung-Hye Choi, Young-Yeul Lee, Il-Young Choi, In-Soon Kim, Sung-Soo Yoon, Sun-Yang Park, Byung-Kook Kim, Cheolwon Suh, Hee Jeong Son, Cheol-Won Jung, Jae Hoon Lee, Ju-Myung Sung, Suck-Ah Im, Doyeun Oh, So-Young Jung, Hwi-Joong Yoon, Kyung-Sam Cho, Jung-Ae Lee, Young-Jin Yuh, Sung-Rok Kim, Moran Ki. (2003) Outcome of Adult Severe or Very Severe Aplastic Anemia Treated with Immunosuppressive Therapy Compared with Bone Marrow Transplantation: Multicenter Trial. International Journal of Hematology 78:2, 133-138
CrossRef53
Klaus Geissler. (2003) Pathophysiology and treatment of aplastic anemia. Wiener Klinische Wochenschrift 115:13-14, 444-450
CrossRef54
Eliane Gluckman, Riitta Rokicka-Milewska, Ian Hann, Emmanouel Nikiforakis, Filipos Tavakoli, Sophie Cohen-Scali, Andrea Bacigalupo, . (2002) Results and follow-up of a phase III randomized study of recombinant human-granulocyte stimulating factor as support for immunosuppressive therapy in patients with severe aplastic anaemia. British Journal of Haematology 119:4, 1075-1082
CrossRef55
Akira Matsuda, Kuniya Kishimoto, Katsuhiko Yoshida, Fumiharu Yagasaki, Yoshihiro Ito, Tohru Sakata, Nobutaka Kawai, Hirohide Ino, Kunitake Hirashima, Masami Bessho. (2002) 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. International Journal of Hematology 76:3, 244-250
CrossRef56
Senji Kasahara, Takeshi Hara, Hiroyasu Itoh, Kazuki Ando, Hisashi Tsurumi, Michio Sawada, Toshiki Yamada, Hiroo Ohnishi, Hisataka Moriwaki. (2002) Hypoplastic myelodysplastic syndromes can be distinguished from acquired aplastic anaemia by bone marrow stem cell expression of the tumour necrosis factor receptor. British Journal of Haematology 118:1, 181-188
CrossRef57
M. Aivado, A. Rong, M. Stadler, U. Germing, A. Giagounidis, C. Strupp, J. Novotny, K.M. Josten, G. Kobbe, B. Hildebrandt, N. Gattermann, C. Aul, R. Haas, A. Ganser. (2002) Favourable response to antithymocyte or antilymphocyte globulin in low-risk myelodysplastic syndrome patients with a 'non-clonal' pattern of X-chromosome inactivation in bone marrow cells. European Journal of Haematology 68:4, 210-216
CrossRef58
Hiroko Otsubo, Ken Kaito, Yoji Ogasawara, Takaki Shimada, Noriko Usui, Masayuki Kobayashi. (2002) Successful Immunosuppressive Therapy With Cyclosporine A for Posthepatitis B-Cell Deficiency With Activated Cytoplasmic Interferon-γ—Positive T-Lymphocytes. International Journal of Hematology 75:3, 285-288
CrossRef59
Neal S. Young. (2002) Immunosuppressive Treatment of Acquired Aplastic Anemia and Immune-Mediated Bone Marrow Failure Syndromes. International Journal of Hematology 75:2, 129-140
CrossRef60
P. Mollee, N. Woodward, S. Durrant, L. Lockwood, E. A. Gillett, J. Morton, J. Rowell. (2001) Single institution outcomes of treatment of severe aplastic anaemia. Internal Medicine Journal 31:6, 337-342
CrossRef61
Arnon Nagler, Memet Aker, Reuven Or, Elizabeth Naparstek, Gabor Varadi, Chaim Brautbar, Shimon Slavin. (2001) Low-intensity conditioning is sufficient to ensure engraftment in matched unrelated bone marrow transplantation. Experimental Hematology 29:3, 362-370
CrossRef62
Ryoji Kobayashi, Hideki Arioka, Makoto Yoshida, Yuko Cho, Akihiro Iguchi, Makoto Kaneda, Takaaki Shikano. (2001) Prolonged Bone Marrow Failure With Monosomy 7 After Engraftment Failure Following Bone Marrow Transplantation. International Journal of Hematology 73:2, 258-261
CrossRef63
Mary Eapen, Norma K. C. Ramsay, Ann C. Mertens, Leslie L. Robison, Todd DeFor, Stella M. Davies. (2000) Late outcomes after bone marrow transplant for aplastic anaemia. British Journal of Haematology 111:3, 754-760
CrossRef64
S. B. Killick, C. V. Cox, J. C. W. Marsh, E. C. Gordon-Smith, F. M. Gibson. (2000) Mechanisms of bone marrow progenitor cell apoptosis in aplastic anaemia and the effect of anti-thymocyte globulin: examination of the role of the Fas-Fas-L interaction. British Journal of Haematology 111:4, 1164-1169
CrossRef65
John Tung, Nedim Hadzic, Mark Layton, Alastair J. Baker, Anil Dhawan, Mohamed Rela, Nigel D. Heaton, Giorgina Mieli-Vergani. (2000) Bone Marrow Failure in Children With Acute Liver Failure. Journal of Pediatric Gastroenterology and Nutrition 31:5, 557-561
CrossRef66
John F Tisdale, Daniel E Dunn, Nancy Geller, Michelle Plante, Olga Nunez, Cynthia E Dunbar, A John Barrett, Thomas J Walsh, Stephen J Rosenfeld, Neal S Young. (2000) High-dose cyclophosphamide in severe aplastic anaemia: a randomised trial. The Lancet 356:9241, 1554-1559
CrossRef67
Seiji Kojima, Keizo Horibe, Jun Inaba, Ayami Yoshimi, Yoshiyuki Takahashi, Kazuko Kudo, Koji Kato, Takaharu Matsuyama. (2000) Long-term outcome of acquired aplastic anaemia in children: comparison between immunosuppressive therapy and bone marrow transplantation. British Journal of Haematology 111:1, 321-328
CrossRef68
E. C. Gordon-Smith, J. C. W. Marsh. (2000) Management of Acquired Aplastic Anemia. Reviews in Clinical and Experimental Hematology 4:3, 260-278
CrossRef69
S.B. Killick, J.C.W. Marsh. (2000) Aplastic anaemia: Management. Blood Reviews 14:3, 157-171
CrossRef70
S. E. Ball. (2000) The modern management of severe aplastic anaemia. Review. British Journal of Haematology 110:1, 41-53
CrossRef71
Vinod A. Pullarkat, Hyan Rho, Joyce L. Murata-Collins, Howard A. Liebman. (2000) Ticlopidine-induced aplastic anemia: Development of chromosomal abnormalities and response to immunosuppressive therapy. American Journal of Hematology 63:3, 141-144
CrossRef72
Andrea Bacigalupo, Ronald Brand, Rosi Oneto, Barbara Bruno, Gerard Sodé, Jakob Passweg, Anna Locasciulli, Maria Teresa Van Lint, André Tichelli, Shaun McCann, Judith Marsh, Per Ljungman, Jill Hows, Pedro Marin, Hubert Schrezenmeier. (2000) Treatment of acquired severe aplastic anemia: Bone marrow transplantation compared with immunosuppressive therapy-the European group for blood and marrow transplantation experience. Seminars in Hematology 37:1, 69-80
CrossRef73
Norbert Frickhofen, Stephen J Rosenfeld. (2000) Immunosuppressive treatment of aplastic anemia with antithymocyte globulin and cyclosporine. Seminars in Hematology 37:1, 56-68
CrossRef74
Piernicola Boccuni, Luigi Del Vecchio, Rosa Di Noto, Bruno Rotoli. (2000) Glycosyl phosphatidylinositol (GPI)-anchored molecules and the pathogenesis of paroxysmal nocturnal hemoglobinuria. Critical Reviews in Oncology/Hematology 33:1, 25-43
CrossRef75
John Barrett, Yogen Saunthararajah, Jeffrey Molldrem. (2000) Myelodysplastic syndrome and aplastic anemia: Distinct entities or diseases linked by a common pathophysiology?. Seminars in Hematology 37:1, 15-29
CrossRef76
John F Tisdale, Daniel E Dunn, Jaroslaw Maciejewski. (2000) Cyclophosphamide and other new agents for the treatment of severe aplastic anemia. Seminars in Hematology 37:1, 102-109
CrossRef77
Piaggio, Podesta, Pitto, Sessarego, Figari, Fugazza, Benvenuto, Bruno, van Lint, Truini, Frassoni, Bacigalupo. (1999) Coexistence of normal and clonal haemopoiesis in aplastic anaemia patients treated with immunosuppressive therapy. British Journal of Haematology 107:3, 505-511
CrossRef78
E. Di Bona, F. Rodeghiero, B. Bruno, A. Gabbas, P. Foa, A. Locasciulli, C. Rosanelli, L. Camba, P. Saracco, A. Lippi, A. P. Iori, F. Porta, V. De Rossi, B. Comotti, P. Iacopino, C. Dufour, A. Bacigalupo. (1999) Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. British Journal of Haematology 107:2, 330-334
CrossRef79
Joseph W. Leach, Khader K. Hussein, James N. George. (1999) Acquired pure megakaryocytic aplasia report of two cases with long-term responses to antithymocyte globulin and cyclosporine. American Journal of Hematology 62:2, 115-117
CrossRef80
Alexei Maschan, Natalia Bogatcheva, Oleg Kryjanovskii, Maria Shneider, Dimitry Litvinov, Tatiana Mitiushkina, Andrei Timakov, Maria Timakova, Elena Samotchatova, Alexander Rumiantsev. (1999) Results at a single centre of immunosuppression with cyclosporine A in 66 children with aplastic anaemia. British Journal of Haematology 106:4, 967-970
CrossRef81
Masaki Yamaguchi, Steve Nadler, Jong-Wook Lee, H Joachim Deeg. (1999) Induction of negative regulators of haematopoiesis in human bone marrow cells by HLA-DR cross-linking. Transplant Immunology 7:3, 159-168
CrossRef82
YASUHIKO AZENISHI, ETSUKO UEDA, TAKASHI MACHII, JUN-ICHI NISHIMURA, TOSHIYUKI HIROTA, MASARU SHIBANO, SHINJI NAKAO, TAROH KINOSHITA, HIDEAKI MIZOGUCHI, TERUO KITANI. (1999) CD59-deficient blood cells and PIG-A gene abnormalities in Japanese patients with aplastic anaemia. British Journal of Haematology 104:3, 523-529
CrossRef83
Zonghong Shao, Yulin Chu, Yizhi Zhang, Guibin Chen, Yizhou Zheng. (1998) Treatment of severe aplastic anemia with an immunosuppressive agent plus recombinant human granulocyte-macrophage colony-stimulating factor and erythropoietin. American Journal of Hematology 59:3, 185-191
CrossRef84
Ken Kaito, Masayuki Kobayashi, Toshio Katayama, Hidekazu Masuoka, Takaki Shimada, Kaichi Nishiwaki, Toru Sekita, Hiroko Otsubo, Yoji Ogasawara, Tatsuo Hosoya. (1998) Long-term administration of G-CSF for aplastic anaemia is closely related to the early evolution of monosomy 7 MDS in adults. British Journal of Haematology 103:2, 297-303
CrossRef85
Hubert Schrezenmeier, Martin Griesshammer, Alex Hornkohl, Janet L. Nichol, Thomas Hecht, Herrmann Heimpel, Bernhard Kubanek, Aruna Raghavachar. (1998) Thrombopoietin serum levels in patients with aplastic anaemia: correlation with platelet count and persistent elevation in remission. British Journal of Haematology 100:3, 571-576
CrossRef86
Josefa Piedras, Guadalupe Hernández, Xavier López-Karpovitch. (1998) Effect of androgen therapy and anemia on serum erythropoietin levels in patients with aplastic anemia and myelodysplastic syndromes. American Journal of Hematology 57:2, 113-118
CrossRef87
André Tichelli, Jakob Passweg, Catherine Nissen, Mario Bargetzi, Till Hoffmann, Aleksandra Wodnar-Filipowicz, Erich Signer, Bruno Speck, Alois Gratwohl. (1998) Repeated treatment with horse antilymphocyte globulin for severe aplastic anaemia. British Journal of Haematology 100:2, 393-400
CrossRef88
Eva C. Guinan. (1997) CLINICAL ASPECTS OF APLASTIC ANEMIA. Hematology/Oncology Clinics of North America 11:6, 1025-1044
CrossRef89
Hartmut Link, Hans-Jochem Kolb, Wolfram Ebell, Dieter Kurt Hossfeld, Axel Zander, Dietrich Niethammer, Hannes Wandt, Hans Grosse-Wilde, Ulrich W. Schaefer. (1997) Die Transplantation hämatopoetischer Stammzellen. Medizinische Klinik 92:9, 534-545
CrossRef90
Elizabeth R. Lawlor, Ronald A. Anderson, Jeffrey H. Davis, Christopher J. H. Fryer, Sheila L. Pritchard, Paul C. J. Rogers, John K. Wu, Kirk R. Schultz. (1997) Immunosuppressive Therapy: A Potential Alternative to Bone Marrow Transplantation as Initial Therapy for Acquired Severe Aplastic Anemia in Childhood?. Journal of Pediatric Hematology/Oncology 19:2, 115-123
CrossRef91
Rafael Fonseca, Ayalew Tefferi. (1997) Practical Aspects in the Diagnosis and Management of Aplastic Anemia. The American Journal of the Medical Sciences 313:3, 159-169
CrossRef92
HIROYUKI SHICHINO, HIDEO MUGISHIMA, MAYUMI TAKAMURA, TOSHIAKI SHIMADA, TAKASHI SUZUKI, MOTOAKI CHIN, KENSUKE HARADA, SIGEO RYO, SEIJI KOJIMA. (1996) Treatment of aplastic anemia with antithymocyte globulin, cyclosporin A, methylprednisolone, danazole and recombinant human granulocyte-colony stimulating factor. Pediatrics International 38:6, 644-647
CrossRef93
B.J.P. Huntly, I.M. Franklin, M.J. Pippard. (1996) Unrelated bone-marrow transplantation in adults. Blood Reviews 10:4, 220-230
CrossRef94
Vicki Dorr, Gary Doolittle, Janet Woodroof. (1996) First report of a B cell lymphoproliferative disorder arising in a patient treated with immune suppressants for severe aplastic anemia. American Journal of Hematology 52:2, 108-113
CrossRef95
Taroh Kinoshita, M.D, Norimitsu Inoue, M.D, Junji Takeda, M.D. (1996) ROLE OF PHOSPHATIDYLINOSITOL-LINKED PROTEINS IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA PATHOGENESIS. Annual Review of Medicine 47:1, 1-10
CrossRef96
Nancy Bunin, Ann Leahey, Naynesh Kamani, Charles August. (1996) Bone Marrow Transplantation in Pediatric Patients with Severe Aplastic Anemia. Journal of Pediatric Hematology/Oncology 18:1, 68-71
CrossRef97
Mario J. Bargetzi, Eliane Gldckman, Andre Tichelli, Agnes Devergie, Helene Esperou, Janusz Kabata, Alexandra Wodnar-Filipowicz, Catherine Nissen, Bruno Speck, Alois Gratwohl. (1995) Recombinant human interleukin-3 in refractory severe aplastic anaemia: a phase I/II trial. British Journal of Haematology 91:2, 306-312
CrossRef98
M. Horstmann, M. Stockschläder, W. Krüger, M. Hoffknecht, R. Betker, H. Kabisch, A. Zander. (1995) Cyclophosphamide/antithymocyte globulin conditioning of patients with severe aplastic anemia for marrow transplantation from HLA-matched siblings: Preliminary results. Annals of Hematology 71:2, 77-81
CrossRef99
N.S. Young. (1995) Aplastic anaemia. The Lancet 346:8969, 228-232
CrossRef100
Malte Peters, Martin Trippler, Hanns Löhr, Werner Gödderz, Wolfgang Herr, Stefan Störkel, Karl-Hermann Meyer Zum Büschenfelde, Guido Gerken. (1995) Posttransfusional, LKM-1-autoantibody-positive hepatitis C virus infection, cryoglobulinemia, and aplastic anemia. Digestive Diseases and Sciences 40:4, 763-773
CrossRef101
E. V. Planken, G. J. Ottolander, P. M. Kluin, R. Bieger. (1994) A 43-year-old woman with severe pancytopenia and a splenic hematoma. Annals of Hematology 69:5, 265-270
CrossRef102
Mark S. Cattral, Alan N. Langnas, Rodney S. Markin, Dean L. Antonson, Thomas G. Heffron, Ira J. Fox, Michael F. Sorrell, Byers W. Shaw. (1994) Aplastic anemia after liver transplantation for fulminant liver failure. Hepatology 20:4, 813-818
CrossRef103
Hubert Schrezenmeier, Gudrun Noe, Aruna Raghavachar, Ivan N. Rich, Hermann Heimpel, Bernhard Kubanek. (1994) Serum erythropotietin and serum transferrin receptor levels in aplastic anaemia. British Journal of Haematology 88:2, 286-294
CrossRef104
M. Schleuning, C. Thomssen, H.-J. Kolb, H.-J. Sauer, W. Wilmanns. (1994) Treatment of refractory severe aplastic anemia with granulocyte colony stimulating factor and interleukin 3. American Journal of Hematology 46:3, 250-251
CrossRef105
M. N. Narayanan, C. G. Geary, A. J. Freemont, J. R. Kendra. (1994) Long-term follow-up of aplastic anaemia. British Journal of Haematology 86:4, 837-843
CrossRef106
H. Schrezenmeier, P. Marin, A. Raghavachar, S. McCann, J. Hows, E. Gluckman, C. Nissen, E. T. van't Veer-Korthof, P. Ljungman, W. Hinterberger, M. T. Van Lint, N. Frickhofen, A. Bacigalupo. (1993) Relapse of aplastic anaemia after immunosuppressive treatment: a report from the European Bone Marrow Transplantation Group SAA Working Party. British Journal of Haematology 85:2, 371-377
CrossRef107
J. C. W. Marsh, A. Zomas, J. M. Hows, M. Chapple, E. C. Gordon-Smith. (1993) Avascular necrosis after treatment of aplastic anaemia with antilymphocyte globulin and high-dose methylprednisolone. British Journal of Haematology 84:4, 731-735
CrossRef108
W. Schwinger, C. Urban, H. Lackner, C. Mache. (1993) Treatment of aplastic anemia with a monoclonal antibody directed against the interleukin-2 receptor. Annals of Hematology 66:4, 181-184
CrossRef109
U. Mentzel, H. Vogt, R. Rossol, R. G. Geissler, A. Maurer, A. Ganser, W. E. Trommer, D. Hoelzer. (1993) Analysis of lymphocyte subsets in patients with aplastic anemia before and during immunosuppressive therapy. Annals of Hematology 66:3, 127-129
CrossRef110
Catherine Nissen, Alois Gratwohl, André Tichelli, Christine Stebler, Andreas Würsch, Yolanda Moser, Verena Dalle Carbonare, Erich Signer, Mauro Buser, Rudolf Ritz, Bruno Speck. (1993) Gender and response to antilymphocyte globulin (ALG) for severe aplastic anaemia. British Journal of Haematology 83:2, 319-325
CrossRef111
A. Bacigalupo, M. Chaple, J. Hows, M. T. Lint, S. McCann, D. Milligan, J. Chessells, A. H. Goldstone, J. Ottolander, E. Th. Veer, B. Comotti, P. Coser, G. Broccia, A. Bosi, A. Locasciulli, L. Catalano, R. Battista, W. Arcese, M. Carotenuto, A. M. Marmont, E. C. Gordon Smith. (1993) Treatment of aplastic anaemia (AA) with antilymphocyte globulin (ALG) and methylprednisolone (MPred) with or without androgens: a randomized trial from the EBMT SAA working party. British Journal of Haematology 83:1, 145-151
CrossRef112
H. Schrezenmeier, M. Schlander, A. Raghavachar. (1992) Cyclosporin A in aplastic anemia — report of a workshop. Annals of Hematology 65:1, 33-36
CrossRef113
Theodore Wun, Jerry P. Lewis. (1992) Clonal remission in aplastic anemia after treatment with antithymocyte globulin. American Journal of Hematology 40:3, 229-231
CrossRef114
M. BJÖRKHOLM. (1992) Aplastic anaemia: pathogenetic mechanisms and treatment with special reference to immunomodulation. Journal of Internal Medicine 231:6, 575-582
CrossRef115
Jayesh Mehta, Seema Singhal, B. C. Mehta. (1992) Letter to the editor: Low-dose cyclosporin for severe aplastic anemia. American Journal of Hematology 40:1, 73-73
CrossRef116
Eliane Gluckman, Hélène Esperou-Bourdeau, André Baruchel, Michel Boogaerts, Jean Briere, Daniel Donadio, Guy Leverger, Michel Leporrier, Josy Reiffers, Maud Janvier, Mauricette Michallet, Pierre Stryckmans. (1992) A multicenter randomized study comparing cyclosporin-A alone and antithymocyte globulin with prednisone for treatment of severe aplastic anemia. Journal of Autoimmunity 5, 271-275
CrossRef117
F. Herrmann, A. Lindemann, W. Lange, G. Köchling, A. Raghavachar, H. Schrezenmeier, N. Frickhofen, R. H. Mertelsmann. (1991) Medullary histiocytosis following treatment of severe aplastic anemia with recombinant human interleukin-3 in combination with antilymphocyte globulin, cyclosporin A, and methylprednisolone. Annals of Hematology 63:4, 229-231
CrossRef118
J.-F. Bach. (1991) Cyclosporin and autoimmune disease. The Lancet 338:8758, 59-60
CrossRef119
Richard Horton. (1991) Cyclosporin. The Lancet 337:8753, 1338
CrossRef120
Moore, Malcolm A.S., Castro-Malaspina, Hugo, . (1991) Immunosuppression in Aplastic Anemia — Postponing the Inevitable?. New England Journal of Medicine 324:19, 1358-1360
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