Bone marrow cytogenetic abnormalities of aplastic anemia

Cytogenetic abnormalities in association with aplastic anemia have been reported fairly infrequently. Clonal cytogenetic abnormalities at initial diagnosis are uncommon. A retrospective study was performed of the cytogenetic findings in patients with typical morphological and clinical features of severe aplastic anemia from a single institution for the years 1988 through 1998. A total of 30 cases of aplastic anemia, 16 men and 14 women, were identified. The median age was 60 with females being significantly older (67.5 years) in comparison to males (44 years). Bone marrow specimens failed to yield metaphases in 16 cases and normal karyotypes were detected in 11 cases. Cytogenetic abnormalities were detected in 3 cases. Clonal abnormalities, as defined, occurred in only 2 cases (6.7%). A review of the literature identified a total of 24 cases of aplastic anemia with abnormal cytogenetic findings. Overall, the most common chromosome abnormalities are trisomies of 6 and 8 and loss of chromosome 7. Trisomy 6 is more common at diagnosis while loss of chromosome 7 is more common after therapy.     

Clonal cytogenetic abnormalities in patients with otherwise typical aplastic anemia

Between June 1981 and August 1986, 183 patients with the referring diagnosis of aplastic anemia were evaluated with cytogenetic studies and marrow biopsies. Seven patients (4%) on biopsy were found to have myelodysplasia. Seven of the 176 patients (4%) with marrow biopsies that confirmed the pathologic diagnosis of severe aplastic anemia were found to have clonal cytogenetic abnormalities in unstimulated marrow samples. Among the 169 patients with typical aplastic anemia and no cytogenetic abnormalities, 5 (3%) subsequently developed either myelodysplasia or leukemia. Two of three patients with pathologically confirmed aplastic anemia and clonal cytogenetic abnormalities, who were not transplanted, developed myelodysplasia. These results demonstrate that approximately 4% of patients with aplastic anemia have clonal cytogenetic abnormalities of marrow cells, and that while all patients with aplastic anemia may have some risk of developing leukemia, those with a cytogenetic abnormality have an especially high risk.     

Clinical relevance of cytogenetic abnormalities at diagnosis of acquired aplastic anaemia in adults

The outcome of 81 adult aplastic anaemia patients who had successful cytogenetics at diagnosis and received immunosuppressive therapy was evaluated. Ten patients had an abnormal karyotype, six of which had a trisomy. Four of five evaluable patients with a trisomy responded. One patient with monosomy 7 achieved a complete response and later developed haemolytic paroxysmal nocturnal haemoglobinuria but no recurrence of monosomy 7. None of the patients with a non-numerical karyotypic abnormality responded. No significant differences in survival or later clonal disorders were observed between patients with a normal karyotype and those with an abnormal karyotype.     

Myelodysplastic syndrome evolving from aplastic anemia treated with immunosuppressive therapy: efficacy of hematopoietic stem cell transplantation

A proportion of patients with aplastic anemia who are treated with immunosuppressive therapy develop clonal hematologic disorders, including post-aplastic anemia myelodysplastic syndrome. Many will proceed to allogeneic hematopoietic stem cell transplantation. We identified 123 patients with post-aplastic anemia myelodysplastic syndrome who from 1991 through 2011 underwent allogeneic hematopoietic stem cell transplantation, and in a matched-pair analysis compared outcome to that in 393 patients with de novo myelodysplastic syndrome. There was no difference in overall survival. There were no significant differences with regard to 5-year probabilities of relapse, non-relapse mortality, relapse-free survival and overall survival; these were 14%, 40%, 46% and 49% for post-aplastic anemia myelodysplastic syndrome, and 20%, 33%, 47% and 49% for de novo myelodysplastic syndrome, respectively. In multivariate analysis, relapse (hazard ratio 0.71; P=0.18), non-relapse mortality (hazard ratio 1.28; P=0.18), relapse-free survival (hazard ratio 0.97; P=0.80) and overall survival (hazard ratio 1.02; P=0.88) of post-aplastic anemia myelodysplastic syndrome were similar to those of patients with de novo myelodysplastic syndrome. Cytogenetic risk was independently associated with overall survival in both groups. Thus, transplant success in patients with post-aplastic anemia myelodysplastic syndrome was similar to that in patients with de novo myelodysplastic syndrome, and cytogenetics was the only significant prognostic factor for post-aplastic anemia myelodysplastic syndrome patients.     

CD5- CD11c+ CD23- small lymphocytic lymphoma evolving from aplastic anemia

A 91-year-old woman was hospitalized with acute respiratory distress syndrome due to pneumonia in June 1997. Since she had pancytopenia and a bone marrow aspirate indicated hypocellularity with no increase in myeloblasts, dysplasia or abnormal chromosomes, aplastic anemia (AA) was diagnosed. Pulse therapy with methylprednisolone and antibiotics proved successful, and blood cell numbers stabilized. In June 2001, she was readmitted to our hospital with persistent low grade fever and leukopenia. A bone marrow aspirate from the sternum and iliac bone biopsy revealed compact proliferation of small lymphocytes, and the surface marker CD5- CD10- CD11c+ CD19+ CD20+ CD23- was detected through immune staining and flowcytometry. CD30+, CD34+and CD56+cells were scarce. Tests for surface immunoglobulins, IgG, IgA, IgM and IgD, were negative. No nodal or extranodal lesions were evident. Since Southern blot analysis of bone marrow cells indicated rearrangement of the immunoglobulin heavy chain and abnormal chromosomes were evident, small lymphocytic lymphoma (SLL) was diagnosed. Four intravenous infusions of rituximab (375mg/m2) were administered without critical adverse effects. Tests conducted four weeks later revealed saturation of CD20+ antigens of lymphoma cells and chromosomal abnormalities and rearrangement of the immunoglobulin heavy chain were still apparent. Though complete remission of the pancytopenia was not achieved, serum concentrations of lactate dehydrogenase and soluble interleukin-2 receptor decreased, and the numbers of platelets and erythrocytes increased. There was also an improvement in systemic condition. This was a rare case of SLL having the surface marker of CD5- CD10- CD11c+ CD19+ CD20+ CD23-, which had evolved from AA and infiltrated bone marrow.     

慢性再生障碍性贫血的治疗

阐述在慢性再障碍性贫血（CAA）治疗过程中应遵循的治疗原则，对补肾中药，雄激素，环孢菌素A，免疫调节剂及神经兴奋剂等药物的临床应用及作用机制作简要介绍，认为正确运用治疗原则，合理选药组方，坚持全疗程3年以上（即治疗1年使达到正常，以后维持治疗2年），是提高CAAI台愈率和长期生存率的关键。     

Cyclosporin therapy for aplastic anemia

We treated 14 patients with aplastic anemia (6 severe, 8 moderate) who did not respond to high dose methylprednisolone, antilymphocyte globulin, or anabolic steroid with cyclosporin (CyA) for more than 4 weeks. Four of them (29%) showed clinical improvement to transfusion-independence. The response rate of patients who received CyA more than 5 weeks was 50% (4 out of 8). The dose of CyA given to the 4 patients who improved after the therapy was 5 to 9 mg/kg/day. One patient needed 11 weeks until the first sign of response (increase of reticulocytes) appeared. In the other three patients, platelets increased first in response to CyA within 5 weeks. Side effects such as hypertricosis and gingival hyperplasia were frequently seen during the CyA therapy, but since they were not so severe or transient, almost all patients tolerated the therapy. These results indicate that CyA can be an efficacious drug for patients with refractory aplastic anemia. Long term treatment with a relatively low dose of CyA may be important for obtaining a high response rate.     

Lymphokine abnormalities in aplastic anemia: implications for the mechanism of action of antithymocyte globulin

Anti-thymocyte globulin (ATG) provides effective therapy for many patients with aplastic anemia, and its mechanism of action has been presumed to be secondary to lymphocytotoxicity. However, our studies of lymphocyte function in aplastic anemia show marked abnormalities of lymphokine production, which ATG may modulate. In 12 of 17 patients with aplastic anemia, interleukin 2 (IL2) production was markedly elevated in vitro (P less than .01 by paired statistical analysis). Expression of the IL2 receptor, or Tac antigen, on peripheral lymphocytes assessed by flow microfluorometry was also increased above the normal range in 11 of 15 cases. Studies of ATG suggested that it might act to stimulate lymphocyte function. In vitro, ATG is a mitogen, as measured by incorporation of 3H-thymidine into blood mononuclear cells; the response of cells to ATG from patients with aplastic anemia was exaggerated in comparison with normals. Cell proliferation was accompanied by production of IL2 to levels that were, in some cases, similar to those obtained with lectin stimulation. Finally, supernatants from lymphocytes cultured in the presence of ATG were able to replace adherent cells in providing growth factors for the support of nonadherent cells in methylcellulose hematopoietic colony assays. These results provide a mechanism for an "immunostimulatory" action of ATG in effecting hematopoietic response in some patients with aplastic anemia.     

Effect of race on outcomes after allogeneic hematopoietic cell transplantation for severe aplastic anemia

We compared outcomes after hematopoietic cell transplantation in patients of African American (n = 84) and Caucasian (n = 215) descent with severe aplastic anemia. African Americans and Caucasians were matched for age, donor–recipient human leukocyte antigen match, graft type, and transplantation year. The median follow‐up of surviving patients was 5 years. In multivariate analysis, overall mortality risks were higher for African Americans compared to Caucasians (relative risk 1.73, P = 0.01). The 5‐year probabilities of overall survival adjusted for interval from diagnosis to transplantation, and performance score was 58% for African Americans and 73% for Caucasians. The day‐100 cumulative incidence of grade III–IV, but not grade II–IV acute graft‐versus‐host disease (GVHD), was higher in African Americans compared to Caucasians (29% vs. 13%, P = 0.006). Although the 5‐year cumulative incidence of chronic GVHD was not significantly different between the racial groups, African Americans were more likely to have extensive chronic GVHD compared to Caucasians (72% vs. 49%, P = 0.06). Survival differences between Caucasians and African Americans can be attributed to multiple factors. Our data suggest that some of the observed survival differences between Caucasians and African Americans may be explained by higher rates of acute GVHD and severity of chronic GVHD. Am. J. Hematol. 89:125–129, 2014. © 2013 Wiley Periodicals, Inc.     

Ticlopidine-induced aplastic anemia: development of chromosomal abnormalities and response to immunosuppressive therapy

Severe aplastic anemia is a well-recognized complication of ticlopidine therapy that carries a high mortality. Therapy with colony-stimulating factors or corticosteroids has been largely ineffective in this disorder. We report a case of ticlopidine-induced aplastic anemia that was successfully treated with cyclosporine and high-dose dexamethasone. The patient rapidly responded to immunosuppressive therapy and had a normal hemogram after cessation of immunosuppression. On long-term follow-up, the patient developed a progressive macrocytic anemia. Repeat bone marrow evaluation demonstrated myelodysplasia with erythroid hypoplasia. An associated chromosomal abnormality consisting of a t(3;16) (q21; p13.3) translocation was detected. This is the first report of a chromosomal abnormality associated with ticlopidine induced marrow aplastic anemia.