Androgen therapy in inherited bone marrow failure syndromes: analysis from the Canadian Inherited Marrow Failure Registry.

Progressive cytopenia is a serious complication among paediatric patients with inherited bone marrow failure syndromes (IBMFS). Androgens have been used to improve blood counts in different bone marrow failure conditions. Little is known about efficacy and toxicity with new androgens (i.e., danazol) in different types of IBMFS. We identified 29 patients from the Canadian Inherited Marrow Failure Registry, who received oxymetholone or danazol. Sixteen (55%) had haematological response including patients with unclassified IBMFS (45%). Danazol showed a better toxicity profile and similar efficacy compared to oxymetholone. Androgens are an effective and safe option to ameliorate bone marrow failure in IBMFS.

Trilineage Hematopoiesis Induced by Low-dose Eltrombopag in a Patient With Fanconi Anemia can be Used as a Bridge to Hematopoietic Stem Cell Transplant.

Fanconi anemia (FA) is an autosomal recessive, progressive bone marrow failure disorder characterized by congenital defects and marked cancer predisposition. Hematopoietic stem cell transplant is the therapy of choice for FA patients with progressive pancytopenia. These patients receive multiple transfusions for cytopenias. Oxymetholone has been used with variable success to improve cytopenias. Eltrombopag has been shown to induce bilineage or trilineage hematopoiesis in aplastic anemia and patients with myelodysplastic marrow. We report a case of FA where eltrombopag in conjunction with oxymetholone induced trilineage hematopoiesis and eliminated transfusion requirement before transplant, thereby enhancing favorable outcome after hematopoietic stem cell transplant.

Treatment of inherited bone marrow failure syndromes beyond transplantation.

Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.

Biomarkers of angiogenesis as prognostic factors in myelodysplastic syndrome patients treated with hypomethylating agents.

Angiogenesis occurs in response to tissue ischemia and wound healing, and contributes to the pathogenesis of a variety of diseases, such as benign and malignant neoplasia. Several studies have measured bone marrow microvessel density (MVD) in MDS patients and acute myeloid leukemia (AML) patients transformed from MDS, and MVD was higher in MDS patients than controls, but was lower than in AML patients. Vascular endothelial growth factor (VEGF) is expressed in bone marrow blast cells, and an autocrine VEGF signaling mechanism has been established in MDS. Increased bone marrow angiogenesis and VEGF concentrations are adverse prognostic features in all of these patients. In this study, 69 patients were treated in two groups: hypomethylating agents or supportive care with oxymetholone±pyridoxine. We evaluated the MVD and VEGF expression of paraffin-embedded bone marrow samples from patients. We also investigated the relationship between angiogenesis-related biomarkers including MVD, VEGF expression, and clinical factors. The patient median age was 65 years, and the median follow-up duration was 28 months. MVD assessment among subtypes of WHO MDS classification showed that the MVD of RCUD was significantly lower than in other types (p=0.02). However, there was no significant difference in VEGF expression according to the subtype of MDS. Although MVD and VEGF expression did not differ between risk groups based on the IPSS, the low risk group tended to have lower expression of angiogenesis-related biomarkers. MDS patients receiving hypomethylating agents had significantly lower MVD expression in responders than in non-responders (6.13±3.38 vs. 9.89±2.10, respectively, p=0.039). In a consecutive evaluation at the time of diagnosis and 3 months after the initial treatment, the group with a decrease or no change of MVD had a higher response rate compared to that in the group with an increase of MVD (92.9% vs. 58.8%, respectively, p=0.045). Adverse prognostic factors included older age, MDS type other than RCUD, a higher IPSS risk group, and abnormal cytogenetics. Although angiogenesis-related markers did not demonstrate any significant prognostic association with survival, MVD (≥10n/mm2) and a strong expression of VEGF seemed to be associated with lower survival rate. These data suggested that the MVD value might be helpful in predicting responsiveness to treatment, especially in MDS patients treated with hypomethylating agents. Although angiogenesis-related markers including VEGF did not demonstrate a significant association with survival outcomes, we observed that high MVD and strong VEGF expression seemed to be associated with lower survival rate. Therefore, biologic markers related to angiogenesis might have a potential as prognostic factors for MDS patients.

Oxymetholone therapy of fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling.

Androgens are widely used for treating Fanconi anemia (FA) and other human bone marrow failure syndromes, but their mode of action remains incompletely understood. Aged Fancd2(-/-) mice were used to assess the therapeutic efficacy of oxymetholone (OXM) and its mechanism of action. Eighteen-month-old Fancd2(-/-) mice recapitulated key human FA phenotypes, including reduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia. As in humans, chronic OXM treatment significantly improved these hematological parameters and stimulated the proliferation of hematopoietic stem and progenitor cells. RNA-Seq analysis implicated downregulation of osteopontin as an important potential mechanism for the drug's action. Consistent with the increased stem cell proliferation, competitive repopulation assays demonstrated that chronic OXM therapy eventually resulted in stem cell exhaustion. These results expand our knowledge of the regulation of hematopoietic stem cell proliferation and have direct clinical implications for the treatment of bone marrow failure.

Does anything work for anaemia in myelofibrosis?

Anaemia is a common finding at diagnosis in myelofibrosis, and becomes a symptomatic problem in most patients with time. There are several treatment options for specific anaemia treatment, none of which has been tested in large, randomized, controlled trials. However, as myelofibrosis is not a disease with spontaneous remissions, even non-randomized trials carry weight. In this survey, the existing evidence will be analysed, both for the commonly used treatments like erythropoiesis-stimulating agents, androgens and thalidomide and for the new drugs in the area, and conclusions will be drawn concerning standard clinical anaemia treatment in myelofibrosis, which according to evidence from studies has a 40-50% chance of response in patients with not too advanced disease.

Improvement in erythropoieis-stimulating agent-induced pure red-cell aplasia by introduction of darbepoetin-α when the anti-erythropoietin antibody titer declines spontaneously.

Anti-erythropoietin antibodies usually cross-react with all kinds of recombinant erythropoietins; therefore, erythropoiesis-stimulating agent (ESA)-induced pure red-cell aplasia (PRCA) is not rescued by different ESAs. Here, we present a case of ESA-induced PRCA in a 36-yr-old woman with chronic kidney disease, whose anemic condition improved following reintroduction of darbepoetin-α. The patient developed progressive, severe anemia after the use of erythropoietin-α. As the anemia did not improve after the administration of either other erythropoietin-α products or erythropoietin-ß, all ESAs were discontinued. Oxymetholone therapy failed to improve the transfusion-dependent anemia and a rechallenge with ESAs continuously failed to obtain a sustained response. However, her anemia improved following reintroduction of darbepoetin-α at 3 yr after the initial diagnosis. Interestingly, anti-erythropoietin antibodies were still detectable, although their concentration was too low for titration. In conclusion, darbepoetin-α can improve ESA-induced PRCA when the anti-erythropoietin antibody titer declines and its neutralizing capacity is lost.

Clinical course of non-severe aplastic anemia in adults.

The clinical course of non-severe aplastic anemia is variable, and risk factors related to disease progression are not well known. We reviewed clinical and laboratory data of the patients who were diagnosed with non-severe aplastic anemia from 1997 to 2007 at Seoul National University Hospital and analyzed the clinical course and outcomes in these patients. We defined non-severe aplastic anemia as hypocellular marrow with cytopenia in the peripheral blood, which does not meet the criteria for severe aplastic anemia (at least two of the following: ANC < 500/microl, platelet < 20,000/microl or reticulocyte < 20,000/microl). Among a total of 96 patients, 53 (55.2%) were male and the median age was 37.6 years old. As much as 41.7% (40) of the patients were initially asymptomatic. Sixty-two patients who were treated with oxymetholone, ATG/ALG, cyclosporin or other agents after initial diagnosis showed significantly lower levels of initial hemoglobin, red blood cell count and platelet count than those who did not receive any treatment. During the follow-up period, 18 patients progressed to severe aplastic anemia. Their median age was 29.9 years and the median progression time was 18 months. Initial white blood cell count and absolute neutrophil count in the evolution group tended to be lower than in the other group. The patients whose thrombocytopenia did not respond to treatment showed markedly higher frequency of progression to severe aplastic anemia. Treatment itself and responsiveness in reticulocyte and absolute neutrophil count were not correlated with their clinical courses. Sixteen patients showed overall improvement, whereas three patients developed secondary hematologic disease, acute myeloid leukemia, myelodysplastic syndrome and paroxysmal nocturnal hemoglobinuria. Non-severe aplastic anemia has a relatively indolent and mild clinical course. However, 18.8% of the study population progressed to severe disease. White blood cell and absolute neutrophil count at diagnosis and treatment responsiveness of thrombocytopenia were associated with disease progression. Careful monitoring and early management are needed for patients at risk.

Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema.

OBJECTIVE: To provide a summary of the literature regarding the use of attenuated androgens during the past 40 to 50 years for the treatment of hereditary angioedema (HAE). DATA SOURCES: MEDLINE and PubMed were searched to identify studies involving the treatment of HAE with androgens. STUDY SELECTION: Studies were selected based on their relevance to the use of androgens for the treatment of HAE. RESULTS: Attenuated androgens have proven successful for the short- and long-term treatment of HAE. Adverse effects are still concerning, and their use in children and pregnant women must be undertaken with great caution. Scheduled monitoring of liver function tests and lipid profiles in patients treated with these medications is critical. CONCLUSIONS: Attenuated androgens have been successful in the short- and long-term treatment of HAE, and they are still the most frequently used medications in the United States for the treatment of this disease. There is a lack of readily available options for the treatment of acute HAE attacks apart from the administration of fresh frozen plasma or safe prophylactic therapies; however, several appropriate agents currently in clinical trials in the United States appear promising.

Oral oxymetholone reduces mortality induced by gamma irradiation in mice through stimulation of hematopoietic cells.

Oxymetholone is a 17alpha -alkylated anabolic-androgenic steroid. This drug can stimulate bone marrow cells and increase the blood cells in the peripheral blood vessels. It has been used for the treatment of anemia caused by low red cell production. Since oxymetholone has hematopoietic effect, we studied radioprotective effects of this drug in mice. In this study, we determined percentage of survival, dose-reduction factor (DRF) and hematological parameters in irradiated mice which treated with or without oxymetholone. Oxymetholone administrated at different doses 80, 160, 320, 640 mg/kg by gavages at 24 h before 8 Gy gamma irradiation. At 30 days after treatment, the following percentage of animals survival in each group was as: 80 mg/kg, 50%; 160 mg/kg, 50%; 320 mg/kg, 55%; 640 mg/kg, 75% and vehicle, 15%. Percentage of survival increased in all of treated groups statistically compared with irradiated-vehicle group. In the groups treated by oxymetholone, maximum protection was realized at 640 mg/kg. In order to calculate the DRF for oxymetholone, mice were exposed to whole-body gamma irradiation with dose ranges between 5.83 and 11.23 Gy. The probit line for oxymetholone-treated mice was shifted to the right with a DRF of 1.14. In mice exposed to whole-body gamma-irradiation (4 Gy), an oral administration of 640 mg/kg oxymetholone ameliorated radiation-induced decreases in circulating platelets and erythrocytes, but had a less effect on total number of WBC. These results demonstrate that oxymetholone stimulates myelopoiesis and thrombocytopenia and enhances survival in mice after ionizing radiation.

Clonal monosomy 7 in a megakaryoblastic leukemia developed on the basis of Fanconi anemia.

A 13-year-old girl with a history of Fanconi anemia developed acute myeloid leukemia of the M7 subtype with a 45,XX,-7 karyotype, which is rare in M7 subtype. Treatment protocols were set up, but she died of sepsis and osteomyelitis during induction.

Littoral cell angioma of the spleen in a patient with severe aplastic anaemia.

Littoral cell angioma (LCA) is a rare benign tumour of the spleen. We describe a patient with aplastic anaemia who, following multiple treatments with rabbit and horse Anti-Thymocyte Globulin and anabolic steroids developed marked splenomegaly and hypersplenism. LCA was diagnosed post splenectomy. This is the first case of LCA associated with aplastic anaemia and its treatment.

Inherited aplastic anaemia.

A number of inherited (constitutional/genetic) disorders are characterized by bone marrow (BM) failure/aplastic anaemia (AA) usually in association with one or more somatic abnormality. Occasionally, these patients may present with AA alone and be labelled to have idiopathic AA. In recent years, there have been significant advances in the genetics of Fanconi anaemia (FA), dyskeratosis congenita (DC) and other BM failure syndromes. This is facilitating accurate diagnosis and beginning to unravel their pathophysiology. Furthermore, these advances are also providing important insights into normal haemopoiesis and how this might become defective in some patients presenting with the more common idiopathic AA. Indeed, a link between DC and idiopathic AA and in turn to defective telomerase has now been established. This advance also suggests that treatments directed at correction of telomerase activity might benefit AA patients who do not respond to conventional therapy.

Review of oxymetholone: a 17alpha-alkylated anabolic-androgenic steroid.

BACKGROUND: Oxymetholone (17beta-hydroxy-2-[hydroxymethylene]-17-methyl-5alpha-androstan-3-one) is a 17alpha-alkylated anabolic-androgenic steroid and a synthetic derivative of testosterone. It has been approved by the US Food and Drug Administration for the treatment of anemias caused by deficient red cell production. OBJECTIVES: This review summarizes the pharmacokinetics, current and future clinical applications, and adverse effects of oxymetholone. Relevant studies were identified using a search of MEDLINE through March 2001, supplemented by conference abstracts and presentations. RESULTS: Because of its anabolic properties, oxymetholone has been studied for the treatment of HIV-associated wasting, antithrombin III deficiency, pediatric growth impairment, and damaged myocardium, with varying degrees of success. Hepatotoxicity is a major adverse effect associated with the use of oxymetholone, with cholestatic jaundice the most important hepatic side effect. Less common hepatic side effects associated with the use of anabolic-androgenic steroids include peliosis hepatis and formation of hepatic tumors. All anabolic-androgenic steroids can cause androgenic side effects, including acne, hirsutism, hair loss, clitoral/phallic enlargement, vocal changes, erectile tissue stimulation, gynecomastia, amenorrhea, and changes in libido and sexual potency. CONCLUSIONS: As is the case with many anabolic-androgenic steroids, few pharmacokinetic and tolerability studies were performed before oxymetholone's approval in the 1960s. It has proved, however, to be an appropriate treatment choice for selected patients with anemia, if carefully monitored.

Ampullary carcinoma developing after androgenic steroid therapy for aplastic anemia: Report of a case.

Sex steroids influence the development and course of human genital carcinomas including breast, testis, prostata, and ovarian cancers. (1) Other carcinomas such as hepatoma, cholangioma, and pancreatic cancer have also been reported to be related to sex hormones. (2-4) The existence of sex hormone receptors has been demonstrated immunohistochemically in specimens of these diseases. We recently encountered a patient in whom an ampullary carcinoma developed 39 months after the start of androgenic steroid therapy for aplastic anemia. Immunohistochemic analysis of resected tumor specimens of the patient suggested a possible hormonal effect on the tumor oncology.

Multiple hepatic adenomas caused by long-term administration of androgenic steroids for aplastic anemia in association with familial adenomatous polyposis.

We report a rare case of hepatic adenomas (HA), in a 20-year-old Japanese girl treated for 6 years with anabolic androgens for aplastic anemia. In a review of the world literature using computer MEDLINE search, we found only 17 cases of androgen-induced HA published between 1975 and 1998 in the English-language literature. The patient was referred to us because of liver lesions detected during a follow-up examination for familial adenomatous polyposis. After being diagnosed with aplastic anemia at 14 years of age, she had been treated with oxymetholone (30 mg/day) for 6 years. Laboratory evaluation revealed normal liver function. Ultrasonography (US) and computed tomography (CT) demonstrated multiple liver lesions. Histopathological examinations of biopsied specimens from the liver tumor showed HA. After the patient was diagnosed with HA, oxymetholone was tapered off. Patients taking androgenic-anabolic steroids should be carefully monitored with US and CT and tumor markers should be measured. This report may be helpful in identifying the population who is at risk of developing hepatic sex hormone-related tumors.

Refractory anemia with excess of blasts: increased survival when treated with cyclophosphamide, methotrexate and 6-mercaptopurine.

Owing to the lack of efficacious treatments for refractory anemia with an excess of blasts (RAEB), evaluation of other therapeutic strategies is necessary, especially in elderly patients. We report herein our experience with an oral triple drug regimen with cyclophosphamide 200 mg/m2 and methotrexate 20 mg/m2 once a week, and 6-mercaptopurine 50 mg/m2 daily for the treatment of RAEB. Eighteen patients with a median age of 62 yr (range 17-80) received a triple drug regimen (TDR), and they were compared with 6 patients who received oxymetholone (2 mg/m2/d) and 9 who received supportive therapy only. Partial response was achieved in 45% of patients receiving TDR. In 77% of patients treated with TDR the number of bone marrow blasts decreased to <5%; however, they persisted with trilineage dyspoietic morphologic changes. Median survival for TDR was 23 months (range 1-96), which was longer than that for the other groups. A slight rise in liver enzymes was the only side effect of TDR. TDR seems to be a useful alternative in patients with RAEB, a finding to be confirmed in further prospective studies.

A case of aplastic anaemia in pregnancy.

Aplastic anaemia in pregnancy is an extremely rare condition with high maternal morbidity and mortality rates. Intensive haematological support remains the mainstay of therapy and a successful obstetric outcome can be best accomplished with the close clinical collaboration of the haematologist and the obstetrician as occurred with our patient reported here.