Edward C. Gordon-Smith

Guidelines for the diagnosis and management of aplastic anaemia

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

Bone marrow transplantation for Fanconi anemia

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.

The effect of treatment with Campath‐1H in patients with autoimmune cytopenias

We describe 21 patients with severe and life‐threatening autoimmune cytopenias resistant to standard immunosuppression who were treated with the monoclonal antibody Campath‐1H. Four patients had autoimmune neutropenia, four had autoimmune haemolytic anaemia, four had pure red cell aplasia, one had immune thrombocytopenia purpura (ITP), three had autoimmune haemolytic anaemia and ITP (Evans syndrome), three had autoimmune pancytopenia (ITP, autoimmune neutropenia and autoimmune haemolytic anaemia), one had ITP (associated with acquired Glanzmanns disease) and autoimmune neutropenia, and one had ITP and red cell aplasia. Campath‐1H was administered at a dose of 10 mg/d as an intravenous infusion for 10 d. Responses were seen in 15 patients, which were sustained in six. Relapse occurred in eight patients after Campath‐1H treatment. Patients entering the study later, received cyclosporine after Campath‐1H in an attempt to reduce the incidence of relapse. Three patients received a second course of Campath‐1H; all responded but later relapsed. Fourteen patients are alive at a median of 12 months (range 4–61) after Campath‐1H. Campath‐1H represents an alternative therapeutic option for severe, refractory autoimmune cytopenias.

Guidelines for the diagnosis and management of acquired aplastic anaemia.

The purpose of this guideline is to provide a rational approach to the investigation and management of patients with acquired aplastic anaemia. These guidelines have been produced by both specialists in the field of aplastic anaemia and experienced district general hospital haematologists, and reviewed by members of the British Committee for Standards in Haematology (BCSH) General Haematology Task Force. Because aplastic anaemia is a rare disease, many of the statements and comments in the first part of this manuscript are based on review of the literature and expert or consensus opinion rather than on clinical studies or trials. Medline, Cinahl and Embase databases were searched for this purpose. Levels of evidence for treatment of aplastic anaemia also reflect the rarity of this condition. To ensure wide dissemination of these guidelines, they are also available on the BCSH website and will be reviewed on a three yearly basis.

Diamond‐Blackfan anaemia in the U.K.: analysis of 80 cases from a 20‐year birth cohort

The U.K. Diamond‐Blackfan Anaemia (DBA) Registry was established with the aim of providing a representative database for studies on the aetiology, pathophysiology and treatment of DBA. We have analysed retrospective data from 80 cases (33 male, 47 female) born in the U.K. in a 20‐year period (1975–94), representing an annual incidence of 5 per million live births. Ten children from seven families had an apparently familial disorder. 13% were anaemic at birth, and 72.5% had presented by the age of 3 months. 67% had macrocytosis at presentation. 72% responded initially to steroids, and at the time of study 61% were transfusion‐independent (45% steroid‐dependent) and 39% required regular transfusions. Unequivocal physical anomalies, predominantly craniofacial, were present in 37%, and were more likely in boys (52%) than girls (25%). 18% had thumb abnormalities. Height was below the third centile for age in 28%, and 31% had neither short stature nor physical anomalies. Four children without physical abnormalities had normal red cell indices, and achieved steroid‐independent remission, suggesting transient erythroblastopenia of childhood rather than DBA. The birth month distribution of children with sporadic DBA and craniofacial dysmorphism showed a possible seasonality, consistent with a viral aetiology.

Human recombinant GM-CSF in allogeneic bone-marrow transplantation for leukaemia: double-blind, placebo-controlled trial

In a randomised, double-blind trial 20 patients with leukaemia received human recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) and 20 received placebo, for 14 days after allogeneic, matched sibling, bone-marrow transplantation. The neutrophil count recovered to 0.5 x 10(9)/l 3 days earlier in the GM-CSF group than in the placebo group (not significant), and the median neutrophil count at 14 days was significantly higher in the GM-CSF group (1.90 vs 0.46 x 10(9)/l). The lymphocyte count was significantly higher in the GM-CSF than in the placebo group between days 10 and 15 after transplantation, but this difference was not associated with a higher incidence of graft-versus-host disease. There was no evidence that GM-CSF was associated with a greater incidence of leukaemic relapse. The GM-CSF group had lower haemoglobin concentrations and platelet counts and higher plasma urea, creatinine, and bilirubin than the placebo group. The duration of hospital stay was the same for both patient groups. Further studies are now indicated to assess the overall effect of GM-CSF on outcome after allogeneic bone-marrow transplantation.

A pilot study of antithymocyte globulin (ATG) in the treatment of patients with ‘low‐risk’ myelodysplasia

Summary. We report 30 ‘low‐risk’ patients with myelodysplasia (MDS) (defined as < 10% bone marrow blasts) who were treated with antithymocyte globulin (ATG). In total, 20 patients were evaluable at the study end‐point (response to treatment at 6 months). The diagnosis in these 20 patients was refractory anaemia (RA) in 13, RA with excess blasts in four, and RA with ringed sideroblasts in three. Median age was 54·5 years (range, 31–73 years). There were two cases of secondary MDS. The bone marrow was hypocellular in eight cases and cytogenetics were abnormal in four cases. All patients received lymphoglobuline (horse ATG; Sangstat, France) at a dose of 1·5 vials/10 kg/day for 5 d. The treatment was well tolerated. Three patients in the study died (disease progression, invasive aspergillosis and lung carcinoma respectively); 10 out of 20 evaluable patients (50%) responded to treatment and became transfusion independent; eight out of 13 (62%) patients with RA responded. The median duration of response was 15·5 months (2–42+ months) at the time of analysis.

Serum thrombopoietin levels in patients with aplastic anaemia

Endogenous serum thrombopoietin (TPO) levels were measured in 31 patients with aplastic anaemia (AA) using an enzyme immunoassay with a sensitivity of 20 pg/ml. The median platelet count for all AA patients was 30 ± 29 × 109/l (range 5–102) compared with a median of 284 ± 59 × 109/l (range 148–538) for normal controls. Serum TPO levels were significantly elevated in all patients compared with normals (1706 ± 1114.2, range 375–5000 v 78 ± 54, range 16.5–312.9, P < 0.0001). There was no correlation between serum TPO levels and the degree of thrombocytopenia in AA patients, but TPO levels were significantly higher in patients who were platelet transfusion dependent than in patients who were transfusion independent (P < 0.01). There was a trend for higher TPO levels in patients with severe AA compared with non‐severe AA patients. Clinical trials of TPO and a related truncated, pegylated molecule, megakaryocyte growth and development factor (PEG‐rHuMGDF), are awaited to determine whether treatment with these drugs will result in increased platelet counts in patients with AA.

Bone marrow transplants for paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare clonal haematological disorder characterized by intravascular haemolysis and increased risk of thrombosis. PNH is associated with bone marrow failure syndromes including aplastic anaemia, myelodysplasia and leukaemia. Bone marrow transplants are sometimes used to treat PNH, but small series and reporting biases make assessment of transplant outcome difficult. The outcome of 57 consecutive allogeneic bone marrow transplants for PNH reported to the International Bone Marrow Transplant Registry (IBMTR) between 1978 and 1995 was analysed. The 2‐year probability of survival in 48 recipients of HLA‐identical sibling transplants was 56% (95% confidence interval 49–63%). Two recipients of identical twin transplants remain alive 8 and 12 years after treatment. One of seven recipients of alternative donor allogeneic transplants is alive 5 years after transplant. The most common causes of treatment failure were graft failure and infections. Our results indicate that bone marrow transplantion can restore normal bone marrow function in about 50% of PNH patients.

Use of cyclosporin A in allogeneic bone marrow transplantation for severe aplastic anemia.

We report on 18 months of experience with cyclosporin A (Cy A) in allogeneic bone marrow transplantation for severe aplastic anemia (SAA). Twenty-three patients treated with Cy A for postgraft immunosuppression are described and compared with 14 similar patients with SAA in whom methotrexate (MTX) was used. The early results are encouraging with 73% survival in the Cy A group compared with 43% in the MTX group. The improvement is partly attributable to the low incidence of graft failure. Graft-versus-host disease (GVHD) remains a problem with an overall incidence of 70% in Cy A-treated aplastic patients, although mortality has been only 14%. Toxicity attributable to Cy A has so far been acceptable and nephrotoxicity is usually mild and reversible. However, three aplastic patients have developed clinically significant renal impairment while receiving both Cy A and aminoglycoside antibiotics.