J. C. W. Marsh

Autologous stem cell transplantation for systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is responsive to treatment with immunosuppressives and steroids, but often pursues a relapsing or refractory course resulting in increasing incapacity and reduced survival. Autologous stem cell transplantation (ASCT) following immunoablative chemotherapy is a newer therapy for autoimmune disease of potential use in severe SLE. A retrospective registry survey was carried out by the European Blood and Marrow Transplant and European League Against Rheumatism (EBMT/EULAR) registry. Data was collected from 53 patients with SLE treated by ASCT in 23 centres. Disease duration before ASCT was 59 (2-155) months (median, range), 44 (83%) were female, and median age was 29 (9-52) years. At the time of ASCT a median of seven American College of Rheumatology (ACR) diagnostic criteria for SLE were present (range 2-10) and 33 (62%) had nephritis. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony stimulating factor in 93% of cases. Ex vivo CD34 stem cell selection was performed in 42% of patients. Conditioning regimens employed cyclophosphamide in 84%, anti-thymocyte globulin in 76% and lymphoid irradiation in 22%. The mean duration of follow-up after ASCT was 26 (0-78) months. Remission of disease activity (SLEDAI < 3) was seen in 33/50 (66%; 95%CI 52-80) evaluable patients by six months, of which 10/31 (32%; 95%CI 15-50) subsequentlyrelapsed after six (3-40) months. Relapse was associated with negative anti-double stranded DNA (anti-dsDNA) antibodies before ASCT (P 0.007). There were 12 deaths after 1.5 (0-48) months, of which seven (12%; 95%CI 3-21) were related to the procedure. Mortality was associated with a longer disease course before ASCT (P 0.036). In conclusion, this registry study demonstrates the efficacy of ASCT for remission induction of refractory SLE, although mortality appeared high. The safety of this procedure is likely to be improved by patient selection and choice of conditioning regimen. The return of disease activity in one-third of patients might be reduced by long-term immunosuppressive therapy post-ASCT.

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.

The EBMT activity survey: 1990-2010

A total of 654 centers from 48 countries were contacted for the 2010 survey. In all, 634 centers reported a total of 33 362 hematopoietic SCT (HSCT) with 30 012 patients receiving their first transplant (12 276 allogeneic (41%) and 17 736 autologous (59%)). Main indications were leukemias: 9355 (31%; 93% allogeneic), lymphoid neoplasias specifically Non Hodgkin’s lymphoma, Hodgkin’s lymphoma and plasma cell disorders: 17 362 (58%; 12% allogeneic), solid tumors: 1585 (5%; 6% allogeneic) and non-malignant disorders: 1609 (6%; 88% allogeneic). There were more unrelated donors than HLA-identical sibling donors (53% versus 41%); the proportion of peripheral blood as stem cell source was 99% for autologous and 71% for allogeneic HSCT. Cord blood was primarily used in allogeneic transplants (6% of total) with three autologous cord blood HSCT being reported. The number of transplants has increased by 19% since 2005 (allogeneic 37% and autologous 9%) and continued to increase by about 1100 HSCT per year since 2000. Patterns of increase were distinct and different. The data show the development of transplantation in Europe since 1990, with the number of patients receiving a HSCT increasing from 4200 to over 30 000 annually. The most impressive trend seen is the steady increase of unrelated donor transplantation, in parallel to the availability of unrelated donors through donor registries.

Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party

Summary:We have developed a reduced-intensity conditioning regimen for patients with severe aplastic anemia (SAA) undergoing alternative donor transplants, which includes fludarabine (120 mg/m2), cyclophosphamide (1200 mg/m2) and antithymocyte globulin (7.5 mg/kg). Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine and methotrexate. We have enrolled 38 SAA patients in this trial: median age of 14 (3–37) years, transplanted from unrelated (n=33) or family mismatched (n=5) donors, with unmanipulated marrow (n=36) or peripheral blood (n=2). Seven patients (18%) had evidence of graft failure, 11% developed grade II–III acute GvHD and 27% developed chronic GvHD. The actuarial 2-year survival is 73%, with a median follow-up of 621 days. Younger patients (⩽14 years) had a lower risk of rejection (5%) and improved actuarial survival (84%). Causes of death were infections (n=3), graft failure (n=2), Epstein–Barr virus lymphoma (n=2) and hemorrhage (n=2). In conclusion, the actuarial 2-year survival is encouraging in young SAA patients receiving a radiation-free conditioning regimen. The significant risk of graft failure in patients 15 years or older may require modification of the conditioning regimen in adults.

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.

Matched-related donor transplantation for sickle cell disease: report from the Center for International Blood and Transplant Research

We report outcomes after myeloablative haematopoietic cell transplantation (HCT) from human leucocyte antigen (HLA)‐matched sibling donors in 67 patients with sickle cell disease transplanted between 1989 and 2002. The most common indications for transplantation were stroke and recurrent vaso‐occlusive crisis in 38% and 37% of patients respectively. The median age at transplantation was 10 years and 67% of patients had received >10 red blood cell transfusions before HCT. Twenty‐seven percent of patients had a poor performance score at transplantation. Ninety‐four percent received busulfan and cyclophosphamide‐containing conditioning regimens and bone marrow was the predominant source of donor cells. Most patients achieved haematopoietic recovery and no deaths occurred during the early post‐transplant period. Rates of acute and chronic graft‐versus‐host disease were 10% and 22% respectively. Sixty‐four of 67 patients are alive with 5‐year probabilities of disease‐free and overall survival of 85% and 97% respectively. Nine patients had graft failure with recovery of sickle erythropoiesis, eight of who had recurrent sickle‐related events. This report confirms and extends earlier reports that HCT from HLA‐matched related donors offers a very high survival rate, with few transplant‐related complications and the elimination of sickle‐related complications in the majority of patients who undergo this therapy.

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.

Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin

Immunosuppressive therapy has been shown to induce sustained hematological responses in a subset of patients with myelodysplastic syndromes (MDS). In particular, antithymocyte globulin (ATG), a polyclonal immunoglobulin induces hematological responses in up to 60% of MDS patients. We report herein on the results of a retrospective multicenter study on the use of ATG in the treatment of 96 patients with MDS. Patients were evaluated for duration of response to ATG, as well as survival after administration of ATG. The median age of the cohort was 54.7 years (range: 19–75 years), with a median follow-up of 33.8 months (range: 0.8–133 months). A total of 40 patients (42%) achieved a hematological response, of which 30 patients (75%) had a durable hematological response lasting a median duration of 31.5 months (range: 6–92 months). On multivariate analysis, both low International Prognostic Scoring System (IPSS) and bone marrow (BM) hypocellularity were independent predictive factors for improved response to ATG (IPSS Int-2/high: odds ratio (OR) 0.08, P=0.018 and BM normo/hypercellularity: OR 0.49, P=0.012). In addition, IPSS was the sole predictor of overall survival, with Int-2/high risk patients having a significantly poorer survival outcome (OR 0.08, P<0.01). In conclusion, this study identifies BM hypocellularity and a low IPSS as important factors predicting response to ATG.

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.