Current use of androgens in bone marrow failure disorders: a report from the Severe Aplastic Anemia Working Party of the European Society of Blood and Marrow Transplantation

Androgens have represented the historical therapeutic backbone of bone marrow failure (BMF) syndromes. However, their role has been rarely analyzed in prospective setting and systematic and long-term data are currently unavailable regarding their usage, effectiveness and toxicity in both acquired and inherited BMF. Here, taking advantage of a unique disease-specific international dataset, we retrospectively analyzed the so far largest cohort of BMF patients who received androgens before or in absence of an allogeneic hematopoietic cell transplantation (HCT), reappraising their current use in these disorders. We identified 274 patients across 82 EBMT affiliated centers, 193 with acquired (median age of 32) and 81 with inherited BMF (median age of 8 years). With a median duration of androgen treatment of 5.6 and 20 months respectively, complete/partial remission rates at 3 months were of 6%/29% in acquired and 8%/29% in inherited disorders. Five-year overall survival and failure free survival (FFS) were respectively 63% and 23% in acquired and 78% and 14% in inherited contexts. Androgen initiation after second line treatments for acquired, and after > 12 months post-diagnosis for inherited group were identified as factors associated with improved FFS in multivariable analysis. Androgen use was associated with a manageable incidence of organ-specific toxicity and low rates of solid and hematological malignancies. Sub-analysis of transplant-related outcomes after exposure to these compounds showed probabilities of survival and complications similar to other transplanted BMF cohorts. This study delivers a unique opportunity to track androgen use in BMF syndromes and represents the basis for general recommendations on their use on behalf of the SAAWP of the EBMT

Graft-versus-host disease and relapse/rejection-free survival after allogeneic transplantation for idiopathic severe aplastic anemia: a comprehensive analysis from the SAAWP of the EBMT.

Survival after Allo-HSCT for severe idiopathic aplastic anemia (SAA) has improved in recent years, approaching 75% at 5 years. However, an SAA-adapted composite endpoint, GVHD and relapse/rejection-free survival (GRFS), may more accurately assess patient outcomes beyond survival. We analyzed GRFS to identify risk factors and specific causes of GRFS failure. Our retrospective analysis from the SAAWP of the EBMT included 479 patients with idiopathic SAA who underwent Allo-HSCT in 2 conventional situations: i) upfront Allo-HSCT from a matched related donor (MRD) (upfront cohort), and ii) Allo-HSCT for relapsed or refractory SAA (rel/ref cohort). Relevant events for GRFS calculation included graft failure, grade 3-4 acute GVHD, extensive chronic GVHD, and death. In the upfront cohort (n=209), 5-year GRFS was 77%. Late Allo-HSCT (i.e., >6 months after SAA diagnosis) was the main poor prognostic factor, specifically increasing the risk of death as the cause of GRFS failure (HR: 4.08, 95% CI [1.41-11.83], p=0.010). In the rel/ref cohort (n=270), 5-year GRFS was 61%. Age was the main factor significantly increasing the risk of death (HR: 1.04, 95% CI [1.02-1.06], p<0.001), acute GVHD (HR: 1.03, 95% CI [1.00-1.07], p=0.041), and chronic GVHD (HR: 1.04 95% CI [1.01-1.08], p=0.032) as the cause of GRFS failure. GRFS after upfront MRD Allo-HSCT was very good, notably with early Allo-HSCT, confirming that younger patients with a MRD should be transplanted immediately. GRFS was worse in cases of salvage Allo-HSCT, most notably in older patients, questioning the utility of Allo-HSCT earlier in the disease course

The potential utility of B cell-directed biologic therapy in autoimmune diseases

Increasing awareness of the importance of aberrant B cell regulation in autoimmunity has driven the clinical development of novel B cell-directed biologic therapies with the potential to treat a range of autoimmune disorders. The first of these drugs—rituximab, a chimeric monoclonal antibody against the B cell-specific surface marker CD20—was recently approved for treating rheumatoid arthritis in patients with an inadequate response to other biologic therapies. The aim of this review is to discuss the potential use of rituximab in the management of other autoimmune disorders. Results from early phase clinical trials indicate that rituximab may provide clinical benefit in systemic lupus erythematosus, Sjögren’s syndrome, vasculitis, and thrombocytopenic purpura. Numerous case reports and several small pilot studies have also been published reporting the use of rituximab in conditions such as myositis, antiphospholipid syndrome, Still’s disease, and multiple sclerosis. In general, the results from these preliminary studies encourage further testing of rituximab therapy in formalized clinical trials. Based on results published to date, it is concluded that rituximab, together with other B cell-directed therapies currently under clinical development, is likely to provide an important new treatment option for a number of these difficult-to-treat autoimmune disorders

Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study.

peer reviewedAllogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT

ERYTHROCYTE CALMODULIN LEVEL IN GDB- TYPE OF G6PD DEFICIENCY

WOS: A1987F528500083

ERYTHROCYTE-MEMBRANE ATPASE ACTIVITY OF G6PD-DEFICIENT INDIVIDUALS AND THE EFFECT OF PRIMAQUINE METABOLITE(S) ON MEMBRANE ATPASE ENZYMES

WOS: A1984AFN7600007PubMed ID: 6152296

Erythrocyte membrane ATPase activity of G6PD-deficient individuals and the effect of primaquine metabolite(s) on membrane ATPase enzymes

PubMedID: 6152296Erythrocyte membrane Na+/K+, Ca2+/Mg2+ and Mg2+ ATPase activities in addition to the calmodulin-activated Ca2+/Mg2+ ATPase enzyme were measured in both G6PD-deficient and normal individuals. Although all three membrane ATPase activities were somewhat higher in the G6PD-deficient erythrocytes, only activated Ca2+/Mg2+ ATPase activity was significantly increased. The effect of primaquine on the membrane ATPases was also compared with other ATPase inhibitors. Primaquine was ineffective on erythrocyte membrane ATPase in vitro. However, sera containing primaquine metabolite(s) were inhibitory to Ca2+/Mg2+ and Mg2+ ATPase systems of only G6PD-deficient erythrocytes. Other ATPase inhibitors showed a similar inhibitory effect in G6PD-deficient and normal erythrocytes, indicating a specific influence of primaquine on ATPase system in G6PD-deficiency. It is suggested that this effect of primaquine may be an additional factor for haemolysis observed in the people with GdB- type of G6PD-deficiency among the Mediterranean populations

Rhino-orbital-cerebral mucormycosis with different cerebral involvements: Infarct, hemorrhage, and ophthalmoplegia

PubMedID: 17987470Rhino-orbital-cerebral mucormycosis is a rare but often fatal opportunistic necrotizing infection of the sinuses, orbit, and brain caused by saprophytic fungi. It usually develops in patients with diabetes or immune system deficiency. In this study, imaging features in 3 patients with rhino-orbital-cerebral mucormycosis who presented with various symptoms and different cerebral involvements are discussed. Headache, blurred vision, fever, painful ophthalmoplegia, and cranial nerve involvement were among the clinical findings. Computed tomography and magnetic resonance imaging are the best imaging methods for assessing the extent of this disease. Relatively typical but nonspecific characteristics are bone destruction, vascular invasion, and central hypointensity in the paranasal sinuses or an intracranial mass that is revealed by T2-weighted magnetic resonance imaging. Imaging findings include cavernous sinus involvement, cerebral infarct, and intracerebral hemorrhage. Because of the invasive and fulminant nature of rhino-orbital-cerebral mucormycosis, successful treatment seems to be based on early diagnosis and on the management of underlying immunologic problems. Copyright © 2007 Informa Healthcare USA, Inc