Stef Meers

Bronchoalveolar Lavage Fluid Galactomannan for the Diagnosis of Invasive Pulmonary Aspergillosis in Patients with Hematologic Diseases

BACKGROUND Prompt diagnosis of invasive pulmonary aspergillosis (IPA) remains a challenge. Galactomannan (GM) detection in bronchoalveolar lavage (BAL) fluid by the Platelia enzyme immunoassay aims to further improve upon the tests utility by applying it directly to specimens from the target organ. METHODS A retrospective analysis of the Platelia assay was performed on BAL samples from 99 evaluable high-risk hematology patients, including 58 with proven or probable IPA. RESULTS BAL GM demonstrated an improved sensitivity profile (91.3% with an optical density [OD] index cutoff of >or=1.0) in comparison with culture and microscopy (50% and 53.3%, respectively). The diagnostic accuracy as given by the area under the receiver operating characteristic curve was 0.93 (95% confidence interval, 0.88-0.99); further decreasing the OD index cutoff to 0.5 compromised specificity more than it improved sensitivity. Estimates of the positive and negative predictive value of the Platelia assay on BAL samples (OD index, >or=1.0) were 76% and 96%, respectively. The mean BAL GM OD index was not different in neutropenic versus nonneutropenic case patients (3.9 and 4.5, respectively; P = .3); however, a trend toward decreased sensitivity in patients receiving mold-active prophylaxis was noted. CONCLUSION BAL GM is a valuable adjunctive diagnostic tool to other conventional microbiologic and radiologic studies.

Myeloablative Conditioning Predisposes Patients for Toxoplasma gondii Reactivation after Allogeneic Stem Cell Transplantation

BACKGROUND Toxoplasmosis is an often fatal opportunistic infection following allogeneic hematopoietic stem cell transplantation and is largely due to deferred diagnosis. In addition, breakthrough infections occur during prophylaxis with trimethoprim-sulfamethoxazole. METHODS From November 2001 onwards, we routinely monitored all stem cell transplant recipients who were seropositive for Toxoplasma gondii and/or who received a transplant from a donor who was seropositive for T. gondii reactivation by polymerase chain reaction of peripheral blood samples. The aim of this study was to evaluate the incidence of and the risk factors for Toxoplasma reactivation in this population not receiving specific prophylaxis. We also studied the feasibility of a preemptive treatment approach based on this routine monitoring. RESULTS We report a toxoplasmosis incidence of 8.7% (18 of 208 patients). Twelve patients (5.8%) had a T. gondii infection at diagnosis; 6 patients (2.9%) had Toxoplasma disease, including cerebral toxoplasmosis (n = 5) and cardiopulmonary toxoplasmosis (n = 1). We identified myeloablative conditioning and conditioning with high-dose total body irradiation (10-12 Gy) as risk factors for T. gondii reactivation, whereas patients with a seropositive donor were less likely to experience reactivation. Patients with T. gondii disease had a significantly higher number of transcripts in blood than did patients with a T. gondii infection. Finally, with a strategy of routine monitoring and preemptive treatment with clindamycin-pyrimethamine, we only had 3 Toxoplasma-related deaths among our patients, which is a much lower rate than that reported in the literature. CONCLUSIONS Systematic monitoring with polymerase chain reaction is a good means to detect T. gondii reactivation and could reduce T. gondii-related mortality among hematopoietic stem cell transplant recipients.

Monocytes are activated in patients with myelodysplastic syndromes and can contribute to bone marrow failure through CD40-CD40L interactions with T helper cells.

Immune mechanisms have been shown to contribute to the process of myelodysplastic syndromes (MDS)-related bone marrow (BM) failure. The aim of this study was to evaluate the possible contribution of activated monocytes through CD40–CD40L(CD154) interactions with activated T helper cells. We demonstrated in 77 predominantly lower risk MDS patients that the CD40 receptor was expressed significantly higher on monocytes and that CD40L was expressed significantly higher on T helper cells in peripheral blood (PB) and BM. Increased levels of CD40 and CD40L were detected in the same patients. In addition, stimulation of the CD40 receptor on purified PB monocytes led to a significantly higher tumor necrosis factor alpha production in patients. Co-culture of BM mononuclear cells of 21 patients in the presence of a blocking CD40 monoclonal antibody (ch5D12) led to a significant increase in the number of colony-forming units. A correlation was seen between increased CD40 expression on monocytes with patients’ age below 60 years and with the cytogenetic abnormality trisomy 8. These results demonstrate that CD40 expression on monocytes may identify a subgroup of MDS patients in whom immune-mediated hematopoietic failure is part of the disease process. As such, the CD40–CD40L-based activation of monocytes might be a target to counteract MDS-related BM failure.

Rectal non-Hodgkin's lymphoma in an infliximab treated patient with ulcerative colitis and primary sclerosing cholangitis

A 20-year old man with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC) was diagnosed with a rectal non-Hodgkins lymphoma (NHL) at surveillance endoscopy while being in remission on infliximab therapy. Further staging identified a diffuse large B-cell NHL, EBV negative restricted to the rectal submucosa (stage IA). Until now, there has not been any evidence of an increased risk of NHL in patients with UC nor of an increased risk of lymphoproliferative disorders in IBD patients. Hence, the role of concomitant PSC in the pathogenesis of intestinal NHL is unclear. However, IBD patients treated with purine analogues and with anti-TNF are at risk of NHL, especially hepatosplenic T-cell lymphoma. The management of this particular young patient is further complicated by the possibility of a future colectomy due to intractable disease which compromises the use of radiotherapy for this localized disease.

Management of myelodysplastic syndromes in adults: guidelines from the Belgian Haematological Society.

Abstract Myelodysplastic syndromes (MDS) represent a heterogeneous group of haematological disorders characterized by ineffective haematopoiesis and an increased risk for leukemic transformation. In recent years several new therapeutics have emerged that have demonstrated to alter the natural course of the disease. This document summarizes the state of the art in diagnosis and treatment of this heterogeneous disease, as proposed by a group of expert haematologists in the field of MDS from the Belgian Haematological Society. Its main purpose is to guide clinicians in daily practice to treat patients with this disease, within the limitations of current reimbursement modalities in Belgium.

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey

Abstract Objectives: We evaluated azacitidine (Vidaza®) safety and efficacy in patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), in a real-life setting. Treatment response, dose, and schedule were assessed. Methods: This non-interventional, post-marketing survey included 49/50 patients receiving azacitidine at 14 Belgian haematology centres from 2010–2012. Treatment-emergent adverse events (TEAEs), including treatment-related TEAEs, and serious TEAEs (TESAEs) were recorded throughout the study. Treatment response [complete response (CR), partial response (PR), haematological improvement (HI), stable disease (SD), treatment failure (TF)) and transfusion-independence (TI) were evaluated at completion of a 1-year observation period (1YOP) or at treatment discontinuation, and overall survival (OS), at study conclusion. Results: The median age of patients was 74·7 (range: 43·9–87·8) years; 69·4% had MDS, 26·5% had primary or secondary AML, and 4·1% had CMML. Treatment-related TEAEs, grade 3–4 TEAEs, and TESAEs were reported in 67·3%, 28·6%, and 18·4% of patients, respectively. During 1YOP, patients received a median of 7 (1–12) treatment cycles. Treatment response was assessed for 38/49 patients. Among MDS and CMML patients (n = 29), 41·4% had CR, PR, or HI, 41·4% had SD, and 17·2% had TF. Among AML patients (n = 9), 44·4% had CR or PR, 33·3% had SD, and 22·2% had TF. TI was observed in 14/32 (43·8%) patients who were transfusion-dependent at baseline. Median (95% confidence interval) OS was 490 (326–555) days; 1-year OS estimate was 0·571 (0·422–0·696). Conclusions: Our data support previous findings that azacitidine has a clinically acceptable safety profile and shows efficacy.

Results from the Belgian mantle cell lymphoma registry.

Introduction: Mantle cell lymphoma is a B-cell non-Hodgkin’s lymphoma characterized by a t(11;14), resulting in overexpression of cyclin D1. Conventional chemotherapy obtains frequent (but short) remissions, leading to a poor median overall survival (OS) of 3–5 years. To obtain more information about the prevalence and current treatment of Mantle cell lymphoma (MCL) in Belgium, we collected data in a Belgian registry of MCL. Materials and methods: All Belgian MCL patients, t(11;14) and/or cyclin D1 positive, seen in hematology departments over a one-year period (April 2013–March 2014) were included. Data about patient characteristics, histology, treatment lines, and response were compiled and retrospectively analyzed. Results: Four hundred and four patients were included with a median age at diagnosis of 64 years (range 23–96 years) and a male predominance (72%). For 2013, we calculated a prevalence of at least 36.2 per million and an incidence of at least 7.0 per million in the Belgian population. Characteristics at diagnosis involved lymphadenopathy (82%), splenomegaly (44%), B-symptoms (39%), and hepatomegaly (10%). Bone marrow invasion was present at diagnosis in 77%. Stage at diagnosis was advanced in the majority of cases. The median number of treatment lines was 1. Type of first line treatment included a combination of anthracyclin and cytarabine-based regimen (34%), anthracyclin (39%), and other. Rituximab was used in 88% of first line treatments. In 44% first line treatment was followed by autologous stem cell transplantation. Conclusion: The analysis of this Belgian MCL registry provides insight in the epidemiology, demographics, and current treatment of our Belgian MCL population.

Diagnosis and management of PNH: Review and recommendations from a Belgian expert panel

Despite its considerable morbidity and mortality, paroxysmal nocturnal haemoglobinuria (PNH) is still underdiagnosed. Patients with PNH can suffer from cardiovascular, gastrointestinal, neurological or haematological symptoms and refer to several specialists. The aim of this paper is to review the diagnosis and the management of PNH patients, with the primary focus on identifying high‐risk groups. Additionally, the implementation and prognostic value of the defined high‐risk groups will be commented on and the management of PNH patients is discussed from a Belgian perspective. Finally, based on the available data, recommendations are provided. Eculizumab is a potent C5 complement inhibitor and reduces intravascular haemolysis and thrombosis in PNH patients and improves their quality of life. As thrombosis is the main cause of death in PNH patients, identifying high‐risk PNH patients in need of therapy is essential. Currently, novel complement inhibitors are in development and the first data seem promising. Another challenge in PNH is to identify new markers to assess the thrombotic risk to achieve a better risk‐based prophylactic anti‐thrombotic management. Finally, because of the low prevalence of the disease, PNH patients should be included in the prospective PNH registry, which will offer new insights on the natural course of the disease and the impact of treatment of PNH.

Monocytes from patients with myelodysplastic syndromes are more resistant to inhibition by thalidomide

The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias and marrow dysplasia. Immune mechanisms are in part responsible for the marrow failure observed in MDS patients [1]. We have recently provided evidence for the involvement of CD40-CD40L interactions between monocytes with T helper cells in the pathogenesis of this marrow failure [2]. More specifically, we have shown that monocytes from MDS patients produce more TNF-α in response to stimulation of the CD40-receptor than control monocytes. Thalidomide is a potent immune-modulating agent with a broad spectrum of immunologic effects and has been used in MDS patients as single-agent therapy [3-5] or in combination with other agents [6-9]. Inhibition of TNF-α production is believed to be the primordial mechanism by which thalidomide acts in MDS. However, in vitro data on the effect of thalidomide on TNF-α production in MDS currently lack. With this study, we provide the first data of the effect of increasing doses of thalidomide on the production of TNF-α by monocytes from MDS patients in response to lipopolysaccharide (LPS) or CD40-agonists. We show that only a high concentration of thalidomide is able to inhibit the TNF-α production of MDS monocytes stimulated by CD40-agonists.