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Patients with myelodysplastic syndromes suffer from an impaired quality of life that is only partially explained by physical symptoms. In an observational study, we aimed to investigate the impact of current MDS treatments and the influence of disease perception on quality of life. Serial measurement of health-related quality of life was performed by ‘the QUALMS’, a validated MDS-specific patient reported outcome tool. Disease perception was evaluated by means of the Brief Illness Perception Questionnaire (B-IPQ). We prospectively collected data on 75 patients that started on a new treatment and could not demonstrate a significant change in QUALMS score or B-IPQ score during treatment. Six out of eight items evaluated in the B-IPQ correlated significantly with QUALMS score. In this small sample, no significant difference in QUALMS score was found between lower vs. higher risk MDS patients or other studied variables, e.g., targeted hemoglobin showed no correlation with QUALMS score. In daily practice attention must be paid to initial formation of disease perception as it correlates independently with health-related quality of life and does not change during treatment (clinicaltrials.gov identifier: NCT04053933).

Simple Summary Patients with simultaneous diagnosis of haematological malignancies (HM) and COVID-19 are an even greater challenge for hematologists. To better clarify their outcome, we describe the clinical features and outcome of a cohort of 450 patients with simultaneous diagnosis of HM and COVID-19 registered in the EPICOVIDEHA registry between March 2020 to February 2022. Overall, 343 (76.2%) patients received treatment for HM, and an overall response rate was observed in 140 (40.8%) patients after the first line of treatment. Thirty-day mortality was significantly higher in patients not receiving HM treatment (42.1%) than in those receiving treatment (27.4%, p = 0.004). Statistical analysis showed that, together with age, severe/critical COVID-19, >= 2 comorbidities, lack of HM treatment was an independent risk factors for mortality. These observations suggest the importance of HM treatment in these patients; therefore, it should be delivered as soon as possible for patients requiring immediate therapy. Background: The outcome of patients with simultaneous diagnosis of haematological malignancies (HM) and COVID-19 is unknown and there are no specific treatment guidelines. Methods: We describe the clinical features and outcome of a cohort of 450 patients with simultaneous diagnosis of HM and COVID-19 registered in the EPICOVIDEHA registry between March 2020 to February 2022. Results: Acute leukaemia and lymphoma were the most frequent HM (35.8% and 35.1%, respectively). Overall, 343 (76.2%) patients received treatment for HM, which was delayed for longer than one month since diagnosis in 57 (16.6%). An overall response rate was observed in 140 (40.8%) patients after the first line of treatment. After a median follow-up of 35 days, overall mortality was 177/450 (39.3%); 30-day mortality was significantly higher in patients not receiving HM treatment (42.1%) than in those receiving treatment (27.4%, p = 0.004), either before and/or after COVID-19, or compared to patients receiving HM treatment at least after COVID-19 (15.2%, p < 0.001). Age, severe/critical COVID-19, >= 2 comorbidities, and lack of HM treatment were independent risk factors for mortality, whereas a lymphocyte count >500/mcl at COVID-19 onset was protective. Conclusions: HM treatment should be delivered as soon as possible for patients with simultaneous diagnosis of COVID-19 and HM requiring immediate therapy.

SARS-CoV-2; Hematological malignancies SARS-CoV-2; Neoplasias hematológicas SARS-CoV-2; Neoplasies hematològiques Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States, Grant/Award Number: Project 2020-8223.

Objectives: Currently, there is no standard treatment for patients with acute myeloid leukaemia (AML) ineligible for standard induction chemotherapy (IC). This study aimed to report real-world evidence data on the efficacy and safety of decitabine in this patient group.Methods: This study was a Belgian, retrospective, non-interventional, multicentre registry of patients ≥ 65 years, with newly-diagnosed de novo or secondary AML ineligible for IC. Patients were treated according to routine clinical practice. Overall survival (OS), progression-free survival (PFS) and transfusion independence for ≥8 consecutive weeks were evaluated.Results: Forty-five patients were enrolled, including 67% (n = 30) with secondary AML. Median OS and PFS were 7.3 months (95% CI: 2.2-11.1) and 4.1 months (95% CI: 2.1-7.6) respectively. A subpopulation analysis showed that patients treated with ≥4 cycles (n = 21) had significantly better outcomes compared to patients receiving

Data on clinical use of ponatinib are limited. This prospective registry aimed to evaluate outcomes of ponatinib treatment in routine practice over 3 years (2016–2019) in Belgium (NCT03678454). Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) were treated with ponatinib per current label. Fifty patients (33 CML and 17 Ph+ ALL) were enrolled. Fifty-five percent of CML and 29% of Ph+ ALL patients had received ≥3 prior tyrosine kinase inhibitors (TKIs). Reasons for starting ponatinib were intolerance (40%), relapse or refractoriness (28%) to previous TKIs, progression (16%), or T315I mutation (16%). Median follow-up was 15 months for CML and 4.5 months for Ph+ ALL patients. Best response was a major molecular response in 58% of CML and 41% of Ph+ ALL patients. Of 20 patients who started ponatinib due to intolerance to previous TKIs, 9 (64%) CML and 4 (67%) Ph+ ALL achieved a major molecular response. Three-year estimates of overall survival were 85.3% and 85.6%, respectively, in CML and Ph+ ALL patients; estimated progression-free survival was 81.6% and 48.9%. Adverse reactions were reported in 34 patients (68%); rash (26%) and dry skin (10%) were most common. Reported cardiovascular adverse reactions included vascular stenosis (3), arterial hypertension (2), chest pain (1), palpitations (1), and vascular occlusion (1). This Belgian registry confirms results from the PACE clinical trial and supports routine ponatinib use in CML and Ph+ ALL patients who are resistant or intolerant to previous TKIs or with the T315I mutation. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04507-x.

Background Iclusig (ponatinib) is a third-generation tyrosine kinase inhibitor (TKI) indicated for adult patients with chronic, accelerated or blast phase CML resistant or intolerant to nilotinib or dasatinib or with Ph+ ALL resistant or intolerant to dasatinib or for patients with the T315I mutation. Long-term efficacy and safety of ponatinib have been demonstrated in clinical trials, but real-world data are still limited. Here, we report the data on ponatinib use in CML and Ph+ ALL patients in routine clinical practice collected over 3 years in Belgium. Methods This ongoing prospective registry (NCT03678454) is conducted in Belgium and includes patients ≥18 years of age eligible for ponatinib treatment per product label. Data on demographics, medical history, disease characteristics, treatment patterns, treatment outcomes and safety were collected for patients enrolled from 1 March 2016 (ponatinib reimbursement in Belgium) onwards. Median follow-up was 15 and 4.5 months for CML and Ph+ ALL patients, respectively. All analyses were descriptive. The study received Ethics Committee approval and patients' consents were collected as per Helsinki Declaration. Results In total, 50 patients (33 CML and 17 Ph+ ALL) were enrolled from 20 hospitals. The median age of CML and Ph+ ALL patients was 58 and 56 years, respectively. 91% of CML and 94% of Ph+ ALL patients had received ≥2, and 54% of CML and 29% of Ph+ ALL patients had received ≥ 3 prior TKIs. Potential risk factors for TKI cardiovascular toxicity were observed: hypertension (17 patients), history of cardiovascular disease (19), smoking (13), hypercholesterolemia (6), hyperlipidemia (5) and diabetes (8). The reasons for starting ponatinib were: intolerance to previous TKIs (20, 40%), refractoriness to previous TKIs (14, 28%), disease progression (8, 16%) or T315I mutation (8, 16%). At entry, 22 patients (44%; 11 CML and 11 Ph+ ALL) had a confirmed BCR-ABL mutation. Of these, 12 (55%; 6 CML and 6 Ph+ ALL) had the T315I mutation. Starting doses of ponatinib in CML patients were: 45 mg (70%), 30 mg (12%) and 15 mg (15%) once daily. One patient with CML started with 15 mg every 2 days. Starting doses in Ph+ ALL patients were: 45 mg (76%), 30 mg (12%) and 15 mg (12%). The median treatment duration was 380 days (range 15-2777) for CML patients and 123 days (range 13-2114) for Ph+ ALL patients, which included recently enrolled patients. Major molecular response (MMR) was achieved as best response in 19 (58%) CML patients and 7 (41%) Ph+ ALL patients; while 2 (6%) of CML and 3 (18%) of Ph+ ALL patients achieved complete cytogenetic response (CCyR) as best response. Of patients who started ponatinib due to intolerance to previous TKIs, 9 CML (64%) and 4 Ph+ ALL (67%) achieved MMR. There were 57 cases (38 in CML and 19 in Ph+ ALL) of dose reduction or interruption, due to AEs (74%), to prevent AEs (25%) and other reason (2%). There were 24 cases (19 in CML and 5 in Ph+ ALL) of dose increase: due to good tolerance of treatment (54%) and absent or low response (46%). At time of analysis, 29 patients (15 CML and 14 Ph+ ALL) had discontinued treatment, for the following reasons: AEs (34%), planned allogeneic transplantation (21%), disease progression (14%), intolerance (3%) and other reasons (28%). Treatment-related adverse events (AEs) were reported in 34 patients (68%); the most common were rash (26%) and dry skin (10%). Six (12%) patients reported ≥1 treatment-related serious AE (SAE): thrombocytopenia (2), palpitations (1), hypertension (1), pneumonia (1), coeliac artery stenosis (1), cholecystitis (1) and hyponatremia (1). One patient, with a history of congenital cardiomyopathy and aortic prosthesis, reported 3 serious cardiovascular events; these were considered as not related to ponatinib by the investigator. Conclusion Results from this real-world Belgian registry support the use of ponatinib in CML and Ph+ ALL patients who are resistant or intolerant to previous TKIs or have the T315I mutation. Most CML and a large proportion of Ph+ ALL patients obtained deep molecular responses. No new safety signals emerged with ponatinib treatment. The obtained results were in line with those of the PACE clinical trial, with the frequency of cardiovascular events apparently lower, possibly due to selection or improved monitoring of patients, or possible under-reporting vs clinical trial. Longer follow-up will be done to assess the long-term clinical efficiency in this real-life population. Disclosures André: Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda Millenium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding. Bailly:Incyte Biosciences: Other: Local PI of the Study. De Becker:Celgene: Other: ad hoc member of advisory board; Pfizer: Other: ad hoc member of advisory board; Sanofi Pasteur: Other: ad hoc member of advisory board; Incyte: Other: ad hoc member of advisory board. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bekaert:Incyte Biosciences: Employment. Beck:Incyte Biosciences: Employment. Selleslag:INCYTE: Consultancy, Other: Travel Expenses.

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. ispartof: EUROPEAN JOURNAL OF HAEMATOLOGY vol:101 issue:6 pages:737-749 ispartof: location:England status: published

Introduction: Mantle cell lymphoma is a B-cell non-Hodgkins 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 35 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 2013March 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 2396 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 cytarabinebased 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.

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.

Background Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) indicated for adult patients with resistant or intolerant chronic phase (CP), accelerated phase, or blast phase chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), or those with the T315I mutation. In Belgium, ponatinib has been commercially available since March 2016. The goal of this registry was to collect efficacy and safety data in CML and Ph+ ALL patients and to evaluate ponatinib in routine clinical practice in Belgium. Methods This ongoing, prospective, multi-center registry includes patients ≥18 years of age with CML or Ph+ ALL, who have initiated ponatinib treatment. Demographic, efficacy and safety data were collected for patients enrolled from March 2016 (day 0) onwards. Results up to study month 24 are presented. Data were analyzed by descriptive statistics. Ethics Committee approval was obtained and all patients provided informed consent. Results At time of data analysis, 34 patients (21 CP-CML and 13 Ph+ ALL) were enrolled. The median age of CP-CML and Ph+ ALL patients was 57 and 55 years, respectively. Patients were heavily pretreated: 90% of CML and 92% of Ph+ ALL patients had received ≥2 prior TKIs. Several patients had one or more risk factors for TKI cardiovascular toxicity: hypertension (10), history of cardiovascular disease (11), smoker (10), hypercholesterolemia (5), and diabetes (4). Median follow-up was 539 days for CML and 135 days for Ph+ ALL patients. The reasons for starting ponatinib therapy were related to refractoriness to previous TKIs (36%), progression (18%), presence of the T315I mutation (18%) or intolerance (29%). Eighty percent (8/10) of the patients who started ponatinib due to intolerance to previous TKIs had received ≥3 prior TKIs. At entry, 17 of the 34 patients (50%) had a confirmed BCR-ABL mutation. Of these 17, 10 (59%; 5 CML and 5 Ph+ ALL) had the T315I mutation. Starting doses of ponatinib in CML patients were 45 mg (76%), 30 mg (10%) and 15 mg (14%) once daily. Starting doses in Ph+ ALL patients were 45 mg (85%), 30 mg (8%) and 15 mg (8%). At latest follow up, the median treatment duration for the 21 CML patients was 531 days (range 15 - 2483) and for the 13 Ph+ ALL patients it was 123 days (range 13 - 1945). Best response was a major molecular response (MMR), which was obtained in 71% of CML patients and 38% of Ph+ ALL patients. The median time-to-best response was 175 days in CML and 35 days in Ph+ ALL patients. In the 10 patients (7 CML and 3 Ph+ ALL) who started ponatinib because of intolerance to several previous TKIs, 80% achieved MMR. The median time to achieve best response in these patients was 192 days for CML and 31 days for Ph+ ALL patients. Treatment-related adverse events (AEs) were reported in 20 patients (59%); the most common were rash (26%), dry skin (9%) and constipation (9%). Three patients reported ≥1 treatment-related serious AE (SAE): thrombocytopenia (n=1), cholecystitis (n=1) and hepatocellular injury (n=1). Three serious cardiovascular events were observed in 1 patient, who had a history of congenital cardiomyopathy and aortic prosthesis. They were scored as not related to ponatinib. Dose reductions or interruptions occurred in 33 cases (20 in CML and 13 in Ph+ ALL patients), with the following reasons most frequently mentioned: AEs (76%), to prevent AEs (18%) and other (6%). Dose increases occurred in 12 cases (10 in CML and 2 in Ph+ ALL patients), for the following reasons: good tolerance of treatment (58%), no or low response (33%) or other (8%). At time of analysis, 19 patients (9 CML and 10 Ph+ ALL) had discontinued treatment, of which 32% due to AEs, 5% due to an SAE, 21% due to planned allogeneic transplant, 16% due to disease progression and 26% due to other reasons. [Note: Percentages may not total 100 due to rounding] Conclusion Real-world evidence from this Belgian registry shows that ponatinib has a favorable efficacy and safety profile in, and supports its use in CML and Ph+ ALL patients who are resistant or intolerant to previous therapies or those with the T315I mutation. Deep molecular responses were obtained in the majority of patients. No new safety signals emerged with ponatinib treatment than those previously reported. Funding: Incyte Biosciences Benelux BV Disclosures Devos: Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Theunissen:Incyte: Honoraria. Van Eygen:Janssen: Consultancy, Research Funding; Roche: Research Funding; Amgen: Research Funding. Kuipers:Incyte Biosciences Benelux BV: Employment.

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. ispartof: CLINICAL INFECTIOUS DISEASES vol:50 issue:8 pages:1127-1134 ispartof: location:Berlin status: published

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 test's 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.

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. ispartof: Leukemia vol:21 issue:12 pages:2411-2419 ispartof: location:England status: published

Objectives: We evaluated azacitidine (Vidaza (R)) 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.

Myelodysplastic syndromes are a heterogeneous group of clonal haematological stem cell disorders. Allogeneic stem cells transplantation remains the only curative treatment but only a minority of patients are eligible for this treatment. In spite of this, it has become clear that treatment with lenalidomide and azanucleotides can lead to increased overall survival in particular subsets of patients with MDS. The relative silence on the therapeutic side is counter-balanced by major advances in the understanding of this heterogeneous disease. The introduction of high-throughput molecular techniques has resulted in the discovery that most patients harbour molecular aberrations, including pathways such as the spliceosome machinery previously not known to be involved. These newly discovered pathways will undoubtedly result in new therapeutic strategies for this difficult to treat disease.

Background Transplant-related thrombotic microangiopathy (TMA) is a well-recognized complication of all types of transplantations. Despite its known relationship with immunosuppressive therapy, only a few cases have been reported following intestinal transplantation. Methods We retrospectively reviewed the medical files of nine consecutive intestinal transplant patients between 2000 and 2008. Results The diagnosis of TMA was established in 3 patients (33%). At diagnosis the immunosuppressive therapy consisted of tacrolimus (n = 3), combined with azathioprine (n = 1) or sirolimus (n = 2) and steroids (n = 2). The median time between transplantation and TMA was 104 days (range, 55–167 days). Levels of ADAMTS13, a von Willebrand protease, were within normal ranges in all 3 patients. Treatment consisted of stopping/tapering of tacrolimus, together with initiation of plasma therapy, leading to complete remission in all 3 patients. During further follow-up, all 3 patients showed severe graft rejection necessitating more profound immunosuppressive therapy, leading to graft loss in 1 patient and infection-related death in the 2 others. At a median follow-up of 52 months (range, 9–100 months) all remaining TMA-free patients (n = 6) were alive with functioning grafts under minimal immunosuppression. Conclusion Herein we have described 3 intestinal transplant patients who were diagnosed with transplantation-related TMA. Despite excellent disease control the final outcomes were dismal, which clearly contrasts with the outcome among TMA-free patients, who were all well with functioning grafts at last follow-up.

A 20-year old man with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC) was diagnosed with a rectal non-Hodgkin's 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.

We studied the immune compartment in patients with myelodysplastic syndromes. We show increased surface expression of activation markers (HLA-DR(+), CD57(+), CD28(-), CD62L(-)) on T lymphocytes in blood and bone marrow (n=131). T cell activation was not restricted to any relevant clinical subgroup (FAB, IPSS, cytogenetics) and did not correlate with blood counts or need for treatment. In vitro clonogenic growth of marrow mononuclear cells (n=18) was not influenced by T cells expressing these markers. In addition, using X-chromosome inactivation analysis (n=12) we demonstrate clonal involvement of NK and B cells in half of these patients. We conclude that although activated T lymphocytes can be found in MDS, their role in disease pathogenesis remains unclear in the majority of patients. ispartof: Leukemia Research vol:32 issue:7 pages:1026-1035 ispartof: location:England status: published

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. ispartof: American Journal of Hematology vol:84 issue:11 pages:769-770 ispartof: location:United States status: published

There is increasing evidence that the immune system can promote cytopenia in myelodysplastic syndromes (MDS) to a variable extent. The interaction between CD40 and its natural ligand CD40L (CD154) plays a critical role in the regulation of humoral and cellular immune responses. The aim of this study was to investigate the role of the CD40/CD40L interaction in the pathogenesis of MDS. For this purpose, we looked at the presence of the CD40 receptor and its ligand in MDS peripheral blood (PB) and bone marrow (BM), and we studied the in vitro effects of inhibition and stimulation of the CD40 receptor on MDS monocytes. 1) Expression of CD40/CD40L. We analysed PB samples of 40 patients with MDS (19 RCMD, 15 RCMD-RS, 3 RAEB-1, 3 5q- syndrome) and 29 age-matched control subjects by flow cytometry. We observed that MDS patients have significantly higher percentages of circulating CD40+/CD14+ cells (8.34 % +/− 1.28 vs. 2.78 % +/− 0.31, p=0.0004) and CD40L+ T helper cells (4.44 % +/− 0.52 vs. 2.16 % +/− 0.22, p=0.001). In addition, we found higher percentages of CD40+/CD14+ cells (9.47 % +/− 1.96 vs. 3.53 % +/− 0.63, p=0.03) and CD40L+ T helper cells (5.13 % +/− 0.86 vs. 2.60 % +/− 0.53, p= 0.008) in BM of 22 patients (1 RA, 11 RCMD, 4 RCMD-RS, 5 RAEB-1 and 1 5q- syndrome) compared to 11 donor samples. 2) Stimulation of CD40. Selected CD14+ cells from PB of 21 patients (1 RA, 12 RCMD, 6 RCMD-RS, 2 RAEB-1) and 25 control subjects were stimulated for 24h with LPS or an agonistic anti-human CD40 antibody (clone 64, PanGenetics NV, The Netherlands). We observed that anti-CD40 induced significantly higher TNF-alpha levels in patients than in controls (436 vs. 64 pg/mL, p=0.008), whereas LPS induced comparable TNF-alpha levels. 3) Blocking of CD40. We cultured 5x105 BM mononuclear cells of 22 patients (1 RA, 12 RCMD, 3 RCMD-RS, 4 RAEB-1 and 2 5q- syndrome) in methylcellulose supplemented with growth-factors in the presence or absence of 5D12 (antagonist chimeric monoclonal anti-human CD40 antibody, PanGenetics NV, The Netherlands). The presence of 5D12 significantly increased colony-formation at day 14 (140 vs. 112, p=0.002). 5D12 did not affect colony formation in CD14-depleted cultures, nor in controls. In conclusion, we have demonstrated elevated levels of CD40 receptor on PB and BM monocytes of patients with MDS compared to age-matched control subjects. In addition, we have demonstrated increased levels of its ligand CD40L on T helper cells in PB and BM. Stimulation of CD40 on monocytes from patients induces significantly higher TNF-alpha levels, a cytokine known to inhibit colony formation. Moreover, we demonstrated that inhibition of this CD40 receptor with 5D12 can increase colony formation and that its effect is specific monocyte-dependent. Our observation together with the proven safety of 5D12 in phase 1 trials for patients with inflammatory bowel disease, might justify a phase I trial of 5D12 to improve cytopenia in patients with MDS.