International, prospective haemovigilance study on methylene blue-treated plasma.

BACKGROUND AND OBJECTIVES: Methylene blue is a phenothiazine dye, which in combination with visible light has virucidal and bactericidal properties, disrupting the replication of a broad range of enveloped viruses and some non-enveloped viruses. The study objective was to collect data on adverse reactions occurring with methylene blue plasma administered in a routine clinical practice environment and document their characteristics and severity. MATERIALS AND METHODS: This was an open label, multicentre, non-controlled, non-randomized, non-interventional study. Patients who receive a methylene blue plasma transfusion were observed for any signs and symptoms (adverse reactions) within 24 h safter the start of the transfusion, in different hospitals for a study duration of at least 1 year. RESULTS: A total of 19 315 methylene blue plasma units were transfused. There were eight patients with adverse reactions recorded during the study, one of them serious. Two had more than one reaction (two and four, respectively). Three patients had previous transfusions with methylene blue plasma only. CONCLUSION: Methylene blue plasma has a very acceptable safety profile with a rate of serious adverse reactions of 0·5/10 000 units.

Long-term survival data from a phase 3 study of Filgrastim as an adjunct to chemotherapy in adults with de novo acute myeloid leukemia.

We previously reported the results of a double-blind, placebo-controlled study of Filgrastim in patients with de novo AML undergoing induction and consolidation chemotherapy. The study demonstrated that Filgrastim was effective and well tolerated and had no impact on complete remission or survival. We now report follow-up data on these patients, assessing long-term effects with emphasis on prognostic indicators. After a median follow-up of 7 years, 434 (83%) patients were dead, 73 (14%) were alive, and 14 (3%) were lost to follow-up. The proportions of deaths were similar in the Filgrastim (83%) and placebo (84%) groups. No differences in median time to death (1.04 years Filgrastim, 1.13 years placebo; P = 0.97) or median disease-free survival (0.86 years Filgrastim, 0.79 years placebo; P = 0.52) were evident. Proportional hazard modeling identified age, performance status, and French-American-British subtype as independent predictors for survival (P < 0.001, P = 0.005, and P = 0.036, respectively), whereas cytogenetic status was not (P = 0.118). Filgrastim had no effect on overall survival in any of these subgroup analyses as none of the treatment comparisons were statistically significant. These findings indicate that Filgrastim can be effectively used to support patients with AML undergoing induction and consolidation chemotherapy without worsening long-term disease outcome.

Hand grip strength as a screening tool for frailty in older patients with haematological malignancies.

OBJECTIVES: Frailty is a geriatric syndrome characterized by decreased physiological reserves and an age-related vulnerability to stressors with higher risk of adverse health outcomes. Comprehensive geriatric assessment (CGA) might detect frailty but is time-consuming, implying the need for initial frailty screening. Most frailty screening tools do not include functional measures. Hand grip strength (HGS) is a reliable surrogate for overall muscle strength and predicts functional decline, morbidity and mortality. No studies are available in cancer patients on HGS as screening tool for frailty. We aimed to assess whether HGS can be used as a screening tool to predict an abnormal CGA and therefore frailty. METHODS: Single centre cohort study in 59 patients aged 70 years or more with a haematological malignancy. HGS was measured using a vigorimeter. A patient was considered frail if any of the CGA elements were impaired. RESULTS: Mean HGS before start of therapy in women was 37.0 ± 14.3 kPa and in men 66.1 ± 13.1 kPa. An abnormal CGA was present in 52 subjects (88%). HGS was associated with concurrent abnormal CGA (p = 0.058 in women, p = 0.009 in men). AUC was 0.800 (SE = 0.130) in women and 0.847 (SE = 0.118) in men. Optimal HGS cut-off points for likelihood of abnormal CGA were ≤52 kPa in women and ≤80 kPa in men. DISCUSSION: In older patients with haematological malignancies, impairment in muscle function is present at diagnosis. HGS seems a promising screening tool to identify patients with abnormal CGA.

Molecular cytogenetic analysis of 10;11 rearrangements in acute myeloid leukemia.

MLLT10 (previously called AF10) is a moderately common MLL fusion partner predominantly occurring in acute monoblastic leukemia (AML-M5). 10;11 rearrangements require at least three breaks in order to generate an in-frame MLL-MLLT10 fusion as a result of the opposite orientations of both genes on the respective chromosome arms. In this study, we describe a detailed molecular cytogenetic analysis of MLL-MLLT10 positive 10;11 rearrangements in two patients. We observed an as yet unreported chromosomal mechanism with at least four breakpoints, leading to MLL-MLLT10 gene fusion in a 24-year-old male. An inversion of 11q13-q23 with a breakpoint in the MLL gene was followed by an additional break 3' of MLL prior to insertion of the 11q segment into MLLT10. In a second patient, a 37-year-old male with AML-M5b, molecular cytogenetic analysis of an apparent 10;11 reciprocal translocation showed an intrachromosomal inversion of 3'MLLT10followed by a reciprocal translocation between 10p12 and 11q23. Review of the literature showed that all cases were the result of an inversion of either 10p or 11q followed by translocation 10p;11q or insertion of the inverted segment into MLLT10 or MLL.

Plerixafor prescription modalities in autologous haematopoietic stem cell mobilization in Belgium.

OBJECTIVES: The efficacy and safety of plerixafor, an antagonist of the CXCR4 receptor, in combination with G-CSF has been demonstrated in patients suffering from Iymphoma and multiple myeloma (MM) eligible for autologous haematopoietic stem cell collection. However, different reimbursement criteria have been applied in different countries to select patients eligible for treatment with plerixafor. The objective of this observational study was to describe the plerixafor prescription modalities in daily practice in Belgium. METHODS: This open-label, prospective, observational study was conducted in 11 Belgian centres in 114 patients with lymphoma (Hodgkin's and non-Hodgkin's lymphoma) or MM who were treated with plerixafor according to the SmPC between April 2011 and October 2012. Patients included in another clinical trial with plerixafor were excluded from the study. RESULTS: The use of plerixafor in patients with MM or lymphoma was effective, with a success rate (defined as a total yield >2×10(6) CD34+ cells/kg) of 77%, and well tolerated (one SAE reported). Optimal collection (defined as a total yield >4×10(6) CD34+ cells/kg) was obtained for 43% of the study population (31% in lymphoma patients, compared to 61% in patients with MM). The use of plerixafor was in line with the SmPC and the Belgian reimbursement criteria for all patients. CONCLUSION: This study is showing that the use of plerixafor according to Belgian reimbursement criteria results in similar efficacy and safety as in other centres and countries worldwide.

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.

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.

Myelofibrosis patients in Belgium: disease characteristics.

OBJECTIVE: To date, only a small number of epidemiological studies on myelofibrosis have been performed. The current study aimed to characterize the myelofibrosis patient population in Belgium according to pre-defined disease parameters (diagnosis, risk categories, hemoglobin <10 g/dl, spleen size, constitutional symptoms, platelet count, myeloblast count), with a view to obtaining a deeper understanding of the proportion of patients that may benefit from the novel myelofibrosis therapeutic strategies. METHODS: A survey was used to collect data on prevalence and disease parameters on all myelofibrosis patients seen at each of 18 participating hematologic centers in 2011. Aggregated data from all centers were used for analysis. Analyses were descriptive and quantitative. RESULTS: A total of 250 patients with myelofibrosis were captured; of these, 136 (54%) were male and 153 (61%) were over 65 years old. One hundred sixty-five (66%) of myelofibrosis patients had primary myelofibrosis and 85 (34%) had secondary myelofibrosis. One hundred ninety-three myelofibrosis patients (77%) had a palpable spleen. About a third of patients (34%) suffered from constitutional symptoms. Two hundred twenty-two (89%) myelofibrosis patients had platelet count ≧50 000/µl and 201 (80%) had platelet count ≧100 000/µl. Of 250 patients, 85 (34%) had a myeloblast count ≧1%. Six (2%) patients had undergone a splenectomy. Thirteen (5·2%) patients had undergone radiotherapy for splenomegaly. CONCLUSIONS: The results of this survey provide insight into the characteristics of the Belgian myelofibrosis population. They also suggest that a large proportion of these patients could stand to benefit from the therapies currently under development.

Cytogenetic and clinical investigations in 76 cases with therapy-related leukemia and myelodysplastic syndrome.

Clinical, cytomorphologic, and cytogenetic investigations were carried out in a series of 76 secondary MDS and ANLL. Chromosome abnormalities were more frequent in patients with a history of multiple myeloma or macroglobulinemia (92%) and myeloproliferative disorders (82%) than in patients with previous breast cancer (40%). The secondary hematologic malignancies were mostly a trilineage bone marrow disorder. The most commonly found cytogenetic anomaly was monosomy 7, followed by total or partial loss of chromosome 5. In addition six other chromosomes, i.e., chromosome 3, 8, 9, 12, 17, and 21 seemed to be consistently involved in the pathogenetic mechanisms of secondary leukemia and MDS.

Interstitial 9q- deletions in hematologic malignancies.

Sixteen patients with interstitial deletions of the long arm of chromosome #9 (9q-). were studied. From our observations and the findings of ten other cases in the literature, it can be deduced that the anomaly is almost exclusively found in myeloproliferative disorders and that it rarely occurs as the sole anomaly; however, in more than one-third of the cases, it was associated with a t(8;21) and occurred as a secondary event. The deletion appears to be interstitial, the breakpoints are somewhat variable, and the region carrying the abl oncogene was never involved.

Anomalies of the long arm of chromosome 11 in human myelo- and lymphoproliferative disorders. I. Acute nonlymphocytic leukemia.

In a series of 365 consecutive ANLL cases of which 45.1% had abnormal karyotypes, 13 cases were detected with a structural abnormality of the long arm of chromosome 11. Besides one isochromosome 11q, there were six deletions and six translocations. Of these 12 patients, seven had acute monocytic leukemia (FAB-type M5), two had an M4, two had an M2, and one case of secondary leukemia had an M3-like disorder. Similar results with regard to the type of leukemia were obtained upon analysis of 41 cases of ANLL with an 11q anomaly described in the literature. This study confirms that a high proportion of acute monocytic leukemias and a lesser proportion of acute myelomonocytic leukemias are characterized by an 11q anomaly, mostly involving bands q22 and/or q23. Acute monocytic leukemia with an 11q structural anomaly appears to have a poor prognosis.

HLA typing in birdshot chorioretinopathy.

We examined 49 patients with birdshot chorioretinopathy in whom HLA typing had been performed. Of these 49 patients, 47 (95.9%) had the HLA-A29 antigen. The HLA-B12 (B44) antigen was also significantly associated with the disease, but this antigen is known to be in linkage disequilibrium with the antigen HLA-A29. The HLA-A2 antigen was less frequent in patients with birdshot chorioretinopathy than in the control group of normal European individuals (20% as compared to 44.6%).

Enzymatic erythrocyte creatine determinations as an index for cell age.

Creatine concentration in red blood cells was determined after ammoniumsulfate precipitation on a clear hemoglobin-free filtrate with a new enzymatic assay making use of bacterial creatinase. The method described is more specific than Griffiths' method and can easily be mechanised and adapted for use in a routine laboratory using classical automated equipment. By contrast with Griffiths' method no significant interferences of amino acids and creatine-like molecules were found. Reference values for this method were 0.379 +/- 0.076 mmol/l. In patients with high turnover of erythrocytes, e.g. haemodialysis patients (0.529 +/- 0.122 mmol/l), and renal insufficiency patients (0.565 +/- 0.145 mmol/l), significantly increased creatine concentration in erythrocytes were observed. Low erythrocyte creatine concentrations were found in chronic ambulatory dialysis patients (0.311 +/- 0.042 mmol/l).

18FDG PET versus high-dose 67Ga scintigraphy for restaging and treatment follow-up of lymphoma patients.

To date, only one published study has directly compared 67Ga scintigraphy (low dose, planar) with planar dual-head gamma camera 18F-fluorodeoxyglucose (18FDG) imaging for the purpose of treatment follow-up monitoring in lymphoma patients, and no data on restaging are available. The present study reports the direct comparison of high-dose (297-370 MBq) 67Ga planar and single photon emission computed tomography (SPECT) imaging and conventional 18FDG positron emission tomography (PET) for restaging and treatment follow-up of lymphoma patients versus a gold standard consisting of morphological imaging, including plain radiography and computed tomography (CT) scanning, bone marrow examination and long-term follow-up (<12 months). Sixteen patients, 10 with non-Hodgkin's lymphoma and six with Hodgkin's disease, were included (10 men, six women; median age, 43 years; range, 16-64 years). The median follow-up time was 27 months (range, 12-34 months). In two patients, 67Ga and 18FDG PET (370 MBq) were performed twice, resulting in 18 cross-sectional episodes. In 11 episodes, the results obtained by both imaging modalities were in agreement with regard to the presence or absence of disease when compared with the gold standard. However, the abnormalities found on 18FDG PET were always more extensive. In two episodes, 67Ga imaging normalized after treatment, whereas PET showed significant regression followed by subsequent normalization. In four additional episodes, 67Ga images were negative, whereas 18FDG PET visualized non-tumour-related pathology, such as lung infection, rib fracture or dense thymic tissue. In one gold standard-negative patient, the underlying cause of sternal FDG uptake remained undetermined. The data presented, although limited in number, suggest that 18FDG PET performs better than Ga imaging in monitoring lymphoma disease status. However, a correlation with clinical history and a knowledge of the characteristics of benign lesions are mandatory. Further studies are recommended.

Aseptic necrosis. A scintigraphic imitator of osseous involvement in Ga-67 avid lymphoma.

Based on the data by Armas et al, avascular necrosis, a not uncommon treatment-associated complication in patients with lymphoma, it should be easily distinguishable from osseous lymphomatous involvement in patients with Ga-67 avid lymphoma. In avascular necrosis, Ga-67 uptake will be either absent, decreased, or normal, whereas in lymphoma Ga-67 uptake will be increased. The authors present a patient with Hodgkin's disease who had new foci of simultaneously increased Ga-67 and Tc-99m MDP uptake because of avascular necrosis as proven by biopsy and long-term follow-up. The authors hypothesize that a possible-explanation for the discrepancy between this patient report and the series by Armas et al may be that increased Ga-67 is a delayed phenomenon related to healing.

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

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.

Long-term outcomes and quality of life in critically ill patients with hematological or solid malignancies: a single center study.

PURPOSE: Data concerning long-term outcomes and quality of life (QOL) in critically ill cancer patients are scarce. The aims of this study were to assess long-term outcomes and QOL in critically ill patients with hematological (HM) or solid malignancies (SM) 3 months and 1 year after intensive care unit (ICU) discharge, to compare these with QOL before ICU admission, and to identify prognostic indicators of long-term QOL. METHODS: During a 1 year prospective observational cohort analysis, consecutive patients with HM or SM admitted to the medical or surgical ICU of a university hospital were screened for inclusion. Cancer data, demographics, co-morbidity, severity of illness, organ failures, and outcomes were collected. The QOL before ICU admission, 3 months, and 1 year after ICU discharge was assessed using standardized questionnaires (EuroQoL-5D, Medical Outcomes Study 36-item Short Form Health Survey). Statistical significance was attained at P < 0.05. RESULTS: There were 483 patients (85 HM, 398 SM) (64% men) with a median age of 62 years included. Mortality rates of HM compared to SM were, respectively: hospital (34 vs. 13%), 3 months (42 vs. 17%), and 1 year (66 vs. 36%) (P < 0.001). QOL declined at 3 months, but improved at 1 year although it remained under baseline QOL, particularly in HM. Older age (P = 0.007), severe comorbidity (P = 0.035), and HM (P = 0.041) were independently associated with poorer QOL at 1 year. CONCLUSIONS: Long-term outcomes and QOL were poor, particularly in HM. Long-term expectations should play a larger role during multidisciplinary triage decisions upon referral to the ICU.

Early recognition of malignant lactic acidosis in clinical practice: report on 6 patients with haematological malignancies.

BACKGROUND: Malignant lactic acidosis is a potentially overlooked but life-threatening complication in patients with haematological malignancies. The aim of this study is to describe the features of six patients with malignant lactic acidosis and to discuss how its initial presentation can be differentiated from that of severe sepsis. METHODS: We prospectively collected data of all consecutive patients with haematological malignancies, admitted to the Ghent University Hospital Intensive Care Unit (ICU) between 2000 and 2007. RESULTS: Of 372 patients with haematological malignancies admitted to the ICU for life- threatening complications, 58 presented with lactic acid levels > or = 5 mmol/L. Six were diagnosed with malignant lactic acidosis. All patients with malignant lactic acidosis had high-grade lymphoblastic malignancies and were referred with a tentative diagnosis of severe sepsis or septic shock; lactic acid levels exceeded 9.45 mmol/L and lactate dehydrogenase (LDH) levels were at least 1785 U/L. Two patients had hypoglycaemia. All had a pronounced polypnea. In all patients hepatic malignant involvement was suspected. Two of the six patients survived their episode thanks to the early recognition of malignant lactic acidosis and the prompt administration of chemotherapy. One patient was still alive 6 months after initiating chemotherapy. CONCLUSION: Malignant lactic acidosis is a rare and often rapidly fatal metabolic complication if not promptly recognized and treated. An elevated lactic acid concentration, in disproportion with the level of tissue hypoxia, together with high serum LDH are cornerstones in the diagnosis. In contrast to septic shock patients, pronounced polypnea (Kussmaul's breathing pattern) rather than the haemodynamic instability is prominent.

High dose chemotherapy and stem cell rescue for metastatic germ cell tumours: long-term results from a single institution.

PURPOSE: To evaluate the long term results and the characteristics of patients treated with high dose chemotherapy (HDCT) for an advanced germ cell tumour at Ghent University Hospital from 1996 to 2010. MATERIALS AND METHODS: A retrospective analysis of patients treated with HDCT for germ cell tumours was performed. Data about stage at diagnosis, different prognostic scoring systems, timing of HDCT, response to HDCT and relapse-free period were collected. The following endpoints were evaluated: complete or incomplete response to HDCT, relapse free survival and overall survival time. RESULTS: Of the 148 patients treated with chemotherapy for an advanced germ cell tumour from 1996 to 2010, 10 (6.8%) needed salvage treatment by means of HDCT. Six patients achieved a complete response to one cycle of HDCT and 2 additional patients achieved a complete response to a second cycle of HDCT. A retrospective analysis showed 8 long-term survivors with a maximum follow-up time of 152 months. Two patients were recently transplanted and are not evaluable for survival yet. CONCLUSIONS: Our study suggests that long-term survival can be obtained by means of HDCT for metastatic germ cell tumours, even in patients with bad prognostic features at diagnosis. The question of whether to use 1 or 2 cycles of HDCT still remains unanswered.

Outcome in critically ill patients with allogeneic BM or peripheral haematopoietic SCT: a single-centre experience.

Outcome in haematological patients who develop critical illness has significantly improved over the last two decades, but less so in allogeneic BMT recipients. We prospectively investigated the outcome of 44 haematological patients with allogeneic BM or haematopoietic SCT (ABMT/AHSCT) requiring admission to the intensive care unit (ICU) of Ghent University Hospital between January 2000 and December 2007. We related outcome to the cause of critical illness, which was categorized as documented or clinically suspected bacterial infection, non-bacterial infection and non-infectious disease. Mechanical ventilation was required in 32 patients, and 12 patients received renal replacement therapy. Overall ICU-mortality, in-hospital mortality and 6-month mortality rates were 61, 75 and 80%, respectively. Hospital mortality rates in patients with bacterial infection (n=14), non-bacterial infection (n=13) and non-infectious disease (n=17) were 43, 85 and 94% (P=0.003). After adjustment for severity of illness sequential organ failure assessment (SOFA) score, bacterial infection (odds ratio 0.06, 0.01-0.36, P=0.002) was associated with significantly lower odds for hospital mortality. On the basis of our experience, ICU referral of ABMT/AHSCT patients is justifiable, as an acceptable fraction of these patients have longer-term survival. Documented or clinically suspected bacterial infection as the cause of critical illness is associated with better prognosis in comparison with other causes.