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.

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia.

OBJECTIVE: Azacitidine (Vidaza *) is approved in Europe for treatment of myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20-30% bone marrow (BM) blasts, and chronic myelomonocytic leukemia (CMML) with 10-29% BM blasts and no myeloproliferative syndrome (i.e. <13.000/µL white blood cells). In Belgium, the azacitidine reimbursement process can take several months, and is often delayed at submission for medical assessment by the Belgian National Institute for Health and Disability Insurance of incomplete patient dossiers, due to disease complexity and classification, and administrative burden. We describe the Vidaza Access Program and its application to an initial 175 patients. Individual medical dossiers were reviewed for completeness to facilitate patient access to treatment in Belgium. METHODS: A standardized anonymized patient information form is completed by the physician and sent for review to the Belgian Celgene Medical Department. The form is reviewed within three working days and, for complete dossiers, Celgene grants a financial guarantee for treatment with azacitidine. The patient can then be treated without the hospital being subjected to financial risk. RESULTS: Between January 2013 and June 2014, 63 physicians (53 Belgian hospitals) recruited 175 patients. In total, 163 patient dossiers were approved by Celgene (120 MDS, 36 AML, and 7 CMML), of which 104 dossiers were also approved by the review committee and 49 have been waiting for a final decision for a median of 6 months; no information is currently available for the remaining 10. No dossiers approved by Celgene have been rejected by the review committee. CONCLUSIONS: The Celgene Vidaza Access Program offers support to healthcare professionals in the appropriate use of azacitidine. By facilitating the assessment of patient dossiers and providing a financial guarantee for prescribers and hospitals, treatment can be initiated more rapidly and patients may better benefit from azacitidine treatment.

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.

Plerixafor in poor stem cell mobilizers: the Belgian Compassionate Use Program.

INTRODUCTION: Currently available stem cell mobilizing regimens (G-CSF +/- chemotherapy) show high failure rates, especially in heavily pretreated patients. Plerixafor, a new stem cell mobilizing agent blocking the CXCR4-SDF-1 interaction, offers a new strategy for stem cell mobilization, especially in poor mobilizers.This study reports on the outcome of the Belgian compassionate use program (CUP). MATERIALS AND METHODS: Between July 2008 and July 2009, 14 Belgian transplant centres participated in plerixafor CUP. In total, 22 poor stem cell mobilizers were included. Patients who previously failed stem cell mobilization received a combination of G-CSF (morning of Day 1-5) and plerixafor (evening of Day 4). Apheresis was performed on Day 5. G-CSF, plerixafor and apheresis were continued until at least 2 x 10(6)/kg CD34+ cells were obtained in a maximum of 3 collections. RESULTS: A mean of 2 plerixafor administrations was needed to reach > or = 2 x 10(6)/kg CD34+ cells. The overall cumulative success rate (defined as the proportion of patients achieving a successful collection after a maximum of 3 apheresis days) was 64%. Half of the heavily pretreated patients ( 3 prior chemotherapy regimens) could be mobilized successfully. Patients who received < or = 2 prior chemotherapy regimens mobilized successfully in 75% of the cases. Thirteen patients (59.1%) underwent autologous stem cell transplantation with normal neutrophil and platelet recovery times. CONCLUSION: For patients failing previous mobilization attempts, the combination of plerixafor and G-CSF is a successful mobilizing strategy, even in poor mobilizers who received > or = 3 prior chemotherapy regimens.

Effect of body composition on diet selection in finishing pigs.

The objective of this work was to determine if pigs of similar BW, but differing in 10th-rib backfat thickness, would differ in their selection of dietary protein. The first experiment was conducted with gilts and was designed in a 2 x 2 factorial arrangement with the main effects of body fat (lean vs. fat) and feeding program (single vs. choice). Crossbred gilts (n = 32) with an initial BW of 79 kg were sorted into high (2.24 cm, fat) and low backfat (1.51 cm, lean; P < 0.001) groups based on real-time ultrasound scans at the 10th rib. Diets were 1) a low-protein corn-based diet supplemented with crystalline AA (8.5% CP, 0.58% Lys) and 2) a high-protein corn- and soybean meal-based diet (22.7% CP, 1.275% Lys). During wk 1, all pigs were fed a 50:50 mix of the low-protein and high-protein diets. From d 7 to 28, one-half the pigs in the lean and fat groups were given a choice of low- and high-protein diets in separate feeders, whereas the others remained on the 50:50 mix. Initial differences in 10th-rib backfat thickness were maintained through d 28 (fat, 3.02 cm; lean, 2.42 cm; P < 0.001). Circulating leptin concentrations were greater in the fat pigs than in the lean pigs (3.84 vs. 3.35 ng/mL; P < 0.05). Average daily gain (1.06 kg/d) and ADFI (2.64 kg/d) were not different between treatment groups. However, the pattern of selection was different in the choice groups such that lean pigs consumed more (64.4%) of the high-protein diet than did fat pigs (35.6%, P < 0.01), resulting in a difference in the percentage of protein consumed (lean = 16.9% CP; fat = 12.8% CP; P < 0.01). A second experiment of similar design, but with barrows (n = 32; initial BW 69 kg), was conducted. Barrows classified as fat had 2.33 cm of 10th-rib backfat as compared with 1.75 cm in the lean group (P < 0.01). The percentage of protein in the diet selected by the fat barrows was not different from that selected by the lean barrows (15.9 vs. 17.4%). The lack of difference in selection pattern in barrows may be accounted for by the relatively smaller difference in body composition between the fat and lean classifications in the barrows in the choice feeding program as compared with body composition of the gilts. These results demonstrate that gilts of similar BW, but differing in composition, likely have different nutrient requirements and diet selection patterns. Although allowing pigs to self-select did not alter growth rate, the results indicated that diet selection can be used to allow pigs to meet their individual nutrient requirements more closely.

Thrombotic microangiopathy following intestinal transplantation: a single center experience.

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.

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.

Effects of ractopamine on performance and composition of pigs phenotypically sorted into fat and lean groups.

Crossbred barrows (n = 144; 80 kg) from four farrowing groups were phenotypically selected into fat (FAT) and lean (LEAN) pens using ultrasound. The difference in 10th-rib fat depth between the LEAN and FAT groups was > or =0.5 cm. Within a farrowing group, pigs were assigned to pens (five pigs per pen and eight pens per phenotype) to equalize pen weight and fat depth. Pigs were fed a corn-soybean meal diet containing 19% CP, 1.0% added animal/vegetable fat, and 1.1% lysine (as-fed basis). Half the pens received 10 ppm (as-fed basis) of ractopamine (RAC) during the 28-d finishing phase. At 7-d intervals, live weight and feed disappearance were recorded to calculate ADG, ADFI, and G:F, and 10th-rib fat depth and LM area were ultrasonically measured to calculate fat-free lean and fat and muscle accretion rates. During the first 7 d on feed, LEAN pigs fed RAC gained less (P < 0.05) than FAT pigs fed RAC or LEAN and FAT pigs fed the control diet (RAC x phenotype; P = 0.02); however, RAC did not (P > 0.25) affect ADG after the second, third, and fourth weeks, or over the entire 28-d feeding period. Although wk-2 and -3 ADG were higher (P < or = 0.03) in LEAN than in FAT pigs, phenotype did not (P = 0.08) affect overall ADG. Dietary RAC decreased (P < or = 0.05) ADFI over the 28-d feeding trial, as well as in wk 2, 3, and 4, but intake was not (P > 0.20) affected by phenotype. Neither RAC nor phenotype affected (P > 0.10) G:F after 7 d on trial; however, RAC improved (P < or = 0.04) wk-3, wk-4, and overall G:F. Lean pigs were more efficient (P < or = 0.05) in wk 2 and 3 and over the duration of the trial than FAT pigs. Ultrasound LM accretion (ULA) was not (P > or = 0.10) affected by RAC; however, LEAN pigs had greater (P < or = 0.02) ULA in wk 2 and 4 than FAT pigs. Although fat depth was lower (P < 0.01) in RAC-fed pigs than pigs fed the control diet, ultrasound fat accretion rate indicated that RAC-pigs deposited less (P = 0.04) fat only during wk 4. In addition, calculated fat-free lean (using ultrasound body fat, ULA, and BW) was increased (P < 0.05) in RAC pigs after 3 and 4 wk of supplementation. In conclusion, RAC enhanced the performance of finishing swine through decreased ADFI and increased G:F, whereas carcass lean was enhanced through decreases in carcass fat and increases in carcass muscling.