[Show abstract][Hide abstract] ABSTRACT: Acute myeloid leukaemia mainly affects elderly people, with a median age at diagnosis of around 70 years. Although about 50–60% of patients enter first complete remission upon intensive induction chemotherapy, relapse remains high and overall outcomes are disappointing. Therefore, effective post-remission therapy is urgently needed. Although often no post-remission therapy is given to elderly patients, it might include chemotherapy or allogeneic haemopoietic stem cell transplantation (HSCT) following reduced-intensity conditioning. We aimed to assess the comparative value of allogeneic HSCT with other approaches, including no post-remission therapy, in patients with acute myeloid leukaemia aged 60 years and older.
[Show abstract][Hide abstract] ABSTRACT: Hepatosplenic T-cell lymphoma (HSTCL) is a rare malignancy of unknown incidence that has been associated with immune-mediated disease. This study explored the incidence and patient characteristics of HSTCL in a population of 15.5 million over a 13-year period using a comprehensive national pathology database in The Netherlands (Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief) with 100% capture. Twelve cases of HSTCL were identified during this period. The overall incidence of HSTCL in the Dutch population over this period was estimated at 0.06 per million inhabitant-years. All but 2 of the patients were adults at the time of diagnosis (median age, 34.5 years), and most patients died within a year of diagnosis. Three patients had a history of immune-mediated disease, 1 of whom was receiving azathioprine at the time of HSTCL diagnosis. Azathioprine as well as anti-tumor necrosis factor-α agents have been reported as possibly being associated with HSTCL. None of the 12 HSTCL patients had been treated with an anti-tumor necrosis factor-α agent.
[Show abstract][Hide abstract] ABSTRACT: The preferred type of post-remission therapy (PRT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1) is a subject of continued debate, especially in patients at higher risk of non-relapse mortality (NRM), including patients >40 years of age. We report results of a time-dependent multivariable analysis of alloHSCT (n=337) versus chemotherapy (n=271) or autologous HSCT (n=152) in 760 patients aged 40 and 60 years with AML in CR1. Patients receiving alloHSCT showed improved survival (OS) as compared to chemotherapy (respectively 57±3% vs 40±3% at 5 years, P<0.001). Comparable OS was observed following alloHSCT and autoHSCT in patients with intermediate risk AML (60±4% vs 54±5%). However, alloHSCT was associated with less relapse (HR 0.51, P<0.001) and better RFS (HR 0.74, P=0.029) as compared to autoHSCT in intermediate risk AMLs. AlloHSCT was applied following myeloablative conditioning (n=157) or reduced intensity conditioning (n=180), resulting in less NRM, but comparable outcome with respect to OS, RFS, and relapse. Collectively, these results show that alloHSCT is to be preferred over chemotherapy as PRT in patients with intermediate and poor risk AML aged 40-60 years, while autoHSCT remains a treatment option to be considered in patients with intermediate risk AML.Leukemia accepted article preview online, 27 November 2014. doi:10.1038/leu.2014.332.
[Show abstract][Hide abstract] ABSTRACT: Introduction:Many patients with sickle cell disease (SCD) have a reduced exercise capacity and abnormal lung function. Cardiopulmonary exercise testing (CPET) can identify causes of exercise limitation.Methods:44 consecutive SCD patients (27 HbSS, 11 HbSC, and 6 HbS-beta thalassemia) with a median age (interquartile range) of 26 (21-41) years underwent pulmonary function tests, CPET, chest x-ray and echocardiography to further characterize exercise limitation in SCD.Results: Peak oxygen uptake (V'O2-peak), expressing maximum exercise capacity, was decreased in 83% of the studied patients. V'O2-peak correlated with hemoglobin levels (R=0.440, P=0.005), forced vital capacity (FVC) (R=0.717, P<0.0001). Cardiothoracic ratio on chest x-ray inversely correlated with FVC (R=-0.637 P<0.001). According to criteria for exercise limitation, the patients were limited in exercise capacity due to anemia (n=17), cardiovascular dysfunction (n=2), musculoskeletal function (n=10), pulmonary ventilatory abnormalities (n=1), pulmonary vascular exercise limitation (n=1) and poor effort (n=3).Conclusion: In the present study we demonstrate that anemia is the most important determinant of reduced exercise tolerance observed in SCD patients without signs of pulmonary hypertension. We found a strong correlation between various parameters of lung volume and cardiothoracic ratio and we hypothesize that cardiomegaly and relative small chest size may be important causes of the impairment in pulmonary function, i.e. reduced long volumes and diffusion capacity, in SCD. Taking into account anthropomorphic differences between SCD patients and controls could help to interpret lung function studies in SCD better.
Full-text · Article · Aug 2014 · American Journal of Hematology
[Show abstract][Hide abstract] ABSTRACT: In adult patients with sickle cell disease two distinct subphenotypes have previously been defined: patients with the viscosity-vaso-occlusion subphenotype (VVO) suffer mainly from vaso-occlusive pain crises and have a relatively high hemoglobin concentration. Patients classified as the hemolysis-endothelial dysfunction subphenotype (HED) suffer from stroke and pulmonary hypertension and have an elevated concentration of lactate dehydrogenase. However, this classification is not possible in children due to low rates of complications. We used laboratory markers to classify children into the two subphenotypes, and measured vWF and vWF propeptide as markers of endothelial dysfunction. We included 106 children with sickle cell disease (mean age 8.7years), 74 (70%) with HbSS/HbSβ° genotype and 32 (30%) with HbSC/HbSβ(+) genotype. vWF and vWF propeptide were significantly elevated in patients with sickle cell disease; this was more pronounced in patients with the HbSS/HbSβ° genotype. Patients with the HED subphenotype had higher levels of vWF propeptide, and a trend towards higher levels of vWF compared to those with the VVO subphenotype. We demonstrated that even young children in a stable clinical condition show signs of persistent endothelial dysfunction. A prospective study should demonstrate whether elevated levels of vWF and its propeptide are associated with an increased risk of complications specific for the HED subphenotype.
Full-text · Article · Oct 2013 · Thrombosis Research
[Show abstract][Hide abstract] ABSTRACT: Half the patients with acute myeloid leukemia (AML) who achieve complete remission (CR), ultimately relapse. Residual treatment-surviving leukemia is considered responsible for the outgrowth of AML. In many retrospective studies, detection of minimal residual disease (MRD) has been shown to enable identification of these poor-outcome patients by showing its independent prognostic impact. Most studies focus on molecular markers or analyze data in retrospect. This study establishes the value of immunophenotypically assessed MRD in the context of a multicenter clinical trial in adult AML with sample collection and analysis performed in a few specialized centers.
In adults (younger than age 60 years) with AML enrolled onto the Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research Acute Myeloid Leukemia 42A study, MRD was evaluated in bone marrow samples in CR (164 after induction cycle 1, 183 after cycle 2, 124 after consolidation therapy).
After all courses of therapy, low MRD values distinguished patients with relatively favorable outcome from those with high relapse rate and adverse relapse-free and overall survival. In the whole patient group and in the subgroup with intermediate-risk cytogenetics, MRD was an independent prognostic factor. Multivariate analysis after cycle 2, when decisions about consolidation treatment have to be made, confirmed that high MRD values (> 0.1% of WBC) were associated with a higher risk of relapse after adjustment for consolidation treatment time-dependent covariate risk score and early or later CR.
In future treatment studies, risk stratification should be based not only on risk estimation assessed at diagnosis but also on MRD as a therapy-dependent prognostic factor.
[Show abstract][Hide abstract] ABSTRACT: Activated polymorphonuclear neutrophils play an important role in the pathogenesis of vaso-occlusive painful sickle cell crisis. Upon activation polymorphonuclear neutrophils can form neutrophil extracellular traps. Neutrophil extracellular traps consist of a meshwork of extracellular DNA, nucleosomes, histones and neutrophil proteases. Neutrophil extracellular traps have been demonstrated to be toxic to endothelial and parenchymal cells. This prospective cohort study was conducted to determine neutrophil extracellular trap formation in sickle cell patients during steady state and painful crisis. As a measure of neutrophil extracellular traps, plasma nucleosomes levels were determined and polymorphonuclear neutrophil activation was assessed measuring plasma levels of elastase-α1-antitrypsin complexes in 74 patients in steady state, 70 patients during painful crisis, and 24 race-matched controls using Enzyme Linked Immunosorbent Assay. Nucleosome levels in steady state sickle cell patients were significantly higher compared to levels in controls. During painful crisis levels of both nucleosomes and elastase-α1-antitrypsin complexes increased significantly. Levels of nucleosomes correlated significantly to elastase-α1-antitrypsin complex levels during painful crisis, (Sr = 0.654, P < 0.001). This was seen in both HbSS/HbSβ0-thalassemia (Sr=0.55, P<0.001) and HbSC/HbSβ+-thalassemia patients (Sr=0.90, P=<0.001) during painful crisis. Levels of nucleosomes showed a correlation with length of hospital stay and were highest in patients with acute chest syndrome. These data support the concept that neutrophil extracellular trap formation and neutrophil activation may play a role in the pathogenesis of painful sickle cell crisis and acute chest syndrome.
[Show abstract][Hide abstract] ABSTRACT: Tyrosine kinase inhibitors treatment in responding chronic myeloid leukaemia (CML) patients is generally continued indefinitely. In this randomised phase II trial, we investigated whether CML patients in molecular response(4.5) (MR(4.5), quantitative reverse-transcription polymerase chain reaction (RQ-PCR)) after previous combination therapy with imatinib and cytarabine may discontinue imatinib treatment safely.
Thirty-three patients from the HOVON 51 study with an MR(4.5) for at least 2 years who were still on imatinib treatment were randomised between continuation of imatinib (arm A, n=18) or discontinuation of imatinib (arm B, n=15).
After a median follow up of 36 months since randomisation, 3 patients (17%) in arm A and 10 patients (67%) in arm B had a molecular relapse. All 3 relapsing patients in arm A had also stopped imatinib after randomisation. All but one relapsing patient relapsed within 7 months after discontinuation of imatinib. The molecular relapse rate at 12 and 24 months after randomisation was 0% and 6% (arm A) and 53% and 67% (arm B) respectively. As-treated analysis revealed 56% and 61% relapses at 1 and 2 years since cessation in patients who discontinued imatinib, in contrast to 0% of patients who continued imatinib. All evaluable patients remained sensitive to imatinib after reinitiation and regained a molecular response.
Our data suggest that discontinuation of imatinib is safe in patients with durable MR(4.5).
Full-text · Article · Jul 2013 · European journal of cancer (Oxford, England: 1990)
[Show abstract][Hide abstract] ABSTRACT: During febrile neutropenia in only 30 to 60 percent an infectious agent is identified. This diagnostic gap could hypothetically be reduced with the broad implementation of molecular detection techniques like PCR, which has revolutionized the detection of infectious diseases during the last two decades.
We performed a longitudinal prospective study (N = 81) of neutropenic patients to assess the role of respiratory viruses in neutropenic fever and to determine the clinical relevance of blind screening for these viruses. Respiratory viruses were recovered in 14% of the patients prior to neutropenia. In 13% of neutropenic patients without fever and in 19% of those with fever, a respiratory virus was detected. Comparing different sample types; nasal swabs performed significantly better (16/117 = 43%), than throat swabs (6/106 = 6%). Throat gurgles did not show significant differences from the latter sample types.
Blind diagnostic screening for respiratory viruses before or during neutropenia is not useful. Nasal swabs are sensitive and practical option for screening on respiratory viruses.
[Show abstract][Hide abstract] ABSTRACT: The differential diagnosis of chest pain in a patient with sickle cell disease is difficult and may encompass several serious conditions, including chest syndrome, pulmonary embolism and infectious complications. In this manuscript we provide an overview on the various underlying diseases that may cause chest pain in patients with sickle cell disease and provide clues for a proper diagnostic workup.
No preview · Article · Jun 2013 · The Netherlands Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: Background:
The aim of this study was to investigate the effects of red blood cell (RBC) transfusion on the hemorrheologic properties and microcirculatory hemodynamics in anemic hematology outpatients receiving 2 to 4 RBC units of either "fresh" (leukoreduced storage for less than 1 week) or "aged" (leukoreduced storage for 3-4 weeks) RBCs.
Study design and methods:
Measurements were performed before and 30 minutes after RBC transfusion in hematology outpatients. Leukoreduced RBC suspensions were stored in saline-adenine-glucose-mannitol (SAGM) additive solution. Whole blood viscosity was measured using Couette low-shear viscometry, RBC deformability and aggregability were measured using laser-assisted optical rotational cell analysis, and microcirculatory density and perfusion were assessed using sidestream dark field imaging.
One group of patients (n = 10) received a median (interquartile range) of 3 (2-3) RBC bags that were stored for 7 (5-7) days (fresh) and the other group of patients (n = 10) received 3 (3-3) RBC bags that were stored for 23 (22-28) days (aged). After transfusion of fresh versus aged RBCs, hematocrit increased to 32 ± 3% versus 31 ± 2% (p < 0.363), whole blood viscosity increased to 4.2 ± 0.4 Pa/sec versus 4.2 ± 0.6 Pa/sec (p < 0.912), RBC deformability index remained unaffected, RBC aggregability index increased to 55 ± 10 versus 55 ± 13 (p = 0.967), microcirculatory flow remained unaffected, and microcirculatory density increased to 19.3 ± 2.5 mm/mm(2) versus 18.7 ± 1.9 mm/mm(2) (p = 0.595), respectively.
Storing leukoreduced SAGM-suspended RBCs for 3 to 4 weeks did not affect their ability to improve hemorrheologic properties and microcirculatory hemodynamics in our small group of anemic hematology outpatients. Larger studies are needed to confirm this finding.
[Show abstract][Hide abstract] ABSTRACT: Treatment of acute lymphoblastic leukaemia (ALL) is frequently complicated by venous thromboembolism (VTE). The efficacy and optimal approach of VTE prevention are unclear, pa rticularly in adult patients. We assessed the effect of thromboprophylaxis on symptomatic VTE incidence in cycle 1 of ALL treatment in adult patients. Secondly, we explored potential etiologic factors for VTE and the clinical impact of VTE on ALL outcome. We retrospectively assessed symptomatic VTE incidence and use of thromboprophylaxis in 240 adults treated for newly diagnosed ALL in the Dutch-Belgian HOVON-37 multicentre study (1999-2005). Potential etiologic factors were explored by analysis of patient and disease characteristics, impact of VTE on ALL outcome by analysis of complete remission and overall survival rates. Symptomatic VTE was observed in 24 of 240 patients (10%). Thromboprophylaxis differed by centre (prophylactic fresh frozen plasma (FFP) supplementation or no thromboprophylaxis) and was applied only during L-asparaginase in cycle 1. VTE incidence was significantly lower with FFP supplementation than without FFP (6% vs. 19%; adjusted odds ratio [OR] 0.28; 95% confidence interval [CI] 0.10-0.73). FFP did not influence antithrombin or fibrinogen plasma levels. Patients with VTE in cycle 1 had a significantly poorer complete remission rate (adjusted OR 0.18; 95% CI 0.07-0.50), particularly patients with cerebral sinus thrombosis (adjusted OR 0.17; 95% CI 0.04-0.65). Our study suggests that prophylactic FFP supplementation effectively reduces symptomatic VTE incidence during ALL treatment in adults. This should be confirmed in a randomised controlled trial.
No preview · Article · Jan 2013 · Thrombosis and Haemostasis
[Show abstract][Hide abstract] ABSTRACT: An urgent need for new treatment modalities is emerging in patients with elderly AML. We hypothesized that targeting VEGF might furnish an effective treatment modality in AML. Elderly patients with AML or RAEB and an IPSS of 1.5 or higher were randomly assigned in this Phase II study (n=171) to receive standard chemotherapy (3+7) with or without bevacizumab at adose of 10 mg/kg iv in 60 minutes at days 1 and 15. In the second cycle patients received cytarabine 1000 mg/m(2) twice daily on days 1- 6 plus or minus bevacizumab. The primary endpoint was CR. The CR rates in both arms were not different (65%). The EFS at 12 months was 33% for the standard arm vs 30% for the bevacizumab arm and at 24 months 22% vs 16% (p=0.42). The frequencies of severe AEs (SAE) were higher in the bevacizumab arm (63) as compared to the control arm (28; p=0.043), but the percentages of death or life threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). Although it is feasible the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of AML at older age. (NTR904 www.trialregister.nl).