The EORTC Children's Leukemia Group: Preclinical and clinical research and resulting achievements

The EORTC Children's Leukemia Group (CLG) is a spin-off from the EORTC Hemopathies Working Party (adults and children). After a decade of collaboration in the adult-pediatric group it became clear that there was not only a large difference in cure rates between children and adults, but many chemotherapeutic-toxic borders were substantially different. During the following decade the CLG was not only a witness of a very exciting battle against childhood leukemia, but it also contributed substantially to better cure rates for these diseases.The main activity of the CLG was concentrated on the field of acute lymphoblastic leukemia (ALL). Fine tuning of treatment elements using the BFM design as a backbone has been done very successfully over the past decades. The CLG has many achievements, and the major ones include: the 58831 trial showing the superfluity of the prophylactic Central Nervous System (CNS) radiotherapy in ALL patients when a adequate systemic and CNS directed chemotherapy is ascertained. The 58881 trial demonstrated that the assessment of minimal residual disease (MRD) at completion of induction in ALL is a key step in the process to categorizing and allocating patients into different risk groups, and that MRD is a powerful and independent prognostic factor. This same 58881 trial showed the clear difference in efficacy of different asparaginases resulting in an optimization of the use these drugs and a revival of interest for the asparaginases in the treatment of ALL.In the near future the CLG will focus mainly on translational research projects and innovative biologically targeted treatment approaches, on collaborations with other children's leukemia groups in intergroup studies, and on the evaluation of the long-term outcome of childhood cancer survivors.     

Autologous stem cell transplantation in myelodysplastic syndromes

Allogeneic stem cell transplantation (SCT) is the treatment of choice for the majority of young patients with myelodysplasia (MDS) who have a histocompatible donor (sibling or unrelated donor). For some patients lacking a human leukocyte antigen (HLA)-compatible donor, chemotherapy followed by autologous SCT may be a reasonable alternative, especially for patients with therapy-related MDS/acute myeloid leukemia (AML). A substantial number of candidates may not be eligible for autologous SCT due to failure to induce remission or failure to collect sufficient numbers of stem cells. Careful clinical evaluation of the prognostic factors, such as age, cytogenetic characteristics, chances of achieving complete remission (CR), and availability of a matched unrelated donor, may guide the treating physician in advising the patient about the available treatment options. Mobilized peripheral blood stem cells are the preferred stem cell source for young patients, especially in view of the more rapid hematopoietic recovery after transplantation with mobilized stem cells, but bone marrow stem cells also may be considered for patients older than 50 years. Further development of precise prognostic classification systems, including an accurate evaluation of cytogenetic/molecular response to chemotherapy, is needed to develop a risk-adapted strategy for individual patients.     

The Alcohol Perception (AP) Project: A Study of the Perceptions of Adolescents toward Alcohol

Four million individuals under the age of 21 admit to consuming alcohol in any given month. This is a significant statistic considering alcohol is responsible for most health problems related to drugs among adolescents. Research has shown that the high influence of alcohol advertising may encourage adolescents to emulate the behaviors seen in alcohol commercials. Further, those who begin drinking before age 13 are seven times more likely to consume 4+ drinks at least 6 times a month. The authors sought to show causality between the positive social perception of alcohol and the ability to influence drinking behavior. Survey findings of the study suggest that adolescents are more likely to be influenced by those who drink than those who do not. Therefore, measures to change this perception (in order to avert addiction and disease) must be put in place at an early age, much as they are (at both the academic and professional level) for combating tobacco.     

Statistical methodology for personalized medicine: New developments at EORTC Headquarters since the turn of the 21st Century

Since the creation of the EORTC Headquarters in 1974, major advances have been made in the methodology used in the design and analysis of cancer clinical trials. However, the speed of these developments in the fields of biology, medicine, and statistics has greatly increased since the turn of the 21st century. These changes have all become possible because of the increased computer power now available.The landscape of therapeutic anti-cancer development changed completely with the advent of the so-called “targeted agents” that treat the underlying molecular basis of the disease rather than the symptoms of tumor proliferation. The new challenges posed by the clinical development of these numerous new agents that are expected to work in often yet-to-be-identified subgroups of patients induced a new wave of methodological developments. Some of these were readily embraced by the EORTC Headquarters statistics department, while others met with opposition. Our assessment is still in progress in many areas. Trials tend to become increasingly complex so that their planning relies on an increasing number of unknown parameters that need to be monitored during the trial itself, one development being “adaptive” design methodology.Because the knowledge required to design these new and more complex clinical trials and associated research program spans more disciplines (biology, genomics, radiology) and involves specialized knowledge within those disciplines, continued success requires further developing our partnerships with specialized departments (imaging, bio-informatics, biology, etc.) within EORTC Headquarters and in EORTC affiliated centers as well as collaborations with specialized statisticians from academia.     

Oxidized low density lipoproteins: The bridge between atherosclerosis and autoimmunity. Possible implications in accelerated atherosclerosis and for immune intervention in autoimmune rheumatic disorders

Atherosclerotic vasculopathy is a multifactorial process causing vessels damage and cardiovascular diseases, the leading causes of death worldwide. Atherosclerotic plaque is the asymptomatic primary, elementary, lesion of atherosclerotic vasculopathy. Accumulation of the oxidized low-density lipoprotein (oxLDL) at sub endothelial sites is now recognized as one of the major trigger events in plaque formation. The concomitant presence at the plaque site of cells belonging to either natural or adaptive immunity, the detection of autoantibodies to oxLDL, the cross-reactivity of oxLDL with anti-phospholipid antibodies, in addition to the clinical evidence of increased rates of cardiovascular events in several rheumatic diseases, has stimulated intensive research to define interconnections between the immune system and traditional risk factors at the molecular levels in order to explain accelerated atherosclerosis. Here, we critically review the results of previous and recent studies, which have disclosed molecules of both innate or adaptive immunity involved in atherosclerosis, focusing primarily on B cells and autoantibodies, where data are more consolidated. Particular attention has also been paid to molecules that may be predictive markers of atherosclerosis progression and can be potential targets for immune intervention to delay the atherosclerotic process. The latter include CD20 antigen, molecules involved in the BAFF-BAFF receptor axis, inflammatory molecules and modified LDL. The successful results of a recent randomized controlled clinical trial targeting inflammasome with anti-IL1β monoclonal antibody in non-autoimmune conditions, prove that specific immunotherapy can be a promising and effective strategy to control atherosclerosis in rheumatic diseases as well.     

The prognostic value of IKZF1plus in B-cell progenitor acute lymphoblastic leukemia: Results from the EORTC 58951 trial

Background

IKZF1 gene deletion is an indicator of poor prognosis in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The AEIOP/BFM group proposed that the prognostic strength of IKZF1 deletion could be remarkably improved by taking into account additional genetic deletions and reported that among patients with an IKZF1 deletion those with deletions in CDKN2A/2B, PAX5, or PAR1 in the absence of ERG deletion, grouped as IKZF1^plus, had the worst outcome.

Procedure

Between 1998 and 2008, 1636 patients under 18 years of age with previously untreated BCP-ALL were registered in the EORTC 58951 trial. Those with multiplex ligation-dependent probe amplification data were included in this analysis. Unadjusted and adjusted Cox model was used to investigate the additional prognostic value of IKZF1^plus.

Results

Among 1200 patients included in the analysis, 1039 (87%) had no IKZF1 deletion (IKZF1^WT), 87 (7%) had an IKZF1 deletion but not IKZF1^plus (IKZF1^del) and 74 (6%) had IKZF1^plus. In the unadjusted analysis, both patients with IKZF1^del (hazard ratio [HR] = 2.10, 95% confidence interval [CI]: 1.34–3.31) and IKZF1^plus (HR = 3.07, 95% CI: 2.01–4.67) had a shorter event-free survival compared with IKZF1^WT. However, although the IKZF1^plus status was associated with patients’ characteristics indicating poor prognosis, the difference between IKZF1^plus and IKZF1^del was not statistically significant (HR = 1.46, 95% CI: 0.83–2.57, p = .19). The results of the adjusted analysis were similar to the unadjusted analysis.

Conclusions

In patients with BCP-ALL from the EORTC 58951 trial, the improvement of the prognostic importance of IKZF1 by considering IKZF1^plus was not statistically significant.