EHA Press Releases

• Home
• News
• Press
• EHA Press Releases

Report on first EHA-SWG Scientific Meeting

The meeting was organized with the main support of the EHA in collaboration with the Hematology Unit of G. Gaslini Children’s Hospital and was sponsored by Novartis and Alexion. 

This meeting was the first organized after the resolution of the EHA SWG Unit to implement the activity of SWG's via this networking instrument. In this pilot meeting the most eminent experts of different marrow failure diseases in a friendly and productive atmosphere presented, discussed and shared experiences and views that widened scientific and cultural horizons. The program was specifically set to voice Pharma Companies, Parents’ Associations, Regulatory Authorities like EMA. One session was dedicated to interactive clinical case presentations. Wrap-up voting session as an instrument for learning self-assessment was introduced for the first time. All these ingredients contributed to the success of this layout as confirmed by the evaluation forms that provided an overall mean score of the meeting of 9.2 in a scale from 0 to 10.

The most relevant highlights of the meeting can be summarized as follows.

• Even if mutated genes (ELA-2, HAX 1, G6PC3) have been demonstrated to be pathogenic in Severe Congenital Neutropenia (SCN) and Cyclic Neutropenia(CN) and even if  critical players (LEF-1 and CEBPa)have been identified, the mechanism underlying  the phenotype is still under debate. This holds true also for neutropenia in the context of GSD 1b, of Barth Syndrome and for those forms associated to primary immune- deficiencies (WASP, Griscelli syndrome type 2, Hermansky Pudlack syndrome type 2b, Di George Syndrome, IPEX, ALPS). In WHIM, neutropenia is attributed to a defective release of neutrophils into the bloodstream because of genetically dysfunctional CXCR4 protein that keeps these cells bound to CXCR4 receptor of the stromal marrow cells.
• Formerly unknown immune dysregulations like defective maturation, function  and proliferation of NK and reduced quantities  of mantle zone  B cells and of pre-immune immunoglobulin directed to T-cell independent antigens, were shown to be present  in SNC and in autoimmune neutropenias thus pointing to the immune component as new field to look at for monitoring and infection prevention in neutropenia patients.
• Exome sequencing techniques showed that leukemic evolution of SCN under G-CSF occurs overtime through a number of known and novel mutations. Of these, a new one in the extracellular domain of CSF3R was proven to confer cells a growth factor independent proliferative advantage, thus strengthening the concept that CSFR3R mutations represent a critical step towards leukemic progression of SCN.
• As for the clinical management of SCN an algorithm, validated by guideline methodology, aiming to properly allocate the diagnosis of patients presenting with neutropenia, has been presented. Long term surveillance over clonal evolution in SCN patients is highly recommended. The infection prophile of SCN subjects was shown to be mainly characterized by bacterial episodes. Fungal ethiologies accounted for only 5% of infections. The highest risk was within the first 3 months of life. Risk increases with age (40% at 10 years and 59% at 20 years). The role of genetic counseling for women with SCN reaching pregnancy age has been addressed. Pros and contras of standard treatment and of hematopoietic stem cell transplantation (HSCT) were also discussed. Though not many studies are available, HSCT looks indicated in case of high G-CSF dose requirement and of clonal transformation and/or monosomy 7.
• Chronic Idiopathic neutropenia, a rare disorder mainly occurring in older age, has been shown to belong to the spectrum of acquired marrow failure disorders like aplastic anemia and refractory cytopenia, since it looks due to increased apoptosis of CD34+/33+ granulocytic progenitor cells occurring in a pro-inflammatory bone marrow microenvironment comprising activated T lymphocytes and inhibitory cytokines like TNF-alfa, IFN -gamma, Fas ligand and CD40 ligand.
• In Fanconi Anemia (FA), a newly discovered gene (FANQ) has been presented as an exquisite news of the meeting. The role of the remaining 15 FA genes underlying the disease and the importance of patient genotyping for clinical/therapeutic implications has been outlined.
• The mechanisms underlying clonal evolution in FA were shown to include hyperactivation of some known pre-leukemic gene like HOXA 9 and c-myb. These genes confer to stem cell resistance to TNF-a which is a characteristic of the clonal evolution of FA cells.
• The molecular pathogensis of Dyskeratosis Congenita (DC) is related to excessive telomere shortening due to impaired functioning of the telomerase-shelterin complex that normally maintains telomere length. This leads to excessive apoptosis, shortened cell survival and chromosomal instability of the cells, accounting for the clinical picture including cancer proness. So far 8 mutated telomerase-shelterin genes are known but at least 40% of patients are gene orphan. Exome sequencing is likely to drop this percentage.
• In Schwachman-Diamond syndrome (SDS) defective SDS protein leads to impaired release of EIF 6 peptide impeding the formation of actively translating 80S ribosome.  EIF 6 gene is located in the band q11.22 of the long arm of chromosome 20 that is often deleted in SDS patients with benign course probably because of gene/dosage effect of the EIF6 protein in the cells of the abnormal clone. The i(7)(q10) change allows the duplication of the recurrent c258+2T>C mutation thus enabling the production a small amount of normal SDS protein and probably accounting for the benign course of subject with this mutation.
• Treatment options in FA were illustrated. HSCT still represents the only chance to restore long-term hematopoiesis.  Results of HSCT from unrelated donor (UD) are now close to those from matched family donor (MFD) both overcoming, in some studies, an overall survival (OS) of 90 %.  Attention should be placed to prevent GVHD that increases the risk of cancer. The use of irradiation is still an unresolved issue and should be ideally confined to transformed patients receiving MUD grafts.
• Treatments for marrow failure in DC includes oxymetholone (a syntehic androgen) to which a good proportion of patient respond. HSCT from MFD gives higher OS (71% at 2 yrs) than from MUD (31% at 2 yrs). Recently OS in MUD HSCTs seems to have improved. In the absence of malignant transformation a reduced intensity conditioning regimen with no irradiation should be indicated. Since HSCT increases the frequency and the severity of restrictive lung disease, accurate lung but also liver and GI function assessment should be done before making the decision of HSCT in DC.
• The importance of the Registries (SNFR, SCNIR and FA Italian DB) as instruments for networking, for feeding clinical studies and driving better clinical care of the patients has been presented and widely discussed. In this view the collaborative participation of the family associations, voiced in this circumstance by the FA Italian Association (AIRFA), has been very contributory.
• The itinerary from the key molecular mechanism of some disease to the targeted treatment has been discussed and future phase II pilot clinical trials (anti IFN-gamma in HLH) and concluded pilot studies (Plerixafor in WHIM) were illustrated. Plerixafor, by antagonizing CXCR4 (the mutated pathogenic molecule that- when faulty- binds neutrophils to the stromal marrow cells) allowed mobilization from the marrow and the rise of circulating neutrophils in peripheral blood.
• The difficulties of running clinical trials generating valuable information in rare diseases, has been addressed by EMA representative. Encouraging message was delivered to the clinicians suggesting that highest level of evidence, unachievable in rare disorders, do not necessarily preclude the chance for EMA to accept clinical trials. Early contact with EMA experts during the study design and Bayesian analysis method were also recommended.
• A new gene therapy protocol in FA has fully accomplished all the regulatory issues and is ready to start in Spain. Candidate patients are identified and likely to enter the study shortly.
• An example of new treatments targeted to key molecules has been illustrated in FA. This multisystem program aims to counteract at least three fundamental aspects of the FA cellular phenotype: TNF-alfa hyper-production and hypersensitivity (that can be achieved by p38 MAPK inhibitors), genome instability (aimed to be corrected by activating ubiquitinylation of FANCD2 and FANCI performed by FANCL) and excess sensitivity to ROS (antagonized by antioxidants). A number of small molecules are under investigation. Phenotype correction, if achieved in one system needs to be confirmed in mice and human primary cells. Before to initiate clinical trials in humans, the clonal excape potential of these molecules needs obviously to be tested in reliable preclinical models.

 More information on the EHA-SWG Scientific meeting is available here