EuroDBA: Building Global Bridges (2nd symposium, October 2017)

The 2nd “EuroDBA: Building Global Bridges” meeting in Freiburg, Germany commenced on 5th October 2017. Over 115 clinicians, researchers or family support group representatives were in attendance, spanning 27 countries, including China.  

The meeting represented an opportunity to share experiences of living with DBA, understand developments in research and working towards greater global collaboration in our efforts to find a cure….. 

Day 1 (Thursday)

After a long journey for many, we checked into the Hotel Stadt and made our way to the seminar rooms at the University Children’s Hospital. The patient representatives were tasked with giving an overview of their respective countries support group. (Number of patients supported/ structure of support groups/challenges etc).

We had a very constructive discussion, however, there are a number of common themes that still need to be addressed:

  1. There remains a lack of standardisation/disparity with respect to DBA care & management across Europe and the rest of the world. (Steroids/Blood transfusions/Chelation).
  2. Knowledge sharing and communication – How do we inform families of latest research developments and DBA news?
  3. Travelling abroad – Who should we contact if our child becomes ill? 

Actions: (Patient Support Group):

We agreed the following:

  1. An email group will be set up to facilitate communication between EuroDBA reps (Primary owner: Martin Winter) eurodbapatientreps@yahoogroups.com – joining invitation to follow/please check Trash
  2. Travel Map – Finalisation of the travel map detailing primary hospitals with knowledge of DBA. This will be posted on the euroDBA website and facebook page. (Primary Owner: Hans Dabelsteen, Denmark (building on the work by Karina)
  3. EuroDBA Facebook page for Support group primary reps) – (Primary owner: Hans Dabelsteen, Denmark) 
  4. DBA Passport – Production of passport style document detailing patients treatment. This will need to be validated by the EuroDBA consortium)(Primary Owner: Wilma, Germany with input from Marcel Hibert (France)
  5. Investigate feasibility of periodic publication re DBA developments. (Primary Owner: Martin Winter, UK)

 Actions: (EuroDBA Consortium)

  1. Finalise carepathway/handbook with EuroDBA consortium.(Primary owner: Marcin W, Freiburg (Target Date for completion: March 2018)
  2. Provide central point of contact for EuroDBA patient reps (within consortium) in the event they have specific questions/concerns re treatment)

After dinner at a local restaurant, we headed back to our hotel for some much need rest. We needed to register the next day by 7:45am!

 Day 2 (Friday)

In the morning, we were escorted to the auditorium within the University Medical Centre. Registration followed and we sat down to listen to the welcome address/introductions by Marcin Wlodarski (Germany) and Martin Winter (DBAUK)

The next 8 hours (we did stop briefly for lunch/coffee!) focused on:

  • Ribosome Biogenesis (ie the process of making Ribosomes that are protein builders within each cell);
  • Disease Pathophysiology (the study of the changes in the way the body works that result from disease)
  • Novel Causes and Basic Mechanisms and;
  • Experimental treatments and drug discovery.

 The final presentation was probably the most relevant to the EuroDBA patient reps community. Sergey Doulatov (Washington) and Colin Stieff (Harvard) gave an overview of their respective models used (knockout mouse/patient iPS cells (Sigmura et al) and Johan Flygare/Ross Hannan gave an overview of the identification and screening of novel drugs.

Ross Hannan (Australia) has tested 4,169 compounds to date using A549 cells

A number of potentially effective compounds/drugs that may lead to a cure include SMER 28 and Dexamethasone.

At 4:30pm we left the conference centre to visit a local vineyard in Schallstadt. This gave us an opportunity to discuss DBA in further depth over a glass (or two) of Germany’s finest offering.

 Day 3 (Saturday)

 A slightly later start (8:45am) kicked off with an overview of hematopoietic stem cell transplantation experiences and data from France, Germany, Brazil, USA, Austria and the UK.

It was widely accepted that the higher risks associated with non-sibling (vs sibling) HSC transplants have significantly diminished. Drug conditioning/regimes also differ between countries; Dr Josu De La Fuente shared some interesting data re reducing the levels of conditioning drugs (and toxicity as a result) and inclusion of T-cells to promote the patients immune system. Other data that maybe of interest included the DBAR registry (US); out of 761 patients enrolled, 101 patients had undergone SCT with a median age of 8.

Session 2 focused on Iron Chelation, with presentations by Italy, Greece and France.

 There remain 2 primary iron chelation drugs – Exjade (Deferasirox) and Deferoxamine (Desferal). Thierry LeBlamc from France shared some data re the effectiveness of the drugs if used together. He also stated Ferriprox could be used as an alternative chelator for adults if properly managed (neutropenia risk).

Endocrine dysfunction remains the most common complication with iron overload. Complications include Diabetes (Pancreas), Cirrhosis (Liver) and hypogonadism (Pituitary Gland – diminished functional activity in the gonads)

Post an extended lunch at the local farmers market, we listened to presentations on steroids from Germany, Sweden and the US.

 Marcin Wlodarski provided patient data detailing the success of a second trial of steroids.

 More research has been undertaken with respect to how steroids work targeting the BFU-E stage of red blood cell production and prevention of p53 activation. (Flygare/Narla)

 Other discussions included the development of target steroid therapy rather than the systemic medication currently used (Prednisolone). (J Flygare/Narla – Glucocorticoids).

 We also heard from Regine Grosse (Hamburg regarding hormone imbalance in DBA patients (most noteable in transfusion dependent patients)

 Session 4 focused on gene therapy with presentations from Germany, Sweden and Spain. Stefan Karlson stated gene therapy would provide a solution to patients in 2-3 years (RPS19). This has already been undertaken for patients with Fanconi Anaemia. CDK8/19 inhibitors were also sighted as a candidate for DBA (Patent pending).

 The final presentation by Adrianna Vlachos (NY) provided an update on the clinical trials for L-Leucine, Trifluoperazine, SMER 28 and Sotatercept.

 In summary:

Leucine – 46 patients, 700mg dose orally x3 per day, 9 month duration, finalized Feb 2017.

Result: 4 patients responded with 3 categorised as having a complete response (maintaining Hb over 90)

Next steps: Analysing of data including weight (gain), retic counts. Future study will be based on a higher dose of Leucine.

 Sotatercept – initially used to increase bone density, trail began in 2013.

 8 patients completed 4 cycles each with no response initially, however, a good response has been seen with MDS and thalassemia patients using a higher dose.

 Next steps: The next study has now commenced with a population of 20 patients over a 24 month period. If there is a response, study will be undertaken with Luspatercept (next generation drug without bone side effects)

 Trifluoperazine (TFP) – Identified as a chemical screen using zebra fish. TFP is an anti psychotic medication with a well known profile. Maximum duration of study will be 9 weeks with a 6 week post drug observation period.

 Next steps: October 2017 – Awaiting board approval (IRB) to proceed with 1st subject. If drug trial is successful then a modified agent will be developed without the neurological side effects.

 SMER 28 – rescues erythroid defect in DBA; a second agent is in the pipeline.

 The meeting was concluded by Alyson MacInnes with a brief summary from Steve Ellis (DBAF). Should DBA be re-clasified as a syndrome (DBS) as some patients do not have congential anomalies or anaemia?

 The majority of participants attended the dinner at the local “schlossle”. On Sunday, after a visit to the Black Forest it was time to return home for a much needed rest!

 There is a significant amount of research being undertaken with respect to DBA and progress is being made.

We clearly need to work with Euro DBA to provide funding, support and build global bridges…..

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