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  Welcome
  SESSION I – STEM CELL BIOLOGY: FROM STRESS TO FAILURE
Chairs: Tim Brümmendorf and Markus Manz
  Introduction
  Haemopoietic stem cell activation and failure
Andreas Trumpp (Heidelberg)
  Genotoxic stress and repair in stem cells
Ketan J. Patel (Cambridge)
  Inflammageing of the haemopoietic system
Markus Manz (Zürich)

Question from Marc Raaijmakers:
Given the wide repertoire of inflammatory molecules that can be secreted by neutrophils/myeloid cells, are we looking at the tip of the iceberg focusing on IL1 and should we ultimately aim for targeting ‘master regulators of inflammation’ to attenuate aging? If so, what would be candidates?

Answer from Markus Manz:
Yes, IL-1 a/b is the “tip of the iceberg”. Difficult to say what are the candidates as it is such a complexly regulated system that evolved in evolution with the aim to protect short-term from lethal infections. Living long now is paying some price for that.

  Immunologic Basis to Poor Graft Function Post Allogeneic Transplantation
Ashvind Prabahran (Melbourne)
  Discussion
  SESSION II – CONSTITUTIONAL MARROW FAILURE 1: FANCONI ANAEMIA (FA)
Chairs: Carlo Dufour and Inderjeet Dokal
  Introduction
  Fanconi anaemia : diagnostic and natural history in the bone marrow
Jean Soulier (Paris)
  Classical and new treatment of Fanconi anaemia
Carlo Dufour (Genova)
  Gene therapy for Fanconi anaemia
Juan Bueren (Madrid)
  Genetic Rescue of Fanca -/- HSPCs with Evi-1 Overexpression Suggests a Mechanistic Link with DNA Damage Response
Susanne Lux (Heidelberg)
  Discussion
  SESSION III – CONSTITUTIONAL MARROW FAILURE 2: RIBOSOME DISEASES
Chairs: Marc H. G. P. Raaijmakers and Alan Warren
  Introduction
  Diamond-Blackfan anaemia (DBA), ribosomes and haemopoiesis
Vijay Sankaran (Boston)
  Shwachman-Diamond syndrome (SDS) and related ribosomopathies
Alan Warren (Cambridge)
  Management of ribosomopathies
Yigal Dror (Toronto)
  A Single Base Change Makes the Cure: Correcting the Most Common SBDS Mutation in Shwachman-Diamond Syndrome
Chi-Yuan Zhang (Boston)
  Discussion
  SESSION IV – CONSTITUTIONAL MARROW FAILURE 3: TELOMERE BIOLOGY DISEASES
Chairs: Inderjeet Dokal and Tim Brümmendorf
  Introduction
  Telomeres and telomerase in health and ageing
Alison Bertuch (Houston)
  Dyskeratosis congenita and related haematological diseases
Inderjeet Dokal (London)
  Diagnosis and clinical presentation of adult onset telomeropathies
Fabian Beier (Aachen)
  Natural History and Outcomes Depending on Organ System Involvement in Patients with Clinically-Relevant Short Telomeres
Abhishek Mangaonkar (Rochester)
  Discussion
  Poster walks
Leaders: Tim Brümmendorf and Marc H.G.P. Raaijmakers
  SATELLITE SYMPOSIUM: Beyond current endpoints: a patient-centric approach to PNH treatment
Chair: Régis Peffault de Latour
Speakers: Pascale Burmester, Talha Munir and Jens Panse
This symposium is organized by Roche
  SESSION V – IMMUNE APLASTIC ANAEMIA AND PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA
(PNH) 1. PATHOPHYSIOLOGY AND DIAGNOSIS
Chairs: Neal Young and Regis Peffault de Latour
  Introduction
  Pathophysiology of immune aplastic anaemia
Neal Young (Bethesda)
  Pathophysiology of PNH
Rosario Notaro (Florence)
  Modern diagnosis of aplastic anaemia and PNH
Austin Kulasekararaj (London)
  Single Cell eQTL Mapping Identifies Cell-Type Specific Control of Autoimmune Disease
Kirsten Fairfax (Hobart)
  Discussion

In pediatrics patients, <18 years do you recomend use Eltrombopag?
Our forthcoming Br H Haematol is relatively small and retrospective. It would be better if there were more evidence! But it is difficult to recommend based on our findings.

To Austin (and everybody): somatic mutations are frequent in AA, but emergind data clearly show that in addition to “myeloid cancer genes” they may affect “immune-privilege genes”, such as PIGA or HLA. Can we conclude that we are looking at standard rate of mutations, keeping in mind that these 2 types are simply the ones that we may detect because they lead to expansions of mutant clones? Thus, are we overestimating the risk of MDS or leukemia by simply looking to NGS data? Antonio
From my reading of the literature, there is very little evidence of altered intrinsic rates of mutation (MMR has not been generalizable!). But the inflammatory environment is mutagenic.

For panel (from Olaia Naveiras, Lausanne Switzerland): Have you observed a clinical overlap of SAA and late onset telomere biology disorders? Else how would you interpret this case? Young (29yo) patient with classic presentation of SAA (with autoimmune hepatitis) and partial response to hATG/Cs/eltrombopag (full response for neutrophils), Telomere attrition was detected and confirmed in the parents. No donor available. He remained fully dependent on platelet transfussions and partially transfussion-dependent for RBCs. He was started in danazol. Platelet transfussion independency was reached 18 months after danazol introduction. Ciclosporine and eltrombopag have not yet been fully tampered due to neutrophil dependency. Cytogenetics are normal at the last BM control (24 months after danazol introduction). Thank you for the great session!
Hard to say from the description of the case. As I stated categorically, acute presentation of severe pancytopenia rarely germline disease, in our experience and analysis. Typical autoimmune hepatitis also linked to immune AA, but the liver disease has to be clearly distinct from the hepatic manifestations of telomere disease. Telomeres can be short in marrow failure, without mutations, due to regenerative stress. A germline marrow failure genomic panel would be helpful! A good PR (based on CBC) strong evidence of an immune pathogenesis.

To Neal Young: Thank you for the outstanding review! Why – if evasion of IFNg competition for the MBL-receptor binding by eltrombopag is one of the major mechanisms of action in AA patients does romiplostim also seem to work, even in patients not responding to eltrombopag. And is the timing of the addition of eltrombopag to IST essential? Jens Panse
The mechanism is not clear but not direct competition for the mpl receptor (Andre’s paper shows evidence of binding of TPO to IFN) so no reason romiplostim shouldn’t be effective. And that romiplostim may rescue eltrombopag failures does not have a clear explanation, but then neither does efficacy of rabbit ATG is some horse ATG failures. I don’t think the timing of eltrombopag is critical but it is not a problem to administer early, and getting all the drugs in ASAP seems the important point to me—block the immune system, stimulate HSCs early.

@Neal: excellent talk ! Do you thinks the the lower risk of clonal evolution for patients under IST + ELT as opposed to ELT monotherapy (and probably also IST alone) would also hold true fror the combination of CSA + ELT (compared to ELT or CSA mono therapy) in elderly, frail AA patients (who are in any way at higher risk of clonal evolution ? Thanks Tim Brümmendorf
We don’t know for sure the risk is lower (but it is not higher than historical data and not the risk it is in refractory AA). Yes, I would expect it to be helpful to add eltrombopag in the elderly (see above). The idea is to preserve telomeres, prevent DNA damage from reactive species/inflammation environment. ‘Figuring it out hard as older persons likely have a poorer HSC reserve to begin with (maybe why they benefit most from eltrombopag, compared to children).

What would you recommend for a 25 y/o male who relapsed 2 years post sib allogeneic HCT, did not respond to salvage with eltrombopag and cyclosporine and had a second allogeneic HCT from the same sibling. no GVHD – prolong CSP duration? add sirolimus?
Our transplanter Richard Childs always recommends stem cell boosts with continued immunosuppression. I think the role of sirolimus is at disease onset (as in a mouse model) or onset of relapse (“reboot”). It is probably useless when combined with CsA (as cells are functionally blockaded and presumed quiescent).

Is it possible to accelerate clonal evolution with immunosuppressive therapy in severe aplastic anemia? (Abhishek Mangaonkar – Mayo Clinic)
Really unanswerable with the data we have and trials we could perform.

  SATELLITE SYMPOSIUM: A journey through the SAA and PNH treatment landscapes
Chair: Régis Peffault de Latour and Antonio Risitano
Speakers: Régis Peffault de Latour and Antonio Risitano
This symposium is organized by Novartis
  SESSION VI – IDIOPATHIC APLASTIC ANAEMIA AND PAROXYSMAL NOCTURNAL
HAEMOGLOBINURIA (PNH) 2. DIFFERENTIAL DIAGNOSIS AND CLONAL EVOLUTION
Chairs: Neal Young and Jaroslaw P. Maciejewski
  Introduction
  Keynote Presentation: Bone marrow failure and somatic mutations: the PNH paradigm
Lucio Luzzatto (Dar-es-Salaam)
  Discussion
  Innate immunity and clonal evolution in bone marrow failure
Alan List (Tampa)
  Impact of clonal haemopoiesis in aplastic anaemia
Jaroslaw P. Maciejewski (Cleveland)
  Health-related quality of life and its assessment in aplastic anaemia and paroxysmal nocturnal haemoglobinuria
Jens Panse (Aachen)
  The Metabolomic Status of the Differentiating Myeloid Lineage in MDS with Low and High Bone Marrow Blast Counts
Aikaterini Poulaki (Athens)
  Discussion
  SATELLITE SYMPOSIUM: Current unmet need and the future of complement inhibition in PNH
Chair: Peter Hillmen and Antonio Risitano
Speakers: Peter Hillmen and Antonio Risitano
This symposium is organized by Apellis
  SESSION VII – TREATMENT OF IMMUNE APLASTIC ANAEMIA (AA)
Chairs: Andrea Bacigalupo and Carlo Dufour
  Introduction
  Immunosuppression and TPO agonists
Régis Peffault de Latour (Paris)
  Transplantation for acquired SAA: are we making progress?
Andrea Bacigalupo (Rome)
  How to handle moderate aplastic anaemia
Britta Höchsmann (Ulm)
  Blockade of Common Gamma Chain Cytokines with REGN7257, an Interleukin 2 Receptor Gamma (IL2RG) Monoclonal Antibody, Protected Mice from T Cell-Mediated Disease
Audrey Le Floc’h (Tarrytown)
  Discussion
  SESSION VIII – TREATMENT OF PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA (PNH)
Chairs: Regis Peffault de Latour and Hubert Schrezenmeier
  Introduction
  Classical treatment of PNH
Hubert Schrezenmeier (Ulm)
  Challenging situations
Peter Hillmen (Leeds)
  Novel complement inhibitors
Antonio Risitano (Naples)
  Results of the Pegasus Phase 3 Randomized Trial Demonstrating Superiority of the C3 Inhibitor, Pegcetacoplan, Compared to Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria
Regis Peffault de Latour (Paris)
  Discussion
  SESSION IX – EMERGING AREAS AND NEW CHALLENGES
Chairs: Marc H. G. P. Raaijmakers and Lucy Godley

  Introduction
  Genetic editing of haemopoietic stem cells. Are we getting there?
Matthew Porteus (Stanford)
  Unraveling the biology of normal and malignant haemopoietic stem and progenitor cells at the single cell level
Sten Eirik Jacobsen (Stockholm)
  Genetic predisposition for myeloid malignancies: clinical management
Lucy Godley (Chicago)
  Prevalence of Inherited Predisposition Syndromes in Young Patients with Acute Myeloid Leukemia and Aberrant Karyotypes
Fabian Beier (Aachen)
  Discussion
  Closing remarks