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.

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.