Latest / EHA Unplugged / Hematology Portraits: Prof Maria Domenica Cappellini

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Hematology Portraits: Prof Maria Domenica Cappellini · EHA Unplugged

• 0:03
  Greetings and welcome to EHA Unplug, the official podcast
• 0:06
  channel of the European Hematology Association EHA.
• 0:10
  Hello, I am Isabella Livera, a medical writer for EHA.
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  Today we're thrilled to have with us Professor Maria Domenica
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  Capellini. Professor Capellini is a
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  Professor of medicine at the University of Milan, and she's a
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  leading authority in hematological disorders such as
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  thalassemia, sickle cell disease and anemia.
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  For her outstanding career dedicated to the understanding
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  and management of these diseases, she received the John
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  Bernard Lifetime Achievement Award at the EHA Congress in
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  this year, 2024. And so we want to revisit your
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  career with you in this podcast. Welcome, Professor Cappellini,
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  and thank you very much for being with us today.
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  Thank you. For inviting me.
• 1:00
  To start off, I wanted to go really back in time and can you
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  explain us what inspired you to work on Telecenia and hemoglobin
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  at the parties in general? We have to go back to.
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  My. Residency time which?
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  Means the end of 60, early 70 when I was doing my training in
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  internal medicine. And they was.
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  Trying to find out something. Interesting to develop.
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  And to get involved and. I had to.
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  Thank my mentor. Who at that?
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  Time he inspired me. Because, he said listen.
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  Could you be interested in a disease?
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  Which is not. So common now in internal
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  medicine. But it will.
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  Be in the. Future because pediatrician are
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  started to take care properly. Of this patient.
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  They. Are the thalassemia patients?
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  I was a bit shocked because thalassemia.
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  Was not common in our region. I'm living in northern Italy in
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  Milan. Was more common in South in the
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  island. So I say both.
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  That's quite strange, but. Let me see.
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  So I started. To look more.
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  Carefully. In In in patients admitted to
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  the internal medicine world. I started.
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  To look more carefully to the anemia in this patient, any kind
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  of anemia. And at one point I encountered
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  the patients admitted for mild anemia, mild splenomegaly, mild
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  jaundice. And he was admitted because.
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  Of persistent. Fever He.
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  Was a man of. 45 years of age and what was surprising me was
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  the microcytic. Anemia.
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  So he had the. Small red cells.
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  But of course he is. Iron was totally normal, so I
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  said let's see, he was. From Sardinia a.
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  Region. With a high prevalence of
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  thalassemia. So I said, let's see, maybe.
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  He's a carrier, but it. Turn out that he was not a
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  carrier. But he he was an affected
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  patient. With severe thalassemia, the one
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  we used to call thalassemia major.
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  And that was really surprising because.
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  How can a 45 year man? Be alive.
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  Being a thalassemia major. So that's actually excited.
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  Me I. Started.
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  I asked him to. Look at all the family and.
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  He has three children and the three children.
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  Two of them. Were carrier of.
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  Beta thalassemia, but. They had unexpectedly high
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  level. Of fetal hemoglobin, which was
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  not common in a. Carrier.
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  Something like around 810%. This was another.
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  Surprising finding in the family.
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  So I say what? What is going on here?
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  So I. Start to contact expert in the
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  field Professor Bernini Leyden, who confirmed the my observation
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  and then. I contacted Professor Weatherall
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  in. Oxford and starting from this
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  family. I was.
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  Becoming very much interested in the field of hemoglobinopathies
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  and just happened that. Professor Weatherall invited.
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  Me to attend the course in Columbavion, IN.
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  Crete where the. Biggest name in the field where
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  meeting. To share the.
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  Starting molecular work on the. Field so I.
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  Went there and my family was becoming a important.
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  Core of discussion. And then I went to Oxford.
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  For a period. And and and my interest was
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  focused. On that, that was.
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  About was around the end of 70 when the treatment the.
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  Standard of. Care for thalassemia.
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  Was just let's. Say define better in terms of
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  transfusion and iron. Chelation.
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  And at that time it was very demanding because particularly
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  iron chelation was mainly on using diferioxamine.
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  Which? Needed to be.
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  Efficacious. To be infused with the pump for
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  more than 7/8. Hours per day all over the life.
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  So I said that that's. Really something very demanding
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  for the patients, why we are not going to find something new for
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  iron chelation. And since I came back from
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  Oxford, I, I. Started to.
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  Work with Novartis. That at that.
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  Time was, was. Producing the cerioxomy.
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  To find that there are alternative chelator and it come
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  out. That by the.
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  End of 90. The Ferrazirox.
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  Was identified among more than 700 compounds.
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  I was. Leading clinical trial which is
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  novel. Oral iron chelator, which is
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  now. The standard of.
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  Care. And.
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  I personally believe that this was.
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  Really an important step for the management of thalassemia.
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  Because it really. Change.
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  The quality of life of. Patients adherence was increase,
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  compliance were increase. And so so.
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  Since then I will do I maintain contact.
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  With the Oxford. Group and we did some other
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  scientific work, but I. Focus.
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  Mainly starting from the 19. Early 2000.
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  I. Focus a lot.
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  On. Therapeutic approaches in order
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  to offer to these. Patients better.
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  Quality of life. Trying to identify.
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  Some alternative to transfusion and so on.
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  When did you discover the molecular basis of thalassemia?
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  Because that was before knowing your work.
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  In exactly the definition of. Thalassemia, clinically
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  speaking, was given to Doctor Cooley in 1925.
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  But it was. Only after.
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  The 60. When a technique.
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  To separate the. Globin chain of hemoglobin.
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  Was set up that it was possible to say.
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  Thalassemia is a type of anemia due to globin chain deficiency.
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  And that. Was an important step, and that
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  was in 1966. After that.
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  When in. The 80, the.
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  Molecular techniques were made available.
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  Thalassemia was. Characterized at genetic level.
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  And of course, hemoglobin is for.
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  My alpha. And beta globin.
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  Chain so two major group of. Thalassemia were identified
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  according to. The molecular defects on the
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  alpha. Globin or beta globin?
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  Of course, the beta. Thalassemia are the most
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  important clinically speaking. Because you have only. 2 gene
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  which are controlling the. Beta globin production where
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  they ask for alpha you have 4 gene.
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  So I'm not going into. Details, but we focus on beta
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  thalassemia. We characterize the molecular
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  defects of. Vitasalasemia in Italy, but then
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  we did in many. Other we collaborate.
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  To do in many other countries and for.
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  That. Patient I mentioned for that
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  family. What was?
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  The important. Observation was that he was
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  carrier of two affected the. Beta globin drain.
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  So he was hemodigos for the defect, but he had a persistence
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  of. Fetal hemoglobin.
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  So he. Continue after birth during his
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  life to produce fetal hemoglobin.
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  Which compensate the deficiency of beta, so this.
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  Was an important discovery. Which actually open the view of.
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  Finding the. Possibility to treat and to
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  correct beta. Thalassemia inducing the fetal
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  hemoglobin production. This is gene therapy now.
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  And now, now the gene editing based on stimulating the
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  hemoglobin production is becoming a reality.
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  So. I think that.
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  That that discovery, which was then supported also by.
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  Study from Sweele, Tain and the other group.
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  But that was. Really a important.
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  Step for. Working on this.
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  Direction. Direction.
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  And my. Fortune, I have to say, was the
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  the possibility of. Following the natural.
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  History of thalassemia. Changing a long time from the
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  very beginning. When I started.
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  When little rose down for treating these.
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  Children who used. To die within.
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  At most the second decade of life.
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  So I had the opportunity to follow step by step.
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  The improvement because. Of iron chelation, the.
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  Improvement on proper transfusion and now I have
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  patients who have. Over 60.
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  And now I'm so happy that these curative treatment.
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  Are probably available. In the near future.
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  We are all very excited about the gene therapy, about the fact
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  that now you can with Crisp Casket 9, reactivate fetal
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  hemoglobin, but you had also before used hematopoietic, Yeah,
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  I mean. The first, let's say curative
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  approach. Was.
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  Bone marrow transplantation. And the first bone marrow
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  transplantation. Was.
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  Performed in 1981 and there. Was a huge debate at that.
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  Time because you know. That for.
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  Performing bone marrow transplantation you need to do
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  myroblation, which. You know.
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  Both will fun and very. Difficult drugs and.
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  The very beginning. Actually, we lost.
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  Several patients because was not clear how to conditioning them.
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  How to they? May have.
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  Graft versus source. The reaction?
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  So all these things were a bit difficult to face.
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  Because thalassemia is different than leukemia, I mean we have to
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  consider many different factors involved in bone marrow.
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  Transplantation. So at the beginning there was a
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  lot of debate. Among those who.
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  Sustained the. Idea of.
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  Bone marrow transplantation. And those who were more in
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  favour of improving the standard of care.
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  But then step by step. And thank you to the Italian
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  group. Of.
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  Professor Luccarelli in Pesaro, all these let's.
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  Say difficulties were overcome. Improving the protocol.
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  Of. Myroblation improving the.
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  Selection of donors. Now we may.
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  Say that the European Bomar Transplantation Group suggest
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  that. BMT remained.
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  The first choice. In patient age less than 14,
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  having an HLA identical donor. So if.
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  You want to get the. Best result?
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  For bone. Marrow transplantation.
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  This is the. Ideal patient.
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  Still there is a small. Percentage of risk.
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  Of a graft versus soft rejection.
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  What? Is the advantage of gene therapy
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  or genome editing? Where similarly we have to.
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  Perform the mylobulation. But we are.
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  Using the patient. Stem cell.
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  They are manipulated and then they are reinfused.
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  To the patients. So in so in this way we are.
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  Avoiding the risk of. Rejection and that.
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  Is a step forward. Any anyway today having gene
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  therapy approved in United States and having a genome
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  editing approved in Europe and in the United.
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  States still the, the the. Agency are suggesting to.
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  Perform these approaches. In patients who don't have any
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  HLA identical donor for bone marrow.
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  Transplantation. So the problem which in therapy
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  that always comes up is the price tag, obviously.
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  The cost is very high due to the.
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  You know. All the step.
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  You need to do the. Affairs.
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  And then you need to send the stem cells.
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  To a specific lab who? Can do the insertion of gene in
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  case of gene addition gene. Therapy or?
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  Modifying the genome in the case.
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  Of. Gene editing by.
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  Crisp gas. What is extremely important is.
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  To look carefully to the characteristic.
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  Of patients. To be eligible for this.
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  Kind of treatment. I don't believe.
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  That any patients can be treated with gene therapy or genome
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  editing, but. To be successful, I personally
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  believe that as it was for bone marrow.
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  Transplantation is extremely. Important to identify the right
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  patients with low. Comorbidity, for example.
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  And that's. Bring me back.
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  Again to consider. The younger.
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  Population instead of the oldest because.
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  In older. Patients who already have a lot
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  of comorbidity, you know. Take into account the.
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  Cost we have to. Balance the the.
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  Decision. But and hopefully.
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  As it happens. In.
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  For other the. Treatment if this kind of.
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  Approach starts. To be implemented.
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  Probably the cost also will drop hopefully.
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  These diseases are very prevalent in the South of
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  Europe, middle income countries or low income countries, and you
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  have been also very involved collaborating with these
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  countries. Absolutely see how to manage
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  this. Is there?
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  Yeah, gene therapy there. It seems impossible I think.
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  I actually collaborated a lot with.
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  Middle East country. Especially Egypt.
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  Lebanon, Oman and so on. And they did a lot of progress
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  is I have to say. But then I also contributed to
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  improve the standard of care in India, in China where the all,
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  in Thailand where the number of patients are so.
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  Huge in. India, for example and often.
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  It's difficult for. Them even to.
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  Get blood or iron collision. Now I, I.
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  Should say that a lot. Has been done for.
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  Thalassemia, but also for sickle cell disease all over the.
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  World and thanks. Also to the.
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  Thalassemia International Federation.
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  Which is a. Patient association the
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  knowledge is and the management background has been.
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  Spread over the world, so the level is quite good, but there
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  are. Countries where still.
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  There are a. Lot of unmet.
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  Need, but paradoxically. I want to tell.
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  You that for example in. India where there?
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  Is a huge. Bias between rich and poor
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  population or. In other country.
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  Some families are. Ready to move?
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  To gene therapy. Even if the cost is very high
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  because they are rich people. And they can do that.
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  I feel that we are moving to the equity.
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  You know. Is a huge a huge problem to
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  face. You have also been involved in
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  the development of a TGF beta inhibitor Leuspater Sept.
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  Yes, other approaches to treating these that should be
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  cheaper. How is this going?
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  Yeah, and now there are. Other molecules.
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  Such as Metapivat. Which is a PK stimulator.
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  I was involved in leuspatercept trials.
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  Leuspatercept is. Now registered and.
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  Officially available. In the market in many countries
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  in this case. The treatment is not.
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  A definitive cure? But.
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  Is improving the burden of blood transfusion and iron chelation
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  and that. Was part of.
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  My. Let's say vision.
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  And my dream to to to find out how to improve the treatment and
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  quality. Of life for this patient.
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  In term of. Cost.
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  It's definitely cheaper, but you have to consider that this
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  treatment should be done for life.
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  So if you collect all together the cost for a life life.
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  Long time it may be. Quite high.
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  Gene therapy genome editing is one shot.
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  If it works. Is done.
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  Of course. The major problem is OK is.
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  One shot, but. Who is supporting?
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  Such a cost. So you have witnessed all these
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  advances from identify even the molecular bases, the genetic
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  bases, identify on the 1st treatments possible so that
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  people could live longer and even now gene therapy, all these
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  creative options. What has been your most
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  enjoyable part of this path, or what have you enjoyed about
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  this? Well.
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  Any opportunity make me enthusiastic and very much
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  looking. Forward I still believe that
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  the. Introduction of the oral iron.
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  Chelator. That's really.
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  Was an important step forward along the thalassemia journey.
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  Although we had. The serioxamine as I mentioned
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  by pamps abacutaneously. But this was.
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  Extremely demanding and at that time around the 80.
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  Were still losing patients because the compliance drop.
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  They didn't want to go on with this difficult.
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  Treatment and that. Was painful because instead of
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  losing. Patient at the age of 10 or 15.
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  But we were. Losing them at the age of 20 or
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  25 with an oral treatment. Which is a pills now.
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  I mean, that's. That's change completely, the
• 23:47
  adherence, the compliance. And nowaday?
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  Is quite rare to. See patients dying.
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  For heart failure. Due to iron overload.
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  In the heart. We see.
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  Some, of course, because there are patients who are.
• 24:05
  Resistant to treatment, but now I mean the principal, the main.
• 24:12
  Cause of death which was heart failure is not.
• 24:19
  Seen anymore? And that's actually.
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  Made me really. Excited.
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  And that is back to 2000. 5. 2006.
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  When? The Ferraz Xerox was approved
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  there by FDA. And Giba and now is the.
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  Achelators use almost all over the world.
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  With everything that is available, how do you see the
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  management of these patients in the next 10 years advancing?
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  Is it going to advance a lot but or?
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  We have now a huge scenario with some.
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  Pharmacological approaches and some molecular approaches.
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  All of them may have some. Pros and cons?
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  And what I. Believe is.
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  The main. Let's say.
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  The main war. Is really to be able to follow
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  in real life the result of this? Clinical trial and to define the
• 25:35
  profile of patients who may go in One Direction.
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  Or in other direction and not. Accepting without thinking.
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  Which is the best one because the.
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  Patients have different 1 by 1, so the near future and I will
• 25:55
  not. Be there to look at that, but
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  for. Something that I really.
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  Suggest to the. Younger Fellow.
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  Facing the treatment. Of thalassemia.
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  To look carefully at the profile.
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  Of the patient. So now is to be very careful
• 26:13
  which patient gets which type of.
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  Type of therapy. Yeah, that's where we're at,
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  which is a very nice place to be.
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  Wow, compared to where you started?
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  I work on this field. For more than 45 years and for
• 26:27
  40 years. I had nothing else than.
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  Transfusion and collision. Now with, you know.
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  A. New scenario, an exciting time
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  and. Must be really, you know,
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  satisfying to have dedicated your life to this.
• 26:47
  Yeah, this is. And to see where this is
• 26:52
  progressing. It's been a pleasure talking to
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  you. Thank you.
• 26:56
  Thank you very much for coming and participating in this
• 27:00
  podcast, and thank you to all of our listeners and stay tuned for
• 27:05
  our next episodes.