Latest / EHA Unplugged / EHA Clinical Excellence Award 2025: Prof Khaled Musallam

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EHA Clinical Excellence Award 2025: Prof Khaled Musallam · EHA Unplugged

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And from those studies, there were two key, let's say
0:03
thresholds that came out. First, that the hemoglobin of 10
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is, is the, let's say the magic number where all patients who
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had the hemoglobin of 10 and above almost never had a
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morbidity. In our cohorts at least patients
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who had hemoglobin of less than 10, they started having
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morbidities and once it goes less than 7, it dips, it becomes
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very probable that they will get morbidity.
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So that level of hemoglobin of 10 is what we took as the
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threshold that you need to do something to the patients.
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Welcome to EHA Unplugged, the official podcast channel of the
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European Hematology Association. EHA.
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I am your host, Isabella Libera, and today we have the pleasure
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to have with us Professor Khaled Musalem.
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Professor Khaled Musalem is currently serving as the Group
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Chief Research Officer at Burger Holdings and he is the founding
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director of the Center for Research on Rare Blood Disorders
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at Burgell Medical City in the United Arab Emirates.
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Under his leadership, this center has become a regional and
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global hub for research and innovation focusing on improving
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the outcomes of patients with rare blood diseases such as
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thalassemia. Professor Musalam's work has
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transformed the management of non transfusion dependent Vita
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thalassemia and TDT worldwide through international
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collaborations across the Middle East, Europe and the United
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States. Doctor Mussalam has authored
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highly cited guidelines that serve as global standards for
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NTDT management. He's the recipient this year at
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the EHA Congress of the EHA Clinical Excellence Award.
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Congratulations, Doctor Mussalam, and thank you for
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being with us today. Thank you.
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It's a pleasure to be here. So in this podcast, we will
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review how did you go from observation to intervention in
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NTDT patients, how you contributed to the discovery of
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different morbidities effects in NTDT patients and in particular
2:23
the unexpected iron overload and the consequences of moderate
2:27
anemia. We will look at the revised
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guidelines on NTDT and the novel therapeutics Luz Patersept and
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Mita Pivot. So welcome to this podcast.
2:43
Our first question for you is what initially drew you to beta
2:50
thalassemia research? Well, it all started actually
2:52
when I was in medical school. I started being geared more
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towards clinical research and I wanted, if I wanted to take a
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full career in clinical research, I wanted it to be
3:03
relevant to my region, which is the Middle East broadly.
3:06
So I was at the American University of Beirut at the
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time. And thalassemia was one of those
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diseases that has a lot of unmet needs.
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But we certainly had a lot of patients for historic regions
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for evolutionary reasons related to our region being part of the
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initial malaria bell. So the Mediterranean and Middle
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East had a lot of carrier states of bit of thalassemia.
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So we ended up having a lot of patients in this region.
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So that's what made me interested.
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And I was very lucky to have a very great mentor, Professor Ali
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Taher, who was actively working in that field.
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So that actually LED one thing to another and that became the,
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let's say, research program or research subject that I'm
3:43
interested in to take forward for my clinical research
3:46
journey. Can you explain the types of
3:49
beta thalassemia under severity? Sure.
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So this has been, it is actually an active transformation, the
3:56
terminology, the one thing we always advise our colleagues,
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don't get stuck on the terminology.
4:00
What matters for you to know the patients.
4:02
But that aside, theoretically speaking, with the thalassemia
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is an inherited disorder of hemoglobin synthesis.
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So patients usually need to inherit 2 defective genes from
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both parents. It's a recessively inherited
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disease, and they will end up with a mutation or a change in
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the gene that caused the beta globin chain of our adult
4:22
hemoglobin molecule that carries oxygen in the red cells.
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Consequently, the result is ineffective, what we call
4:28
ineffective erythroporesis, and that's when the bone marrow in
4:31
the body cannot release enough red cells because of that
4:35
defective chain imbalance in them.
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They got they die prematurely in the bone marrow or even if they
4:40
escape to the circulation. We have what we call hemolysis
4:43
and that's both combined they lead to a chronic state of
4:46
anemia. So when we looked at beta
4:49
thalassemia in the past, we were mainly looking at their initial
4:52
presentation. So if patients presented very
4:56
young, younger than two years of age with severe anemia, we're
4:59
talking about the hemoglobin in the range of 345.
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Immediately, we labeled these patients as having beta
5:04
thalassemia major and they're put on regular transfusion
5:06
programs. Now the the other group of
5:10
patients, which still inherited both genes that are defective,
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so they're not just carriers of the disease, but they present a
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bit later in childhood and they have mild to moderate anemia,
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usually in the range of seven to 10 grams per day.
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See liters of hemoglobin. These were patients that were
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labeled as having beta thalassemia intermedia, and the
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normal course of action was just to observe these patients, maybe
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give them some folic acid, something to sustain a little
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bit of hemoglobin. But we didn't feel the need that
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we need to do something about this anemia, assuming that they
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can tolerate and sustain it now around 10 years ago.
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And that's where we started realizing that this beta
5:44
thalassemia intermediate is not an intermediate.
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It's not so benign as a disease. So we thought these
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terminologies are a little bit fooling both the patient and the
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physician that they shouldn't expect anything bad to happen in
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the disease in the long run. So we decided to change the
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terminology, not that the old terminology is not valid, we
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still use it actually on day-to-day basis.
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But we started calling the thalassemia intermedia patients
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are non transfusion dependent thalassemia and TDT and that
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thalassemia major patients as transfusion dependent
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thalassemia TDT simply because we wanted to signify the
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importance of receiving or not receiving transfusion, which is
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a physician choice at the end of the day in the pathophysiology
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that follows in this disease. So that's why the whole field
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got split now into NTDT TDT. All the novel therapy trials are
6:31
done separately for NTDT TDT. The guidelines that were
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released with the Thalassemia International Federation are
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also split as NTDT, TDT. So one thing that we realized
6:41
after introducing the terminology is that there's a
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population that we're missing in this definition because it's too
6:46
cross-sectional. It's just looking at the patient
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now, are they getting transfusion or not?
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But the disease can be dynamic. So patients could be and TDT and
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then they transition to become TDT and so on a period of 10
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years, around 15% of patients good transition from NTDT to
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become transfusion dependent. Again, that could be just a
7:05
physician choice or a patient choice.
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But we also saw some risk factors which is anemia and
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multiple morbidity is making patients transition to become a
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TDT which we called pheno conversion for these patients.
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So there are dynamic terminologies and we usually
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again, as I said, try to to educate our colleagues that
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don't just get stuck with the name, just focus on the patient
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and observe the patient for a while for you to understand
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their underlying disease severity.
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When you evolve from non transfusion dependent to
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transfusion dependent, yeah, can you go back to non transfusion?
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It would be hard to have that without something being
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introduced to the patient. So now all the novel therapies
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that are being used in transfusion dependent
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thalassemia are reducing the transfusion requirement for
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those patients and sometimes they're reaching transfusion
7:49
independence. So in reality they are becoming
7:51
non transfusion dependent, but that is hard to happen just
7:55
naturally in the disease. So the disease doesn't get
7:57
better on its own. Now there could be some
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mutations that we're unaware of that happen get acquired that
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lessen the burden of the disease.
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But usually if a TDT patients become NTDT, there has been some
8:08
intervention involved. You let initial observation of
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studies that real three major causes of morbidity for NTDT.
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So I don't overload ineffective erythropoiesis with anemia,
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ipercoagulability with vascular disease.
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So let's start with iron overload.
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This is a cause of morbidity that was unknown.
8:35
Can you explain how iron overloads occurs in patients
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that are not receiving transfusions?
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That was what amazed us to begin with.
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So when we wanted to study NTT to begin with, we started
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actually uncovering the science from the clinics backwards.
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So at the time, as I said, I was working with Professor Ali Taher
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in Lebanon and then I was working also with Professor
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Maria Capellini and at the University of Milano.
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And we started realizing that doctors beta thalassemia and to
9:02
the media, the NTDT are coming to their clinics later in life
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with severe complications with thrombosis, palmera,
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hypertension, liver disease, sometimes reaching
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hepatocellular carcinoma. So the first step, we wanted to
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see if this is something that is shared by others.
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So we, we asked our neighbors, that's the best thing to do.
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We've done a study called the Optimal Care study, which was
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the highlight of of looking at the morbidity profiles and of
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NTDT patients. And we discovered that it is the
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same everywhere. So these patients are not
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receiving blood, but they're still coming with these serious
9:33
complications. And then we started actually
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looking at those risk factors that could lead to those
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complications. So the story of iron also
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started, I would say, 15 years back very, you know, high credit
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goes to our translational science colleagues who were
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looking at how could that happen?
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How could a patient that is not receiving blood have excess iron
9:55
in their body? Because usually the iron and TDT
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patients come from the external transfusion.
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Our body doesn't have a mechanism to excrete extra iron.
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So if you're receiving red blood from outside and this has its
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own iron, excess iron, your body cannot to get rid of it.
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It starts accumulating in the heart primarily and the liver.
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But an NTDT patient, what's happening is different.
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It's those patients are not getting transfusion.
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Maybe sometimes, occasionally, but that's not the source of
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iron. What happens is that the body's
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fooling itself into believing that it can produce red cells.
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So the bone marrow starts sending erythroid signals to the
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liver that releases a specific hormone called hepcidin.
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And that's what you regulates how much iron we absorb from our
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gut. So as long as there is
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ineffective erythropoiesis, the body is telling the gut, please
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absorb more iron, absorb more iron.
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I need to make red cells, but it's not making those red cells.
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So the iron starts to accumulate.
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So that was clear for us that there is a pathophysiology
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undergoing, we're not imagining iron in these patients.
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So clinically speaking, we wanted to say should we, should
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we care about this iron? Is it accumulating that fast
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similar to someone who's getting transfusion?
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And we've done a lot of observation studies.
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We learned that it is a slow process, lower than transfusion
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of iron overload, but it can reach really significant levels.
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So patients can reach those high serum ferritin liver iron
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concentration levels that we see in transfused patients.
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And we've done a lot of correlation studies to see are
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these iron, high iron levels related to those morbidities
11:22
that we saw in patients in the clinics.
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And the answer was yes, at least for endocrine disease, for liver
11:27
disease, sometimes even for vascular disease, We saw that
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there is a link between iron overload.
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Now it could be confounded by many things happening in the
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body, but at least for the majority of morbidity, iron was
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a causal factor. And obviously you don't need to
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stop there. You need to do something about
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it. You just we don't want to just
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tell patients now we know what's going on, but we don't have a
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solution. Luckily in the iron overload
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world, iron collation has been there.
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We've been using it for decades in transfusion dependent
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patients. So all we needed to see, can we
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apply the same in non transfusion dependent patients.
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First, we've done observation studies to see what levels of
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iron we need to start a chelation on what should be our
12:08
target iron overload level. This all came from observation
12:11
studies, hence why from observation to intervention and
12:14
that informed the clinical trials.
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So the first clinical trial of iron chelation, NTDT was called
12:18
Thalassa with a drug called the Ferrocirox and oral iron
12:21
chelator. And it met its primary and
12:23
secondary endpoints and it led to registration and FDNEMA and
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iron chelation became a standard for NTDT patients as well.
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And that's actually the time where we issued our first NTTT
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guidelines ever because now we have something to give.
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At least the iron overload story was mastered.
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So we put it in the first guideline supported or published
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by the Thalassemia International Federation that focus mostly on
12:48
on iron at that time. That was back in 2013.
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So that's, in a nutshell, The Iron Story.
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And how is it managed today? Are there new solutions?
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So iron creations do the job really well.
13:02
It's it's a very chemical interaction that you have extra
13:05
R and the body, an R insulator, which is just a molecule that
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takes the extra R and gets it out of the body.
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The R insulators that are available today, they, if
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they're taken in an adherent way, they will do the job.
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The main problem with iron collision therapy is patient
13:20
adherence. You can imagine if you need to
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take a drug every day for the rest of your life, you might
13:25
have periods where you're not so keen to do that.
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And those are the periods that we see the iron going back up
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also for non transfusion dependent patients because this
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is new information to them that they have iron and they need to
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get iron chelation. So we still also have some
13:39
struggle convincing patient that this is an issue and they need
13:42
to actually get iron chelation therapy to begin with.
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These patients also don't get blood so they don't come that
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frequently to the center. So NTDT patients come every
13:52
three to four weeks. You have that touch point to
13:55
remind them about the iron chelation etcetera.
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But NTDT patients could go on for a while without visiting the
14:02
doctor, you know, and that is enough time to, to miss some
14:05
doses and to, to have iron overload level.
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There are other new iron chelators on the market, but
14:11
more or less they're going to be doing the same job.
14:13
It's just a different formulation, different schedule
14:15
of iron chelation. But in terms of technology,
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let's put it this way, we, we're still just rely on iron
14:21
chelation therapy for iron. There's also ineffective
14:25
erythropoiesis that leads to anemia or myelanemia.
14:30
Can you explain why this is a problem?
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Because sure, it wasn't thought to be a problem with myel
14:35
anemia, correct? So ineffective erythropoesis is
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the core of the problem. So it's actually the one also
14:40
leading to IRN overload, like I mentioned, because it it sends a
14:43
signal to to receive. But we wanted also to look at
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anemia itself because that's the easiest thing to measure in a
14:48
patient, the hemoglobin level. Now whether this anemia is just
14:52
a marker of ineffective erythropoesis.
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It's not directly causing damage to the organs.
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We, we believe part of it is true because it's causing damage
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through those other pathways in effective erythropoiesis and as
15:03
we will talk later, hypercrylability.
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But also it's still anemia. So if you have a hemoglobin of
15:09
eight or nine and a normal hemoglobin value is in the range
15:12
of 1213 up to 1516, something must go wrong.
15:16
The body, there's a chronic state of hypoxia, maybe slow but
15:20
chronic tissue damage that could result in something.
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So obviously we wanted to test that and we've done again
15:26
observation studies cross section and retrospective
15:31
prospective to actually try to find what's the level of
15:35
hemoglobin that should be OK. You know, when, when do patients
15:39
actually start having mobility. And from those studies there
15:42
were two key, let's say thresholds that came out.
15:45
First, that the hemoglobin of 10 is, is the, let's say the magic
15:49
number where all patients who have the hemoglobin of 10 and
15:52
above almost never had a morbidity.
15:54
In our cohorts at least patients who had the hemoglobin of less
15:57
than 10, they started having morbidities and once it goes
16:00
less than 7, it dips, it becomes very probable that they will get
16:04
morbidity. So that level of hemoglobin of
16:06
10 is what we took as the threshold that you need to do
16:09
something to the patients. If the hemoglobin is less than
16:11
10, you cannot let the patients live for the rest of their life
16:14
on hemoglobin of 7.5 or 8 or 9. We'll talk later about what that
16:19
what you could do about that. And one thing also we learned is
16:23
that even if you change the hemoglobin by 1g per deciliter
16:26
only, which might sound small, but that again was able to
16:30
reduce the morbidity risk by around 28%.
16:33
So that's significant obviously, because we again, we're talking
16:35
about serious complications. This is not just immediate
16:39
effect of anemia like fatigue or the typical symptoms that
16:43
anybody gets. It's the anemia of ineffective
16:45
erythropoiesis. And that's linked to many, many
16:47
of those morbidities that we mentioned in the beginning.
16:50
So that became more or less our target.
16:52
Now the the problem was, is what do we do about it?
16:57
Again, we always ask this question.
16:58
The only option that we have is transfusion.
17:00
If you take genetics in general, you should have almost the same
17:05
number or a bit less of NTD patients as there are TDT
17:09
patients. But because they don't come to
17:11
the center, sometimes they're lost in the system being treated
17:13
as just any other anemia. In a typical thalassemia center,
17:17
you would see maybe two third TDT and 1/3 entity that's in a
17:20
very significant number. So for you to take all these
17:23
patients and make them transfusion dependent, that's a
17:26
burden to the patient, burden to the healthcare system and burden
17:30
to the whole public health sector in in a country.
17:35
In many countries, around 50% and above of the national blood
17:38
bank consumption goes to TDT and many areas of the world, like
17:43
90% of patients in the world live in those low resource
17:46
countries that cannot even keep up with transfusing the TDT
17:50
patients. So now to add another group that
17:52
requires CV transfusion might not be the wisest thing to do,
17:56
but if we need to do it for the sake of the patients, we need to
17:59
do it. So that's why we have studies
18:00
that many patients were transitioned to become TDT,
18:04
maybe in their teens when they started growing, having
18:08
developmental delays or anything apparent, they started becoming
18:11
transfusion and they did do better.
18:12
We know that transfusion do the work, but we wanted to have an
18:17
option. So which are the solutions for
18:20
anemia for this mild anemia? Yes, so for this mild to
18:24
moderate anemia, there were two drugs that came out in the last
18:27
five years or so. The first one is the
18:29
spattercept. It's first in class erythroid
18:31
maturation agent working on late stage erythropoiesis.
18:34
So this is genetic disease. So the genetic defect is still
18:36
there. But what it does it to put it in
18:39
a simple way, it helps that it cells exit the bone marrow more
18:41
commonly. So that's why you can improve
18:44
the hemoglobin of the patients. And it was evaluated in a in a
18:47
randomized trial called the Beyond trial.
18:51
Patients that were recruited were adults with a hemoglobin
18:53
less than 10 for the objective of increasing the hemoglobin by
18:56
1g per deciliter. That was the primary endpoint
18:59
and it met that primary endpoint and it that was approved in
19:03
Europe by EMA. It's subcutaneous taken every
19:07
three weeks. Metabolite, which is another
19:10
novel drug. It's in its latest stages of
19:13
development. Metabolite was also evaluated in
19:16
a phase three randomized trial which read out for the core
19:21
period for the primary endpoint last June.
19:23
It was presented actually at the HA as a plenary presentation.
19:28
It also looked at the same thing at the adult patients with a
19:31
hemoglobin less than 10 MTDT patients for the primary
19:34
objective of increasing hemoglobin by 1g only.
19:38
The only difference is in the energized line, we included both
19:41
beta and alpha thalassemia, so not only beta and TDT and also
19:45
it's an oral drug given daily, twice per day.
19:48
So the, the, the landscape is gonna change now.
19:51
So at least the prospect of patients is gonna change because
19:54
now we have for the first time a treatment options for this
19:56
anemia. Obviously there is a, a need to,
20:01
to educate the, the, the, the community still.
20:04
And the patient said that you need to do something about this
20:06
anemia because someone can just tell you, I've been living with
20:08
this hemoglobin, I feel OK. And usually it's hard for you to
20:12
convince patients with a long term risks, but hopefully we're
20:16
doing a good job with that with a lot of education, the patient
20:19
level and the physician level. In collaboration with the
20:21
Thalassemia International Federation.
20:23
But at least now we have treatment options for these
20:25
patients. Now what probably you would
20:27
start seeing next is that the doctors would start but trying
20:30
different combinations, trying a bit of transfusion with a bit of
20:33
a drug. This is what the phase that we
20:36
always rely on called the real world evidence phase where you
20:39
know, we are following the prescribing information of the
20:42
drugs, but doctors also want to be innovative and try to find
20:46
the right regimen for their individual patient.
20:48
And we start seeing some combinations in action that we
20:52
again put back into studies to try to to confirm if these
20:55
combinations are better. So as much as the iron overload
20:57
story has been in a steady state, it's stable for these
21:00
patients. Now we know when to assess the
21:02
patients and how to treat them with our creation.
21:05
I think the next few years will be about learning back again how
21:08
to handle the anemia for these patients.
21:10
And this is what we introduced in our revised Thalassemia
21:13
International Federation guidelines from 2023, where we
21:17
will not no longer only talk about iron as a as a need for
21:20
treatment, but also anemia. With everything that I mentioned
21:23
that hemoglobin less than 10, we need to have treatment
21:25
especially in symptomatic patients to improve hemoglobin
21:28
by at least 1g. And we introduce also even the
21:30
sponsorship in these guidelines as an option alongside
21:33
transfusion to to treat the patients.
21:36
Are these new drugs available in Low in income countries where
21:40
this is more prevalent? So Lewis Partnership is, so it's
21:43
after the EMA approval for NTDT, many countries adopted it.
21:48
Mitapivat is still under review now for by the FDA and the EMA.
21:52
So we'll know the results by September.
21:54
There's always an issue, obviously with affordability and
21:56
access to these drugs. And we always call on pharma to
21:59
try to find innovative ways to to make it affordable to
22:03
patients because as I said before, 90% of patients are in
22:05
low resource countries. So if we're not even able to
22:08
find blood, how can we afford targeted therapies that come at
22:12
high cost? So that everyone needs to work
22:15
on this, physicians, patient organizations, the industry
22:19
together to see how we are able to actually offer these advances
22:23
to patients in need. And what about the third
22:28
morbidity cause hypercoagulability?
22:31
Yeah. That that's always an
22:32
interesting one. We started calling out
22:33
thalassemia as a hypercoagulable state also.
22:36
It was a surprise in one way or another because it's an anemia,
22:38
why would you have hypercoagulability?
22:40
But there is a lot of studies that came 20 years plus ago that
22:46
actually found out that those red cells that are hemolyzing
22:49
and the circulation of the patients, they expose certain
22:52
markers on them that makes them thrombogenic.
22:54
So the red cells are actually what's causing the the, the
22:56
hypercoagulability along with other let's say dysfunctions and
23:01
the coagulation cascade increased platelets.
23:04
We've started seeing specially in patients who remove the
23:06
spleen because that was a relatively older practice that
23:09
if you remove the spleen of the patients, you are actually able
23:12
to raise the hemoglobin by 1-2 grams.
23:15
Now it's less commonly practiced because we realize when you
23:17
remove the spleen, you remove the ability of the body to to
23:20
get rid of those hemalized red cells.
23:23
So if they stay in the circulation, that can cause
23:24
clots. That's why patients present with
23:27
deep vein thrombosis or even arterial thrombosis.
23:30
And we think that at least that partially explains the pulmonary
23:32
hypertension because of microthrombi and the and the
23:35
pulmonary circulation. So hypercoagulability has been
23:38
established as a cause for thrombotic disease, but we
23:41
didn't do much about this one. So that's one area that I think
23:44
we need to do some work. Obviously there's a lot of anti
23:46
platelets anticoagulants out there, but they were never
23:49
specifically tried out in thalassemia population 11.
23:53
Difficulty here is that the the thrombotic activity happens a
23:58
bit late. So you need to run really long
24:01
trials to see if you can really prevent thrombotic events.
24:05
So most of the time now we rely on the usual standard medical
24:08
and surgical guidelines for, for risk assessment and prevention
24:12
of, of, of thrombotic events in the, you know, general
24:16
population or in, in other patient subgroups.
24:18
But that's one area that requires a little bit of of work
24:21
still from our end. If you want the audience
24:23
remember just one thing from this podcast, what would it be?
24:28
Well, I would have to think of multi stakeholder audience.
24:32
So if it's a General practitioner audience, keep NTDT
24:38
on top of your mind when you're looking at the patient that's
24:41
presenting with anemia that's not clearly identified as iron
24:45
deficient or they're not responding to iron and consult
24:48
with a hematologist. And for our hematology
24:51
colleagues and let's say thalassemia traitors, I think
24:56
we, we, we want them all to understand that we can no longer
24:59
say that anemia and NTDT patients is fine.
25:03
So that's, that's a main message.
25:04
We need to do something about it.
25:06
Do we have the optimal right solutions now?
25:08
Maybe, But at least we need to. We know that we need to to do
25:12
something about it. So thank you very much for being
25:15
with us today. Oh.
25:16
Thank you for having me.