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«New York Forum Part 1 September 20, 2014 Page 1 of 30 Speakers: Virginia Klimek, MD Boglarka Gyurkocza, MD Simon Yeung, PharmD, MBA, Lac Jayshree ...»

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(Applause) Boglarka Gyurkocza, MD: Hi. So, my name is Boglarka Gyurkocza and thank you, Virginia, for inviting me and the MDS patient forum. So, I am an internist and a hematologist and oncologist who has been specializing into bone marrow transplantation. I just want to clarify a few things and then talk about the basic concept of bone marrow transplant today. I could talk about this for about two days, but I’m trying to limit to for 15 minutes. So, the old name, the old terminology, for this is bone marrow transplantation because that’s how it all started that people transplanted bone marrows, but today it comes there’s more inclusive of a term of any kind of hemopoietic cell transplantation and it just means that we are transplanting stem cells that are committed to make blood. So, these are blood forming stem cells. These are very different from the embryonic stem cells that can differentiate into anything. The stem cells we are transplanting are able to differentiate into blood components.

So, this… I would love to talk about the history of stem cell transplantation because we learned a lot from that history, but here I’m just going to mention that this procedure was pioneered by Dr. Don Thomas who recently passed away. I had the good fortune to know him and he got a Nobel Prize in 1990 for this work and basically we learned a lot from him and he was the one who was able to transfer this procedure from the animal models to humans in the late ‘70s and early ‘80s.

So, here is the basic principle of marrow grafting or bone marrow grafting but, again, these days we use this as synonym for any kind of stem cell transplantation. So, the basic idea, the very basic principle, is that there are these hematopoietic stem cells residing in the bone marrow. So, these stem cells, the one characteristic that differentiate these stem cells from other cells that they are able to renew themselves. So, they are able to undergo this asymmetric division when one cell will go down MDSF2014-NYC-1 New York Forum Part 1 September 20, 2014 Page 14 of 30 on the road of maturation, mature into different type of cell components, but the other one will be able to renew itself and continue to be a stem cell and this is what differentiates it’s from other cells that are more mature. These cells are differentiated into specific cell types and they are not able to renew themselves anymore. They are gaining function, but they are using different (inaudible 55:50) of renewing themselves. So, this stem cell here it tries to lymphoid progenitors or lymphoid stem cells and myeloid stem cells and as they undergo their maturation, eventually they will enter the blood stream as mature cell forms of different cells.

So, the idea of bone marrow transplantation is to replace this cell that may be diseased by MDS or other type of malignant diseases with a healthy stem cell from the donor. Again, there are different types of stem cell transplant. There’re autologous and allogeneic. When we say allogeneic we mean that the stem cell is coming from someone else. Autologous stem cell transplants usually are not effective in leukemias or MDS or these type of diseases, but that’s another story.

So, the whole principle of stem cell transplantation is that we give when it was started, stem cell transplantation, the idea was to give high dose chemo radiation therapy. That will eventually destroy the diseased marrow and also at the same time suppresses the patient’s immune system. So, the marrow graft from the other person or the donor can be accepted and then the healthy marrow graft from the donor will replace the diseased marrow and repopulate the marrow and make healthy cells that eventually enter the blood stream. As they started doing bone marrow transplantation in the late ‘70s, early ‘80s, it has been increasingly recognized that this is not the only mechanism in how stem cell transplantation works. So again, the initial idea was by replacing the stem cell, we are able to give higher doses of chemotherapy and radiation. However eventually, it was recognized that when we do bone marrow transplantation or hemopoietic cell transplantation, we practically transplant a new immune system to the recipient and this new immune system, true immunologic ways and methods eliminates contributes to the elimination of the diseased marrow. So in addition to the chemotherapy, the high dose chemotherapy and radiation there is an immunologic component of the efficacy of this procedure and that’s what we call alloimmune reactions and these reactions when they are directed to the diseased cell called graft versus tumor or graft versus leukemia effect meaning that the graft from the donor attacks the diseased cells and this has, again, this contributes to the success of the process. The problem is, however, and one of the biggest limitation of this procedure that this a double edged sword and this immune reaction does not occur exclusively against the diseased cells or the leukemia cells but also healthy tissues of the recipient. This is what we call graft versus host disease and very unfortunately many times they go hand in hand and this represents today one of the major limitations or barriers to the success of this procedure, but I will get back to that.

So, this is just some statistics from the TCIBMTR, The Center of International Bone Marrow Transplant Research, transplant performed in the United States. This is the most recent data we have in 2011. In orange you can see the allogeneic stem cell transplants and in purple the autologous. As you can see, autologous stem cell transplants work for different set of disease. For MDS, we exclusively use allogeneic stem cell transplantation and there was about 10,000 transplants performed in 2011 for MDS. We would like to change that obviously.

MDSF2014-NYC-1 New York Forum Part 1 September 20, 2014 Page 15 of 30 So, here are the components or how this procedure looks. Allogeneic hematopoietic cells transplantation. So, there are three main components for these procedure. The first is the conditioning regimen. The second is infusion of the cells or the graft from the donor and the third is immunosuppression that we give to try to modulate this reaction that I mentioned to prevent graft versus host disease.

So, let’s start with the conditioning regimen. So again, when I talked about on my first slide I mentioned that initially stem cell transplantation we used high dose or what we call myeloablative doses of chemotherapy and radiation to eradicate the marrow. However when this role of graft versus tumor and graft versus lymphoma or leukemia effects were recognized, people started thinking we may not need those high doses of chemotherapy and radiation when most of the effect is coming from these immunological reactions and that’s when people started performing reduced intensity conditioning regimens and this just means we don’t have to give those very high doses of chemotherapy and radiation before infusing the graft, but just enough to suppress the recipient’s immune system to enable engraftment and this concept itself resulted in a paradigm shift in our field because it enabled more mature or older people to undergo this procedure and people who had underlying medical conditions that would have excluded them from high dose conditioning, but because this is a myelo type of conditioning, now we are able to transplant more mature and not quite healthy people at the same time. So, this is a big breakthrough in the late ‘90s and early 2000s.

The next big component is the infusion of the graft. So, I will talk a little more about different donor options. As I said earlier, the early times people used marrow. These days we like to use mobilized peripheral blood stem cells. This just means that we give the donor growth factors and some of the stem cells in their bone marrow get detached from the bone marrow and start circulated in the bloodstream and we are able to sort of fish them out through a procedure that is very similar to hemodialysis. It’s a one or two day procedure. We call it athyreosis. We just take some… We have two lines, IV lines, going in the donor, take some blood out, put it in the little centrifuge and take the current… the refraction out where we think the stem cells are and the rest of the blood is returned to the donor. The major difference between marrow and mobilized peripheral blood stem cells is the composition. When we do mobilized peripheral blood stem cells, there are lot more components, mature T cells and more mature progenitor cells in that graft and this will result in different characteristics in terms of graft versus host disease and graft versus leukemia effect. So, we still use marrow grafts for certain types of diseases and mobilized peripheral blood stem cells for other diseases and of course, this also depends on the donor. People are not able to receive growth factors.

So for them, we would just take marrow and other people just don’t want to go to the OR to get marrow harvested. So, there we do appreciate the donors’ wishes or do. Of course, we have to work with the donors, so we do respect the donors’ wishes.

The third important part of transplantation is the immunosuppression. As I talked about these alloimmune reactions and graft versus host, host versus graft reactions, we find ourselves having to give prophylaxis or preventative therapy to prevent these reactions in the beginning and very gradually taper these off as time goes by. There again, many different ways to do this. Many ways to skin a cat. The traditional way has been a pharmacologic immunosuppression and here at the

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Memorial Sloan Kettering this other approach has been developed, T cell depletion. This is sort of manipulating the graft to take out the cells that we think are responsible for this reaction.

Any questions? If anybody has any questions, please ask. I think it’s better if it’s interactive.

So, this would be a typical treatment scheme, but this is just an example. I will show you some other ones. So normally, we call the zero the day when the marrow graft is infused. This is very similar to a blood transfusion. I will show you pictures of a bone marrow graft how it looks. This is the hematopoietic cell transplant day. That is what we call day zero and right before we would infuse the stem cells, we gave some combination of chemotherapy. For MDS we mostly use chemotherapy based conditioning regimens. This, I’m just showing an example that is very commonly used in the nation for MDS, for example, which would consist of busulfan and fludarabine. In the previous, so from day negative five to day negative two, we usually give a day of rest between the chemotherapy and the transplant to let the chemotherapy to wash out, not to damage the graft and then on day zero infuse the graft. These two medications would serve to prevent graft versus host disease or the alloimmune reactions. This is the classic. Again, this is the standard or again I can’t emphasize enough that here at the Sloan Kettering we use alternative strategies which would be T cell depletion.

So, the classic way would be either to (inaudible 1:05:54) or cyclosporine which we usually continue until day 56 or 60 and very gradually over months and the months (inaudible 1:06:04) off and the other is the traditionally is Methotrexate, but again because graft versus host disease is one of the major barriers of transplant. It is one of the major focus of for research. So, this is a moving target these days and a lot of lot of research focusing on how to prevent and how to treat graft versus host disease.

So, this… here I wanted to show you that a spectrum of conditioning regimens. Again with the advent of reduced intensity conditioning, we have many, many different regiments. You don’t need to memorize this. As Virginia said, there won’t be a test in the end of the day, but I just wanted to show that if you have… we have to imagine this as a spectrum of intensity. So on this axis, I wanted to represent the intensity of the regimen. This would be the lowest intensity. TBI means total body irradiation of two grade. This is a very small dose. We are not able to go below this dose because people would reject their grafts. So, this would be as low as it gets, the intensity. On the other end of the spectrum is this very high intensity regimen containing Cytoxan and total body irradiation more than 12 grades. In between, it’s a continuous spectrum of intensity, but what is important here that as the intensity goes up, the toxicity associated with that regimen also goes up and as the intensity goes down, the particular regimen is more and more relying on this graft versus leukemia or graft versus tumor effect. So, it’s as Dr. Klimek said, this is… I think the beauty of this field that there are so many options that we are able to customize treatment and, again, one size does not fit all. We have many and many different options for many, many people depending on how we think they would be able to withstand the toxicity and we still think this works because of the GVR effect.

So, this curve just shows that since 1998 how the use of reduced intensity conditioning regimen evolved or increased in the United States for different diseases. This purple line represents MDS and as you can see since 1998, there was a dramatic increase in the use of reduced intensity regimens for

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MDS and mainly because this is a disease of people in their 60s and 70s. So, we do need a therapy that fits people in their 60s and 70s and that is reduced intensity conditioning.

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