«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 ...»
So, let’s talk about the donor options. As it was mentioned before, previously a lot of people were not able to undergo hematopoietic cell transplantation because they did not have good donors. The best possible donor traditionally, again, would be an agely identical sibling. Agely means human leukocyte antigen. These are low proteins on the white cells that we test. These have to match between the donor and the patient and there is approximately one in four chance or 25 percent chance that a sibling will be matched. These are always… These numbers are always based on large numbers, these statistics. So, when it comes to a single person and they have one sibling, that sibling may or may not be a match. That’s what I always say. So, it’s impossible to predict whether a patient and his or her sibling will be matched. We just have to test that. If they don’t have agely identical siblings, we start looking for an agely matched unrelated donors. There are good statistical chances that volunteer donors registered in the National Marrow Donor Program through the National Marrow Donor Program will be agely matched and acceptable matches. The good news is that large centers that perform many, many transplant, hundreds of transplants a year have equally good results with agely identical siblings or agely matched unrelated donors. So, we do not really differentiate between the two.
Last but not least is the possibility of an agely haploidentical family member which means half matched donors. It just means that when we use… and there’s more disparity between the donor and the patient. We just have to use stronger immunosupressents to prevent graft versus host disease. In this decade, the use of haploidentical transplantations started propagating and, again, this is a very active field of research. So technically, we would like to stay here at the Memorial Sloan Kettering that we do not want to turn anyone away because of lack of donors. We should be able to find some
donor to everyone because with the agely half matched, this basically means that either a parent or a child is going to be half matched by definition.
So, this just shows statistics from the CIVMTR of how unrelated donor transplants or past related donor transplants in the recent years. In orange, you see autologous transplants but, again, that’s a little different animal. We use autologous transplants for different diseases for different diseases. So, that’s a big element for us, but the use of unrelated donor grafts is increasing.
This is how it looks. Marrow harvest product. Again, this is done in the OR. It’s very similar how a peripheral blood stem cell collection looks and then this is the graft that we infuse into the patient on day zero. Very, very similar to a blood transfusion and then the cells first just go to the lung and then eventually find their way to the bone marrow. They stick out in the bone marrow. We call that process homing and they start producing blood components then.
Just a few more words.
Supportive care… So, recent events in supportive care make this procedure safer and one of the… I’m listing a few of these here. We have better antibiotics to prevent certain infections (inaudible 1:15:05) for (inaudible 1:15:06). This was (inaudible 1:15:08) in the older time. Acyclovir for herpes and (inaudible 1:15:14) cell line infections. CMBs, a very important virus for us. It can cause severe morbidity and mortality. So, we are very aggressively treating CMB reactivation, better antifungal, prophylaxis and treatment medications. Still, I have to say very unfortunately this procedure is not without risks. There is substantial and significant morbidity and mortality that can develop during a bone marrow transplantation and there is an associated risk of dying from the transplant and this can be 20 to 30 percent in the four years after transplant and this is why we are not transplanting everyone. Right? So, this is, again, a major limitation to this procedure. We would like to transplant everyone, but we recognize that this is not for everyone. This is a high risk high regard approach. The aim of transplant is always cure, but it doesn’t come cheap unfortunately and this is a little chart that shows you what factors may go into the decision of how to transplant someone. So, there will be patient associated and diseases associated characteristics pre-transplant. If people have comorbid conditions that may sway us to do a more reduced intensity conditioning. For people more mature in age, we tend to do reduced intensity conditioning. The disease characteristics may sway us. If it’s an aggressive disease then we may want to do a more high dose conditioning regimen then, again, depending on what donor we have and, again, disease relapse risk can decide whether we want to do mobilized stem cells or marrow infusions and last but not least post-transplant interventions, maintenance or preemptive therapy post-transplant. That is a very important of field of research these days that after transplants for patients who either have mixed chimerism or high disease risk we may introduce intermit prevention after transplant. Mixed chimerism that both the donor and the patient contribute to blood formation.
So, the million dollar question arises when should MDS patients undergo transplant and this is important as Dr. Klimek said that MDS is a very heterogenous disease and some people do very well for many, many years with minimum therapy. Should we subject those people to this high risk approach? Absolutely no, but on the other hand the other end of the spectrum is aggressive disease MDSF2014-NYC-1 New York Forum Part 1 September 20, 2014 Page 19 of 30 that within months would transform into leukemia and we definitely want to do transplant early as possible. So for us transplanters and for MDS doctors, the question is always how can we predict who has a more aggressive disease and who has a less aggressive disease and as Dr. Klimek already talked to you we use tools to predict the transformation to leukemia. There are many different tools.
I’m just showing one. There are many others. The problem is that none of them is perfect. Right? We are not able to predict in every single case who is going to do what and who’s MDS will transform sooner or later.
The International Prognostic Scoring System takes into consideration a few factors. The marrow blast percentage, the karotypes. This means the chromosome aberrations and cytopenias meaning how many cell lines have low blood cell counts and based on that we come up with a number and based on that number we stratify people into risk categories, low risk, Intermediate 1, Intermediate 2 and high and in large… again, in large number of patients this is how these risk categories behave in terms of progressing into AML. This again, unfortunately, is not perfect. I think the future may be to incorporate molecular genetic changes into this or further factors that we are not completely aware right now, but Cory Cutler and Dana Farber did a decision analysis for MDS patients using prebaked data basis. The IRA, the IVMTR and the Fred Hutchinson Cancer Center databases and came up with this decision analysis who should be transplanted and who should not be transplanted and based on a large number of people and statistics, they were able to conclude that patients who belonged to the low and intermediate 1 risk MDS would benefit mostly from delayed transplant. That’s when they have the longest life expectancy and those with Intermediate 2 and high risk MDS would benefit from a more immediate transplant. Again, very unfortunately this is not perfect. These tools are not perfect, but this is what we have now and this what we use now to predict… I mean, to kind of try to select people. There are always exceptions, of course. If somebody has very high transfusion requirements and a very young age, we try to transplant them sooner. So and of course, we always have to take into consideration the patient’s approach, the patient’s philosophical approach to life. I always have a very long discussion with everyone because I can’t tell someone this is about taking risks, this is about their own lives and I think they have to tell me what they want and I just help them to get there in general.
So, this just shows some statistics. This is an older one. How the different risk groups do on the long term. So, these are years here that the low risk group… Almost done. Does better. The high risk group does worse. I will get back to that. This is from the NMBP how early disease stages with unrelated or sibling donors do very similarly and more advanced diseases there is separation of (inaudible 1:21:44) between unrelated and related donors. Again, this is a registry based data.
Everybody like all centers contribute their data. In larger centers these curves don’t separate as much between unrelated and related donors.
This is what Dr. Klimek talked about that in an effort to even better stratify disease risk, recently from the three group cytogenetic risk stratification they developed a five group recognize five group risk stratification recognizing that within the poor prognose cytogenetic group there are cytogenetic changes that predict even worse biologic behavior for this disease and they separated those out and the same applied for the good prognostic group that within the good prognostic group there was a subgroup of patients who did much better than the rest of the group. So, this is very recent. Dr.
MDSF2014-NYC-1 New York Forum Part 1 September 20, 2014 Page 20 of 30 Rashaan’s reported it in 2012 in the Journal of Clinical Oncology, but this translates into the transplant world as well. So this five risk… five group karotypes risk stratification does predict behavior after transplant. So, people with bad cytogenetics, obviously, do worse after transplant.
They have higher blast rates and lower survival. This to us does not mean we should not transplant these patients, but this to us means that this group of patients would be the ones who could benefit from further interventions after transplant. These are the patients who it’s not enough to do a transplant. We have to do post-transplant interventions to minimize blast risk because these are the patients we know are at high risk even after transplant. So, the message here, I think, is that the journey does not stop at the transplant. Some people will need post-transplant preemptive therapy to prevent relapse after transplants which still represents one of the major barriers to success.
So in summary, I just wanted to say that because we know that the median age to an MDS is diagnosed is 71. We have to make allogeneic transplant available and accessible to that population, the population that needs it and reduced intensity conditioning regimens make us able to achieve that goal that reduced intensity conditioning regimens make transplant available for older people and for those who have underlying medical condition and that post-transplant relapse remains a major barrier to success and this is where we have to work together with our MDS doctor clinics who develop interventions after transplant that will prevent this relapse and this is where I would like to stop and take questions if there are any questions. Yes?
Q4: If you were accepted for this trial, do they stop all your other medications or do you still take them?
Boglarka Gyurkocza, MD: It’s a very good question. So, it depends on what medication you are talking about. We like to stop medications before transplant about three – four weeks just to minimize toxicity of the transplant, but if it’s Azacitidine or any kind of milder form of therapy we think strongly about reintroducing it after transplant especially with high risk disease… in patients with high risk disease to minimize those transplant relapse. So, we would probably stop the MDS medications for the time of transplant, but for some people we would introduce that after transplant for some time.
Yes? I don’t know who was first.
Q5: Things are always changing, so I was just wondering what your cutoff age is for transplantation and when you talk about reduced intensity do you mean the same drugs but at a lower level or totally different drugs?