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Weighing Decisions & Outcomes for MPN Stem Cell Transplants

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Published on December 21, 2020

What MPN Patients Should Know About Stem Cell Transplants

Weighing all of the variables that are involved in considering a stem cell transplant — pros and cons of treatment, affordability, success rate — can feel suffocating. And that’s before the procedure itself! In this special installation of our MPN Answers Now series, our host and Patient Power co-founder Andrew Schorr speaks with patient advocate Rabbi Ronald Roth and Dr. H. Joachim Deeg, MD, of the Seattle Cancer Care Alliance about transplant decision-making and outcomes.

What does this decision-making process entail? What should a transplant candidate do before and after the procedure? Is there research on the horizon that will change the calculus for patients in the coming years? Keep watching to hear the answers to these questions and more.

This program is sponsored by Incyte and is produced in partnership with the MPNRF. This organization has no editorial control. It is produced by Patient Power. Patient Power is solely responsible for program content.

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Transcript | Weighing Decisions & Outcomes for MPN Stem Cell Transplants

Andrew Schorr: Greetings. It's Andrew Schorr from Patient Power. I am very excited that we're doing this program for the MPN community about really weighing decisions about transplant. Joining us from Fair Lawn, New Jersey, is my friend Ron Roth, and joining us from Seattle, Washington, is Dr. Joaquim Deeg, who's one of the foremost physicians related to transplant in the world. He's at the Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center, really where they developed transplant. I want to start with Ron Roth for a minute in Fair Lawn, New Jersey. Ron, you developed ET, essential thrombocythemia, way back in 1990, right?

Ron Roth: Yes. My doctor said to me, "You have a high platelet count. The worst thing that can happen is, it can go over a million, and we'll give you some medicine, and you'll be fine." That's all I was told then, and that went on for about 25 years.

In 2015, my ET had progressed to myelofibrosis, MF. I would go into Mount Sinai once a week, and I did get a shot of what's called PROCRIT to boost my hemoglobin levels. But again, I had, for the first two years, no other symptoms. I was not on any other medication, continued working full time, long hours at the job. Got a little bone pain then in the third year. My platelet levels kept going down. I was really living in a state of denial about the transplant. I knew what the transplant would be, but I really, of course, didn't want it to happen and didn't want to think about it.

Our transplant doctor called us in, and she said, "You know, I've been reading about some studies, and we've been doing some transplants at Mount Sinai with what's called haploid, a half-match. And your son," I have one natural son, "he might be a half-match." So, they tested my son, and he was.

One of my other doctors said, Dr. Ginzburg said, "You know, you're at the sweet spot. You're at 69 years old. Top age is age 70. You have no comorbidities. You're in relatively good ..." As I like to say, aside from the cancer, I was in good health. And then when I spoke to the transplant doctor, I said to her, "What would happen if I did not have the transplant?" And she simply said, "We'll keep you alive as long as we can."

Andrew Schorr: We have more to talk to you about, about your son's donation and all that. Dr. Deeg, let's resume with you, sir. First of all, transplant. For people with myelofibrosis, it remains a potentially curative option. Am I right?

Are Stem Cell Transplants a Curative Option for Myelofibrosis?

Dr. Deeg: Yes, it is a curative option. What has to be understood up front, it doesn't guarantee it. But it clearly has the potential to cure patients. Now, we have follow-up now up to almost 25 to 30 years, and patients continue to do well.

Andrew Schorr: Help us understand. I mean, you've seen the refinement of transplant over decades. These refinements have made it safer, or more people can have it. Where would you describe it now?

Dr. Deeg: The procedures certainly have become safer. The results have progressively improved. We just published a paper in the Annals, emphasizing on those points.

And so, over the last 10 years or so, these, as we say haplo in Greek, half identical... HLA-identical transplants have been carried out with increasing frequency. A major aspect, a major component of those approaches was, again, returning to old data that come from those animal models that we would give not just chemotherapy and/or radiation in preparation for a transplant, but would give additional chemotherapy in the form of Cytoxan (cyclophosphamide) for a couple of days after transplantation.

That sounds sort of paradoxical in a way since you want these transplanted cells to thrive and recover. But the stem cells that we really need are not sensitive to this approach, to the Cytoxan. However, the lymphoid, the immune cells that are part of what we infuse into patients, get turned on by recognizing the fact that we don't have an identical, but only a half-identical transplant. So, they react against a non-identical component, if you want to look at this way, that transforms them, and they become very sensitive to the Cytoxan.

We can eliminate a good proportion of them. And we are learning, just as we are talking, basically, the presence of this chemotherapy also favors the development of another subset of lymphocytes that we refer to as regulatory T-cells. So, eliminating a lot of the undesired, aggressive T-cells and generating of some of these regulatory T-cells, that has helped to basically overcome this hurdle of only half-identity.

Andrew Schorr: So where are we now with the limit, of age limit or physical limit? How do you see it now, whether you would accept somebody for a transplant?

What Makes an MPN Patient a Good Candidate for a Stem Cell Transplant?

Dr. Deeg: Right. I mean, that is an important question and continues to be debated and evaluated in various analyses. Let me go back to what you said earlier that we have been working on refining the methods that we use for transplantation, in general, not just with haploidentical. One of the big changes was the development of what is referred to as reduced-intensity conditioning regimens, in other words, not so much emphasizing the ability of this regimen chemotherapy, with or without radiation, to kill abnormal cells, malignant cells in the patient, but rather provide an inroad for those donor cells into the patient and let the donor cells, the donor immune cells, attack the abnormal malignant cells, the graft-versus-leukemia effect. That becomes very, very irrelevant in that context with these reduced-intensity regimens.

Because they are of reduced intensity, in fact, that's why they were developed, they are applicable even to patients who would not generally tolerate a higher-intensity regimen, referred to often as myeloablative. And that has allowed to also treat older and older individuals. So officially, there is currently no absolute age limit, although that by itself is certainly worth a long discussion, that has been implemented. There are differences between centers, "Well, we will transplant patient up to such-and-such age."

But as others will say, age is only a number. I disagree with that. Sorry, I am in the same age range. Age is a number with a biology attached to it, and I think this biology is what is important for outcome. We look at what we call the transplantation-comorbidity index, what other issues are there that the patient has to deal with? Those issues are relevant. We know that if you have more and more of those additional conditions, that then are reflected in that scoring by this comorbidity index, then your risk of succumbing to complications related to transplantation goes up progressively. So, there is not maybe directly age limit but rather linked to other changes that happen in our body as we grow older.

Andrew Schorr: So, I know that I'm JAK2-positive. And somebody else may have the MPL gene or CALR gene. Do any of these genes that we know that are driving our myelofibrosis, does that relate at all to whether we're candidates for transplant or how well we'll do?

Do Gene Mutations Affect Transplant Outcomes?

Dr. Deeg: What we do now with patients who do not have any one of those three genes mutated that you just mentioned, JAK2, MPL, and CALR, patients who do not have any of those mutated tend to have a faster progression of the disease. That is, however, most relevant in patients with primary myelofibrosis, and probably much less so in patients such as Mr. Roth, who started out with essential thrombocythemia or with polycythemia and then evolved to secondary myelofibrosis.

And the best prognosis we see in patients who do have the CALR mutation, particularly, the type 1 of the CALR mutation. They tend to have the longest life expectancy without transplantation. Now, in regards to transplantation, yes, there is an impact of those mutations also on transplant outcome. There is very few patients who is MPL1. So, CALR and JAK2 are the major ones that we can really comment on.

It seems to depend, firstly, somewhat on the so-called allele frequency, what proportion of cells is involved by this mutation, and secondly, what other mutations, acquired mutations, are present. It is really the interaction of the whole mutational landscape that is relevant. So, if we have patients who, let's say, are JAK2-positive and have a mutation in the gene called AXSL1 or SRSF2, and a few others, that mutational burden clearly has an impact. The more mutations there are, the lower is the success in transplantation. We have looked at and published on that just recently, and other studies agree with that.

So, it is the whole landscape, as I said, that is relevant. It would not be ... I discourage patients and my colleagues who deal with all the diseases from focusing on an individual gene, but really look at the total.

Andrew Schorr: Where are we though, doctor, with ability to try to limit these side effects of the transplant?

How Can You Reduce Stem Cell Transplant Side Effects?

Dr. Deeg: Well, I mentioned already the introduction of the so-called reduced-intensity conditioning regimens, which clearly have helped in reducing the early toxicity and, certainly, mortality of any patient. Now, what comes along with this reduced-intensity regimen is a slightly higher incidence of recurrence, of relapse of the disease. That's where this graft-versus-leukemia effect is so relevant, of course.

Andrew Schorr: I want to ask about one other area though, and it's been happening there in Seattle and at other places for other blood cancers, is chimeric antigen receptor T-cell therapy. There's even research into CAR-NK therapy. Will any of these come into play that would supersede the traditional stem cell transplant?

Will Chimeric Antigen Receptor (CAR) T-cell Therapy Eventually Replace Transplants?

Dr. Deeg: Oh, yeah. I mean, I think one has to be cautious in projecting a time frame, but those studies, investigational work, is going on, trying to generate either one of those tools and additional ones that would not be referred to as CAR T-cells, but rather as T-cell receptor-modified T-cell therapies, aiming not only at lymphoid diseases, where it is ... that strategy is well-established by now, but also for the so-called myeloid disorder, such as myelofibrosis, myelodysplastic syndrome, acute myeloid leukemia, and so forth.

A major reason why that is lacking behind quite a bit is because the antigen expression, the expression of antigens against which one can generate those therapeutic cells is much more heterogeneous. You have lymphoma for certain type, you have CD20 on your surface, and you can generate CAR T-cells and give them to 100 patients. In the AML, you might have to generate 50 different types of cells in order to get a target, to hit a target that is relevant.

But that is evolving. There are a number of studies going on, as I said, also with modified T-cell receptor expression, which is not necessarily a chimeric receptor, as the CAR T-cells express, against new novel antigens that are being discovered on the surface of the malignant cells. One of the additional challenges is that these cells will be functional only in the context of a certain HLA type because the presentation is, as immunologists say, restricted to the type, only if you have, let's say, HLA-0201, that is one of the major ones in the Caucasian population, anyway, that will restrict what type of antigen presentation can occur. If you don't have that HLA type, then that approach won't work for you. There are many others, actually, they're now working on. So, a lot of work is going on at that front.

Andrew Schorr: We wonder, does our existing or previous therapies affect our ability to have a transplant or how well we'll do, the therapies we've been on?

Do Previous Treatments Affect a Patient’s Eligibility for Transplant?

Dr. Deeg: Right, right. A very, very important question, and yes and no. Personally, it depends on what kind of therapy. In patients who have just received hydroxyurea (Hydrea) or interferon, there was some concern about GvHD, but we haven't seen much of a negative impact. With the JAK2 inhibitors, there has been some concern. You probably know that as well or better than I do since you have investigated your own treatment. As we administer these JAK inhibitors, they affect a lot of things that happen in our body, in the immune responsiveness, so if they can lead, for example, to certain autoimmune diseases, which is, by now, a well-known side effect.

Also, well-established is the fact that patients on these JAK2 inhibitors have a higher probability of developing, of acquiring new mutations and acquire them earlier than one would have expected in a patient who is not on the JAK inhibitor, and these additional mutations, as we said earlier, interact with whatever the underlying mutational landscape was already and may indeed make the prognosis worse. In other words, we may be less successful in transplanting patients because there is a higher risk of relapse.

There's also a concern about the immunological effects of JAK inhibitors, although that concern has been sort of, how should I say, diluted somewhat now, dependent upon what the agent is that has been used, and so forth.

Andrew Schorr: At what point, for those of us who seem to be somewhat stable, but where does the discussion enter into it about transplant, Dr. Deeg?

When Should a Patient Start Considering a Stem Cell Transplant?

Dr. Deeg: The major indications that we have accepted for transplantation has been, and that's the majority of patients, declining blood cell counts, and you heard that from Mr. Roth before, declining blood cell counts in patients who were overproducing cells, which is sometimes a little difficult to completely comprehend, as the marrow is failing and/or patients in whom the direction is in the other direction, meaning on the other side, meaning there is a tendency to develop a frank leukemia.

If we see disease progression, and there's a lot of work going on in that gray zone, currently, with accelerated myeloproliferative, or advanced myeloproliferative neoplasm, if there is evidence that the blast count and many of you are probably familiar with that, is going up, that should be considered really an indication of transplantation because there is no other very effective treatment.

Unfortunately, it is difficult to treat those patients in such a way that they can indeed make it to transplantation because often non-transplant therapy aimed at this evolving leukemia is not well-tolerated or it's not very effective. If it is effective, many of these patients can be transplanted successfully. But those are the two major categories.

Andrew Schorr: All right, I want to thank Dr. Deeg from the Seattle Cancer Care Alliance, University of Washington for joining us. Ron, any final comment you want to make to our audience?

Ron Roth: Well, just again, you need to find a good doctor who's an expert, and you need to find doctors who really understand you and you understand them. That is such a critical part of this. Believe me, I owe so much to my doctors and also to all the nurses, all the medical care. It is incredible what they will do and how they will care for you. It's a tough fight. It's not easy. The decision took me three years to make the decision. But I just wish everyone the best as they make their decision that is right for them.


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