Chapter 13: Drug Treatments, Stem Cell Transplants, and Immunology Issues
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Description
Dr. Keating then sketches the principle of combination therapy: use drugs with different mechanisms of action. He talks about Dr. William Plunkett and his contributions to these efforts and also explains that antibodies use a very different mechanism and do not damage the patient’s immune system or DNA: he explains results with the FCR regimen.
Dr. Keating next explains another feature of Fludarabine that allows its use in conjunction with stem cell transplants, preventing tissue rejection and allowing transplants to be done on elderly and fragile patients. [[CLIP Dr. Keating recalls a patient in her mid-thirties and tells a story demonstrating how grueling the transplantation process is for patients. He explains what he says to patients about the worst-case scenarios, noting that patients must be “pretty heroic” to undertake transplantation “in hopes that you win the war.”]] He then talks about the financial burden that transplants (six to seven hundred thousand dollars at MD Anderson) and cancer place on patients and how he suggests that some patients go to Israel for transplants. He compares insurance coverage in different nations.
Identifier
KeatingM_02_20140520_C13
Publication Date
5-20-2014
City
Houston, Texas
Interview Session
Topics Covered
The Interview Subject's Story - The Researcher; The Researcher The Clinician Definitions, Explanations, Translations Patients, Treatment, Survivors Healing, Hope, and the Promise of Research
Transcript
Michael Keating, MD:
This is then when Plunkett came in again and said we have two active groups of drugs: one is Fludarabine, and the other is the alkylating agents. Some people combined it with Chlorambucil, which caused too much prolonged suppression of blood counts, and we decided we would use Cyclophosphamide because it was much less likely to cause that problem. So we increased the Fludarabine response alone. When we combined it with Cyclophosphamide, it went from 25, 30 percent up to 35, 40 percent complete remission rate. In each of these studies, we provided the rationale for comparative studies by cooperative groups. So Fludarabine was compared to Chlorambucil, which is a nice, gentle oral medication, but it hardly ever got complete remissions, and studies confirmed that in everyone except patients over the age of seventy, probably, it was significantly better in response rate and how long the response lasted. And that led to the two-drug combination being accepted as the new standard. The reason that it was explored was not just A-plus-B, drug-A plus drug-B, but Bill demonstrated that Cyclophosphamide and the other alkylating agents caused damage to DNA, and the cells would then repair the damage once the drug was out of the system. And if you gave Fludarabine, it inhibited that repair, so the drug lasted for a lot longer. So the FC combination now became the doubler that was most important. Just by coincidence, today I’ve been looking at the old study back in ’98, ’99 with this, and there are patients that are still alive fifteen to, oh, twenty years subsequently, with no evidence of the disease coming back. So this was the first time we began to see a potential cure fraction.
Tacey Ann Rosolowski, PhD:
That’s amazing.
Michael Keating, MD:
So we have small percentage of patients that are just going on and on and on. Unfortunately, we don’t have very much of the biology understood to identify which ones they were. Then the next level came when the principles of combination therapy were that you use drugs that had somewhat different mechanisms of action, and, unfortunately, Fludarabine and Cyclophosphamide both had very similar sort of impacts on the immune system and DNA. But at that time, antibodies were coming along, and they had a very different mechanism of action. They didn’t damage DNA or the immune system to a great degree. So the principle was can you add that at full dose to the other chemotherapy, and that led to what we call the FCR regimen with Fludarabine, Cyclophosphamide, and Rituximab. So our complete remission rate then went up to 72 percent. That then led to a third of the patients now being free of recurrence of the disease at more than ten years. So we can now identify which subsets of patients they are. That all sounds wonderful, except that a lot of the patients ended up getting second cancers, and whether it’s due to the immune suppression of the disease so that the surveillance against rogue cancer clones is not intact, or whether it’s due to further suppression of the immune system by the treatments, or whether it’s due to the DNA damage, or whether it’s due to all of the above, nobody really knows, but this is now a serious limitation of the outcome. If patients die of other cancers, they still died. So we’ll now have to see if we can get away from the chemotherapy part of it and get to combination that are not toxic to genes and not toxic to the immune system. The other feature that is an underappreciated feature of Fludarabine is that we’re now able to do what are called non-ablative stem cell transplants, because that decreases the immune system in such a way that you can accept stem cell transplants. When we first started doing them at MD Anderson in the mid-seventies, the upper-age limit was forty years of age, and now we’re able to do the non-ablative transplants.
Tacey Ann Rosolowski, PhD:
What does that mean, non-ablative?
Michael Keating, MD:
Well, when the first transplants were being done, you used very high doses of total body irradiation and very high doses of chemotherapy drugs, and if you didn’t give them stem cells back, their bone marrow couldn’t recover, so it ablated the bone marrow function. Now Fludarabine combinations allow you to decrease the immune system to such a degree that the stem cell transplants can take because the recipient doesn’t reject them, so that it really transformed the way we do these transplants. It got quite silly at one point because we used to call it “transplant lite” or “drive-through transplant”—
Tacey Ann Rosolowski, PhD:
Oh, my goodness.
Michael Keating, MD:
—as though you could just go into the clinic or the emergency room and have your infusion and then you go out again. People would get terribly sick. And it really did transform the way we can do things so that patients can now be transplanted up into their mid-seventies, and that could not have happened without the Fludarabine. We still don’t know what elements of the suppression of the immune system makes Fludarabine so important in that process.
Tacey Ann Rosolowski, PhD:
I was going to ask that, because it’s just kind of an amazing effect.
Michael Keating, MD:
Yes, because you can use other things that are very potent at suppressing the immune system, but it damages too many of the sub-varieties of immune cells, so they end up developing complications of infection, and that carries them off or it doesn’t suppress the immune system well enough so that you get a lot more graft-versus-host disease. Fludarabine just seems to have been the nice balance that you can put in place.
Tacey Ann Rosolowski, PhD:
So the age limit had to do with vitality of the patient or—
Michael Keating, MD:
Basically, if they got a complication, they couldn’t handle the complication, so that commonly you would get serious infections that would occur. You would get diarrhea, and that led to bacteria getting into the system. They would get serious viral infections that they couldn’t get rid of, and if the graft then attacked the patient, it would kill them by damaging the skin and the lung and the bowel and the liver. So it was tough. The first transplant that I participated in was this young woman, and she eventually died of liver complications from the transplant. She was a lovely, vibrant lady in her mid-thirties. When she died, her mother said that she’d given her a poster that she wanted to give to me if she died, and it was a grizzly old cowboy, miserable-looking guy, just not a happy camper, and the poster said “There are a lot of things they didn’t tell me when I signed on for this outfit,” and this whole concept that “I didn’t know that I was going to get this sick, and it was quite miserable.” So that one of the things that transplanters now do is that they give the worst-case scenario to everyone, and it’s really scary to patients to hear all the things that could happen. So the patients have to be pretty heroic to entrust themselves to these crazy doctors that are going to pour in someone else’s cells and hope that you win the war, because that’s really what it is, two competing cell populations.
Tacey Ann Rosolowski, PhD:
Wow. I’m reminded of how last time you talked about the burnout and stress levels in doing this kind of work, and I can see—you know, it sounds so nice and clean and crisp as you’re describing it, just as something that happens in the lab, but that’s not where it really happens. (laughs)
Michael Keating, MD:
Not at all. I saw a woman from Turkey today, and she comes over with her family, and she’d had a gynecologic cancer that’s probably cured now, and then they found she had chronic lymphocytic leukemia, and we treated her for about the last ten years. Then she comes back this time and she gets high fever and is very sick, and so we are now looking at her, and she’s got a third tumor, which is Hodgkin’s disease. So that she’s been through one cancer, the second cancer, a new cancer. This cancer is being driven by a virus, the Epstein-Barr virus, and so that if we’re going to eradicate that tumor, we’re probably going to have to give chemotherapy again and then possible stem cell transplant with either her own cells or something else. And the problem is that coming from Turkey, they have to pay for everything themselves. They don’t have insurance that translates to the United States. And when they go home, they don’t have access to a whole bunch of drugs. So part of what you have to do is to not do the doom-and-gloom scenario, but say, “We are hopeful that if we do this with the conventional drugs at home and after so many months you’ll be at this situation, then we can make a second decision as to what to do.” And then you have to say, “And if you do need a transplant, you can’t afford it here, but you might be able to afford it in Israel,” because in Israel they have a capped amount that you have to pay, so that they average it out and it’s a very democratic process. You average out what has to be paid, and if everything goes smoothly, it ends up being cheaper than what people paid, but if things go badly, the cost of care goes way up, and that’s subsidized by the good things.
Tacey Ann Rosolowski, PhD:
I see. Interesting.
Michael Keating, MD:
So it’s a clever way of doing things, and I wish there was a lot more cleverness in our insurance structure like that.
Tacey Ann Rosolowski, PhD:
Yeah, yeah. How much does it cost to have a transplant of that kind here at MD Anderson?
Michael Keating, MD:
You could start thinking in terms of about, oh, 6[00,000] to 700,000 dollars, and most people can’t just write a check for that.
Tacey Ann Rosolowski, PhD:
Of course.
Michael Keating, MD:
But you have situation where people sell their homes and all that sort of thing, the whole family resources go in. You need to try and save the life of the father or the mother or the child, etc.
Tacey Ann Rosolowski, PhD:
So is the implication that because this is experimental, it would not be covered by insurance, or do people run out of their insurance?
Michael Keating, MD:
They often have a sort of tumor that there’s not enough evidence to satisfy the insurance carriers that it’s worth the expense of doing it. Over in countries like the United Kingdom, things that we sort of take for granted, they say, “Well, this is costing our health care budget so many thousands or tens or hundreds of thousands of dollars to save x number of lives, and we could spend the money better to save more lives.” So that a lot of things for kidney cancer, for example, that are approved, they’re just not able to be prescribed over in the UK. So it’s tough.
Recommended Citation
Keating, Michael MD and Rosolowski, Tacey A. PhD, "Chapter 13: Drug Treatments, Stem Cell Transplants, and Immunology Issues" (2014). Interview Chapters. 1181.
https://openworks.mdanderson.org/mchv_interviewchapters/1181
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