This is the third installment of the Cancer History Project’s series in honor of Cancer Survivors Month.
The interviews are conducted by Deborah Doroshow, assistant professor of medicine, hematology, and medical oncology at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, who is also a historian of medicine and a guest editor of the Cancer History Project in June.
Last week’s oral history with Beth Carner, a stage 4 colon cancer patient who is cancer-free after receiving treatment with Keytruda on a clinical trial, is available here.
“You need to be aware of the cutting-edge science and what’s going on.”
Soon after Dave Boule was diagnosed with polycythemia vera in 2006, he had a hunch that there were better treatment options out there.
“Not too long into my course of treatment with phlebotomy only, my platelets started to rise along with my red count, which is not unusual with the disease, and the doctor wanted to treat me with the anagrelide,” he said to Doroshow.
Boule did his research.
He had found studies by Richard T. Silver, professor of medicine at Weill Cornell Medical College, who is now director emeritus of the Richard T. Silver MD Myeloproliferative Neoplasms Center, and Jerry Le Pow Spivak, professor emeritus of medicine at Johns Hopkins University School of Medicine and director of the Center for the Chronic Myeloproliferative Disorders.
Boule consulted with Silver frequently about the best treatment.
“[Silver] suggested treatment with interferon, which was something he pioneered as a treatment for polycythemia vera many years before,” said Boule, who is retired as a managing partner of the New York and global tax practices at Ernst & Young. “At this point, he’s probably been using it for 30 years.”
In a study of Besremi (ropeginterferon alfa-2b), the interferon that Boule is on now, patients fared better over the long term than if they were treated with phlebotomy alone or hydroxyurea.
“The interferon curve is pretty much flat on the normal life expectancy curve for 20 years or so, even maybe a little longer than that, before it starts to decline, and end up with a little gap with polycythemia vera being a little less good than the normal lifespan,” he said. “But it is wildly better than hydroxyurea and phlebotomy only in the trials that were done in Europe, as opposed to U.S., for this new interferon that just got approved, called Besremi.”
Boule’s hematologist in New York City disagreed with Silver’s approach.
“He said, ‘Oh, I would never use that. It’s toxic.’ And I said, ‘What does that mean?’ He said, ‘Oh, you would just feel terrible when you take it.’ And at that point I had done enough reading to draw my own conclusion that interferon was really the medicine I wanted to be on,” Boule said.
Thus, Boule became a regular patient of Silver’s.
In the early years, Boule’s doctors would write four or five letters to his insurance company so that his treatments were covered.
“It was a struggle to get the approval year after year after year until finally it broke free,” he said. “I think it was a combination of more and more people applying for it—and it became more common as a treatment. The insurance companies had less ability to deny it, because it was having good effect and it could be demonstrated clinically.”
When Silver first started treating patients with interferon, he used the same dose that people used for other cancers—which was fairly high.
“It was a fairly high dose and it did knock people out and a lot of people discontinued it,” Boule said. “And over a period of time, he developed an approach to starting with a very low dose. And so, you didn’t really have any terribly adverse effects with a very low dose. And then, he would build it up very slowly so he’d become more tolerant of it.”
Boule never had an issue with the medication until he went up to a dose of 210.
“I tried that for about two weeks and said, ‘No, I don’t think I’m going to do 210 anymore,’” he said. He had “all the symptoms that you don’t want to get—the feeling tired and achy and flu-like symptoms.”
Around 10 years ago, Boule began experiencing peripheral neuropathy in his feet.
“It was getting worse, and the thought is that potentially it’s a side effect of interferon,” he said.
For the first time since he started the drug, Boule and his doctors made the call for him to try something else—busulfan, a chemotherapeutic drug. However, a second opinion from a neurologist suggested that the neuropathy was not the result of interferon.
Boule agreed—his neuropathy had worsened while he was off interferon.
“I am just going back on interferon with Besremi about three months ago, and we are trying to regulate the blood counts, but we’re complicated by this stint I did on busulfan—because it too has a cumulative effect,” Boule said. And we were [at] a very low dose and we started to increasing the dose slowly, and it really wasn’t controlling the blood counts.”
Boule and his doctors are still trying to modulate the amount of interferon he takes. The brand name, Besremi, was approved by FDA in November 2021.
“Prior to going off interferon, my blood counts were rock solid, stable at acceptable levels for years. And this was at a very low dose,” he said.
With Boule’s knowledge of the science and as a member of two boards of non-profits related to myeloproliferative neoplasms, a category in which polycythemia vera is included, he has advice for newly diagnosed patients with MPNs.
“I make the strong recommendation that they consult with, if not see exclusively, a doctor who specializes entirely in MPNs,” he said. “[For] a difficult-to-understand disease, you need to be aware of the cutting-edge science and what’s going on.”
Transcript
Dave Boule: Well, it’s an interesting place to start, I guess. I am 74 years old and live in Connecticut. I have a home in New Hampshire. I’ve lived in many parts of the United States, probably 20 different places over the course of my life.
DB: And worked for one firm for 33 years, Ernst & Young, and traveled around the country a bit with them. And last five years, I worked, ending in 2008 when I retired, I had a global job and traveled all the time on very long airplane flights most of the time.
DB: I did. I used them all. I gave them to my kids, actually.
DB: Sure. I actually did not realize anything was wrong health wise. I had a requirement of my firm that they made of all the partners have an annual physical, and I had an annual physical, and the red count came back high on a standard blood test.
We repeated the red count—and this was in 2006—and it came back higher. I had a hematocrit of almost 60 the second time. And the doctor sitting across the table from me, he was still using books back in that era. He opened up a great big book and he said, “I think you have probably, polycythemia vera, which is not bad to have, fairly easy to treat and control, but I’m going to send you to a hematologist.”
I went to one whose name I forget, and he sent me for a test called the red cell mass. And it was confirmed that I had the disease polycythemia vera. And at that point, he started to treat me with phlebotomy only as you said, taking something from me.
DB: Yes, I am fairly oriented that way. So, I was on the internet and my theory of looking for things on the internet, is I always want to find reliable sources because who knows what’s out there.
DB: And so, I looked for articles by authors who were associated with places I knew. And one name that kept popping up was Richard T. Silver, MD, associated with Weill Cornell Medical, Weill Cornell Medicine now. And he and Jerry Spivak, who’s with John Hopkins, wrote a lot together about various aspects of polycythemia vera, particularly the treatment thereof.
I was going to say, I learned a lot about the disease and at some point, not too long into my course of treatment with phlebotomy only, my platelets started to rise along with my red count, which is not unusual with the disease, and the doctor wanted to treat me with the anagrelide.
And at that point, because of what I had read on the internet, I was consulting with Dr. Silver on a less frequent basis.
I was seeing the hematologist locally, once every four weeks or so, and I would see Dr. Silver once every quarter or a little bit more. And he suggested treatment with interferon, which was something he pioneered as a treatment for polycythemia vera many years before. At this point, he’s probably been using it for 30 years, I guess.
And I went to my local hematology. He said, “Oh, I would never use that. It’s toxic.” And I said, “What does that mean?” He said, “Oh, you would just feel terrible when you take it.” And at that point I had done enough reading to draw my own conclusion that interferon was really the medicine I wanted to be on. So, I abandoned the first hematologist and became Dr. Silver’s regular patient at that point. So, he put me on interferon, and it’s a unique medicine. I suspect, we’ll talk more about it as we go through the oral history here.
DB: I don’t recall he characterized it at all. The first hematologist I saw—and at the time it was not called a cancer. It was not called an MPN, myeloproliferative neoplasm.
DB: It’s called a myeloproliferative disorder at this point.
DB: It was only later that the World Health Organization changed the characterization of it. When I went to see Dr. Silver, my first appointment with him, after his examination in the examination room, he said, “Come with me.” He took me down to his office and probably spent an hour with me with pen and pad in his hand and drawing diagrams and telling me about the disease and telling me the additional… a lot of information that I needed to know about the disease. So, he characterized it quite thoroughly, which was his style of treatment of people.
DB: Yes. It fit very well. That’s why we’re still very good friends many years later.
DB: It was not something that I was particularly concerned with. It seemed like the disease, which had a very long tail in terms of normal life at that point. And so, it was, I’ve got it. I’m going to see the doctor and we’re working to control it, kind of thing. It wasn’t anything I was particularly worried about.
DB: Actually, much better. It was really strange when they said I was asymptomatic, I didn’t recognize that I had any symptoms of polycythemia, but when I started getting the phlebotomies particularly early on, when I was getting very frequently to drive down hematocrit to something in the mid, low 40s, from where I started, which is up around 62, I think. I would get the phlebotomy and say, “Oh, all of a sudden, I feel like I had more energy. This is pretty cool.” So, aside from not being comfortable during the phlebotomy, I felt a lot better after them.
DB: Right. Yeah. I don’t look.
DB: He described it as a drug that was natural to the body. So, it was not a chemotherapeutic drug, and one which for then unknown reasons, had multiple benefits. The first of which being hematological control, getting control of the blood counts and suppressing it. It was myelosuppressive. So, you were going to end up with fewer red blood cells, which was a good thing. And we had to watch the impacts on the platelets and white blood cells, which would also be impacted.
I honestly don’t recall whether back at that point, the scientific literature had been developed to the point where the now known effects of interferon, of control in the blood marrow, in the bone marrow, actually stopping or reversing the scarring that takes place in the normal course of the disease.
But that’s certainly a feature of it today, and also had the feature of reducing the JAK2 allele burden, which I don’t think was known at that point. JAK2 had only been discovered as the driving mutation I don’t know, 10, 12 years ago at this point.
DB: Right as soon as it was discovered. I’ve always been fairly oriented to the science, and I was diagnosed in 2006, retired in 2008, and in 2007, I went to my first MPN patient symposium, which is the charitable organization that Dick Silver started now about 53 years ago.
We put on a patient symposium once every other year and bring in internationally known people that focused on the MPNs to talk about this particular disease. And so the, when I retired in 2008, I had just heard a speaker at the symposium, a guy named Bob Rosen, who was diagnosed with the disease sometime earlier and started his own foundation called the MPN Research Foundation in Chicago.
And I said, “I’d like to fly out and have lunch with you. I’d like to join your board here.” Not many people asked to join his board, I guess. So he said, “OK.” And I went out, joined his board and mentioned it to Dick, Dr. Silver in a subsequent visit.
He said, “Why don’t you come on my board too?” I said, “OK, I’ll do that.” So, sometimes shortly after that CR&T Cancer Research and Treatment Fund, which is Dick’s charity, started spending 95% of his grant funding on MPN research at Weill Cornell principally, and has since been the major funder of the Richard T. Silver MBN Center at the Weill Cornell Medicine.
So, I’ve been involved with physicians who treat this disease and who do research around this disease for quite some time now. And so, I’ve learned a lot about it.
DB: Well, the two organizations were quite different. The Cancer Research and Treatment Fund revolved around Richard T. Silver and his patients. So, the medical advisory board were all people that he knew. The board itself largely consisted of patients or relatives of patients or other people that he knew, not necessarily oriented to MPNs, kind of a wide swath of at least hematological diseases.
The MPN Research Foundation was started by a patient, Bob Rosen. And it initially for the longest time had only patients on the board. I did get to meet 12 or 15 other patients every time I went to a board meeting, which is very interesting.
DB: Interestingly at that point, no, some were, most were not. It’s kind of the standard treatment was hydroxyurea, which Dick used to rail against as a chemotherapeutic agent that had long-term adverse effects of potentially causing leukemia, which is a natural progression of some aspects of this disease.
People with myelofibrosis often graduate into acute myeloid leukemia. So, I wouldn’t say it was the predominant medication by any stretch, it was prescribed off-label. It was hard to get through the insurance companies because at the time it was thought to be expensive. Now, we have a new form of interferon, it just got it approved by the FDA and it is really expensive.
DB: I would say in the early years, typically Dr. Silva or his nurse would end up writing four or five letters over a course of four or five denials before they finally seceded to paying for it. I never had to pay for it out of my pocket, but it was a struggle to get the approval year after year after year until finally it broke free.
I think it was a combination of more and more people applying for it—and it became more common as a treatment. The insurance companies had less ability to deny it because it was having good effect and it could be demonstrated clinically. It was having a very good effect.
DB: Dr. Silver’s approach, which had been developed over a period of time—when he first started to prescribe interferon, he started to use the same dose that people were using for other cancers, and it was a fairly high dose and it did knock people out and a lot of people discontinued it.
And over a period of time, he developed an approach to starting with a very low dose. And so, you didn’t really have any terribly adverse effects with a very low dose. And then, he would build it up very slowly so he’d become more tolerant of it.
It really was never problematic for me until I got to an extraordinarily high dose. His typical starting point was 45 pipes of interferon, and the syringes were made in 180, I think. This was a little tiny dose out of a syringe. And at one point, when we were trying to kind of get over the hump and get a conversion to a more steady state blood count, he asked me to try 210. And I tried that for about two weeks and said, “No, I don’t think I’m going to do 210 anymore.” And went back to 180, using one full syringe.
DB: All the symptoms that you don’t want to get—the feeling tired and achy and flu-like symptoms, that kind of thing. After I did that for about two weeks, I said, I’m not doing that anymore.
DB: I never took any time off work for this.
DB: No, I never made any announcements of it to anybody that I was working with. So, no, it wasn’t a known fact at work, and it was really a non-issue from a work perspective as I’d been going to the doctor once a month taking or two [days] off, it never really showed up.
I was working in New York at the time. My office was in New York City. The first hematologist I had was also New York-based.
DB: As was my internist. I was very impressed with my internist. He had discovered a couple of things over the period of time that I was going to him in New York City, and was very thorough and really a terrific internist.
DB: Yes. Yes. That is the one.
DB: Yes. I had a bout with prostate cancer that got removed. And I also found out through him that I have an anomaly in my heart, that’s a birth kind of thing that everybody agrees is a non-issue. But I recall very distinctly, when the technician was doing the echo, he looked and he said, “Oh, I didn’t like that. That didn’t sound very good.”
DB: He called a doctor, and the doctor looked at it and said, “Oh, OK.” So, apparently there’s some, I don’t know, string of tissue on the inside of one of my ventricles that goes from one side to the other. Doesn’t interfere with anything. It’s never been a problem. So, hey, I don’t worry about it.
DB: I don’t recall him talking about that specifically as we went on the initial course. interferon is a very unusual drug in this disease. I don’t know if it works like this in all the others, but it’s got a cumulative effect. And when treating polycythemia vera, what you are looking for is to treat two things.
One is a short-term risk of thrombosis, and so, you have to control the red blood cells or the red hemoglobin, however you want to measure it. And then there’s a long term risk of progressing to a more serious post-polycythemia vera myelofibrosis.
And the interferon has a wonderfully positive effect on that, as evidenced by some very recent publications that were done by a doctor, who’s now my doctor at the Silver MPN Center, Dr. Ghaith Abu-Zeinah, and as a result of funding that CR&T is provided to the Silver Center, they worked with a statistician to come up with an approach to categorizing in a searchable way, a big patient cohort, 470 patients.
And they’ve since been able to demonstrate that patients dealing with phlebotomy only, or hydroxyurea, versus interferon, versus the general population, the interferon results are staggeringly much better over the long term.
And the interferon curve is pretty much flat on the normal life expectancy curve for 20 years or so, even maybe a little longer than that, before it starts to decline, and end up with a little gap with polycythemia vera being a little less good than the normal lifespan—but it is wildly better than hydroxyurea and phlebotomy only in the trials that were done in Europe, as opposed to U.S, for this new interferon that just got approved, called, Besremi (ropeginterferon alfa-2b).
It was, essentially, not better than hydroxyurea for about the first, I can’t remember—it was a year or two, but the trials went on for a period and the gap opened up in the clinical trial.
It was done prospectively, which—it was the mirror image or the retrospective study that had been done at Weill Cornell. And both have chosen the same thing. It’s far superior in terms of its long term impacts. Nobody’s quite sure why, but it’s far superior.
DB: Well, I took the interferon from 2006 until probably about at this point a year ago. And at that point, well, I had developed, going back 10 years now, peripheral neuropathy in my feet—and it was getting worse, and the thought is that potentially it’s a side effect of interferon.
I dealt with a neurologist at Cornell and looked at various alternatives that I was given, and we decided I’ll just get off interferon, as opposed to trying to treat virtual neuropathy. And so, I went on another drug that I didn’t like to go on, is called busulfan. It’s a chemotherapeutic drug. And I was on that for a period of months. And we talked about getting a second opinion on the peripheral neuropathy.
I went to see a Dr. Ahmadi. I went to him and Brigham and Women’s, and he’s the head neurologist that deals with this kind of neurology and they did a big workup. And he said, “I don’t think it’s the interferon.” He said, “I think it’s just something that is getting worse as you get older, that’s the way it worked.”
So, I am just going back on interferon with Besremi about three months ago, and we are trying to regulate the blood counts, but we’re complicated by this stint I did on busulfan—because it too has a cumulative effect. And we were [at] a very low dose and we started to increasing the dose slowly, and it really wasn’t controlling the blood counts.
Then, all of a sudden it kicked in and my blood counts went to a flu to the low side. I think my neutrophils get down to 700 or something, which is a little bit low. I got off the busulfan and let it go for, I think, two or three months, and the neutrophils came back up and I took my first dose of Besremi, and they cratered again.
So we then, have been kind of trying to modulate how much of this Besremi I take to see if I can get back in the groove. Prior to going off interferon, my blood counts were rock solid, stable at acceptable levels for years. And this was at a very low dose. I told you I got up to 210.
DB: This was at 45 pipes every three weeks. It was a very low dose of interferon and my blood counts were right exactly where I wanted.
DB: No, not really. Other than this peripheral neuropathy, which we attributed to interferon, and that was the reason I got off it. But now I’m happy to be back on it. And the peripheral neuropathy is what it is.
DB: Yes. I found that it continued to get worse in the time I was off of interferon. So, I became more convinced that it was not the interferon.
It was just a natural process that was occurring.
DB: No. I’d never participated in a clinical trial. We actually thought about one for a drug that I think they went through the phase I and phase II, and then they closed down the phase II, and they haven’t opened the phase III yet called hepcidin mimetic.
And it relies on iron control to control the blood counts and stop the need for phlebotomies. And I was considering that at the point where I was on and off busulfan. But hopefully with the Besremi, I’ll get back to essentially stable blood counts. No phlebotomies and life will be good again.
DB: The phlebotomy requirement went away right about the same time they closed the trial. And in order to get into this trial, the way they measure success is stopping phlebotomies. Well, you have to have had X number of phlebotomies for X period of months before they’ll allow you on the trial, and you have to have the same dose of whatever medication you were taking. Well I was changing the dose of busulfan pretty regularly. So, I never really qualified to get on, and then they closed it.
DB: There was not an opportunity to get on it.
DB: I haven’t done a phlebotomy in a very long while now—six, eight months, something like that. So, it’s been quite a while since I’ve had to do a phlebotomy. They were in this period where we were letting the system cleanse of the interferon, and starting with a very low dose of busulfan. So, my proliferation was up and I was taking phlebotomies to augment the busulfan at that time.
DB: They’re all very interested in what’s going on, and I text them. I have two daughters and my wife, so I text the three of them with the results of my meetings with the doctor, my blood counts and my medication, whether I’m changing anything. They stay pretty much in tune with everything.
DB: They probably are more concerned than I am, I would guess.
DB: I’m tested regularly for it, and I have a very aggressive disease. My first JAK2 test was 93% allele burden or something like that. I had very few normal blood stem cells. With interferon, probably have been more in the 60% range since. Some people I know take very small doses of interferon—minuscule, in the teens of field burden. But I have always been very high.
DB: I don’t know that it was a shock. I think there was a lot of research going on to try and find out what was causing it. And the expectation was that it was a genetic issue of some sort. And the discovery of what the genetic issue was, and then for the longest time after JAK2 was discovered, there was still a large unknown with respect to the other variations of this Philadelphia chromosome negative MPN.
They didn’t know what the driver was. They knew it wasn’t JAK2 because the people didn’t have JAK2 mutations. And then a researcher that I came to know over in Europe discovered it was CALR, and it was a totally different mechanism of causing the problem.
And in the JAK2 and the CALR now, I don’t know, 95% of the genetic basis of the disease is uncovered and there’s another one…MPL.
DB: Most of the disease now is pretty much covered in those three. There’s a very small number of patients that had a disease and they can’t figure out why.
DB: Actually, I have spoken to Dr. Silver’s class twice.
DB: I guess the PSA was elevated. I went for a biopsy, and I was naive enough to not understand when the nurse called me and said, “The doctor wants to see you.” That was not going to be a good news conversation.
DB: I actually went to him for a particular reason. He was at the time, the head of robotic surgery, which was a new thing back in the year I was diagnosed with this. And so he said, “Well, you have it and your score was such and such. So, you’re beyond watch-and-wait. And I think we ought to take action. This is the way we approach it. And you’re going to see a radiologist about radiological treatment. You’re going to talk with me about the laparoscopic kind of approach to the robot. And you’re going to talk with a surgeon who still does open surgery.”
And I said, “No, no. I know me. I want it out. I don’t want radiation. I want the cancer out. I came to you because I want robotic surgery. Let’s schedule it.” And he said, “No, we don’t do it that way.” I said, “Let’s schedule it.” And he said, “OK, I will schedule it, but then you’re going to go through the process. And if at the end you still want it, we’ll do it.”
DB: “OK. I want it done faster.” And that’s when he told me that I couldn’t get it done as quickly as next week, because they had to wait for the prostate to heal from the—
DB: Biopsy before they could take it out. I didn’t quite understand that, but I said, “Okay, if that’s the way it’s going to be, that’s right.” So, I had it out, and life goes on.
DB: Yes.
DB: I was an accountant after all, and consistency counts.
DB: Well, I actually do talk to a number of people about their diagnosis with MPNs—
DB: For one reason or another. And usually the conversations, I make the strong recommendation that they consult with, if not see exclusively, a doctor who specializes entirely in MPNs. [For] a difficult to understand disease, you need to be aware of the cutting edge science and what’s going on.
And currently now, there’s been just a huge increase in clinical trials in the MPNs, and they’re starting to change some of the end points in the clinical trials, which I think is useful because for years they were dominated by what the FDA approved in connection with the Jakafi, which is the medication that was designed for myelofibrosis.
What that medication did, which was symptom relief. Basically, it reduced the spleen size as the major driver. And so, that became the endpoint for every trial for the MPNs and people with the MPNs say, “We want a test. Now, not we’re not concerned about it. We want to cure the disease.” Spleen is a symptom, it’s not to cure.
DB: So, I usually tell folks that if they are not around an academic center with an MPNs specialist, they ought to make a point to go see an MPN specialist at least twice a year, if not quarterly, because they will get better treatment than if they just go to a local hematologist who sees three MPN patients in his practice.
