Will Oncologists Be the First to Cure Heart Disease?


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Robert Peter Gale, MD, PhD, DSc(hc), FACP

No one would die of acute myelogenous leukemia if what we can accomplish in mice were readily transferable to humans. It isn’t.

—Robert Peter Gale, MD, PhD, DSc(hc), FACP
Jargon can be dangerous, not just in this context but in every context. Science requires precision. We should be careful of what we say and how we say it.

—Robert Peter Gale, MD, PhD, DSc(hc), FACP

Oncologists love jargon—a language peculiar to a particular trade, profession, or group that facilitates communication among members. Our day-to-day communications, medical notes, and journal reports are filled with this type of jargon. Other definitions of jargon are less flattering, including unintelligible or meaningless talk or writing (ie, gibberish), talk or writing one does not understand, or language characterized by uncommon or pretentious vocabulary and convoluted syntax, often vague in meaning (like this sentence). And although using jargon usually serves us well, it is this last definition—uncommon or pretentious vocabulary often vague in meaning—that can get us into deep trouble.

Stem Cell Dilemma

Consider our hematology and oncology colleagues who do blood cell or bone marrow transplants for diverse cancers such as leukemia, lymphoma, myeloma, and neuroblastoma. Lately they have taken to calling what they do “stem cell transplants.” Why they use this term is unclear: few scientific data convincingly show we are transplanting stem cells, especially when we do autotransplants after high-dose chemotherapy. Perhaps it is cachet, or a way to increase the likelihood of funding, or merely a comfortable jargon.

And here is where the problem starts. There is substantial disagreement over what a stem cell is. For example, developmental biologists have a completely different definition of a stem cell than hematologists and oncologists. Many biologists consider the term “hematopoietic stem cell” an oxymoron: if a cell is committed to hematopoiesis, it’s not a stem cell.

The public, many of our colleagues, and we all hope stem cells will cure many if not most diseases and even the most dreaded process, aging. Upon hearing that hematologists and oncologists are transplanting stem cells, it was only logical for them to consider whether such a transplant might cure end-stage heart and liver diseases and other ills. The rest is a reasonably predictable story.

Hope Over Reason

Ten to 15 years ago, data from experiments in mice reported that bone marrow–derived cells—let’s call them “hematopoietic stem cells”—could differentiate or transdifferentiate into diverse end cells including heart, liver, and nerve cells, under appropriate conditions. The concept was fascinating, and some of the data were convincing. However, there were already warnings of uncertainty at this early stage. For example, numbers of new end cells in these studies were few, and some techniques used to determine their origin from bone marrow progenitors questionable. Although some of these data came from excellent labs, other scientists could not reproduce the results.

Oncologists know a plausible rationale combined with a strong belief, especially if underpinned by even the most modest supporting preclinical data (mice and cell lines are great for this) are enough to get a clinical trial off and running. This is especially so when the target disease is serious and there are few or no effective other therapies. Some call this “the triumph of hope over reason.”

Which brings us to the question of whether oncologists will be the first to cure heart disease. Beginning about 10 years ago, our cardiology colleagues, often in cahoots with hematologists and oncologists, began clinical trials of blood cell and bone marrow transplants in persons with acute myocardial infarction and/or congestive heart failure. The underlying hypotheses were a bit foggy. Some investigators believed the transplanted hematopoietic stem cells would differentiate or transdifferentiate into new cardiac myocytes. Others thought cells in the graft might reduce ischemia-induced damage via some ill-defined anti-inflammatory effect. Some just hoped for the best: run it up the flagpole, and let’s see what happens.

Clinical trials followed the usual sequence and claims: phase I studies proved feasibility and safety with some encouraging results (“round up the usual suspects”). Results of phase II studies were supportive, but there were questions regarding subject selection because appropriate controls were missing. (Sound familiar?)

So off we go into phase III studies, sometimes controlled, sometimes blinded, often neither. And here is where the real trouble begins. More than 10,000 people have or are participating in these trials, and more are clamoring to join every day. However, results of these studies are inconclusive at best, and most large, properly conducted studies have been either negative or report a modest transient clinical benefit.

Heterogeneity Aplenty

Attempts to critically analyze these clinical trials data nearly gave me a heart attack! (No stem cell transplant, please.) The technician at Kinkos laughed when I tried to put these data into a chart. He suggested I try printing it on the side of the Goodyear blimp.

Studies include different types of subjects, often in the same study, including some with acute myocardial infarction, others with chronic congestive heart failure, and yet others with diverse cardiomyopathies. Transplants (another jargon term, these are really infusions, but that sounds too prosaic) use blood cells, bone marrow cells, or a combination. Cell composition of the graft (jargon again) is rarely defined or quantified. What are we trying to transplant: hematopoietic stem cells, mesenchymal cells, mesecnchymal stem cells (whatever these are), monocytes/macrophages, regulatory T cells, a combination of these, or something else?

Transplant routes are equally complex: intravenous, intra-arterial, into a coronary artery, direct injections into the myocardium at the site of injury, or all of the above. Donors are usually the recipient (autotransplant) but are sometimes another person (allotransplant) who may or may not be genetically related to the recipient. And to get closer to home, some recipients received cyclophosphamide to mobilize (another bit of jargon) the desired hematopoietic stem cells into the blood.

Endpoints of these studies are equally heterogeneous, including changes in cardiac enzymes such as troponins and brain natriuretic peptide, echocardiography (including left-ventricular ejection fraction), quality-of-life measures, freedom from hospitalization, survival, and many more. Cardiologists are fortunate in having lots of things to measure, and some of these, such as left-ventricular ejection fraction and quality of life, are validated endpoints, but only if the subjects and reader are blinded. This is rarely the case. And if a trial has many coprimary endpoints, it’s easy to pick a winner.

Bottom Line

What is the bottom line of these clinical data? The bottom line is that there is no bottom line. A recent review in BMJ by Francis and coworkers1 strongly criticized many of the conclusions of these studies, pointing out numerous biases and errors of commission and omission. Authors of some of these studies seem heavily influenced by their a priori beliefs. (Who isn’t, but this is not science.)

In contrast, two Cochrane reviews concluded this approach was of short-term benefit and the best thing since sliced bread.2,3 However, the Cochrane reviews lumped all studies together and failed to consider discrepancy counts.

After appropriate adjustments, the two camps seem not so discordant. Similarly, an opinion piece in Science declared it a draw.4 Complicating the controversy are recent retractions of several key reports in The Lancet and Circulation and investigations of academic conduct of several key scientists and clinical trialists.

To no one’s surprise, however, recruitment to clinical trials continues. Some prestigious medical centers promote the therapy, others see an important revenue source, whereas most U.S. and European centers think the jury is still out. Nevertheless, this therapy is gaining currency worldwide. If you have heart disease and can’t get a stem cell transplant in the United States or Europe, find a medical tourism agency that can send you to a lovely venue, transplant and all meals included. Recently, I saw a video advertising stem cell therapy for heart disease on the Shanghai metro.

Back to the Drawing Board

As I see it, it’s back to the drawing board. We need to return to animal models and determine the impact, if any, of purified populations of bone marrow–derived cells. And we need to study old mice with heart disease and comorbidities, not 10-week-old healthy mice from Charles River Laboratories (which seems the mouse equivalent to the Golden Door Spa). To put this in context, no one would die of acute myelogenous leukemia if what we can accomplish in mice were readily transferable to humans. It isn’t.

Our experience to date has several important lessons that apply to all fields of medical research and especially oncology. One is that jargon can be dangerous, not just in this context but in every context. Science requires precision. We should be careful of what we say and how we say it. For example, when we talk about “MRD” do we mean minimal residual disease or measureable residual disease? These are different concepts.5 When we discuss outcomes, do we mean freedom from progression, event-free survival, or progression-free survival? Again, these are different.

And can someone explain why we use “overall survival” rather than simply “survival”? Is there some special survival state that is not overall? (Existentialists, attention!) I am reminded of a joke amongst statisticians: One statistician asks another, “What’s your wife like?” After a 10-minute silence, he replies, “Compared to what?”

The confused story about trying to cure heart disease with hematopoietic stem cell transplants has played out in the same unfortunate way in the arena of end-stage liver disease, where hundreds of these transplants are being done globally.6 Not far behind are Alzheimer and Parkinson diseases and aging. Hemorrhoids next? Fortunately, we can successfully transplant kidneys, hearts, and livers, without having to rely on hematopoietic stem cells. If only we had an adequate supply.

So, back to the question: will oncologists be the first to cure heart disease? Who knows? But I think we can play an important and perhaps critical role by integrating our expertise with that of our cardiology colleagues. And if cardiologists are curing Ebola with statins,7 why shouldn’t oncologists cure heart disease? Stay tuned. ■

Disclosure: Dr. Gale reported no potential conflicts of interest.

Acknowledgement: The NIHR Biomedical Research Centre funding scheme. Armand Keating, Darrell Francis and Iman Saramipoor kindly reviewed the typescript.

References

1. Nowbar AN, Mielewczik M, Karavassilis M, et al: Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): Weighted regression and meta-analysis. BMJ 348:g2688, 2014.

2. Clifford DM, Fisher SA, Brunskill SJ, et al: Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev 2:CD006536, 2012.

3. Fisher SA, Brunskill SJ, Doree C, et al: Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev 4:CD007888, 2014.

4. Couzin-Frankel J: The elusive heart fix. Science 345:252-254, 2014.

5. Goldman J, Gale RP: What does MRD in leukemia really mean? Leukemia 28:1131, 2014.

6. Behbahan IS, Keating A, Gale RP: Bone marrow autotransplant for liver disease? Stem Cells 31:2313-2329, 2013.

7. Fedson DS, Opal SM: Can statins help treat Ebola? New York Times. August 15, 2014.

 

Dr. Gale is Visiting Professor of Haematology, Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.



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