Barriers to Successful Hematopoietic Stem Cell Transplantation 

A Conversation with Mary M. Horowitz, MD, MS


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I suspect that in 10 years, there will be a combination of advances in the chemotherapeutic approach, particularly with targeted therapies, improvements in supportive care, and advances in immunotherapy, which will enable us to treat hematologic malignancies with a lot less toxicity and much greater success.

—Mary M. Horowitz, MD, MS

The Center for International Blood and Marrow Transplant Research is a combined research program of the National Marrow Donor Program and the Medical College of Wisconsin, Milwaukee. At the forefront of research to increase access to hematopoietic stem cell transplantation and improve outcomes, the Center has amassed a clinical database containing information on nearly 350,000 transplant recipients.

The Scientific Director of the Center is Mary M. Horowitz, MD, MS, Chief of the Division of Hematology/Oncology, Professor of Medicine, and Robert A. Uihlein, Jr. Chair in Hematologic Research at the Medical College of Wisconsin. She is also Principal Investigator for the Data and Coordinating Center of the Blood and Marrow Transplant Clinical Trials Network.

The ASCO Post recently spoke with Dr. Horowitz about advances and challenges in the use of hematopoietic stem cell transplantation.

State of the Art

How would you characterize the current status of hematopoietic stem cell transplant?

It’s really a very exciting time. Over the past decade in particular, there have been significant improvements in how we do transplants so that they can be used successfully in a broader population. This is particularly true in the area of allogeneic transplantation, where the major barriers to widespread use were the toxicity associated with high-dose chemotherapy and radiation given beforehand, and the high risk of graft-vs-host disease, especially when using donors other than human leukocyte antigen (HLA)-identical siblings.

New reduced-intensity preparative regimens cause considerably less morbidity and mortality, but are still sufficiently immunosuppressive to allow donor cells to engraft. These regimens make it possible for much older—and sicker—patients to undergo allogeneic transplantation. This is important because hematologic malignancies, where allografting has its greatest efficacy, largely affect an older population. Much of the recent increase in the numbers of transplants being performed is in patients older than 60. We are also able to use these regimens in patients with comorbidities, like cardiac and pulmonary dysfunction, who previously were considered to be too sick to receive a transplant.

Another important development is the increased availability of donors. We can find fully matched unrelated donors for about 70% of Caucasian patients, and acceptable donors or cord blood units for most patients. And we are able to do alternative-donor transplants with an acceptable rate of graft-vs-host disease and transplant-related mortality. Previously, allogeneic transplantation was limited to patients who had an HLA-identical matched sibling, or only about 30% of people who might benefit.

These advances make transplantation a viable treatment for many more patients with hematologic malignancies. They also allow us to consider transplantation in other disorders where high transplant-related mortality rates were previously considered prohibitive—for example, in people with severe sickle cell disease or autoimmune disease. The bottom line is that transplantation today is a much more effective therapy and a therapy we are able to apply to many more people.

Major Barriers

What are the main barriers to successful hematopoietic stem cell transplant today, and what will it take to overcome them?

Disease recurrence is the major cause of treatment failure after transplantation. A lot of effort really needs to be devoted to addressing why some patients are cured and others are not after autologous transplant and allogeneic transplant—the answer might differ for those two approaches—and what can we do about it.

In the autologous setting, additional dose intensification of treatment may be possible with targeted therapies like radiolabeled antibodies that deliver higher doses to the tumor. Another approach is maintenance after transplant, which has been shown to prolong not only remission but also survival in the multiple myeloma setting. Furthermore, we may be able to use immune therapy in the autologous setting, perhaps with vaccination strategies or with genetically altered immune cells (ie, chimeric antigen receptors) that target residual cancer.

In the allogeneic setting, we need to understand why some patients are not susceptible to graft-vs-tumor effects. Here, as well, we need to evaluate things like maintenance therapy in the minimal residual disease state, and augmentation of antitumor effects using tumor-specific T cells or natural killer cells.

Also, we still don’t find an optimal donor for everybody, meaning one who will give you the same outcome as a fully HLA-matched adult donor. Additional donor recruitment is probably not going to help much because the diversity of the HLA system in humans is so great that you would essentially have to type everyone on the planet to find a full match for every patient. We need to find ways to do HLA-mismatched transplants with the same degree of success we see with HLA-matched transplantation. That requires us to explore new ways of promoting engraftment with low rates of graft-vs-host disease and good recovery of immune function.

Other Issues

Are there any big-picture issues that stand in the way of progress?

I am greatly concerned that the current very tight research-funding budget at the National Institutes of Health (NIH) will prevent us from continuing the pace of success established in the past few decades. It’s not just that there are some very good ideas that now lack the funding to be explored. I fear we may lose an entire generation of people who could be generating the next big ideas, the things that will keep us moving forward.

Young physicians and doctoral graduates coming out of training now are looking at how hard it is to continue funding throughout an academic career in the current climate and are thinking twice. If they are going to work hard, they want to have some reasonable assurance that they will have a chance at success, and it’s pretty difficult to say that when only 5% to 10% of applications for funding succeed. So we need a continued commitment on the part of the government to fund basic, translational, and clinical research.

Promising Approaches

What emerging therapeutic approaches in the field appear most promising?

Approaches like genetically modifying cells to target the immune response against cancer cells and/or infectious organisms have a lot of potential. One might say that hematopoietic stem cell transplantation is the oldest proven successful adoptive immunotherapy approach. But it’s not specific enough; you could characterize it as bombing a city to take out a building.

We need to enhance our ability to refine the immune effects to be against the cells we want to target while sparing the cells we don’t want to target, thereby increasing efficacy and decreasing toxicity. Combining these immune approaches with targeted therapies—molecules that target specific molecular pathways—is likely to be more effective than the use of targeted molecules alone.

Looking Ahead

Where do you think the field will be in 10 years?

Prediction is prone to error, so it’s hard to say. But I suspect that in 10 years, there will be a combination of advances in the chemotherapeutic approach, particularly with targeted therapies, improvements in supportive care, and advances in immunotherapy, which will enable us to treat hematologic malignancies with a lot less toxicity and much greater success. Our ability to better characterize malignancies at the molecular level will allow us to personalize our therapies. Those developments will increase the safety and efficacy of transplantation and make it a more acceptable therapy for a wider range of diseases, including some common noncancer diseases.

We will likely see more multicenter trials in blood and marrow transplantation. The investment by the NIH in the Blood and Marrow Transplant Clinical Trials Network has led to an effective infrastructure for doing multicenter trials that allow us to make definitive decisions about which approaches work—or don’t—much more quickly than was possible in the past.

Finally, we will increasingly use observational data to assess and improve patient outcomes. The Center for International Blood and Marrow Transplant Research maintains an outcomes registry on 350,000 transplant recipients—it had its beginnings in the 1970s, when the term outcomes registry didn’t even exist. Appreciation of the value of analyzing very large sets of data to determine what’s going on in the population is so much greater now, and I predict it will be even more so in the future.

There will still be a place for clinical trials. But we will more and more expect to have access to data on our patients—and to use those data to inform clinical decisions and to conduct research. Large databases and an increasing array of computational tools available to analyze them will allow us to make faster progress on many fronts, not just in blood and marrow transplantation. ■

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



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