A prescription for bone marrow failure: Diagnose early, monitor often

A closeup illustration of cells in the bone marrow. (Gray's Anatomy via Wikimedia Commons)
A closeup illustration of cells in the bone marrow. (Gray’s Anatomy via Wikimedia Commons)

Akiko Shimamura, MD, PhD, first became fascinated with hematology as a pediatric resident at Johns Hopkins Hospital, an interest that blossomed into a career dedicated to the study and treatment of bone marrow failure (BMF) syndromes, first at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and then at Seattle Children’s Hospital/Fred Hutchinson Cancer Research Center. Last fall, she moved back to Boston to take the helm of the Bone Marrow Failure (BMF) Program at Dana-Farber/Boston Children’s, bringing with her a perspective on pediatric BMF/myelodysplastic syndrome (MDS) that centers on collaboration as a path to deeper understanding of BMF/MDS biology and an approach to patient care.

Notes invited Shimamura to talk about her thoughts on the current and future state of BMF/MDS research and management. Below is a summary transcript of what she had to say.

On classical versus modern diagnosis:

Bone marrow failure syndromes have been widely regarded as these rare, odd disorders that are immediately recognizable when examining the patient. In the old literature, there are classic diagnostic presentations. With the advent of genetics and genomics, we can diagnose patients who present with low blood counts and lack all of the seemingly classical sign and symptoms, but have these syndromes and are still at risk for the complications, namely bone marrow failure and leukemia.

On the importance of early diagnosis:

Akiko Shimamura bone marrow failure myelodysplastic syndome BMF MDS
Akiko Shimamura, MD, PhD

Early diagnosis completely changes how we approach BMF/MDS patients to keep them healthy. The leukemias that develop in these syndromes are exceedingly challenging in many cases to treat. Many of these disorders also have additional medical complications that, if we know to look for them, we can minimize. If we know that there is a risk of bone marrow failure or cancer predisposition, or if multiple members of one family are affected with cancer at a young age, we can monitor and catch complications early before they cause major problems that are very difficult to treat.

The curative treatment for BMF/MDS is a hematopoietic stem cell transplant, and usually the donor of choice is a matched sibling. But if you don’t make the diagnosis, you might accidentally use a sibling who has the same disease, giving the patient all of the toxicity of transplant with none of the benefit.

On the need for vigilant patient monitoring:

A BMF/MDS syndrome can progress at any time in life — early childhood, mid-childhood, late childhood, all the way through to adulthood. There is often a tendency to not pursue monitoring if the patient looks well. The problem is that if you wait until the patient develops symptoms or appears ill, you’ve often missed your chance to intervene while the disease was still curable. Once leukemia develops in these patients, they are extremely challenging to cure.

The BMF/MDS patient and medical communities both need to understand that patients should not be passed over just because they appear to be well. The goal of medical monitoring is to keep them well. Patients need to have regular monitoring of blood counts and bone marrow status, with an eye towards red flags in cytogenetics, blood counts and marrow morphology. These screens are essential for catching things early and starting treatment when the condition is still curable.

On partnership in patient care:

Children with BMF often have multiple other organ systems involved.It takes a team like the one we’ve built here that offers expertise across multiple disciplines, such as gastroenterology, endocrinology, pulmonary, cardiology, surgery and others. It’s very complicated to coordinate care across so many disciplines, but allows for care of the whole patient.

Also, both for patients seen locally and those who travel from far away for consultation but then return home for primary care, it’s important to partner with the primary care provider or primary hematologist. Here our philosophy is to take that kind of partnership approach with the patient’s primary medical team so that the patient receives coordinated care.

I believe that a child who happens to have a rare disease deserves the same chance at a healthy life as children who happen to have more common diseases.On the transition from pediatric to adult BMF/MDS care:

The transition to adult care is not an event — it’s a process. We really want to help the patient and family navigate this process to obtain the best adult care. It’s essential to build partnerships. Here we’re developing a joint pediatric-adult clinical program, and coordinating joint pediatric-adult research studies as well.

On the lessons cancer genomics holds for understanding BMF/MDS syndromes:

Now that we’re looking into the cancer genome, as a field we’re seeing that there are a small but significant proportion of patients who actually have underlying BMF/MDS syndromes. Also, BMF-associated malignancies may in some ways be biologically somewhat distinct from those that arise in the general population. We’re not seeing all the typical spectrum of genetic changes that we associate with childhood leukemia in those in BMF/MDS patients.

On opportunities for improving BMF/MDS treatment:

Transplant can cure BMF and MDS but this treatment still has both short- and long-term potential risks. Conditioning regimens can cause organ toxicities, increase the risk of infection or second cancers, and have long-term effects on fertility. Graft-versus-host disease also remains a significant cause of morbidity and mortality. If we can develop better treatments, we hopefully can avoid these toxicities while still providing safe and effective therapy.

In my lab we are conducting both small molecule compound screens and functional genomic screens to identify novel drugs, genes or molecular pathways for rationally designed targeted, less toxic therapeutics. We’re also investigating novel medications to treat BMF-associated leukemias. These cancers are often unresponsive to standard therapies, which themselves are often exceedingly toxic to BMF patients.

On the need for collaboration and consortia in research:

I’ve been impressed at the success of oncology consortia like the Children’s Oncology Group. They can funnel new studies into their networks in an efficient and collaborative way, and have significantly advanced the field of pediatric oncology, including for really rare tumors.

BMF had not historically had such consortia, but no single center or even handful of centers can get enough patients together to do a meaningful study in BMF/MDS syndromes. You really need a network across the country. When you do that, it turns out that these diseases are not so rare.

In partnership with several pediatric centers, [Dana-Farber/Boston Children’s president] David Williams, MD, and I founded the North American Pediatric Aplastic Anemia Consortium (NAPAAC) so that together we can try to learn from BMF patients and set up collaborative studies.

normal whole blood bone marrow failure myelodysplastic syndrome BMF MDS
An SEM image of normal whole blood. (NCI)

On the role of industry in BMF/MDS therapy development:

We are fortunate to have a very rich biotechnology culture in the Boston area. Once we’ve worked out the science and conducted the pilot studies, the pharmaceutical industry has the resources to move promising concepts into clinical trials on a larger scale.

Also, often what we’re trying to do in the BMF/MDS field is to repurpose drugs are already out there, ones for which pharmaceutical companies have already received adult or pediatric approval. Some of these drugs are in common use for other disorders and look promising in the lab. If they hold up, they could revolutionize how we approach BMF/MDS patients.

On why rare diseases like pediatric BMF/MDS syndromes are more important than their numbers:

The insights we gain from these very rare syndromes often give us unique insights into molecular pathways or treatment approaches that we apply to more common diseases. Rare syndromes like these have also provided critical insight into how we might pursue personalized medicine.

Also, although they’re rare, the health impact of a BMF syndrome is very high for each patient. These are very serious diseases with very high morbidity and mortality. And I believe that a child who happens to have a rare disease deserves the same chance at a healthy life as children who happen to have more common diseases.

On the care and study of BMF/MDS five years from now:

I think we’re going to have much better diagnostics. We’ve already developed a genetic platform to screen all of the known marrow failure genes simultaneously. Our research demonstrated that if you only test the genes that look like they fit the patient’s presentation you’re going to miss the diagnosis in five to 10 percent of your patients. This broad genetic screen will allow clinicians to diagnose patients efficiently and accurately.

We are working towards better, more sensitive, more accurate, ideally blood-based biomarkers to identify patients at high risk of progression and who would benefit from early treatment. It would be wonderful to have some less invasive way than bone marrow aspirations — which some children have to have every year — to monitor for cancer risk.

I think we’ll have novel medical or immunologic or even genomic therapies for both marrow failure and related leukemias, and approaches that could help at least a subset of patients avoid the current toxicities of transplant.

On coming back to Dana-Farber/Boston Children’s:

The reason I came back was the unparalleled depth and breadth of the science and clinical expertise. We want to build on the scientific insights into the mechanisms of how blood cells are formed and how cancer develops, in order to translate these findings into improvements in diagnostics and novel medical therapies. I will work with the outstanding BMF/MDS research and clinical team here to build a program that will improve outcomes for these patients.

Learn more about the Dana-Farber/Boston Children’s Bone Marrow Failure Program.