Michael Deininger, M.D., Ph.D.


Spotlight on SM Q&A with a pioneeing hematologist

Michael Deininger, M.D., Ph.D., is Professor and Chief of Hematology and Hematologic Malignancies for the Huntsman Cancer Institute at the University of Utah. He has extensive experience treating patients with blood cancers as well as with systemic mastocytosis (SM). In this Q&A, he shares his thoughts on the increasing importance of genetic profiling and its role in the diagnosis of SM.

What is your role as a hematologist, and what types of patients do you treat?

I treat patients with blood cancers and have a longstanding interest specifically in myeloid leukemia. As mast cells are part of the myeloid system, I see lots of patients with mast cell disorders – a mixed patient population. At Huntsman Cancer Center we see patients with SM every week because we’ve developed an interest here at Huntsman in managing these frequently challenging cases.

There are several SM subtypes. What treatment options are available for each subtype?

SM is a very broad umbrella of disorders, from the indolent form that can be asymptomatic, to mast cell leukemia, a rare and rapidly progressive condition with a poor prognosis. In most patients with indolent SM, we can achieve improvement by targeting the disease symptoms. On the other hand, the aggressive form of SM may require treatment with some type of chemotherapy. Most patients have the indolent form of SM, and by and large, their life expectancy is quite close to that of the average population. That doesn’t mean, however, that their quality of life is equally good.

Understanding the underlying disease drivers may help improve SM treatment. What is the biological cause of SM?

In a very broad sense, SM is a genetic accident. In the bone marrow, some people acquire a genetic mutation that gives rise to a growth factor signal in a mast cell. This in turn, causes an increase in the number of mast cells and over time, can become SM.

In most patients with SM, the relevant mutation occurs in the KIT gene in a position called D816V. The activity of the KIT protein is normally tightly regulated and adjusted to the body’s needs. The KIT D816V mutation results in an overactive protein that gains the ability to signal on its own. Mast cells responding to this aberrant growth signal increase in numbers and don’t die easily. So, over time they accumulate. In aggressive SM, this accumulation may lead to tissue damage, for example to bone loss with fractures.

How does the KIT D816V mutation occur? Can it be passed on in families?

For clarity: The term, “genetic mutation,” is a bit of a misnomer. Every mutation in the human body is genetic.

There are two types of mutations. A germline mutation, or one found in sperm or egg, is hereditary and can be passed on from parents to their children. That is rare in SM, but there are some families who do have germline mutations. The vast majority of SM patients, however, have a somatic mutation, like KIT D816V, which is an acquired mutation – not inherited, and there is no risk of transmission to the next generation.

The mutation changes the genetic code, the DNA. If the DNA changes, and it happens in a sensitive place, then the protein made from that piece of DNA can be overactive or not active enough. In the case of the D816V mutation, the result is an overactive KIT protein.

How do the results of KIT D816V testing currently inform diagnosis and treatment decisions?

Knowing you have the KIT D816V mutation can help the physician to make a diagnosis of SM. Additional tests are needed, since this is only one of the World Health Organization’s (WHO) diagnostic criteria and not sufficient in its own right.

There are some approved drugs called tyrosine kinase inhibitors, or TKIs, that work as inhibitors of certain mutant versions of KIT. However, these drugs are typically ineffective in patients who have the specific KIT D816V mutation. Knowing whether someone has this mutation helps physicians gauge whether or not these patients are likely to benefit from such drugs.

How do you think knowledge about the KIT D816V mutation will influence future SM research and treatment development?

This knowledge is telling us at a scientific level what to do next because there clearly is a need to develop drugs that specifically target the KIT D816V mutant. The hope is that ultimately, following clinical trials and demonstrated clinical effectiveness, we will have drugs that can inhibit mast cells with these specific mutations. I suspect such a drug would establish a new standard of care for SM.

The hope is that ultimately, following clinical trials and demonstrated clinical effectiveness, we will have approved drugs to help patients with SM and the D816V KIT mutation.

Michael Deininger, M.D., Ph.D.Huntsman Cancer Institute, University of Utah