From left: Cailin Collins, MD, Peter Greenberg, MD, and Gabe Mannis, MD

A Fellowship Investigation Becomes a Lifelong Inquiry

Peter Greenberg’s role in the sea change in MDS research started during his hematology and oncology fellowship at Stanford, which he completed in 1971. “My chief of hematology said, ‘Greenberg, we have a set of patients that are interesting to evaluate. What can you tell us about that? How can you study it?’”

In fact, Greenberg was positioned to tell a lot about MDS, an illness in which blood cells fail to develop normally in the bone marrow. Patients with MDS often experience fatigue, anemia, frequent infections, and easy bleeding, among other symptoms.

“At the time, I was studying the growth of bone marrow cells within tissue culture, and a new system had just become available to evaluate the normal and abnormal growth of bone marrow cells,” Greenberg says. He contrasted MDS, AML, and normal tissue samples. “It turned out that there were marked differences that became quite informative as to trying to understand the nature of the disease.”

He went on to become an internationally recognized leader in the classification and treatment of MDS, with at least 200 papers on the disease. His publications closely parallel medicine’s developing understanding of MDS, from broad questions of what is its biological nature and best treatments to how to determine an MDS patient’s risk of developing acute leukemia and differentiated treatment based on risk level. More recent papers reflect the role that genetic mutations play in disease progression and the significance of particular mutations on prognosis and treatments.

Every answer that you have leads to other questions. The important thing now is that there’s new technology that permits us to ask these questions more effectively.

Question, Answer, Question

“Every answer that you have leads to other questions,” says Greenberg. “The important thing now is that there’s new technology that permits us to ask these questions more effectively.”

One of the biggest questions Greenberg has helped answer is why MDS remains relatively stable in some patients and becomes very aggressive in others. Advancements in technology such as next-generation sequencing — which rapidly analyzes DNA and RNA samples — have helped provide answers.

“Each cancer has its own heterogeneous group of what we call driver mutations that have major implications for responsivity to certain drugs or aggressivity of disease,” Greenberg says. “Understanding that, hopefully, will help us know what specific drugs should be used for different subtypes of MDS.”

A Lethal Disease and a Chance to Make an Impact

“AML is probably one of the most aggressive and lethal hematologic malignancies, and unfortunately, most of my patients will die from their disease,” says Gabriel Mannis.

Patients with AML have immature, abnormal cells called myeloid blasts that crowd out healthy blood cells. In addition to the anemia, infection, and bleeding problems common to MDS, patients with AML are at risk of organ failure and rapidly life-threatening complications.

When Mannis started researching AML in 2013, during his hematology and medical oncology fellowship at UC San Francisco, there were few options available for patients. “I would go to conferences and every trial would be a negative trial,” Mannis says. “There had only been one drug approved for AML since the 1970s, and that drug had been taken off the market.”

He saw an opportunity to make an impact. Once he started seeing patients, his drive to find answers grew even deeper.

When I’m looking at opening different trials, the strategy is ‘How can I best serve the patients that I’m taking care of?’

Patient-Driven Research

“Every patient I see, I think, is there a clinical trial that would be good for this patient?” he says. “Down the road, if this first treatment doesn’t work, what can we then have as a backup for this patient?”

Today, Mannis has opened nearly a dozen clinical trials, most focused on finding better AML treatments. He also sees patients, teaches residents and fellows at the bedside, and teaches part of the hematology course for medical students.

It’s a demanding schedule, but given the fact that most AML patients don’t meet the criteria for the only AML cure — a bone marrow transplant — there’s much to do.

“It’s very difficult, and only a select few are healthy enough to move forward with transplant,” Mannis says. “A transplant is fraught with all sorts of risks and challenges. If we can find the right drugs to eliminate every last leukemia cell without a transplant, that’s really my goal.”

Toward More Elegant Treatments

In the interim, treatment options are improving. “There have been 10 or 11 drug approvals from the FDA, just since 2017,” Mannis says.

Patients are living longer and with better quality of life. With developments in precision medicine, the treatments are increasingly tailored to a patient’s particular disease biology and health status.

“We are able to get more effective treatments with less toxicity,” he says. “We are able to be much more elegant.”