Every physician wants a success story, a disease cured, a life saved. Dr. Soheil Meshinchi wants that, too, except he's picked one of the most challenging diseases within his specialty of pediatric oncology — a cancer fatal in half of all patients.
While some childhood cancers have optimism-inducing cure rates of 90 percent or more, the picture is less than rosy for kids with acute myeloid leukemia (AML). AML makes up about 25 percent to 30 percent of all pediatric leukemia cases — and its cure rate, compared to some other childhood cancers — is dismal. Doctors struggle to heal just 50 percent of children with this aggressive leukemia.
But Meshinchi, a physician-researcher in Fred Hutchinson's Clinical Research Division, isn't easily discouraged. Through research and hands-on care, he's committed to increasing the success rates for AML patients. By better understanding the biology of the disease, identifying those at highest risk for relapse and developing targeted therapies, he wants to improve outcomes for children dealt the low blow of cancer.
Meshinchi spends about one-quarter of his time with patients and the rest in the lab. "In this division, you have clinicians who are running clinical trials, and they work closely with lab-based scientists whose research affects people's treatments and outcomes," he said. "It's a translational research environment that keeps you really grounded to what's important — treating the patient."
"It's a great place for collaboration. No matter what you're interested in or looking at, there's a world expert sitting in a nearby office. There's always someone who can enhance what you're doing — it's a unique setting."
In this setting, Meshinchi and colleagues are looking at the basic biology of leukemia. Better understanding of the disease leads to more appropriate therapy, says Meshinchi. AML is an especially complex disease, in which multiple chromosomal events go awry. The researchers are trying to pinpoint key events in the evolution of leukemia. Leukemia develops as a sequential process, with chromosomes breaking and rearranging in very early stem cells, followed by additional activating episodes. "The holy grail of leukemia therapy has been identifying and targeting the earliest leukemic cells, because if we target something that's too downstream, we're not going to be able to cure the disease," Meshinchi said.
With conventional chemotherapy, about 30 percent to 45 percent of AML patients can be cured. One of Meshinchi's goals is to identify at the time of diagnosis which patients will do poorly with chemotherapy alone. "Right now, we treat patients the same, and then we wait and see which ones are going to relapse," he said. "If we can identify high-risk patients early, then we can treat those patients differently, whether by bone-marrow transplantation — which seems to work in one group — or by other targeted therapies we're working on."
Good news for patients
He's found that one predictor of a bad outcome in AML is a gene mutation called FLT3 internal tandem duplication. Patients with this mutation have a depressing cure rate of 20 percent or less. The FLT3 mutation can be identified at the time of diagnosis. A pediatric clinical trial began last year to validate the findings. If the mutation proves to be reliable indicator, Meshinchi is ready to begin interventions in this high-risk population.
In the lab and early clinical trials, newly developed FLT3 inhibitors have shown promise. Meshinchi predicts that one-third of AML patients would benefit from therapy with these inhibitors. The more targeted therapies work specifically on the abnormal proteins that are fundamental to AML. These therapies act like heat-seeking missiles, aiming for cancerous cells while sparing healthy ones. That's good news for AML patients, where sometimes the cure can prove to be as bad as the disease. Standard treatment is very toxic, with a 10 percent to 15 percent death rate as a result of the therapy itself. For lower-risk patients, Meshinchi hopes to de-escalate treatment, sparing the patients short- and long-term complications.
Minimal residue disease
Identifying minimal residual disease (MRD) is another way to improve AML- cure rates. Meshinchi, Dr. Michael Loken and fellow researchers are using very sensitive tests to find one mutant cell among 10,000 to 1 million in patients who have finished chemotherapy. While such patients are considered in remission by conventional methods, the presence of MRD puts them at high risk of relapse. Meshinchi is the lead biologist on two studies looking at MRD. A national pediatric MRD pilot study ends next year. A three-year, Phase III trial — the largest study of MRD ever — is scheduled to begin soon after. Over 1,300 patients will be enrolled in the trial, which will look at multiple molecular and relapse factors. "The data from this study will provide a definite answer about the effectiveness of risk-based therapy," Meshinchi said.
Meshinchi's ultimate aim is to create a specific risk profile for each patient. By using state-of-the-art molecular testing, MRD assays and other methodologies, he hopes to know early and conclusively which patients would benefit from alternate therapy.
On the clinical side of Meshinchi's work, he and his colleagues published findings last year indicating that a second bone-marrow transplant may offer a cure in a specific subset of high-risk patients who relapse after an initial bone-marrow transplant. "Patients who are deemed to have a very poor prognosis are the ones who interest me in trying to find a way to treat them," he said. "My work in the lab has certainly changed my clinical practice. We're changing the standard of care and improving outcomes for our AML patients at Children's."
Meshinchi loves working with youngsters, both for the success in treatment and for life lessons in optimism. "Overall, we cure cancer in kids far more than we cure adult cancer. Kids are fun to work with, although when they don't do well, it's heartbreaking," he said. "I learn a lot from them. I think part of the reason kids do so well with cancer is that their focus is different than adults. Adults have so many medical and personal concerns, and kids don't carry the same worries, so they get through the day much better. They're very resilient, and they just have a really nice outlook — if you could transplant that, our success rates in adults would go up significantly."
Before Meshinchi could learn about science and medicine, he had to work on his English skills and settle in a foreign land. As a teenager, he arrived in the United States in 1978 after he fled Iran with his family to escape religious persecution. They joined Meshinchi's uncle — a pediatrician — in Michigan. "My uncle was a powerful role model. He is a smart man and a very clear thinker," Meshinchi said. "I think his influence helped me to choose clinical medicine as a component of my work."
There may be something of a genetic predisposition to the medical field in Meshinchi's extended family. In addition to his uncle, his mother is a midwife, his father's a veterinarian, one sister is a surgeon and the other, a dentist. His wife is a pediatrician and researcher at the University of Washington and Children's Hospital. "We've considered starting our own clinic — we can pretty much take care of everything!" Meshinchi said.
Intrigued by science at an early age, Meshinchi says he was enticed by the prospect of new discovery. "When you start out, you think, 'OK, I'll cure cancer,' but then you realize it's a long road," he said. "You just have to define your questions carefully and persevere. You grow to understand that the small steps pay off in the long run."