Marissa Boudreaux was almost 8 years old when her battle with acute lymphoblastic leukemia (ALL) began. In 2005, the little girl enrolled in a St. Jude Children’s Research Hospital clinical trial that adjusted her treatment based on early responses to chemotherapy. Because of careful monitoring and treatment, Marissa was cured. Physicians now know that she had a yet-undiscovered genetic subtype of ALL called Philadelphia chromosome-like ALL (Ph-like ALL). Clues gleaned from her case and those of other children have helped scientists identify the Ph-like ALL subtype, as well as improve treatments for future patients.
“I would go through it again tenfold if it would help someone else,” the now 17-year-old Louisiana native says.
Under the care of Ching-Hon Pui, MD, St. Jude Oncology chair, Marissa enrolled in a clinical trial that used risk-directed chemotherapy to treat B-ALL, a cancer that affects white blood cells called B lymphocytes. Treatment intensity was monitored and adjusted based on minimal residual disease (MRD), or the percentage of leukemic cells remaining in the bone marrow after treatment. This method of evaluating treatment response was pioneered at St. Jude.
Pui and his colleagues recently published a Journal of Clinical Oncology paper showing how children with Ph-like ALL fared in that study. The researchers showed that modifying treatment based on early responses to chemotherapy made life-saving differences to many children and adolescents with the subtype.
Throughout the world, five-year survival rates for Ph-like ALL have hovered at 62 percent. But in the St. Jude clinical trial, Pui and his colleagues reported that 92.5 percent of patients with Ph-like ALL were alive five years after their cancer was discovered.
“This study shows that by measuring minimal residual disease and using the results to guide treatment intensity, patients with Ph-like ALL who have a poor initial response to chemotherapy can, with more intensive treatment, often be rescued and enjoy the same high rates of survival as other patients,” Pui explains.
Scientists once classified all children with Ph-like ALL as high-risk. By taking into account such factors as patient age and white blood cell count at diagnosis, and adjusting therapy based on MRD levels, St. Jude researchers demonstrated that Ph-like ALL is not uniformly high-risk. As a result of that study, St. Jude now classifies Ph-like ALL risk groups as low, standard or high, in part depending on the number of cancer cells found in the bone marrow by pathologists. Low-risk patients have less than one cancer cell in 10,000 in the bone marrow after remission induction chemotherapy. High-risk patients have one cancer cell in 100. Standard patients fall in the middle.
In the St. Jude clinical trial, 40 percent of Ph-like ALL patients were classified as having low-risk disease, making them candidates for less-intensive treatment.
“You don’t want to treat everyone intensively, since a substantial proportion of patients would be over-treated,” Pui explains. “Children with Ph-like ALL who achieve a negative MRD status after remission induction should do just fine with low-risk therapy.”
Pui says children with high MRD levels should not only receive intensive chemotherapy but also further testing. Patients with genetic lesions responsive to specific groups of drugs can then be identified to spare them from bone marrow transplantation.
From lab to clinic
In 2009, St. Jude pathologist Charles Mullighan, MD, MBBS(Hons), helped discover and describe Ph-like ALL. Recently, he led a study that details how often the subtype occurs and pinpoints which genetic changes drive development of the disease.
That study, published in the New England Journal of Medicine, involved 1,725 B-ALL patients between ages 1 and 39. Scientists used next-generation sequencing to identify the genetic missteps that lead to Ph-like ALL. The research was part of the Pediatric Cancer Genome Project, a collaboration between St. Jude and Washington University School of Medicine in St. Louis. The complete normal and tumor genomes of 700 young cancer patients have been sequenced as a result of the project.
“In this study, we were able to identify the full range of genetic changes, the driving force of leukemia in cases of Ph-like ALL,” Mullighan says. “We identified multiple new genetic changes, but at the end of the day, they activate only a limited number of cell growth pathways. And those pathways can be inhibited with drugs which are already available.”
The results pave the way for clinical trials to see if drugs called tyrosine kinase inhibitors (TKIs) can improve outcomes.
Two drugs called dasatinib and imatinib are examples of TKIs that have been used to treat Ph-positive leukemia in children and adults. Researchers recently used these drugs to treat a small group of patients whose Ph-like ALL had not responded to chemotherapy. Five of those eight patients remain in remission with no detectable cancer. A national clinical trial is being planned, using existing TKIs to treat children with Ph-like ALL.
“There are children and adults alive today as a result of this research,” Mullighan says. “It has truly made a difference for at least a handful of people, and that number is likely to grow.
“At St. Jude, we will soon be sequencing every child with cancer, and we will be able to rapidly identify those with Ph-like ALL,” Mullighan continues. “We’re proud that we’ve been able to identify this subtype and move toward an effective treatment in such a short period of time. It’s the most exciting and satisfying project I’ve been involved with.”
More than magic
Marissa’s experience at St. Jude not only saved her life but also directed it. The college sophomore is now preparing for a career as a labor and delivery nurse. “I want to witness life not only as a survivor, but also as one who will help to bring it into the world,” she says.
Ten years ago, Marissa could never have dreamed that her treatment would one day affect the lives of other children. She remembers 2005 as the year her brother and father had surgery, Hurricane Katrina hit her hometown and she received a cancer diagnosis. She remembers Pui, not as a celebrated researcher, but as a doctor who entertained her with magic tricks.
“He had a magic set kit with little foam balls under plastic cups. He would do a trick and frustrate me,” she says. “Then he would stick a pen through a dollar bill, and there would be no hole in it. Being 9, I was like, ‘Oh my gosh.’”
Marissa’s mom, Tanya, recalls Pui’s swift attention when Marissa had complications or when she had questions.
“He was always there, always reachable,” she says. “We love Dr. Pui. We love St. Jude.”
Abridged from Promise, Winter 2015