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March 2016 Affiliated with Columbia University College of Physicians and Surgeons and Weill Cornell Medical College
Precision Medicine Offers Targeted Transplants, Novel Therapeutics for Children
Leading the Way to Precision Medicine

In his State of the Union address in January 2015, President Barak Obama announced the launch of the Precision Medicine Initiative, whose mission is “To enable a new era of medicine through research, technology and policies that empower patients, researchers and providers to work together toward development of individualized treatments.”

For children with cancer and blood disorders, President Obama’s vision fortunately has already been achieved. Since January 2014, the Precision in Pediatric Sequencing (PIPseq) program at NewYork-Presbyterian/Morgan Stanley Children’s Hospital at Columbia University Medical Center, in New York City, has been using the technologies of tomorrow to deliver precision medicine to patients today. This New York State–approved precision medicine platform has had a wide impact not only on the care of children with cancer, but also patients referred for bone marrow transplantation.

“‘Precision medicine’ is kind of a loose term,” said Prakash Satwani, MD, a specialist in pediatric hematology-oncology and bone marrow transplantation at NYP/Morgan Stanley Children's, where he is Associate Professor of Pediatrics at Columbia University Medical Center.

“But there are two ways I look at it. One way is treating patients precisely, based on their disease characteristics or their bodily functions,” Dr. Satwani explained. “The second aspect is doing sophisticated molecular diagnostic testing on patients and donors to determine the best modality to do a transplant, or even whether or not to do a transplant.”

Dr. Satwani specializes in transplanting bone marrow in order to treat pediatric patients with leukemia, lymphoma or hemophagocytic lymphohistiocytosis (HLH). Genomic sequencing through the PIPseq program has enhanced his practice in a number of ways, allowing for improvements in diagnostic accuracy, clinical decision-making and patient safety.

A Mystery Solved

“We had a patient with leukemia who was referred from Long Island [N.Y.] for a bone marrow transplant,” Dr. Satwani said. “After one course of chemotherapy, we expect patients to recover their bone marrow functions in about five to six weeks, but somehow this child took around five to six months to recover.

“At the time, it was deemed to likely be a genetic problem causing the delay in recovery, but we did all the standard genetic testing, and we found no abnormality in the patient,” Dr. Satwani said. “However, the comprehensive genomic sequencing through our PIPseq program found a particular genetic mutation in the RUNX1 gene, that explained both the poor blood recovery and why the patient developed leukemia.”

Dr. Satwani and his colleagues had planned to replace the patient’s bone marrow with that of her perfectly HLA-matched sibling, but the sibling’s low normal platelet count was a concern. Genomic testing revealed that the sibling also had the RUNX1 mutation. Rather than use the sibling’s bone marrow, they found a different donor. A year and a half after the transplant, the patient is completely healthy.

“Two or three years ago, we would have used the sibling as the donor and transplanted the same mutated bone marrow,” Dr. Satwani said. “So we prevented an erroneous transplant because of this technology.”

In the intensive care unit, Dr. Satwani and his colleagues are using precision medicine techniques to offer targeted therapies to patients with multiple organ failure as a result of HLH or overwhelming infections. Based on the cytokine levels in a patient’s blood, they are able to treat patients with precision monoclonal antibodies, rather than with more nonspecific treatments. “We are also using genomic sequencing in these patients to see if there is a genetic cause for their illness,” Dr. Satwani said. “And that helps us to decide on future therapies.”

Matching Patients to New Therapies

The PIPseq program is also impacting the treatment of children and adolescents with solid tumors and leukemia, said Julia Glade Bender, MD, Medical Director of PIPseq at NYP/Morgan Stanley Children’s and Associate Professor of Pediatrics at Columbia University Medical Center, where she specializes in treating neuroblastoma, sarcoma, germ cell tumors and other rare tumors, as well as in treating refractory and relapsed tumors.

The PIPseq precision medicine program was the brainchild of Andrew Kung, MD, PhD, Chief, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation at NYP/Morgan Stanley Children’s and Robert Ellen Kapito Professor of Pediatrics at Columbia University Medical Center. “Dr. Kung’s goal was to offer molecular profiling and sequencing of patients’ cancers, but he wanted to leapfrog the old technology—or rather the technology of today—which is to look at panels of potentially actionable genetic mutations,” Dr. Glade Bender said. “Instead, he wanted to take a much more comprehensive approach, so we developed a platform using whole-exome sequencing not only of the cancer but also normal tissue, as well as sequencing of the RNA from the cancer.”

The PIPseq program allows Dr. Glade Bender and her colleagues to, as she explains to her patients, “read the encyclopedia” of their individual cancers, “from the first letter of DNA to the last.” By sequencing both cancerous and normal tissues, “the PIPseq program allows us to find out what genetic changes resulted in development of the cancer, but also to find out what genetic predispositions there may have been to form the cancer in the first place.”

Dr. Glade Bender explained that by incorporating RNA sequencing and analysis, the PIPseq program utilizes a unique multilayered molecular approach that leads to a more precise understanding of what is driving tumor growth, and thus more targeted treatment approaches, than DNA sequencing alone. Dr. Glade Bender also directs the Pediatric Cancer Foundation Developmental Therapeutics Program at NYP/Morgan Stanley Children’s, which works to make available to children targeted treatments, some of which have only been approved for use in adults. Molecular diagnoses enable her to match pediatric patients with clinical trials for the drugs most likely to help them.

“Prior to molecular profiling, matching patients with clinical trials was mostly a marriage of convenience. It came down to whether the trial was open and whether the patient met the eligibility criteria,” Dr. Glade Bender said. “Now we’re trying, if we can, to make a match.”

When matching patients with clinical trials isn’t possible, Dr. Glade Bender and her research team obtain single-patient INDs, or investigational new drugs applications, to test new drugs in a single child. “Because we are well known for running first-in-child clinical trials, and doing so safely and within regulatory compliance, we have been successful in getting single-patient INDs approved,” Dr. Glade Bender said. “But it’s extremely labor-intensive and not reimbursed, so it’s really a labor of love.”

Similarly, Dr. Glade Bender said, insurance covers only a small part of the costs for the sequencing that the PIPseq program offers. However, her vision is one of long-term benefits. “We’re taking the calculated risk that over time, the cost of the technology will come down and reimbursement will be better, but we’ll have gained the experience in terms of interpreting and translating the data into patient care,” Dr. Glade Bender said. “We cannot wait until other people figure out how to do this. We are committed to be the pioneers that demonstrate the impact and value of using these state-of-the-art technologies to improve the lives and outcomes for children with cancer.”

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