ursuing the Better Answer P TORY AND HOTOS BY PRIL ILKERSON OU bone marrow transplant specialist Jennifer Holter S P A W is conducting promising research that could provide physicians with significantly superior diagnostic tools.

ncologists, perhaps more than other types of physicians, can quickly retrieve memories of patients they’ve treated. 0ey remember the faces and stories of those whose cancers have retreated and celebrate with them a new chance at life. OAnd they mourn those who lost the battle, haunted by the stopping point where medicine had no more miracles in store. Such is the mix of emotions for any physician, but it is also what propels them toward seeking new op- tions in diagnosing and treating disease. For Jennifer Holter Chakrabarty, M.D., that’s a powerful motivator to blend research into her clinical practice. “Almost all of us have a reason that we get into research that is uniquely personal. For some people, it is a family member who had a disorder, and they want to 2nd better answers for that person. For the vast majority of oncologists, it was a patient who they wanted to help more, but they didn’t have the tools to do so. For me, it was a cord blood transplant patient who never grew her cells back. I couldn’t identify that fast enough, and she developed an infection and passed away,” says Holter, who goes by her maiden name in her medical practice. Holter is a hematology oncologist specializing in bone marrow transplants at the OU Health Sciences Center, and she is an associate professor in the OU College of Medicine. She performs about 120 trans- plants a year, most of which are for patients su1ering from acute leukemia, multiple myeloma and lym- phoma. About 2ve years ago, Holter started a research project that is now poised to o1er signi2cant new options in the diagnosis of those disorders. About half of the transplants Holter performs use patients’ own cells, called stem cell rescue. 0e other half is primarily patients with acute leukemia who receive bone marrow cells from a donor. Such donor cells are transplanted because the patients have a malignancy in their native bone marrow that, even with chemotherapy, will cause relapse. “Based on that, it’s really important to be able to identify patients who have the kind of leukemia that will come back versus the kind that, if I give chemotherapy, will go into remission,” Holter says. “But the ultimate reason is that there is quite a bit of toxicity associated with doing a bone marrow transplant. Patients are in the hospital for a month, and they take immuno-suppressive medicines for upwards of two years, sometimes lifelong. Even with perfect matches as we can assess them, there can be a lack of tolerance between the new bone marrow and the patient who receives it, manifested by something called graft-versus- host disease.” continued

At right, using a plastic model of the hip, Jennifer Holter, M.D., demonstrates the current method of diagnosing bone marrow PET imaging to provide a more comprehensive look at a patient’s bone marrow.

26 SOONER MAGAZINE SUMMER 2013 27 he current standard for diagnosing bone marrow with leuke- mia is to insert a large Tneedle into the patient’s hip bone and withdraw a column of liquid. 0at sample is assumed to be rep- resentative of all the bone marrow in a patient’s body. 0e possibil- ity of sampling error exists, but no other diagnostic test is avail- able. In addition, Holter cannot predict as well as she’d like which patients will ultimately need a transplant, or which will get graft- versus-host disease. Jennifer Holter, center, discusses a case with her hematology/oncology colleagues Patty Whitt, Holter’s research directly ad- dresses those concerns. Her proj- nurse. A large group of health care providers makes the bone marrow transplant unit possible, ect centers on a new way to assess including nurses, social workers, transplant coordinators, physician assistants and nutrition- a patient’s bone marrow cells using ists, along with the leadership of hematology/oncology physicians Robert Epstein, George Jennifer Holter, a hematology oncologist who specializes in bone marrow transplants, shows her research images captured by PET PET imaging. Positron emission Selby, and Carrie Yuen. imaging to George Selby, chief of the Section of Hematology-Oncology in the OU College of Medicine. tomography produces a three-di- mensional image of how the body is functioning at the molec- very well and a bone marrow that is working inappropriately ular and cellular level, but it is normally used to diagnose solid and growing too many cells.” says that if Holter’s research comes tumor malignancies. When Holter and her mentor, Robert 0at part of her research project was representative of pa- to fruition, it would be a boon for Epstein, M.D., professor emeritus of hematology-oncology at tients with disorders who have not received treatment. Her transplant physicians. By deter- the OU College of Medicine, read a paper by researchers at the next step was to prove that PET imaging would work in mining earlier that a transplant University of Groningen in 0e Netherlands about a similar patients who receive chemotherapy or bone marrow trans- isn’t working, physicians could project, her mind was soon spinning with the possibilities. plants. Holter returned to the laboratory and performed bone perform a second transplant be- “I thought, ‘Could that work with my transplant patients? marrow transplants in mice. 0e mice were given radiation fore the patient encounters signi2- Could I see bone marrow repopulating in a transplant host? that killed o1 their bone marrow, then cells from a genetic cant complications. Could I document bone marrow that wasn’t repopulating?’ I match were given back. At increments during the process, “It’s a di4cult process after a thought there ought to be a way to do this,” she says. PET imaging was performed in conjunction with traditional transplant because you see the pa- To use PET imaging to see a patient’s bone marrow, it has bone biopsies to validate this innovative approach to measur- tient every day, and he or she asks, to be “tagged” with something that will illuminate the cells. ing cellular growth. ‘What’s my blood count?’ 0e an- In her research, Holter used a new imaging agent called FLT, 0e results are promising and show the potential for PET swer may be ‘200,’ and that can go or 3uorothymidine. It is a 3uorescent version of thymidine, imaging with FLT to replace the more invasive and less accu- on for weeks, which is discourag- which is a building block in DNA replication. Every time a rate biopsy as a measure for successful bone marrow transplants ing,” Selby says. “It’s discouraging cell divides, thymidine is incorporated into new strands of or chemotherapy responsiveness. Holter is excited because of for the patient, everyone caring chromosomal DNA. Tagging it with FLT and conducting the enhanced tools it would provide transplant physicians. She for the patient, and it makes fami- PET imaging details the extent that each bone cell took up would be able to tell, much earlier, if a leukemia patient is re- lies anxious. Nothing good comes FLT, enabling Holter to identify which and how many cells sponding to chemotherapy. She could determine, with much from waiting that long.” were dividing. more speci2city, if and where new cells are growing after a 0e research also is characteris- “It was the 2rst time that I could visually see proliferat- transplant. Right now, all she can do is wait two weeks after tic of the trend toward personalized ing bone marrow,” Holter says. “It was a ‘wow’ moment for an initial round of chemotherapy, insert the needle into the medicine. “0is will diagnostically a transplanter and bone marrow specialist. It turned a little hip bone again, and hope it is representative of the entire body. make your disease more objective Hematology oncologist Jennifer Holter, left, talks to Frances Lee, a bone marrow transplant biopsy into a picture of the entire skeleton. It allowed me to George Selby, M.D., professor and chief of the Section so that I can treat your particular patient from Norman. Holter’s research stands to transform the way she sees bone marrow tell the di1erence between a bone marrow that is not working of Hematology-Oncology in the Department of Medicine, disease in a more objective man- repopulating in patients like Lee.

28 SOONER MAGAZINE SUMMER 2013 29 Jennifer Holter and George Selby stand next to a positron emission tomography machine at the Stephenson Cancer Center. Holter’s research the Section of Hematology-Oncology, for which Selby serves as chief.

OUHSC Prepared with Quick Disaster Response s an academic medical campus with a robust bone campus was selected for RITN because of its central location marrow transplant program, the OU Health Sciences in America, access to several airports, including Air Force bas- Center and OU Medical Center are poised to help es, and a solid reputation for its pediatric and adult transplant notA only Oklahomans, but people across the nation at a mo- programs, Selby says. also has seen its share of di- ment’s notice. sasters and has a respected emergency management system. This image from the research of Jennifer Holter shows Jennifer Holter looks at slides on her computer showing how an OUHSC is a member of the Radiation Injury Treatment A variety of health care providers across OUHSC undergo how PET, using imaging agent FLT, can illuminate bone imaging agent called FLT illuminates a patient’s bone marrow Network, a national organization that coordinates prepared- continuing education annually on how they would respond marrow in the body. when a PET scan is conducted. If her research project is suc- ness to a mass casualty incident with bone marrow injuries. to a radiation event. cessful, the PET scan could replace the more invasive and less According to the RITN, mass casualty incidents that could “One of our exercises was being presented with a scenario accurate biopsy of a patient’s hip bone. result in marrow-toxic injuries include an improvised nuclear that a 10-kiloton improvised nuclear device exploded on the device, a radiological dispersal device (aka “dirty bomb”), a East Coast, and we’ll be receiving 150 patients on 0ursday,” ner,” Holter says. “I believe that, eventually, I will be able to see or someone who tweaks your work, you don’t really know radiological exposure device, a catastrophic nuclear power Selby says. “What is each department going to do? We think your disease better than I could otherwise. Or I could see your what you know. You only know what you think. Having sev- plant accident, or exposure to a mustard agent. it through.” lack of cellular recovery, then 2gure out how to 2x it.” eral people in the same room who are all invested in making OUHSC is among 54 transplant centers across the United 0e research of Jennifer Holter Chakrabarty, M.D., stands Holter is about halfway down the long path toward get- something happen is always better.” States that could accept victims from a radiation event, deter- to strengthen and expand OUHSC’s response in such a sit- ting the investigational process approved for use at the pa- Carrying out her research in the setting of an academic mine who needs bone marrow transplants and perform them. uation. Her research using PET imaging to provide an en- tient’s bedside. She has traveled to 0e Netherlands to work medical center is especially gratifying for Holter. As an as- By taking patients from a mass casualty, RITN hospital mem- hanced look at bone marrow in leukemia patients also applies with researchers on the original paper she encountered, and sociate professor of hematology-oncology, she constantly in- bers would free up facilities near the event to focus on the to a person who has been exposed to radiation. For example, now she is collaborating with the National Cancer Institute teracts with students who challenge her with their questions. immediate disaster. a radiation event survivor may have been sitting behind a to study the use of PET imaging in humans. Ten patients “I think an academic center allows us to treat the sickest George Selby, M.D., professor and chief of the Section metal desk, therefore receiving more radiation to the upper have been enrolled in the trial, including three Oklahomans. of the sick very well, but also to be able to constantly im- of Hematology-Oncology in the Department of Medicine, half of his body. However, there is currently no sure way to 0e NCI is funding much of the work, along with a sig- prove on those who came before you,” she says. “Students says RITN is an outgrowth of the National Marrow Donor know whether someone has received a lethal dose. ni2cant private donor, the Mex and Cli1ord Frates Fund are part of that process because they are always asking ques- Program, which is now a database of millions of people who “If I can tell the di1erence between normal bone mar- for Leukemia Research. 0e Jones Family Foundation also tions. Several times, students have asked me a question that are willing to donate their bone marrow. But the program row and bone marrow that’s not working, then I can identify has sponsored her research, along with support from the has changed the course of how I was going to treat a patient’s saw its start many years ago in the military as the Navy was those that need rescue with bone marrow transplant from ex- Stephenson Cancer Center, the OU College of Medicine and disorder. 0ere is an unwritten drive in each of us that what is building its nuclear force—if a reactor accident occurred on a cessive radiation,” she says. “If my research were able to do the State of Oklahoma. good enough today is not good enough tomorrow.” ship and sailors were irradiated, they needed a source of bone that, then I could identify those patients more readily, and it “Collaboration in science is the only way things happen, marrow. would augment treatment in the RITN.” in my opinion,” Holter says. “Until you 2nd someone who ei- April Wilkerson is the editor of OU Medicine, the publication of OUHSC was one of the early members of the group. 0e —April Wilkerson ther disagrees with you and makes you learn something new, the College of Medicine.

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