Knowing the Half of It
2019 Alumni Achievement Award Recipient
“There was once a man named Paul Revere who rode under the midnight moon. He knew he might never return, but he went riding, riding, riding—because he wanted a country without a king, a country where all men would be free.” These opening lines of Walt Disney’s Paul Revere, a children’s book about the famed silversmith’s journey to warn American patriots of incoming British troops on the cusp of the Revolutionary War, grabbed preschooler Neal Flomenberg instantly. Captivated by Revere’s fearlessness, but unable to read on his own, he made his mother repeat the story over and over until she became hoarse.
“I was taken by Paul Revere’s courage and drawn to people who exhibited courage in real life. Even as a kid, I wanted to hang with people like him,” Flomenberg, MD ’76, recalls.
And, in a way, he does. As chair of Jefferson’s Department of Medical Oncology and director of the Blood and Marrow Transplant Program, Flomenberg treats patients who bravely face what he calls “some of the riskiest procedures a person can undergo.” His work to advance these procedures led to his recognition as the 2019 Alumni Achievement Award recipient during SKMC Alumni Weekend in October.
If Flomenberg—a graduate of the joint Jefferson–Penn State accelerated medical degree program—had to credit a single date with charting his career trajectory, it would be September 13, 1979. That day, the “father of bone marrow transplant,” E. Donnall Thomas, MD, reported curing close to two-thirds of acute myelogenous leukemia patients who underwent transplantation when their disease was in chemotherapy-induced remission. Previously, transplant had been used only as a last-ditch effort in late-stage disease, with survival rates hovering around 15%. The publication had a profound effect on the field and on Flomenberg, a fellow in his first month on the bone marrow transplant unit at Memorial Sloan Kettering (MSK) Cancer Center in New York.
“Going forward, every transplant consult ended in tears—one-third because there was this curative treatment and patients were lucky enough to have a family member who was a match, and the other two-thirds because there was this curative treatment, but it was not available to them because they didn’t have a match,” Flomenberg says. “We recognized quickly that we had to find ways to cross the matching boundary.”
“We” in this case included Flomenberg’s mentors, MSK pediatric oncologist Richard O’Reilly, MD, and immunogenetics researcher Bo Dupont, MD, along with a large number of MSK transplant team members. Together, they explored ways to transplant marrow from unrelated donors, as well as from donors who were not a perfect match.
Flomenberg continued these studies at Memorial Hospital for Cancer and Allied Diseases in New York and the Medical College of Wisconsin. He then returned to Jefferson, where he was charged with building a bone marrow transplant program from the ground up. He arrived in fall 1994 and spent his next birthday—September 20, 1995—performing Jefferson’s first bone marrow transplant. By that time, a national registry of bone marrow volunteers was well established, but he still saw an urgent need to expand the donor pool.
“For reasons known only to God, people of African descent are much more diverse in terms of HLA [human leukocyte antigen, the cell surface markers used to match patients and donors for bone marrow transplants] background than Caucasians, so donors for these individuals were very limited,” he says.
Institutions had been exploring half-matched bone marrow or stem cell transplants for blood cancer patients for years with largely disappointing outcomes. Results showed more promise, however, when a team from Johns Hopkins began administering one chemotherapy drug, cyclophosphamide, after transplant rather than before. When Flomenberg and his “right-hand person,” Dolores (Lori) Grosso, DNP, CRNP, heard the Hopkins clinician-scientists present their findings at a meeting, light bulbs flashed in both of their heads.
“When you performed a transplant, you always gave both components of a graft at once: stem cells and T cells, a type of immune cell that fights infection,” Grosso says. “I was flummoxed because you didn’t give a specific dose of T cells and just took however many tagged along for the ride, even though T cells are so important.
“And now, we were concerned by this new idea because stem cells were being exposed to a chemotherapy drug that could harm them. Neal mentioned the possibility of splitting the procedure into two parts so the stem cells could remain untouched. It was a real ‘eureka!’ moment,” she remembers.
The colleagues conceptualized the first iteration of the protocol for a new two-step half-match procedure in the car on the way back to Jefferson. Their plan was for patients to receive chemotherapy or radiation before an infusion of donor lymphocytes that contained an optimized number of T cells to attack their cancer. A subsequent round of cyclophosphamide would then temper those T cells to curb graft–versus–host disease, a condition in which donated cells view the recipient’s body as foreign and turn against it. Next, patients would receive a donor’s hematopoietic stem cells, which would replenish their marrow and enable them to generate their own healthy stem cells within a matter of weeks.
“This was night-and-day different,” Flomenberg says. “We had started trying to deal with half-match transplants in the early 1980s and had struggled to make it consistently successful, and here we were putting our two-step program together in 2005.” They did their first transplant using this approach in 2006 and have performed nearly 400 to date at Jefferson; success rates are on par with transplants from fully matched donors.
Flomenberg refers to the procedure as “the equalizer,” since it puts transplant within reach for minority and mixed-ancestry patients, many of whom lack a full match. A person has a guaranteed half-match in their parents and children. Moreover, while two siblings have only a 25% chance of being fully matched, they have a 75% chance of being fully matched or half matched and thus representing a viable donor.
The two-step protocol also benefits older patients, Flomenberg notes. “When I started, we never, ever, ever, did a transplant in someone over 40—that was considered advanced old age in our world. The oldest person we successfully transplanted here in our program was 77,” he says.
As he continues to refine bone marrow transplantation, Flomenberg, who became chair of medical oncology in 2008, puts just as much energy into leading his department. The administrative responsibilities can be draining, he admits, but time in the clinic leaves him revitalized.
“Neal can come in after some rough early-morning meeting about something tedious like our budget, but after a minute in a patient’s room, he is smiling,” Grosso says. “People tell me that when they are with him, they feel like they are his only patient. He remembers their families, their interests, what they do for fun. He gives them hope and the best possible care, but they give him something, too, and I think they can feel that he is drawing strength and energy from them.”
She recalls tearing up at the Eastern Pennsylvania Chapter of the Leukemia & Lymphoma Society’s 2019 Red & White Ball, where he received the Lifetime Achievement Award and dedicated it to his patients, several of whom he’d brought to the event as guests, along with his wife, Phyllis Flomenberg, MD, a professor of infectious diseases at Jefferson, and two of their three children.
As for Paul Revere: Flomenberg has been rapt by his heroic acts since childhood, but he is well aware that Revere did not work alone—and that he doesn’t, either.
“Paul Revere got up on the horse and made the ride, but he couldn’t have pulled it off without his team. There were the people who rowed him across Boston Harbor, the ones who set up the light signal in the church tower … in the kids’ version of the story, the family dog even played a role,” he says. “It’s like that with bone marrow transplant, which is the ultimate team sport in medicine. Let me be very clear: I could not do this work without Lori and the rest of our team.”
Then there are his patients’ teams. “The patients have to get up on the horse and undertake the ride, but their family and friends display a different kind of courage. In some respects, it can be easier to deal with your own problems than those of someone you really care about. My patients are inspiring, but the people around them are inspiring in a different way,” he says. “It is truly amazing what you can accomplish with the combination of courage and teamwork.”