Chasing My Cure

by David Fajgenbaum

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  January 5, 2015, marked one year since my last relapse ended and my fifth overtime began. But I was cautious. I had been here before—indeed, I’d tentatively celebrated one-year remissions twice before—and remembered all too well that I relapsed soon thereafter.

  As I approached the sixteen-month mark—the longest I’d ever gone between relapses—I started to feel some low-grade flu-like symptoms. Caitlin became so worried that she took a leave from her job to maximize her time with me and give us the flexibility to travel together for vacation…or go to Little Rock on short notice. But my blood test results kept looking great. Those inflammatory markers I’d found during the fifth episode, showing elevated VEGF and T cell activation, remained normal. I just had the flu. No one has ever been more excited or relieved to have the flu. After a short break, Caitlin felt comfortable returning to work.

  And then, one day, I crossed that dreaded sixteen-month threshold. I was in uncharted territory. I felt like I had been in some disaster movie, holed up in my bunker, and I’d finally emerged, blinking into the brightness of the sun. The meteor hadn’t struck after all—Will Smith had saved the day. Or sirolimus, in my case. But I knew this still didn’t mean that my disease would never be back. Those movies almost always have sequels.

  * Before we tried to build a registry study, we decided the best option for generating insights in the short term was to conduct a study that analyzed data on the treatments given to iMCD patients in previously published case reports. We learned of a lot of drugs that had been tried, but the data on how effective they were were inherently biased. Case reports are typically published only when a relatively novel treatment works (unfortunately, physicians and researchers often don’t publish when things don’t work), so our study likely highlighted the exceptions more often than the rules.

  “YOU’RE GOING TO die in this role.”

  This assessment came from a new colleague who thought I was in way over my head when I accepted an offer to join the full-time faculty as an assistant professor of medicine at the University of Pennsylvania after graduating from Wharton. I think he meant it idiomatically or must not have known that I had a terminal illness. But part of me had to laugh, privately, at his faux pas. I had important work to push forward and was very much planning not to die in my new role. I would be happy to prove him wrong.

  In my new position, I would be able to focus almost entirely on conducting and coordinating research to cure Castleman disease and solve mysteries of the immune system. And all from the place where this awful and awe-inspiring journey had started. I would create and direct a research program that would include both what we call a wet bench lab—a laboratory set up to work with patient tissues, cell lines, model systems, and other biological material—and a computational lab, focused primarily on big data analytics. In scientific terms, this is translational research: We translate what we learn from in-depth clinical data analyses to guide which lab experiments to perform on patient biospecimens; we translate those findings back to the clinical research arena for further testing; and then, we try to translate it all into new drugs or diagnostic tools for patients.

  In my new faculty role, I also codirected a one-week course to teach fourth-year medical students about precision medicine and, indirectly, how to think outside the box (without needing to nearly die five times first). Precision medicine, or personalized medicine as it’s sometimes called, is a new approach to disease management whereby each patient is treated based on her or his precise genetic makeup and specific disease characteristics, rather than treating everyone with a particular disease in the same way. Using sirolimus, which is typically prescribed to kidney transplant patients, to treat me, an iMCD patient, based on results from studies done on my samples, is an example of precision medicine in action. I’m a walking, talking advertisement for its value.

  I also took on an official role in the Orphan Disease Center, combining everything I had learned from my CDCN commando team to help accelerate rare disease research. And I continued to lead the CDCN as volunteer executive director. I’d been dreaming of doing this kind of work since I was eighteen, when my mom first got sick. It was often thrilling. And it was sometimes horrible.

  My new office would be in the same hospital building where I first became so ill and in which I nearly died. It was…unpleasant initially. I ticked the boxes on a few PTSD symptoms every time I walked through those doors, for sure. But I was determined to replace my memories from weeks of agony with positive memories of making progress against Castleman disease.

  One of the first of these memories came quite suddenly. One day in March 2016, I got multiple emails and phone calls within minutes. There was a newly diagnosed iMCD patient in the ICU: a military veteran in his mid-forties named Gary. As it happened, I’d managed to avoid the ICU as a patient for a couple of years and as a physician-scientist for even longer. First unconsciously, and then quite consciously indeed. I guess I just needed some space from the place. We’d been intimate for a long time and the relationship had been rocky. Off and on; on and off.

  But no more. I needed to see how I could help this patient and then find out if he was interested in joining one of our studies. I got his room number and took the elevator up a couple floors from my office. Gary’s wife was standing against the window when I came in—and something in the view beyond her looked familiar, though I couldn’t pinpoint what it was.

  I was immediately struck by how sick Gary was—filled with fluid, tubes and probes all over his body, a dialysis machine continuously doing the work of his failing kidneys, two units of blood transfusing into his veins, and a ventilator that he had just been weaned off of still in the room—and how much he looked like I did when I was at my sickest. His wife’s eyes radiated pain, and I recognized that too.

  I explained my research and the work of the CDCN. They had heard of it already and were glad to be able to have a direct connection to it. “We are going to beat this disease,” I said.

  The look in their eyes began to change. I could tell that they were also both surprised. They told me that they had expected someone much older, who, according to them, was “detached, ailing, and preferred to be hidden away behind a microscope.” Seeing me walk into the room, looking completely healthy, gave them hope that he could get out of there.

  I told Gary about a study that I was running and how his blood samples could be helpful for better understanding this disease. It’s rare to be able to get patient samples before major treatments have been administered, so these samples would be quite precious. He agreed to provide blood samples for the study—he seemed to be thrilled by the idea that he could be of material assistance. He was unable to lift his hand off the bed because of his full-body weakness, so we placed the necessary paperwork under his hand for a scribbled signature to memorialize his consent.

  “We are going to beat this disease,” I repeated. Gary later told me that the we was important. Just like me, Gary had felt as if iMCD had singled him out and he was on his own. Now he felt like he was part of something bigger than himself. I could relate.

  As I walked out of the room, I saw Ashlee, who had been my own nurse for much of my stay in this same ICU. I hadn’t seen her since. “David, is that you? Wow, you look great. You know that was your room, right?” Now I knew why that view had caught my attention. I don’t remember too much from that first hospitalization, but I had stared out that window dreaming of what could be if I would survive. Here I was right back where it all started.

  A lot had changed since then. It had taken months for me to be diagnosed; Gary was diagnosed within two days of arriving. That didn’t happen by chance. Or by mere hope.

  Six months prior, in a building across the street from Gary’s ICU room, I had chaired a CDCN meeting of the top thirty-four iMCD experts from eight countries on five continents to establish the diagnostic criteria for iM
CD. Amazingly, up to that point there was no agreed-upon checklist for physicians to determine if a patient had iMCD. Nearly every disease had one of these checklists, but not iMCD or any of the other subtypes of Castleman disease. It had taken about two years to aggregate the data and biospecimens from 244 patients, which we used to develop the diagnostic criteria. The meeting went close to how you’d expect a meeting of thirty-four international experts to go. Everyone had an opinion about what the criteria should include. There were a lot of disagreements. Some over substance, others over misinterpretation due to language barriers. But we kept coming back to the data, which helped us to eventually agree on the first-ever diagnostic criteria for iMCD. Our work was subsequently published in the journal Blood.

  More than sixty years had passed since Benjamin Castleman’s first published paper about the disease. Now physicians finally had a checklist to use when considering a diagnosis of iMCD, a map and instructions for how to get to their destination.

  This was a huge win. You can’t treat or save a single patient’s life if you can’t properly diagnose the disease. Another problem with not having diagnostic criteria is that incorrectly diagnosing people when they don’t have Castleman disease sets back research and drug development, because these patients skew the results of studies. As expected, the new criteria have greatly sped up the time to diagnosis for patients and systematized their identification for research.

  And I could see the results of that work right in front of me. Gary’s doctors recommended performing a lymph node biopsy based on the new criteria. The pathologist who reviewed his biopsy was a key contributing author of that very paper. In fact, she and I had reviewed lymph node tissue from more than one hundred iMCD patients as part of the project. So when she looked at Gary’s lymph node that day, she knew immediately that it was iMCD, and she had a checklist of criteria to prove it.

  Most important, Gary’s rapid diagnosis meant that he got a dose of siltuximab—which had been approved by the FDA for iMCD in 2014—right away and slowly improved. There really had been a sea change in treatment since I had first become ill, in 2010.

  As Gary continued to improve, he provided repeated blood samples, and we were able to run experiments in real time. We were surprised by the changes we were observing: His T cells were even more highly activated and out of control than mine had been. The implication was obvious and scary: His was a serious case. I remembered how terrible my symptoms had been, and it seemed like he was suffering even more. But finally, after being hospitalized for two months, he was discharged to a rehab facility, where he would have to learn to walk again. We needed to continue to analyze samples, and I liked visiting with him, so I regularly drove to get vials of blood from him. When I told him that I’d keep the vials of blood in my chest pocket to keep them warm for the drive back to Philadelphia, he said I was just like a mother hen. His comment sparked an idea: Maybe I should just sit on them for the ride back. The plastic tubes were virtually unbreakable. And—think it, do it! (We’ve subsequently discontinued the “mother hen” mode of transportation since we determined that I’d need to sit on every sample we received to ensure identical experimental conditions. It was an easy decision.)

  Gary’s case felt like such a triumph. He was alive because of two major accomplishments that the CDCN, Dr. van Rhee, and I had played major parts in: the diagnostic criteria now being used worldwide to diagnose iMCD and the FDA’s approval of siltuximab. I saw the impact of this work firsthand only because it happened a couple of floors above my office. Though I got lots of emails from physicians and patients, I still wondered about how many thousands of other patients around the world were benefiting from our work that I didn’t know about. It was an awesome feeling. Even more, the data from Gary’s samples would lead to new insights that could save other patients’ lives too.

  But a month later, Castleman disease pulled me back down to reality. Gary relapsed while on siltuximab. Nothing worked. Carpet bombing was commenced of cytotoxic chemotherapies that I was all too familiar with. But he didn’t even respond to those. When his ICU nurse overheard me saying to his wife that there was still hope and that Gary could still pull through, she pulled me aside to say, in fact, there was no way he’d make it through the night and I needed to temper my optimism.

  I hugged Caitlin a little longer than usual and spent more time on the phone with my family that night. I could finally understand how scared and helpless this disease makes those we love. Amazingly, however, the chemo kicked in just in time and Gary began to improve. He eventually walked out of the hospital and has been relapse-free for the last two years. It’s always better not to anthropomorphize illness, especially as a doctor, but I’ve grown to hate the chaotic nature of iMCD as much as anything. Its brutality at least is knowable, and we’ve been able to glean evidence of its inner workings from its aggression. But as it did many times with me, when it seems to arbitrarily “choose” to relent in the face of some treatments but not others—and to storm back unexpectedly—it highlights just how little we know.

  And sometimes I despaired that we could never learn fast enough. Elyse was a twelve-year-old girl from Boston and typical for her age in many ways: quiet and anxious around big groups, but totally comfortable around her family and friends. She loved to bake cakes and cookies and even dreamed of having her own bakery one day. But then she started having unexplained abdominal pain and skin rashes. Frequent ER visits didn’t lead to any answers. Then, just three days after her thirteenth birthday, she told her mom that she was feeling “off,” a feeling that escalated enough to get her admitted to the hospital and then the ICU. When her doctors finally diagnosed Castleman disease, Elyse and her mom went through many of the same things that my dad and I had gone through three years before. Her mom, Kim, googled Castleman disease; the results weren’t helpful. Elyse asked the doctor if she was going to be okay. “Well, not much is known about this disease, but it’s not lymphoma or another type of cancer, so we hope so.” Kim grabbed on to that hope with everything she had. Kim never left Elyse’s side. Elyse spent the next eight months battling Castleman disease, mostly in the ICU, but nothing could stop it. It was relentless.

  Elyse passed away despite months of her physicians’ best attempts to apply the best tools available. It wasn’t that she was at the wrong hospital, that they didn’t have enough time, or that someone else could have done something differently. Nothing more could have been done even based on what we know today. Sadly, Elyse’s story happens all too often. She was truly special, and you can see that in the legacy she has left through her family and friends, but what happened to her is not unique. I look at her picture on the wall in my office every day—she would have turned eighteen this year and would probably have baked her signature tie-dye-frosted cupcakes. Her picture—among those of other patients who have died and those who are still fighting—reminds me that we’ve just scratched the surface with our understanding of Castleman disease.

  Every patient who dies battling Castleman disease and every biospecimen removed during a patient’s battle harbors microscopic clues into the mysteries of this beastly disease, how the immune system works, and how it may be manipulated to treat Castleman disease and potentially other illnesses too. Simply put, the cure for this disease is within each of us. It’s just waiting to be pieced together. Therefore, we collect medical data and samples from deceased patients as a final legacy to try to harness the clues they leave so we can better help future patients.

  It’s not just Elyse’s samples and data that continue to be a lasting legacy in this fight against Castleman disease. Kim now serves on the board of the CDCN, and she leads a motorcycle ride fundraiser every year. The ride memorializes Elyse’s life and raises money to help find treatments and a cure for other young people with Castleman disease. Kim is creating silver linings every day, and the rest of us are in her debt for it.

  THE LEGEND OF the Faustian bargain goes like this:
Faust was a doctor who wasn’t satisfied with what he knew (which was a lot). So he made a deal with the devil: He would gain all of the knowledge in the world, and all the power and pleasure that comes with it, but he would have to give up his soul. It was a pretty good bargain—right until he was dragged down to hell by a bunch of demons come to collect.

  Before I got Castleman disease, I was well on my way to an education and career that promised close to supreme authority. We live in a mostly secular, individualistic age, but can you tell me there’s nothing sacred about the symbols of medicine? The white coat and the staff of Asclepius, the waiting room and the inner chambers, the pronouncements, the scribbled commandments. I was ready to join that priestly class and tap into the knowledge of the ages. I would be an instrument of life and death.

  And then my own life got very tenuous, almost hell-like. So I did what I was supposed to do: I appealed to the authority and supremacy of medicine. I got the wrong answer back. I appealed again. I got the wrong answer back. I didn’t die, but that was providence.