Chasing My Cure Read online

  My blood platelet level was lower than 7,000. That’s even lower than it was when Francisco’s stethoscope slammed into my forehead. It’s less than one-twentieth of the lower level you should have of these tiny cells that circulate to prevent bleeding throughout the body. And so the risk of a fatal, spontaneous brain bleed was constant. The only warning would be an intense headache, and then I’d be gone. Castleman disease would finally have won. My father tried to keep my spirits up by telling jokes. I asked him to stop. I could easily have died if I laughed too hard.

  My sisters, my dad, Caitlin, and my mother-in-law, Patty, stood by the door, waiting, hoping for matched platelets to arrive every day so that I could get a transfusion. Fortunately, they did arrive, every day. But even then, we had another hurdle to overcome. We had to blunt my fevers before the platelets could be transfused. Things got primitive. The nurses and my family spent hours cooling my body with ice packs every night.

  Strangely, my kidney function didn’t deteriorate as much as it had during previous relapses. That meant that as my other organs failed and fever burned through my body, my blood was still filtering somewhat, and my thoughts could remain relatively clear. It was a mixed blessing. There were times when I might have given up some of my cognition, frankly. Thoughts can’t do much except exacerbate pain, and it was no consolation that I could still piece together complex thoughts like Will I make it long enough to marry Caitlin?

  The save-the-date postcards for our wedding were put aside.

  Even with all of the transfusions, my platelets remained critically low. The doctor on the hematology unit encouraged me to put together a makeshift will. This recommendation shook all of us. As soon as the doctor left the room and I looked at Caitlin, my mind flashed back to the wife of the first patient I encountered in medical school, on my first day of the psychiatry consult service. I remembered the tears that had dripped down her face, untouched, and eventually made their way in between her hands, where she’d gathered some blanket. And now Caitlin’s tears followed a similar path. I had swollen cheeks as a side effect of my medications just like that woman’s husband. And soon, I too would likely not have the capacity to make medical decisions for myself. Since Caitlin and I were not married, the nurse witnessing the will would not allow Caitlin to help with it, so my sister Gena offered to write down my last wishes on a blank piece of printer paper. Distraught about my deteriorating health and the implications of my doctor’s suggestion, Caitlin and her mom walked out of the room in tears.

  I was actually glad that Caitlin had to leave the room, because I had a secret and I needed Gena to make note of it: Right before my second round of combination chemotherapy, I had banked a sperm sample, knowing that my counts would plummet with each subsequent round. I had hoped to use it to have children with Caitlin that we could raise together. I was now acutely aware that my dreams for the future had collapsed. I told Gena about the sample, where it was being stored, and gave her power of attorney over it. I explained to Gena that I hadn’t told Caitlin about the sample, because I didn’t want her to feel any pressure to use it to have a child with me by in vitro fertilization after I was gone.

  I know that sounds crazy, but Caitlin knew how much I had dreamed of having a family with her, and I didn’t want her to make any decisions because I was sick. Rather, I wanted Gena to know about this sample, just in case Caitlin ever asked her about it. And if she did ask, I wanted Gena to make it available to her. But of course, this wasn’t what I really wanted at all. Not by a long shot. What I really wanted was to have a child with Caitlin that we could raise together. Matters like whether I wanted CPR to be performed on me, how I felt about life support, and whom I wanted to receive my limited assets somehow felt much less significant. My sister wrote down everything. Then, the nurse and I signed the paper. As soon as I signed it, my sluggish mind shifted back to the looming possibility of a splitting headache that would signal a fatal brain bleed had begun. I quietly hoped it wouldn’t come.

  The next morning, it arrived. When I told the nurse and doctor about my headache, they immediately knew what it meant. Soon, I was being rushed down the hall to the CT scanner and the fluorescent ceiling lights flashed before my eyes. I knew this was it. My thoughts fixated on Caitlin and my family. Tears dripped onto my gown. They had tilted my bed all the way upright, so that gravity could help with blood return if there was a brain bleed, just as we had done with my first stroke patient in medical school, who had died in front of me in a similar way. As I returned to thinking about Caitlin and my family and crying, I realized that my ruminations were going on longer than I had expected they would. The scan was done. I was back in my room. I wasn’t deteriorating the way I had expected. The scan revealed no signs of a brain bleed, just evidence of a nasty sinus infection, which was likely causing the headache. It was a false alarm.

  Once again, the cytotoxic chemotherapy did its vicious job, just in time. After being taken to hell and back, I recovered. I was grateful, but I knew it wasn’t a permanent solution—if such a thing even existed for me. I was now even closer to the lifetime max dose of these drugs. There are only so many bombs you can drop on one man, during one lifetime; my liver cancer was possibly born of these health-annihilating treatments. We also knew that the chemo provided only a temporary reprieve from the Castleman disease. I couldn’t continue this cycle of remissions and then deadly relapses as soon as my immune system strengthened enough to strike again. I was playing Russian roulette with each relapse and needed to figure out a new approach to prevent them.

  My lab tests showed the first signs of improvement on New Year’s Eve. We all drank sparkling cider on the three-year anniversary of my being mistaken for my dad’s pregnant wife. We even took a walk around the floor to commemorate it. We were asleep by 9:00 P.M. I wanted my life back.

  THERE’S NO MORE stable cliché in medical fiction than the epiphany.

  For decades TV writers especially have seemed transfixed by this magical Archimedean moment: the doctor, squinting in concentration (or rubbing his eyes), leaning back in his chair. Then: His head cocks toward something, a memory made visible by a picture on the wall—a connection!—a realization!—and then a scramble. He clears his desk and begins to scribble. Eureka!

  But there’s a hard truth about epiphanies: They don’t materialize out of thin air. They are not magical moments when your IQ ratchets up ten points. They come from what you’ve already done, your persistent hard work, and usually after years of it. Just as football had increased my pain tolerance and muscle mass, and these things were key in enduring the early days of my illness (but in ways I could never have imagined), epiphanies come to us in surprising ways, bearing the fruits of labors we’ve already done.

  I desperately needed one.

  * * *

  —

  Once my mind cleared from the last round of chemo, disappointment rushed in to fill in the emptiness.

  It wasn’t lymphoma; it was worse.

  Siltuximab hadn’t worked.

  It wasn’t the liver cancer.

  Weekly chemo infusions to prevent a relapse hadn’t worked.

  Cyclosporine hadn’t worked.

  Prayer hadn’t stopped it.

  Hope hadn’t prevented it.

  And though I’d thought I had a breakthrough—an epiphany—with my new theory of this disease, it still hadn’t led to an effective treatment.

  I had given it my best shot and Castleman disease won the battle again. The only thing that was keeping me alive was also killing me—the repeated rounds of chemo couldn’t last forever. The rhythm of my health was no longer tenable. I no longer wanted to limp toward health, and life.

  My disappointment didn’t last long. I didn’t have time for that. While I was still recovering in my hospital room, my sister Gena and I made a list of all the institutions that had my medical records and leftover biospecimens from the last thr
ee and a half years. Then she contacted each of the institutions to have those precious data points and specimens sent to Philadelphia. For too long I’d been relying on a disparate network of institutions to test my blood and sift through my data for anything that might be a clue. It was time to centralize and apply my hyperfocus. I had been hospitalized for the start of my second semester of business school and decided to take the remainder of the semester off. I didn’t want to pretend things were back to normal. Until I had a way to reliably fight back, nothing would be normal again.

  After being discharged, I went home to Philadelphia and made my headquarters there. I had two interconnected questions on my mind: Could Caitlin and I realistically keep our May 24, 2014, wedding date, and what treatment should I start on to prevent a relapse? The former was very much dependent on the latter.

  I spent weeks working from 6:00 A.M. to midnight, poring through thousands of pages of medical records, CDCN research data, and medical literature on Castleman disease and the immune system. Caitlin was my source of strength and inspiration. After moving to Philadelphia, she had found a sales job in the fashion industry, and fortunately for me, she worked from home. So we both worked from our one-bedroom apartment on days that I wasn’t in the lab. We didn’t talk very much, but I loved having her near me. Every few hours, I pulled myself out of the matrix to spend time with her. She reminded me to eat and also why I was doing all this: I needed to identify a new drug so that we could get married and have a family together.

  I was still stuck on the idea that the immune system was the real site and source of the ultimate target. We knew my immune system was going out of control during relapses—it seemed like the whole system, the entire intricate network of billions of cells, got activated each time, but among all those cells, we still didn’t know which type was responsible for initiating or propagating iMCD. Or if not a specific cell type, was there a shared communication line that was turned on across various cell types? Or a single molecule, like IL-6, responsible for initiating or driving the iMCD? There would be no treatment without a target to attack.

  So the task before me yet again was to find a target. I started with the data I had used at the beginning of my recent relapse. I added the data that were generated from that flare alongside a very important additional data set—those immunological tests that I had requested monthly for the year leading up to my recent relapse. We knew that the activation levels of various components of my immune system were off the charts at the peak of my relapses’ fury. But could we find the spark that ignited the fire if we looked at these levels over time? I was hoping to spot any hint of a pattern, any possible entry point for a new kind of treatment that could prevent another flare. I needed to find a weakness in the defenses of the beast, its Achilles’ heel. That meant looking for a pattern in the thousands and thousands of pages of test results, medical journal articles, and reports we’d collected. Something that emerged from the noise, as yet unaccounted for.

  It was in a series of test results that I found something significant (at least to my hyperfocused mind). I saw that two things happened in my blood just before I experienced my familiar symptoms. Actually, months before the symptoms materialized. The data indicated that well before I experienced any of the fatigue and before any of the organ trouble, my T cells activated in a big way, preparing for a fight even though there was no apparent threat. We’d previously observed the increased T cell activation during flares and even targeted them the last go-round, but the improvement was only temporary. That they were ramping up before my symptoms began was very interesting. Simultaneously, levels of a protein called vascular endothelial growth factor, or VEGF, also began to rise in my blood. This protein is instrumental in causing blood vessels to grow, something that didn’t seem immediately germane. Perhaps it was just another piece of biological noise and not a true signal—lots of stuff happens in a deteriorating body. But…the numbers were striking. The levels of both activated T cells and VEGF were about ten times above what were considered to be the upper limits of the normal range.

  But at this point we had looked at the levels of only thirteen immunological factors. Remember: You can see only what you look for in medicine. Laboratory tests don’t answer the question What is wrong? Laboratory tests answer the question What is the level of x? or Is y present? Then, it’s the job of the physician or researcher to piece these individual data points together to determine “what is wrong.” What if there were other key factors that we had missed because we weren’t measuring them?

  Those stored blood samples would come in handy. I measured the levels of 315 molecules—most of which were involved in the immune system—in those samples. Again, VEGF and the marker of T cell activation were very elevated, both emerging in the top 5 percent of the most elevated proteins.

  Though I had already considered T cells as a potential target during my recent relapse, finding signals for T cell activation before and during relapse in two separate data sets strengthened my conviction. The activation of the T cells also supported my suspicion that immune system hyperactivation was at the root of my iMCD. Perhaps the T cells were involved in the mechanism through which the whole shebang started and spread throughout my body. They certainly had access to all parts of it. But suppression of T cell activation with cyclosporine hadn’t made a major difference for me with episode five. Maybe my T cells needed to be suppressed in a different way or something else needed to be hit too.

  What about VEGF? I knew quite a bit about this protein because of its crucial role in increasing blood vessels and blood supply for cancers. Decades of research had established the following: Blood vessel growth orchestrated by VEGF is essential to meet the blood supply needs of cancerous tumors. Could a similar line be present in iMCD?

  I began to piece together a plausible and utterly novel linkage between my symptoms, iMCD, and what I was seeing in the data I’d gathered. And it all started with those irritating and nasty things that the doctors had been imploring me to ignore for years. Those pesky blood moles, which grew when I was sick and shrank when I was well. Vascular endothelial growth factor was likely the signal causing them to grow. A representation on my skin of what was going on throughout my body: uncontrolled blood vessel growth.

  In hindsight, the VEGF-iMCD connection had showed its hand early, but none of us had recognized it. It had been quietly revealing itself for years. Missed signs began to pile up in my memory: an internationally renowned hematopathologist, Dr. Elaine Jaffe, saying to me once that my lymph nodes were some of the most blood vessel–rich nodes she’d ever seen; an ophthalmology appointment I had as a teenager when I was told that I had more blood vessels in my retinas than my doctor had ever seen; a benign polyp in my colon, identified at the beginning of medical school, that was engorged with blood vessels. This went way back. Even earlier than the blood moles, earlier than the liver cancer, earlier than everything. It also quickly became clear that VEGF could easily have contributed to the fluid that accumulated all over my body during each episode by opening up channels in blood vessels for fluid to pour out. Many of my symptoms were finally pointing back toward a common source.

  The best thing about the emerging VEGF connection was that a drug already existed to block it specifically. This wouldn’t be a shotgun fired in the dark; it would finally be a sniper shot. Blockers of VEGF were developed to treat cancer by shutting off the blood vessel growth the tumors needed, adding months to survival for patients with some of the worst cancers, like the form of brain cancer that my mom had (unfortunately, the VEGF blocker trial began enrollment just after her death). Yes, the possible adverse effects of the VEGF blocker were major, like uncontrolled bleeding and strokes, but…so were chemotherapy’s. Could this drug that was not developed enough in 2003 to help my mom end up helping me?

  Let me back up. The immune system works as a mind-bogglingly complex web of communication lines within cells and between cells through wh
ich cells speak to one another, keeping one another in a careful balance by indicating when each should come online, and when it should switch off. The complexity is fine-tuned—and when something goes wrong in one place, it can cascade, and the whole thing can fall apart. Quickly.

  Many of the pieces of hardware that make up the cells composing the human body have been studied, named, categorized, and tested. That’s not to say we know everything there is to know—not by a long shot—but we do have a good idea about how some things work normally and about how they work in disease states. Like so much else, a lot of this comes down to proteins.

  Basically, every cell is a machine. Think about a computer. It comes programmed with a series of codes for it to perform a variety of functions. Every time the computer performs a function, such as calculating a math problem or making a sound, it relies on the series of codes that it was programmed with to execute the command. Similarly, the genetic code, which is a long sequence of about 3 billion nucleic acids that code for approximately twenty thousand different genes, is the instruction manual for making each protein that the cell could ever need to perform its functions. One marvel is how it all fits inside each microscopic cell. The DNA sequence in every single cell would stretch six feet long if fully unraveled, but it is wound up so tight into chromosomes that it fits into a space just 0.0002 inches across. And if the DNA sequences in all of just your cells were strung together, they would be about twice the diameter of the solar system.

  The other marvel is how all of these individual machines with identical blueprints begin to differentiate, integrate and share information, and work together so seamlessly. Based on their particular cell types and demands on them at any given moment, cells use their genetic code to make specific proteins, which then perform the specific functions needed at that moment. Those functions may be to catalyze another protein to do something else, bind to another protein, or activate yet another. Biology is amazingly tangible, stepwise, and in no way magical. Think about your computer: It can’t do anything that it doesn’t have the software for or that it wasn’t programmed to do.