We soon learned about a physician at Duke with “some experience,” so I was moved to the hematology/oncology ward at Duke. The sign AT DUKE, THERE IS HOPE didn’t provide the same comfort that it had seven years before, when I saw it hanging in the waiting room while my mom was undergoing brain surgery. Every day, teams of five to eight physicians and doctors in training would come into the room to discuss my case and observe me. My new team agreed that the corticosteroids weren’t working and that the next step would be treatment with a chemotherapy agent. They were also candid with us about how little experience they had—the physician we’d heard of with “some experience” had actually treated only “a few” Castleman disease patients and none with my subtype. I felt like an experiment, and my family quickly grew frustrated because nothing seemed to change, even after the chemotherapy was administered. I just got worse. My doctors stayed the course. There wasn’t anything else they knew to do.
They did want to make sure I was at least getting nutrition. I had been vomiting any time I tried to eat, so the team decided to place a feeding tube through my nose down into my stomach to pump in liquid nutrition. Every time the tube got blocked—a not infrequent occurrence—they pulled it out and placed a new one. I’m not sure which was worse. Both directions were pretty terrible. I had done this frequently as a medical student without ever realizing the pain or disgusting tastes that accompany it. I had an insight: Maybe all of us doctors should have some of these procedures done on us a couple times during medical school so we can understand what they’re like.
At Duke, I got worse, and worse, and worse, and then I fell off a cliff. I went through MSOF again, and again I felt the whole-body pain of simultaneous organ collapse. I lay in my hospital bed, parts of my body filling with fluid, my organs shutting down, my consciousness flickering on and off like an old television set. Once again my memories grew seams and slipped apart from one another. “You can endure anything for a day,” I said, to Gena, I think.
I was at the precipice of death. The simultaneous failures of my kidneys and liver were causing toxins to accumulate in my blood in sufficient concentrations to keep me unconscious and to forestall whole days and weeks of memories from ever forming. Sometimes I wish the memory blankness was more comprehensive. Some memories serve little purpose if you go on living. For instance, there’s this: I remember when my family summoned the priest. He didn’t come for a social visit. He was there to administer last rites at my hospital bed. I don’t recall the laying of hands, or the oil; I do remember it was dark and I was scared to die.
And for a second time, Caitlin came to see me, this time flying down to North Carolina. Though I’d recently had the epiphany that I would prioritize the people I loved, I was still not ready for her to see me. One of the only coherent sentences I spoke over a two-week period was to tell my sisters that I didn’t want Caitlin to visit. I didn’t want her to remember me like this. Lisa texted Caitlin to let her know that now wasn’t a good time without letting on that I was getting worse by the day and approaching death’s door. Caitlin filled her time in Raleigh by visiting friends as she waited for news about a good time to come to the hospital—totally unaware of just how sick I was or that I could die at any moment—before she flew back to New York. She left heartbroken again. I regret to this day that for a second time I turned her away.
I’d been anointed and blessed and sent on my way to die. Then the chemo kicked in. And the drugs kept me tethered to where I was, at least for the time being. It could not have happened any later. It had taken eleven weeks from my first hospitalization to be diagnosed with idiopathic multicentric Castleman disease and receive my first chemotherapy treatment. If it had taken eleven weeks and one day, I probably wouldn’t have survived. I barely did anyway.
I had now experienced twice in three months a rough equivalent of dying. It was likely I would again, but I knew what happened to your odds the longer you played Russian roulette. So I didn’t celebrate when I was awake and cognizant again. I could not accept living like that. I couldn’t accept living in between almost dying, or what that was doing to my family, or what it was making me do to Caitlin. I was done not knowing. I was done hoping that my doctors would get lucky. I was done making my family prepare to let me die. I was done turning the love of my life away so she wouldn’t have to remember me as a confused, bloated ghoul. From that point on, I was going to take control of my life as much as my body would allow me. I would face up to idiopathic multicentric Castleman disease, or iMCD, take it on like an adversary. My tactics would change over time, but the mission remained clear.
For the time being, I put on a happy face as I slowly recovered in the hospital. And I was happy. I was grateful to be alive and too focused on my next steps to waste any time—even a moment—on self-pity or sadness. It was late November now, so my dad cooked Thanksgiving dinner and brought it to my bedside. I had had my feeding tube removed, so my sisters, dad, several family friends, and I ate a feast together. It was my first real meal in weeks, and I got to feel normal for an afternoon. After the meal my sisters and I watched Borat and Saturday Night Live clips on YouTube and laughed and talked about absolutely nothing important.
The next morning, I got to work from my hospital room.
UPTODATE IS THE top online resource that doctors use to collect and access all the latest knowledge on any number of subjects, including diseases and treatments. It’s trustworthy because it’s made by doctors and for doctors. And it’s kept up to date. Hence the name. That’s the idea, at least. I had certainly used it all the time back in medical school.
The entry on Castleman disease said that there had been only four reported cases of my subtype (idiopathic multicentric)—ever—and in only one of those cases was the patient still alive. I was shocked. One of my resident doctors at Duke and I incorrectly assumed this meant I was the fifth case ever. It was hard to imagine that any effective treatment would have been developed for such a small community. Efforts to develop a cure for a disease with such a small incidence could even be considered by some to be an irresponsible use of limited research resources, though I would not have complained. With the kind of desperation that a shipwreck survivor might lash together a raft, we did some frantic research in the hope that there were more of us—idiopathic multicentric Castleman disease patients—out there. It turned out that a single clinical trial had recently enrolled over seventy-five patients with the idiopathic multicentric subtype of Castleman disease. And a quick search of PubMed revealed that there were actually hundreds of published case reports of this subtype. The UpToDate page was, in fact, not up to date.
I am now the author of the UpToDate page on Castleman disease, so I can tell you that it is up to date. We now know that there are an estimated six to seven thousand individuals diagnosed with Castleman disease each year in the United States, which makes this disease about as common as ALS. And about one thousand of those patients are diagnosed with my subtype, iMCD, each year. With an average survival of about seven years for iMCD patients, there are an estimated seven thousand patients alive in the United States. Not one.
But at the time, it was enough to know that there were clinical trials going on. That meant that the disease was rare but not irrelevant. Which meant that I needed to get out of the hematology ward at Duke and find myself an expert. There was bound to be one. I was willing to travel anywhere. These kinds of diseases can often attract the brightest minds, who are drawn to the pursuit of complex and under-studied problems. I would soon dream of joining one of those teams.
Sure enough, after a little digging online, Gena and I found who we were looking for: one Dr. Frits van Rhee, a professor with an MD, a PhD, and distinguished fellowships from a number of international institutions, who received significant research funding from the NIH (the top badge of honor in the research community) to study multiple myeloma, and held a reputation as the foremost expert on Castleman disease anyone could f
ind. He was now down at the University of Arkansas for Medical Sciences.
I emailed Dr. van Rhee to ask if he’d see me in Little Rock once I was healthy enough to be discharged from Duke. I was happy to be going right to the top, but the process brought with it an undeniably grave significance. It was like appealing to the Supreme Court. He was the undisputed authority on what was killing me. I dared not think about the possibility that he didn’t have all the answers.
Dr. van Rhee wrote back right away and said that he’d be happy to see me. I decided to interpret his punctuality as a good omen. Anyone that busy but that prompt must have an extra gear.
My appointment with Dr. van Rhee would be on December 26. I’d need to get a PET scan, bone marrow biopsy, and blood work. I’d been at Duke for a month, I’d received last rites and chemotherapy. I wasn’t feeling at all well, and my blood work looked terrible. I had just three weeks to build up my strength before traveling to Little Rock and to learn as much as I could about Castleman disease. My story no longer had a fable-like quality of mysterious misery. I was no longer in a heroic saga, being ground down by some unknowable force. In that sense, my story had turned the corner. It was a detective story now, and there was a ticking time bomb buried deep within my body that needed to be defused.
But first I needed some new clothes after discharge. Due to all of the excess fluid, my belly was bigger than my seven-months-pregnant sister’s. Nothing I’d owned before this crisis would fit. I wasn’t about to just wear hospital gowns everywhere. I still had some pride. So my sister and I purchased a number of logo-less XXXL outfits for me to wear. I looked like a mafia don in prison clothes.
I also needed to mend some fences, if I could. The first person I called when I got to my dad’s house was Caitlin. Again, I tried to explain why I had turned her away. Again, she accepted my apology, but again, I’d later learn, she thought it had been my sisters protecting me. There were many more emotions and thoughts bubbling below the surface that were not being said—I think we were both just so exhausted from the ups and downs of the last few months. She did reveal more about what it had been like for her during those visits when she couldn’t see me. I could feel us getting closer when we spoke. The tension between us faded away, and that old feeling of pure happiness I remembered so well from when we dated took over. But I tried not to think too far ahead about our relationship. Who knew what tomorrow would bring with my awful disease? I tried to just savor it for what it was: a phone call with the woman I loved. To be awake for it.
IN 1954 A pathologist from Massachusetts first observed a pattern of microscopic irregularities in lymph nodes from about ten patients suffering from similar symptoms. His name was Benjamin Castleman, and this complex disease was named in his honor. But that’s where the simplicity of the name ends.
The first clue to the complication at the heart of my disease is how it is named: the i of iMCD refers to it being “idiopathic.” That just means more or less that we don’t know what causes it.
As far as we knew when I was diagnosed, iMCD came down to cytokines, those immune cell secretions that do so much to trigger and coordinate the initiatives of the whole system. Well, one cytokine in particular: interleukin-6 or IL-6. Everyone makes and secretes IL-6; you’re probably secreting some right now. It helps us to fight off infections and cancer. But, in iMCD, IL-6 production goes into overdrive and doesn’t stop—friendly fire run amok—causing flu-like symptoms and life-threatening disturbances to the liver, kidneys, heart, lungs, and bone marrow. Why was it overproduced to start? That’s one of the things we didn’t know. Perhaps it was triggered by a particularly obnoxious foreign agent like a virus, or perhaps the emergence of cancer cells set it off. Or perhaps the trigger was endogenous: a mutation in the genetic code—either programmed from birth or acquired during the course of life—of an immune cell. No one knew. So, we didn’t even know if iMCD should be called an autoimmune disease, a cancer, or a virally driven disease. It defied classification, seeming to act like a cross between the cancer lymphoma and the autoimmune disease lupus and occupying a no-man’s-land between the two.
I also learned that all cases of Castleman disease are not alike and the subtype—as in cancer—has important implications. After “idiopathic,” my subtype is called “multicentric Castleman disease,” because there are multiple regions of enlarged lymph nodes that have a microscopic appearance similar to what Dr. Castleman first described. The lymph nodes are the home bases for immune cells to get their marching orders: whom to fight, what to do, and how to avoid damaging healthy cells along the way. This extremely complex process, which is occurring all day, every day for every one of us, requires that various immune cells go to precise locations in the lymph node to give and receive the correct messages. In Castleman disease, the lymph nodes have blood vessels abnormally traversing everywhere and immune cells that are packed in an abnormal distribution and, thus, at risk of receiving incorrect messages that send them out into the body in attack mode.
There are three other forms of Castleman disease that share this strange appearance under the microscope. One is unicentric Castleman disease (UCD), which involves milder symptoms than iMCD and a single confined region of enlarged lymph nodes; surgical excision of the nodes is often curative. Another is POEMS-associated MCD, where a small number of cancerous cells cause clinical and laboratory abnormalities just like in iMCD. Eliminating those cancerous cells abrogates the MCD. The last is human herpesvirus 8 (HHV-8)–associated MCD, which also involves a syndrome almost identical to iMCD, but it is caused by uncontrolled infection with the HHV-8 virus. Research is quite advanced for this subtype. Before the cause and key immune cell types had been worked out, HHV-8-associated MCD had an even worse prognosis than iMCD. Now that the cause and mechanisms of HHV-8-associated MCD have been untangled, effective treatments have led to significant improvements in long-term survival. The take-home message for me: My form of the disease wasn’t invincible if we could just uncover what was underlying it.
But even buoyed by this insight, I found the data on survival tough to read. As with multiple system organ failure, what I had theoretically understood in medical school about survival data now took on a new and personal meaning. About 35 percent of iMCD patients die within five years of diagnosis. This is identical to the average survival rate when you combine all cancers together and worse than lymphoma, bladder cancer, breast cancer, multiple sclerosis, and prostate cancer. And about 60 percent of iMCD patients die within ten years of diagnosis. Unlike many of those other terrible diseases, iMCD can be diagnosed at any age, so children and young adults are also often in this battle against the odds.
I scanned papers multiple times to find any clues about the cause, the immune cell types, or the cellular communication lines primarily involved in my disease. Five and a half decades had passed since Dr. Castleman reported the first case, but the cause, key cell types, and key cellular communication lines were all unknown; the only breakthrough was the finding that IL-6 production is in overdrive, which came from a few studies of a few iMCD patients. But an issue in medicine is that you can see only what you look for. Of the hundreds of known cytokines, IL-6 was one of the few that had ever been measured in iMCD, so there could have been other important cytokines that just hadn’t been measured. Nevertheless, a drug called tocilizumab, which blocks the receptor for IL-6, was approved for the treatment of iMCD in Japan based on its efficacy in a portion of patients. But it never met the thresholds for efficacy, safety, and rigorous study design demanded by the FDA for approval for iMCD treatment in the United States. However, it was eventually approved for the treatment of rheumatoid arthritis in the United States, and thus available if my doctors at Duke had wanted to try it and if they could have gotten insurance approval. But they hadn’t known about it.
And at this early stage in my own Castleman disease education and research, I didn’t know about the use of tocilizumab for iMCD in Japan eith
er. All I knew was that Castleman disease was an amazingly complex and indisputably fascinating disease. Separate from the misery it inflicted, the disease—as well as we knew it—was a marvel, and the ability of my immune system to attack my organs was awesome, in a way.
Right around the same time that I was trying to learn as much as I could about iMCD to help myself, researchers were leveraging some of what had been learned about cytokines in iMCD to fight cancer. This is one of the seminal achievements of medicine: our ability to learn from threats to our health, and our shamelessness in copying weapons from our enemies in order to fire back.
For cancer, the hope and plan is to carefully direct the immune system’s firepower at the cancer itself (and the cancer only). Of course there are risks. Unleashing these powerful weapons and pointing them in the “wrong” direction means that patients often get sicker before they get better. Over the last two decades, colleagues of mine at the University of Pennsylvania and elsewhere have figured out ways to reprogram specialized killer immune cells, called T cells, to target and kill cancer cells that are expressing certain molecules on their surface. They do this by removing T cells from the patient and actually harnessing components of the HIV virus to insert genetic material into these cells. Once the cells, called chimeric antigen receptor or CAR T cells, are reinfused, they go on a killing spree, releasing cytokines and activating the immune system to destroy cancer cells displaying specific cellular markers. Not surprisingly, these patients often get very sick, very quickly. In fact, one of the first patients ever treated with CAR T cells was dying in the ICU with symptoms, organ dysfunction, and immune hyperactivation almost identical to iMCD. Her IL-6 levels were off the charts. The doctors decided to try tocilizumab, the IL-6 receptor-blocking drug originally developed for the treatment of iMCD in Japan.
Chasing My Cure Page 8
