by Azra Raza
Around that time, my colleague, fellow oncologist Siddhartha Mukherjee, and I were planning a fund-raiser for our laboratory research. With shrinking governmental support and increasing costs of cutting-edge technology, we desperately needed every extra dollar we could raise for our research program. Hugh Jackman, the great actor (of Wolverine fame), and his beautiful wife, Deborra-Lee, generously offered their home for the event, and a lineup from Who’s Who was coming. Nobody wants to hear long, boring speeches at such events, yet we somehow needed to convey the gravity and urgency of the occasion. As we chatted one morning in clinic, I mentioned the fund-raiser to Kitty.
She exclaimed, “I worship Hugh Jackman! Wouldn’t I love to be a fly on the wall at this function.”
A light bulb blazed on in my head, and I asked her to be the featured speaker on the spot. At first, she demurred. She had never spoken in public before, let alone in front of so many famous people. I tried to reassure her. All she had to do was read the gorgeous note she had brought me. She finally agreed.
She arrived looking lovely on that evening in an off-white linen frock with her hair freshly styled, a string of pearls elegantly encircling her long, tanned neck. The quiet dignity she exuded that evening was captivating. We shared a glass of Prosecco, and she became engrossed in spotting the VIPs she could recognize. Standing around the cavernous Jackman living room was the top leadership of Columbia University, along with Wendy and Rupert Murdoch, Ivanka Trump, Donna Karan, and many other luminaries. Kitty C. did not show an iota of nervousness. She was deeply compelling in her honesty and sincerity. Her poignant story, a success story, told with heartfelt appeal to fund our program, was duly rewarded. We raised over a million dollars that evening. Money dedicated to cancer research. She was ecstatic. She posed for pictures with the Jackmans and sent them around to friends and family, reporting their delight during subsequent clinic visits. We were not just friends now, we were partners, sharing a passion to raise awareness and support for cancer research.
She remained in remission, taking Revlimid, seeing me once a month now instead of once a week. During these visits, we mostly talked about less pressing issues like how best to handle the diarrhea, a well-known side effect of the drug that came on with ferocious urgency, making her nervous about going out, reluctant to take longish subway rides across Manhattan. She tried many remedies over the next few months and eventually evolved a regimen combining Lomotil and altered timing of taking Revlimid to suit her individual needs. She found a modicum of relief. The couple of years that followed were remarkable in Kitty’s enjoyment of the city; of her beloved sister and son, her friends; of her trips to see her brother, and a long-anticipated visit to China. Through it all, we met regularly, talking about everything under the sun, from Kafka to Stendhal, from the electrolyte imbalance and weight loss the diarrhea brought on, to her newfound love for ice cream and cookies. We recommended movies to each other, exchanged books and magazines, reviewed plays we had seen, trashed politicians we did not approve of, debated how to handle our adult children, and in particular, celebrated her marvelous response.
THE LOWER-RISK TYPE of MDS, as a disease, does not progress in a linear manner but rather in fits and starts. I call it punctuated equilibrium, after Stephen Jay Gould’s description of the process of evolution. Periods of stability are punctuated by a crisis, likely a genetic event leading to a new disease manifestation, followed by relative stability at the new normal. The stable period, during which a homeostasis of sorts is reached between the marrow’s normal and abnormal cells, can last anywhere from months to years or even decades. During this state of relative quiescence, blood counts tend to remain unchanged. Then a subsequent event, probably another mutation, leads to the expansion of another clone with further deterioration in blood counts. Once again, a period of stability follows. And so on. Thus, lower-risk MDS tends to progress in more or less a stepwise fashion rather than following a pattern of gradual worsening.
The general rule is of course toward worsening blood counts, but applying it to patients is not always as neat. Occasionally, I have witnessed spontaneous intervals of improvements as well. The natural history of MDS can present with unexpected twists in individual cases.
For Curt Worden, another MDS patient, the question was whether the drug Revlimid that had produced a complete response could be stopped. In 2018, twenty years after his diagnosis in 1998, he reflected on what brought him to that point.
For me it came as a slow evolving surprise, seemingly out of nowhere. I realized there was something just not right—I was tired, and it was difficult to be active without shortness of breath. My skin was pale, colorless and sickly looking. I had never felt this way before. I was at the apex of my career, engaged as a news and documentary cameraman, travelling extensively, covering wars, conflicts and various assignments throughout the world. It was a physical job and now these symptoms created a significant obstacle to engaging my life’s work. I distinctly remember working one day in Mexico City at a high elevation. To get the shots needed I had to climb a hill for the best view. I barely made it to the top and was exhausted and shaken from my inability to catch my breath. This was now very serious.
His case was indeed very serious. His hemoglobin had fallen to only 6.6 g, less than half of the normal value, and he was being transfused with three units of blood every three to four weeks. Blood transfusions are given most commonly in acute settings of trauma, gastrointestinal bleeding, during surgical procedures, and in cases of hemolysis. Although normal ranges of hemoglobin are between 12.5 and 15 g, getting a level past 8 g provides instant relief, and studies have shown that raising the hemoglobin to higher than 10 g provides no additional benefit than a level of 8 g. But the benefit is only short term, which explains the chronic, long-term transfusion dependency of individuals with congenital anemias like sickle-cell disease or thalassemia, or patients with bone marrow failure syndromes like aplastic anemia and MDS. Blood transfusions given in this setting improve the physical condition, but only transiently. Within days of experiencing relief, the symptoms creep back as the donor’s blood cells start dying off in the recipient, until the low point of discomfort and weakness prompts the next transfusion. Any stabilization of hemoglobin, even at lower levels, is a relief compared to this repetitive cycle, a jagged edge of ups and downs, improvement and deterioration coming with the precision of cardiac systole and diastole. Imagine the chaotic thunder of Mr. Worden’s normal daily life spent on war fronts, dashing between enemy lines, dodging bullets, observing, recording, writing, filming stories of mayhem and massacre. The abrupt onset of anemia sapped his energy, muddled perceptive acuity, left him breathless and weak, unable to meet the demands of his high-pressure job.
Upon returning home, I went to my Internist and after a blood test was told that my Hemoglobin was 6.6 and I would need a blood transfusion. No diagnosis was available to me at that time—my age was 48, 20 years ago in 1998. Now, I found myself facing a very serious medical issue. I continued to have blood transfusions, taking in 3 units every 3 to 4 weeks. As this went on I still did not have a diagnosis, and I began receiving various treatments such as Aranesp with no valuable results. But one thing was clear, my Ferritin (Iron) levels were climbing at a significant rate and had to be reduced. I continued to have chronic fatigue and to keep the iron levels in check I began chelating by injecting desferrioxamine subcutaneously, using a portable battery-operated infusion pump that was on my nightstand for 8 hours every night pumping fluid into my body that would bond with the iron and flush it from my system through urination. I was buying time.
Mr. Worden first came to me in 2005. I diagnosed him with MDS and asked if he would allow me to store a bone marrow sample in the tissue bank my lab maintained. He agreed, eager to participate in medical research. At the same time, I wanted to start him on Revlimid. He didn’t have the del5q abnormality, but I was preparing to publish a large clinical trial in which a quarter of the patients who lacked del5q nevertheless became t
ransfusion independent on Revlimid within three months. “I was ready to try anything to get out from under the cycle of transfusions and chelation,” he wrote. In 2006, he started on a daily 10 mg dose of Revlimid. Within a few months, he was free of transfusions, although he needed the chelation therapy a bit longer.
Remarkably, I was able to continue with my career and the physical demand it imposed on my body. I was strong again… I was happy to feel the way I did even with the knowledge there were no guarantees the future would be so bright as it was at that time.
Although Revlimid does sometimes work for patients without the chromosome 5 abnormality, the median duration of response is a mere ten months compared to two years for those who have it. Only a rare, anecdotal case is the exceptional responder, like Mr. De Noble is to Vidaza. Mr. Worden happily turned out to be another unicorn.
I moved to New York, and we lost touch. Ten years later, Mr. Worden abruptly returned to see me in New York with a curious question. He wanted, for financial reasons, to stop taking the Revlimid, as he was contemplating retirement. He was reluctant to do it on his own and wanted to know what I thought would happen if he stopped the Revlimid after all these years. I tried to go about it in a scientific, evidence-based manner and proceeded to compare genetic, cytogenetic, and clonal abnormalities between a fresh bone marrow sample and the old one that I retrieved from storage in my tissue repository. We found no new mutations, though he still had clear evidence of persistent lower-risk MDS by morphology. I agreed that it would be reasonable to stop the Revlimid. Surprisingly, his hemoglobin began to drop within two months of stopping. “Even after all those years, the MDS exploded into action without the brakes provided by Revlimid,” he wrote. We resumed the drug as he became rapidly transfusion dependent, and fortunately, within a month of restarting at a lower dose of 5 mg, his hemoglobin returned to a steady 12.5 g.
Generally, if a patient is responding to any therapy, oncologists don’t want to rock the boat and simply continue until it stops working. The concern is that once we stop the drug, the abnormal clone of cells that had been held in check by the drug would start multiplying with a good likelihood that the predominant outgrowth of subclones would not be as sensitive to the previously administered drug. There are no guidelines about how to proceed when someone has been responding for a decade because unicorns like Mr. Worden are exceedingly rare. His case underlines the peculiar and patient-specific dynamics of MDS. He is responding thirteen years later to the same drug. This by itself is an anomaly. Additionally, he was able to resume taking the drug once again with a terrific response.
Beyond the rarity of his response, several additional peculiarities in this case were perplexing. The first was that the MDS clone of cells had been producing all the blood in his body for more than twenty years. This is not surprising in patients with lower-risk MDS who have not responded to any therapy. The proof that MDS cells are producing all the blood is evident from their transfusion dependency; they are requiring blood transfusions because their own bone marrow is not producing healthy enough cells. But Mr. Worden had become transfusion independent immediately after starting Revlimid and had remained that way over the course of twelve years of treatment, I had expected that the abnormal clone of cells in his marrow must have shrunk. Yet in his case, Revlimid had clearly done nothing to diminish the clone size. Second, the cells had remained exquisitely sensitive to Revlimid even after twelve years of treatment. He is presently leading a happy, retired life and comes to see me periodically. We have his bone marrow and blood samples saved in our tissue repository, and I am anxious to apply the latest technology to understand the biologic reasons for his exceptional responsiveness.
IN 1975, MY brother Javed got married in Karachi. Among guests who came from America was Pam, a friend and pediatrician colleague of my sister Atiya. It was a hot July, and during many long, lazy afternoons, Pam and I bonded over books and mangoes as we sweated it out in hundred-degree temperatures, swooning over Bob Dylan, Shirley Bassey, and James Taylor. She was reading a book, the title of which fascinated me: Zen and the Art of Motorcycle Maintenance by Robert Pirsig. She left it for me, and over the next few months, I read the book several times. It left me profoundly moved and actually changed. Through this book, which I cannot claim to appreciate fully even now, I became interested in thinking more about issues of quality. To Pirsig, quality can be static or dynamic. Static quality represents everything definable. Then there is the dynamic type, driven by indefinable engines. Pirsig calls this the metaphysics of quality. Imagine being viscerally attracted to something before your intellect provides an objective reason for the appeal. This experiential, dynamic quality is beyond definition or expression in language. It is something that precedes intellectual comprehension, not something imposed but something deeply immanent within the realm of possible experiences.
Pirsig deconstructs both types of quality as he and his eleven-year-old son negotiate the mountains of Montana on a Honda 305 Superhawk, obsessed with the question of how to define, at an atomic level, that which makes a thing good. His meditations are a giddy tour de force consolidating physical, intellectual, and spiritual experiences, revealing glimpses of the essential, metaphysical mystery behind even the most rigid, stylized, and formal of scientific enterprises. Pirsig describes it all through the simple analogy of working on his motorbike; studying and exploring each aspect of the problem systematically, examining everything in the minutest detail, deconstructing endlessly, until finally discovering the root of the problem. The stringent, arduous labor alone, however, does not always lead to the moment of discovery. What drives his science, its crucial vitality that makes it come alive in all its throbbing, pulsating vibrancy is not the tedious planning but instinct, intuition—the metaphysics of quality. This impulse possesses the power to guide us as we negotiate our lives in the context of the larger universe around us, making the journey itself as important as arriving at the peak. “The only Zen you find on tops of mountains is the Zen you bring there.”
Reading this book as a very young medical student, I felt as if Pirsig were speaking directly to me, providing me with a road map. There I was, a twenty-two-year-old with no experience but with lofty goals, embarking on a hybrid career that would combine an examination of the physical world through experiments and observations with the practice of medicine, the most humane, compassionate, empathic of sciences, where exceedingly intimate physical and psychological details are shared between two strangers within minutes of first contact. The answer I found in that book was how a dynamic, metaphysical quality could, and why it should, drive both my impulses of practicing medicine and science—why I should not recoil from but open myself wholeheartedly to feelings and emotions, to becoming deeply involved with patients, to exposing my own vulnerabilities without hesitation. At the same time, while designing exacting, methodical, rigorous basic science experiments, Pirsig taught me to welcome instinct, to examine its dictates, and to apply them fearlessly.
What I did not appreciate back in 1975 was how often during the most painful of journeys, as I witnessed dread and disease in others, I would experience sublime moments of grace. The Zen moments. Indeed, only the greatest of art can elevate without comforting. Pirsig freed me to partake of little pleasures while trapped and thrashed around in cyclones of sorrow.
I had no time to hate, because
The grave would hinder me,
And life was not so ample I
Could finish enmity
Nor had I time to love; but since
Some industry must be,
The little toil of love, I thought,
Was large enough for me
—EMILY DICKINSON
Kitty provided me with ample time for little toils of love, bringing moments of intense joy and satisfaction. The leisure of meeting regularly, every week or two, thirty or forty times a year, for years, allows discussions to continue in installments. Patients suffer much as a result of low blood counts; innumerable transfusion
s, recurrent infectious episodes land them in hospitals with life-threatening sepsis. We live through the travails together. Kitty and I had such a relationship. There was a Pandora’s box of topics available to us when we met on a weekly basis; we opened it once and out came the practical implications of walking around the world deficient in hemoglobin; another time it yielded old age; another time sprang on us the issues of iron accumulation in the body from all the blood transfusions. We saw derangement and disorder arrive unexpectedly and often, after running a bruising painful course, settle down or vanish. We talked about the coming tornadoes about which we could do little. We prepared ourselves by dissecting with care and concern the finite disappointments in store. Kitty was always realistic and accepting of her disease. We took small pleasures in celebrating an unexpectedly high hemoglobin one week and Sheherzad’s admission to Columbia University next. We counted bruises; we marveled at hematomas forming at phlebotomy sites. Most days, we did not feel heroic, but we did our best to adjust to the ever-changing realities of her disease. We alternated between cringing and celebrating, but through it all, we stuck together as a team.