by Azra Raza
Kitty was one of my best teachers. She took me from crayons to perfumes.
FIVE
JC
One Touch of Nature Makes the Whole World Kin
JC WAS VERY SICK WHEN I FIRST MET HER. SHE WAS DIAGNOSED with acute myeloid leukemia days before our first encounter in clinic at Roswell Park Memorial Institute in the early 1980s. She would make me acutely aware of the inadequacy and dismal failings of the cancer paradigm, the ghoulish therapies, their macabre side effects. It was the first time I felt like a fraud, having only the same old dreadful drug combinations to offer her, knowing that since she had a particularly virulent form of secondary AML, her chances of surviving two years were essentially zero point zero zero. After meeting her, I desperately yearned to be a more effective healer, a smarter scientist, a better person. I was thirty-two years old at the time, having just completed my fellowship in medical oncology. Most of the AML patients I had seen until then had been older, sixty and above. JC was someone I could picture myself having a drink with, hanging out, having fun. She was thirty-four.
She was dazzling—tall, with gorgeous blue-black skin, astonishingly graceful, hysterically funny, with an infectious laugh. “Artificial intelligence is no match for natural stupidity. If a girl is smart, Dr. Raza, she does not need brains!” JC was both smart and had brains. She was admitted for weeks on end to receive aggressive courses of 7+3 or one of its variations. As the chaos of a day in a busy leukemia service subsided, my long list of must-do things mostly checked off, I would invariably find my way around dinnertime into her room. Weary, exhausted, like an addict, I sought her grace. She would be waiting. We were like vitamins, supplementing each other’s minimum daily requirements. One evening, as I arrived in her room around 9:00 p.m., she handed me the Jell-O she had saved from the dinner tray, asking, “Are you always on call?” Before I could say anything, she roared with laughter, infinitely pleased to provide the answer herself. “Of course you are! You are an on-call-ogist!” Death-bound, she remained irrepressible.
She gagged, puked, retched, and carried on with rampant good cheer. “They are looking for pneumonia in my lungs like its buried treasure!” She laughed with an unbearable lightness. “I had a lot of notions today, but no motions,” she would seriously report. Instead of recounting some fresh horror that life in a cancer ward, with its indifferent, bizarre twists, had dumped her way, JC would recount mother-in-law jokes (“Dr. Raza, my mother-in-law has only one problem. Breathing. She also has a strange growth on her neck. Her head.”), or report upon the harried young intern who had seen her earlier (“He is so green, he thinks I left my white cells and platelets at home!”). She would complain about the blood transfusion (“I feel woozy. My donor had so much alcohol in his blood, you should be cleaning OR instruments with it!”) or how hard it was to eat (“This morning when the food cart came by and the lady asked me if I wanted my eggs fried or scrambled, all I could say was, ‘Intravenous, please.’”). In those days, I was obsessed with Louis Safian’s 2000 More Insults, which my sister Atiya, in her infinite wisdom and consummate familial insight, had sent to Karachi in 1973, knowing how her siblings would shriek maniacally with delight, trading caustic one-liners from the book. The only person I ever met outside of the Raza family who shared our corny sense of humor and kept a copy of the book by her side was JC. “Your favorite pulmonologist came to see me today,” she would deadpan. “I wish I used a hearing aid so I could shut him off.”
I would shoot right back, “Agreed. He is a constant source of ear-itation!”
We would high-five and dissolve into hysterics.
She also arrived with a fantastic story. While pregnant two years earlier, she had developed an inexplicable fetish for the smell of gasoline. Against her better judgment, this led her to the corner gas station, where she’d regularly purchase a dime’s worth that she kept in a little bottle, tucked away in her bag. JC was no fool. She knew it was wrong. She knew it could harm not just her but the precious cargo on board. With the compulsion of a doper, she stole moments throughout her crazy-busy working day to unscrew the tiny bottle, inhale the toxic fumes deeply as if they were specially concocted fragrances sent from high heavens for her private consumption. After nine months, she delivered a healthy set of twin girls. Shortly thereafter, a profound drop in her blood counts appeared on a routine postpartum check.
She had been unconsciously expecting it and was prepared for the worst. The obstetrician referred her to a hematologist. A bone marrow study showed myelodysplastic syndrome. Cytogenetic analysis revealed a total mess. Multiple chromosomes were randomly broken up, damaged, duplicated. Some were missing whole arms, others had additional material piled on, still others had translocated and exchanged reams of DNA with fellow chromosomes. Practically none was entirely normal. A textbook case of aneuploidy. Such a complex picture is most commonly associated with a secondary type of MDS, one with a traceable primary cause such as exposure to DNA-damaging agents. Almost certainly, she had brought this upon herself with the gasoline fixation during pregnancy.
Her only chance of any reasonable long-term survival was an allogeneic bone marrow transplant. She had no siblings, which, especially in those early days, meant finding an unrelated donor for her was next to impossible. Even today, the national bone marrow registry shows that only 25 percent of African Americans find an unrelated donor, versus 75 percent for Caucasians, 45 percent for Hispanics, and 40 percent for Asians. If an African American does match to a donor, 80 percent of the time, it is the only potential match in the registry. One of the biggest problems for all races is that only 2 percent of the population is on the donor list. An incredibly brave woman, Susan Brecker, set out to change this bleak outlook.
In 2013, I was seeing an MDS patient in clinic when her daughter asked me if I knew Susan Brecker. I did not. It turned out that Susan’s husband, the great jazz saxophonist Michael Brecker, was diagnosed with high-risk MDS, and his only chance was a stem cell transplant. No match could be found for him in time. Susan had made a film, recounting the story of three cancer patients, two of whom received matched unrelated transplants, survived, and are leading normal lives, while her husband died for lack of a donor at fifty-seven years of age. My patient’s daughter had seen the film and sent it to me. More to Live For tells deeply moving stories. I immediately started searching the internet for Susan’s contact information and eventually found her. My colleague Siddhartha Mukherjee and I met her together for lunch at the Columbia University Faculty Club. It was the start of a wonderful partnership.
More to Live For was successfully screened at dozens of schools, college campuses, churches, and social events. After the film, drives recruited potential donors for the national bone marrow transplant registry. All it requires is a cheek swab, not even blood, to be registered as a potential donor on the list, and if called upon to donate, stem cells are recovered from the blood in 70 percent of the cases. It is that easy. Susan’s efforts have saved more than a hundred lives already. She said she was ready to do more for MDS patients now that the film project was over and the awareness campaign for increasing donor registry was well on its way independently. Siddhartha and I jumped at her offer, as we were planning our next fund-raiser to support research efforts in MDS.
Susan is a rare combination of high intelligence, total commitment, deep empathy, and a one-woman powerhouse of infinite, indomitable energy. Within weeks, she had recruited big-name artists like Paul Simon, James Taylor, Diana Reeves, and a host of others, along with an incredible emcee for the evening titled, “The Nearness of You Concert,” held on January 20, 2015, in the Appel Room of Jazz at Lincoln Center. The artists volunteered their time because of their deep love for Michael, and Susan added to their commitment to cancer research. The elegant and articulate ABC anchor of Good Morning America, Ms. Robin Roberts, an exceptionally courageous woman who agreed to serve as the welcoming host for the evening and who has talked about her MDS diagnosis and subsequent stem cell transplant publi
cly, was an honored guest for the evening. I felt oddly drawn to her, following her with my eyes as she mingled with the guests—many of them my MDS patients—exchanged stories with them, and posed for photographs, and I suddenly realized the source of that inexplicable connection. She reminded me very much of JC. The same body language, easy laugh, extraordinarily charming personality, empathy oozing out of every pore in her body.
JC was not fortunate enough to find a matched unrelated donor, which meant that, until her MDS developed into acute myeloid leukemia, there was not much that could be done. Once she had AML, her doctor told her, they would use “the big guns.” She began seeing the hematologist every few weeks, until her anemia became profound and she required regular blood transfusions. This continued for another few months. It was a few months after that when she had developed acute leukemia in 1984 that she came to see me. I treated her, attempting to improve her chances of survival, but it was JC who ended up improving my life.
JC WENT THROUGH the painful phases of induction and consolidation chemotherapies under my direct care. Once, during a particularly savage cycle, I sat on the edge of her bed, and, in a feeble attempt to distract her, instead of telling her a joke, I recited a poem I love:
This condition of life
is not for the whole year
only the few months when it rains.
The blazing fire of the drywood
will cook rice in no time.
And
whatever is there
will come back into view
sharp and clear.
When the rains depart
we will put out in the sun
everything that is wet
woodchips and all.
Put out in the sun
we shall
even our hearts.
—SUBHASH MUKHOPADHYAY
She burst out crying. So did I. It was unreal. I was thirty-two, starting my career. She was thirty-four, dying.
JC SURVIVED THE sickening rounds of chemotherapies and did get better. There was nothing more to do but wait and hope that she did not have a relapse. I began to follow her in my outpatient clinic once every two to three weeks, and then once every four to six. She and I started talking more about nonmedical issues, and as we learned about each other’s lives, we became closer and closer. Both of us knew that her chances of a durable remission were not great, given the high-risk nature of secondary leukemia like hers. I can still feel the anxiety we tried to hide from each other as we waited for the results of her blood tests in clinic, distracting ourselves with small talk.
The leukemia relapsed a year and a half after her initial diagnosis. Most of this time had been spent in the hospital, her gorgeous body racked with fevers, her insides eviscerated as the gut revolted against the cytotoxic drugs that did little good and much harm. The end came faster than either of us suspected. Her disease spun out of control in a matter of days as the malignant cells started doubling exponentially. When she realized that we had emptied our arsenal, JC requested admission to the hospital for her terminal illness. I admitted her and started low doses of chemotherapy to control the rapidly increasing blasts in the blood, knowing perfectly well that it would do nothing for the underlying bone marrow disease.
As I rounded each morning, making believe with all sincerity that balancing her intake and output of fluids was the crucial order of the day, the inadequacy of my pathetic nontreatment plan slapped me in the face. JC was dejected, withdrawn. I longed for the days when she teased me, but a wan smile would be all she could muster, gently, almost tenderly, acknowledging my feeble attempts at lightheartedness, successfully aborted before they began. I listened to her heart and lungs, palpated her abdomen, examined the swollen ankles, shiny now with skin stretched tautly, nauseated by my own bogus good cheer. Young bodies are not made for dying. They are hard to demolish even for so malignant a disease: two steps forward for cancer, one back toward life, as the body staged astonishing comebacks, rallying organs in a confounding, irregular sequence. One day, the lungs look clearer on x-ray; the next, the creatinine levels tank, then the pneumonia improves only to be followed by the liver starting to shut down. She lost weight and hope, she stopped eating, forgot how to laugh, quit the morning and evening walks around the ward. She hardly left the room anymore.
And then, suddenly, something snapped in her. An unexpected vehemence resurrected her withering, skeletal frame, imbuing her with a newfound palpable energy. JC asked for pen and paper, and she started writing. Furiously. Gone was the exhaustion and lassitude, gone the dozing stupor; the internal dismantling was abruptly suspended by the force of her intellectual zeal. She was a woman possessed. She filled legal-sized notepads, emptied pens, demanded more paper and extra ballpoints at odd hours of the night and day. There were few tomorrows remaining, and she was not wasting a single one of them. Her mind composed feverishly as the body decomposed. Over the course of a long career spent taking care of countless terminally ill patients, I have witnessed this sporadic burst of end-of-life force enough times to know it is real; dishevelment of a body being gradually laid to waste, reassured sweetly through a cleansing, terminal lucidity. How this happens—how she got enough strength in those emaciated carpals and metacarpals to balance pen on paper for hours on end, how she reassembled her dwindling psychic resources, how she filled page after page as her head pounded from profound hypoxia—remains a mystery.
She did not volunteer information about what she was writing. I was too afraid to ask. Until one evening, when we were alone, I did. “Sit down,” she said. For a while, she remained silent, looking out the window. In that moment, as the fading sunlight cast oblique shadows on the pale walls of her hospital room in the newly renovated Carlton House, I became acutely aware of the glaring disparity—the fragile, crumbling state of her body, a sorry vessel to house so capacious a soul. She, of the 2000 More Insults camaraderie, seemed ready to put the body away for good. It was humbling to imagine the gravity of her task. In telling me what she wrote, she was acknowledging the end. Khattam-Shud. She turned her face and looked at me with a shadow of the old smile. “Even the germs can’t stand me anymore. I guess it’s time to go.” She swallowed hard and blurted out, “I am writing letters I want my two-and-a-half-year-old twin daughters to open on each of their birthdays.” She hesitated, looked askance at me, almost bashful. “Keep me alive until I reach their twenty-first?”
By the time JC died two days later, she had barely completed the letter for their twelfth.
I HAD MY eureka moment as I signed her death certificate. JC died because her leukemia was too advanced by the time I saw her. It had taken her a year to cross over from preleukemia to leukemia. I should have treated her at the earliest, preleukemic stage of the disease. Surely, it would be easier to control MDS rather than AML. From that day on, I announced to Harvey that evening, because of JC, I was going to concentrate on studying and treating MDS. Even at the ripe old age of thirty-two, it was clear to me that the animal models were far too simplistic and artificial, utterly incapable of recapitulating a fraction of the complex disease I had seen evolve in JC’s case. The only hope of dealing with so deadly a foe was to detect it at its earliest stage and apply the best available scientific technology to find ways to arrest it before all hell broke loose. If I studied both MDS and AML stages of the disease, I thought, I could define the biologic milestones that mark how preleukemia cells cross over to the frankly leukemic stage. From that, a better understanding of the natural history of the malignant process would emerge, hopefully, yielding novel potential therapeutic targets on the way.
Harvey’s response was, “Az, your idea is spot-on, but I can warn you right now, you will never get a grant funded. MDS is too rare a disease. No one can even pronounce it properly, let alone support your work.” Of course, I did it anyway. And also got grants funded. Had I gone to school in this country, my research would have involved attempts to reproduce the disease in mouse models or to create tissue-culture cell
lines from patients’ malignant cells. Being an outsider, I had the audacity to follow instinct rather than custom. I would save every cell I could from every future patient I saw and study them thoroughly. It never occurred to me to do otherwise. While Harvey always provided his intellectual and moral support for my work, he never got interested in MDS and continued his AML work as before. Ours proved to be a great complementary partnership as the two of us were studying different stages of the same disease and compared notes constantly, learning from each other, providing unique new insights for experiments we designed independently and jointly.
To that end, I began my tissue repository, collecting sequential samples from each of my patients throughout the evolution of each patient’s disease. The repository was and is backed by a computerized data bank containing detailed clinical and pathologic information on each patient. The repository is unique in that it provides the ability to look back on survival data spanning three decades. Such a retrospective view of the disease is critical to understanding what makes some MDS patients develop AML or why some succumb to MDS within two years while others survive five, ten, or even twenty years. The serial samples can be interrogated using the latest technologies encompassing genomics, transcriptomics, proteomics, metabolomics, and even panomics. The resulting biologic insights will be invaluable. It is the only way to understand the initiation, progression, invasion, and lethality of the disease, responsiveness to given treatments, the natural history. Once important biomarkers of leukemia cells emerge through this high-throughput technology, identifying and targeting the first leukemia cell will be possible. It is because of the repository that I was able to define detailed cell cycle kinetics of both MDS and the leukemia that subsequently develops, giving patients infusions of the thymidine analogs bromo- and iododeoxyuridine in those early days, so the dividing cells could be labeled in vivo. We showed that, contrary to previous assumptions, the bone marrow cells in MDS patients are hyperproliferative. I also used the precious samples from hundreds of MDS patients to figure out that the low blood counts—despite a proliferative marrow—result from premature death of the clonal cells by a peculiar mode of suicide called apoptosis. Finally, we showed that this cell death is, at least in part, mediated and accelerated by pro-inflammatory proteins, tumor necrosis factor (TNF), and transforming growth factor beta (TGFb). It naturally followed that blocking TNF and TGF would lead to less cell death, more mature cells entering the bloodstream, and improved counts. The first such drug with anti-TNF effects was thalidomide, and when I gave it to MDS patients, it produced complete responses in 20 percent of the cases. This led to the development of Revlimid, the drug from which Lady N., Kitty C., and Harvey benefited. More recently, the drug luspatercept has shown activity in MDS. It acts by inhibiting the TGF family of proteins.