The First Cell

by Azra Raza

  Was Lady N. wrong to trust me? Where is my shifa?

  TODAY, ANY TALK of death is considered morbid and unhealthy, but in the mind-set a century ago—when war, disease, and famine raged unchecked—it was an ever-present threat. Life expectancy was in midforties at best. Rather than being a sad ending, often death was treated as a new beginning. Emily Dickinson, imagining the scene of her final moments from beyond the grave, an unfathomable point of eternity, paints death arriving with the gallantry of a dignified escort:

  Because I could not stop for Death—

  He kindly stopped for me—

  The Carriage held but just Ourselves—

  And Immortality.

  We slowly drove—He knew no haste

  And I had put away

  My labor and my leisure too,

  For His Civility—

  Not so, our Lady N. Drama queen that she was, she was not fading quietly into the twilight anytime soon, and no one was going to drive her carriage gently into the sunset.

  Over the next week, an unrelenting chaos descended upon her unconscious body. She suffered every ignominy that a mechanical life-support system could possibly visit upon its subjects. Her body expanded grotesquely, unevenly, to accommodate six extra liters of fluid pumped in to combat hypotension, the fluid stagnating in strange crevices of her body because her failing kidneys were unable to expel most of it. Her eyes, circled by blue-black rings due to periorbital edema and bleeding, bulged from a shiny, swollen, unrecognizable, raccoon-like face. Her entire skin, forced to lodge pound upon pound of relentlessly multiplying, roving, vagrant leukemia cells, became studded with a smattering of rock-hard little mounds, referred to as chloromas because of their sickly green color, sprouting amid flowery patches of tiny red-and-purple petechial spots announcing shattered capillaries and profoundly low platelets. She had tubes coming out of every orifice, lines placed in multiple large veins from the jugular to the femoral. Monitors recorded everything from oxygen saturation and vital signs to the pulmonary arterial pressure and cardiac rhythm; colorful screens blinked from adjustable metal poles on wheels, beeping insistently, alarming visitors, alerting nurses, ignored, switched off, only to restart screeching in unison moments later.

  Mortality steadily eroded the searing desire for eternity, piling a thousand humiliations at once on her decaying, battered, abused, assaulted, gigantic frame, shackled to the gadget-rich MICU bed with a hundred tubes and pipes. Lady N., suspended in a bizarre state between life and death, fought the funeral in her brain. Every groove, ridge, and fold in her cerebrum revolted. Every hair follicle on her skin, every cell in her organs, put up a fight. She refused to die. She pushed back, drawing upon astonishing psychological and physical reserves, producing a multifaceted tour de force of rebellion that challenged the limits of medical imagination and decorum. She managed to subvert the crippling blows of her fatal disease into an epistemology of endurance by her unyielding, uncanny, scandalously defiant posture of refusal.

  Her 101-year-old mother finally stepped in. A devoted aide wheeled her into the MICU. Accompanied by friends of Lady N. and by her lawyer, she formally petitioned for her daughter to be taken off life support. An abrupt, eerie, unnerving silence replaced the racket of beeping and pinging alarms as machines switched off, IV lines were pulled, tubes yanked, monitors unplugged.

  KEY OPINION LEADERS providing therapeutic algorithms rely on studies demonstrating success or failure of a strategy in the populations as a whole, but management of patients and the questions of existential challenges posed by each unique individual remain the responsibility of the treating oncologist. No degree of technologic improvement, national debates on “right to life” issues, or guidelines from evidence-based medicine can help in these deeply personal, intimate moments. Repetitive transmission of clinical trial results or regurgitation of statistical probabilities about chances of response and survival do not necessarily help patients. Devoid of emotions, recitation of facts is like a jockey without a horse. This moment calls for a serious reckoning. Patients disoriented and confused by the caprice of their rapidly evolving cancer and the absurdities of medical choices need more than medical advice from their oncologists. For their part, physicians must now harness all their own emotional, psychic, social, intellectual, philosophical, and even literary resources to engage with the patient and their families in repetitive, substantive conversations informed by empathy, kindness, and understanding. A more balanced, candid conversation about end-of-life issues, a frank explanation regarding the limits of medical and scientific knowledge should supplement the discussions of treatment options from the first meeting and continue as often as possible through subsequent encounters. Nowhere is the science of medicine replaced by the art of caring as in the final days of a terminal illness. Yet that is precisely where oncologists turn over the care of patients they have looked after for years to a new hospice team.

  In addition to the end-of-life and do-not-resuscitate conversations, an equally important question is, why could I not offer Lady N. anything better than 7+3? Most large clinical trials conducted by cooperative groups of oncologists across the country in the past decades have concentrated on tweaking the doses, schedules, or formulation of the two drugs with minor improvements in the response rates. Harvey and I became so allergic to 7+3 discussions in every national meeting we attended that, following the formula of the great Paul Farmer, we also started using it to refer to individuals who use seven words when three would suffice. In the midst of a perfectly serious scientific session, or during a dinner conversation with guests, if anyone appeared to drone on tediously, Harvey would lean over and whisper, “Seven and three.”

  The latest entry into this arena, hailed as a paradigm shift by many reviewers and editorial contributors, is the lipid-encapsulated combined version of 7+3. In a large phase 3 clinical trial conducted at the cost of tens of millions of dollars, this new 7+3 version improved survival by 9.6 months compared to 5.9 months for the standard 7+3. Why is our bar for improving survival so low? Is 3.7 months the best we can offer our patients at almost ten times the cost of the previous regimen?

  An improvement in the last fifty years in AML treatment has been that by using multiple parameters—including clinical presentation and biologic and genetic characteristics of leukemia cells—we can identify individuals likely to benefit from chemotherapy alone or those who are at high risk of relapse. Studies have shown that for the elderly (defined as anyone over sixty) or those with high-risk acute myeloid leukemia (that is, AML arising from MDS or after exposure to toxins like chemotherapy), even if a complete remission is produced in response to 7+3, the overall survival is not improved. The leukemia such as Lady N.’s that arises in the background of a myelodysplastic syndrome is notoriously resistant. In her case, 7+3 could be used to reduce the burden of leukemia in the bone marrow but would have to be followed by a stem cell transplant if the aim was to improve survival. Given her age and other comorbid conditions, a transplant was out of the question (it would kill her faster than anything else). Then what would be the point of torturing her in the hospital for weeks, treating her with agents that carry potentially lethal side effects? Why not simply provide the best supportive care available, with transfusions of platelets and blood, and treat infections as needed? Why not let them pass their last days at home with loved ones? Actually, oncologists do offer the choice of aggressive cytotoxic therapy versus supportive care with transfusions and antibiotics as needed. This is where we enter the strange circle where denial of the outcome of terminal illness, extreme fear of death, and the inextinguishable flame of hope merge together to cloud judgments. Almost all patients refuse supportive care and choose the aggressive approach. As did Lady N.

  LADY N. PASSED away due to complications related to her MDS. Yet in a larger sense, MDS could not, and did not, defeat her. She defeated MDS by inspiring countless others she met because of her MDS. She dared to play Russian roulette with a loaded gun. She was the loaded gun po
ssessing the power to die but without the agency to pull the trigger:

  My Life had stood—a Loaded Gun—

  In Corners—till a Day

  The Owner passed—identified—

  And carried Me away—

  —EMILY DICKINSON

  I miss her greatly. At the oddest of moments—like when I see a cat, or an especially funny cartoon, or a scared young medical student, and most of all, because of a comment, a gesture, an expression, or a question from an MDS patient—her laughing face accosts me. I smile. I silently mouth the words…

  Lady N., Zindabad! (Live long!)

  FOUR

  KITTY C.

  What Wound Did Ever Heal but by Degrees?

  SUBWAY STATIONS IN MANHATTAN CAN TAKE YOU BY SURPRISE ON early Monday mornings before the rush-hour hullabaloo. One such morning, as I descended the steep stairs of the Fifty-Seventh Street and Eighth Avenue entrance to Columbus Circle for the A train to Columbia University Medical campus on 168th Street, I was struck by how pristine the place looked. Gone was the mess and mayhem of the weekend, the drunk, sweaty, overexerted, overpartied colliding bodies, rushing through stations, cramped into carriages. Every last discarded beer can and soda bottle, stray straw, soiled, drifting Kleenex, and plastic bag had been swept off the steps. Even the wet hobos had wandered off in flabbergasted weariness. Such moments are tender ones, with that unexpected morning neatness; the freshly swept floors exposing patterns of geometric formality, tiles radiating from a central pillar, stealing toward revolving horizontal arms of the entrance, almost nostalgic for the falls of boots and stilettos. The underground Turnstyle market was not humming yet, but the Bee Gees were:

  Suddenly you’re in my life

  A part of everything I do

  You got me workin’ day and night

  Just tryin’ to keep a hold on you

  … We can take forever just a minute at a time

  More than a woman

  More than a woman to me

  I was heading to a packed clinic where I would see anywhere from twenty to twenty-five patients and perform five to ten bone marrow biopsies on MDS and AML patients in the next twelve hours. From the car, I peered into the pitch black of the underground tunnel, overlaid with reflections of bodies bent on iPhones, half-asleep teenagers propped into upright postures by oversized backpacks, smartly dressed young professionals adjusting earphones. In the cool, quiet carriage, I opened the New York Times but was unable to concentrate, distracted by the mental cataloging of tasks ahead, matching actions to bodies, prescriptions to faces, wincing as I acknowledged the imperfection of my knowledge with each image. Still, some faces attached to precise clinic appointment times surfaced in my mind: 8:00 a.m. RG, 8:30 a.m. L. W., 9:00 a.m. Kitty C.

  I devised oblique methods for imparting bad news to one; to propose, with cheerful caution, a new experimental trial to another. I shored up the psychic reserves to negotiate impossible options with RG. I had become close to her through weekly encounters over years. I would be speaking on the phone to her scared and anxious daughter in Australia, who was unable to hop on the next plane because of her children. What were her worries and hopes? How could I help her take better care of her mother, living in the Bronx, who, with a hemoglobin of 7 g, practically fainted every time she climbed five flights of stairs yet who refused to take the elevator on the Sabbath? And that morning, as blasts were starting to show up in low numbers but with a disturbing consistency in her blood, I would be performing a bone marrow biopsy, checking for disease transformation from MDS to AML. Then what? In clinic with RG and her sweet, quiet, gentle husband, I would call her daughter in Australia and son in Boston, and when all of us had been connected, I’d discuss the next steps of treatment. They would all be tense, because last week, I had warned them of the coming bone marrow examination.

  RG is seventy-one years old. She is an extremely loving and extremely anxious woman, and a frail one, weighing ninety-two pounds. She hugs me at least five times during every clinic visit. She reminds me how much trust she has in my ability to help her. Her children want her to move to be with one of them, but she refuses to go because she does not want to change hematologists. She cannot bear to see anyone else but me. It pained me deeply to think of how pathetic my abilities were (and are), how hopeless the treatments I would propose in case her MDS had turned to AML. After forty years, there was still only 7+3 to offer poor RG?

  I suddenly felt a profound sense of grief. I felt lost. I thought of my friend Sara Suleri reading from her book Meatless Days when she came to speak at the University of Chicago: “For to be lost is just a minute’s respite, after all, like a train that cannot help but stop between the stations of its proper destination in order to stage a pretend version of the end. Dying, we saw, was simply change taken to an extremity, and wasn’t a thing to lose us but to find us out, to catch us where we least wanted to be caught.”

  The hurtling subway stopped at the 125th Street station in a fleeting impersonation of its grand finale, precisely matching the punctuated equilibrium of the clonal progression I was imagining for MDS cells in the marrow of another patient I would be seeing that morning, Kitty C. Her disease seemed to be stable for the moment, the dominant clone lying low, the smaller subclones coasting between spontaneous expansions and regressions. Nevertheless, she was harboring a time bomb in that marrow. How long, I wondered, before the cells march to the next stop, acquire a new mutation, rest awhile, restart, and spin out of control? How long until the train wreck?

  KITTY C., IN her early seventies, had been diagnosed with MDS in June 2009 after her primary care physician noted that her hemoglobin was dropping. When it had fallen below 8 g/dl of blood, my hematology colleague David saw her and performed a bone marrow biopsy. The biopsy revealed that she had a lower-risk MDS with normal cytogenetics. In 2009, she became transfusion dependent, receiving blood every six to eight weeks or so. Initially, she was treated by David with erythropoietin, which stimulates the growth of red blood cells, and then with the FDA-approved chemotherapy Dacogen. After treatment, the intervals between transfusions increased, but not for long; within four months, she returned to her baseline frequency of blood transfusions.

  David asked me to consider her for one of my clinical trials. When I first saw her in June 2010, she was profoundly anemic, receiving two units of blood every two weeks. Kitty and I instantly clicked. She was a quintessential New Yorker. Thin, scandalously liberal, single, given to long walks in Central Park and the New York Botanical Gardens in the Bronx, taking regular subway rides to attend lectures at the 92nd Street Y, art shows at MoMA, and classical music concerts at Lincoln Center. She was a voracious reader. We exchanged books and music, we talked about children and politics, Nora Ephron, dry skin, and Moby Dick. We laughed and we joked and we had serious discussions about every aspect of her profound anemia and the treatment options. We became friends.

  I repeated a bone marrow biopsy and was pleased to see that the MDS was still of the low-risk variety, and the chromosomal test revealed a pleasant surprise. A small clone of cells in her bone marrow now showed a deletion of the long arm of chromosome 5, known as del5q. This is the same del5q abnormality that Lady N.’s diseased cells showed, associated with exquisite responsiveness to Revlimid. I gave Kitty the good news at our next meeting: almost 70 percent of MDS patients with del5q become transfusion independent for prolonged periods of time when treated with Revlimid. She looked surprised. “How come I was not treated with this before?” I explained that at diagnosis, her cytogenetics were normal, but with time, and following treatment with Dacogen, a subclone of cells emerged carrying this chromosomal damage. Clonal evolution in cancer is usually a sign of disease progression, but for once, chemotherapy had unraveled the presence of a “good” clone.

  Kitty had a dramatic response to Revlimid. Within a month, her hemoglobin began to rise on its own, without transfusions. Week after week, we sat in clinic, gobsmacked as her blood counts steadily rose toward normal; hig
h-fiving, we’d dance out of the consultation room into the hallway together, hugging, ready to declare victory from the citadel.

  When she first hit the normal range of hemoglobin after several years of functioning with suboptimal oxygenation of the cells in her body, she sat in clinic, pensive, unusually quiet. “I feel so different suddenly. There is a new clarity. I can’t explain what I am feeling. I need to sort things out.” We talked for a long time about the toll anemia had exacted from her body. She remained thoughtful, trying to quantify, catalog, define her newfound old self. “Why don’t you write about it?” I suggested.

  “Not a bad idea,” she said.

  On her next visit, she brought me this:

  I’ve been paying attention to my body as it responds to the new medication—as my hemoglobin ratchets up into the realms of the normal. I’ve been concentrating on the physical gains—being able, once again, to negotiate subway stairs, return to my daily walks around Fort Tryon Park, hills included, and in general, to just keep up. I’ve observed all this carefully and have been so grateful. But the big surprise came when I noticed something that I hadn’t realized I had lost—my head. I have a sense of exhilaration as I find myself filled with ideas, making connections, feeling stimulated and finding it so much easier to express what’s on my mind (nothing, mind you, brilliant or original, but still me). I’m thrilled with this recovery, doubly so because I hadn’t realized how much I had lost and what a struggle it’s been. I did not know how badly I felt all these years until I felt better.