The First Cell

by Azra Raza

  We started Harvey on thalidomide at 50 percent of the recommended dose because of the toxicity I had seen in MDS patients. The results even with this reduced dose were spectacular. Within forty-eight hours of starting, Harvey’s facial edema started to melt visibly. By week’s end, the pitting, uneven, grotesque puffiness had entirely disappeared, and his fine features reappeared.

  LADY N.’S BLOOD counts eventually dropped, requiring intervention. As hoped, she responded well first to the red cell–stimulating hormone Procrit and then to Revlimid. The anemia improved beyond expectation, and she had an excellent quality of life, caring for her many cats, taking long drives visiting her numerous best friends, shopping and dining with her ninety-nine-year-old mother, and generally enjoying life to the full.

  Lady N. would come to clinic for follow-ups regularly and endeared herself to everyone she encountered. Her openness, loud and hilarious remarks, self-deprecation, and a poignant concern for—and astonishing ability to recall—others’ personal lives made her easy to like. Another unique quality was her matchless ability to communicate with the younger individuals who inevitably follow me in clinic. Whether they were high school students interning during summers, doctoral candidates writing dissertations on MDS, or fellows training in hematology, she would inquire about their backgrounds in a few sentences and then proceed to engage them through anecdotes and personal stories that were somehow tailored for their individual needs. I can recall numerous young fans, Matt Markham in particular, who kept in touch with her long after their rotations with me were done. Such was her attraction, such her charm.

  She was a cat lady. Lady N. and her late husband toured with their beautiful feline army throughout America and Europe, earning admiration, winning awards, breeding and showing oriental shorthairs, amusing the clinic staff with endless, entertaining stories of her various award-winning trips. She created a memorial fund at Cornell University Feline Health Center dedicated to improving the care and well-being of cats in honor of her favorite cat, William. Lady N. was also an accomplished photographer of nature and of birds. She participated in research projects at the University of Vermont, including a study of the Indiana bats of East Dorset. She was a member of MENSA, played tournament bridge and chess, and was a natural with computers. She greatly enjoyed sharing her vast resources of knowledge in diverse fields and astonished her listeners by citing extraordinary facts during ordinary conversations. I adored her.

  Lady N. was constantly examining her past to determine the root of her MDS—wondering if the kerosene heaters in a cabin where she spent holidays as a child might have contributed to her condition—and was always picking my brain for more satisfying answers than Google was able to provide about her future. She was especially eager to learn where the latest research on targeted therapy was heading. As I would describe some new drug we were testing in a phase 1 or phase 2 trial, she would become quite excited. “I am counting on you, my dear, dear friend, to make sure that I have at least another ten, if not twenty, years. Between the two of us and your colleagues, I am counting on it!” And she told me several times, “I want to be there when you make MDS a chronic disease like AIDS is now.”

  And then the inevitable happened, and she stopped responding to Revlimid. That left her transfusion dependent. Even as she was being pumped full of red blood cells from matched donors, her wicked sense of humor was ever present, and she would send me weekly cartoons that would make me smile or burst out laughing in the middle of clinic. Eventually, she was started on chemotherapy with Vidaza. It was not a pleasant experience. As the Vidaza continued into the fourth and then fifth month without any relief in the frequency of blood transfusions, an unexpected new symptom crept in. Lady N. began to experience inexplicable fatigue. She would wake up in the morning after an eight-hour sleep feeling like she had been pulling a cart all night. She was totally worn out by the simple act of brushing her teeth; washing and blow-drying her hair required at least three intervals of rest. Her arms felt like lead. She pumped herself full of coffee and took Excedrin and then Ritalin to shake herself out of the doldrums. Nothing worked. Week after week, she sat across from me in clinic and recounted the list of chores she had been unable to complete. We tried hyper-transfusing her with blood, maintaining her hemoglobin above 10 Gm at all times (the normal range is 12.5–16 Gm). Even she was perplexed by the profundity of exhaustion. She used to feel better when the hemoglobin was 7 Gm than she did now at 10 Gm. Ultimately, after ruling out all possible causes like nutritional deficiencies, thyroid dysfunction, drugs causing a side effect, we had to admit that she was suffering from a paraneoplastic syndrome.

  We stopped the Vidaza, and that brought her temporary relief. She sent me the following note:

  Lately I’ve had so many transfusions I feel like changing my profession to “vampire” on hospital forms.… And as I like to tell people, I’ve done so much “blood doping” that I probably wouldn’t be allowed to watch the Olympics on television.… Ok I jest, but I feel so much better. Gone is the peripheral neuropathy, the hot flash-like fevers at night, the dizziness and the mental foggies and a whole host of unpleasant side effects not the least of which is that when I’m on chemo I’ve felt like I’ve lost at least 50 IQ points.… It’s nice to have them back.

  We began to relax, celebrating her temporary deliverance from the deeply discomfiting symptoms, knowing full well that it would not last forever. She would storm into clinic, blowing kisses, handing out utterly unhealthy delights—cookies and doughnuts—high-fiving nurses and arguing with the receptionists, happy to be something of her usual unusual self once again. Everyone breathed a sigh of relief.

  We continued to treat Lady N. symptomatically, but she was visibly getting worse, requiring more transfusions of blood and now occasional platelets as well. We became quite worried when Christmas 2014 rolled around and she told us that she was going to drive her mother to Vermont to visit family and friends. She tried to assuage our concerns about her “running around in these days of the new normal.” “It just takes planning,” she told us, “sort of like a military campaign.” She insisted anything she could do sitting down, including driving a car, wasn’t a problem—“that is, unless my hemoglobin is really tanking and my mind starts to get fuzzy.” She did admit that “the vertical activities,” like walking from her car to a shop’s front door, do “have to be planned for rather carefully.” And she had plans, including favoring stores where she could park near the entrance and lean on a shopping cart, but they were all clearly a willful denial of reality. Her absolute refusal to see what stared her in the eyes, her persistent demands for solutions from me, and her outrageous expressions of supreme confidence in my abilities in particular and of science in general to provide a cure for her left all of us involved in her care a little unsettled.

  How someone with her level of high IQ, a member of MENSA, an extremely well-read and well-traveled woman of Lady N.’s extraordinary caliber managed to steadfastly, categorically, and decisively resist, ignore, and reject out of hand any acceptance of her looming mortality remains one of those perplexing things about humans that make us such complicated creatures. Since I had recently gone through the Omar debacle, it was only natural to compare Lady N.’s responses to her cancer with his. At thirty-eight, Omar, a brilliant young professor, distracted himself by obsessively researching treatment options and remaining hopeful until the end, yet at some intangible level, I sensed in him a silent, deeply melancholic prescience of impending doom. From the moment of diagnosis, he existed in a liminal space, suspended between life and death, waiting impotently, not knowing, perched on a threshold, unable to cross over or retreat, powerless to fully explain his own location. There was a delicate perishability about him, an unspoken despondency even as he ostensibly engaged in carefree celebrations of living. At other times, like the magician Prospero, reminding his daughter of the brevity of mortal life in The Tempest, Omar, too, seemed prepared to declare an end to the revels, “We are such stuff a
s dreams are made on, and our little life is rounded with a sleep.” The aesthetic dignity of Omar’s acceptance coming from inexplicable, peculiar, deep crevices of his psychic interior contrasted sharply with the flamboyant refutation of reality by Lady N., her obsessive postures of waiting, her perpetual expectancy, the flows and eddies of her piercing, scorching desire to live at all costs.

  Celebrating her mother’s hundredth birthday provided Lady N. with further reassurances of an inherited, robust, indestructible genetic makeup and presented her with a model to emulate: “The woman is a machine! She is also extremely stubborn! In many (but not all) ways, I’d love to grow up to be just like her. Especially to be one hundred years old, mentally together and well enough physically to be able to live by myself and do for myself the way she does. I mean, the woman is truly remarkable.”

  Around this time, Lady N. informed me that she had developed a whole new philosophy about her disease and how to cope with it. I asked her to write it down for my other MDS patients:

  My mantra:

  I am NOT my cancer.

  I am not a “victim” because I have cancer.

  I am not a “hero” because I’m fighting cancer.

  I have no contract with life that will stand up in court. I could be crossing the street on my way to the garage to get my car and get nailed by a garbage truck.

  I will NOT allow people to marginalize me because I have cancer. (I find that people tend to marginalize you once they find out that you have cancer.)

  She also wrote down what the worst part of having MDS was, and how she responded. For her, cancer was like “climbing a mountain while wearing a knapsack and with every step it is as if someone is putting another brick or two in the knapsack. It is truly remarkable how much heavier and weaker I feel with each upward step. How do I deal with this? I try to get the same satisfaction from climbing a flight of stairs as I used to get from climbing a glacier, a mountain or the Alps as I did when I was a kid.” And then she advised others about how to choose which mountains to climb:

  I have only a certain amount of energy each day and if I choose to expend that energy going out for a drive or for lunch in a restaurant or to the movies instead of making the bed or picking up or doing the laundry, that’s fine. And if you come to visit me and disapprove of the mess or the unmade bed or unwashed dishes you have three choices: 1) you can ignore the mess, 2) you can clean it yourself if it really bothers you or, 3) you can leave.

  LADY N. RETURNED from Vermont and almost immediately afterward presented to the ER with a high fever, shaking chills, wild episodes of sweating, severe nausea, and uncontrolled vomiting. She was on the verge of septic shock. We admitted her to the hospital. The routine exhaustive workup for infections followed. Intravenous treatments to cover every possible pathogen were initiated. Again, as with the majority of such patients, no source for the fever was discovered. She began to deteriorate rapidly. Each morning, I stopped by to see her in the hospital. She looked at me wistfully from her bed, complaining about the shower and imparting acute asides. “The spaghetti they serve is so fake in this hospital,” she said. “I call it impasta.” As we tried to control the unidentified infection, presumably a fungal pneumonia, her white blood cells stopped maturing and started a steady, ominous climb in the blood. The MDS was transforming into acute leukemia in front of our eyes.

  Talking to Lady N. as she fought the sepsis, I felt seriously deficient in my ability to explain the many paradoxes and uncertainties we were dealing with. In her case, the telltale signs of impending disaster had begun appearing a good six months before all hell would break loose. Back then, the leukemia cells brewing in her bone marrow were only just starting their hostile takeover and were still manageable in quantity. A new cytogenetic abnormality, along with a higher percentage of immature cells, was detected in the marrow. When I told her, she paled. “Okay. I guess this is not the news I was hoping for.” But true to her motto—“Never give up—never give in!”—she said, “Why not treat me aggressively now? You always say, Dr. Raza, that the time to fix the roof is when the sun is shining. Not only is the sun going down rapidly for me, leaks are already appearing. How about doing something definitive now? Use me as your guinea pig. Try whatever you want. I trust you and will do exactly what you tell me.” She was absolutely correct in demanding me to act then, a time when the leukemia was just starting to rear its ugly head. Isn’t that why I had turned my attention to studying MDS in the first place—to find the leukemia early and treat it with a curative, preventive intent?

  The problem for Lady N.—and for all cancer patients—is that unless the cancer presents early as a solid mass that can be surgically removed, there is no definitive, curative treatment that can be safely given to eliminate a small number of circulating cancer cells. All we have as treatment is chemotherapy that would end up destroying more normal cells than the few abnormal ones. In the presence of full-blown leukemia, chemotherapy is worth giving because the majority of cells in the bone marrow are leukemic. It is like saying we cannot treat your common cold, but if it develops into a pneumonia, we can.

  In the background of MDS, a clonal cell had mutated in Lady N.’s marrow, losing any capability of differentiation, remaining an immature blast, a cell whose entire existence consisted of unceasing cycles of doubling its DNA followed by mitosis. The only potential cure for her would have been a bone marrow transplant. This involves killing every last cell in the patient’s bone marrow, normal as well as malignant, and then trying to restart the empty marrow with fresh cells from a matched donor. Destroying the bone marrow carries with it so much toxicity and such a high risk of death that the procedure must remain limited to a select few, handpicked younger MDS patients. Lady N. was not a candidate for a bone marrow transplant due to her age and multiple comorbidities with suboptimal function of heart, lungs, kidneys, and liver.

  At that point, almost six months since we first detected the earliest signs of transformation in her marrow, sepsis was complicating a rapidly advancing leukemic takeover in her body. Treat her for the infection alone, and the leukemia would get her. Treat the leukemia with the same old chemotherapy regimen and she would die faster from the suppressed, empty marrow, unable to hold the infection back. No matter what we did, her chances of survival would not improve. It was now a battle between the devil and the deep blue sea.

  THE STRATEGY FOR treating acute leukemia, followed for the past fifty years, is to kill as many abnormal cells as possible with a round of aggressive “induction” chemotherapy. This requires patients to be admitted to the hospital for several weeks, during which they receive what is known as the 7+3 protocol: seven days of a drug called cytosine arabinoside, or cytarabine for short, and three days of the drug daunorubicin. These cytotoxic agents kill both the leukemia cells and all other rapidly dividing cells in the body, leading to the three most common side effects associated with chemotherapy—killing hair follicles, leading to baldness; killing cells in the gastrointestinal tract, leading to nausea and vomiting; and killing normal residual bone marrow cells, causing low blood counts and making patients susceptible to infections. Because those cell types proliferate at breakneck speeds, they are most sensitive to destruction by the chemotherapy. The bone marrow alone makes close to a trillion cells every twenty-four hours in a healthy adult. Once chemotherapy empties out the bone marrow, a period known as aplasia, it takes two to four weeks to recover. During this interval, patients end up with life-threatening infections requiring aggressive intravenous therapy with multiple antibacterial, antifungal, and antiviral drugs. If the marrow recovers with less than 5 percent leukemia cells, it is a complete remission, or CR. This is indeed cause for short-term celebration.

  The problem is that a CR by itself is not sufficient. In a bit of mathematical medical jargon, one round of 7+3 only destroys several “logs” of leukemia cells (where each log is a reduction by 1/10, so three logs would mean 1/1000 of the original leukemia cells). If the patient is left untreated after
this, even when the bone marrow shows no microscopically recognizable leukemia, the disease relapses. In order to “consolidate” the CR, repeated rounds of 7+3 or one of its variations must be administered in cycles. Because the human body can only tolerate a certain amount of cytotoxic assault at one time, a cycle is generally a month long with five to seven days of chemotherapy followed by a recovery period of two to four weeks. The patient is sent home briefly and readmitted for the next cycle within seven to ten days. When I started my training in oncology in the early ’80s, we did some of the pioneering trials to determine the optimal number of “consolidations,” comparing three, four, and eight follow-up, or postinduction, chemotherapy cycles. Eight was clearly too much; I recall only a handful of patients who completed this draconian prolonged torture. Today, two to four postinduction cycles are the standard.

  The “hope” is to reduce the number to such a low level that the patient’s own immune system can somehow deal with the “minimal residual disease,” or MRD. Multiple technologies have evolved to detect one in a million or even one in a billion abnormal MRD cells. Even though we can detect those cells, we don’t have anything more effective to offer than 7+3 to kill them. Using the protocol again, however, would kill billions of normal cells while having a good chance of not killing those rare leukemic ones. The strategy fails in about one-third of patients, either from the beginning, because the dominant leukemic clone is entirely resistant to the 7+3 and there is no complete remission to begin with, or because the MRD causes relapse of the disease.