2 A Bleak Start to Life

of darkness, you will learn the trick of making.

You shall make your consolation all your life.

—Amanda Jernigan, “Lullaby,” 2005

“Our next patient is a transfer from Obstetrics.” The junior resident John said, as I left Mr. Sweeney’s room. Our eyes locked for a second as we shared our mutual worry.

“What trimester is she?” I asked.

“Second.”

I nodded and exhaled. “Well, at least she has that going for her.”

Cancer is always a serious diagnosis. Leukemia is a serious cancer diagnosis. Leukemia in a woman who is pregnant takes on a whole other level of danger, for a couple of reasons.

First, leukemia cripples the immune system’s ability to fight infections, and the chemotherapy we give to treat the leukemia just makes the immune system all that much worse. Pregnancy can also impair the immune system, albeit mildly. But add that to an immune system already on the ropes from leukemia, and the risk of acquiring a life-threatening infection becomes much higher.

Second, the chemotherapy I described to the Sweeneys could cause severe birth defects in an unborn child, or worse. The likelihood that a woman would be able to keep her baby if this had occurred during the first trimester was nil. The chemotherapy, which works by killing growing cancer cells (remember the Trojan Horse cytarabine), crosses the placenta and instead kills the rapidly dividing cells in a fetus that is trying to grow limbs and organs. During the second trimester, when the cells aren’t dividing quite as much, there would be a chance for the baby to survive, though risks of birth defects and fetal death were still quite high.

I carry around my own baggage regarding pregnant women with leukemia. My very first month of being a staff physician, right after my fellowship training, I cared for a pregnant woman who was also in her second trimester. She had acute lymphoblastic leukemia, which can affect the bone marrow cells like acute myeloid leukemia but can also, rarely, grow as solid tumors almost anywhere in the body. In fact, her leukemia was diagnosed when she was undergoing a routine ultrasound of her baby and the radiology technician noticed a mass on one of her kidneys, nearby the uterus. It was biopsied, leukemia was diagnosed, and she was admitted to my service.

We started chemotherapy and asked the Obstetrics team to round on her every day and to perform ultrasounds on the unborn child. Boy, did she look great, teasing us and telling jokes during rounds every morning. The baby was doing wonderfully, too. She taped ultrasound photos of her baby on her hospital wall, which buoyed all of our spirits, and reminded us of what was at stake here.

But then, one week into her treatment, she spiked a fever. That morning when I went in to see her, she looked worried for the first time since I had met her.

“Something’s wrong. Something’s really wrong,” she told me. Even at that early stage of my career, I had enough sense to trust my patients when they told me there was a significant change in their well-being. I looked down at her legs, which stuck out from under the bed sheets, and saw livedo—a medical term for when a body part looks mottled, as if it has lost some essence of life. It is frequently associated with sepsis—an infection that has entered the blood stream and is starting to wreak havoc with the body.

“We’ll take care of you,” I told her, trying to reassure her as much as myself. But I was worried too.

We gave her antibiotics immediately, but within 2 hours she had to be transferred to the intensive care unit because her blood pressure dropped. Within 8 hours, she had been placed on a ventilator. At 12 hours after the fever started, the baby had died. By hour 18, she too had died.

“Ms. Badway is a 36-year-old woman who is G6 P3”—shorthand for “gravida 6 para 3,” meaning she has been pregnant six times and has delivered three children. “She went to see her OB at week 20 of her pregnancy when a routine CBC showed a white blood cell count of 330,000, a hemoglobin of 10.3, and a platelet count of 470,000.”

“Wait,” I interrupted John. “Did you say her platelet count was 470,000?” He nodded. “That’s high. The hemoglobin’s a bit high too. It’s pretty unusual for someone with acute leukemia to have preserved platelet counts.” Joan’s numbers—with a hemoglobin near 7 and a platelet count south of 20—were far more typical. I started to feel a glimmer of hope. Maybe Ms. Badway didn’t have acute leukemia after all.

John, along with the rest of the team, stared at me, not sure where I was going with this. Rachel, a hematology/oncology fellow who was in her second year of training after her three years of internal medicine residency, emerged from Ms. Badway’s room. I assumed she had just performed a bone marrow biopsy, as she stripped off a blue paper surgical gown, crumbled it into a ball, and threw it in the trash. She put her white coat back on and joined us.

Bone marrow biopsies have been used to evaluate disease causes for more than a century. The contemporary biopsy needle was invented by the Iranian hematologist Khosrow Jamshidi in 1971. This is the procedure we follow: We stick the needle into the flat part of the pelvis, in the back and just below the spine, and remove some of the marrow so a pathologist can analyze it. We choose the pelvis because it contains some of the most fertile bone marrow “soil” in the body. The biopsy needle is almost comically long, as it needs to reach the bone that is sometimes buried deeply beneath the skin. A few years ago, I probably forfeited any parent-of-the-year aspirations I had by bringing one as a visual aid to my son’s elementary school when I taught his classmates how blood was made. Looking at the needle, which evokes a prop for a movie about a mad scientist, they unsurprisingly recoiled at its size. Two of his horrified classmates even asked to leave the room.

The needle has recently been replaced by a drill that was shown in one study to work just as well and to cause less discomfort.1 Though anecdotally some patients have told me they feel less pain with the drill, others say it gives them even more anxiety, as they associate it with sounds they normally hear when thrust into an uncomfortable position in a dentist’s chair.

“How’d the biopsy go?” I asked Rachel.

“It was a little tricky. She couldn’t lay on her stomach because of the pregnancy, but we were able to prop her up to lay on her side with pillows, and I think we got a good sample.”

I followed up by asking, “Did you learn anything else about Ms. Badway while you were in there?”

“Well, I know she doesn’t work for a cardboard box company.” We all laughed.

“John, can you read off the blood counts again to Rachel?” He repeated them. “What do you think Rachel?” I asked.

She considered the lab results for a second and asked him, “What was the patient’s differential?” The differential is a description of the subtypes of white blood cells that appear in the blood stream. Normally, it consists mainly of neutrophils (around 60 percent of the white blood cells), which fight bacterial infections; lymphocytes (around 30 percent), which attack viruses; and maybe a few eosinophils, which become elevated when we have allergies, or monocytes, which attack atypical infections like tuberculosis. With acute leukemia, the differential shifts markedly: we might see 1 percent neutrophils, 10 percent lymphocytes, and 89 percent of those blasts that started their lives in the bone marrow.

John started reading a string of percentages from the computer on his WOW: “neutrophils (50), lymphocytes (15), eosinophils (10), monocytes (6), basophils (8), promyelocytes (7), metamyelocytes (2), and blasts (2).” He looked up, first at Rachel and then at me, waiting for us to interpret what he had just said.

“Are you worried about those blasts, Rachel? Should we start her on daunorubicin and cytarabine, like Mr. Sweeney?” I asked, knowing she was too smart to be tricked by the leading question.

She crinkled her nose. “This sounds much more like a myeloproliferative disorder. Could it be CML?”

I nodded. “I think that’s exactly what it is, which is great news for her.”

Myeloproliferative disorders, as the name implies, occur when the myeloid cells in the bone marrow grow (proliferate) rapidly. Unlike acute leukemia, in which the immature blasts—the kindergarteners—grow too fast because they stop maturing, with myeloproliferative disorders, more advanced stages in bone marrow cell development (promyelocytes, metamyelocytes, basophils, neutrophils) grow too fast—call them the high schoolers. That was the explanation for Ms. Badway’s unusual differential.

Here’s the really odd thing about myeloproliferative disorders: for some reason we don’t quite understand, the rapidly growing cells also release chemicals in the bone marrow. Those chemicals can eventually lead to a type of scar tissue called fibrosis accumulating within that high-rent, precious space. The remaining normal bone marrow cells recognize that their home is rapidly becoming inhospitable. So they decide to get the heck out of Dodge and find somewhere else in the body to reside.

When we were all at the developing fetus stage, none of us actually had a functional bone marrow. Instead, those bone marrow cells created red blood cells, white blood cells, and platelets from what’s called our reticuloendothelial system—the liver, spleen, and lymph nodes. Remarkably, in people with myeloproliferative disorders, the bone marrow cells somehow remember where they were born, even decades later, and return to those organs as safe havens when the disease worsens. Consequently, people with these disorders often have enlarged spleens, livers, or lymph nodes. Blood passing through these organs picks up some of the young progeny of the bone marrow cells, and thus the reason for the unusual white blood cells in Ms. Badway’s differential.

“Let’s go in and chat with Ms. Badway,” I said to the team after they told me a little more about her medical history.

“She asked if she could just talk to you and me,” Rachel interjected. “There was a lot of traffic in and out of her room overnight.” I could just imagine it: the registered nurse who would have admitted her, the licensed practicing nurse who would have taken her vital signs every couple of hours, the on-call resident, and then, crossing the 7 a.m. shift change, a whole new crew of nurses and residents—then Rachel, and now me.

We walked into her room, Rachel leading me, as she had already met our new patient. Ms. Badway was lying in bed, sleeping on her side. No surprise, given what must have been a busy night and the pain medications we administer prior to a bone marrow biopsy. She was wearing black sweatpants and a matching, zippered sweatshirt. Her designer hospital gown and an extra pair of bed sheets lay carefully folded on the windowsill.

A lot of my patients won’t wear a gown for a number of days into their hospital admission—some because their street clothes are simply more comfortable; some because they still can’t believe they have a leukemia diagnosis and aren’t ready to dress as if they are ill; and still others to remind themselves what life outside the hospital feels like. Sun streamed through the windows in a rare break from the slate gray skies that blanket Cleveland every fall and only rarely lift before late April. The skyline, two miles away, looked magnificent.

Rachel gently rubbed Ms. Badway’s leg and called her name. She sat up in bed and Rachel introduced me.

“Hi,” I said, sitting at the edge of her bed.

“Hey,” she answered, rubbing the sleep from her eyes. “So, you’re the guy who’s going to make all of this better?”

“Well, we’re sure going to try,” I answered. “Did Rachel talk to you about what’s going on?” She nodded. “How do you feel?”

“That’s the crazy thing!” she almost shouted. “I feel fine. I mean, don’t get me wrong. I’m pregnant and all, and after barfing for three months now I get to be just exhausted and fat. My clothes not fitting, that sucks. And it doesn’t help that I’ve got three kids at home who are pains in my ass. My husband Joe is with them now. Especially my daughter, who is in high school where the only thing she seems to learn is how to push my buttons.” She paused, as if contrasting the routine of her life—and what she might have characterized as “frustrating” 24 hours earlier—to where she was right now. “But leukemia? No way.”

She looked at me, waiting for me to agree with her, that it was impossible that she could have leukemia.

“We’re going to find out one way or the other what is making your blood counts so abnormal. That’s why Rachel attacked you with a big needle just now,” I said.

“This is insane. This can’t be happening.” She shook her head again. “You don’t understand, my life is finally settling out. Before this . . .” She shook her head again. “You wouldn’t want any part of me.”

“What do you mean?”

She looked me in the eyes, defiantly this time. “I was bad news. I first met Joe in high school, but I was too much of a wild child even for him!” She laughed. “Back then it was just a lot of drinking. And pot. Landed me in the emergency room a couple of times to get my stomach pumped, when I was at Tri-C.” The Cuyahoga Community College. “But I only lasted there a couple of years. School wasn’t really for me. So a girlfriend of mine got me a job dancing.”

“Dancing?” I asked. “What kind?”

A smile crept over her face, and she looked at me with pity for all those years I had kept my nose stuffed in medical textbooks. “Of the pole variety. At the Crazy Horse, downtown. Those were some rough times. The drinking got pretty bad, too, until one time I was at this party and fell out a window and landed on my back. I fell two stories. Broke my pelvis.” John had alluded to some past trauma she had sustained. “That scared me straight. I quit the Crazy Horse. Finished school at Tri-C. And then Joe came back into my life.” She smiled again, but fleetingly. “And now this.”

I nodded, holding her gaze but fighting the urge to say anything. It’s such a normal, even empathic human tendency, to want to fill these spaces in conversation with reassuring words, to somehow take this weight—of her past life, her present life as a busy mom, her pregnancy, and now her leukemia—off her shoulders. Studies in which doctor-patient interactions are observed have found that, on average, we interrupt patients after they have been talking for only 11 seconds when they are trying to tell us their stories, and perhaps clue us in on what led to the illnesses that have altered their lives.2 So we sat together, in silence, as she processed where she was in the world.

Eventually she sighed. “So tell me what’s the next step. I gotta get this fixed so I can get back home and take care of my rotten kids.” She started to cry. Rachel grabbed the tissue box and handed it to her. The tissues were part of our daily routine.

“We’re worried that you have leukemia,” I answered. “We don’t mess around even when we just suspect it, and that’s why you came straight to our floor. But there are a couple of flavors of leukemia: the acute kind, which we do consider a medical emergency, and which would require immediate chemotherapy and a stay here of four to six weeks . . .”

Her eyes widened at the thought, and if she was like any other parent of school-age children I had treated, she was probably trying to figure out how their lives would stay on track if she were incapacitated in the hospital. I’m sure it was no easy feat just for her to be admitted and for her husband to stay home from work for the day.

“. . . and the chronic kind, which can be treated as an outpatient, actually with chemotherapy pills. We have some early results from your blood counts, and they seem more typical of the latter, the chronic form of leukemia. Chronic myeloid leukemia, CML.” I said the words deliberately because other patients have told me how meaningful it was, that initial time when I gave their leukemia a name. “I’m keeping my fingers crossed that we’re right.” I smiled at her.

“Yeah, me too,” she said, thinking over what I had just told her. “Any idea what caused it? Was it the drugs and the booze?”

Scores of my patients have posed a similar question to me, wondering about a cause.3 I suppose it reflects an innate need to revisit whether all the small decisions we make, about the foods we eat, the habits in which we indulge, and the steps we should have taken to mitigate harm, could have avoided an untoward outcome.

But truthfully, except in very obvious cases, it is difficult to determine if a specific environmental exposure triggered a person’s cancer. Most cancers arise spontaneously, as if thumbing their nose at our primal need to establish a cause.

But I still try, as the residents learned with Mr. Sweeney. And sometimes, I even convince myself that, like some sorcerer of truth, I have uncovered THE EVENT that caused the cancer.

One patient with myelodysplastic syndrome told me she used to live in Nevada. I asked her whether she had been exposed to any chemicals or radiation.

“Well,” she said, laughing to herself, as if marveling at the foolishness of what she was about to tell me. “Our family lived there when I was a girl, in the 1950s. Every so often, someone in the town posted flyers on the telephone poles inviting us to gather outside and watch the mushroom cloud that would follow the nuclear bomb testing nearby. That was big entertainment!” She laughed. “So we’d all wait for the big explosion, and then as the cloud formed, the hot winds from it would blow through the town, and almost knock us over.”

I imagined the radioactive noxious breeze, encircling her impressionable bone marrow stem cells when she was just a girl.

Another time, a man in his 70s with acute leukemia told me he’d served in the navy. I asked him if he’d seen any action.

“I was on a ship during the Cuban Missile Crisis,” he said, shaking his head. “It was hotter ’n hell down there. And humid.”

I laughed. “Wow! That’s incredible. How’d you stay cool?”

“I didn’t!” This time he laughed. “Except at night. Instead of lying in our bunks, a couple of guys and I would lug a mattress down to the hull and lay it on the ground, in between some metal cases that were cool at night. We kept the nuclear weapons in those cases.”

Nuclear arsenal only a foot or two from his bone marrow? Perhaps this exposure, half a century earlier, was the culprit.

I’ve had patients who worked in shoe stores and used fluoroscopy (X-ray) imaging to visualize the bones in a customer’s foot. This popular gimmick, used from the 1930s to the 1950s or so, was said to help determine the right shoe size—but no one, neither shopkeeper nor customer, wore a lead vest for protection. Other patients employed by a well-known tire manufacturer south of Cleveland described to me how they would soak their hands, for hours at a time, in a vat of benzene, similar to the formaldehyde Mr. Sweeney mentioned.

Doctors themselves recommended similar exposures before they recognized the downstream consequences of their treatment. My uncle had the acne on his back treated with radiation in the late 1940s, when he was a teenager. He died of leukemia in his 70s.

It is true that environmental factors can cause CML, but recreational drugs and alcohol have not been linked to this cancer (though alcohol does increase the chance of developing head and neck cancers). Most cases arise spontaneously, the exception being in people exposed to the atomic bombs the United States dropped on Japan in 1945.

Although it seems intuitive now that people exposed to the atomic bombs would be at higher risk for cancer, that was not the case in real time. It took the death of a 12-year-old girl named Sadako Sasaki to bring attention to the hibakusha, the survivors of the bombings at Hiroshima and Nagasaki. Before she died of leukemia in 1955, she folded 1,000 origami cranes as a response to a legend that doing so would grant her a wish. The cranes have subsequently become a symbol of the victims of nuclear warfare.

The Atomic Bomb Disease Institute, subsequently established in 1962 in Nagasaki, Japan, conducts basic research in radiation medicine and the late effects of radiation on the human body. Ten years later, the Medical Data Center for the Atomic Bomb was established with the purpose of data collection and arrangement and preservation of materials from atomic bomb victims to better understand the effects of the disaster. These materials include information on precisely where each person was located in relation to the bomb’s epicenter, which allows scientists to calculate how much radiation that person was exposed to.4

Some early studies (done in the 1980s) saw a spike in survivors having CML in the years immediately following 1945, but those numbers leveled off to almost normal thereafter.5 In another study, scientists from the Atomic Bomb Disease Institute reported the incidence of myelodysplastic syndrome, diagnosed between 1985 and 2004, 40 to 60 years after the atomic bomb explosion. As you might expect, people who were younger and received higher doses of radiation because they were closer to the explosion were at highest risk of developing the cancer. The average age at the time of exposure to radiation was 9 years, and at the time of the myelodysplastic syndrome diagnosis the average age was 71 years. In other words, the radiation set in motion the first step of developing a cancer that wouldn’t become manifest until decades later.6

Another example of an environmental cause is therapeutic radiation exposure. I have also cared for patients who developed CML decades after being treated with radiation therapy for Hodgkin lymphoma.

Hodgkin’s was one of the first successfully treated cancers ever. People like Henry Kaplan, considered one of the pioneers in radiation therapy for cancer during his years at Stanford University, were considered heroes in the 1950s and 1960s for doing what was thought impossible: helping people with a cancer diagnosis to survive for years, and even to be cured. The timing and location of his work were not an accident: he co-opted the linear accelerators required to deliver radiation with the help of the Stanford physicists who had developed and used the technology to create the atomic bombs.

This initial euphoria around the success of radiation therapy was tempered when, years later, patients returned to Dr. Kaplan’s clinic with new cancers: cancers of the skin and soft tissues (sarcomas) in the areas overlying the cancer-containing lymph nodes treated with the radiation; breast cancers, if those treated lymph nodes were deep in the chest, behind the breasts; and leukemias, when the radiation struck the bone marrow. Henry Kaplan suffered a deep depression afterward, when he realized that his treatment had caused significant enough genetic damage in normal cells in the body to make them cancerous. And not just cancerous—deadly. Cancers that arise as a result of treating other cancers, with radiation therapy or chemotherapy (which also can damage normal cells), are often the hardest to cure.7

I asked one patient who had been diagnosed with CML decades after her treatment for Hodgkin’s lymphoma if she had any regrets, facing leukemia long after she was cured of her lymphoma.

She shook her head immediately and smiled at me. “No way. None. I have two beautiful children now, who I never would have had otherwise, and a loving husband. I’ve had an incredible life.” She paused then, as if revisiting all that had transpired since her lymphoma diagnosis. “And I’m the only one still alive, out of all those people in the waiting room from when I was treated. The only one.”

I reassured Ms. Badway that neither booze and drugs, nor any of her past activities, had caused the leukemia.

She exhaled, relieved, not so much for herself, I guessed, but because she didn’t want to haunt her family with the thought that her previous behavior had so drastically affected her health.

“Okay, next question. What about the baby, can he get it?”

I remembered John telling me that she was having a boy.

“The short answer is no.” I hesitated before answering, and she picked up on that.

“Gimme the long answer,” she said. I liked her. No nonsense. Street smart. And she had lived a life, despite only being in her mid-thirties.

There are three ways in which a child can theoretically “get” a parent’s leukemia: the child and the parent can all be exposed to the same radiation or chemical (as might happen to a family living near ground zero in Hiroshima in 1945) and contract the same cancer, which would be very unusual; the child can inherit it; or it can be passed from parent to child.

Leukemia can run in families as a heritable genetic predisposition, but it is exceptionally rare. In my decade-and-a-half of practice, I might have referred a patient approximately once every year or two for genetic counseling to determine if that patient had a chance of passing cancer on to children and grandchildren.

I did take care of one patient, a man in his mid-60s, who told me his identical twin brother also had leukemia, and that his father had died of leukemia. His brother came to see me too, and both donated blood samples for our research team to analyze. We discovered that they shared the same genetic abnormality and that they had both inherited it. (We can distinguish genetic abnormalities someone is born with and thus can pass on to children, called germline mutations, from those that are acquired randomly or from environmental exposures, called somatic mutations.) Both had leukemia that improved to a specific drug, too, and when we went back to our database of genetic abnormalities in people with leukemia and identified those who had the same genetic abnormality as these brothers, all improved if they had been treated with the same drug. It was remarkable.8

Classically, cancers that run in families tend to strike when people are young. Some cancers require that multiple genetic errors must occur before the cancer becomes manifest, though. And we are learning, as my twin-brother patients illustrate, that for those multiple genetic error cancers, like myelodysplastic syndromes or acute leukemias, they may run in families even when the cancer strikes at advanced ages. The germline mutation is just the first genetic step of many.

Cancers can be passed from parent to child, or one person to another, but again this is exceptionally rare. There are a few case reports in the medical literature of a person receiving a solid organ transplant from a donor—say, a heart, kidney, or even liver—and developing cancer in the months following the transplant.9 That cancer can be linked back genetically to the donor. And although a detailed medical history is obtained from the donor’s medical record and family at the time of organ donation, and the surgeons removing an organ from a donor look for any signs of obvious cancer, that donor was likely carrying a cancer that was still in its microscopic stages, only blossoming when placed in another person’s body.

Only a couple of case reports, ever, have documented leukemia passing from a pregnant woman to her unborn child.10 The placenta serves as a barrier between mother and child, protecting the fetus from much of what occurs in the mother’s body, and vice versa. But it isn’t a perfect system. As any pregnant woman who eats a sugary dessert and reports her baby “rockin’ and rollin’” afterward can tell you, the baby gets the sugar load too. Blood cells can pass back and forth between mother and infant across the placenta, which means so could leukemia. Despite that, for the thousands of women who have had cancer while pregnant, to only have a couple of case reports of vertical transmission of cancer, the placental barrier must work pretty well.

I explained all of this to Ms. Badway, and asked her if she had any other questions.

“When will we know for sure what I have?” she wondered. She was rubbing her belly gently, as if reassuring her son that he would be okay.

“We should hear back from the pathologists this afternoon. As soon as we know, you’ll know.”

She thanked us and we left her room to finish rounds.

“Let’s take a field trip,” I suggested to our team after we had seen our final patient. “I wonder if those bone marrows are ready for our viewing pleasure.”

We took the stairs down to the second floor, and then followed one connecting hallway to another, over Carnegie Avenue, through the entrance to the old Packard automobile dealership building, which houses our pathology department. Down some more stairs to the basement, through a locked door that my ID badge sometimes opens, and sometimes doesn’t, and down another hall to the farthest room. This is where the multiheaded microscopes live—they make it possible for a group to examine the same slide at the same time—and where the bone marrow biopsy specimens are evaluated.

Karl, one of my favorite pathologists, was sitting by one of the scopes. He has a few years on me, both at our hospital and in life, and he remains one of the most thoughtful and gentle people I know. Outside of work, he collects player pianos, of all things. He is a renowned morphologist, meaning he can look at the shape of cells in the bone marrow—along with their numbers, where they are located, and what they look like in relation to each other—and almost invariably come up with the right diagnosis before additional, specialized test results returned.

“I bet I know why you’re here,” he said, smiling at me. “Business always seems to be good when you’re on-service.”

“That’s good news / bad news,” I answered, grimly. “I’d love to have treatments that put us both out of business, Karl.”

He nodded in agreement. “So, would you like to review the bone marrow slides from Mr. Sweeney first, or the new gal with CML?”

“Does she have CML for sure?” I asked.

“Well, it sure looks like it. Of course, we’ll have to wait for the tests to come back to see if she’s BCR-ABL positive.” He pulled out a thick cardboard panel from a stack of them on his desk and opened the front flaps. It looked like one of those old cardboard displays that held coins tucked into individual flaps, or like an Advent calendar board. But instead of coins, it held slides, each with a smudge of pink at the center. Karl picked one out and placed it under his microscope. We all gathered around one of the other two microscope heads. Karl walked us through the different cell types quickly, moving the slide around expertly, and efficiently increasing the magnification of the lens on the scope to make the cells bigger and bigger.

“Ninety-five percent cellular, here you see some myelocytes, metamyelocytes, eosinophils, band neutrophils. Here’s even a blast,” he said, identifying the large, pink and purple-colored blobs that would become mature white blood cells and red blood cells. “I’m counting only 1 percent blasts. These cells are pretty mature. There’s a lot of them,” he commented. “Classic bone marrow aspirate for CML.”

We lifted our heads from the microscope as Karl grabbed another cardboard folder.

“Now this young man,” he said, referring to Mr. Sweeney, “he has a lot of these.” He stopped, as a scrum of large, menacing, irregularly shaped cells crowded almost half of the microscope’s viewing field. Blasts.

“What percentage are you getting?” I asked, knowing the answer but hoping Karl would give me a different number.

“Between 40 and 45 percent,” he answered. “I did a 500-cell count.” Meaning, he went above and beyond what was standard, a 200-cell count, in which he literally counts the different cell types and adds up the percentages for 200 or 500 cells. “I’m sorry,” he said. That’s one thing I love about Karl. He knew that behind these slide there were people whose lives had just changed drastically for the worse.

“Thanks for taking some time out with us,” I responded.

“I heard through the grapevine another is on the way?” He was alluding to Joan Walker. I nodded. “We’ll be waiting for her.”

As we headed back to the floor I said to the team, “Let’s go tell Ms. Badway the good news.” Well, relatively good news. I shook my head, reflecting on my own callousness. She still had leukemia, just not acute leukemia.

CML is defined by a specific genetic abnormality—what Karl referred to as the BCR-ABL translocation, in which chromosomes 9 and 22 switch “legs” with each other. (The first part of the abbreviation stands for “breakpoint cluster region,” and the second part is shorthand for the Abelson oncogene, initially discovered by Herbert Abelson in 1970.)

Our DNA is housed in 23 pairs of chromosomes numbered from 1 to 22 (the 23rd being a pair of sex chromosomes designated as either XX for women or XY for men). During mitosis, as our genes make copies of themselves, the duplicate pairs of chromosomes all gather in the middle of the cell, as if they are line dancing. The cell then pinches itself in the middle and separates into two cells, with half of the chromosomes going one direction into one new cell, and half the other direction into the second cell.

But cells don’t always make perfect copies of themselves, or of their chromosomes and DNA. Occasionally, chromosomes next to each other will trade genetic material. And when that trade gives a cell a growth advantage compared to other cells around it, cancer may result.

The field of human genetics began with the discovery of the 23 chromosome pairs in 1956. In 1960 a team of researchers, Peter Nowell and David Hungerford, obtained bone marrow samples from patients admitted to Philadelphia General Hospital in the late 1950s.

They noticed that seven patients with CML had cells with a normal number of chromosomes, but that one was shortened—chromosome 22, which became known as the Philadelphia chromosome.11 This was the first time a genetic abnormality was consistently linked to cancer. Actually, what they didn’t notice was that another chromosome, 9, had extra genetic material that came from chromosome 22.

So for more than 10 years, CML was thought to come from a loss of genetic material in the Philadelphia chromosome. It wasn’t until 1972 that Janet Rowley, at the University of Chicago, showed that the Philadelphia chromosome resulted from a translocation—a switching of genetic material—between chromosome 9 and chromosome.12

It took almost another 20 years for researchers, led by George Daly and the Nobel laureate David Baltimore, to show that introducing this translocation to genetic material in mice caused CML to occur in the rodents.

Why was it important to give mice leukemia? Two reasons. First, it proved that the genetic abnormality alone was enough to cause the disease. Unlike acute leukemia or myelodysplastic syndromes, which required multiple genetic abnormalities to occur before the cancer blossomed, CML was a “one-hit wonder.” And second, now investigators had a small mammal with the same disease, in which they could test drugs to see if they could beat back the leukemia.

Rachel entered Ms. Badway’s room again, where she sat in a chair, sending a text message. The window now framed clouds, which had moved in to displace the sun.

“Just finishing this up,” she said to us, distractedly. “Joe got the older kids off to school but forgot to pack their lunches. Hopefully they’re at least wearing clothes.” Leukemia or not, she had a household to run. She shut off her phone and looked up at us. I sat at the edge of her bed. “Okay, waddaya got for me?”

“We just took a look at the samples from your bone marrow, with our pathologist. It looks like you have chronic myeloid leukemia, not the acute leukemia we were worried about. This is good news,” I told her, despite myself.

“The chronic leukemia.” She repeated, processing what I told her. I nodded. “The one where I can go home?”

“That’s right. We can actually send you home later this afternoon.” I smiled. She didn’t smile back, still thinking through the implications of this new information.

“Does that mean this isn’t serious?”

I paused before answering. “It’s still a serious diagnosis, and to be honest, we aren’t 100 percent sure of the diagnosis yet. I’d put us at about 90 percent. We’re waiting for another test to come back to be absolutely confident, and we’ll get those results in a couple of days. But I’m comfortable enough at 90 percent to recommend you start taking the chemotherapy pills that work for this leukemia.”

“And what exactly is the treatment for the chronic leukemia?” she asked.

Twenty years earlier, if I had faced the same question by a patient in her mid-30s, I would have answered without hesitation “a bone marrow transplant.” With this procedure, a patient with CML receives a high dose of chemotherapy to essentially obliterate her bone marrow, and then receives another person’s healthy bone marrow, which then takes up residence in her now-empty marrow space to produce new blood cells. It is potentially curative in over half the patients with CML who receive it, but bone marrow recipients can also die from this aggressive approach, or experience long-term side effects that can be quite debilitating.

Probably the first drug used to treat CML was the poison arsenic, initially given by Thomas Fowler (and henceforth referred to as Fowler’s solution). In fact, a letter appeared in the British medical journal Lancet in 1882 describing the use of arsenic in a patient who likely had CML by no other than a general practitioner named Arthur Conan Doyle, who gained fame (and later, knighthood) for his stories about the detective Sherlock Holmes!13

More contemporary nontransplant treatments included interferon, an immune therapy that brought about complete remissions, even resulting in a return of normal chromosomes, but in fewer than 10 percent of patients. The side effects to the drug were awful, even leading some patients to commit suicide rather than trying to withstand them. The typical survival for someone with CML was about three and a half years.

Following the development of a “mouse model” of CML, the opportunity arose to start screening existing drugs that had been developed (but were not yet necessarily FDA approved) to see how well these drugs worked to kill CML cells. The drugs were first tried in test tubes that held cells with the Philadelphia chromosome abnormality—essentially, CML cells. If the drugs performed well in test tubes, they were then tried in mice with CML.

One investigator, Brian Druker, who at the time (in the late 1980s) had just finished his training as a hematologist/oncologist at the Dana-Farber Cancer Institute in Boston, dedicated his research to this issue. He focused on CML knowing that because it is a much simpler cancer than other leukemias—a one-hit wonder—the likelihood increased for him to find a single drug to work on the CML cells in a test tube, on CML mice, and eventually on people with CML.14

So in collaboration with Nick Lyden, who led a drug discovery group at the pharmaceutical company Novartis, Druker started screening drugs and applied for funding to support his research.

And he applied. And he applied.

But funding agencies, including the National Institutes of Health, thought his research proposals were too risky, and likely to fail, so they rejected his grant applications. New laboratory investigators at an academic institution are usually provided some money by the institution to support them and their research for a couple of years, but if that research doesn’t take off, they are politely (or sometimes not so politely) asked to leave. Dr. Druker was asked to leave.

He landed at Oregon Health Sciences University in 1993, and he didn’t give up. He finally discovered a drug—at the time, called STI-571—that worked incredibly well in CML cells in test tubes, with high kill rates, and in CML mice. It actually was able to rid those mice of their CML entirely, resulting in a rodent remission. The next step was to try the drug in people with CML.

But Novartis, the company that now owned the drug—subsequently called imatinib or referred to by the brand name Gleevec—wasn’t so sure. After all, only 6,000 to 9,000 people in the United States were diagnosed with CML each year. Compare that to the almost 20,000 diagnosed with AML, or even the 180,000 people diagnosed with lung cancer, or the more than 200,000 diagnosed with breast cancer or prostate cancer. How would Novartis make enough money to cover the research and development costs?

Dr. Druker appealed to Novartis multiple times, and eventually he prevailed. If the drug worked this well in mice, it had a high likelihood of working well in people and the potential to satisfy a huge public health need. Patients were desperate. At that time, treatment for solid tumors usually lasted for three or four months. CML patients, on the other hand, would have to stay on this drug, daily, for life, meaning they would be paying tens of thousands of dollars per year for the drug, potentially for decades.

You can imagine which one of those arguments Novartis found most compelling.

A clinical trial was initiated in 1998, in which 83 CML patients for whom interferon therapy had not worked or had stopped working were eventually enrolled. The very first patient was a retired railroad engineer from a small town on the coast of Oregon called Tillamook. These folks had few options outside of standard, intravenous chemotherapy, which would only hold their leukemia at bay for a short period of time, if at all.

Something special happened.

Within just a few months, the blood counts of 98 percent of these people, for the first time (for some) in years, returned to being normal. In almost one-third, their Philadelphia chromosome was eradicated, meaning the drug worked at such a deep level that the abnormal genetics driving the disease were corrected. These once-dying patients got out of bed, went dancing or on hikes, even did yoga. And 96 percent of those patients who achieved normal blood counts maintained those normal blood counts a year later. And counting.15

When the results of this study were reported, CML patients and their doctors from around the world fell over themselves trying to get access to imatinib. Other CML studies were initiated, enrolling 1,000 patients at 27 medical centers in six countries within just six to nine months.

Dr. Druker had told the drug company that people were desperate. And in May 2001, the US FDA listened and approved imatinib for the treatment of CML. The confirmatory, Phase 3 study, reported in March 2003, randomized over 1,100 CML patients to receive imatinib or interferon combined with cytarabine (the chemotherapy we suggested for treating David Sweeney’s AML). The results were equally dramatic: After a year and a half of follow-up, 95 percent of patients treated with imatinib had normalization of their blood counts, compared to 55 percent of those treated with interferon and cytarabine; 85 percent had some degree of eradication of their Philadelphia chromosome with imatinib, compared to 22 percent with interferon and cytarabine. And side effects were much, much more tolerable. Unequivocally, imatinib had changed forever the treatment of CML.16

But then something really special happened.

After more than a decade of follow-up, it was found that those patients treated with imatinib on the randomized study had a life span that was about the same as age-matched controls without a CML diagnosis.17

As if they never had leukemia to start with.

Since the early 2000s we have seen the development of a second- and even third-generation of drugs that also can eradicate the Philadelphia chromosome (and indeed, are better at doing so than imatinib), and which can be used to treat people for whom imatinib didn’t work. The drugs have been so successful that bone marrow transplant for CML is only used now as a last resort, when in rare cases all of these drugs have failed.

“We would recommend a pill called imatinib, also known as Gleevec,” I told Ms. Badway. I discussed with her the chances that it would work, the side effects, and how her blood counts would change over the next few weeks. I paused, about to raise the most difficult issue about her treatment, but she beat me to it.

“How will it affect the baby?” She started rubbing her belly again as she asked the question.

I exhaled a while before giving her an answer that was not straightforward. “I don’t know whether this is reassuring to you or not, but there are actually some case reports of people with CML who have either been pregnant at the time of their diagnosis, like you, or got pregnant while being treated for CML. So you’re not alone.

She smiled at me wryly. Some consolation, but she’d rather not be a member of this elite club.

“If you read therapy guidelines from CML experts on treating pregnant women, they recommend interferon because it does not cross the placenta, and thus won’t affect the baby. But it also doesn’t treat the CML nearly as well as imatinib.”

She nodded, listening, still rubbing her belly as if she were reassuring the baby, it’s okay, I’ll keep you safe.

“To be honest, one problem with the writers of such guidelines is that they tend to be extra conservative, and don’t always provide the best basis for their recommendations.”

“Why’s that?” she asked.

“Well, I think it’s because they don’t want to suggest a treatment that doesn’t fall in line with what everyone else recommends, for one. And perhaps because they don’t want to be named in a lawsuit if a doctor somewhere in the world uses the recommended treatment, and a patient has a complication.”

Rachel was listening intently to this backstory behind the guidelines, which she was probably using to prepare for her hematology boards.

“So, our leukemia group reviewed the guidelines, the case reports of pregnant women treated with imatinib for CML, and case reports of pregnant women treated with interferon. And it turns out the rates of birth defects, or of lost pregnancies, was the same for either drug.”

“Really?” Rachel asked, incredulous. “What about for other tyrosine kinase inhibitors?” She referred to the class of drugs, similar to imatinib and developed subsequently, that treated CML even better than imatinib.

“There aren’t as many reports about those drugs being used in pregnancy, because they haven’t been on the market for as long, and because pregnant women are almost uniformly excluded from clinical trials of new cancer drugs. That’s one reason we have to rely on case reports to determine what is potentially safe for the baby. That’s also why I would recommend imatinib, because at least there has been some experience with its being used in pregnancy.”

“So,” Ms. Badway said, “bottom line, you’re saying I should take the chemo pill and the baby will be okay.”

“Given the potential benefit of the imatinib, and the risks, I’m recommending you take the pill. But I can’t guarantee you won’t have the side effects we discussed, and I can’t promise that the baby will not be affected, that he won’t have birth defects. From all of those case reports the risk of a birth defect—many of which are minor, but some of which aren’t—is about 10 percent.”

“And if I don’t take the pill?”

“Well, we would try the interferon,” I answered.

“And if I don’t take anything?” she countered, rubbing, rubbing, calming.

I thought about her question for a few seconds. “That’s always an option. I do worry that with your blood counts so abnormal, and the guarantee that they will continue to worsen over the next few months if your leukemia isn’t controlled, you’d be at risk of infections and bleeding or forming blood clots, and those could all affect the baby’s health too.”

She nodded, rubbing, rubbing. “I’d like to think about it before deciding.”

“That’s exactly what I would do,” I told her.