Vital Signs: How Do You Treat a Watermelon in the Belly?

Early diagnosis and a fruit of modern medicine keeps a killer at bay.

By Tony Dajer|Monday, February 08, 2010

The triage nurse had written: “Forty-five-year-old man, chief complaint: not feeling himself, blurry vision. Fell three days ago. No loss of consciousness. Skin intact.” So here he was in the emergency department at 10 p.m. on a Sunday night. Why now? I wondered.

Jadesh, my resident, went into the examination area to visit Mr. Sullivan. Twenty long minutes later, Jadesh returned. “I think the spleen is very enlarged,” he said, a trace of awe in his voice. The spleen, located just under the left lower ribs, filters debris and abnormal cells from the bloodstream. You normally can’t feel a spleen.

“You sure?” I asked.

“He has been having night sweats for the past three days since he fell. Changes his clothes several times a night.”

“How did the fall give him night sweats?”

Jadesh shrugged. Add night sweats to an enlarged spleen and most doctors guess a diagnosis of lymphoma or leukemia. Missing, however, was the usual story of weeks or months of fatigue and weight loss, and maybe some easy bruising. “But he’s here because of the fall, right? He was fine until he fell?” I asked.

“So he says.”

As we walked over, Mr. Sullivan eyed us expectantly. With a puckish belly and thin limbs, he couldn’t have weighed more than 120 pounds. I introduced myself, then laid a hand on his abdomen. On the right, the liver edge felt OK. Moving across, my fingers kneaded the soft, thin flesh until they hit an edge as hard as a two-by-four. Stretching from rib cage to pelvis, the spleen filled half his abdomen. Straining to keep my eyebrows from hitting my hairline, I carefully asked, “You were OK until three days ago?”

“That’s right, doctor. I slipped walking down the stairs.”

I motioned for Jadesh to follow me out of the room. “He’s been carrying a watermelon around in his abdomen,” I said. “Must have been there for months. Good pickup on your part. Could be mistaken for his entire abdominal wall.”

“But why no symptoms?” Jadesh asked.

I flipped to the chart’s face sheet. Mr. Sullivan owned a small business and had no health insurance. Stoicism, American style. His white blood cell count had come back a whopping 318,000 white cells per cubic millimeter—30 times normal.

“CML, right?” Jadesh asked.

“Looks like it,” I told him. “But I’m no cancer expert.”

CML, chronic myelogenous leukemia, stems from white blood cells’ multiplying like rabbits in the Australian outback. During my internship complainers were told: “Could be worse. You’re not in blast crisis.” That doomsday term refers to a stage in CML when, after three to five years of steadily increasing white cell counts, the dam bursts: The bone marrow spews huge numbers of blasts (immature cells), the immune system collapses, and eventually you die. Chemotherapy, I knew, could slow the disease, but only a bone marrow transplant—grueling and sometimes fatal—could cure it. And only about 30 percent of patients find a good donor match. There were newer treatments, but I hadn’t followed the long-term survival data. My guess was, Mr. Sullivan had three or four years to live. “We need to tell him,” I said to Jadesh.

Back in the room, Mr. Sullivan had been joined by his partner. I looked from one to the other, then started in. “Your white count is very high. White cells are the infection-fighting cells in your bloodstream.” I paused. “You very likely have leukemia.”

Mr. Sullivan didn’t flinch. More puzzled than scared, he said, “That’s pretty serious.”

“Yes. We need to admit you for more tests.”

“Leukemia,” he repeated. I held his gaze and nodded.

CML is a peculiar beast. The first human cancer to be tied to a visible (under a microscope) chromosomal abnormality, it has become to cancer research what the Galápagos were to Darwin: a stripped-down, elegant illustration of how bigger, messier systems work. Chromosomes—we humans have 46 of them—are the big packets of DNA in a cell’s nucleus that contain hundreds of genes apiece. Every time a cell divides, the chromosomes duplicate. Sometimes they swap chromosome chunks with each other. The genetic scramble known as the Philadelphia chromosome (because it was discovered there in 1960) is one such hybrid. As bad luck would have it, the improper swapping of two gene fragments—from chromosomes 9 and 22—produces a mutant protein, a type of tyrosine kinase, which triggers the leukemia.

Cells rely on a variety of protein stimulators to tell them when to divide. Other molecules called enhancers and inhibitors in turn modulate the stimulators. In the case of CML, the tyrosine kinase produced by the Philadelphia chromosome scoffs at natural inhibitors. It juices up white cells like a floored gas pedal: “Multiply!”

In 1993 Brian Druker, a young researcher at Oregon Health & Science University who had worked on a variety of tyrosine kinases that trigger CML, had the idea of knocking them out. He approached scientists at the pharmaceutical company that is now Novartis, who had already synthesized some tyrosine kinase inhibitors. Together, they painstakingly constructed a molecule that would zero in on the cause of CML. The problem at the time was that CML was considered a “rare disease,” recalls Jerry Radich, a leading CML researcher at the Fred Hutchinson Cancer Research Center in Seattle. “With less than 5,000 new cases a year in the United States, the company felt the market wasn’t big enough to justify R&D costs,” he says. “But Druker pointed out that if you keep people alive, you create a bigger market.”

In 1998 Druker started a clinical trial with his tyrosine kinase inhibitor. In short order, 53 of 54 patients—all of whom had failed conventional therapy with interferon—saw their white blood cell counts drop to normal. Side effects were minimal. Traditional chemotherapy is supposed to kill rapidly dividing cells; this inhibitor, called imatinib, or Gleevec, evidently targeted only cancer cells.

Too good to be true? The FDA approved Gleevec in 2001. The five-year survival rate is almost 90 percent, at least double what CML patients could expect before. But Gleevec is not perfect, Radich cautions. “Some patients have mutations in their tyrosine kinase that keep the drug from docking to it. Also, it must be taken for life because some CML cells quietly survive. And the drug is much less effective in patients already in the accelerated and blast crisis phases.”

The dreaded blast crisis of CML results when the uncontrolled proliferation of cells yields new clones with further genetic mutations. After years of rapid replication, some descendants of the overactive white blood cells give rise to mutant forms armed with new aberrant growth promoters. Blast crisis occurs when cells begin dividing at a faster rate and fail to mature, causing an excess of immature (dysfunctional) cells to replace the normal cells. Imatinib shuts down tyrosine kinase, preventing it from spurring the growth that can lead to mutations.

Unfortunately, other cancers aren’t as simple to treat. By the time they are clinically detectable, most have already motored through the single-mutant phase into their own version of blast crisis: lots of different fast dividers fueled by multiple mutant growth factors. “We’re trying targeted therapies with other cancers,” Radich says, “but the results aren’t as dramatic. Mature cancer growth is fed by a grid of protein pathways, not a single highway like early CML. Block one intersection and traffic just flows around it; you have to block multiple pathways. The obvious solution is to create cocktails of Gleevec-like inhibitors. They’re probably already sitting on shelves somewhere. Problem is, they’re owned by different drug companies. Getting big companies to work together to try combinations of two, three, or even four agents is pretty challenging, but it’s our best bet.”

Mr. Sullivan benefited from the earlier bets that led to imatinib. He stayed in the hospital for two days while the doctors brought down his sky-high white blood cell count—dangerous because it could literally clog his blood vessels—with IV fluids and hydroxyurea, a fairly potent chemotherapy agent. Then he started on Gleevec.

I ran into his oncologist three months later. “He’s doing great. Full response,” he told me.

“What about that spleen?”

“Oh, that takes a while. Maybe a year to shrink back.”

“So it boils down to ‘CML? Just take two pills and call me in the morning’?”

“Not quite.” He smiled. “But close. Welcome to the 21st century.”

Tony Dajer is chairman of the department of emergency medicine at New York Downtown Hospital in Manhattan. The cases described in Vital Signs are real, but names and certain details have been changed.

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