Targeted Power: Improving Prognoses for Patients With Chronic Myeloid Leukemia

CUREHematology Special Issue (October)
Volume 1
Issue 1

Targeted drugs known as TKIs have improved the prognosis for patients with chronic myeloid leukemia.

It was at the tail end of 2001 when Joannie Clements decided she’d had enough. For six months, she had suffered severe and unusual bruising, fatigue, extreme weight loss, eye bleeds, unusual infections, loss of appetite, inability to smell or taste, headaches, enlarged lymph nodes, loss of toenails, and a spleen so enlarged it was like a “football pushing all the other organs aside,” she says.

Frustrated with her doctor, who had dismissed some of her symptoms and been unable to determine the reason for others, she demanded an MRI. That led to a blood test, and then to two bone marrow biopsies that revealed she had chronic myeloid leukemia (CML).

“Before that had happened, my body swelled up like a Stay Puft man, which meant my kidneys were shutting down,” she says. By the time she was diagnosed and admitted to the hospital, “They gave me two to four years. I wouldn’t have lived another year because of the state I was in.”

But her oncologist put her on Gleevec (imatinib), a brand-new drug approved just seven months earlier, in May 2001, which seemed to promise at least a twoyear extension on her life. Before that, the only approved treatment for CML was the immunotherapy interferon, which could extend a life a few years, but often with severe flu-like side effects.

Another option was stem cell transplant, but that can involve some challenges. Usually, only patients who aren’t elderly are eligible for transplants, and only if they can find a match. Then there’s the fact that transplants are only curative in 30 to 70 percent of the patients who get them. But without a transplant, a CML diagnosis was a certain death sentence — until Gleevec.

“As it turns out, I’m still on Gleevec,” says Clements, now 73 and living in Costa Mesa, California. “It revolutionized the world. Our spirits lifted. It gave me hope and strength to fight it.”

Time magazine, the New York Times and dozens of other publications agreed: Gleevec was truly a miracle drug that, for many, turned the “doom and gloom” of CML that Clements found everywhere online into an opportunity for hope. Today, the drug and others like it offer people with CML the possibility of a normal life expectancy.

For Tom Reek, an 82-year-old volunteer with The Leukemia & Lymphoma Society living in Alberton, New York, Gleevec meant the end of interferon’s awful side effects. Diagnosed in January 1999, he described the alternating freezing and sweating from interferon as brutal and insisted on enrollment in the Gleevec trials. Three months after starting Gleevec, he says, his leukemia cells dropped by 85 percent and he was “feeling like Clark Kent.”

Before Gleevec, nearly all patients with CML would die within 10 years, many of them in half that time or less. “Today, what dictates mortality with CML is not as much the CML, but the patient’s other comorbidities,” says Ehab Atallah, M.D., an associate professor of hematology and oncology at Medical College of Wisconsin and Froedtert Hospital in Milwaukee.

Although CML is still considered a rare disease, with about 4,000 to 5,000 new diagnoses in the U.S. each year, the number living with it today has ballooned into the tens of thousands thanks to Gleevec and similar drugs that followed, says Brian Druker, M.D., director of Oregon Health & Science University’s Knight Cancer Institute and the oncologist-scientist who developed Gleevec.


Gleevec’s power lies in targeting the protein that tells white blood cells to divide out of control, which, in turn, inhibits other marrow cells from fully differentiating. That protein results from the errant fusion of chromosomes 9 and 22: The ABL gene on chromosome 9 merges with the BCR gene on chromosome 22, creating the BCR-ABL fusion gene on chromosome 22, christened the “Philadelphia chromosome.” Using a fluorescent in situ hybridization test to dye the chromosomes, it’s possible to see whether the translocation from chromosome 9 to 22 has occurred. Chromosome 9 turns red and 22 turns green, so if red and green are melded together, that’s the hallmark of CML.

“Chromosomes are like little computer cells,” explains Atallah. “When a piece of 9 goes to 22, it puts these two computers next to each other and they make a fusion protein, which is BCR-ABL.”

The BCR-ABL protein produced from the BCRABL gene is a type of tyrosine kinase protein, and Gleevec, a tyrosine kinase inhibitor (TKI), flips off the protein’s signal. Since Gleevec’s debut in May 2001, four more FDA-approved TKIs have followed: Sprycel (dasatinib), Tasigna (nilotinib), Bosulif (bosutinib) and Iclusig (ponatinib).

The majority of CML patients are diagnosed in the chronic phase, when fewer than 10 percent of their blood or bone marrow samples contain immature cells called blasts. In the accelerated phase, patients have between 10 and 20 percent blasts, a low platelet count that does not improve with treatment, or a white blood cell population that is at least 20 percent basophils, a type of cell associated with an inflammatory reaction. In blast phase or blast crisis, the most severe phase, blasts account for more than 20 percent of a patient’s bone marrow or blood cells, and these may have spread to other tissues or organs beyond the marrow.

“Up front, if patients are in accelerated or blast phase, the TKIs can work, but the chances that they work are less, and they work for a shorter time,”Atallah says. It’s in blast phase and some acceleratedphase patients that doctors recommend a stem cell transplant. Otherwise, the first step is picking a TKI.

When newly diagnosed, it’s important for a patient to find an oncologist with experience and expertise in treating CML, and also to talk to others with CML and do his or her own research, ultimately getting onto a medication and continuing to take it consistently — unless the patient’s response rate is poor (blood and other tests should be done regularly to check the level of specific abnormalities associated with CML) or the side effects are unbearable, says Greg Stephens, executive director and founder of The National CML Society, who lost his mother to the disease. “Determine your goals and what the diagnosis is, get on the right drug and arrest this disease as well as possible and as quickly as possible.”

Determining which first-line TKI a newly diagnosed CML patient should take — Gleevec, Tasigna or Sprycel — depends on the patient’s comorbidities, age, lifestyle and karyotype (the status of chromosomes in cancer cells). The patient’s tolerance for the side effects associated with a particular drug is a secondary concern. Doctors monitor patients’ responses to the drugs with regular polymerase chain reaction (PCR)testing, typically every three months during the first two years of the disease.

“PCR is the gold standard for testing patients,” Stephens says. “Some insurance companies are saying that’s an elective test, but it’s really necessary. We have to know how low the level of the disease is in our body, and that’s the only test that can indicate that.”


The long-term goal of TKI treatment is not to cure CML, which only a transplant can do, but to achieve a major molecular response (MMR). The first level of response is called a hematological response, a 10-fold reduction of leukemia cells within three months. A cytogenetic response means the marrow has cleared of cells containing the Philadelphia chromosome; MMR is the deepest level of response.

“What we’re looking for is about a 1,000-fold decrease in the number of leukemia cells,” Druker says. “If they haven’t achieved that response in 12 to 24 months, they have a higher risk of resistance. If they haven’t had a 10-fold decrease within three months, they’re also at a higher risk for resistance.”

Resistance means that the patient responds to a drug but relapses, or doesn’t respond optimally to the TKI in the first place. Up to a quarter of CML patients develop some form of resistance. It tends to develop in the first three years after diagnosis, after which the risk falls considerably, Druker says. Diagnosis at a later phase increases the likelihood of resistance. Treatment with Gleevec in the accelerated phase, for example, results in about a 50 percent risk of relapse, he says.

“We know that about 60 percent of that resistance is caused by mutations that render the drug inactive against its target, and about 40 percent are due to other mechanisms,” Druker explains. Most of those mutations can be treated by Tasigna, Sprycel and Bosulif. But among the group whose resistance is caused by mutations, about 10 perccent have the T315I mutation, which only Iclusig can treat. Still, some patients with the T315I mutation may develop resistance to Iclusig, too.

“It’s almost as though the cancer evolves and then it becomes progressively more resistant,” Druker says. That calls for a stem cell transplant, which only about 1 percent of patients with resistant CML need.


Just because TKIs have almost completely reversed the prognosis for patients with CML does not mean it’s easy to take these drugs for life, as patients need to do. Right from the start, some people may dismissively suggest that CML is “the good cancer” now that such effective treatment exists, minimizing the natural reaction of shock and fear that most people feel at diagnosis.

“When you hear the ‘cancer’ word, your jaw drops and the hair stands up on the back of your neck,” Stephens says. “When I heard it, I was physically sick to my stomach.”

Some family, friends, coworkers or employers might not take the disease seriously because it’s managed with a pill or patients “don’t look sick,” he says. Gail Sperling, an Information Resource Center specialist with The Leukemia & Lymphoma Society, says she has heard of families saying to patients, “You have all your hair and weight, and you don’t look gaunt, but you’re always complaining you’re tired.” Those responses don’t take into account the burden CML can be.

Even patients can become complacent over time.

“Back before 2001, stem cell transplants were probably the Holy Grail,” says Stephens. “Today, it’s so vastly different that newly diagnosed patients can’t fathom the magnitude of this disease. Sometimes, there’s a bit of a disconnect between how one feels, physically, and the seriousness of the disease and the commitment needed to staying the course of treatment.” Atallah also notes that sticking with medication regimens, or adherence, is a significant problem: Approximately 20 percent of patients have poor compliance, and after symptoms disappear, by the seventh or eighth year of diagnosis, patients often become less conscientious about taking their medication. The side effects of TKIs are another reason compliance may decline, although support groups can help. It’s in the group Clements founded, CML Busters, that patients taking Gleevec learn about the “Gleevec sandwich” to lessen the likelihood of nausea with the drug: They eat half their meal, take Gleevec and then finish the meal.

When she began treatment, Clements experienced periorbital edema (swelling around the eyes), pale skin, fatigue, a full-body rash, short-term memory loss (“chemobrain”) and alternating diarrhea and constipation. Some of these have faded over time, while others continue indefinitely.

“For a patient to know that he or she is not alone with a side effect is hugely important,” Sperling says. “Some of these things take months to go away. Just being able to vent within the context of a support group or discussion board and hear that you’re not alone can go a long way.”

Some TKIs are associated with a heightened risk of heart problems, and oncologists or cardiologists may prescribe aspirin or statins to lessen that risk, especially for patients predisposed to cardiovascular issues even before starting treatment for CML.

The best thing to do after a diagnosis — after crying and drying your tears — Stephens says, is to carry on with life, staying active despite the fatigue and bone pain you might have. Patients can find support groups through The National CML Society or The Leukemia & Lymphoma Society, which offers trained information specialists, online discussion boards and chats, information on local support groups, peer-to-peer support, webcasts, videos and information booklets.


In addition to the side effects many patients experience, people with CML may be thinking about the financial implications of taking a very expensive drug — whose prices can vary dramatically based on insurance coverage — for life. Others may be worrying about family planning. Women with CML can become pregnant, but must work with their doctors to develop a plan prior to conceiving, as TKIs should not be taken during pregnancy; then, they must undergo close monitoring for disease activity, Stephens says.

The combination of side effects, cost and the overall burden of taking a drug for life have led researchers to begin trials that attempt to wean patients off drugs without relapse. Atallah describes studies going back to 2010 in France where patients who had been taking TKIs for at least three years and had maintained a deep molecular response for at least two years stopped their medication; 50 percent needed to restart the drug, but 50 percent did not, though they continued to undergo monitoring.

Atallah himself is currently enrolling patients from 15 sites into the LAST trial — Life After Stopping TKIs. The LAST trial is assessing quality-of-life outcomes while monitoring patients after they stop their treatment. The overarching goal is to learn how to predict who can and cannot successfully halt treatment and then figure out why so that, down the road, researchers may be able to use this knowledge to help other people with CML stop treatment after a deep response.

Different trials are combining TKIs with other drugs to see if the disease can be decreased in patients with resistance or completely eradicated in others, says Druker. One laboratory trial, for example, tested the combination of chemotherapy drug Jakafi (ruxolitinib), which is known as a JAK-2 inhibitor, and Tasigna, and phase 1 and 2 trials in patients are recruiting. A proteasome inhibitor named Velcade (bortezomib), a type of drug that breaks down proteins, has been tested in phase 2 studies as a treatment for CML, and phase 1 and 2 studies are investigating the effects of adding the diabetes drug Actos (pioglitazone) to treatment with TKIs.

Previous studies have tested lonafarnib and Zarnestra (tipifarnib), both farnesyl transferase inhibitors, in patients resistant to Gleevec; at least one phase 1/2 study of Zarnestra in patients with CML is ongoing. A drug called Farydak (panobinostat), a histone deacetylase inhibitor, had been tested in patients resistant to Gleevec, but the drug showed little activity against Gleevec resistance, Druker says. While a cancer vaccine called CMLVAX100 had shown promise a decade ago, study of the drug seems to have slowed.

As researchers explore ways to beat treatment resistance and improve quality of life, people like Clements are focused on living as normal a life as possible with their disease. Clements says being proactive with her team of caregivers helps her manage stress and stave off depression.

“I get to know myself, my body and what’s going on, and I’m as much a manager of my disease as my husband and my doctors are,” she says. “That’s 50 percent of the battle, feeling like you have some control.”

Recent Videos
Image of Dr. Jorge Cortes; a man with short dark hair wearing a suit.
Image of a man with brown hair.
Image of a woman with short brown hair and glasses.
Image of a woman with short brown hair and glasses.
Image of a man with brown hair and a suit and tie.
Image of a woman with brown bobbed hair with glasses.