Thirty-eight-year-old Danijela Djureinovic recently celebrated one of the most important milestones of her life, though it surely wasn’t one she would ever have wished for herself. It was Friday, November 3, 2017: the first anniversary of the day she found out why she had been feeling so fatigued.
“Everyone is tired,” she says. “Everyone has tired days. I was tired just waking up and getting out of bed in the morning.”
Djureinovic had known for a couple of months that her health was going from bad to worse. She couldn’t explain the exhaustion or why her body was suddenly bruising so easily even when she couldn’t remember having bumped into anything. Despite the crippling fatigue, despite the mysterious bruises up and down her sides, she’d gotten up and headed to work as usual at the Cleveland Clinic, where she worked as a critical care nurse. Her patients needed her. As she walked from the parking garage to the hospital, she could feel her legs cramping up. It felt as though her heart was going to beat right out of her chest just from the effort it took to continue putting one foot in front of the other.
Djureinovic confided in a coworker, who ordered lab tests for her during her lunch break. Later, after leaving work, she looked at the results. Djureinovic didn’t need a doctor to tell her, at least roughly, what they must mean. She’d seen labs like that before, belonging to some of her critically ill patients in the intensive care unit. Instead of going home, she went straight to the emergency room, accompanied by her best friend. “I think I have leukemia,” she told her friend.
A Medical Emergency
In fact, Djureinovic had acute myeloid leukemia (AML). Like all leukemias, AML is a form of blood cancer. As the American Cancer Society explains, it’s called “acute” as opposed to “chronic,” like some other leukemias, because, if left untreated, AML can progress rapidly. It’s both intense and aggressive; AML is capable of turning deadly in a matter of months, weeks, or even days.
“Myeloid” refers to the type of cells in bone marrow from which the leukemia cells form. Myeloid cells arise from blood-forming stem cells. Those myeloid cells should go on to form many of the other blood cell types you’d find in a perfectly healthy person: red blood cells, white blood cells, and platelets. But in AML, myeloid cells head off in the wrong direction, forming myeloblasts (often referred to as “blasts”). Those blasts never progress beyond an immature state; they typically carry mutations that encourage their proliferation and prevent them from dying after a reasonable period of time in the way normal cells should. They have become cancer cells.
As those cells continue to divide and grow, they can quickly crowd out healthy cells, leaving people with leukemia at risk of infection, anemia, and bleeding. They also leave people feeling fatigued and downright awful in just the way Djureinovic did. Even with the best treatments available, the majority of patients who develop AML ultimately die of serious infections due to bone marrow failure.
AML isn’t all that common. It accounts for less than 2 percent of all cancers, but it is the most common form of acute leukemia in adults. That means about 21,000 Americans will learn they have AML this year, while 10,500 people will die from it in the U.S. alone. AML might strike fewer people than melanoma skin cancer does, but it still manages to kill hundreds more.
When a diagnosis of AML comes in, there’s no time to spare. Studies have shown that essentially any delay in treatment, particularly for relatively young patients like Djureinovic, leads to worse outcomes. As a result, AML is treated as a medical emergency. Djureinovic found out she had AML on November 3, 2016. On November 4, she started her first round of intensive chemotherapy.
“Having an answer you don’t want was terrible, although at least it had a name,” she says. Her life had taken a sudden and unexpected turn for the worse, but she really doesn’t remember feeling any sense of shock. She didn’t even stop to cry. “I didn’t feel too much,” she says. “It was more about survival at that point.”
Facing the Red Devil
The emergency treatment regimen Djureinovic received is often referred to simply as “7+3.” A chemotherapeutic drug called cytarabine is delivered intravenously and continuously for seven days. That weeklong treatment is given with three days of another chemotherapeutic drug, often daunorubicin. The 7+3 regimen is intense and difficult by design, aimed to knock down those leukemia cells as rapidly as possible in an aggressive attempt to put a newly diagnosed patient into remission immediately.
Djureinovic found the treatment terribly grueling — the daunorubicin especially. She started to refer to the daily infusion as the “red devil,” inspired by its red color and the miserable side effects it caused, which can include nausea, vomiting, and diarrhea. In Djureinovic’s case, the treatment temporarily weakened her heart muscle.
When she finally made it through the seven-day treatment regimen, she found out her blast count (meaning the number of abnormal cells in her bone marrow) was still too high, at 8 percent. She’d have to start all over again and repeat the same regimen to try to eliminate even the smallest amount of residual disease. In the midst of the chemo treatments, Djureinovic had also gotten more discouraging news. A genetic analysis had found that the leukemia cells in her bone marrow carried an internal tandem duplication (ITD) mutation in a gene called FLT3. “They’d all told me FLT3 is the one I didn’t want to have, and I ended up having it.”
The mutation turns up in 25 to 30 percent of AML patients, so the result wasn’t really a big surprise. But it did place Djureinovic in a higher risk category. Her doctor recommended a bone marrow transplant, after she achieved remission, to follow the 7+3 chemotherapy as her best chance at survival. On February 15, she received the transplant, a steady drip of stem cells from an unrelated, matched donor, following yet another round of chemo intended to wipe out what was left of her diseased bone marrow. Hopefully, those donor cells would find their way back home in Djureinovic’s bones, to replace her diseased marrow with healthy tissue and give her a shot at remaining leukemia-free.
They’d all told me FLT3 is the one I didn’t want to have, and I ended up having it.
One Size Doesn’t Fit All
That difficult 7+3 treatment regimen Djureinovic went through is essentially the same one that any AML patient might have gotten since the early 1970s. According to Harry Erba, an oncologist at the University of Alabama at Birmingham, who doesn’t know Djureinovic, AML treatment has “really been 40 years of using the same regimen of very intensive chemo, and that’s all.”
Amid great progress in new and more targeted treatments, immunotherapies, and more for many other cancer types, AML treatment hadn’t changed in decades, despite the fact that the standard treatment comes with serious side effects and simply doesn’t work for a large swath of AML patients. For an “ideal” patient, one who is younger and whose leukemia cells have the “right” kind of abnormality, 7+3 treatment leads to complete remission about 85 percent of the time. It can keep people alive and well in the longer term about six times out of 10. But for most patients — those who are older, have a secondary AML, or whose leukemia cells aren’t abnormal in the right way — the chances of complete remission are 50 percent at best.
For many older patients, if the leukemia didn’t kill them, the treatment would. Treatment-related death is a well-known complication of the 7+3 therapy used to treat AML. Among older patients with other health problems, mortality rates related to the intensive chemo can be much higher than in younger patients. In fact, Erba says, it’s not uncommon for older patients to decide not to even try the chemotherapy, because the treatment is both so toxic and, in many cases, likely to be ineffective. That’s especially unfortunate, because most people with AML are older at diagnosis, between the ages of 65 and 74. For older patients or for those in poor health, treatments are often adjusted: for example, by lowering the doses of chemo.
In recent years, this woefully inadequate “one-size-fits-all” approach to AML treatment has slowly but surely begun to shift, fueled by a better understanding of AML biology. Last April, the Food and Drug Administration (FDA) announced approval for Rydapt (midostaurin) for the treatment of adult patients with newly diagnosed AML carrying the FLT3 mutation. The drug is given alongside — not in place of — the standard chemo. The FDA also approved a companion diagnostic assay, which can be used to detect the FLT3 mutation. That’s especially useful for patients who don’t find themselves at a major research hospital.
Although Rydapt’s benefits are considered modest — the drug extended the time to progression by about five months — the approval was nonetheless met with considerable enthusiasm. That’s because the announcement made Rydapt the first drug to receive approval for AML treatment in more than 15 years. (See sidebar “Mylotarg: Take Two,” page 63.) Rydapt is a kinase inhibitor, meaning that it works by specifically blocking enzymes tied to the growth of leukemia cells. Some heralded the news as the beginning of a new era in targeted AML treatment.
“Rydapt is the first targeted therapy to treat patients with AML, in combination with chemotherapy,” said Richard Pazdur, the director of the FDA’s Oncology Center of Excellence, in an FDA press announcement. “The ability to detect the gene mutation with a diagnostic test means doctors can identify specific patients who may benefit from this treatment.”
In August, there was more good news, as the FDA announced the approval of a drug called Idhifa (enasidenib) for adults with relapsed or refractory AML and specific mutations in another gene, called IDH2. Again, the drug’s approval came alongside approval for a companion diagnostic used to detect the specific mutations that would recommend the drug for a particular AML patient.
Erba says that about 10 to 12 percent of AML patients have the IDH2 mutation and the corresponding faulty protein that gums up the works by preventing the normal development of myeloid cells into mature blood cells. As a result, immature blood cells accumulate. Idhifa blocks the faulty protein, thereby allowing blood cells to fully develop, and then live and die more normally. In some cases, he adds, the drug seems to work a little too well, leading to overproduction of white blood cells, causing fevers and weight gain. Called differentiation syndrome, it can be fatal if not treated, but it can be managed with corticosteroids and early intervention.
They’re waiting for us to come up with the drug that cures cancer. But it’s more complex than that. What we need to do is target the genetic changes that lead to cancer [in each particular patient].
“Things have definitely changed,” says Anjali Advani, one of Djureinovic’s doctors at the Cleveland Clinic. Over the last 10 years, scientists have developed a more thorough understanding of the molecular abnormalities underlying AML. That enhanced biological understanding has finally started to translate into clinical advances, as evidenced by the FLT3 inhibitors and IDH2 inhibitors. “It can take time once you understand the science,” she says. But, ultimately, “that really helps us in understanding the disease and treating it the best we can.”
But the approvals of Rydapt and Idhifa highlight another unfortunate reality: Cancer, and AML in particular, is complicated. “A lot of people don’t understand,” Erba says. “They’re waiting for us to come up with the drug that cures cancer. But it’s more complex than that. What we need to do is target the genetic changes that lead to cancer [in each particular patient].”
Rydapt and Idhifa are exciting examples, but they are just the start. The FDA recently fast-tracked another FLT3 inhibitor, called gliteritinib, that might prove to work even better than Rydapt. And in August, the FDA approved Vyxeos, a new combination formulation of the 7+3 chemo drugs shown to boost survival in more than 300 newly diagnosed AML patients with myelodysplastic changes. Erba noted that a targeted drug called Venclexta (venetoclax), recently approved for chronic lymphocytic leukemia (CLL), is likely to gain approval for AML patients too. It works against another protein, called BCL-2, which may prevent cancer cells from dying.
The vast majority of AML cases involve a mutation in one gene or another that might serve as a viable target. In fact, most leukemia patients will carry at least two. A genomic study of AML reported in The New England Journal of Medicine in 2016 identified more than 5,000 mutations in 76 different genes or genomic regions that drove the blood cancer. The researchers found that patients could be divided into at least 11 groups, each with its own unique genetic and clinical features. In other words, AML isn’t really one disease, even if it usually looks the same under a microscope. It’s more of an umbrella term, encapsulating many conditions driven by multiple underlying genetic abnormalities. Those various AML forms will surely respond differently to treatment and come with different outcomes. Ideally, there would be a menu of targeted treatment options that doctors could match up to suit each of their patients and his or her cancer. A recent search on clinicaltrials.gov turns up nearly 500 trials that are now recruiting AML patients.
The nonprofit Leukemia & Lymphoma Society (LLS) recently launched a multi-center clinical trial, the Beat AML Master Trial, to test just such an approach. So far, the study has 10 open treatment arms covering the genetic mutations that turn up most prominently in AML patients, and a group whose leukemia cells don’t carry any of those more common genetic variants. Researchers have enrolled more than 180 patients age 60 or older.
Some patients in the trial will receive the FDA-approved Idhifa, but as a first-line treatment rather than in the relapsed and refractory setting for which it is now approved. The other treatment arms will assign patients to promising investigational drugs that are as-yet unproven. It’s unusual for a nonprofit to sponsor such a trial. But, explains Amy Burd, who is leading the LLS research team, when they asked themselves what could be done to push AML treatment forward and help patients, it became clear that the timing for such a trial was right. She says the nonprofit was also uniquely situated to bring all the stakeholders together, including patients, pharmaceutical companies, and the FDA.
The hope is that the Beat AML Master Trial and many other ongoing trials can keep the FDA approvals coming. Burd points out that it will be just as important to show it’s possible to make an informed treatment decision based on thorough genetic information within seven days. AML patients are often treated on the same day they are diagnosed. To convince doctors and patients it’s okay to wait a week for the genomic information needed to take a precision medicine approach, Burd says, is a “huge hurdle.”
As more drugs come along, there will be plenty of issues to sort out, including how best to combine them. There will be questions about whether patients can safely forgo chemotherapy or perhaps move to chemo treatments that aren’t quite so hard to live through. Progress in the development of immunotherapies, which aim to unleash the immune system against a cancer, has been slower for AML than for other forms of leukemia. Still, advances are being made there, too.
Many Rivers to Cross
The advances in AML treatment have helped Djureinovic. She received a drug called sorafenib, a multikinase inhibitor approved for liver and kidney cancer, for her FLT3 disease. And her FLT3 status helped determine whether she would receive a transplant. The good news is she’s in remission. She says the first 100 days following the transplant were tough. There were and still are many precautions she has to follow. She’s had to be extra careful to avoid exposures to everyday illnesses like the flu. For months, she slept a lot. For a while just the simple act of getting up and taking a shower or getting something to eat would leave her so tired she’d have to take a nap.
After the first three months, she started feeling better; in September, she went back to work full-time. She still has to avoid crowds and limit her activities. One thing she actually misses is being able to clean and vacuum the house, something she’d always found therapeutic. Her older sister, who moved in with her after the transplant, makes sure Djureinovic follows the rules and leaves the vacuuming to her. She says her sister will stay “until she deems me competent enough to live on my own.”
They’re trying to stay positive. Djureinovic is well aware of Rydapt’s approval for people with FLT3-mutant AML, which could be used post-transplant. She’s paying close attention to all the latest advances and ongoing research. “I do keep close tabs on what’s coming up, because I’m not out of the woods,” she says. “The first two years are tough. If you survive five years without relapse, chances are you won’t [relapse.] I keep a close eye so in case I do relapse, I’m informed.”
Mylotarg: Take Two
In September, the FDA approved a drug called Mylotarg (gemtuzumab ozogamicin) for adults newly diagnosed with AML whose tumors express an antigen called CD33 on their cell surfaces. Mylotarg is what’s known as an antibody-drug conjugate — consisting of an antibody attached to a toxin. The antibody directs the drug to cancer cells, which then take up the toxin and die.
“It acts like a Trojan horse,” says Harry Erba, an oncologist at the University of Alabama at Birmingham. In other words, it gets into cancer cells before releasing a toxin. “It’s taking an incredibly toxic drug and giving it only, or at least mostly, to the leukemia cells.”
For Mylotarg, it was a second chance. The FDA originally approved the drug 17 years ago for older patients whose CD33-positive AML had relapsed. Pfizer voluntarily withdrew it in 2010 in response to an unexpected number of deaths and unproven benefit. But the research continued, and now Mylotarg has earned its FDA approval again, at a lower recommended dose, for newly diagnosed adults with CD33-positive AML and for kids age 2 and older whose cancer has either relapsed or failed to respond to initial treatments.