IN MARCH 2017, 30-year-old Amanda Ferraro of Manalapan, New Jersey, went to the emergency room feeling weak and fatigued. The ER doctor suggested she had contagious mononucleosis and sent her home to recover with rest. But her condition didn’t improve, and a return trip to the ER in May revealed that the percentage of blast cells in her bloodstream had skyrocketed from 11% in March to over 80%. Ferraro was diagnosed with acute myeloid leukemia (AML), the most common form of leukemia in adults.
Blast cells are immature white blood cells that form in bone marrow. In a healthy person, blast cells mature into different types of white blood cells. But in a person with AML, these immature blasts, called myeloid cells, build up, crowd the bone marrow and start spilling into the bloodstream. As a result, a person ends up without enough of other critical blood cell types. A normal blast count is 5% or less in bone marrow and 0% in the blood. A person diagnosed with AML will have 20% or more blast cells in their blood or bone marrow. The person may feel symptoms, including fever, bone pain, fatigue and frequent infections. The five-year relative survival rate for AML is about 30%.
Given Ferraro’s dangerously high blast count, she was admitted to the hospital two days after her diagnosis to start an intensive combination chemotherapy regimen. She spent the next 33 days in the hospital undergoing treatment. She learned that her cancer had an inversion on chromosome 16, an abnormality sometimes found in AML that’s associated with a more favorable outcome. But her leukemia cells also carried a mutation in a gene called TP53, found in 5% to 10% of AML cases, and this feature is associated with a worse AML outlook. The genetic findings prompted her doctor at Robert Wood Johnson University Hospital in New Brunswick, New Jersey, to put her on a more intensive chemotherapy regimen known as MEC (short for the three drugs used: mitoxantrone, etoposide and intermediate-dose cytarabine). This combination has been shown to be more effective in treating people with high-risk AML.
The first phase of AML treatment, when a person is given chemotherapy to rid the blood of cancer cells, is known as induction. The goal of this intense treatment is remission, with normal blood counts and no sign of leukemia. To deepen that response, most patients with AML will need additional treatment, known as consolidation, which may include a stem cell transplant, more chemotherapy or a combination of both approaches. Ferraro ultimately needed four rounds of additional high-dose chemotherapy after the induction phase. She achieved complete remission on Valentine’s Day, Feb. 14, 2018, and hoped it would last.
Many Different Diseases
A month before Ferraro got her good news, 30-year-old Ryan Candler of Dayton, Ohio, also found out he had AML. After a painful cyst on his finger wouldn’t heal, his doctor ordered blood tests, which showed a dangerously low platelet count. In January 2018, a bone marrow biopsy revealed an overabundance of blast cells characteristic of AML. Candler was told he had “six to 10 weeks to hurry up and treat his cancer.” Within 24 hours of his diagnosis, he was admitted to the acute leukemia unit at the Ohio State University Comprehensive Cancer Center in Columbus to start chemotherapy.
Candler’s cancer differed from Ferraro’s in an important way. It carried a mutation in a gene called FLT3, which led his doctors to add a targeted drug called Rydapt (midostaurin). Rydapt was first approved by the Food and Drug Administration in 2017 as a treatment to accompany chemotherapy in newly diagnosed patients with FLT3-mutation-positive AML. Research leading to the approval showed the drug improved survival for patients with this mutation over chemotherapy alone. The combination didn’t control Candler’s cancer after two cycles, however, so he was given another FLT3 inhibitor called Xospata (gilteritinib), months before that drug received FDA approval as a single agent for relapsed or refractory FLT3-positive AML. A study showed that about 20% of 138 patients with these features who took Xospata achieved remission after a median follow-up of 4.6 months. The treatment with Xospata sent Candler’s AML into complete remission. Because FLT3 mutations are associated with a poor prognosis, his doctor recommended a stem cell transplant to keep the AML at bay. After treatment with chemotherapy to destroy his bone marrow cells, he received an infusion in September 2018 using stem cells extracted from his mother’s bone marrow. Candler has been in remission ever since.
“I tell my patients that AML is not just one big diagnosis,” says hematologist-oncologist Alice Mims, the acute leukemia clinical research director at the Ohio State University Comprehensive Cancer Center in Columbus. Mims treated Candler. “It’s hundreds of diseases lumped under a single category that vary by different genomic features seen in leukemia cells.”
Patients can discuss genetic testing, clinical trials and the potential need for a stem cell donor in the future.
People diagnosed with acute myeloid leukemia (AML) should ask their doctor about genetic testing, says Alice Mims, a hematologist-oncologist at the Ohio State University Comprehensive Cancer Center in Columbus, noting that this type of testing may not be routine in every hospital. She also recommends newly diagnosed patients ask whether a stem cell transplant might be necessary; asking early allows more time to find a suitable donor.
One new approach is whole-genome analysis, which can detect chromosomal abnormalities and specific gene mutations in a single test by rapidly sequencing more than 20,000 genes, says David Spencer, a pathologist who studies AML at Washington University School of Medicine in St. Louis. Spencer notes that cytogenetic tests have limitations, including failing to yield results for chromosomal abnormalities in up to 20% of patients, either because the cells don’t grow or there aren’t enough cells to make an accurate determination. However, whole genome testing is not widely available for AML.
“[Whole genome sequencing] is on the horizon, and we hope it will streamline how AML patients are diagnosed and how treatment decisions are guided,” Spencer adds.
With continued advances in diagnosis and treatment, experts expect to see more precise approaches to treating AML and improved patient outcomes. If patients are newly diagnosed with AML or if their cancer doesn’t respond to approved treatments, they can ask about clinical trials based on the genetic characteristics of their cancer, says Mims.
“There are efforts to look at specific subsets [of patients]—younger versus older, fit versus nonfit,” she says. “We want to better under-stand the mutations that are found together and how to better select therapy based on them. There’s a lot coming up, and I think things will improve in the next five years.”
A Precision Approach
Once AML is confirmed, genetic testing helps to determine a patient’s likely prognosis and to make treatment decisions, says hematologist-oncologist Mikkael Sekeres, who is the chief of the division of hematology at the Sylvester Comprehensive Cancer Center of the University of Miami Heath System. Human cells have 23 pairs of chromosomes, each containing thousands of genes, and many of the telltale changes in AML occur at the chromosome level. Testing to look at these changes is known as cytogenetics or karyotyping, and it involves doctors growing the cancer cells in the lab to look at chromosomes under a microscope. “It can tell you globally, for example, if you’re missing a portion of chromosome 7 or have an additional chromosome 8 or a switch within or between two chromosomes,” Sekeres says.
About half of patients with AML have cancer that has chromosomal abnormalities, which can be used to determine the aggressiveness of the cancer and subsequent treatment, including whether a stem cell transplant is warranted once the cancer is in remission or if more chemotherapy is likely to be enough. For instance, patients whose cancer shows a swapped segment, or translocation, between chromosomes 8 and 21 have a good prognosis, while loss of part of chromosome 5 or 7 suggests a poorer outcome and need for more aggressive treatment or stem cell transplant.
Genetic testing for AML has expanded to identify the mutational status of dozens of genes, including FLT3, TP53, IDH1 and IDH2, that can play a role in AML and the expected outlook for patients. “There are certain mutations we know will make leukemia a bad actor,” Sekeres says. “For example, if there’s a TP53 molecular mutation, we know chemotherapy alone is unlikely to cure that person.”
These small but significant changes take place within the chromosome and can’t be seen under a microscope; they require molecular analysis or DNA sequencing, which examines the nucleotides (or order of the chemical bases, known as AGCT) in the DNA molecule. Using these two types of testing has helped to ensure that the treatment chosen will provide the best chance of putting the cancer into complete remission. Approximately 50% to 70% of adults with AML will achieve complete remission after intensive chemotherapy. Close to half of those who reach complete remission will survive three or more years and may be cured. But for others, the cancer either doesn’t go away completely or comes back. Relapses affect about half of all AML patients who reach complete remission after initial treatment. When this happens, genetic testing can help to decide on the next treatment options.
Doctors have typically recommended starting chemotherapy immediately for AML before getting cytogenetic or molecular genetic results from patients. However, that practice is beginning to change. Results from the Beat AML Master Trial reported in the December 2020 Nature Medicine showed advantages for patients who wait to receive genetic testing results prior to starting chemotherapy. In 395 previously untreated patients age 60 or older, the testing, which returned results in seven days, led to lower 30-day mortality and longer overall survival when compared to patients who received the standard of care.
“For patients who don’t need urgent intervention, it is safe to wait a week to get results back,” says Mims, who was one of several researchers involved in the Beat AML trial.
Waiting times to get results will vary depending on where people are treated; it may take longer than the seven-day period in the Beat AML Master Trial. But, in cases where the AML doesn’t appear to be overly aggressive based on blast counts, the general consensus is to “try to wait for [genetic test] results to come back,” Mims says, noting that this approach has the added advantage of allowing patients more time to process their diagnosis.
“Having the week or 10 days gives patients and their families time to think about what their goals are and have a better discussion with their doctors as far as long-term outcomes,” Mims says.
Growing Number of Targeted Treatments
The growing number of drugs targeting specific mutations in AML has made testing valuable in guiding treatment decisions, not only after an initial diagnosis, but also if the cancer stops responding to treatment or returns after a remission, Sekeres says. About 20% of people with AML have mutations in IDH1 or IDH2, for which targeted treatments—Tibsovo (ivosidenib) and Idhifa (enasidenib), respectively—are available for when the cancer doesn’t respond to induction chemotherapy or comes back. In May 2019, the FDA extended the approval of Tibsovo for use as a first-line treatment for patients aged 75 or older with newly diagnosed AML carrying an IDH1 mutation who are unable to undergo intensive induction chemotherapy due to other health conditions.
Sekeres also notes evidence from an international trial presented at the American Society of Hematology annual meeting in December 2021 showing that adding Tibsovo to a low-intensity chemotherapy drug called azacitidine tripled survival in newly diagnosed adults who had IDH1-mutant AML and weren’t considered good candidates for intensive chemotherapy. In the study, the median overall survival improved from 7.9 months with azacitidine and placebo to 24 months with azacitidine plus Tibsovo. Patients also tolerated the treatment well, leading Sekeres to suggest that the combination, while not yet approved, might be a “very real option” for some patients who have AML with IDH1 mutations. The current standard in the U.S. for these patients is azacitidine plus Venclexta (venetoclax), another targeted therapy, but Sekeres says that this regimen can be difficult to tolerate for older patients with other health conditions.
“We’re going to be seeing these [targeted] approaches move more toward the front line,” Sekeres says, either alone or in combination with induction chemotherapy.
A clinical trial of IDH inhibitors—Tibsovo for AML that has IDH1 mutations or Idhifa for IDH2 mutations—together with intensive chemo for patients 18 and up is underway now in Europe, Mims notes. Therapies targeting other common mutations in AML are also in the works. For instance, Mims says there’s excitement about novel menin inhibitors, which may be effective in patients with hard-to-treat AML that carries mutations in a gene called NPM-1, the most common gene alteration in adult AML, as well as in patients with chromosome rearrangements that can affect another gene known as KMT2A. There still isn’t an approved treatment to target the TP53 mutation that Ferraro’s cancer carries, which is known to come with a higher chance of relapse. Treatment for this subset of AML is recognized as an area of significant unmet need, with clinical trials ongoing.
Despite hoping for the best after her initial treatment, Ferraro found out the blast cells in her bloodstream were back in September 2018, just seven months after tests showed her AML was in remission. Her doctors then made the discovery that the TP53 her leukemia carries runs in her family and is present in all her cells, not just the cancer cells, which is exceedingly rare. While it’s unclear how this germline mutation changes her risk of relapse, it does put Ferraro, and other members of her family who carry the same mutation, at greater risk for developing other cancers. Another hospital stint with intensive chemotherapy put the AML back into remission, and Ferraro, now 33, received a stem cell transplant from a matched donor. “It’s hard being diagnosed with cancer,” Ferraro says. “Even when I had the transplant, sometimes I felt like giving up because of the mutation. But if you can try and just be positive and voice your concerns and ask questions and recognize that the research and medications are improving—if you have faith and trust your doctors, you can have hope.”
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