New developments in the complex and rapidly changing world of acute myeloid leukemia (AML) promise to improve health outcomes for people with the disease. They include:
Medical oncologist Mary-Beth Percival, MD recently provided a review of AML and the latest news during the 13th Annual Comprehensive Hematology and Oncology Review Course. Dr. Percival and her colleagues at Fred Hutchinson Cancer Center provide leading edge AML care. Fred Hutch was created by the merger of the Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center.
AML accounts for about 1% of the nearly 1.8 million new cancer cases each year, says Dr. Percival. Its five-year survival rate today is 30.5% compared to 6.3% in 1975—a nearly fivefold increase.
“AML is a rare cancer with an improving outlook,” she says. “Though we have a long way to go, research is improving our understanding of AML and how to manage it.”
AML is a heterogenous condition driven by a wide range of genetic changes. Making an accurate diagnosis and assessing risk — which is important in determining treatment — requires in-depth testing, including:
Using the results from these tests, physicians consult the WHO and ELN guidelines to determine the diagnosis and prognosis.
The WHO classification of AML was recently updated, separating the disease into two categories:
These new guidelines eliminated the 20% blast requirement for certain AML types with defining genetic abnormalities. “Having fewer than 20% blasts is diagnostic in the presence of certain genetic changes, such as the well-known RUNX1-RUNXT1 and CBFB-MYH11 fusions,” says Dr. Percival. “The WHO also added several other genetic anomalies as AML-defining, including the NPM1 mutation, which is the most commonly mutated gene in AML.”
AML subtypes determine a patients’ prognosis and help physicians select the most appropriate therapy. ELN risk classification is a widely used tool to establish risk and was recently updated.
“ELN changed the classification of NPM1, so the mutation is only considered favorable if it occurs in the absence of a FLT3-ITD mutation,” says Dr. Percival. “And the previous requirement for biallelic CEBPA mutations is now a monoallelic bZIP in-frame mutated CEBPA. This latter update is challenging for pathologists because that’s not how they have been classifying these mutations.”
Other changes include the addition of several new genes to the adverse risk category.
AML treatment involves a series of steps to control and possibly cure the disease, including:
At each step, multiple treatment options require complex decision-making. And while the range of treatment options is expanding, the use of new therapies is not always clear cut, says Dr. Percival.
Some of the drug approvals are based on single arm or phase 1/2 two studies. Also, the FDA label is not always consistent with the population studied.
“We need more data on drug combinations, hierarchy, and sequencing, which mutations to prioritize, and defining fit or unfit patients,” she says. “It’s important to understand the primary literature when you're trying to figure out how to treat the patient in front of you.”
Current strategies at each step of AML treatment include:
The mainstay for induction therapy for nearly 50 years has been one to two cycles of “7+3” therapy (7 days of cytarabine and 3 days of anthracycline). Physicians at Fred Hutch often use a high dose cytarabine-containing regimen called CLAG-M, says Dr. Percival.
Recently approved drugs may enhance or replace 7+3 induction:
Following induction, the next steps depend on ELN risk, age and measurable residual disease (MRD) after treatment. MRD is an important factor for predicting prognosis. Studies show that the relapse rate is much lower in patients in complete remission (CR) without MRD.
For patients who achieve complete remission, physicians can consider:
Induction therapy is generally for fit patients. Those who are not eligible for induction may receive less intensive chemotherapy, a clinical trial or supportive care.
Venetoclax plus azacitidine is a less intensive chemotherapy regimen that was approved in 2018 for treatment-naïve patients not eligible for induction therapy. The phase 3 trial showed a median overall survival of 14.7 months vs. 9.6 months with azacitidine alone.
Consolidation generally includes three to four cycles of high-dose cytarabine (HiDAC). There are several variations in dosing. A recent study found faster white blood cell recovery using 3 g/m2 HiDAC every 12 hours on days one, two and three followed by administration of pegylated filgrastim.
Maintenance is a relatively new option for people who are not candidates for alloHCT. Regimens include midostaurin for patients with FLT3 mutations or azacitidine. A large randomized trial of patients over age 55 found median overall survival was significantly longer in those receiving oral azacitidine compared with placebo (24.7 months vs. 14.8 months).
Note that patients reported significant GI toxicities requiring ondansetron to control nausea. And oral azacitidine is not bioequivalent to subcutaneous or IV azacitidine.
For patients who relapse, the goal is to achieve remission with salvage therapy so they can receive alloHCT. For example, one study found that 88% of favorable-risk patients who relapsed and received transplant survived at least 5 years compared with 33% who received chemotherapy.
Many potential salvage chemotherapy regimens exist, but Dr. Percival recommends a clinical trial, when possible. Other treatment options include:
Transplant is typically an option for:
Having MRD predicts a poorer prognosis, but that’s probably not enough of an indication alone for transplant, says Dr. Percival. Patients who have MRD and receive transplant have a similar outlook to patients who had active disease at the time of transplant.
“This is why we call it measurable and not just minimal residual disease anymore,” says Dr. Percival. “With MRD, you still have a better chance of a cure with a transplant compared with chemotherapy. But not nearly as good as if you're in a complete MRD negative remission.”
Fred Hutch physicians have deep expertise in the complexities of diagnosing and treating AML. They also offer participation in clinical trials that offer access to the most innovative therapies.
The AML team at Fred Hutch is available to consult with community oncologists to discuss treatment options and available clinical trials. To consult with a Fred Hutch physician, contact 800.4UW.DOCS.