AML Review: Diagnosis, Treatment and What’s New

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:

  • Advances in diagnostics 
  • Development of new therapeutic agents
  • Revised risk stratification criteria from European Leukemia Net (ELN)
  • Updated classification guidelines from the World Health Organization (WHO)
Mary-Beth M. Percival, MD sits for a portrait in front of a white board

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.”

Diagnosing and Assessing Risk in AML

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:

  • Blood counts and assessment of the morphology and percentage of myeloblasts
  • Cytogenetics and fluorescence in situ hybridization (FISH) to identify chromosomal changes (though about 40% of people with AML have normal cytogenetics)
  • Immunophenotyping (flow cytometry) to characterize the blasts based on antigen expression
  • Molecular genetic testing to identify specific gene mutations

Using the results from these tests, physicians consult the WHO and ELN guidelines to determine the diagnosis and prognosis

Updated WHO Diagnostic Criteria for AML

The WHO classification of AML was recently updated, separating the disease into two categories:

  • AML with defining genetic abnormalities
  • AML by differentiation 

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.”

Revised ELN Risk Classification

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. 

Deciding the Right AML Treatment Path

AML treatment involves a series of steps to control and possibly cure the disease, including:

  • Induction therapy
  • Consolidation therapy
  • Maintenance therapy
  • Allogeneic hematopoietic cell transplantation (alloHCT)

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:

Induction Therapy

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:

  • Midostaurin: Approved in 2017 for AML with a FLT3 mutation, midostaurin is a multikinase inhibitor added to 7+3 induction and consolidation, and then used as single agent maintenance. Clinical trial results showed a median overall survival of 74.7 months compared with 25.6 months in the placebo group. Side effects include cytopenias, GI toxicity and rash. 
  • Gemtuzumab ozogamicin (GO): GO was the first antibody-drug conjugate ever developed. It combined a CD33-targeted antibody with a chemotherapy drug. GO was reapproved by the FDA in 2017. The induction regimen used at Fred Hutch, includes GO administered during induction on days one, four and seven. 
  • Vyxeos (CPX 351): This drug was approved in 2017 as an alternative to 7+3 induction. A study of previously untreated patients aged 60 to 75 found Vyxeos improved the median overall survival modestly (9.6 months vs. 6.0 months with 7+3 therapy). In addition, more patients in the Vyxeos arm underwent alloHCT, and survival was better after alloHCT.

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:

  • Favorable risk: Consolidation chemotherapy
  • Intermediate or adverse risk: Consolidation chemotherapy, alloHCT or maintenance therapy

Treating Patients Who Are Not Fit for Induction Therapy

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 Therapy

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 Therapy

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.

Managing Relapsed AML

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:

  • IDH inhibitors: About 10% to 20% of people with newly diagnosed AML have IDH mutations. IDH inhibitors include ivosidenib for IDH1 mutations and enasidenib for IDH2 mutations. Enasidenib is FDA-approved only for relapsed or refractory AML. 
  • Gilteritinib: This drug is an oral FLT3 inhibitor for relapsed or refractory FLT3-mutated AML. A large randomized trial led to FDA approval after demonstrating a median overall survival of 9.3 months with gilteritinib vs. 5.6 months with salvage therapy. 

Indications for Allogeneic Hematopoietic Transplant 

Transplant is typically an option for:

  • Intermediate and adverse risk patients in their first CR
  • All patients in their second CR 
  • Patients with primary refractory AML

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.”

AML Care at Fred Hutch

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
 

Anthracycline A type of antibiotic that comes from certain types of Streptomyces bacteria. Anthracyclines are used to treat many types of cancer. Anthracyclines damage the DNA in cancer cells, causing them to die. Antibody A protein made by immune system cells and released into the blood. Antibodies defend the body against foreign substances, such as bacteria. Antigen A foreign substance, such as bacteria, that causes the body’s immune system to respond by making antibodies. Antibodies defend the body against antigens. Chemotherapy Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It may be given alone or with other treatments. Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Chemotherapy may be given by mouth, injection, infusion or on the skin, depending on the type and stage of the cancer being treated. It may be given alone or with other treatments, such as surgery, radiation therapy or biologic therapy. Chemotherapy Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It may be given alone or with other treatments. Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Chemotherapy may be given by mouth, injection, infusion or on the skin, depending on the type and stage of the cancer being treated. It may be given alone or with other treatments, such as surgery, radiation therapy or biologic therapy. Clinical trial A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis or treatment of a disease. Differentiation In cancer care, differentiation describes how much a tumor looks like the normal tissue it came from. It is used in tumor grading systems, which are different for each type of cancer. In biology, describes the processes by which immature cells become mature cells with specific functions. In cancer, this describes how much or how little tumor tissue looks like the normal tissue it came from. Well-differentiated cancer cells look more like normal cells and tend to grow and spread more slowly than poorly differentiated or undifferentiated cancer cells. Differentiation is used in tumor grading systems, which are different for each type of cancer. Fluorescence in situ hybridization A laboratory method used to look at genes or chromosomes in cells and tissues with the help of fluorescent dye. It is used to help diagnose diseases such as cancer and to help plan treatment. A laboratory method used to look at genes or chromosomes in cells and tissues. Pieces of DNA that contain a fluorescent dye are made in the laboratory and added to a cell or tissue sample. When these pieces of DNA bind to certain genes or areas on chromosomes in the sample, they light up when viewed under a microscope with a special light. FISH can be used to identify where a specific gene is located on a chromosome, how many copies of the gene are present and any chromosomal abnormalities. It is used to help diagnose diseases such as cancer and to help plan treatment. Gene The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. Gene The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. Genetic testing Tests that can be done to see if a person has certain gene changes known to increase cancer risk. Immunophenotyping A process that uses antibodies to identify cells based on the types of antigens (markers) on the surface of the cells. A process that uses antibodies to identify cells based on the types of antigens (markers) on the surface of the cells. This process is used in basic research and to help diagnose diseases, such as specific types of leukemia and lymphoma. Immunophenotyping may also be used to separate cells into different groups based on the markers they have on the surface. Medical oncologist A physician who has special training in diagnosing and treating cancer in adults using chemotherapy, hormonal therapy, biological therapy and targeted therapy. A physician who has special training in diagnosing and treating cancer in adults using chemotherapy, hormonal therapy, biological therapy and targeted therapy. A medical oncologist is often the main health care provider for someone who has cancer. A medical oncologist also gives supportive care and may coordinate treatment given by other specialists. Mutation Any change in the DNA sequence of a cell. Mutations may be caused by mistakes during cell division, or they may be caused by exposure to DNA-damaging agents in the environment. Any change in the DNA sequence of a cell. Mutations may be caused by mistakes during cell division, or they may be caused by exposure to DNA-damaging agents in the environment. Mutations can be harmful, beneficial or have no effect. If they occur in cells that make eggs or sperm, they can be inherited; mutations that occur in other types of cells are not inherited. Certain mutations may lead to cancer or other diseases. A mutation is sometimes called a variant. Pathologist A physician who has special training in identifying diseases by studying cells and tissues under a microscope. Prognosis A statement about the likely outcome of a disease in a patient. Refractory In medicine, refractory disease is a disease or condition that does not respond to treatment. Relapse The recurrence (return) of disease after an apparent recovery. Relapse The recurrence (return) of disease after an apparent recovery. Remission A decrease in, or disappearance of, signs and symptoms of cancer. A decrease in, or disappearance of, signs and symptoms of cancer. In partial remission, some (but not all) signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although cancer still may be in the body. Side effects A problem that occurs when treatment affects healthy tissues or organs. Some side effects of cancer treatment are nausea, vomiting, fatigue, pain, decreased blood cell counts, hair loss and mouth sores. White blood cell A type of blood cell that is made in the bone marrow and found in the blood and lymph tissue. White blood cells are part of the body’s immune system and help the body fight infection and other diseases. A type of blood cell that is made in the bone marrow and found in the blood and lymph tissue. White blood cells are part of the body’s immune system. They help the body fight infection and other diseases. Types of white blood cells include granulocytes (neutrophils, eosinophils and basophils), monocytes and lymphocytes (T cells and B cells). Checking the number of white blood cells in the blood is usually part of a complete blood cell (CBC) test. It may be used to look for conditions such as infection, inflammation, allergies and leukemia. Also called leukocyte and WBC.

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