Targeted Therapy Drugs for Acute Myeloid Leukemia (AML)

In recent years, drugs that target specific parts of cancer cells have been developed. Targeted drugs work differently from standard chemotherapy (chemo) drugs, and they tend to have different side effects. They can sometimes be helpful even when chemo isn’t, or they can be used along with chemo to help it work better.

Some targeted drugs can be useful in treating people with certain types of acute myeloid leukemia (AML).

FLT3 inhibitors

In some people with AML, the leukemia cells have a change (mutation) in the FLT3 gene. This gene normally helps the cells make a protein (also called FLT3) that helps the cells grow, and the gene change causes the cell to make more of this protein. Drugs that target the FLT3 protein can help treat some of these leukemias. Your doctor can test your leukemia cells to see if they have an FLT3 mutation. If so, one of these drugs might be helpful.

• Midostaurin (Rydapt) and quizartinib (Vanflyta) are FLT3 inhibitors that can be used along with certain chemotherapy drugs to treat newly diagnosed adults whose leukemia cells have a mutation in the FLT3 gene.
• Gilteritinib (Xospata) can be used to treat adults whose leukemia cells have a mutation in the FLT3 gene and whose AML has not gotten better on previous treatments or has recurred (come back).

These drugs are taken by mouth as pills or tablets, typically once or twice a day.

Common side effects of FLT3 inhibitors can include fever, low levels of white blood cells (with increased risk of infection), nausea, vomiting, diarrhea, redness or sores in the mouth, muscle or bone pain, headache, abnormal liver tests, and respiratory infections. Other side effects are also possible, depending on the drug.

Less often, these drugs might cause serious side effects. For example:

Quizartinib and gilteritinib may cause serious heart rhythm problems. This might lead to an irregular heartbeat, which could be life threatening. Your doctor will check your blood mineral levels and get electrocardiograms (EKGs) to test your heart rhythm before and during treatment with one of these drugs.

Gilteritinib might cause serious nervous system problems, which could show up as seizures or confusion. Tell someone on your cancer care team right away if you have either of these symptoms.

Midostaurin can sometimes cause serious lung problems, which might show up as a cough, chest pain, or shortness of breath. Tell someone on your cancer care team right away if you have any of these symptoms.

Rarely, gilteritinib might cause a serious side effect known as differentiation syndrome. This occurs when the leukemia cells release certain chemicals into the blood. It most often occurs during the first treatment cycle. Symptoms can include fever, breathing problems from fluid buildup in the lungs and around the heart, low blood pressure, liver or kidney damage, and severe fluid buildup elsewhere in the body. It can often be treated by stopping the drug for a while and giving a steroid such as dexamethasone.

IDH inhibitors

In some people with AML, the leukemia cells have a mutation in either the IDH1 or IDH2 gene. These genes help the cells make certain proteins, which are also called IDH1 and IDH2. Mutations in one of these genes can stop blood cells from maturing the way they normally would.

Targeted drugs called IDH inhibitors can block these IDH proteins. These drugs seem to work by helping the leukemia cells mature (differentiate) into more normal cells. Because of this, they are sometimes referred to as differentiation agents.

These drugs can be used to treat AML patients who have  an IDH1 or IDH2 mutation. Your can have your blood or bone marrow tested to see if your leukemia cells have one of these mutations.

• Ivosidenib (Tibsovo) is an IDH1 inhibitor. It can be used to treat AML with an IDH1 mutation, either as the first treatment in people who are older or are not healthy enough to tolerate strong chemo, or to treat AML that comes back after treatment or is no longer responding to other treatments.
• Olutasidenib (Rezlidhia) is an IDH1 inhibitor that can be used to treat AML with an IDH1 mutation that comes back after treatment or is no longer responding to other treatments.
• Enasidenib (Idhifa) is an IDH2 inhibitor. It can be used to treat AML with an IDH2 mutation, either as the first treatment in people who are older or are not healthy enough to tolerate strong chemo, or to treat AML that comes back after treatment or is no longer responding to other treatments. 

These drugs are taken by mouth, once or twice a day.

Common side effects can include nausea, vomiting, diarrhea, fatigue, joint pain, shortness of breath, increased levels of bilirubin (a substance found in bile), and loss of appetite. 

An important possible side effect of these drugs is known as differentiation syndrome. This occurs when the leukemia cells release certain chemicals into the blood. It most often occurs shortly after starting treatment, but sometimes it can happen months later. Symptoms can include fever, coughing or breathing problems (from fluid buildup in the lungs and around the heart), dizziness or lightheadedness (from low blood pressure), urinating less often (from damage to the kidneys), and severe fluid buildup elsewhere in the body. It can often be treated by stopping the drug for a while and giving other medicines (such as dexamethasone or hydroxyurea).

Gemtuzumab ozogamicin (Mylotarg)

This targeted therapy consists of a monoclonal antibody (a lab-made immune protein) linked to a chemotherapy drug. Once inside the body, the antibody attaches to a protein called CD33, which is found on most AML cells. The antibody acts like a homing device, bringing the chemo drug to the leukemia cells, where it enters the cells and kills them when they try to divide into new cells.

This drug can be used along with chemo as part of the initial treatment of AML that has the CD33 protein. It can also be used by itself, either as the first treatment (especially in people who might not be healthy enough for intense chemo), or if other treatments are no longer working. It is given as an infusion into a vein (IV).

The most common side effects are fever, nausea and vomiting, low levels of blood cells (with increased risks of infection, bleeding, and fatigue), swelling and sores in the mouth, constipation, rash, and headaches.

Less common but more serious side effects can include:

• Severe liver damage, including veno-occlusive disease (blockage of veins in the liver)
• Reactions during the infusion (similar to an allergic reaction). You will likely be given medicines before each infusion to help prevent this.
• Serious or life-threatening infections, especially in people who have already had a stem cell transplant
• Changes in heart rhythm

BCL-2 inhibitor

Venetoclax (Venclexta) targets BCL-2, a protein in cancer cells that helps them live longer than they should. This drug can be used with chemo in people newly diagnosed with AML who are 75 years or older, or who are not healthy enough to tolerate strong chemo. It's taken by mouth once a day.

Side effects can include low levels of certain white blood cells (neutropenia), low red blood cell counts (anemia), diarrhea, nausea, bleeding, low platelet counts, and feeling tired. Less common but more serious side effects can include pneumonia and other serious infections.

Tumor lysis syndrome (TLS) is another possible side effect of this drug. It's more common in people who have large numbers of leukemia cells in their body when treatment starts. When the leukemia cells are killed, they break open and release their contents into the bloodstream. This can overwhelm the kidneys to the point that they get rid of all of these substances quickly. This can lead to the build-up of too many minerals in the blood and even kidney failure. The excess minerals can also cause problems with the heart and nervous system. To help keep this from happening, you may start at a very low dose and then slowly increase it over time. Sometimes, other medicines may be given to help lower your white blood cell count below a certain level before starting this drug. Your treatment team will do blood tests and also watch for signs of TLS.

Hedgehog pathway inhibitor

AML cells can have mutations (changes) in genes that are part of a cell signaling pathway called hedgehog. The hedgehog pathway is crucial for the development of the embryo and fetus and is important in some adult cells, but it can be overactive in leukemia cells.

Glasdegib (Daurismo) is a drug that targets a protein in this pathway. It can be used with chemotherapy in people with newly diagnosed AML who are 75 years or older, or who are not healthy enough to tolerate strong chemo.

This drug is taken by mouth once a day.

Side effects can include muscle and bone pain, fatigue, low white blood cell counts (neutropenia), low red blood cell counts (anemia), bleeding, nausea, low platelet counts (thrombocytopenia), and redness or sores in the mouth.  

Because the hedgehog pathway affects fetal development, this drug should not be taken by women who are pregnant or could become pregnant. It is not known if this drug could harm the fetus if taken by a male partner. Anyone taking this drug should use reliable birth control during and for some time after treatment.