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On October 28th, 2021, Dr. Eytan Stein joined our Adult AML Chapter as part of the HealthTree Community for AML program to discuss the importance of a personalized medicine approach for treating your acute myeloid leukemia.

Dr. Stein is an Assistant Attending Physician, Clinical Investigator and Director of the Program for Drug Development in Leukemia on the Leukemia Service at Memorial Sloan Kettering Cancer Center. He conducts phase I clinical trials of compounds that target the genetic and epigenetic basis of myeloid cancers, making him the perfect person to speak with us on the topic of personalized medicine. Dr. Stein led the clinical studies of the IDH2 inhibitor Enasidenib and the IDH1 Inhibitor Ivosidenib in patients with relapsed and refractory AML that led to their FDA approvals in 2017 and 2018. His current research focuses on explaining mechanisms of resistance to IDH inhibitors and the use of Menin inhibitors in patients with MLL-rearranged acute leukemia. His work has been published in many prestigious journals.

You can watch the video below or read the summary in order to learn more about this excellent event: 

Understanding AML

To understand AML, it's important to first understand what normal bone marrow is supposed to do. Cells in your bone marrow called stem cells or "baby blood cells" mature into myeloid stem cells and then end up becoming either red blood cells, platelets or white blood cells. The primary problem in AML is that the cells cannot mature past the myeloid stem cell stage of development to go on and become red blood cells, platelets and white blood cells. These immature cells are called "blasts". These blasts accumulate within the bone marrow and keep the normal healthy cells from developing. The goal of AML therapies are to eliminate all of these blasts and restore the normal operation of the bone marrow.

AML Demographics

As the population of the US is aging, the total number of patients with AML is increasing. Ten years ago, there were 16,000 cases per year in the United States, now there are about 20,000 per year and that number is expected to continue to increase as the population ages. AML is a rare disease. To give context to its rarity, there are 200,00 breast cancer cases per year in the United States, showing that AML makes up about 1/10th of the number of cases that breast cancer does. The median age of diagnosis is 68 years old. Younger patients can get AML but in general, it is a disease of aging. 

Every Person's AML is Unique

AML isn't just one disease. It's a bunch of different diseases where you have the same problem in the inability of the myeloblast to mature into healthy cells.

Previously, pathologists used to only look at the myeloid cells under a microscope to diagnose it. Now, the genetic mutations that are in your bone marrow are considered. No two patients have exactly the same genetic mutations. This tells us that the way we had to treat AML previously where all patients got the same treatment isn't the best way to treat AML. We need to find not only a general approach but also targeted approaches that can personally and very carefully treat the underlying gene mutations that are leading to AML in each particular patient.

Patients are classified into 3 groups: favorable, intermediate or adverse risk depending on the genetic mutations the patient has. Today in 2021, all of these categories are considered treatable and potentially curable. 

Personalized Treatment for AML

In giving treatment for AML, doctors have the goal of making a patient's blood counts normal again because this is why patients have complications. Doctors give therapy that lowers the number of blasts of <5% of the bone marrow which allows the bone marrow to recover to produce normal blood cells to avoid infections and the patient doesn't need recurring blood and platelet transfusions.

Intensive induction chemotherapy with 7 days of cytarabine and 3 days of daunorubicin is often given after diagnosis to those who are younger and "fit". For those who could not tolerate this, they would get Vidaza and Dacogen or low dose cytarabine. There were a large group of patients not offered any treatment at all but there wasn't any active treatment that would help them with their disease. In the past 10 years, there have been an explosion of drug approvals which include:

• 7+3 with midostaurin
• 7+3 with gemtuzumab
• liposomal 7+3 (Vyxeos)
• hypomethylating agents with venetoclax
• glasdegib
• ivosidenib
• enasidenib
• gilteritinib

The goal of these above treatments is to get the leukemia cells or "blasts" to die. There are various ways this can be done depending on the unique make-up of a person's leukemia cell. 

Targeted Drugs Given During Induction

Gemtuzumab (Mylotarg): this drug targets a protein that sits on the surface of the leukemia cell called CD33. The drug binds to CD33, drags the chemotherapy into the leukemia cell and causes the cell to die. It is a targeted therapy for patients with CD33 positive AML. Adding gemtuzumab to intensive chemotherapy leads to better outcomes

Midostaurin: an oral medication that targets a mutation called FLT3. Patients with this mutation who get intensive induction with midostaurin vs only intensive chemotherapy do better. 

A Drug for Therapy Related and Secondary AML

Some patients get AML because they received treatment for a different cancer that caused DNA damage that lead them to develop leukemia or they had a disease called MDS that turned into AML called secondary AML. 2-3% of women who get a certain chemo for their breast cancer go on to develop AML and this is called therapy-related AML. There is now a liposomal drug called Vyxeos for therapy related and secondary AML. A liposome is a soap bubble. Instead of traditional chemotherapy that drips into your vein and goes all over your body, Vyxeos is 7+3 chemotherapy collected within a soap bubble so you are better able to deliver more precise amounts of chemotherapy to the bone marrow. Patients with secondary AML who got Vyxeos do better than the patients that got regular 7+3. 

The Introduction of Venetoclax

Venetoclax targets a protein in leukemia cells called BCL-2 which is a protein that lives in your cells that tells cells not to die. Leukemia cells are smart and work to make themselves indestructible. They produce extra copies of BCL-2 so the cell can live on and cause disease. Venetoclax blocks the signal telling the cell to stay alive and causes the cells to die. Venetoclax given with azacitidine offers a successful treatment option to patients for who we used to not have options for. Patients can be on this therapy for years and live high-quality lives.

Targeted Therapy for Relapsed and Refractory AML

Until 7 years ago, we had no good treatment for relapsed or refractory AML. The only option for these people was to offer them more chemotherapy. This changed with the introduction of targeted therapies such as the approval of another FLT3 inhibitor called gilteritinib which is a very potent oral FLT3 inhibitor that targets the FLT3 mutation. 

Other new targeted therapies include enasidenib for patients with mutations in IDH2 and ivosidenib for patients with IDH1 mutations.

Sometimes a patient will have an IDH1 mutation, get ivosidenib and then develop a mutation in FLT3. At Memorial Sloan Kettering, there is a clinical trial about to open that combines different targeted therapies in patients with multiple mutations in order to offer promise to patients with dual mutations

Maintenance Therapy

Induction and consolidation were the classic two steps to treating AML, but now there is a lot of talk about giving maintenance therapy after a patient has completed consolidation to prevent the patient from relapsing. This is a very new strategy for AML. Patients who received maintenance therapy with Onureg (oral azacitidine) did better and lived longer than patients who didn't receive any maintenance therapy. Now many patients who do not have a transplant are offered maintenance. After a stem cell transplant, targeted therapies can be offered as maintenance.

Personalized Treatments in Development

• Combining IDH inhibitors with intensive induction chemotherapy (Dr. Stein recently did a study that showed this improved survival for patients)
• New class of compounds called menin inhibitors which may be very effective. These oral drugs target NPM1 mutations and MLL rearrangements. 

The Future of AML is Bright!

For AML we now have multiple new drugs that improve patients' lives. We have extremely effective low-intensity therapy that is safe and provides significant improvements in survival. Despite this, we still have a lot more to do. We need to quickly accelerate research in order to find a cure for every person with AML. 

It's important for patients to participate in clinical trials. This is the only way to make advances in AML treatment. Only 10% of patients go in clinical trials, but if we can get this up to 50%, we have the ability to cure every person with AML. 

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