Earlier this year, The Leukemia & Lymphoma Society hosted a presentation by Dr. Eunice Wang, Clinical Leukemia Service, Professor of Oncology, Roswell Park Comprehensive Cancer Center.
Dr. Wang’s presentation was entitled “Understanding Your Diagnosis: Acute Myeloid Leukemia (AML).”
AML is an extremely complex disease. Dr. Wang describes AML as an aggressive blood cancer that occurs mostly in older adults (60s and 70s). As our population ages, AML cases will increase accordingly. Learn more about acute myeloid leukemia here.
AML is Biologically Diverse
When researchers studied four hundred AML patients, they found four hundred different AML types. These AML cells evolve and are altered (mutated) which is one of the reasons that, until now, AML has been difficult to target.
There is not one dominant mutated gene defining AML. In fact, it is defined through multiple mutations that exist in one gene.
Symptoms may occur over weeks rather than months. For some newly-diagnosed patients, blood counts may be normal a few months prior to an AML diagnosis. Other patients may experience anemia, low blood counts, or infections. Bleeding may occur due to lower platelet counts. If patients have other disorders this will complicate AML therapies.
Dr. Wang explains that it is important to have a comprehensive workup. The oncologists look at cell structure, tumor markers, abnormalities in chromosomes, and DNA deficiencies.
The researchers extract RNA and DNA from the affected cells and then run tests for each mutation.
With the sophisticated testing equipment that is currently available, it is possible to look at hundreds or even thousands of genes to determine how many genes are altered by the disease. Dr. Wang emphasizes the importance of these tests stating that the information gained offers prognosis and targets specific mutations.
A question arises quite frequently from both doctors and patients asking if it is safe to wait for the test results when AML is such an aggressive disease.
Studies have shown that it is safe to wait a few days for the test results. Dr. Wang confirms that waiting for that information is important.
AML Therapy From the 1970s
Dr. Wang gave a brief history of an AML therapy that was developed at the Roswell Park Cancer Center in the 1970s. The therapy consisted of a seven-day regimen of cytarabine, a chemo drug, and a three-day regimen of daunorubicin, also a chemo drug.
The regimen is intensive and therefore must be administered in the hospital for over four to six weeks. The drug is effective in that it kills cancer cells but it also impacts normal cells. This results in patients requiring transfusions and antibiotics to combat the effect of the drugs on their immune system.
The therapy is called 7+3. It has been the standard of care for treating AML until 2017 when a series of eight new AML drugs were approved by the FDA to treat specific mutations.
Matching New Drugs to Mutations
The newly-approved drugs to treat AML are midostaurin, enasidenib, CPX-351, gemtuzumab, ivosidenib, gilteritinib, glasdegib, and venetoclax.
There are three mutations that are considered to be “actionable”. Dr. Wang discusses these in her presentation. They are IDH1, IDH2, and FLT3. The term “actionable” means that these newly approved drugs can target these mutations.
Dr. Wang explained that the most progress with AML has occurred in the patient population that is over the age of sixty and usually not able to tolerate a high dose of chemotherapy. These patients generally have conditions affecting their heart or blood pressure that present further complications.
Published data shows that low dose chemotherapy administered to AML patients will bring about a low response. But when you add venetolax to even a very low dose of chemotherapy, the response rates double.
Venetoclax appears to be the first drug specifically developed for patients seventy-five or older and patients with medical problems that preclude them from receiving the standard of care (7+3).
For patients who do not have the aforementioned mutations, other newly-approved and well-tolerated drugs are now available.
Venetoclax is considered one of the most important new drugs to be used in the treatment of AML. It is an oral drug that has been used in the treatment of chronic lymphocytic leukemia. Venetoclax has recently been approved in combination with three other drugs to treat AML.
Cancer can be viewed as a disturbance in the balance between cell death and cell growth. Without cancer therapy, leukemia cells are able to escape cell death. When they are treated with chemotherapy alone, the cancer cells can activate processes that prevent them from dying.
However, when you block a process called BCL-2 with venetoclax, the leukemia cells become sensitive to the chemotherapy and are destroyed.
About Response Rates
Results show that sixty to seventy percent of patients have benefited from venetoclax plus chemotherapy.
For years it was believed that patients 75 years or older would be unable to tolerate a bone marrow transplant that could completely eradicate AML. In a small study, thirty-one patients were administered venetoclax plus low dose chemotherapy.
These patients were eventually able to receive a bone marrow transplant and were still in remission after twelve months with two-thirds of those patients still alive at the two year mark.
About Maintenance Therapy
Looking back several decades we find that after the first round of the aggressive 7+3 induction, patients had been expected to undergo bone marrow transplant.
There are many reasons why this is not feasible. In lieu of a bone marrow transplant, two or three additional doses of chemotherapy would be administered to prevent the return of cancer. Many older patients were not able to tolerate these additional rounds.
Now a new oral drug called CC-486 has been developed and approved. It is being used as maintenance therapy for AML patients who are older or who have other illnesses that preclude them from receiving a bone marrow transplant.
CC-486 is taken fourteen days out of each month for one year. So far, it has been fifty percent effective in prolonging survival and delaying the time before the cancer returns. Its companion drug is decitabine which some clinicians claim is also effective in this setting.
One type of immunotherapy involves activating antibodies to recognize and bind to immune cells as well as cancer cells.
Another type of immunotherapy involves removing immune cells from patients and genetically modifying them in the lab. Then they are re-infused back into the body and target the AML cells.
Both of these processes have generated encouraging responses.
About Pediatric ALL
Dr. Wang ended her excellent presentation with very good news about acute lymphocytic leukemia (ALL). She explained that in the 1960s and 1970s the disease was ninety percent fatal.
By the year 2000, ninety percent of children with ALL survived. It is extremely encouraging to see the survival rate for these children change from only ten percent survival to over ninety percent.
Dr. Wang and her associates hope to see the same results for AML.