Global Perspectives: FLT3 Inhibitors for AML - Episode 1
Richard F. Schlenk, MD: Acute myeloid leukemia [AML] is a hematological disease focused on myeloid cells. It’s characterized by different mutations, which occur in the hematopoietic stem cells but also the hematopoietic progenitor cells to completely disrupt the differentiation of normal hematopoiesis into neutrophils, platelets, and red blood cells. This results in the most common symptoms of acute myeloid leukemia. If we have a decrease in platelets, bleeding may occur; if we have a decrease in neutrophil count, infection will occur; and if we have a decrease in red blood cell count, we have dyspnea, tachycardia, and what we know as the results of anemia.
Acute myeloid leukemia is a disease of older patients. The median age is 70 years. Half of the patients are older than 70 years of age and half of the patients are younger. Most of the research was done in younger patients so far. Acute myeloid leukemia is associated with a very dismal prognosis if not treated. Of patients who were not treated—and this we know from the 1970s and 1980s, where we just started to treat acute myeloid leukemia with chemotherapy—half of the patients were dead within 3 months. Acute myeloid leukemia has to be urgently treated with intensive chemotherapy, and this is done normally on an inpatient basis.
Acute myeloid leukemia has an incidence reported between 3 and 4 per 100,000 men and women per year. However, it may differ a little bit according to country. For example, in the south of France, an incidence of 2.0 to 2.5 per 100,000 has been reported; whereas in the United States, there is an increasing incidence that has been reported of up to 4.4 per 100,000 inhabitants.
Acute myeloid leukemia can be distinguished in 3 broad groups. The first group is newly developing acute myeloid leukemia called de novo AML, compared with treatment-related AML. These are AMLs occurring after patients receive intensive chemotherapy or radiotherapy for another malignancy or another disease. Finally, there is a third group of patients that can be distinguished. These are patients who develop an acute myeloid leukemia from another myeloid disease, either from a myelodysplastic syndrome or a myeloproliferative disease.
The heterogeneity of the disease was identified early, and this was done by morphology and introduced to the classification of acute myeloid leukemia in the 1970s through a French-American-British classification. This only looks at morphology. However, 7 subgroups were already identified. Over the years, more and more we learned that there is an enormous heterogeneity. If we look at the genetic background of the disease, we identify type 1 mutations, which induce proliferation and block differentiation; and type 2 mutations, which impact self-renewal and also differentiation.
However, additional mutations are coming up and interfering with epigenetics. We know now, for example, of mutations coming up in ADH1 and ADH2, but also TET2, and they interfere with the epigenetic makeup of the disease. If we look at the heterogeneity, different groups of mutational classes can be classified. However, this process is still ongoing because of the heterogeneity; in the prospect of specific inhibitors, this is an ongoing process.
Acute myeloid leukemia could first be treated in the 1960s to 1970s, where cytarabine and anthracyclines were introduced to the treatment of acute myeloid leukemia. Before that, patients really had a dismal prognosis, and half of patients were dead within 3 to 6 months. With only supportive therapy, the prognosis was very dismal. Then, with chemotherapeutic agents in the late 1990s, the prognosis clearly improved because for the first time with intensive induction therapy, complete remissions could be induced. A complete remission means that the disease is no longer identifiable in the bone marrow smears or in the peripheral blood smears.
However, we learned very rapidly that without consolidation therapy, all patients will relapse. And then in the late 1990s, intensive consolidation therapy was introduced. However, focusing on acute myeloid leukemia of younger patients, their prognosis improved. In contrast, the prognosis in older patients was still very dismal after or with chemotherapy. For example, the 5-year survival was below 5% in patients above the age of 60 even 10 years ago. I think this changes more and more in this landscape. First of all, even older patients receive consolidation therapy and allogeneic transplantation, which are very important treatment components in acute myeloid leukemia. But targeted agents are now included in the treatment landscape of AML, and thus we will gradually improve the prognosis.
Transcript Edited for Clarity