In this presentation, the speaker argues that acute myeloid leukemia (AML) is entering a revolutionary era driven by a suite of targeted and immunologic therapies that can overcome the curability ceiling imposed by traditional chemotherapy regimens such as 3+7, FLAG‑IDA, and high‑dose cytarabine. The talk outlines several high‑impact strategies: (1) monoclonal antibodies and antibody‑drug conjugates against CD33 and CD123, including CAR‑T approaches that could address virtually all AML patients; (2) small‑molecule inhibitors targeting FLT3 mutations (present in ~33% of AML) and IDH1/2 mutations (≈20%), which show strong response rates when used in combination; (3) BCL‑2 inhibition with venetoclax, which, although modest alone, yields powerful results when paired with epigenetic agents or intensive chemotherapy; (4) checkpoint‑inhibitor immunotherapy, anticipated to become a mainstay when combined with other agents, mirroring successes in solid tumors; and (5) next‑generation chemotherapy formulations such as CPX351 and vosaroxin that may deliver cytotoxic drugs more effectively with reduced toxicity. The speaker emphasizes that optimal, rational combination of these modalities is expected to raise cure rates in AML, expressing clear enthusiasm for the ongoing development of antibody constructs, CAR‑T cells, targeted inhibitors, immune‑modulatory drugs, and improved chemotherapeutics.
Chapters
My perception for both acute leukemias is that we are in a revolutionary period that is going to change how we treat and cure both acute myeloid leukemia and acute lymphocytic leukemia in the near future. In acute myeloid leukemia, I think we have hit a wall with the curability with chemotherapy combinations, be it 3+7 or the more intensive FLAG-IDA where you— we use high-dose RAC during the induction and we use additional nucleoside analogs. So at this stage in acute myeloid leukemia, in fact, we have many targeted therapies against the leukemic cells and also immune modulatory strategies that could help the environment kill the leukemia cells. So to start with, we know that acute myeloid leukemia cells express CD33 and CD123, and now we have different forms of monoclonal antibodies conjugated to toxins as well as antibody constructs against CD33 and CD123. So these are 2 targeted therapies that could target 100% of patients with acute myeloid leukemia and improve their outcome. Moreover, we know that a third of patients with acute myeloid leukemia have expression of FLT3 abnormalities, and about 20% have mutations in IDH1 and IDH2. So we have now multitudes of FLT3 inhibitors as well as inhibitors of IDH 1 and 2 that are progressing with very positive results. I do not think that we're going to use them as single agents, but in combinations they are giving very powerful response rates and durable responses. Another aspect which is very interesting is the development of BCL-2 inhibitors that shorten the life of the leukemic cells. So now we have ABT-199 or venetoclax, which alone has very modest activity, but in combination with either epigenetic therapy or intensive chemotherapy is giving also very powerful results. As it relates to the microenvironment, as with all the other solid tumors, we're finding that checkpoint inhibitors are active in hematologic malignancies, and I think they could have very positive results, perhaps not as single agents, but again in combinations or in combined checkpoint inhibitor modalities as was done in melanoma. So the checkpoint inhibitors are going to be an important research today and perhaps a mainstay of therapy in the future. Finally, there are a couple of new modified chemotherapy agents such as CPX351 and vosaroxin, which may improve on our capacity to deliver chemotherapy more effectively and perhaps with less results. So I think we have in our hands several agents, both targeted immune oncology strategies and better chemotherapy agents, which when we learn how to use them, optimally and in combinations will probably increase the cure rate in acute myeloid leukemia. So I mentioned I'm very excited about the monoclonal antibodies, the antibody constructs, the CAR T-cells against CD33 and CD123, the targeted therapies against FLT3, IDH1/2, checkpoint inhibitors, and some of the new chemotherapy improved agents such as CPX351 and vosaroxin. And I mentioned already the venetoclax, which I think is going to be also a very effective anti-AML therapy.
