Sony introduced the Walkman in 1979. At the time, it was revolutionary, but when compared with the technology available today, it is woefully outmatched.
A similar technological discrepancy has existed in acute myeloid leukemia (AML). Before 2017, the last novel treatment options in AML were approved the same year that the Walkman hit the U.S. market. This anemic pace of innovation left physicians treating AML with chemotherapy agents cytarabine and daunorubicin, while other malignancies gained groundbreaking targeted agents and immunotherapy options. Over the last four decades, there was minimal improvement in patient outcomes, creating an unmet need. Thankfully, this trend was finally reversed in 2017 with four FDA approvals in AML.
Research presented at the 2017 American Society of Hematology (ASH) Annual Meeting in Atlanta reinforced and advanced a few key trends in AML. The following trends show promising signs of continued improvement in AML and have the potential to drastically change the AML treatment landscape:
1. Genetic fragmentation: Previously, AML was considered a single disease with limited treatment options. However, with an improved understanding of the biological disease drivers and advances in genetic testing, AML is now characterized by the specific genetic profile of the individual disease. Two of the products approved in 2017, Rydapt and Idhifa, target genetic disease drivers: FLT3 and IDH2 mutations, respectively. Several additional targeted therapies in late-stage development are poised to enter the market in the short term. We can look at non-small-cell lung cancer as an analog malignancy, which has already undergone this shift to a biomarker-driven treatment landscape with targeted therapies. Research presented at ASH went so far as to identify mutations that accumulate years before AML disease onset, which may enable early intervention.
2. The new frontier: combinations of targeted therapies: The arrival of multiple targeted agents approved in combination with chemotherapy or as monotherapy is an essential first step to improved patient outcomes. However, physicians will need to determine how these targeted therapies can work together in combination with each other to make strides over the baseline monotherapy or chemotherapy regimens. As genetic fragmentation of the AML continues to improve, more focused groups of patients will have therapy designed to fit more than one mutational driver of disease. This is especially true in the relapse/refractory setting where disease progression can emerge as the result of several added mutations. Early research presented at ASH explored a BCL-2 inhibitor + MEK or MDM2 inhibitors while a second study looked at BCL-2 inhibitor + FLT3 inhibitor. While further research is conducted, the prospect of targeted therapy combinations has the potential to treat high-risk patients with several mutational disease drivers.
3. Advancement of immunotherapy: Immunotherapies such as checkpoint inhibitors and CAR-Ts have achieved impressive recent advances in other malignancies such as acute lymphoblastic leukemia. The promise to harness the immune system and achieve dramatic improvements in AML took early steps forward at ASH. A phase 1 trial demonstrated safety and initial anti-leukemic activity for a bispecific DART protein used to redirect T-cells to kill cancer cells expressing biomarker CD123. A second phase 1 trial utilized CD123-specific CAR-T cells to achieve promising anti-leukemic activity along with safety.
Despite the recent approvals, the unmet need in AML is still very apparent, with a five-year survival rate of only 27%, according to the National Cancer Institute. However, for the first time in decades, there are reasons to be optimistic for the future of AML. Improved genetic testing, combinations of targeted therapies, and the advancement of immunotherapies will finally provide physicians options to advance beyond Walkman-era treatments.