Older adults with acute myeloid leukemia (AML) are frequently ineligible for intensive chemotherapy regimens and need other treatment options. Recent data with targeted therapies are promising for these patients and may help improve their outcomes.

We are fortunate that there are many new therapies for older patients who are newly diagnosed with AML. However, treatment selection has become more complicated as more therapies have become available. On average, patients present with AML in their late 60s, with a median age at diagnosis of 68 years. The age of diagnosis has increased, partially because of our aging population and also because we have gotten better at treating other cancers and medical events. People are simply more likely to develop a therapy-related myeloid malignancy over time.

When choosing treatment for the newly diagnosed older patient, the first main decision point is whether we should start with an intensive induction treatment or with lower-intensity treatment. In general, fewer than half of patients are eligible for intensive chemotherapy, but, within that group, there are many different genomic classifications. For example, if a patient has core-binding factor AML characterized by inv(16) or t(8;21), it would be appropriate to add gemtuzumab ozogamicin to their intensive chemotherapy regimen. If a patient has an FLT3-ITD mutation, an FLT3 inhibitor that targets FLT3 proteins with ITD mutations, such as quizartinib, should be added. If a patient has an FLT3-ITD mutation and an FLT3-TKD mutation, an FLT3 inhibitor that targets FLT3 proteins with both ITD and TKD mutations, such as midostaurin, should be added. Ongoing trials are examining the combinations of different medications for these patients with AML.

I very rarely give intensive chemotherapy to any patient who is older than 75 years, and I often avoid it even in most 70-year-old patients. An exception would be if I have a particularly fit patient who has a core-binding factor leukemia because I know that such individuals can be exquisitely curable with intensive chemotherapy. Otherwise, I opt for a lower-intensity approach for almost all older patients with AML.

Chemotherapy comes with complications. If we can achieve similar response rates but with better tolerability, especially if the plan is to proceed with hematopoietic stem cell transplantation, then we can potentially reach that curative goal with less morbidity by choosing a lower-intensity combination.

For older patients with newly diagnosed AML who are not appropriate candidates for intensive chemotherapy, the current standard of care is a hypomethylating agent (typically azacitidine or decitabine) plus venetoclax. However, there are 2 populations for whom we should be thinking beyond this backbone. For patients with IDH1-mutated disease, azacitidine plus the IDH1 inhibitor ivosidenib is a compelling frontline treatment option. It seems to be better tolerated and has better outcomes data. On the other hand, patients with TP53 mutations do not have a clear survival benefit from the addition of venetoclax, so I would worry about adding toxicity without improving their overall outcomes.

Menin inhibitors are an exciting new class of therapy. We are seeing responses in high-risk, treatment-refractory patients in the preliminary trial data that have been presented thus far. The 2 patient populations that appear to benefit the most from menin inhibitors are those with NPM1 mutations or KMT2A rearrangements. It is currently difficult to say exactly where the menin inhibitors will fit best because we are still in the early days of data collection. It is important to remember that targeted therapies work well, but they typically should not be used in isolation because there are many different resistance mechanisms. The combinations are likely to be more effective choices.