Aref Al-Kali, MD
For patients with acute myeloid leukemia (AML), emerging regimens are likely to have a significant impact on clinical practice, according to Aref Al-Kali, MD.
The April 2017 FDA approval of midostaurin (Rydapt) in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation, for example, is the first approved targeted treatment option for adult patients with newly diagnosed FLT3
Moreover, the histone deacetylase inhibitor pracinostat in combination with azacitidine was granted a breakthrough therapy designation by the FDA in August 2016 for elderly patients with AML who are ineligible for intensive chemotherapy. The decision was based on phase II findings that demonstrated a median overall survival of 19.1 months with the combination, along with a 42% complete response rate.
Al-Kali, a hematologist and oncologist at Mayo Clinic, reviewed the management of AML during the 2017 OncLive®
State of the Science Summit on Hematologic Malignancies. In an interview, he discussed some of the recent advancements, exciting ongoing trials, and the largest unanswered questions.
OncLive: Can you provide an overview of your presentation on AML?
We talked about the standard regimens, practice, and the new trials and new drugs [coming down the pipeline] in AML. We talked about some of the changes that have been happening in the management of AML, in both adult and elderly patients. Specifically, we talked about some of the new data—about the differences between daunorubicin at 90 mg/m2
versus 45 mg/m2
and 60 mg/m2
. We talked about some of the changes coming to the NCCN guidelines showing that both the 90 mg/m2
and 60 mg/m2
approaches are acceptable.
We also talked about some of the new trials with the 90 mg/m2
versus 60 mg/m2
of daunorubicin, and about the important role of FLT3
in both prognosis and treatment of [patients with] AML. We spoke specifically about the allele burden and the difference between ITD
mutation and TKD
We also discussed the standard treatments in elderly patients with AML, reviewed what is available, and the current management. We also reviewed the newer trials that seem to be very promising in AML, especially combinations with standard regimens for elderly AML.
There is a histone deacetylase inhibitor called pracinostat, and based on a combination trial of pracinostat plus azacitidine, it seems to be more powerful and less toxic, and seems to be increasing the response and potentially the survival rate. There are ongoing phase III trials right now to hopefully answer that question.
We also spoke briefly about venetoclax (Venclexta) in combination with low-dose cytarabine about how there is a good response rate. This might hopefully be something that will change the practice, although phase III studies are still ongoing.
There were also exciting results about a new combination with a new formula called CPX-351. With this liposomal formula, it seems that the response is better and the toxicity is less, specifically in elderly patients with AML. There was a phase III study that was presented at the 2016 ASCO Annual Meeting, and more results were presented at the 2016 ASH Annual Meeting. All of that supports that the combination seems to be very effective, especially in these elderly patients who have high-risk features by being secondary AML or have genetic abnormalities predicting that they will be not good candidates for standard chemotherapy. In this trial, the responses were better, the mortality was less, and the survival was potentially better than 7+3—even in the patients who proceeded with stem cell transplantation.
What does FLT3 tell us about prognosis and how it affects treatment decisions?
We do know that the prognostic risks for any acute leukemia depend on both the patient and the disease itself. For the acute leukemia itself, FLT3
is a marker that is present on our blood cells; however, it could be abnormal or mutated in patients with AML. This is usually abnormal in about 1 of every 3 patients. If that mutation is present, we know that the presentation tends to be a bit more aggressive, patients tend to have higher white cells, and they have a higher chance for relapse.
We have several trials with several drugs showing that combinations with a FLT3 inhibitor may be very helpful. In fact, even a single-agent FLT3 inhibitor could be helpful. We have data on combining midostaurin plus 7+3—which is standard chemotherapy—helping patients by having a better survival and longer duration of response. We hope that this new combination will pave the road for other drugs to be used.