Challenges Remain Amid Rapid Advances in AML
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Eytan M. Stein, MD, discusses the introduction of novel agents, the relevancy of chemotherapy, and assessing minimal residual disease in acute myeloid leukemia.
Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center
Eytan M. Stein, MD
An explosion of approved agents has transformed the treatment paradigm in acute myeloid leukemia (AML), according to Eytan M. Stein, MD. 
“For about 40 years, we didn’t have much when it came to the treatment of [patients with] AML,” said Stein, a hematologic oncologist at Memorial Sloan Kettering Cancer Center. “Until about 3 years ago, we essentially had chemotherapy and hypomethylating agents. Now, [we are in] the dawn of a new era in AML.”
CPX-351 (Vyxeos), FLT3- and IDH1/2-targeting agents, for example, have demonstrated promising activity in patients with relapsed/refractory AML and, in some cases, those with newly diagnosed disease.
In the randomized phase III ADMIRAL trial, for example, the FLT3 inhibitor gilteritinib (Xospata) demonstrated an improvement in overall survival (OS) compared with salvage chemotherapy for patients with FTL3-mutated relapsed/refractory AML. The median OS was 9.3 months versus 5.6 months, respectively, leading to a 36% reduction in the risk of death (HR, 0.64; 95% CI, 0.49-0.83; P <.001).
In November 2018, the FDA approved gilteritinib for the treatment of adult patients with  FLT3  mutation—positive relapsed or refractory AML; the agency updated the drug’s label in May 2019 to include the addition of OS data.
Despite these additions to the paradigm, challenges remain, said Stein.
“There is a misunderstanding in AML that because we have these new drugs, we don't have to do more research, but this is still AML,” he added. “Although OS is improved with these new drugs, nearly every patient who received FLT3 or IDH1/2 inhibitors had passed away after 2 years. We are lengthening life, but not curing the disease.”
In an interview during the 2019 OncLive®  State of the Science Summit™ on Hematologic Malignancies, Stein, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, discussed the introduction of novel agents, the relevancy of chemotherapy, and assessing minimal residual disease (MRD) in AML.
OncLive: What treatments were available to patients prior to this therapeutic explosion?
Stein: Until 3 years ago, we traditionally split up [patients with] AML into 2 treatments. Patients fit for induction chemotherapy would receive a strong regimen during a 30-day stay in the hospital. If in remission, most patients would go on to receive an allogeneic bone marrow transplant. Some patients with favorable-risk disease may have received consolidation chemotherapy. 
Patients who are older than 65 years old would receive a hypomethylating agent because they may have not tolerated, [or could not tolerate] induction chemotherapy well. Currently, there are 2 hypomethylating agents on the market—azacitidine (Vidaza) and decitabine (Dacogen). The remission rates with those drugs were quite low in AML, and the OS was less than 12 months. 
How has the treatment paradigm evolved?
We have a new chemotherapy in AML, including chemotherapy that is specifically for patients with secondary AML that stemmed from a prior myelodysplastic syndrome, or from prior exposure to chemotherapy or radiotherapy from a different malignancy. We can treat those patients with CPX-351. We also have add-ons to chemotherapy. For example, we are giving patients with FTL3-mutated AML a drug called midostaurin (Rydapt) in combination with chemotherapy. 
Additionally, we have new FTL3- and IDH1/2-targeting agents that seem to [elicit remissions] in 20% to 30% of patients in the relapsed/refractory setting. 
Could you expand on the novel agents that have become available?
The data that support the use of CPX-351 were based on a randomized, open-label, phase III study, results of which showed a median OS of 9.56 months with CPX-351 compared with 5.95 months with standard 7+3 chemotherapy. 
For FTL3-positive patients, adding a FLT3 inhibitor to chemotherapy showed an OS benefit. Of patients who received midostaurin plus chemotherapy, 7% more of patients were alive versus those who received chemotherapy alone. 
Gemtuzumab ozogamicin (Mylotarg) is a CD33-directed antibody-drug conjugate that has shown an event-free survival benefit when combined with induction chemotherapy in patients with favorable- and intermediate-risk disease who are fit for induction chemotherapy. 
In the relapsed/refractory setting, there are so many drugs that it is hard to talk about all of them. One question in this space was, “If a patient with FLT3-mutated AML relapses, is it better to give re-induction chemotherapy or the targeted, oral pill gilteritinib?
The phase III ADMIRAL trial randomized patients with relapsed FLT3-positive AML to either chemotherapy or gilteritinib. The complete remission rate with gilteritinib was [21.1%], and median OS was 9.3 months with the oral pill compared with 5.6 months with chemotherapy. 
The available IDH1/2 inhibitors were approved in the relapsed/refractory setting, based on trials that showed remission rates with these agents on the order of 25%. Again, these are oral pills taken at home with limited toxicity. 
Another exciting agent is venetoclax (Venclexta), which targets BCL-2, an anti-apoptotic protein. Targeting BCL-2 causes leukemia cells to undergo apoptosis. 
The combination of azacitidine and venetoclax in newly diagnosed older patients with AML leads to CR rates on the order of 70% compared with 20% to 30% with azacitidine alone. A phase I/II study also showed a median OS of 17.5 months with the combination versus 8 months to 10 months with azacitidine alone.  Additionally, venetoclax can be combined with low-dose cytarabine with similar response rates. 
Finally, glasdegib (Daurismo), a hedgehog inhibitor, was approved. A randomized phase II trial combined glasdegib with low-dose cytarabine in older patients with AML. The combination led to a doubling of median OS compared with low-dose cytarabine alone. 
What are your thoughts on iodine-131 apamistamab (Iomab-B)?
We have that clinical trial open at our institution. I am excited about Iomab-B for the group of patients with newly diagnosed AML in which chemotherapy doesn't work. For these patients, you don't want to try 3 other treatments and risk an infection that would make them ineligible for transplant. 
In a lot of patients, the goal is transplant. Although we have a lot of new strategies for patients with refractory disease, they work best in older patients who may not be candidates for transplant. 
The data we have seen with Iomab-2 show that these patients are able to get a transplant that sticks. A subset of those patients will stay in long-term CR, and potentially be cured. 
How does the role of chemotherapy optimally fit in this current landscape?
That is a good question; I think it breaks down to a generational divide. The younger generation [of researchers] is hoping to make chemotherapy irrelevant, while the slightly older generation still sees a place for chemotherapy in our armamentarium. 
I am an old man at heart; chemotherapy has an important place in AML. These new agents are likely going to work better if you combine them with chemotherapy as shown with midostaurin plus chemotherapy for FLT3-positive patients. 
How is the role of MRD evolving in AML?
It has become clear that the presence of MRD at the time of CR is an adverse prognostic factor.  Patients with MRD going into an allogeneic bone marrow transplant are at a higher risk of relapse posttransplant versus if they had MRD negativity. Also, [the presence of MRD] seems to predict if a patient with favorable-risk disease who is not having a transplant will relapse or not. 
Therefore, it is important to check for MRD, but what do you do if you find it? Right now, we don't have an MRD eraser in AML. In acute lymphoblastic leukemia, blinatumomab (Blincyto) is approved with the specific purpose of erasing MRD. 
We need clinical trials to test whether erasing MRD is possible in AML and, if so, what drugs can do that? Additionally, by erasing MRD, are we improving survival? 
I tend to use flow cytometry to measure MRD. It is a specialized, technical procedure that must be interpreted correctly; therefore, it is not possible at every institution. There is an ongoing effort to harmonize the way MRD is assessed. 
Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Eng J Med. 2019;381:1728-1740. doi: 10.1056/NEJMoa1902688.
