Exploring Non-Intensive Treatment Options for Elderly/ Unfit Patients With AML

Tapan M. Kadia, M.D.

The treatment of acute myeloid leukemia (AML) has evolved significantly with new clinical trials investigating combinations of intensive chemotherapy with venetoclax (Venclexta) and FLT3 inhibitors, IDH1 and IDH2 inhibitors, hypomethylating agents, and more.

Risk stratification practices for patients with acute myeloid leukemia (AML) have also helped hematologists/oncologists determine which treatment-naïve patients are candidates for chemotherapy or transplantation. The addition of targeted therapies into the landscape even have provided a way to address the unique genetic makeup of some patients with AML.

For elderly and unfit patients with AML, therapies have changed drastically as experts have found ways to maintain or improve efficacy without intensifying the treatment. “There are a lot of options for older patients with AML and those patients who are unfit for intensive chemotherapy with low intensity therapy plus venetoclax and other targeted agents,” stated Tapan M. Kadia, MD, in an interview with Targeted Oncology^TM.

To further build on treatment options for elderly/ unfit patients with AML, investigators must acknowledge the fact that venetoclax changes the activity of some of agents used to treat AML, use a different backbones of lower intensity, and more.

“The future is bright in AML, particularly with the better understanding of disease biology and disease heterogeneity. As we continue to dissect these different subgroups biologically, we're going to be able to understand what the sort of Achilles heel of these different subgroups are and how we can target them better. The next big thing may be Menin inhibitors in AML,” added Kadia, professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.

In the interview, Kadia discussed the changes seen in the treatment landscape for patients with AML, specifically highlighting elderly and/or unfit patients.

Targeted Oncology: What does the current treatment landscape look like for AML?

Kadia: The treatment of AML has evolved significantly just in the last several years. We typically characterize patients at the start, not only their disease, whether it be genomically, heterogeneous, favorable-risk, high-risk, or intermediate-risk. We also look at the patients themselves and whether they can tolerate intensive chemotherapy, or where we would prefer a more lower intensity approach that is associated with less toxicity. Among younger fit patients, we generally consider intensive chemotherapy.

There are new trials now investigating the combination of intensive chemotherapy, with drugs like venetoclax, as well as FLT3 inhibitors. FLT3-mutated patients as a standard of care will receive 7+3 plus midostaurin [Rydapt]. There are trials now looking at intensive chemotherapy plus quizartinib and a recent trial demonstrated the overall survival benefit of quizartinib added to intensive chemotherapy in FLT3-mutated patients and other patients. We have given intensive chemotherapy with a regimen called CLIA of cladribine, idarubicin, cytarabine, with venetoclax, demonstrating high rates of response and high rates of minimal residual disease negativity, allowing these patients to move forward with transplant and hopefully cure their disease and older patients.

What changes in this space have shifted this treatment landscape?

The biggest change has occurred with the development of drugs like venetoclax, as well as IDH1 and IDH2 inhibitors. The use of hypomethylating agents has allowed us to treat a higher proportion of older patients with semi-curative attempts where we are achieving higher rates of complete remission with a combination and improving overall survival. The use of other targeted therapies is also important in this population. For example, those who are unable to tolerate chemotherapy, there are now options in the frontline of using single agent IDH1 and IDH2 inhibitors in patients who have those mutations.

There are also now trials looking at combination strategies with IDH inhibitors with 5-azacytidine, the most prominent being the recent AGILE study [NCT03173248], which demonstrated the improvement in outcomes with the combination of azacitidine

and ivosidenib [Tibsovo]in newly diagnosed patients with IDH1-mutated AML, which I think will become a standard of care in that subset in patients who are unable to tolerate intensive chemotherapy. There are a lot of options in older AML and those patients who are unfit for intensive chemotherapy with low intensity therapy plus venetoclax and other targeted agents.

In younger patients, there are clinical trials looking at combinations with venetoclax, FLT3 inhibitors, and upcoming studies that are going to read out looking at the combination of IDH inhibitors in that significant subset. After people achieve remission among those people who are not eligible for transplant, we now have an option of oral azacitidine based on the QUAZAR [NCT01757535] trial showing a survival benefit. Maintenance therapy is now standard in those patients who are ineligible for transplant, but there are also clinical trials in that area to try to improve outcomes combining oral azacitidine and other agents with some of the target agents I described.

What have been some pitfalls faced by investigators for older/unfit patients with AML? What is needed to overcome them?

The therapy for older patients or for patients who are unfit for intensive chemotherapy has evolved significantly. What happened is that we've been able to maintain or even improve efficacy without intensifying the treatment. One of the big setbacks or drawbacks of giving more intensive therapy in these older, unfit patients is that there's increased risk of toxicity, there's an increased risk of early mortality, there's more complications, a higher frequency of hospitalizations, and a potentially lower quality of life.

In the past, the way we improved efficacy was by intensifying many of these agents. But now with small molecule drugs that target the biology of AML, we can now deliver efficacy while still maintaining safety and tolerability. The first big wave has been the combination of venetoclax with low intensity therapies such as hypomethylating agents which have demonstrated improved response rates, improved CR rates, and improved overall survival.

The next question is how do we build on it? How do we improve further on lower intensity therapy in this patient population while still maintaining a good tolerability profile? One option is to take that backbone HMA plus venetoclax and add drug X. That drug x could be a targeted agent such as FLT3 inhibitor, which is being studied now in patients with FLT3-mutated AML, adding other drugs such as IDH inhibitors.

Ivosidenib, the IDH1 inhibitor, is being combined with azacitidine and venetoclax, demonstrating response rates that are super, 92% with a significant 1-year survival of 76% in newly-diagnosed patients, which is phenomenal. Alternatively, the third drug could be a monoclonal antibody, several are active in AML. We know gemtuzumab ozogamicin [Mylotarg] can be combined and has been in clinical trials with azacitidine plus venetoclax, potentially in the relapsed and refractory setting and these are demonstrating activity. Other immune antibodies such as magrolimab, a CD47 antibody or sabatolimab, the TIM3 antibody, are being investigated as well.

Another way to improve on outcomes for the older patients with the lower intensity therapy is to change the backbone, acknowledging the fact that venetoclax does augment the activity of some of these agents, and can we use a different backbone that's lower intensity, and has been previously shown to be potentially more active than hypomethylating agents to further improve efficacy.

We've been studying a combination of cladribine and low-dose cytarabine for many years in AML, demonstrating excellent response rates. We recently studied the combination of venetoclax combined with cladribine and low-dose cytarabine in patients older than 60 years of age, with newly diagnosed AML, which demonstrated very high rates of complete remission of overall 93% with about 80% of those patients having MRD negative remissions, which is unheard of with lower intensity therapy. Now many of these patients were still fit for chemotherapy, and indeed about 30% to 35% of patients went to allogeneic stem cell transplant, but it's a non-anthracycline based lower intensity therapy that was able to achieve high rates of response with very low early mortality and excellent tolerability.

What excites you most for the future of AML?

I think the future is bright in AML, particularly with a better understanding of disease biology and disease heterogeneity. As we continue to dissect these different subgroups biologically, we're going to be able to understand what the sort of Achilles heel of these different subgroups are and how we can target them better. The next big thing may be menin inhibitors and in AML.

They've demonstrated some early and promising signs of activity in subgroups such as MLL-rearranged or KMT2A-rearranged AML or those patients who have NPM1-mutated AML in the relapsed/refractory setting. I think using Menin inhibitors and demonstrating their activity and understanding their safety profile and schedule and dosing and then eventually combinations of those drugs in those subsets will help. The better we dissect our populations, the better we understand the popular biology in each of the subsets, the better that we can focus on that subset and develop a therapy that is optimal for that group of patients.