Improving Low-Intensity Therapy for Older Patients With AML

Tapan Kadia, MD, professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, discusses potential improvements to lower intensity therapy for less fit patients with acute myeloid leukemia (AML).

Kadia says that following the success of venetoclax (Venclexta) plus hypomethylating agents (HMAs), investigators are looking into more improvements to low-intensity regimens such as adding another drug to this combination. These include FLT3 inhibitors or IDH inhibitors.

In particular, the IDH1 inhibitor ivosidenib (Tibsovo) demonstrated a 92% overall response rate and 76% 1-year overall survival rate when combined with azacitidine and venetoclax. The antibody-drug conjugate gemtuzumab ozogamicin [Mylotarg] has also shown efficacy as an additional agent. Monoclonal antibodies being investigated include magrolimab and sabatolimab.

Another option is the combination of cladribine and low-dose cytarabine, which is effective on its own. When added to venetoclax as frontline AML therapy for patients older than 60, it showed a 93% composite complete remission rate and a 84% minimal residual disease (MRD) negativity rate. Getting strong responses from low-intensity regimens enables older and less fit patients to tolerate treatment better and helps reduce early mortality.

TRANSCRIPTION:

0:08 | 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, for example, 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.

0:47 | Alternatively, the third drug could be a monoclonal antibody, several are active in AML. We know gemtuzumab ozogamicin can be combined and has been in clinical trials with azacitidine plus venetoclax, potentially in the relapsed and refractory setting, demonstrating activity. Other immune antibodies such as magrolimab, a CD47 antibody, or sabatolimab, the TIM3 antibody, [are] being investigated as well.

1:14 | 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, can we use a different backbone that's lower intensity, and has been previously shown to be potentially more active than HMAs 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.

1:41 | 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.