Exploring Triplet Therapy for Patients With AML Ineligible for Intensive Induction Chemotherapy

At the 2024 Great Debates and Updates (GDU) in Hematologic Malignancies meeting in Los Angeles, California, Curtis Lachowiez, MD, Oregon Health and Science University, Portland, Oregon, participated in a debate in which he argued in favor of triplet therapy for patients with acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy.

“Fortunately, the data coming out of these studies is encouraging. It looks like the triplets can be delivered safely. They're tolerable by patients using appropriate surveillance techniques, such as early bone marrow examinations and drug interruptions [that] were able to mitigate some of the cytopenias associated with the combinations,” said Dr Lachowiez.

Transcript:

Hi, I’m Curtis Lachowiez, I’m an assistant professor within the Knight Cancer Institute Center at [the] Oregon Health and Science University. I will be presenting some of the data that I presented at the Great Debates and Updates (GDU) in Hematology meeting [in] LA.

My stance was to debate on behalf of, is it the era of triplet therapy in (acute myeloid leukemia) AML and [in] patients [who] are ineligible for intensive induction chemotherapy? This was a great discussion that I had with Dr. [Richard] Stone, who debated from the other perspective. And, I think we had a lot of similar perspectives. When we think about triplet therapy for patients with newly diagnosed AML, there is not a lot of data that has been published to date, but fortunately, we're starting to see more of this data readout, whether in actual manuscript form or at annual congresses such as American Society of Hematology or European Hematological Association meetings every year.

The data looks very promising. If we look at triplet therapies, we're starting to see benefit, or we believe there is a high level of activity within molecularly targeted subgroups in particular. So, using azacitidine and venetoclax, which is the standard of care treatment for patients that are unfit or older in lieu of intensive chemotherapy, then, adding a third targeted agent to the azacitidine venetoclax backbone. That's really what's been studied and published to date. In patients with IDH1-mutated AML, there's been studies of the first generation IDH1 inhibitor ivosidenib added to azacitidine and venetoclax. This has reported very high overall response rates ranging from 90% to 100% with composite complete remission (CR) rates ranging from approximately 80% to 100%. And importantly, a lot of these patients are clearing evidence of these mutations at a very low molecular level. We call this measurable residual disease (MRD) negative remissions. When we look at other targeted therapies that have been combined with [azacitidine and venetoclax] triplets, another one is the FLT3 inhibitor gilteritinib, [and that’s] been combined with azacitidine and venetoclax in a small study in the frontline setting of 30 patients. This similarly resulted in high composite CR rates—96% was the exact number—with over 60% of patients achieving measurable residual disease [(MRD)] negativity.

And then lastly, the combination of azacitidine with the first generation menin inhibitor revumenib has been studied in NPM1 or KMT2A-rearranged AML. And again, we're seeing overall response rates in the 90% to 100% range, and same with composite complete remission rates and high rates of MRD negativity. If you look at this general trend, when you add that third targeted agent to [azacitidine and venetoclax], we see very high composite complete remission rates, MRD negativity rates. I think where the area is a little bit unclear: Is this translating to a survival benefit? The data would suggest yes, especially in IDH1, FLT3, ITD-mutated AML. Most certainly, the reported survival from those studies that I mentioned investigating the triplets has been favorable to date: 2-year overall survival with the IDH1 inhibitor ivosidenib with [azacitidine and venetoclax] was around 67%, and 18-month survival with the combination of [azacitidine and venetoclax] with the FLT3 inhibitor gilteritinib exceeded 70%. As some historical benchmarks, these are patient populations that typically would have a median survival of just less than to approximately 1 year with [azacitidine and venetoclax].

It does look like these triplets are improving outcomes and survival. However, it's important to note that we really need to see randomized comparisons before we adopt these regimens as standard of care. And equally is important when we think about toxicity of these treatments and effect on myelosuppression and ongoing cytopenias, which is an issue with azacitidine and venetoclax therapy already, is that we need to know that these triplets are safe. Fortunately, the data coming out of these studies is encouraging. It looks like the triplets can be delivered safely. They're tolerable by patients using appropriate surveillance techniques, such as early bone marrow examinations and drug interruptions [that] were able to mitigate some of the cytopenias associated with the combinations. But this all really needs to be confirmed in prospective randomized fashion compared to standard of care, which is azacitidine and venetoclax. And fortunately, we have some of those studies ongoing within the (National Cancer Institute) NCI myeloMATCH initiative.

Source:

Lachowiez C. Debate- It Is the Age of Triplets for Treatment of Adults Who Are Ineligible for Intensive Chemotherapy – YES. Presented at the Great Debates and Updates in Hematology meeting. July 27-28, Los Angeles, California.