Targeted Agents Transforming AML Paradigm

Elias Jabbour, MD

The FDA approval of multiple targeted agents in recent years is transforming the treatment landscape in acute myeloid leukemia (AML), explained Elias Jabbour, MD, professor of medicine, Department of Leukemia, MD Anderson Cancer Center.

Treatments such as the FLT3 inhibitors midostaurin (Rydapt) and gilteritinib (Xospata), the IDH1 inhibitor ivosidenib (Tibsovo), and the BCL2 inhibitor venetoclax (Venclexta), are offering new hope to subsets of patients with AML.

In an interview with OncLive, Jabbour highlighted the evolving armamentarium and next steps in the treatment paradigm for AML.

OncLive: Looking at the preferred frontline treatment options for AML, is there still a role for 3+7?

Jabbour: 3+7 has been standard of care for patients who are "fit for chemotherapy" with Ara-C (cytarabine) being given at 100 to 200 mg/m² for 7 days, and then the daunorubicin it was agreed that the dose [should be] 60 mg [for 3 days], [or of] idarubicin.

I think that, in young patients, there's good data showing that high-dose Ara-C may be a better induction regimen. The FLAG-IDA [study] from MD Anderson Cancer Center and MRC, for example, have shown that if you give 4 FLAG-IDA (fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor) courses, you can improve survival mainly, in younger patients. I think for somebody young and fit (like 50, 40, and younger), I prefer to choose a high-dose cytarabine-based regimen over 3+7.

In other patients, of course, 3+7 would not be my best choice. We have data about HMAs and venetoclax, as well as other similar regimens.

How has this treatment landscape developed in more recent years?

In AML, it has been a great 2 years after a long period [in which] no drugs were approved or available. We [now] have several [new] compounds. Among them, we have the FLT3 inhibitors, midostaurin (Rydapt), and recently gilteritinib (Xospata). We had IDH1 and [IDH2] inhibitors available and approved. Starting in an upfront setting, ivosidenib (Tibsovo) was approved for a frontline indication. CPX-351 was approved for patients with secondary AML [who are] 60 years and older. We had monoclonal antibodies re-approved, such as gemtuzumab ozogamicin (Mylotarg)—it was on the market, was withdrawn, then came back. It did improve outcomes in patients who [have] core-binding factor or intermediate risk. Then, the breakthrough treatment venetoclax was approved in combination with HMA therapy. [It shows a] high response with HMA therapy alone (67%) and a survival of 17 months. Historically, [the rate was] 7 to 9 months. Finally, glasdegib (Daurismo), which is a [Hedgehog pathway] inhibitor, was approved plus low-dose Ara-C for patients who are unfit for chemotherapy. Of course, this is an approval, but I think we’re working on optimizing this regimen with a better combination to improve outcomes further.

What challenges still exist for oncologists regarding treating patients with AML?

We are learning and improving outcomes. I think leukemia is a rare disease, and we all need to work together by referring these patients to academic clinical trial settings. As an academic, I work with my colleagues to deliver the best care to these patients.

What should community oncologists know about frontline therapies for acute myeloid leukemia?

In AML, things are changing. For example, the majority of patients are elderly and unfit for chemotherapy. Historically, the survival for these patients was very bad. Today, with HMA and venetoclax, we have a 2-year survival of 40%, which is much better than what we had before. The FLT3-ITD—mutated patients used to have poor outcomes with survival at 15% and transplant indicated. Today, with the FLT3 inhibitors added to a chemotherapy backbone, we have [better] long-term outcomes.

[There are] still a lot of [combinations] being evaluated and we should fine-tune the safety concerns. For example, with venetoclax, the approval is [for the drug] to be given continuously. We know that can cause myelosuppression. [We are learning] not to give the treatment continuously, but to give it for maybe 21 days then maybe hold [the drug] and see when you should resume it. The point here is, yes, we have good drugs. I still think that physicians should refer to clinical trials in academic settings and carefully learn about the safety of these drugs.