Expert Weighs in on Recent AML Advances

Harry Erba, MD, PhD

Four major approvals this year have dramatically improved the treatment landscape for acute myeloid leukemia (AML).

In April, FDA approved midostaurin (Rydapt) for adult patients with newly-diagnosed FLT3-positive disease. With August came approvals for enasidenib (Idhifa) for patients with relapsed or refractory IDH-2 mutated AML and CPX-351 (Vyxeos) for newly-diagnosed adult patients with therapy related disease or myelodysplasia-related changes. Most recently, the FDA approved gemtuzumab ozogamizin (Mylotarg) in September for the treatment of patients with newly-diagnosed CD33-positive AML.

OncLive: What have been the significant updates in AML over the past year?

What is the impact of the gemtuzumab ozogamizin approval?

In an interview with OncLive during the 2017 SOHO Annual Meeting, Harry Erba, MD, PhD, professor of medicine, director, University of Alabama (UAB) Hematologic Malignancy Program, UAB School of Medicine, reflected on these approvals and their effect on the treatment of AML moving forward.Erba: For the clinician, the most important updates in AML are really the FDA approvals, because now we have to think about how we are going to incorporate these new drugs into our clinical practice. For decades, we have been using 3-and-7 daunorubicin-idarubicin with cytarabine as initial induction therapy for AML. Following the initial approval of gemtuzumab in 2000 based on relapsed/refractory patients with AML, there were a number of studies looking at the combination of gemtuzumab with chemotherapy in previously-untreated patients. There was a meta-analysis that combined gemtuzumab in various doses with induction and consolidation chemotherapy. Robert Hills published results from that meta-analysis which showed that there was a benefit in terms of overall survival, and event-free survival for CD33-positive AML patients who receive gemtuzumab ozogamizin during induction consolidation.

In my opinion, the 2 studies that drove that meta-analysis and the positive outcome were the French ALFA-0701 study that used a fractionated dosing schedule of 3 mg/m2 on days 1, 4, and 7, with standard daunorubicin 60 mg/m2 for 2 days, and cytarabine in patients ages 50 to 70. In that study, there was no benefit in terms of complete response rate for the addition of gemtuzumab, there was more thrombocytopenia, and a few cases of veno-occlusive disease—but importantly, there was an improvement in event-free and overall survival in the publication.

Have you seen progress with FLT3 inhibitors? Are any distinguishing themselves?

Then there is the MRC United Kingdom data showing that there was benefit, especially in younger patients who had core-binding factor AML, to adding a single dose of gemtuzumab ozogamizin, again 3mg/m2, on day 1 of induction. The first drug approved this summer for AML was midostaurin. Midostaurin has actually been around for a long time. It is a kinase inhibitor that is not very specific for FLT3 and actually inhibits a number of kinases, serine-threonine kinases, and tyrosine kinases, which have been implicated in AML. As you know, it was studied in FLT3 AML and when added to chemotherapy, showed an improvement in event-free survival and disease-free survival for younger patients.

However, there remains the question as to what is really the target for midostaurin in that population. Is it just FLT3 or could it be any of the other kinases that it inhibits? If you use a more specific FLT3 inhibitor, does it benefit patients with FLT3-mutated AML? We were hoping that we'd see marginal additional improvements on the outcomes that were seen with midostaurin by really targeting FLT3, but that is yet to be seen.

There are a number of drugs in development that are not yet approved for FLT3-mutated AML. The ones that are the furthest along would be gilteritinib (ASP2215), an inhibitor of both the FLT3 ITD and tyrosine kinase domain mutation; quizartinib (AC220), an inhibitor of the ITD; and crenolanib, a dual inhibitor of both ITD and TKD mutations. And there are others. As single agents, all of those drugs have shown biologic activity. Blast counts go down and you see differentiation of blasts. However, very few patients achieve complete remissions with restoration of blood counts. I think the future is going to be looking at the addition of those novel FLT3 inhibitors to induction and consolidation treatment.

How will this year’s successes influence AML treatment going forward?

The challenge we have is designing those studies. Do we just compare head to head chemotherapy with midostaurin versus chemotherapy with the new FLT3 inhibitor, assuming that they are both working through FLT3 inhibition? Or, do you assume that the midostaurin is actually targeting many different kinases and actually do a study of chemotherapy with midostaurin plus or minus your new FLT3 inhibitor? Probably both types of studies will be done. With 4 new drugs, including a small molecule inhibitor of IDH2 for relapsed/refractory AML with IDH2 mutation, there is definitely renewed enthusiasm after 40 years of not having any drugs approved in AML. It has clearly renewed interest among investigators in developing therapies that can propel outcomes for patients.

Having looked at all of these studies, the data is clearly there, but in my opinion, marginal with the addition of gemtuzumab or midostaurin in FLT3-positive AML and even with CPX-351. These are all marginal improvements—we have a long way to go.

Is there anything else exciting going on in the AML space?

Now that these drugs have been approved, we have to learn how to use them together. For example, combining gemtuzumab with CPX-351 or FLT3 inhibitors like midostaurin with CPX-351, those things will have to be evaluated. What we are hoping is that with these new drugs as a baseline, a new standard of care will incrementally improve overall survival for patients with AML. A major topic of discussion at the AML session at this year’s SOHO meeting was the use of minimal residual disease (MRD), or measurable residual disease, to aid prognostication and guide therapy for patients with AML. There was a debate and a number of other sessions and presentations on that subject. I could summarize that discussion as the following: In single institution studies or small cooperative group studies, you can clearly show that the presence of MRD at the time of a morphologic complete remission is associated with a worse outcome.

We can use this information for prognostication. However, no one knows what to do with the data. It is clear that patients with MRD have poorer outcomes if they don’t have transplant. But, the same is true with chemotherapy consolidations. It has also been shown that patients who are MRD-negative can still relapse.

So, how to use this data to actually guide future treatment or postremission treatment to improve cure rates is really completely unclear and should be the subject of the next generation of cooperative group studies.