Midostaurin Approval an Encouraging Advance in AML, Expert Says

Gail J. Roboz, MD, discusses the recent FDA approval of midostaurin and what else is emerging in the treatment landscape in AML.

Gail J. Roboz, MD

The recent approval of midostaurin (Rydapt) has brought new hope to the field of acute myeloid leukemia (AML), explains Gail J. Roboz, MD.

“We have had our first approval in a long time for a new drug for AML,” said Roboz.

Midostaurin is specifically approved for adult patients with newly diagnosedFLT3-positive AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.

Additionally, chimeric antigen receptor (CAR) T-cell therapy and immunotherapy agents continue to be investigated to further improve the treatment landscape for patients with AML. Clinical trial data are anxiously awaited to discover how these treatment modalities will benefit patients.

Roboz, a professor of Medicine and director of the Clinical and Translational Leukemia Program at Weill Cornell Medicine/NewYork-Presbyterian Hospital, dicussed the recent FDA approval of midostaurin and what else is emerging in the treatment landscape in AML during an interview withTargeted Oncology.

TARGETED ONCOLOGY:Can you provide an overview of your presentation on AML?


Oncologists are used to hearing that AML is often the forgotten one of the hematologic malignancies. With myeloma and CLL, it seems as if there is a new drug approved every 5 minutes with improving outcomes. Somehow, AML has languished behind the others. One of my objectives was to bring across the message that things are finally changing in AML.

There are several promising combination therapies that are building on standard chemotherapy backbones.

For older patients, hypomethylating agents and low-dose cytarabine are regimens that don't yield many complete remissions (CRs) or satisfactory long-term outcomes. However, they are being combined successfully with novel agents.

One of the things that Weill Cornell Medicine and NewYork-Presbyterian Hospital have been focused on are some of the potential combinations with hypomethylating agents and low-dose cytarabine. Outcomes may be better. CR rates of the early trials are more than 60% at this point, which is much better than the 15% to 25% CR rate that we are used to.

AML is moving away from conventional immunophenotype and cytogenetic morphological baseline diagnosis due to new technologies taking us in a different direction. Next-generation sequencing is now standard of care for patients with AML to determine if there may or may not be clinical trials or standard-of-care opportunities for FLT3-mutated patients.

There has been a guideline change for outcomes in the AML. CR is no longer just morphology-based. CR is also going to include a subclassification of minimal residual disease (MRD)—negative or -positive. This is controversial—but it is important to assess for MRD for both flow cytometry and by molecular assessment for molecularly defined AML.

In combination treatments, new types of evaluations with both sequencing strategies and with more detailed flow cytometry-based assessments and remission are very important. Novel clinical trials are using immunotherapeutics, whether they are antibody designs or CAR T-cell designs for AML. We are anxiously awaiting some clinical trial data to see what these therapeutic modalities are going to offer for patients with AML.

TARGETED ONCOLOGY:The midostaurin approval is very exciting for this field. Can you discuss its impact?


There is no doubt that we are all encouraged and happy to see the approval of midostaurin, which is going to be standard of care forFLT3-mutated patients in combination with chemotherapy.

We still have much to learn regarding the best way to treatFLT3-mutated patients. If you look at the overall survival curves that resulted in the approval of this agent, we still are not curing all of our patients.

There are many questions that community oncologists who don’t have experience with the drug will be asking in terms of when to start it, when to stop it, whether to continue during consolidation, or if you should get the drug for posttransplant maintenance? I suggest a collaboration with the academic centers that have used the drug during trials in order to get some hands-on experience of what we had with our patients.

An interesting question for patients who are not eligible for standard chemotherapy is what options for combinations with hypomethylating agents or low-dose cytarabine. We are going to need more trial data in order to get the answers. In general, it is well tolerated.

TARGETED ONCOLOGY:Can you discuss some ongoing trials looking at immunotherapy?


Patients and oncologists are used to hearing about the wonders of immunotherapy. We are trying to do better in harnessing the immune system, either by delivering drugs to their target by using a patient's own immune system or, in the case of an allogeneic CAR T-cell program, using healthy immune system cells to see if that can help eradicate disease.

The real question is not the science or the technology, but do they work? That's why we want to get patients on as quickly as possible to see which one of these newer [therapies] is going to work best for the patient and with what toxicity profile.

A challenge we are facing is the need to determine which patient should go on a specific trial depending on what other therapies they have had, the overall shape they are in, and our best guess as to which trial will benefit them the most. It's hard to figure out inwhich trial to enroll an individual patient, especially if you have several trials open.

TARGETED ONCOLOGY:If you had to look ahead, what role could CAR T-cell therapy have in AML?


CAR T-cell therapy has been a very interesting and exciting treatment modality, but we aren't curing people yet. One of the major limitations has been for patients who have received multiple other therapies, since they may not be in shape to either deliver T cells or to wait until their own T cells are engineered. For some patients, they may also have disease progression in 3 months or so until those cells are available. Overall, it's a therapeutic modality, that has some logistical difficulties associated with it.

We are trying to make inroads into earlier phases of disease so that we are not waiting until patients have relapsed disease and when they are more difficult to treat. There is an interesting study that I am leading at Weill Cornell Medicine/NewYork-Presbyterian Hospital that uses a new idea of using healthy T cells to try to knock out the T-cell receptor and hopefully eliminate or minimize the potential for a graft-versus-host disease. We are hoping to use this in an “off-the-shelf” manner so that patients could get them faster.