The treatment paradigm of acute myeloid leukemia has not changed much in the last several decades, but with 4 new drugs approved by the FDA within the span of a few months, 2017 easily became the most promising year yet for the treatment of AML.
Daniel J. DeAngelo, MD, PhD
The treatment paradigm of acute myeloid leukemia (AML) has not changed much in the last several decades, but with 4 new drugs approved by the FDA within the span of a few months, 2017 easily became the most promising year yet for the treatment of AML.
In April 2017, the FDA approved midostaurin (Rydapt) for the treatment of patients with newly diagnosed AML who have a FLT-3 mutation, followed by CPX-351 (Vyxeos) in August for patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Enasidenib (Idhifa) was also approved that month for the treatment of patients with relapsed or refractory AML with an isocitrate dehydrogenase-2 (IDH2) mutation. Additionally, shortly after in September, the FDA moved forward in approving gemtuzumab ozogamicin (Mylotarg) for the treatment of newly diagnosed patients with AML whose tumors express the CD33 antigen.
While these agents have made a significant impact in the treatment of patients with AML, an unmet need still lies in identifying which therapy is best for which patient.
In an interview withTargeted Oncology, Daniel J. DeAngelo, MD, PhD, an associate professor of medicine at Harvard Medical School and a member of the Adult Leukemia Program at Dana-Farber Cancer Institute in Boston, Massachusetts, reflected on the current state of drug development and treatment of AML, the impact of recent advancements in AML research, as well as the obstacles investigators will face moving forward.
TARGETED ONCOLOGY: Patients with AML who have relapsed or refractory disease have limited treatment options available to them. What studies are currently ongoing for these patients?
DeAngelo:For patients with relapsed/refractory AML, we are looking at targeted approaches. For those patients withIDH1orIDH2mutations, we will put them on a particular trial. We’re focusing on combination therapy as things move on. We are also exploring the role of venetoclax (Venclexta), which is targeting the BCL-2 molecule.
There are a variety of phase I therapies looking at CD33-directed and CD123-directed therapies, cereblon modulators, as well as CAR T-cell therapies for myeloid leukemia. Even though that is still in its infancy, those are some of the trials that we are using.
TARGETED ONCOLOGY: What has it been like to have all these new treatment options and how have the 4 approvals last year impacted the field?
DeAngelo:The last year has been a really amazing year with 4 new drugs approved for AML. Midostaurin (Rydapt), the first FLT3 inhibitor, was approved in combination with chemotherapy. That has become our standard of care. The RATIFY study was done in patients under 60, but the label was age agnostic. So we are giving midostaurin in patients that are newly diagnosed withFLT3mutations, both during induction as well as consolidation.
CPX-351 (Vyzeos) was FDA approved for patients with secondary or therapy-related AML or patients with AML with MDS-related changes. Even though the study was done only in patients over 60, the label was agnostic to age as well. We have mostly been using this in patients over 60, but we’ve extended it to some patients under 60 as our standard of care.
Gemtuzumab ozogamicin (Mylotarg), a drug that was approved a decade and a half ago, and then removed, is now back again. That is an interesting molecule where with fractionated lower dosing it was shown to improve event-free survival in patients between ages 50 and 70, based on the French ALFA-0701 trial.
In our institution, we are mirroring this trial, so for patients who would have been eligible for the ALFA-0701 trial between ages 50 and 70, we are adding gemtuzumab ozogamicin to standard 3 + 7. We also include another subset of patients, those with core binding factor, which came across in all the studies as having improvement in event-free and overall survival with the addition of gemtuzumab ozogamicin. Regardless of age, we are using it in these patients.
And finally, the fourth drug is enasidenib.That was approved in patients withIDH2mutations in the relapsed/refractory setting, and that is predominantly where we are using it. There are ongoing trials in newly diagnosed patients in combination with chemotherapy, standard induction or hypomethylating agents (HMA), but those are clinical trials. [In the clinic], we are using it in relapsed/refractoryIDH2-mutant patients.
TARGETED ONCOLOGY: Looking back at the 2017 ASH Annual Meeting, what were some exciting data presented in AML?
DeAngelo:I think the most exciting data that was presented at ASH 2017, as well as ASH 2016, is the idea that BCL2 inhibitors may really have a role in the treatment of patients with at least relapsed/refractory AML, but also patients with newly diagnosed AML. These are early studies. The studies were limited at least in the newly diagnosed population – to patients who were elderly and unfit for standard chemotherapy, but remission rates upwards of 70% have been seen and we have never seen that in a patient with HMA therapy. These are not single-agent drugs, these are drugs that are being combined, so I think that’s some of the most exciting data.
And then the other data, which is slightly different, is just trying to break apart the disease entity. In AML, we always just throw everybody together under the same umbrella, but it represents 20, 30, 40 different diseases, and trying to tease out based on the molecular characteristics and maybe some of the better approaches is something that we’ve learned over the last few years, including at ASH 2017.
TARGETED ONCOLOGY: Where are we currently with defining which patients respond to which therapies?
DeAngelo:We are still learning. For example, what’s the best patient with anFLT3mutation,TKD,ITD? What is the allele frequency that best determines how those patients respond? I don’t think we know. At least at our institution, outside of a clinical trial, any patient with anFLT3,TKD, orITDmutation, regardless of the allele frequency, is being offered midostaurin. And those patients are often eligible for clinical trials, so they may be enrolled on a clinical trial. It’s the same thing withIDH2mutations, so it’s the context that matters, as well as the varying allele frequencywhen an allele frequency is too low, a patient may not respond to ivosidenib. And the other important question that we don’t know yet is what other code mutations may render patients withIDH2mutations less responsive or even more responsive. These are things we are trying to sort out.
TARGETED ONCOLOGY: When treating patients with AML, what are the obstacles that exist that need to be tackled in the next few years?
DeAngelo:Though we are able to get a lot of patients into remission, what do we do with the relapsed/refractory setting which is somewhat difficult and 2-fold? That is still a big challenge. It’s difficult, because patients with recurrent disease often are too ill to receive the most aggressive therapy.
The second issue is in younger patients. Most patients are getting stem cell transplantation, so relapse after stem cell transplantation is an entire different entity. You’re dealing with the graft, you’re dealing with graft versus host, both acute and chronic, trying to manipulate through that, as well as the patient having ongoing disease, so those are issues that we just don’t know how to tease forward.