Rethinking Clinical Trial Endpoints in Targeting IDH Mutations in Elderly Patients With AML

James McCloskey, MD

James McCloskey, MD

In clinical trials, patients with acute myeloid leukemia (AML) have shown significant responses to isocitrate dehydrogenase (IDH) inhibition.^1,2Based on expert opinion, however, the primary endpoints, complete remission (CR) or complete remission with incomplete blood count recovery (CRi) are not the only significant endpoints to consider when looking at response in elderly patients withIDH-mutated AML.

Remission rate is currently considered the gold standard for determining how all patients benefit from IDH inhibition. James McCloskey, MD, has questioned this though, suggesting that, “maybe CR is not the endgame for our 80-year-old patient with AML who’s failed 2 other lines of therapy.” The other important endpoints for these patients might include transfusion independence or stable disease, according to McCloskey.

When designing clinical trials for this patient population in the future, it is important to consider that older patients may be less tolerant of intensive therapies required to bring them to remission, and their goal for treatment may be different. Therefore, CR or CRi may not be the appropriate primary endpoint in these trials.

In an interview withTargeted Oncology,McCloskey, interim chief of leukemia, John Theurer Cancer Center, explained the need for consideration of elderly patients when designing clinical trials forIDH-mutated AML and other considerations when treating this patient population.

TARGETED ONCOLOGY: What advances have you seen in targetingIDH-mutant AML over the past few years?

McCloskey: In terms of targeted therapies, I think one of the greatest achievements has been our ability to targetIDHmutations.IDH1andIDH2mutations are seen in up to 20% of patients with AML. They are enriched in the elderly patient population and in patients with normal karyotypes. By targeting this mutation, we're able to restore normal hematopoiesis in these patients.

IDH inhibition is a molecularly targeted therapy that spares a lot of the cytotoxic [adverse events] of chemotherapy and is very rewarding in terms of its responses and the toxicity profile, particularly in older patients.

TARGETED ONCOLOGY:Can you discuss the current therapies available for patients withIDH-mutated AML?

McCloskey:In terms of current available forIDH-mutant patients, we have 2 approved agents. We have ivosidenib (Tibsovo) forIDH1-mutant patients and enasidenib (Idhifa) forIDH2-mutant patients. TheIDH2mutation is a little more common but these drugs have similar toxicities, some nuances but also similar efficacies.

I think if we take the IDH1 and 2 inhibitors together, these drugs have proven to be very effective. There's been a lot of debate about what efficacy means, particularly for older patients with relapsed/refractory AML.

Typically, in AML, like in a variety of other malignancies, we have set a remission rate as our gold standard. In terms of remission rates, we see that in relapsed/refractory patient populations, somewhere around 24% of patients will have a CR or CRi. At first glance, that CR rate is a little disappointing. Some of other agents we've had in leukemia and other solid tumors have CR rates higher than that. But I think that many of us who use the drug, especially in the clinical trials, said "pause a moment, because maybe CR is not the endgame for our 80-year-old patient with AML who’s failed 2 other lines of therapy."

There were other valid endpoints from that trial that I think are important to consider. One of those is transfusion independence. Thirty-three percent of patients become transfusion independent with IDH2 inhibition particularly. Up to 45% of patients can have a response if we incorporate stable disease. Many of us feel that if you're a patient with relapsed/refractory disease and if at 6 months you have stable disease, that's some kind of response.

For me, if I had an 80-year-old patient that is at home taking oral therapy and not receiving chemotherapy or transfusions, then that's an achievement for me, even if they're not in remission.

TARGETED ONCOLOGY:How do you decide which endpoints are important when designing clinical trials for patients withIDH-mutated AML?

McCloskey: I think it depends on the context in which we're using it. The field is changing so rapidly that there are many new effective therapies that were not available when these drugs were approved in the relapsed/refractory setting. I think it depends on the patient in front of us.

Is our goal to cure that patient and take them to transplant? [In that case] these drugs may have an important role in improving remission rates and improving minimal residual disease (MRD) negativity rates so that transplant is more effective.

If the drug is being study in a patient population who is older and who are not able to tolerate some of the [adverse effects] of intensive induction therapies, then our goals might be different. They might be a quality-of-life measure or transfusion independence for those patients.

TARGETED ONCOLOGY: What is your take on combining molecular targeted therapy like IDH inhibition with chemotherapy for patients with AML?

McCloskey:In terms of combining IDH inhibitor with chemotherapy, I think this is a very exciting notion. I don't think it's ready for primetime, in my opinion. I know that some of my peers are combining these therapies but currently, they are only approved as single-agent therapies.

TARGETED ONCOLOGY: Is there any research looking at this type of combination right now?

McCloskey: There have been preliminary data that are promising. If you look at response with hypomethylating agents in combination with the IDH inhibitors, some of those studies have shown up to a 70% overall response rate and a 50% CR rate. That's certainly promising.

If you look at the phase II data that have been published about IDH inhibitors in combination with 7+ 3, the responses there we saw were very promising. There were high CR rates in a very high-risk patient population. Also, these CRs were deep remissions, so 88% of those patients were MRD-negative by flow cytometry and up to half of them (40%-45%) were MRD-negative byIDH2mutation testing. So, those are deep remissions that, in theory, we believe will translate to improved transplant outcomes and long-term remission rates.

Combination therapy is not something I'm doing outside of a clinical trial at this time, but I think it will come eventually.

TARGETED ONCOLOGY: What are the ongoing challenges with treating patients withIDH-mutated AML?

McCloskey: Some of the challenges with treating this patient population come with the patients themselves. If we think about older patients, more frail patients, or patients who may not have as many resources or support to get back and forth to see us, those are some of the issues we face.

Another issue we face is managing some of the toxicities, especially if we think about the fact that only 20% of patients have these mutations. If we think about a clinical practice in a more rural area where a physician sees all kinds of oncologic conditions, they might only have anIDH-mutant patient once every few years. It does some unique toxicities, and I think being aware of the management and clinical presentation of differentiation syndrome, which is unique to this subclass of drugs, [is very important] in terms of IDH inhibition. We've seen it otherwise in acute promyelocytic leukemia. But these patients presenting with a capillary leak, fluid retention, and pulmonary symptoms are folks that we want to rapidly address and treat with steroids.

The IDH1 inhibitor ivosidenib has some important implications regarding QT prolongation and monitoring but, otherwise, these are usually easier complications to manage than what we're used to with chemotherapy.

References

1. DiNardo CD, Stein EM, de Bottom S, et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.N Engl J Med. 2018;378(25):2386-2398. doi: 10.1056/NEJMoa1716984.
2. Stein EM, DiNardo CD, Fathi AT, et al. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib.Blood. 2019;133(7):676-687. doi: 10.1182/blood-2018-08-869008.