Expert Recaps Advances in AML

Rami S. Komrokji, MD

Now that physicians have access to novel therapies for patients with acute myeloid leukemia (AML) following a 30-year gap in therapeutic development, physicians must now aim to understand their optimal placement in treatment, explained Rami S. Komrokji, MD.

“The landscape is changing; it’s an exciting time,” said Komrokji. “We have midostaurin (Rydapt), gemtuzumab ozogamicin (Mylotarg), and CPX-351 (Vyxeos) as new upfront therapies. We have IDH1/2 inhibitors, and gemtuzumab ozogamicin in the relapsed setting. Hopefully, we’ll soon have 2 FLT3 inhibitors—quizartinib and gilteritinib approved for patients with relapsed/refractory AML with a FLT3 mutation.”

Most recently, the FDA approved ivosidenib (Tibsovo) for the treatment of adult patients with relapsed/refractory IDH1-mutant AML in July 2018. The approval was announced following the results of a single-arm, phase I study of patients with IDH1-positive relapsed/refractory AML. The complete remission (CR) rate was 24.7% (95% CI, 18.5%-31.8%). The rate of CR with partial hematologic improvement was 8% (95% CI, 4.5%-13.1%).

OncLive: How has the treatment landscape of AML changed in recent years?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Komrokji, principal investigator, MDS Research Consortium, Aplastic Anemia and MDS International Foundation, clinical director, Hematologic Malignancies, Moffitt Cancer Center, reflected on the diverse AML treatment landscape and touched on the prognostic importance of biomarkers.Komrokji: It’s been an exciting time for researchers and patients. Now, we have more options that we can offer patients than we had in the past 30 years. In the last 2 years, we’ve witnessed the approval of several drugs in AML. I started the presentation by discussing the current risk stratification for AML, which is all based on cytogenetics and molecular data. I then went through all of the new drugs and where they are to be positioned in the management of patients.

We discussed treatment for younger patients with good-risk disease who have core binding factor abnormalities, which include t(8;21) or inv(16). Those patients seem to derive a favorable outcome and significant survival advantage from the incorporation of gemtuzumab ozogamicin into induction and consolidation. This is a lower dose of gemtuzumab ozogamicin than we’ve traditionally used in the past. Now, incorporating gemtuzumab ozogamicin is becoming standard of care for patients who are known to have good- or favorable-risk disease.

We also discussed patients who have FLT3 mutations. The incorporation of midostaurin with a chemotherapy backbone has become the standard of care for patients and has demonstrated an overall survival (OS) benefit.

Challenges sometimes include getting this information on time for patients. Now, the academic centers and the labs that perform those tests have a rapid turnaround time of a few days, and [we can get] those results and make decisions based on the molecular status and cytogenetics.

The other drug we discussed that has now been approved and become one of the standards for therapy is CPX-351. This is approved for patients with therapy-related AML, AML from myelodysplastic syndrome (MDS), AML with a carrier type similar to MDS, or AML with MDS-related dysplastic changes. CPX-351 is a fixed molar ratio of cytarabine and daunorubicin, which is packaged in a better way to ensure delivery of the 5:1 ratio. It has a better [ability to] kill the leukemia cells and has a slower release. In phase III trials comparing it with traditional cytarabine and daunorubicin (7+3), it demonstrated higher response rates, less mortality at day 30 or 60, and improved OS. That led to its approval. [We expect to see] a little bit more delay in the recovery of the blood count as the duration of myelosuppression is longer by 1 or 2 weeks than with the 7+3.

Then, there are promising data coming down the pipeline with venetoclax (Venclexta) plus hypomethylating agents. There is a study that randomized patients to low-dose cytarabine or low-dose cytarabine and venetoclax. If the study is positive, that may lead to venetoclax’s upfront approval in patients with AML who are not candidates for intensive chemotherapy.

In the relapsed/refractory setting, there are 2 drugs approved for patients who have IDH mutations. For IDH2 mutations, enasidenib (Idhifa) was approved by the FDA. It’s an orally administered drug that led to a complete response rate of nearly 20%, a 40% overall response rate, and a median duration of response around 9 months. In terms of adverse events (AEs), we watch for hyperbilirubinemia and differentiation syndrome.

Are there other biomarkers on the horizon beside FLT3 and IDH1/2?

For IDH1 mutations, we have ivosidenib. Ivosidenib had shown similar results to enasidenib in IDH1-mutated patients who were refractory or relapsed in a phase I dose-escalation and phase II dose-expansion study. It demonstrated 20% response rates and a median duration of response of 8 to 9 months. In terms of AEs, we look for what we call IDH inhibitor differentiation syndrome and prolongation of the QTc. We also discussed gemtuzumab ozogamicin as an option for patients with CD33-positive relapsed/refractory AML.We know about the mutation landscape for those patients. There are different mutations that one could target, but it depends on the mutation and its complexity. Some of those mutations are gain-offunction [mutations] that are easier to target; some of them are loss-of-function mutations.

IDH1/2 mutations are gain-of-function. The p53 mutation is known to be a very poor prognostic mutation associated with a bad outcome, whether it’s a patient with MDS or AML. We’ve been looking at a drug called APR-246 that modulates p53 and restores its function. We observed very promising results in the phase I study that we presented primary data on.

What has it been like to see all of these recent milestones in the AML landscape?

Targeting p53 is an unmet need. It’s not easy, but there are drugs already in phase I and II trials. Many patients who have secondary AML have a group of mutations called splicing mutations. There are splicing inhibitors already in clinical trials. Interestingly, patients with an IDH mutation seem to be sensitive to venetoclax. There is a sign that those patients may have higher responses to venetoclax.For a long time, we did not have options. We still offer patients clinical trials, but to have new options for patients is really exciting. It’s a good start, but we want to improve on this. We want to get better treatments for patients.

In community settings, AML is not the number 1 treated type of cancer. Patients are often referred to academic centers, though some [of these patients] are treated in a community setting. We want [to send] the message that there are new drugs available for patients. Then, [we need to] incorporate those treatments in the right way.

There is always the worry about the cost of new drugs and the magnitude of benefit. AML is becoming like several diseases. A patient who has a FLT3 mutation [is going to benefit from] certain targeted therapies. If patients have good-risk disease, they will get certain treatment. AML [stemming] from MDS requires a different treatment. It’s a very exciting time, but we still have a lot to do. It’s good to have options for patients, but we need to have everybody become familiar with those options.

FDA Grants Approval of TIBSOVO®, the First Oral, Targeted Therapy for Adult Patients with Relapsed/Refractory Acute Myeloid Leukemia and an IDH1 Mutation. Agios. Published July 20, 2018. https://bit.ly/2mwqScv. Accessed September 7, 2018.