Influx of Novel Agents in AML Leads to Role for Up-front Molecular Testing

William G. Blum, MD

A string of recent approvals in acute myeloid leukemia (AML) has not only altered the treatment paradigm, but it has also underscored the need to conduct molecular testing upon diagnosis to guide therapy decisions, said William G. Blum, MD.

“Eight drugs have been approved in the past 2 years,” said Blum, a professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine. “That is 8 more than there had been in the past 30 years. It is important to understand the mutations of a particular patient’s leukemia so that we can best capitalize on available treatment options.”

For example, the FLT3 inhibitor gilteritinib (Xospata) was FDA approved in November 2018 for patients with FLT3- mutated relapsed/refractory AML, based on an interim analysis of the phase III ADMIRAL study. Earlier results showed a rate of complete remission (CR) or CR with partial hematologic recovery of 21% (95% CI, 14.5-28.8) after a median follow-up of 4.6 months.¹

In May 2019, the label was updated to include overall survival (OS) data from the study. The median OS from date of randomization to death from any cause was 9.3 months for patients who received gilteritinib versus 5.6 months for those who had chemotherapy (HR, 0.64; 95% CI, 0.49-0.83; 1-sided P = .001).²

Additionally, results of the ongoing AG-221-AML-005 trial (NCT02677922), which were presented at the 2019 ASH Annual Meeting, showed that the IDH2 inhibitor enasidenib (Idhifa) significantly improved complete remission and overall response when combined with azacitidine versus azacitidine alone in patients with newly diagnosed AML with IDH2 mutations.³ At a median followup of 14 months, the median event-free survival (EFS) was 17.2 months in patients randomized to receive the combination. Although this EFS was numerically greater than the value of 10.8 months in those who were given azacitidine alone, the difference failed to reach statistical significance (HR, 0.59; 95% CI, 0.30-1.17; P = .1278).

In an interview during the 2019 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Blum, who is also director of the Acute Leukemia Program at Winship Cancer Institute, discussed the introduction of novel agents into AML treatment and how this is impacting the role of molecular testing for patients.

OncLive^®: What does the current treatment landscape look like in AML?

Blum: There is still conventional chemotherapy, both intensive and less intensive [regimens]. Then, there are also targeted therapies [that can be used as] monotherapy or, increasingly, in combination with chemotherapy.

About 20% of patients with AML have IDH1/2 mutations. Effective drugs that inhibit these mutated enzymes are now available. Although there is still a long way to go, these agents as monotherapy work in about 30% to 40% of patients, and adding them to chemotherapy appears to substantially increase response rates.

Another category of new drugs is the FLT3 inhibitors. Currently, 2 are FDA approved: midostaurin (Rydapt) and gilteritinib.

Midostaurin was initially approved in combination with chemotherapy. [The agent] appears to improve survival and reduce relapse, but transplant seems to remain an important component of treatment. The idea is to get patients to transplant and then potentially maintain them afterward [with midostaurin].

More recently, gilteritinib was FDA approved as a single agent for patients with relapsed disease. It is quite likely that we will see combinations with gilteritinib and chemotherapy.

How did the approval of gilteritinib impact the treatment paradigm?

In the relapsed setting, gilteritinib was compared head-tohead against intensive chemotherapy. For a long time, single agents were not thought to be effective in AML. Multiple mutations can arise in this disease, and many pathways exist [through which] leukemia cells can survive.

Yet, the patients who received gilteritinib as opposed to intensive chemotherapy had higher remission rates and improved survival. [Gilteritinib] is now the standard of care for patients with relapsed/refractory AML who have a FLT3 mutation.

What challenges remain with gilteritinib?

The response rates are still low; less than one-third of patients will achieve a CR. In the next few years, we are going to start seeing combinations of gilteritinib, for example, and other immune-based or targeted novel approaches. It is an incremental progress, but ultimately, we will climb the staircase 1 step at a time.

Could you discuss the IDH1/2 inhibitors ivosidenib (Tibsovo) and enasidenib (Idhifa)?

These drugs are both approved in the relapsed/refractory AML setting, and the remission rates are roughly 30% to 40%. It takes about 4 to 5 months of therapy to achieve remission, so you have to be patient.

They have been [expanded] to the upfront setting. Now, older patients who may not be candidates for intensive chemotherapy can take an oral medication that is generally well tolerated. The response rates are not dramatically better, but there is an improvement. The idea that an older patient can have a remission that is durable for at least 1 year with a relatively nontoxic, oral medication is stunning.

In terms of combinations with chemotherapy, ivosidenib had an expansion of its FDA indication [for use] in combination with azacitidine, which seems to substantially improve the response rate in previously untreated older adults. Because the drugs seem to be similar in terms of mechanism of action and activity, I imagine we will see something similar with enasidenib.

There are some early data looking at combinations of both of these drugs with intensive chemotherapy in younger patients, but it is too early to be considered a standard approach. It is going to take longer because we are looking at reduction of relapse and improved survival, in addition to remission rates.

What other targeted agents would like to highlight?

Venetoclax (Venclexta) may be an exciting addition to our armamentarium, but it has to be combined with chemotherapy. It appears to increase survival rates with low-intensity chemotherapy, so whether that will hold with intensive chemotherapy remains to be seen.

It’s hard to discuss targeted therapy without touching on the importance of molecular testing. What are your thoughts on it?

AML is a heterogeneous disease. Trying to understand how 1 patient is different from another may partially explain why 1 patient may respond to a treatment and another may not.

At Emory [University School of Medicine], we are trying to put that genetic mutational information in the hands of the investigator and the patient before therapy has started. That taps the brakes on the rollercoaster ride of being diagnosed with AML, but it’s important to know what is going on before starting therapy. We are realizing that most patients can wait to start treatment until they have more information to [guide treatment selection].

References

1. Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1—2 study. Lancet Oncol. 2017;18(8):1061-1075. doi: 10.1016/S1470-2045(17)30416-3.
2. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Eng J Med. 2019;381(18):1728-1740. doi: 10.1056/NEJMoa1902688.
3. 3. DiNardo CD, Schuh AC, Stein EM, et al. Enasidenib plus azacitidine significantly improves complete remission and overall response compared with azacitidine alone in patients with newly diagnosed acute myeloid leukemia (AML) with isocitrate dehydrogenase 2 (IDH2) mutations: interim phase II results from an ongoing, randomized study. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 643. bit.ly/2LBNSUu.