Novel Strategies and Agents Emerge in AML Paradigm

Rebecca L. Olin, MD, MSCE

Although the success seen with FLT3 inhibitors may be the most exciting advancement made in recent years in the treatment of patients with acute myeloid leukemia (AML), said Rebecca L. Olin, MD, MSCE, recent data with venetoclax (Venclexta) and maintenance oral azacitidine (CC-486), both in older patients, are also changing practice.

“A big story in AML has been related to FLT3 inhibitors; this story has been evolving over the past couple of years,” said Olin. “We had the RATIFY trial, which led to the approval of midostaurin (Rydapt). Since then, we have had the ADMIRAL trial, which led to the [approval] of gilteritinib (Xospata) in the relapsed/refractory setting.”

Midostaurin received approval from the FDA in April 2017 for use in adult patients with newly diagnosed FLT3-positive AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. The decision was partly based on data from the phase III RATIFY trial, which showed that the addition of midostaurin to standard chemotherapy led to a 22% reduction in the risk of death versus chemotherapy alone in this patient population.¹

More recently, the FLT3 inhibitor gilteritinib was added to the treatment arsenal in November 2018, receiving regulatory approval for use in adult patients with FLT3-mutated relapsed/refractory disease following data from the phase III ADMIRAL trial. Gilteritinib induced a complete remission (CR) or CR with partial hematologic recovery rate of 21% (95% CI, 14.5-28.8) at a median follow-up of 4.6 months.² Updated data published in the New England Journal of Medicine showed that treatment with the agent led to a higher remission rate and a significant improvement in overall survival (OS) versus salvage chemotherapy.³

The accelerated approval of venetoclax in November 2018 for use in combination with azacitidine or decitabine or low-dose cytarabine, solidified the agent as the standard of care for newly diagnosed patients with AML ≥75 years old, according to Olin.

“Venetoclax has really totally changed the landscape of treatment for older adults with AML,” said Olin, an associate professor in the Department of Medicine at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. “Since about 1 year ago, [the agent] has become our standard of care for older adults who are not eligible for intensive chemotherapy.”

With regard to older patients with AML in first remission, maintenance treatment with oral azacitidine was shown to extend the median OS by 9.9. months, according to data from the phase III QUAZAR AML-001 trial that were presented at the 2019 ASH Annual Meeting.⁴

In an interview during the 2019 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Olin, shed light on the pivotal progress made in AML treatment in recent years.

OncLive: Could you speak to the data with FLT3 inhibitors in AML?

Olin: Midostaurin in combination with 7+3 has become the standard of care in patients who have FLT3-positive disease at diagnosis, and that's due to the OS benefit that was seen in the RATIFY trial. Gilteritinib is a different type of FLT3 inhibitor, which was looked at in the relapsed/refractory setting and compared with standard chemotherapy. [Results showed that when given] as monotherapy, gilteritinib led to a pretty significant improvement in response rate and survival. As such, the agent has become a reasonable standard of care in the second-line setting.

All these agents will be looked at in the maintenance setting, as well. We [already have] some data with sorafenib (Nexavar) and midostaurin in the maintenance setting, and an ongoing trial is examining gilteritinib as a maintenance option, as well.

Another interesting development this year was that quizartinib was not FDA approved in the same space that gilteritinib was approved. [As such], we continue to look at the utility of FLT3 inhibitors as maintenance after allogeneic stem cell transplant.

What exciting data in AML were presented at the 2019 ASH Annual Meeting?

The biggest practice-changing [trial] was the QUAZAR [AML-001] study, which looked at oral azacitidine as maintenance after intensive chemotherapy in older patients [with AML]. Results from that study showed a pretty significant survival benefit [with that approach]. Oral azacitidine is a promising drug; it's obviously more convenient for patients to be able to take it in a pill form versus injection. I hope [these data] will lead to the approval of this drug. Then, we'll be able to use it for our older patients who receive chemotherapy as their initial treatment but then are ineligible for an allogeneic stem cell transplant.

What is the role of venetoclax in the treatment of older patients?

Venetoclax has transformed the treatment of older adults with AML. Outcomes with that regimen [of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine] are so good that they're almost blurring the line of [who is] considered eligible for intensive therapy. Previously, we would have offered chemotherapy to patients who may have been borderline candidates for it. Now, we don't need to do that because we have a lower-intensity option that has excellent efficacy. We're using that [type of regimen] a lot in practice, and it's going to be the new standard [and be compared] against any combination [moving forward].

[There are also] some important practice-related tips of how to use this combination in real-world practice: when to do the bone marrow biopsy, whether to use antifungals, and how to adjust the dose and schedule of these drug. That regimen has some art and finesse to it. [The regimen] is resulting in our patients getting into CR more quickly and staying there with really excellent quality of life, so it has been a game-changer for us.

Where is research headed?

The only other up-and-coming data have to do with IDH1/2 inhibitors; some [research presented at] the 2019 ASCO and ASH Annual Meetings looked at the combination of these drugs with a hypomethylating agent in the frontline setting; results [showed] excellent response rates. As such, that [approach is] probably going to [become a] standard of care. Ultimately, I believe we need data looking at the triplet in those patients: a hypomethylating agent, plus venetoclax, plus an IDH inhibitor. I suspect that [combination] will be highly active.

References

1. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for adult myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi: 10.1056/NEJMoa1614359.
2. FDA approves gilteritinib for relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation [news release]. Silver Spring, MD: FDA; November 28, 2018. bit.ly/2Rl4vHc. Accessed January 23, 2020.
3. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728-1740. doi: 10.1056/NEJMoa1902688.
4. Wei AH, Döhner H, Pocock C, et al. The QUAZAR AML-001 maintenance trial: results of a phase III international randomized, double-blind, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia (AML) in first remission. Blood. 2019;134(suppl 2; LBA-3). doi: 10.1182/blood-2019-132405.