Nontransplant options
In the RATIFY trial, patients 60 years and younger with newly diagnosed AML with activating FLT3-mutations were randomized to induction chemotherapy with daunorubicin and cytarabine, consolidation with an histone deacetylase inhibitor, and then maintenance for up to 12 cycles with either midostaurin or placebo.
Although the trial met its primary endpoint of an improvement in overall survival with midostaurin (4-year overall survival, 51.4% vs. 44.3% with placebo), there is still uncertainty as to whether the observed survival benefit was caused by midostaurin or by something else, Dr. Roboz said.
“That said, it certainly has become common to use FLT3 inhibitors as postremission strategy for patients, with consolidation, with allo transplant, after allo transplant – wherever you can get the inhibitor in there,” she said.
The isocitrate dehydrogenase inhibitors ivosidenib (for IDH1) and enasidenib (IDH2) have also been tried in a postremission maintenance-like setting, but have thus far not been demonstrated in clinical trials to be effective in this setting, she added.
Gemtuzumab ozogamicin, an anti-CD33 antibody conjugated to calicheamicin, was approved in 2000 for adults 60 years and older with CD33+ AML in first remission, and in 2017 for adults with newly diagnosed CD33+ AML, as well as adults and children 2 years and older with relapsed or refractory CD33+ AML, but there are no data to show whether this antibody-drug conjugate could have benefit in a maintenance setting.
As previously reported, the combination of the BCL-2 inhibitor venetoclax (Venclexta) with azacitidine was associated with a significant improvement in overall survival, compared with azacitidine alone, in the VIALE-A trial.
“The question now is, in these studies most of the time patients are given a combination of aza and venetoclax that actually continues until they progress; is that called maintenance if you’re getting ongoing cycles? Not sure what to call it, but this is quite myelosuppressive, and there are many, many postremission modifications in dose and schedule that could take up a whole separate lecture,” Dr. Roboz commented.
She added, however, that the combination is effective across nearly all subgroups, and may be more generally applicable for maintenance-style therapy in older patients with AML.
Survival benefit
Dr. Roboz was a coinvestigator for the QUAZAR AML-001 trial (NCT01757535), results of which were reported at the 2019 ASH annual meeting. It was the first trial to show that a maintenance therapy with CC-486, an oral formulation of azacitidine, can improve overall survival in patients with AML in remission.
Among 472 patients with poor-risk AML in first complete remission who were not eligible for transplantation, median relapse-free survival was 10.2 months with CC-486 vs. 4.8 months with placebo plus best supportive care, and median overall survival with CC-486 was 24.7 months vs. 14.8 months, an absolute difference of 9.9 months.
This oral formulation of azacitidine was approved by U.S. Food and Drug Administration on Sept. 1, 2020 for use in adult patients with AML in complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy. It is sold under the trade name Onureg.
“This is likely to become now the standard of care for AML patients, for the group that was shown to benefit in the clinical trial,” Dr. Roboz said.
The drug was effective at prolonging relapse-free survival regardless of sex, age, remission status (complete remission or complete remission with incomplete blood count recovery) at randomization, cytogenetic risk category, or MRD status.
“We were very gratified to see that there was no reduction in health-related quality of life, which meant that the agent was tolerable, it could be continued for multiple cycles, and there are actually patients, including one of mine, who are many years out with ongoing therapy,” she said.
No funding source for the presentation was reported. Dr. Roboz disclosed consultancy/advisory board activity for multiple pharmaceutical companies; data safety and monitoring committee activity for MEI Pharma, Helsinn, and Takeda; and research funding from Cellectis.