Clinical Challenges: Maintenance Therapy for AML

New drug combinations and better supportive care have led to improved outcomes in patients with acute myeloid leukemia (AML). However, even among patients who achieve complete remission with initial therapy, high rates of relapse remain a significant clinical problem, with a probability greater than 50% for all adults with high-risk AML.

While allogeneic hematopoietic stem cell transplantation (HSCT) after induction chemotherapy is potentially curative, this is not an option for many older patients or those with multiple comorbidities.

The standard of care for most patiens with AML who achieve a complete remission with induction and consolidation, and who aren't candidates for transplant, has been observation, Tapan M. Kadia, MD, of the University of Texas MD Anderson Cancer Center in Houston, told MedPage Today. "But, it's clear relapse is a major risk and there is a need for maintenance therapies."

Until recently, no treatment approaches to AML maintenance had succeeded in improving overall survival (OS).

In 2019, results from the phase III QUAZAR AML-001 study finally suggested a benefit. This randomized double-blind trial compared oral azacitidine (Onureg) against placebo in transplant-ineligible AML patients older than 55 who were in complete remission (or complete remission with incomplete blood count recovery) after intensive induction chemotherapy.

At a median follow-up of 41.2 months, the median OS from the time of randomization was 24.7 months for patients treated with oral azacitidine and 14.8 months for those in the placebo arm (P<0.001). Median relapse-free survival (RFS) was 10.2 months versus 4.8 months, respectively (P<0.001). Moreover, the drug had a manageable safety profile, with patients maintaining health-related quality of life comparable to placebo. The results led to FDA's approval of oral azacitidine as maintenance therapy in this population.

"Virtually nobody used maintenance before QUAZAR," Farhad Ravandi-Kashani, MD, also of MD Anderson Cancer Center, told MedPage Today. "There has never been an effective, proven strategy that has been shown to work. More than anything, QUAZAR is demonstrating that maintenance can be useful in AML now that we have relatively non-toxic and effective agents."

Other potential maintenance strategies for AML are also under investigation, Ravandi-Kashani added. Ongoing trials are combining oral hypomethylating agents such as oral azacitidine or oral decitabine and cedazuridine (ASTX727) with IDH inhibitors, FLT3 inhibitors, or venetoclax (Venclexta), he said.

For example, with the discovery of venetoclax's activity in AML, "we're also conducting a study of azacitidine combined with venetoclax as a maintenance strategy in patients in remission," said Kadia. "And we're looking at oral decitabine in combination with various drugs like venetoclax, IDH1 inhibitors, or gilteritinib [Xospata]."

"Immune-based strategies also have potential, but are further back," Ravandi-Kashani noted. He, along with Kadia and others from MD Anderson, conducted a study evaluating the immunomodulatory therapy lenalidomide (Revlimid) in patients with high-risk AML who had achieved first or second remission after induction chemotherapy and at least one consolidation cycle, and were not candidates for immediate allogeneic HSCT.

At a median follow-up of 22.5 months, 12 of the study's 28 patients had relapsed after a median of 3 months. The median duration of remission for all patients was 18.7 months (range 0.7-55.1 months). The 2-year OS and RFS rates from the time of enrollment were 63% and 50%, rates that were "superior to what we would expect from historical controls," Kadia said.

Ravandi-Kashani, Kadia, and colleagues have also investigated the immune checkpoint inhibitor nivolumab (Opdivo) as maintenance therapy in high-risk AML in a single-arm phase II study.

"We saw a modest benefit," Kadia noted. "Eradication of MRD [minimal residual disease] in just two out of 15 patients we treated, and no significant improvement in overall survival. So, that was a lesson that maybe a single-agent checkpoint inhibitor is not the best strategy."

"Maintenance is not only important post-remission after chemotherapy, but also important in the post-transplant setting," Kadia added. "In those people who have completed remission and moved forward with allogeneic transplant, there is a role for maintenance therapy post-transplant with these small-molecule drugs."

According to Kadia, the drug with the most data in this setting is sorafenib (Nexavar), which has been studied in several randomized trials, including the SORMAIN trial for patients with FLT3-internal tandem duplication (ITD)-positive AML. At a median follow-up of 41.8 months, RFS was superior with sorafenib (HR 0.39, 95% CI 0.18-0.85, P=0.013). The 24-month RFS probability was 85.0% with sorafenib versus 53.3% with placebo.

Furthermore, in a Chinese phase III trial, sorafenib maintenance after allogeneic HSCT significantly reduced the risk of relapse versus no maintenance therapy in patients with FLT3-ITD-positive AML. At a median follow-up of 21.3 months, the 1-year cumulative incidence of relapse was 7.0% in the sorafenib group compared with 24.5% in the control group (HR 0.25, 95% CI 0.11-0.57, P=0.0010). The 2-year OS rates were 82.1% versus 68.0%, respectively.

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