Doctors Debate: Should Maintenance Therapy Be Included in the Treatment of Acute Myeloid Leukemia?

Farhad Ravandi, MD

In treating acute myeloid leukemia (AML), some oncologists use maintenance therapy and others do not consider it necessary to achieve optimal outcomes in patients. During the Society of Hematologic Oncology 2021 Annual Meeting, Farhad Ravandi, MD, and Jeffrey E. Lancet, MD, discussed the issue. In separate interviews before the conference, Drs Ravandi and Lancet shared their perspectives.

Despite the success of implementing maintenance therapy in other leukemias, the key challenge with administering maintenance therapy in AML has been identifying an effective drug.

“In hematological cancers, we’ve been using maintenance therapy whenever we have been able to. For example, in acute lymphoblastic leukemia, we’ve been using maintenance therapy with oral agents for 3 or 4 decades. In acute promyelocytic leukemia, before the introduction of arsenic to frontline therapy, we did use maintenance therapy for [approximately] a year,” Ravandi, the Janiece and Stephen A. Lasher Professor of Medicine and chief of developmental therapeutics in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, said.

“In AML, there has been a desire to have maintenance therapy, but, unfortunately, no reasonably effective and nontoxic agent has been available. This is why we haven’t had maintenance therapy. And because of this, we still only cure 40% of [patients with AML]. We do need to use every tool that’s available to us, including maintenance therapy, to try to increase complete remission duration and improve survival. So yes, it’s necessary,” Ravandi stated in explanation of his argument for the debate.

Results from one study on the hypomethylating agent oral azacitidine (CC-486) maintenance versus placebo in patients with AML have indicated that there may be a role for maintenance therapy after all.

QUAZAR AML-001 Supports Use of Maintenance Therapy for AML

Compared with placebo, the use of oral azacitidine as maintenance therapy for older patients with AML showed significantly longer overall survival and relapse-free survival in patients who were in remission, according to the results of the phase 3 QUAZAR AML-001 clinical trial (NCT01757535).¹

Jeffrey E. Lancet, MD

“It is possible that some colleagues would say that we don’t have a really effective agent, and none of the many studies that have been conducted in maintenance therapy in AML have shown survival advantage, with the exception of the most recent one that led to the approval of oral azacitidine. So, the argument would be to show me the proof that it improved survival. Before the study, QUAZAR AML-001, there was no study that showed improvement in survival,” Ravandi said.

In QUAZAR AML-001, 472 patients with AML were randomly assigned to a treatment arm. A total of 238 patients received oral azacitidine and 234 received placebo. The median age of the overall study population was 68 years (range, 55-86) and 52% were men. The majority of the patients (91%) had de novo AML, an ECOG performance status of 0 (48%), and intermediate-risk disease (86%). Nineteen percent of patients had had 2 or more courses of induction chemotherapy and 81 had a complete remission (CR) following induction therapy. In addition, 80% of patients had consolidation therapy.

The primary end point of the study was overall survival (OS) as estimated through Kaplan-Meier analysis. The secondary end points included relapse-free survival, time to relapse, time to discontinuation from treatment, the number of patients with treatment-related adverse events (AEs), and quality-of-life measurements (TABLE 1).

In addition to showing better survival outcomes compared with placebo, patients who received oral azacitidine had low levels of fatigue and physical impairment vs placebo, achieving the key study end points. In terms of safety, 98% of the experimental arm and 97% in the placebo arm experienced an AE of any grade. The most common AEs observed with oral azacitidine were nausea (65%), vomiting (60%), and diarrhea (50%).

When discussing other agents that are being studied as maintenance therapy options for AML, Ravandi explained that conventional chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecules have not shown benefit.

“If you want to show a dramatic benefit early, you really need to have highly effective agents, meaning that as single agents they can produce an 80% response rate. In AML, we are getting there. There are now strategies that do provide that but until now even the hypomethylating agents produced a best response of [approximately] 30% in AML as single agents,” Ravandi said. “There have been studies of hypomethylating agents, both decitabine and azacitidine, that have shown improvement in event-free survival, but not OS. So, despite the fact that many people believe that they are beneficial, they had never been proven to be beneficial. Their uptake had been very limited by AML.”

Based on Ravandi’s argument, oral azacitidine is a maintenance option for patients with AML, but all other therapies investigated for this strategy have not been proven.

On the other side of the argument, Lancet, chair and program leader of the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida, believes the data from QUAZAR AML-001 do show the promise of maintenance therapy, but the field of AML has even farther to go before one could definitively argue for maintenance therapy in AML.

“The argument is whether maintenance therapy in AML is required. I’m arguing, no, it’s not. But really, that argument is nuanced in the sense that we’re trying to look at it from the big picture point of view and to really understand whether maintenance therapy, as it currently exists, provides a critical standard of care for the disease in general. My argument is to try to convince people that maintenance therapy is perhaps beginning to take a foothold in AML but has a long way to go to reach the point where it has a major impact on the disease itself,” Lancet said.

Overall, deciding on whether maintenance therapy is needed in AML, Lancet said, there are a few critical questions to bear in mind.

“I think there are some important questions to consider when it comes to determining whether maintenance therapy in AML should be required,” Lancet said. “Is there clear evidence or a clear understanding of the precise drivers of relapse to warrant the expectation of success for maintenance therapy? Another important question is are there thresholds of residual leukemia that make maintenance therapy impactful? The third would be how strong are the data to support the use of maintenance therapy in general?”

A strong argument against maintenance therapy in AML, Lancet added, is the use of a hypomethylating agent with venetoclax (Venclexta).

Success Without Maintenance Therapy in AML

OS was extended with the combination of azacitidine and venetoclax in the phase 3 Viale-a clinical trial (NCT02993523) compared with azacitidine alone in previously untreated patients with AML who were ineligible for intensive chemotherapy. The study also showed that the combination achieved a higher remission rate compared with azacitidine alone.²

^{“The increasing number of patients receiving the QUAZAR AML-001 regimen is an argument against maintenance therapy because maintenance therapy, as it currently exists, is currently limited to patients who have [had] induction therapy initially. With more patients getting a hypomethylating agent with venetoclax, which is sort of intended as chronic continuous therapy, maintenance becomes a trickier issue,” Lancet said.}

In the multicenter, randomized, double-blind, placebo-controlled Viale-a study, however, one of the key inclusion criteria was to be ineligible for standard induction therapy if patients were 75 years or older or if they had at least 1 of the coexisting conditions precluding intensive chemotherapy. Patients were also required to be 18 years or older with an ECOG performance status of 2 or 3 to be included in the study.

A total of 433 patients in Viale-a were randomized 2:1 to receive either the combination of azacitidine and venetoclax (n = 286) or azacitidine with placebo (n = 145). The study population was a median age of 76 years and 60% of patients in each treatment arm were men. The majority of the patients had de novo AML, and secondary AML was seen in 64% of the venetoclax-containing arm compared with 74% of the azacitidine-alone arm.

Viale-a assessed the coprimary end points of OS and CR rate (TABLE 2). The secondary end points were event-free survival, quality of life, percentage of patients who achieved a CR rate, and composite complete remission.

In terms of the secondary study end points, results from the combination of azacitidine and venetoclax were overall better than with azacitidine and placebo.

The safety of findings showed that nausea in 44% of the azacitidine/venetoclax arm versus 35% in the control arm was the most common AE. The most common grade 3 or higher AE was thrombocytopenia, which occurred in 45% of the experimental arm versus 38% of the control arm. Febrile neutropenia was also a commonly occurring high-grade AE that was observed in 42% of those who received azacitidine plus venetoclax compared with 19% of the control arm.

Further discussion with Lancet revealed that many options in AML for patients outside of maintenance therapy are coming down the pipeline and there may even be a space for maintenance therapy later on.

“The introduction of other new drugs, like targeted therapies, seems to be impactful. Some examples are the FLT3 inhibitors [such as] lazertinib [Leclaza] and gilteritinib [Xospata], and perhaps crenolanib as it evolves. Other potentially useful drugs will be the Menin class of inhibitors that are showing promise. And certainly, both cellular and noncellular immunotherapy options, including bispecific antibodies and CAR T-cell products, are showing early signals of efficacy. I think that will translate into longer-term success once they become more developed,” Lancet said. “I think that CPX-351 [a dual-drug liposomal encapsulation of cytarabine and daunorubicin] has also increased its footprint in AML. CPX-351 has shown a lot of promise in improving remission rates and bridging patients to potentially curative transplants. So, there’s a lot on the horizon.”

_REFERENCES:

_{1. Wei AH, Döhner H, Pocock C. Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Eng J Med. 2020;383(26):2526-2537. doi:10.1056/NEJMoa2004444}

_{2. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971}