Emerging Opportunities: Reevaluating Maintenance Therapy in AML

The concept of maintenance therapy in acute myeloid leukemia (AML) is not new. But for decades, research was unable to show any clear survival benefit for patients who received maintenance therapy after achieving a complete remission (CR).

That may be about to change.

New data have found that certain maintenance strategies improve overall survival (OS) and relapse-free survival (RFS) in patients with AML, suggesting that it may be time to rethink treatment recommendations for this patient population.

Elias Jabbour, MD, Professor of Medicine in the Department of Leukemia at MD Anderson Cancer Center in Houston, Texas, called the new data a first step in establishing maintenance therapy as a standard component of care for patients with AML.

“AML is a difficult disease to treat,” he told ASH Clinical News. “For years we had nothing, and now we have several drugs and tools that will definitely lead to significant improvement in patient outcomes.”

But while hematologists and oncologists are optimistic about the latest research, there are still many unanswered questions about maintenance therapy. These questions range from who will benefit most from it, to whether it is as effective as hematopoietic cell transplantation (HCT) in preventing disease recurrence, to which agents will provide the most substantial gains in survival. ASH Clinical News spoke with Dr. Jabbour and other researchers in the field to understand the history of maintenance therapy in AML and get their predictions for the future.

The Long History of Maintenance Therapy in AML

Researchers have been exploring maintenance therapy for AML since the 1960s.1

Initial maintenance strategies were built on the use of immunotherapy options, such as interferon, interleukin-2, and bacille Calmette-Guérin (BCG) vaccination, or chemotherapy-based strategies, delivered alone or in combination with other drugs. A major limitation of these early strategies was that the drugs used in the maintenance phase were often the same or similar to those used during the induction or consolidation phase. So, their potential contribution to prolonging CR could be limited by the similarities in the mechanisms of action.

Early research regarding maintenance strategies provided mixed results. In the early 1990s, a randomized Eastern Cooperative Oncology Group (ECOG) study compared patients who received no maintenance therapy with those who received 2 years of chemotherapy with thioguanine and low-dose cytarabine.2 Investigators reported that participants who received no additional therapy after CR had significantly shorter remission durations (p=0.002).

Similarly, a Dutch study evaluating the effects of 8 cycles of subcutaneous low-dose cytarabine in patients who had achieved a first CR after induction and one consolidation therapy initially showed that the rate of disease-free survival (DFS) was higher for those who received maintenance chemotherapy compared with those who did not.3 However, researchers were unable to find any differences in OS.

The research into the use of immunotherapy agents also has been disappointing. For example, one randomized control trial studying the use of interferon alfa (IFN-α) as postinduction maintenance therapy found no difference in remission duration among the groups who received no intervention, chemotherapy, or IFN-α, according to a 2016 review of AML maintenance therapy efforts published in Blood.4

As time went on, new therapy options including more targeted agents entered the clinic, but researchers were still unable to find a maintenance therapy option that significantly improved OS without significantly increasing toxicity.

Today, prolonging survival in AML patients continues to be a difficult challenge and the rate of relapse remains high. For those patients who have high-risk forms of AML, for example, the relapse rate continues to be over 60%.1

“The problem is that treatment failure is common and fatal,” said James Foran, MD, Associate Professor in the Division of Hematology and Medical Oncology at the Mayo Clinic in Jacksonville, Florida. “It’s extremely difficult to cure somebody a second time around, and I think the real issue is that we just didn’t have the best agents at the time. It was difficult to come up with something that would work without too much toxicity or too many side effects.”

Promising New Avenues

For decades, research failed to show significant survival benefits for patients with AML using maintenance therapy, causing centers to forgo maintenance therapy for this population.

“Unlike acute lymphocytic leukemia, there is no clear-cut rule for maintenance therapy in AML,” Dr. Jabbour said. “Every time a trial was done, it had negative aspects – it was a phase II, not a phase III, or it improved event-free survival, not overall survival.”

As a result, he noted, there was no accepted concept of maintenance therapy in AML, but new research has shown there could be more promising options in the years ahead.

At the 2019 American Society of Hematology (ASH) Annual Meeting, results from the randomized, phase III QUAZAR AML-001 trial suggested that CC-486 (an oral formulation of the hypomethylating agent [HMA] azacitidine) as maintenance improved both OS and RFS in patients with AML who were in remission after induction chemotherapy.5

“This was the first time that a randomized study of maintenance therapy in AML demonstrated a survival benefit,” Dr. Jabbour said.

QUAZAR randomized 238 patients to receive once-daily CC-486 and 234 patients to receive placebo. Participants had intermediate- or poor-risk cytogenetics, were not eligible for HCT, and had an ECOG performance score ≤3.

Researchers found that those on CC-486 had a significantly longer survival (24.7 months) compared with those in the placebo group (14.8 months; hazard ratio [HR] = 0.69; 95% CI 0.55-0.86; p=0.0009). The median RFS also was longer in the group that received CC-486 (10.2 vs. 4.8 months; HR=0.65; 95% CI 0.52-0.81; p=0.0001).

“The QUAZAR trial showed that, rather than observing patients and waiting for them to relapse, we can now actively engage in trying to reduce relapse risk and improve survival in the postremission phase,” lead investigator Andrew H. Wei, PhD, from the Alfred Hospital and Monash University in Melbourne, Australia, said when the group’s findings were announced.

The study isn’t the only new research to report promising results.

Another recent study exploring the effect of monthly courses of the HMA decitabine in older patients with AML after first CR found that the agent improved OS.5 In an exploratory study of the larger phase II ECOG-ACRIN E2906 trial, 120 participants received either 1 year of intravenous decitabine 20 mg/m2 or underwent observation.6 After a median follow-up of 49.8 months, OS was improved in the decitabine group (HR=0.65; 95% CI 0.37-1.15; p=0.07).

Although the results were discovered in a pilot study and need to be confirmed in a randomized trial, Dr. Foran, who served as the lead investigator of the ECOG-ACRIN E2906 trial, said researchers were “delighted” to see that decitabine maintenance had an effect on patients and was tolerable.

“We know from our ECOG-ACRIN data that the benefit was strongest in patients who did not have a FLT3 mutation,” he explained, adding that the studies showing positive results with maintenance therapy have been conducted in older adults.

Research also has looked into the use of targeted approaches such as FLT3 inhibitors as a maintenance option after allogeneic HCT, but there is still no consensus about whether this maintenance strategy is an effective means of treatment. “We’re going to have to work out whether there is a benefit of an HMA or chemotherapy-based approach in people who have targetable mutations,” Dr. Foran noted, “and whether patients with targetable mutations will perform better with a targeted agent or an HMA that just kind of hits everything.”

New Research Directions

As Dr. Foran noted, both QUAZAR and ECOG-ACRIN E2906 demonstrated an OS advantage with HMAs as maintenance therapy in older adults with intermediate forms of the disease.

“So far, people over the age of 60 have been the big focus [of research], so there are still questions about people younger than 60,” he said.

Researchers also need to determine how these newer promising maintenance strategies compare with HCT. “[Maintenance therapies] are easier and safer, but are they as effective? We need to get a better understanding of that,” he said.

Dr. Foran also believes there will likely be a role for maintenance therapy after HCT, but the research is in the early stages.

Dr. Jabbour added that investigators still need to determine the optimal form of HMAs – whether oral azacitidine is as effective as the intravenous form of the drug, or whether it may be more effective when used in combination with other drugs. “I think many studies will be conducted in the near future to explore the role of HMA oral agents in combination with other targets,” he said.

Quality Versus Quantity of Life

As researchers set off to find more answers as to who will benefit most from maintenance therapy, hematologists will also have to weigh the potential gains associated with maintenance options against the potential effect on a patient’s quality of life.

In the QUAZAR trial, for example, the most common adverse events for patients taking CC-486 were mild grade 1 or 2 gastrointestinal events.

“With this kind of oral agent, the safety question is minimal,” Dr. Jabbour said. “I don’t think it will negatively affect quality of life. In fact, it will improve quality of life because the alternative for these patients will be a relapse.”

Dr. Foran noted that ECOG-ACRIN investigators have collected prospective quality-of-life data, but the results are still being analyzed. “We know, at least from our data, that people tend to run lower blood counts when they are on the maintenance therapy,” Dr. Foran said, referring to the incidences of grade 3 neutropenia and reversible grade 4 cytopenias observed in the study. Also, while researchers have not observed any life-threatening infections, decitabine maintenance was not free from side effects. For example, investigators had intended to give patients 13 cycles of treatment, but participants received a median of 6 cycles.

“We know that sometimes [decitabine] is just a little too hard on the blood count, or sometimes the patient chooses to discontinue,” Dr. Foran said, adding that hematologists will need to make treatment decisions collaboratively alongside their patients.

“Right now, I think the preponderance of evidence shows that maintenance should be considered, particularly in patients over age 50 or 60, in those who do not have a FLT3 mutation, and in those with intermediate-risk disease,” he summarized. “But I’d sure like to figure out who should receive maintenance therapy in a more precise way.”

In the years ahead, Dr. Foran said it is likely that new research will help determine the right approach for each patient, pointing to specific or targeted agents tailored to their unique leukemia phenotype and genotype.

For now, though, the researchers who spoke with ASH Clinical News are pleased just to have new maintenance treatment options on the horizon for a notoriously difficult to treat disease. —By Jill Sederstrom

References

  1. Molica M, Breccia M, Foa R, et al. Maintenance therapy in AML: The past, the present and the future. Am J Hematol. 2019;94:1254-1265.
  2. Cassileth PA, Lynch E, Hines JD, et al. Varying intensity of postremission therapy in acute myeloid leukemia. Blood. 1992;79:1924-1930.
  3. Robles C, Kim KM, Oken MM, et al. Low-dose cytarabine maintenance therapy vs observation after remission induction in advanced acute myeloid leukemia: an Eastern Cooperative Oncology Group Trial (E5483). Leukemia. 2000;14:1349-1353.
  4. Rashidi A, Walter R, Tallman M, et al. Maintenance therapy in acute myeloid leukemia: an evidence-based review of randomized trials. Blood. 2016;128:763-773.
  5. 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. Abstract #LBA-3. Presented at the 2019 ASH Annual Meeting, December 10, 2019; Orlando, FL.
  6. Foran JM, Sun Z, Claxton DF, et al. Maintenance decitabine (DAC) improves disease-free (DFS) and overall survival (OS) after intensive therapy for acute myeloid leukemia (AML) in older adults, particularly in FLT3-ITD-negative patients: ECOG-ACRIN (E-A) E2906 randomized study. Abstract 115. Presented at the 2019 American Society of Hematology Annual Meeting, December 7, 2019; Orlando, FL.