Acute Myeloid Leukemia: Time for New Research Paradigms?

Although molecular and immunological cancer therapies have made great strides across the clinical landscape in recent years, their use in treating acute myeloid leukemia (AML) has met with only modest success. In a recent report published in Blood, a group of experts, led by Elihu Estey, MD, examined the state of AML treatment research and offered six changes to current therapeutic development methods that may yield better results.

“Discovering effective new therapies in AML is often inefficient, with many drugs eventually proven ineffective after considerable expenditure of time and resources,” wrote Dr. Estey, of the University of Washington School of Medicine and the Fred Hutchinson Cancer Research Center in Seattle, and colleagues.

Strengths and Weaknesses of AML Studies

The authors first looked at preclinical studies. In examining their limitations, Dr. Estey and co-authors pointed out one important obstacle: “the genomic complexity of AML and the presence of multiple coexisting molecularly defined clones or subclones.”

Using xenograft assays may be more clinically relevant than testing cell lines, they observed. “Assays done in the presence of supporting stroma might, in principle, provide a more realistic replica of the in vivo situation.”

“The limitations to preclinical studies are probably the biggest obstacle, but those limitations are not susceptible to immediate remediation” in bringing about change in AML therapy development, Dr. Estey told ASH Clinical News. “I think the quicker use of combined therapies (multiple targeted agents and agents + chemotherapy) would have the most immediate potential clinical benefit.”

Given the complex genetic landscape of AML, there is also a need for clinical trials that use more than one targeted agent. For example, the authors pointed out, there is often more than a single driver mutation in AML, with an average of 13 coding mutations reported in de novo AML. They argued for testing combinations of several agents that modulate distinct pathways or targets, which could be administered simultaneously or sequentially in early drug development.

What Needs to Change?

In addition to testing combinations of targeted therapies, the authors strongly supported:

  • Early study of combining targeted agents with chemotherapy (although that could require a more extensive financial outlay on behalf of the agency developing therapies)
  • Inclusion of newly diagnosed patients in targeted therapy trials (rather than the current standard of relapsed/refractory AML patients or those considered unfit for conventional chemotherapy)
  • Early trials of targeted therapies in specific, genotypically defined populations, followed by studies in the broader AML population
  • A reevaluation of commonly used endpoints to assess efficacy

“While truly effective drugs might work even in very advanced disease (as is true with all-trans retinoic acid in acute promyelocytic leukemia) it also seems plausible that conclusions about the value of a targeted therapy based solely on testing in relapsed/refractory patients may be falsely negative,” the authors wrote.

“Likewise, restricting testing to newly diagnosed, unfit patients impedes introduction of combinations of targeted agents with chemotherapy, despite the possible merit of this approach noted above.”

In terms of reassessing efficacy endpoints, Dr. Estey and colleagues advocated for replacing overall survival (OS) with event-free survival. Not only does EFS takes less time to evaluate than OS, but it is a less confounded indicator of a new therapy or new combination’s value than OS.

“I hope that our paper increases awareness that the way we go about studying targeted therapies leaves much to be desired,” Dr. Estey said. “Some of the problem is simple lack of knowledge, as with preclinical studies – that is understandable. Less understandable are the problems raised in the other issues.”

So, what are the biggest barriers to adoption of the changes advocated in this paper? The common culprits with any major change, Dr. Estey said: “Cost and lack of time.”

Unique Complications of AML

Asked to comment on the paper by Dr. Estey’s group, Farhad Ravandi, MD, of the University of Texas MD Anderson Cancer Center in Houston, said he agreed with their assessments.

“The biggest problem in AML research is the heterogeneity of the AML population. The treatment is complicated,” he told ASH Clinical News. “Also, the question of transplant will always affect therapies.”

For example, he explained, if you are assessing a drug in solid tumors, you give the drug to some patients and not to others; then you assess the response and survival for each group at the end of therapy. In leukemia, though, the drug is given and patients are then sent for transplant.

“If transplant was a universally curative and universally nontoxic strategy, it wouldn’t affect the outcome,” he said, “but it is another step that has its own benefits and mortality.”

“AML is a disease with virtually no new drug approvals since 2000. The last drug that was approved was withdrawn from the market,” referring to the voluntary withdrawal of gemtuzumab ozogamicin by Pfizer in 2010 after the agent was found to be associated with veno-occlusive disease in AML patients and failed to show clinical benefit in trials conducted after its approval in 2000.

Why not? Well, the good response rates to current AML therapies may be part of the issue.

“AML doctors set a higher bar for ourselves,” Dr. Ravandi said. “Historically, we have cured 40 percent of AML patients; in diseases like myeloma or solid tumors, however, there has not been a similarly high long-term cure rate.”

That should not be an obstacle to having new drugs approved, he added, encouraging the AML community to “talk to regulatory officials to try to get newer agents more readily available.”


Estey, E, Levine R, Lowenberg, B. Current challenges in clinical development of “targeted therapies”: the case of acute myeloid leukemia. Blood. 2015 March 11. [Epub ahead of print.]

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