Plethora of New Drugs in AML Stirs Hope

Andrew D. Smith
Published: Wednesday, Dec 27, 2017
Martin S. Tallman, MD
Martin S. Tallman, MD
After several decades without a new therapy, the approval of 4 treatments for acute myeloid leukemia (AML) over the span of just 4 months is, depending upon your perspective, either a total coincidence or an inevitable occurrence.

It is a coincidence in the sense that the treatments arose independently and took different routes to market. Each drug targets a different facet of AML, has a unique mechanism of action, and has proved itself in a different patient subset.

On the other hand, each drug owes its existence to basic research, such as the genome sequencing that elucidated disease pathophysiology in recent years and identified possible targets both for new medications and new formulations of old therapies. That fundamental disease knowledge also spurred the development of late-stage trials testing novel agents that may prove even more effective against AML than currently approved drugs.

“The tumor types that have benefited most from targeted therapies in the recent past tend to be those with only a limited number of apparently aberrant pathways rather than very heterogeneous diseases such as AML,” said Martin S. Tallman, MD, chief of the leukemia service at Memorial Sloan Kettering Cancer Center, professor of medicine at Weill Cornell Medical College, and co-chair of the AML Guideline Panel for the National Comprehensive Care Network (NCCN).

“It is very exciting that we finally understand this disease well enough to bring new medications to patients. The indications for which the 4 treatments have been approved to date suggest that a significant percentage of patients with AML should derive some benefit from at least one of the medications, and after 40 years without any new drugs, that’s a good start,” he said.

Four New Drugs in 4 Months


Midostaurin (Rydapt) was the first of the newer medications to win approval from the FDA. An orally administered drug, midostaurin inhibits the function of several kinases, including FLT3, a cell-surface receptor that plays a role in increasing the number of certain blood cells. FLT3 internal tandem duplications (ITDs) and point mutations occur in about 30% of all AML cases, and they tend to make the disease both more aggressive and more resistant to standard chemotherapy.1

The phase III RATIFY trial that secured midostaurin’s approval enrolled 717 patients (aged 18 to 60 years) with newly diagnosed FLT3 mutation– positive AML. Patients received either placebo or midostaurin in addition to the current standard of care: a combination of the chemotherapies daunorubicin and cytarabine. The overall survival (OS) rate 4 years after diagnosis was 51.4% in the midostaurin group compared with 44.3% in the placebo group (HR , 0.78; 1 sided P = .009). Midostaurin use was associated with a similar increase in event-free survival (EFS), and both effects were equally strong in patients who did and did not undergo stem-cell transplantation during the trial period. The number of serious adverse events was similar in both groups.2


The second FDA approval was for the truly novel drug enasidenib (Idhifa), which works by turning cancer cells back into normal cells rather than killing them. It is the first of what will hopefully become an entire class of epigenetic drugs, and it works by correcting mutations in the IDH2 gene that occur in about 9% of all AML3 and ultimately prevent white blood cells from maturing and differentiating. (This process, called differentiation, has proved to be the general mechanism of all-trans retinoic acid in acute promyelocytic leukemia.)

Enasidenib’s approval rests upon the phase I/II AG221-C-001 trial in 176 patients with relapsed or refractory AML. Most of the patients had received and stopped responding to 1 or 2 prior treatments, but the overall response rate (ORR) was 40%, and the median response duration was 5.8 months. Just over 19% of all patients attained complete remissions (CRs), which lasted a median of 8.2 months. The median OS for relapsed/refractory patients was 9.3 months—19.7 months for complete responders—and the 12-month survival rate was estimated at 39%. Adverse effects, compared with those from other cancer treatments, were both mild and rare, presumably because enasidenib does not work by killing cells.4


The enasidenib approval was followed a few days later by the approval of CPX-351 (Vyxeos), a nanotechnology formulation of the chemotherapies cytarabine and daunorubicin. Traditional treatment uses the drugs in a 7+3 formulation: 7 days of cytarabine administered through continuous IV (100 to 200 mg/m2 ) plus IV daunorubicin (45 to 90 mg/m2 ) on the first 3 treatment days. CPX-351 encapsulates cytarabine and daunorubicin, fixed at a 5:1 molar ratio, inside tiny lipid bubbles. Each lipid bubble is designed to deliver more of the medication to cancer cells and less of it to healthy cells, while the 5:1 fixed ratio is thought to maximize chemotherapy efficacy.

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