Plethora of New Drugs in AML Stirs Hope

OncologyLive, Vol. 18/No. 23, Volume 18, Issue 23

After several decades without a new therapy, the approval of 4 treatments for acute myeloid leukemia over the span of just 4 months is either a total coincidence or an inevitable occurrence.

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).

Four New Drugs in 4 Months

“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.Midostaurin

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.

The drug was approved for adult patients with newly diagnosed AML caused by prior cancer treatment or newly diagnosed AML with myelodysplasia-related changes. A phase III study randomized 309 patients, aged 60 to 75, between CPX-351 and the 7+3 protocol. CPX-351 resulted in significant increases in median OS of 9.56 versus 5.95 months for 7+3 (HR, 0.69; 2-sided P = .005), respectively. Complete response rates were 37.3% for CPX-351 and 25.6% for 7+3 (P = .04).5

Gemtuzumab Ozogamicin

The last approval in the series went to gemtuzumab ozogamicin (Mylotarg), which was first approved on the strength of early-stage trials as a stand-alone treatment for older patients with CD33-positive AML. That first approval came in May 2000, but the product was voluntarily withdrawn when larger trials found no clinical benefit and raised safety concerns. The new approval comes from trial results that show the drug to be safe and effective at a lower dose and on a different schedule, either as monotherapy or in combination with 7+3 cytarabine and daunorubicin.

Gemtuzumab ozogamicin combines a monoclonal antibody that is designed to bind to the transmembrane receptor CD33, which is somewhat expressed in 85% to 90% of all AML cases.6 The antibody does not attack cancer directly, but once it has bound to cancer cells, it releases a cytotoxic agent into them. It was originally thought that this would minimize damage to surrounding cells, but the cytotoxic agent escaped into the bloodstream, which is why the original dose proved excessively toxic.

The first of the 3 trials that won gemtuzumab ozogamicin’s reapproval randomized 280 patients aged 50 to 70 years with CD33-positive AML between 7+3 cytarabine and daunorubicin and the 7+3 protocol plus 5 doses of IV gemtuzumab ozogamicin (3 mg/m2 on days 1, 4, and 7 during induction and day 1 of each of 2 consolidation chemotherapy courses). The median EFS was 17.3 months for the combination and 9.5 months for chemotherapy. OS at 2 years was 53.2% (95% CI, 44.6%-63.5%) versus 41.9% (95% CI, 33.1%-53.1%), respectively (HR, 0.69; 95% CI, 0.49-0.98; P = .0368).7

Analyzing the Impact

The second trial randomized 237 patients aged 61 and older who refused chemotherapy to gemtuzumab ozogamicin or best supportive care (BSC); the 1-year OS rate was 24.3% with gemtuzumab ozogamicin and 9.7% with BSC.8 In the third trial, gemtuzumab ozogamicin was administered to 57 patients with relapsed CD33-positive AML; 26% achieved a CR that lasted a median of 11.6 months.9Richard M. Stone, MD, director of the adult leukemia program at Dana-Farber Cancer Institute, has been at the forefront of AML research for 20 years. He was the principal investigator on the pivotal RATIFY midostaurin trial and serves as vice chair of the Leukemia Core Committee for the national cooperative trials group Cancer and Leukemia Group B. Stone, who is also a professor of medicine at Harvard Medical School, discussed how the new therapies are likely to fit into the AML treatment paradigm in an interview with OncologyLive®.

“In theory, most chemotherapy patients could benefit from the addition of gemtuzumab, but I’d be very surprised if the combination becomes a standard of care anytime soon,” said Stone.

“The event-free survival results from the gemtuzumab-chemotherapy combination were good, but the more important overall survival benefits were not as impressive as those from other medications. Factor in the cost, the unfamiliarity, and concerns about side effects, and I’d guess adoption will be slow, if it ever comes.

“CPX-351 provided more substantial increases in overall survival against 2 aggressive forms of AML, and it will likely be valuable, particularly against AML that stems from prior treatment of other tumor types,” he said. “Those cases keep becoming more common as patients with other cancer get more treatments and live longer.

However, just because CPX-351 proved itself superior to standard chemotherapy in those patients does not mean it’s superior to 7+3 in all patients. It would take more trials to demonstrate that, so there’s no reason to think it will become a new standard of care across AML.

“As for the 2 targeted medications, they will only help somewhat small subsets of patients— very small, in the case of enasidenib—but that’s the nature of a heterogeneous disease. No single targeted agent will work on most subtypes. The goal is to chip away at different subpopulation, and these medications are a good start,” he said.

Given that approximately 12% to 15% of all patients with AML have an IDH2 mutation, the enasidenib subset is particularly small, but hopes for the drug are particularly large. Looking just at the trial that won the drug’s approval, the fact that 19% of patients—especially relapsed and refractory patients—experienced temporary CRs has led some to think that using the drug in combination with chemotherapy on newly diagnosed IDH2- mutant AML could cure a significant number of patients. Any cured patients are big news in a disease that kills most patients.10

Enasidenib’s novelty is also cause for hope. Many other epigenetic drugs are under development,11 and the approval of one such drug serves as valuable proof-of-concept for the entire field. It may prove particularly important in cancer, moreover, where combinations tend to be more effective than monotherapies and each new drug class creates the potential for a new ingredient in tumor-fighting cocktails.

Midostaurin does not have a groundbreakingmechanism of action: kinase inhibitors have been used to treat patients with cancer since the FDA approved imatinib (Gleevec) for chronic myeloid leukemia in 2001,12 but it may result in improved OS for nearly one-third of patients with AML, and there is hope that it could also prevent relapses for many years if used as maintenance therapy after successful stem cell transplants.13 (It is already approved for such a use in Switzerland, and there is an ongoing trial of midostaurin in transplant patients,14 but maintenance monotherapy is not among its FDA-approved indications at this time.)15

Under its current indication, midostaurin is used for a limited time while patients are undergoing chemotherapy. The same is true of gemtuzumab ozogamicin, and CPX-351 is a chemotherapy, so it, too, is used for a defined period of time. Enasidenib is the only new AML therapy that patients take indefinitely, but it is an oral medication that is designed to be taken at home, so its demands on patient and caregiver time are minimal.

More Drugs Under Study

Another advantage of all the new treatments, aside from not requiring much more time to administer, is that most of the diagnostic work involved is already recommended for evaluation of acute leukemias.16 NCCN guidelines endorse testing for high-risk cytogenetic factors, including FLT3-ITD mutations for prognostic purposes.16 Companion diagnostics were approved along with midostaurin and enasidenib.Amid this plethora of new therapies, there are many ongoing clinical trials into existing and novel therapies that may generate more new drugs for patients with AML. lists more than a dozen ongoing studies of midostaurin and gemtuzumab ozogamicin, 3 ongoing studies of enasidenib, and 7 studies of CPX-351. Many other compounds, moreover, are in trials against various AML subtypes.

Among the most promosing of the therapies under study is venetoclax (Venclexta), a B-cell lymphoma-2 inhibitor that is approved for the treatment of chronic lymphocytic leukemia. The excitement surrounding venetoclax’s potential as an AML treatment stems from an open-label study of 61 untreated patients aged 65 and older who received venetoclax and low-dose cytarabine because they were deemed unfit for standard chemotherapy. The ORR was 61% and the CR rate was 21%.17

Other targeted drugs that are being tested against AML include the c-KIT inhibitor dasatinib (Sprycel), the polo-like kinase inhibitor volasertib (which has received both breakthrough therapy and orphan drug status from the FDA), the aurora kinase inhibitor barasertib, and histone deacetylase inhibitors such as vorinostat (Zolinza) and panobinostat (Farydak). The proteasome inhibitor bortezomib (Velcade) also is under study in AML.

And that is just the tip of the iceberg. Researchers are also testing a variety of newer chemotherapies (eg, sapacitabine, laromustine, and tipifarnib) against AML because 7+3 cytarabine and daunorubicin tends to be too toxic for older patients and not very effective in fighting their cancers. Further trials are under way with a range of immunotherapies including checkpoint inhibitors, vaccines, and chimeric antigen receptor T-cell therapy.18

All told, it’s a massive amount of clinical research against what remains a relatively rare form of cancer. There are only 21,380 cases of AML diagnosed each year in the United States19 which is less than 10% of the total of new breast cancer cases.20

“The reemergence of Mylotarg is promising, as is the upcoming agent venetoclax, particularly in combination with other chemotherapy agents. And there is optimism that checkpoint inhibitors may demonstrate the sort of efficacy against AML that they have demonstrated against other tumor types. It’s really an exciting time and hopeful time in AML,” said Hetty E.

Carraway, MD, MBA, program director of hematology oncology fellowship at Cleveland Clinic’s Taussig Cancer Institute. “The drugs that are already approved, with nothing more than their current indications, are a real step forward, but there’s already work under way to expand those indications. The approval for CPX-351 is reasonably narrow, so there are likely to be upcoming trials using different patient populations, and opportunities to test combinations with gemtuzumab or midostaurin to determine whether the nanoparticle formulation increases efficacy or at least makes the combinations more tolerable.

“There’s no guarantee that any of these trials will succeed, of course, but there’s certainly a lot of hope,” she added.