Newly Approved Drugs for AML: How to Use Them in Practice

In 2017, the U.S. Food and Drug Administration (FDA) approved several therapies for the treatment of hematologic malignancies, including four for acute myeloid leukemia (AML). With so many new agents reshaping the treatment landscape, the American Society of Hematology (ASH) and the FDA partnered to bring hematologists practical information about using these agents.

At the 2017 ASH Annual Meeting, experts convened for the “ASH-FDA Joint Symposium on New Drug Approvals in Acute Myeloid Leukemia” to offer clinical and regulatory perspectives on:

  • midostaurin – approved August 28, 2017, for the treatment of adult patients with newly diagnosed FLT3 mutation-positive AML
  • CPX-351 (daunorubicin and cytarabine) – approved August 3, 2017, for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC)
  • enasidenib – approved August 1, 2017, for the treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase-2 (IDH2) mutation, as detected by an FDA-approved test
  • gemtuzumab ozogamicin – approved September 1, 2017, for the treatment of newly diagnosed CD33-positive AML in adults and for treatment of relapsed or refractory CD33-positive AML in adults and in pediatric patients ≥2 years

The session, chaired by Kenneth C. Anderson, MD, the 2017 ASH president, featured clinicians with significant experience with the agents discussing treatment challenges, including identification of the appropriate population, dosing, side effects and adverse events (AEs), and off-label use.

“The reason that we’ve had so many novel therapies approved is the incredible, heartfelt commitment of the FDA to look carefully at these many novel agents that we bring forward together to show efficacy and safety,” Dr. Anderson said. “Honestly, the number of agents that have been approved for the last 10 to 15 years, but particularly in the last year, has been phenomenal.”


Ashley Ward, MD, medical officer of the Division of Hematology Products at the FDA, discussed midostaurin, a multi-targeted protein kinase inhibitor approved for the treatment of adult patients with newly-diagnosed FLT3 mutation-positive AML, as well as aggressive systemic mastocytosis (SM) or SM with associated hematologic neoplasm or mast cell leukemia. Approval was granted based on results of the phase III RATIFY trial, in which midostaurin improved rates of overall survival (OS), compared with standard induction chemotherapy (hazard ratio = 0.77; p=0.016).

Midostaurin works by inhibiting oncogenic mutant and wild-type forms of FLT3. “Midostaurin is somewhat more specific than older kinase inhibitors, but less specific than, for example, sorafenib and quizartinib,” Dr. Ward noted.

“Despite a trial design that included maintenance [therapy], the FDA determined that the RATIFY study did not support an indication of maintenance therapy,” she said. “Patients were not pre-randomized before the start of maintenance therapy, making it impossible to determine in a rigorous way whether midostaurin administered as maintenance therapy contributed to the overall treatment effect and the survival benefit observed in the study.” She noted, though, that the labeling for midostaurin includes information about the maintenance-therapy dosing used in the pivotal trial as a reference for physicians.

Though midostaurin 50 mg twice-daily appeared to have a favorable safety profile, Dr. Ward noted certain limitations of the safety reporting in the RATIFY trial. Grade 1/2 AEs were not captured, except for 13 prespecified AEs: neutrophils/granulocytes, platelets, hemoglobin, febrile neutropenia, diarrhea, nausea, vomiting, ataxia, fatigue, rash/desquamation, mucositis/stomatitis, keratitis, and left ventricular systolic dysfunction. The most common AEs (≥20%) were febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infection.

“The seriousness of AEs was not captured by investigators … and several events common to [patients with] AML were exempt from investigational new drug application safety reporting,” she said. “However, the randomized study design allowed us to draw broad conclusions about the safety of midostaurin [in this setting].”

Laura C. Michaelis, MD, of the Medical College of Wisconsin Cancer Center in Milwaukee, offered a clinician’s perspective on using midostaurin, highlighting concerns about the risk of fungal infections during the long induction period. “The label for this drug includes a recommendation that you monitor for increased risk of AEs or don’t use strong inhibitors of CYP3A4, which includes voriconazole and posaconazole,” Dr. Michaelis noted. “We have to remember, however, that fungal and mold [infections] are a devastating complication for our patients, so in our institution, in the absence of any evidence that there is an increased risk of AEs, we include voriconazole or posaconazole for prophylaxis in our patients.”

There are larger logistical challenges to incorporating midostaurin into AML treatment algorithms, Dr. Michaelis noted, such as the urgency to determine FLT3 status. Although some centers can provide results in-house, the typical turnaround time from external laboratories is 10 days. Without the results, physicians have to “guess” about which induction therapy to use, “which is frustrating and scary,” she said. “It shows that, as a care community, we’re still catching up with these approvals and figuring out how to use them.”


In a presentation titled, “What’s Old Is New Again,” reviewer Aviva C. Krauss, MD, medical officer of the Division of Hematology Products at the FDA, discussed CPX-351, a liposomal formulation of daunorubicin and cytarabine, the longstanding backbone of AML therapy.

The new formulation was granted regular approval based on results from the phase III CLTR0310-301 trial. This pivotal trial included patients aged 60 to 75 years with newly diagnosed t-AML or AML-MRC and unfavorable-risk cytogenetics, meaning that “the trial exclusively enrolled patients … who have traditionally been excluded from clinical trials of this disease, due to their particularly poor prognosis, compared with other patients with de novo AML,” Dr. Krauss noted.

OS was selected as the relevant endpoint for the agent’s approval, “given that [patients’] expected survival is so short,” she explained, with “only 20 percent of patients expected to be alive at one year.”

Compared with patients who received standard daunorubicin and cytarabine, those treated with CPX-351 had a longer median OS (9.56 vs. 5.95 months; p value not provided).

The safety profile of the new formulation was similar to each of the agents separately, with two exceptions: prolonged cytopenias and delayed neutrophil recovery, and concerns about acute elemental copper exposure. Because copper is required to create CPX-351’s stable formulation, patients are exposed to 70 times the permitted daily exposure, which could prove dangerous for patients with Wilson disease.

Another safety concern unique to CPX-351 was the potential for serious errors in the prescription and use of daunorubicin and cytarabine, owing to confusion or misconceptions about the interchangeability of each formulation. “Given the availability of various formulations of cytarabine and daunorubicin individually, the agency was concerned that the agents could be substituted for or with the combination liposomal product,” Dr. Krauss said. Because these errors could have considerable consequences for both safety and efficacy, the drug was approved with a boxed warning.

When would hematologists select induction therapy with CPX-351 or standard care? The decision process should consider “patient status, patient wishes, and AML biology,” Dr. Michaelis said, and the choice of treatment depends on the answers to several questions: “Does the patient fit the trial entry criteria? Does [he or she] have fitness for induction? Will [he or she]  be referred for a stem cell transplant? Importantly, what is [his or her]  prior anthracycline exposure?”

Patients should be made aware of the hospitalization time required for treatment, which will be burdensome for most. “With CPX-351, the prolonged neutrophil recovery and infectious risk [windows] can put [patients] at risk for unusual infections [with fungus and molds], so I emphasize the need for vigilance in preventing these and the importance of prophylactic antibiotics.”

Also, because toxicity is a huge concern for patients, Dr. Michaelis encouraged “more transparent conversations about patients’ and [physicians’] expectations of toxicity and expectations of cure.”

As with midostaurin treatment, the timeliness of mutation results is also a challenge to incorporating CPX-351 into treatment algorithms. “We don’t have results from molecular testing – most importantly FLT3 mutation status – by the time we have to make a decision about induction,” she explained. “So, the theoretical question arises, what if you give someone CPX-351 and then midway through, you find out they are FLT3-positive?”

The cost of CPX-351 also is an obstacle: It is roughly 20 times more expensive than traditionally delivered daunorubicin and cytarabine.


Dr. Ward also discussed the approval of the IDH2 inhibitor enasidenib, which is indicated for the treatment of adult patients with relapsed or refractory AML who harbor an IDH2 mutation. Less than 20 percent of patients with AML have this mutation, and its implications for AML pathogenesis and prognosis are unknown, she explained.

Enasidenib was approved based on results from the single-arm, phase I/II AG221-C-001 study. After a minimum of six months of treatment, 23 percent of patients experienced a complete response for a median of 8.2 months. “This was not a particularly stable estimate,” she noted, “as median follow-up time was only 6.6 months and duration of response appeared to improve with longer follow-up.”

The duration of response is also important to consider in the context of time to best response, which was observed to be as long as 11.2 months, Dr. Ward reported. The product label recommends patients receive enasidenib for a minimum of six months to allow adequate time for response.

FDA reviewers found that enasidenib was generally well tolerated, according to study results. “While 53 percent of patients had at least one dose interruption for an AE, most were brief interruptions for infections or hyperbilirubinemia,” she noted. “Just 10 percent of patients required dose reductions or discontinuations for AEs, and no single event prompted dose reduction or discontinuation in more than two patients.”

“The most notable toxicity, as predicted by [enasidenib’s] mechanism of action is differentiation syndrome,” said Jessica Altman, MD, of the Robert H. Lurie Comprehensive Cancer Center at Northwest University in Chicago, Illinois. Enasidenib works by inducing differentiation of leukemic cells, she explained, and responses are seen frequently without the aplasia that is usually observed when treating patients with cytotoxic chemotherapy. “[The differentiation syndrome] should be familiar to us, as it’s akin to the differentiation syndrome observed in patients [with acute promyelocytic leukemia] treated with all-trans-retinoic acid … but [its management] still requires a high degree of vigilance.”

In discussing enasidenib’s role in AML treatment, Dr. Altman also noted a consideration unique to the drug’s mechanism of action: “You don’t often need to know much about the Krebs cycle when taking care of patients with AML; however, in this situation, it’s important due to the mechanism of action of this agent and an expected toxicity.”

“It can also take time to attain a response due to this mechanism of action,” she concluded. “We are still relatively early in predicting who will respond to enasidenib.”

Gemtuzumab Ozogamicin

Gemtuzumab ozogamicin (GO), has a complicated history, said Kelly Norsworthy, MD, medical officer of the Division of Hematology Products at the FDA, during her discussion of GO “then and now.” GO originally received accelerated approval in May 2000 as monotherapy for older patients with relapsed CD33-positive AML. In June 2010, the drug was voluntarily withdrawn from the market after subsequent confirmatory trials failed to verify clinical benefit and demonstrated safety concerns, including early deaths.

“Researchers hypothesized that repeated lower doses of GO may be able to increase the internalization process of the drug into leukemia cells, enhancing safety,” Dr. Norsworthy noted. After further testing in phase I and II trials comparing GO monotherapy administered via the original unfractionated dosing regimen and the new fractionated regimen, GO was resubmitted for regulatory approval in 2017.

The agent was approved based on results from three clinical trials – one investigated GO in combination with chemotherapy, and two investigated GO as a single agent. In the combination study,  patients who received GO plus daunorubicin and cytarabine had a longer median event-free survival (EFS) than those who received chemotherapy alone (17.3 vs. 9.5 months; p value not provided).

In the first monotherapy study, which enrolled patients with newly diagnosed AML who could not tolerate or chose not to receive intensive chemotherapy, GO was superior to best supportive care, with (median OS = 4.9 months vs. 3.6 months; p value not reported). In the second monotherapy trial, which was a single-arm study of people with relapsed CD33-positive AML, 26 percent of patients achieved a complete remission that lasted a median of 11.6 months (range not provided) after receiving a single course of GO.

The observed mortality rate across studies of the new dose was “roughly half of that seen with the old dose,” she reported. Based on these results, “we can comfortably say the new regimen is at least as effective or better than the old regimen.”

“An important point to stress is that there is no benefit to the addition of GO seen in those with adverse karyotype,” added Dr. Altman.

Because the EFS benefit did not extend to this subgroup of patients, the agency recommends that, “when cytogenetic results become available, clinicians should consider whether the potential benefit of continuing treatment with GO outweighs the risks,” Dr. Norsworthy noted.

Select grade ≥3 AEs that were more common in the GO arm than the chemotherapy arm included infection, prolonged thrombocytopenia, hemorrhage, and veno-occlusive liver disease.

Although GO can be used for relapsed disease as a single agent (based on results of the MyloFrance-1 single-arm study), Dr. Altman cited the lack of comparative data between regimens as a barrier to routinely using GO in clinical practice. “We have a plethora of regimens to use in the relapsed setting,” she said, “but it’s hard to know, without comparative data, which is superior.”

“Despite the re-approval of GO, there remain several unresolved questions,” Dr. Altman added, and more clinical trial data are needed to determine how GO should be used with other agents and in adults who are unfit for intensive chemotherapy.