New Treatment Options Lead to New Questions in Acute Myeloid Leukemia

For the past 40 years, the standard remission induction treatment for patients with newly diagnosed acute myeloid leukemia (AML) who are candidates for intensive therapy has been a combination of two types of chemotherapy: cytarabine and an anthracycline antibiotic, most often daunorubicin. The combination is known as “7+3,” in reference to the seven days during which patients receive cytarabine and the three days during which they receive the anthracycline. Both agents prevent DNA replication, while the anthracycline also inhibits the ability of cells to repair deleterious double-stranded breaks in DNA.

For patients who can tolerate it, 7+3 provides a 40- to 70-percent chance of achieving complete remission (CR). Consolidation therapy depends on the risk of disease return; typically, favorable-risk patients receive about three months of high-dose cytarabine, while those at higher relapse risk are offered an allogeneic hematopoietic cell transplantation (AHCT) from a healthy donor to improve the rate of durable remission.

The 7+3 regimen is still a mainstay of therapy; however, in part due to an increased understanding of AML biology, there have been eight new therapies approved by the U.S. Food and Drug Administration (FDA) to treat AML since 2017. Some of the new therapies are intended for use in combination with the standard induction chemotherapy, others replace the 7+3 regimen, and others still are options for those patients whose disease comes back or is refractory to initial treatments.

“AML specialists and patients are definitely excited to have new options for treatment. We have had so many years without new therapies that having eight newly approved drugs – and additional ones likely to be approved soon – makes this an absolutely exciting time in AML,” Gail J. Roboz, MD, professor of medicine at Weill Cornell Medicine/New York-Presbyterian Hospital, told ASH Clinical News. Dr. Roboz also directs Weill Cornell’s Clinical and Translational Leukemia Program.

But she acknowledged that the availability of these therapies has made treatment decisions for patients with AML more complicated: While the new drugs have increased CR rates, the rates of overall and progression-free survival generally are still similar to those associated with older treatment options.

“These drugs are not home runs,” said Laura Michaelis, MD, from the Division of Hematology and Oncology at the Medical College of Wisconsin. “We still need to improve the median survival by quite a lot. Even with these newer agents, we are still sending many people to transplant for the chance of a cure.”

ASH Clinical News spoke with Drs. Roboz, Michaelis, and other clinical researchers about the recently approved therapies for AML and how clinicians are incorporating them into their treatment regimens.

Reframing and Replacing 7+3

The FDA approved two drugs that, when combined with the 7+3 regimen, have been shown to increase CR rates – and slightly improve overall survival (OS) rates – compared with 7+3 alone: midostaurin and gemtuzumab ozogamicin.1,2 Both agents were approved for patients whose disease expresses a specific therapeutic target.

“These drugs are not home runs. … Even with these newer agents, we are still sending many people to transplant for the chance of a cure.”

—Laura Michaelis, MD

In April 2017, the oral multitargeted kinase inhibitor midostaurin was approved for the treatment of patients with newly diagnosed FLT3-mutated AML based on results from the randomized phase III RATIFY trial. Compared with 7+3 alone, the addition of midostaurin prolonged survival and reduced the risk of death by 23 percent (median OS=74.7 months vs. 25.6 months; hazard ratio [HR] = 0.77; p=0.0074).

Then, in September 2017, the FDA approved gemtuzumab ozogamicin, a humanized anti-CD33 monoclonal antibody attached to calicheamicin, an antitumor anthracycline antibiotic, for two patient populations: adults with newly diagnosed CD33-positive AML and children aged 2 or older with relapsed or refractory CD33-positive AML. The approval was based on results from an open-label phase III clinical trial, in which the addition of gemtuzumab ozogamicin to chemotherapy prolonged event-free survival (17.3 months vs. 9.5 months; HR=0.56; p<0.001).

Gemtuzumab ozagamicin originally received accelerated approval in May 2000 as monotherapy for older patients with relapsed/refractory AML, But, in June 2010, the drug was voluntarily withdrawn from the market after confirmatory studies showed more toxicity and less benefit in that setting than suggested by earlier studies. The 2017 approval includes a lower recommended dose, as well as new patient populations and a different dosing schedule.

But, in August 2017, it seemed that everything old was new again: The FDA approved CPX-351, a fixed combination of daunorubicin and cytarabine. The drug, which is a combination of these two existing generic drugs encased in a liposome, received breakthrough-therapy designation in August 2017 for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Its safety and efficacy were demonstrated in a phase III trial comparing CPX-351 with the standard 7+3 regimen of cytarabine and daunorubicin in patients aged 60 to 75 years.3

The FDA next approved two additional therapies for the treatment of patients with newly diagnosed AML who were deemed unfit to undergo standard induction therapy. In November 2018, both the oral BCL2 inhibitor venetoclax and the oral hedgehog inhibitor glasdegib received expedited approval for the treatment of patients aged 75 or older or who have comorbidities that preclude them from the more intensive 7+3 chemotherapy regimen.4,5 For details about these FDA decisions, see “The Year in Drug Approvals.

New Kids on the Block

The FDA also approved several options for patients with relapsed and/or refractory disease, including those whose disease harbors an IDH mutation.

The IDH2 inhibitor enasidenib was approved for the treatment of adults with relapsed/refractory IDH2-mutated AML, along with the RealTime IDH2 assay, a companion diagnostic that can detect specific mutations in the IDH2 gene in this patient population.6 In October 2018, the FDA approved another IDH inhibitor, ivosidenib, for patients with relapsed, refractory disease that expresses an IDH1 mutation, based on results from an open-label, phase I clinical trial.7

The most recent agent to join the AML treatment paradigm is gilteritinib. This FLT3-targeted oral inhibitor was approved for the treatment of adult patients with FLT3-mutated relapsed or refractory AML. The agency’s decision was based on interim results from the phase III ADMIRAL trial, in which 21 percent of patients achieved CR or CRh.8 (More details about these FDA decisions can be found in “The Year in Drug Approvals.”)

An additional FLT3 inhibitor, quizartinib, is currently under review by the FDA for this same patient population.9

The Old Reliable?

Despite the plethora of new treatment options available, 7+3 induction therapy remains a standard. “I think of the cytotoxic agents as the first targeted agents, which home in on rapidly dividing cells,” Dr. Michaelis said. “It would be a mistake to eliminate these from our arsenal just because we have developed ones that are based on new biologic targets.”

“We have had so many years without new therapies that having eight newly approved drugs – and additional ones likely to be approved soon – makes this an absolutely exciting time in AML.”

—Gail J. Roboz, MD

When deciding on the first course of treatment, clinicians assess patients’ overall health and ability to tolerate chemotherapy, as well as whether they have favorable-, intermediate-, or adverse-risk disease characteristics according to cytogenetic and molecular testing – including tests for a FLT3 and other mutations.

For patients who are fit to tolerate induction treatment and who have favorable-risk disease, 7+3 remains the best option, according to clinicians who spoke with ASH Clinical News, possibly with the addition of midostaurin or gemtuzumab for eligible patients. For patients who cannot tolerate intensive chemotherapy and who have adverse-risk disease, options include a clinical trial, venetoclax plus chemotherapy, or glasdegib plus chemotherapy.

Decisions for the other subgroups of patients, including those with favorable-risk disease who are unfit for induction chemotherapy or those with adverse-risk disease who are healthy enough to tolerate the 7+3 regimen – are more complicated.

“The biggest challenge at the clinical level is that we don’t know the best way to integrate these new drugs into clinical practice because there are not enough randomized data to know the best choice for all patients,” Dr. Michaelis added.

Dr. Roboz agreed. “For those patients between the ages of about 50 and 80, the decision of who should receive intensive versus non-intensive induction regimens are often quite complex.”

For example, in clinical trials of venetoclax combinations in older patients with AML, response rates rivaled those achieved with intensive chemotherapy induction, prompting questions about whether these new combinations might benefit younger, fit patients as well.

“Historically, we did not want to deprive patients who are fit to receive 7+3 induction from the benefit of this chemo-therapy regimen,” said Elizabeth Griffiths, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, New York. However, “now, we may need to think twice about whether this is the best way to dichotomize treatment decisions. We may be able to improve on our standard induction with additional drugs or de-escalate to a venetoclax-based regimen.”

Yet Dr. Griffiths advised caution. Venetoclax was approved based on phase II results; clinicians and the FDA are awaiting the results of the ongoing phase III clinical trial of the same combinations to validate the current approval.

In addition, the new combinations carry their own unique side-effect profiles. “Treatment with venetoclax plus azacitidine is a risky venture,” she said. “While the combination is potentially an outpatient treatment, many of us are treating some of our patients in the hospital setting, particularly for the first treatment cycle, because of the potential for profound and prolonged cytopenias and high rates of infection.”

To Transplant or Not To Transplant

Because the newly approved AML agents offer only modest improvements in OS, alloHCT remains the treatment goal for patients who can tolerate the procedure and whose disease is not likely to be cured with chemotherapy alone.

“The goal is always to try to move people to transplant using the novel agents,” said Dr. Michaelis. “A transplant is most effective when the disease is under control, so that the newly transplanted cells work like an immune agent to continue to control the disease.”

Clinicians are refining approaches for determining whether a patient’s disease is under control, including by measuring disease burden through minimal or measurable residual disease (MRD) using genetic sequencing or flow cytometry. Yet, researchers are still learning the optimal method for detecting MRD and interpreting assay results. “It’s not clear whether detection of MRD is a contraindication for transplantation or, if no MRD is detected, which patients might not need a transplant to stay in remission,” Dr. Michaelis noted. “This is one of the reasons why MRD testing is not yet standard of care.”

Still, “just because a patient has a specific mutational target does not necessarily mean that the choice of therapy is obvious,” Dr. Roboz noted. “The paradigm of AML treatment is a complex Venn diagram. Patients often have features that make them candidates for several potential treatment regimens, and choosing between them can be challenging.”

New Agents, New Combinations

Ongoing clinical trials are testing novel agents and combination therapies, including bispecific antibodies that bind to two targets. In the case of AML, these targets include CD33, CD123, and low-affinity IL-3 receptors. Preliminary data also suggest that chimeric antigen receptor T cells might hold promise in this population.

“These immune-targeted agents are still in the early stages of evaluation, Dr. Roboz noted. “The promising aspect of these drugs is that they are likely agnostic to specific mutations and can hopefully be applied to broader populations of AML patients.”

Dr. Roboz emphasized that the continued development of new drugs for AML is welcome because, despite the availability of newly approved drugs, survival for many patients is still measured in weeks to months, not years.

“The enthusiasm for the novel therapies should not make anyone believe that AML has been solved,” she said. “The enthusiasm from clinicians, researchers, and patients should be higher now than ever to take part in clinical trials to understand how to best use our available drugs, as well as newer ones currently in development.” —By Anna Azvolinsky


  1. U.S. Food and Drug Administration. Approved drugs: Midostaurin. Accessed April 5, 2019, from
  2. U.S. Food and Drug Administration. FDA approves gemtuzumab ozogamicin for CD33-positive AML. Accessed April 5, 2019, from
  3. U.S. Food and Drug Administration. FDA approves first treatment for certain types of poor-prognosis acute myeloid leukemia. Accessed April 5, 2019, from
  4. U.S. Food and Drug Administration. FDA approves venetoclax in combination for AML in adults. Accessed April 5, 2019, from
  5. U.S. Food and Drug Administration. FDA approves glasdegib for AML in adults age 75 or older or who have comorbidities. Accessed April 5, 2019, from
  6. U.S. Food and Drug Administration. FDA granted regular approval to enasidenib for the treatment of relapsed or refractory AML. Accessed April 5, 2019, from
  7. U.S. Food and Drug Administration. FDA approves ivosidenib for relapsed or refractory acute myeloid leukemia. Accessed April 5, 2019, from
  8. U.S. Food and Drug Administration. FDA approves gilteritinib for relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation. Accessed April 5, 2019, from
  9. Cortes JE, Khaled SK, Martinelli G, et al. Efficacy and safety of single-agent quizartinib (Q), a potent and selective FLT3 inhibitor (FLT3i), in patients (pts) with FLT3-Internal Tandem Duplication (FLT3-ITD)–mutated relapsed/refractory (R/R) acute myeloid leukemia (AML) enrolled in the global, phase 3, randomized controlled Quantum-R Trial. Abstract #563. Presented at the 2018 ASH Annual Meeting, December 4, 2018; San Diego, CA.