Leukemia Awareness Month: Changing the Future of AML through Precision Medicine


Gwen Nichols, MD, reviews the evolving landscape of acute myeloid leukemia for Leukemia Awareness Month.

Gwen Nichols, MD

Gwen Nichols, MD

As The Leukemia & Lymphoma Society’s executive vice president and chief medical officer, Gwen Nichols, MD, plays a critical role in advancing cures through a unique combination of clinical, academic, and pharmaceutical experience. She oversees LLS’s scientific research portfolio, patient services, and policy and advocacy initiatives. A physician and scientific researcher, she has dedicated her career to helping patients. Most recently, Dr Nichols was oncology site head of the Roche Translational Clinical Research Center. Prior to joining Roche in 2007, Dr Nichols served as the director of the Hematologic Malignancies Program at Columbia University. Dr Nichols trained in internal medicine at the University of Chicago and completed post-doctoral research and a hematology-oncology fellowship at Memorial Sloan-Kettering Cancer Center. She received her medical degree with honors from the State University of New York at Buffalo.

The leukemia treatment landscape is evolving nearly in real time—from the emergence of chemotherapy-free combination regimens for chronic lymphocytic leukemia (CLL) to the rise of CAR (chimeric antigen receptor) T-cell immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Even in acute myeloid leukemia (AML)—a longtime challenge in the hematological malignancies—we are finally seeing the treatment armamentarium expand.

For the patients we serve at The Leukemia & Lymphoma Society (LLS), this evolution can’t come soon enough. For 4 decades, a drought in therapeutic advances for AML meant patients were treated with a one-size-fits-all-approach, centered on traditional cytotoxic chemotherapy and/or a stem cell transplant. But this approach fails too many patients. Long-term survival for older patients, who may not be able to tolerate aggressive therapy, remains dismal. It’s estimated that only 10% of older patients will survive 5 years after diagnosis.1

At the other end of the spectrum, while the standard of care is curative for many children with AML, those who do survive experience long-term complications, such as cardiotoxicity, neurocognitive impairment, and endocrine disorders. New treatments are urgently needed for children who relapse or do not respond to chemotherapy. 

Precision Medicine and FLT3 Inhibitors

Thankfully, state-of-the-art genomic technologies are improving our understanding of the genetic and molecular underpinnings of AML—a complex constellation of diseases—and driving more precision medicine. Recognizing the pressing need for novel therapeutics, LLS invests approximately a quarter of our research dollars annually in AML. This work is complemented by our Beat AML® Master Clinical Trial—the first collaborative precision medicine clinical trial in a blood cancer, which has been in progress since November 2016.

Our long-term investment in research is paying off in the impact for patients. Since 2017, there has been a proliferation of newly approved treatments for AML. The first of these therapies, midostaurin (Rydapt, Tauritmo), was approved for adults with newly diagnosed AML who are FLT3 mutation-positive, in combination with chemotherapy.

Approximately 30% of AML patients have a mutation in the FLT3 gene, which is associated with a particularly poor prognosis.2 As the first FLT3 inhibitor approved by the FDA, midostaurin marked a new wave of treatments targeting specific cytogenetic and molecular abnormalities. Since then, a second FLT3 inhibitor called gilteritinib (Xospata) was approved for adults with relapsed or refractory AML. Today, our Beat AML trial is testing gilteritinib in the frontline setting among newly diagnosed patients with FLT3-mutated AML, as a monotherapy and in combination with other drugs, showing encouraging results.

IDH and BCL-2 Inhibitors

What’s more, IDH inhibitors are improving outcomes for patients with AML. IDH1 and IDH2 mutations occur in about 20% of AML cases.3 Ivosidenib (Tibsovo) is approved for adults with IDH1-mutated relapsed or refractory AML as well as newly diagnosed patients with IDH1 mutation who are at least 75 years old or are ineligible for intensive induction chemotherapy. Most recently, the combination of ivosidenib and azacitidine (Vidaza) has shown impressive improvements in event-free survival and overall survival over azacitidine alone among adults with previously untreated IDH1-mutated AML, based on topline data from the global, phase 3 AGILE trial (NCT03173248).4

Meanwhile, enasidenib (Idhifa)—approved for adults with relapsed or refractory AML with an IDH2 mutation—is showing promise as an effective first-line treatment for older patients who are newly diagnosed. During the 62nd American Society of Hematology Annual Meeting, Eytan Stein, MD, from Memorial Sloan Kettering Cancer Center, presented data from a Beat AML sub-study, which found that 47% of patients had a complete response to enasidenib.5 Patients who did not respond to enasidenib alone were given the drug in combination with azacitidine, and 41% of these patients achieved a complete response. Beat AML continues to test enasidenib with other novel agents in patients who are resistant to the drug on its own.

Another FDA-approved game-changer for both CLL and AML is the BCL-2 inhibitor venetoclax (Venclexta), targeting the apoptotic pathway and metabolic function of leukemic cells. LLS has funded research into the development of venetoclax for over 20 years and continues to advance projects focused on overcoming treatment resistance and optimizing combinations.

For example, LLS-funded researcher Daniel Pollyea, MD, MS, from the University of Colorado, recently showed that venetoclax combined with azacitidine was far more effective than azacitidine alone for previously untreated patients with AML who have IDH1 and IDH2 mutations and cannot withstand intensive treatment due to age or comorbidities. Between 72% to 78% of patients treated with the combination responded, compared with 7% to 10% who received azacitidine with a placebo.6 Further, median overall survival was 24.5 months for the combination vs 6.2 months for the azacitidine and placebo.

Novel Therapies

Among the other recently approved therapies for AML is the anti-CD33 monoclonal antibody gemtuzumab ozogamicin (Mylotarg); the Hedgehog signaling pathway inhibitor glasdegib (Daurismo), CC-486 (Onureg), the first maintenance treatment for AML; and liposomal daunorubicin and cytarabine (Vyxeos), an innovative reformulation of 2 chemotherapies for certain types of newly diagnosed secondary AML. Notably, both liposomal daunorubicin and cytarabine and gemtuzumab ozogamicin are approved for adult and pediatric secondary or therapy-related AML.

LLS recognized the potential of this fixed combination liposomal treatment back in 2009 when we supported it through our Therapy Acceleration Program® (LLS TAP), our strategic venture philanthropy funding initiative. LLS partnered with Celator Pharmaceuticals, which Jazz Pharmaceuticals later acquired, to fast-track development of this therapy for adults with AML.

Through LLS TAP, we’re also advancing next-generation immunotherapies for AML, including a first-in-class antibody targeting myeloid checkpoint LILRB4 from Immune-Onc Therapeutics and an adoptive cellular therapy from NexImmune that leverages nanoparticle-trained CD8-positive T cells.

With AML research flourishing, we can expect to see the rising tide of novel approaches continue. Among the most promising areas are harnessing immunotherapy, identifying pre-leukemia conditions, exploiting metabolic vulnerabilities, and developing epigenetic therapies. For example, with LLS support, Jolanta Grembecka, PhD, from the University of Michigan, is developing first-in-class small molecule inhibitors of the ASH1L SET domain.

The Future of Clinical Trials

While we’re seeing progress in AML, there is still much more work to be done. Clinical research in the era of precision medicine is homing in on ever smaller groups of patients with specific disease subtypes or characteristics. Too many trials fail to meet their goals because there are simply not enough patients enrolled. To address this challenge, we need to reimagine how clinical trials are conducted.

At LLS, our vision is for our Beat AML Master Clinical Trial to not only bring new therapies to patients with AML faster, but also serve as a model for future clinical trials. With its flexible, collaborative structure, the trial is testing multiple targeted therapies among newly diagnosed patients with AML aged 60 or older in multiple study arms simultaneously.

Already, the trial has achieved its primary end point by showing that genomic analysis to identify AML subtypes can be completed within an unprecedented 7 days—giving patients and their providers ample time to make more personalized treatment decisions.7 Further, we’ve demonstrated that using genetic information to match patients to targeted therapies leads to better survival rates. The median overall survival for patients in Beat AML was 12.8 months vs 3.9 months for patients on the standard of care.

Recently, LLS published a paper in Therapeutic Innovation & Regulatory Science that outlines the Beat AML blueprint, including how to integrate operational strategies with new electronic technologies. Our hope is that the scientific and medical communities leverage these learnings to help even more patients with cancer.

At the same time, with the COVID-19 pandemic exacerbating existing health inequities, it’s essential that we ensure equitable access to clinical trials. Racial and ethnic minorities, rural residents, and individuals with low incomes are overwhelmingly underrepresented in clinical research. LLS is setting out to change this through our LLS IMPACT (Influential Medicine Providing Access to Clinical Trials) Research Grants.

By creating a hub-and-spoke infrastructure between clinical trial leaders at major cancer centers and community-based oncologists, this program will help bring more trials to patients at the community setting. We awarded the first round of funding to 3 major cancer centers that reach underserved patient populations in different parts of the country: Mayo Clinic Cancer Center, Vanderbilt University Medical Center, and Weill Cornell Medicine. Partnering with community-based oncologists across the clinical trial ecosystem is key to increasing and diversifying enrollment.

Childhood AML

Finally, it’s vitally important that our youngest, most vulnerable patients benefit from precision medicine. Childhood AML is distinct from adult AML—driven by different mechanisms and with different mutations—yet there is a critical gap in therapies designed just for children. At LLS, our goal is no less than a wholesale shift in the standard of care, moving toward safer, more effective treatments that precisely target cancer without harming the rest of the body.

Achieving this goal requires disrupting the 1-agent-at-a-time model in pediatric oncology drug development. LLS is driving an unprecedented collaboration to launch the first global precision medicine clinical trial for pediatric acute leukemia, called LLS PedAL. LLS PedAL will test multiple novel therapies simultaneously among children with relapsed acute leukemia at more than 200 clinical sites worldwide. Through LLS PedAL, we will identify and validate underlying molecular drivers of disease and match patients with the most promising treatments based on their unique tumor biology. Ultimately, every child who enters the trial will receive screening to determine their specific biological markers. LLS will be submitting the Investigational New Drug Application to the FDA this fall, with the goal of beginning LLS PedAL by the end of the year.

Critical to LLS PedAL is equipping researchers and clinicians with a wealth of clinical and genomic information. A team at the University of Chicago Pediatric Cancer Data Commons (PCDC), led by Samuel L. Volchenboum, MD, PhD, MS, is spearheading a project to gather pediatric acute leukemia data from multiple institutions, establish a common language to analyze the data, and make those data available to researchers worldwide. Clinicians will then be able to assess patterns and identify new areas of exploration much more nimbly.

By breaking down traditional clinical and data silos, embracing new clinical trial models that put patients at the center of their care, and improving access to these trials, we can bring precision medicine to more patients and change the future of AML treatment.


1. Lai C, Doucette K, Norsworthy K. Recent drug approvals for acute myeloid leukemia. J Hematol Oncol. 2019;12(100). https://doi.org/10.1186/s13045-019-0774-x

2. Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33:299–312. https://doi.org/10.1038/s41375-018-0357-9

3. Issa GC, DiNardo CD. Acute myeloid leukemia with IDH1 and IDH2 mutations: 2021 treatment algorithm. Blood Cancer J. 2021;11(107). https://doi.org/10.1038/s41408-021-00497-1

4. Servier. Servier announces positive topline data from the global phase 3 study of TIBSOVO® (ivosidenib tablets) in combination with azacitidine in patients with previously untreated IDH1-mutated acute myeloid leukemia. PR Newswire. Published August 2, 2021. https://www.prnewswire.com/news-releases/servier-announces-positive-topline-data-from-the-global-phase-3-study-of-tibsovo-ivosidenib-tablets-in-combination-with-azacitidine-in-patients-with-previously-untreated-idh1-mutated-acute-myeloid-leukemia-301345783.html

5. Stein EM, Huang Y, Borate U, et al. Enasidenib (ENA) Monotherapy with Addition of Azacitidine in Non-Responders Is Effective in Older Patients with Newly Diagnosed IDH2 Mutated Acute Myeloid Leukemia (AML): A Completed Phase 2/1b Sub-Study of the Beat AML Master Trial. Blood. 2020;136 (Supplement 1):27-30. https://doi.org/10.1182/blood-2020-143265

6. Pollyea DA, DiNardo CD, Arellano ML, et all. Results of Venetoclax and Azacitidine Combination in Chemotherapy Ineligible Untreated Patients with Acute Myeloid Leukemia with IDH 1/2 Mutations. Blood. 2020;136 (Supplement 1):5-7. https://doi.org/10.1182/blood-2020-134736

7. Burd A, Levine RL, Ruppert AS, et al. Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial. Nat. Med. 2020;26:1852–1858. https://doi.org/10.1038/s41591-020-1089-8

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