91 percent response rate for venetoclax against newly diagnosed AML in older adults

November 28, 2018, CU Anschutz Medical Campus
Daniel A. Pollyea, MD, MS, and colleagues report dramatic results for venetoclax against AML in older adults. Credit: University of Colorado Cancer Center

Clinical trial results published in the journal Nature Medicine show 91 percent response rate to the combination of venetoclax with azacitidine in older adults newly diagnosed with acute myeloid leukemia (AML). Of 33 patients given combination venetoclax and azacitidine, 20 experienced a complete response (aka complete remission) and eight experienced a complete response but with continued low blood counts. Of the three patients who did not respond to treatment, two discontinued the study before the first week due to personal reasons unrelated to treatment or side-effects.

Based on these results, on November 21, the U.S. Food and Drug Administration (USFDA) granted accelerated approval for venetoclax to treat who are aged 75 years and older or are ineligible for intensive chemotherapy due to coexisting medical conditions. Updated clinical trial results and will be presented December 1-4 at the 60th annual American Society of Hematology (ASH) meeting in San Diego, CA.

Traditionally, the diagnosis of AML in this population has carried an extremely poor prognosis, with median overall survival of less than a year. Already, patients on the current trial have reached a median follow-up time of 580 days. Because so many patients remain on the trial with controlled disease, it is impossible to predict the average expected duration of benefit from this new combination treatment, implying a remarkably long duration of remission.

"To date, for with AML have been limited. We see this new regimen as a paradigm shift in the way we will treat this disease in this population, moving forward," says Daniel A. Pollyea, MD, MS, investigator at CU Cancer Center, clinical director of Leukemia Services at the CU School of Medicine, and the study's first author.

Azacitidine is a low-dose chemotherapy drug that has long been used in the treatment of AML, with minimal success. Venetoclax is a targeted inhibitor of the Bcl-2 protein, which earned FDA approval in 2016 for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). The current regimen includes a course of azacitidine, followed by the ongoing use of venetoclax.

"Two patients on this study have been off all therapy for nearly three years, and others who remain on therapy seem to be on the same trajectory, suggesting this regimen may be curative in some settings," Pollyea says.

The trial is closely related to the preclinical work of Craig Jordan, Ph.D., investigator at University of Colorado Cancer Center, division chief of the Division of Hematology and the Nancy Carroll Allen Professor of Hematology at the University of Colorado School of Medicine. Basic science describing the underlying mechanism of drug action is published concurrently in the journal Cancer Cell. First author of the Cancer Cell paper Courtney Jones, Ph.D., and others working in the Jordan lab showed that depend on amino acid metabolism to supply themselves with energy. As part of its action against Bcl-2, venetoclax blocks ' uptake of amino acids, and thus blocks the mechanism these cells use to generate energy, killing these cells.

"Leukemia stem cells in newly diagnosed AML patients absolutely depend on amino acid metabolism, but that's not the case for healthy cells. By taking away the ability of leukemia stem cells to metabolize amino acids, we can target these cells without affecting surrounding, healthy tissues," Jordan says.

One factor limiting treatment options in this population is the severity of side-effects associated with current therapies. Newly-diagnosed AML is most often treated with intensive chemotherapy. Unfortunately, while chemotherapy is largely effective against the bulk of leukemia cells, leukemia stem cells are uniquely equipped to resist chemotherapy, and so often survive treatment, leading to relapse. Using azacitidine alone in this population shows 28 percent response rate with response duration of 10 months. At that point, treatment often includes bone marrow transplant—eradicating a patient's cancerous blood system and repopulating a new one using blood stem cells from cord blood or from a matched donor. However, can be poorly tolerated in older and/or more frail patients.

"Many of these patients, you just can't treat in that way," Pollyea says. "They would be too likely to die from the treatment, itself—it does more harm than good."

Combining venetoclax with azacitidine was associated with no more side effects than the use of azacitidine alone.

Patients whose cancers held IDH mutations were more likely to experience long-lasting response; patients with RAS mutations often experienced shorter remissions. Initial findings suggest that of AML patients who have relapsed following standard therapy is a more difficult challenge, requiring more than just venetoclax and azacitidine to achieve substantially improved outcomes.

In addition to AML and CLL, venetoclax is in clinical trials to treat cancers including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), T cell lymphoma, non-Hodgkin lymphoma, myelodysplastic syndrome, and more (full list at clinicaltrials.gov).

The Jordan lab continues to collaborate closely with CU Cancer Center clinicians including Daniel Pollyea to further optimize strategies targeting cancer stem cells in and other cancers.

Explore further: Cancer stem cells get energy from protein, and it's proving to be their Achilles' heel

More information: Daniel A. Pollyea et al, Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia, Nature Medicine (2018). DOI: 10.1038/s41591-018-0233-1

Related Stories

Cancer stem cells get energy from protein, and it's proving to be their Achilles' heel

November 12, 2018
Think of energy metabolism like a party popper: Ripping something apart releases a bang. Most of your cells rip apart sugar to release the "bang" of energy. Sometimes they rip apart fats, and in a pinch, cells can even metabolize ...

Combination chemotherapy and immunotherapy effective in Phase II leukemia study

November 8, 2018
A combination of the standard-of-care chemotherapy drug known as azacitidine, with nivolumab, an immune checkpoint inhibitor, demonstrated an encouraging response rate and overall survival in patients with relapsed or refractory ...

New combination treatment targets pre-leukemia stem cells

September 12, 2018
Your body's blood cells are manufactured by hematopoietic stem cells in bone marrow. But just as regular, mature cells can become cancerous, so too can stem cells. When hematopoietic stem cells mutate in specific ways, the ...

Immunotherapy combination and chemotherapy show encouraging results in Phase II acute myeloid leukemia study

November 13, 2018
A triple therapy combining two immune checkpoint inhibitors (ICPIs) with the standard-of-care chemotherapy, a hypomethylating agent called azacitidine, has shown promising results for treatment of relapsed or refractory acute ...

Ivosidenib earns FDA approval against IDH1+ acute myeloid leukemia

July 30, 2018
Clinical trials at University of Colorado Cancer Center and elsewhere now result in the drug ivosidenib earning approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or ...

AML study reports high response rates with combination targeted therapy

December 11, 2017
Initial findings from a multi-national open-label phase Ib study of inhibitory drug therapy for relapsed or refractory acute myeloid leukemia (AML) have demonstrated a complete response in up to 50 percent patients say researchers ...

Recommended for you

Potential seen for tailoring treatment for acute myeloid leukemia

December 8, 2018
Advances in rapid screening of leukemia cells for drug susceptibility and resistance are bringing scientists closer to patient-tailored treatment for acute myeloid leukemia (AML).

Study may offer doctors a more effective way to treat neuroblastoma

December 7, 2018
A very large team of researchers, mostly from multiple institutions across Germany, has found what might be a better way to treat patients with neuroblastoma, a type of cancer. In their paper published in the journal Science, ...

Inflammatory bowel disease linked to prostate cancer

December 7, 2018
Men with inflammatory bowel disease have four to five times higher risk of being diagnosed with prostate cancer, reports a 20-year study from Northwestern Medicine.

'Chemo brain' caused by malfunction in three types of brain cells, study finds

December 6, 2018
More than half of cancer survivors suffer from cognitive impairment from chemotherapy that lingers for months or years after the cancer is gone. In a new study explaining the cellular mechanisms behind this condition, scientists ...

Scientists develop new technology for profiling unique genetic makeup of myeloma tumor cells

December 6, 2018
Cancer arises when cells lose control. Deciphering the "blueprint" of cancer cells—outlining how cancer cells hijack specific pathways for uncontrolled proliferation—will lead to more efficient ways to fight it. Joint ...

Putting the brakes on tumor stealth

December 6, 2018
New research undertaken at Monash University has shed new light on how some cancers are able to escape our immune system.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.