“These significant advances in AML treatment are a superb testimony to teamwork demonstrated daily by our research team, and to our patients who enrolled in these pivotal trials,” says MD Anderson President Peter WT Pisters, M.D. “I am proud of our dedicated faculty who continue to make a difference in the lives our all cancer patients.”
AML is an aggressive form of leukemia with a low survival rate. Few options are available for patients who are not eligible for intensive chemotherapy.
Research behind the development of venetoclax
Venetoclax, which the FDA has previously approved for chronic lymphocytic leukemia (CLL), has been studied for AML treatment at MD Anderson for over a decade. The first paper describing this class of agents was published by Andreeff and Konopleva in Cancer Cell in 2006, followed by many pre-clinical, mechanism-based combinations that resulted in the first AML trial, chaired by Konopleva.
In 2014, Konopleva, Andreeff and Antony Letai, Ph.D., of Harvard Medical School, published findings on ABT-199, the BLC-inhibitor that became venetoclax, in Cancer Discovery. These prior pre-clinical findings were the basis for the first AML venetoclax trial led by Konopleva. She and Letai, in collaboration with Abbvie researchers, focused on how inhibiting BCL-2 in AML might be a new approach to treating the disease. Initial human trials with a BCL-2 inhibitor showed that as a single agent it had activity in patients with AML.
Targeting a protein that causes resistance
Pre-clinical data also showed that venetoclax plus cobimetinib or idasanutlin may be synergistic. MEK and MDM2 inhibition has been shown to down-regulate Mcl-1, a protein in the BCL-2 family, overcoming the major resistance mechanism to BCL-2 inhibition in AML.
Further pre-clinical findings by Andreeff and Konopleva were published in the Dec. 11, 2017 issue of Cancer Cell. The research demonstrated unprecedented in vivo activity, as well as a new molecular mechanism explaining how the inhibitor drugs impact MDM2, which is tied to regulation of p53 and BCL2 — both of which are linked to cell death.
“We showed that p53 activation overcomes the resistance to BCL-2 inhibition by promoting Mcl-1 degradation and overcoming cell death response by altering cellular response,” Andreeff explains. “These findings laid the foundation for the development of the current combination clinical trial for AML, bringing together different investigations in my group that extended over 15 years.”
Andreeff added that when patients are resistant or later develop resistance to venetoclax, the protein Mcl-1 is the major culprit. Bing Carter, Ph.D., professor of Leukemia, and Andreeff will present pre-clinical studies at the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition that demonstrate how targeted Mcl-1 inhibition with specifically tailored molecules can overcome resistance to venetoclax and result in substantial extension of survival in leukemia-bearing mice. Carter, Andreeff, and Philip Lorenzi, Ph.D., supervisor of laboratory and research in Bioinformatics and Computational Biology, also discovered a novel metabolic function of Mcl-1 inhibitors.
Venetoclax and combination therapy
Preliminary results from a dose-escalation and expansion study led by DiNardo, which combined venetoclax with AZA or decitabine, demonstrated that the combination therapies could be safely administered with minimal side effects. The findings were presented at the 2017 ASH meeting in Atlanta, and led to the FDA’s accelerated approval of venetoclax with AZA or decitabine for newly diagnosed patients with AML who are ineligible for intensive chemotherapy.
DiNardo is leading the Phase III confirmatory clinical trials that combine venetoclax with low-dose cytarabine, and with AZA, as well as the first study of venetoclax in combination with intensive chemotherapy, for either newly diagnosed AML patients, or those who have relapsed or refractory AML.
“We feel that venetoclax is a general sensitizer to many types of therapies, and its favorable safety profile makes it easy to combine with many types of treatments,” Konopleva told Oncolog in a story published in February 2018. “Our task is to determine which subpopulations of patients are most likely to benefit from which treatment combinations.”
Studies to be presented at ASH meeting
Konopleva’s interim analysis of a Phase II study of venetoclax with a 10-day decitabine regimen will be presented Dec. 2 at ASH’s annual meeting. The study found that the regimen had an acceptable safety profile and excellent response rates — complete response rates of 92 percent in newly diagnosed AML patients, and 44 percent in those with relapsed or refractory AML. According to Andreeff, these results are unprecedented for this group of patients and set new standards for AML therapy.
At the 2017 ASH meeting, Daver reported the first clinical results, which showed response rates approaching 50 percent. At this year’s meeting, Daver will present initial findings from a multi-national open-label Phase Ib study of idasanutlin with venetoclax for relapsed or refractory AML that show an overall response rate of 46 percent at the recommended Phase 2 dose levels that are being considered for expansion of the trial.
DiNardo has led clinical trials combining venetoclax with low-dose cytarabine, and with AZA. The placebo-controlled Phase III studies seek to learn about efficacy and safety in studies of patients who have not received prior treatment because they aren’t eligible for intensive chemotherapy. She also is leading a study of patients who are 18 to 65 years old and have newly diagnosed or relapsed or refractory AML and are receiving venetoclax with standard chemotherapy.
Glasdegib for treatment of AML
Glasdegib is the first hedgehog pathway inhibitor approved for treatment of AML in a randomized Phase II trial. The hedgehog signaling pathway is essential for embryogenesis, and abnormal activation of this pathway may contribute to cancer development in adults.
Cortes, who recognized early on that glasdegib had potential as a therapeutic treatment for AML, was lead investigator for the Phase II BRIGHT 1003 trial, which showed that glasdegib in combination with low-dose cytarabine (LDAC) reduced risk of death by 54 percent, compared with LDAC alone. The median overall survival was 8.3 months versus 4.3 months.
“The randomized study, which formed the basis for the FDA approval, included patients with cardiac disease or mild to moderate kidney disease, who are often excluded from clinical trials,” says Cortes. “This combination therapy provides a much needed treatment for patients who do not qualify for intensive chemotherapy.”
The trial followed 115 patients with newly diagnosed AML, with a median age of 77 years. Serious adverse events occurred in 79 percent of study patients, and the FDA label for glasdegib includes a boxed warning for embryo-fetal toxicity.
Glasdegib is among the arsenal provided through a clinical collaboration between MD Anderson and Pfizer that is aimed at studying novel combinations of three Pfizer investigational immune-oncology therapies and other agents in the treatment of hematologic malignancies and various solid tumors. Daver heads the blood cancer clinical trials tied to the collaboration.