Published on June 16, 2021
Low-Dose Chemotherapy for Patients With AML
What is on the horizon for AML patients who are unfit for intensive chemotherapy? What low-dose chemotherapy treatment options are available? Follow along as Eunice Wang, MD, Chief of Leukemia at Roswell Park Comprehensive Cancer Center, explains research information reported at ASCO and what it means for this population of AML patients. Dr. Wang also discusses some of the preconceptions of side effects that can cause patients to discontinue treatment and how to address them.
Transcript | ASCO Update: Low-Dose Chemotherapy Treatment Options for AML
What Non-Chemotherapy Treatment Options Are Available for AML Patients Who Are Unfit for Intensive Chemotherapy?
Dr. Wang: At the ASCO 2021 meeting, we saw many updates for the treatment of acute myeloid leukemia patients who are unfit for intensive chemotherapy. First of all, we saw some very encouraging results showing that administration of the standard venetoclax (Venclexta) and azacitidine (Vidaza) can over time lead to eradication of minimal residual disease in a hundred percent of patients receiving treatment ongoing for months. That's very encouraging because, as we know, minimal residual disease is perhaps the best indicator of long-term response and durability of those remission in patients who are unfit for chemotherapy.
We've also seen a number of new agents appear on the horizon for future development. These include a novel low-dose cytarabine (Cytosar-U) equivalent, which may replace low-dose cytarabine and azacitidine potentially as a backbone therapy for treatment of these unfit patients moving forward. We also saw presentations on the efficacy of a novel IDH inhibitor as well as a novel FLT3 inhibitor for patients with relapsed and refractory disease characterized by IDH and FLT3 mutations. So, more to come over the next few months to years as these novel agents move into the treatment regimen for our patients.
How Is the Negative Perception of Side Effects Leading to Discontinuation of Treatment? How Can We Change This Perception?
So, I think the perception that adverse events should lead to discontinuation of therapy is potentially a dangerous concept. I do think that most of us who have a life-threatening cancer such as acute myeloid leukemia would prefer to put up with some adverse events of treatment to have the benefits of some of these potentially life-changing and targeted therapies. Many of our novel agents for treatment of particularly older patients with AML are what we call continuous oral chemotherapy, meaning that instead of getting intensive, very short acting and short in duration definitive therapy, more and more we're seeing administration of oral medications that patients may need to take for months or even years. So, the impact or the importance of adverse events certainly can't be underestimated, but again, they should be taken in context with the potential life-altering benefits of some of these targeted therapies moving forward.
What Is the Latest Update on the ADMIRAL Phase 3 Trial? Are There Long-Term Follow-Ups?
So, the ADMIRAL trial was a phase three trial randomizing adult patients with relapsed and refractory acute myeloid leukemia characterized by FLT3 mutations into either chemotherapy or treatment with a oral chemotherapy targeted pill, gilteritinib (Xospata). As we know, gilteritinib is now a standard care treatment for patients with relapsed/refractory disease characterized by FLT3 mutations. But this was really based on the results of the ADMIRAL trial showing that a pill targeting FLT3 could be superior in producing better remissions and better long-term survival than high-dose or low-dose chemotherapy for these patients. The updated results of the ADMIRAL trial are taken from at least two years later and demonstrate that a proportion of patients who had relapsed and refractory FLT3 disease treated on the ADMIRAL trial with gilteritinib are still alive and disease-free at long-term follow-up.
Many of these patients have undergone allogeneic stem cell transplantation. But nevertheless, the fact that relapsed refractory FLT3 mutant AML can no longer be considered a death sentence for these patients is highly encouraging and supportive of the long-term benefits of targeted therapy replacing, or supplementing at least, intensive and less intensive therapy for these patients. As our successes mount, we hope to see further follow up, potentially even a three-year or five-year follow up, as we saw in the ASH 2020 meeting with five-year follow-up of a different agent, CPX-351 (cytarabine and daunorubicin). We are achieving real long-term remissions for patients with AML with some of these novel agents alone and in combination, importantly, with stem cell transplantation.
What Are the Biggest Research Advances for Either Newly Diagnosed or Relapsed AML Patients?
I am very encouraged by the advent of novel classes of agents for treatment of patients with AML, specifically immunotherapeutic agents as well as a new class of agents specifically targeting patients with new mutations called menin inhibitors. We saw at this year's ASCO 2020 meeting early results of trials targeting immune markers, and these include antibody therapies as well as CAR T-cell therapies, which up until now have not been highly successful for patients with myeloid malignancies.
We've also seen advents of additional targeted agents targeting IDH1, FLT3, and hopefully in the future another mutation called KMT2A or NPM1 mutation. There is a novel class of inhibitors called menin inhibitors which potentially, in the laboratory, have high efficacy against those new molecularly defined AML patients. So, we hope in the near future that immunotherapies, which have helped so many patients with solid tumors and lymphoid malignancies, can be starting to have an impact in myeloid malignancies. And then menin inhibitors may be the new targeted therapy for a subset of patients with AML as well as other acute leukemias with those specific mutations.