Improved maintenance strategies are needed to prolong remission and improve overall survival in patients with acute myeloid leukemia (AML) after complete response (CR) with induction therapy. In a review article published in the American Journal of Hematology, Bruno C Medeiros, MD, of the department of hematology at the Stanford University of School of Medicine in California, and colleagues discussed risk factors for relapse and potential novel treatment approaches to AML.
Traditionally, consolidation strategies have included single-agent intermediate-dose (IDAC) or high-dose cytarabine (HiDAC) and other cytarabine-based consolidation regimens, the same induction regimen that achieved CR, and allogeneic hematopoietic cell transplantation (HCT). However, the treatment landscape is changing, and novel combination therapies showing promise have emerged.
Optimization of postremission therapies to maintain CR and prevent relapse remains a major challenge in treating patients with AML. Review article coauthor Naval Daver, MD, associate professor in the department of leukemia at the MD Anderson Cancer Center in Houston, Texas, noted that 8 new therapeutic agents for AML have been approved by the US Food and Drug Administration in the last few years. These include molecular targeted therapies such as IDH1/2 and FLT3 inhibitors, immune therapies such as the monoclonal antibody gemtuzumab, and BCL2 inhibitors such as venetoclax in combination with low-dose cytarabine or hypomethylating agents. “These agents have changed the treatment landscape of AML and are improving response rates and survival in both newly diagnosed and relapsed AML,” Dr Daver told Hematology Advisor.
The combination of azacitidine and venetoclax has shown 3 times higher response rates and doubling of median overall survival in older patients with AML. Dr Daver explained that targeted FLT3 and IDH inhibitors are game changers, producing higher response rates as single oral agents compared with multiagent cytotoxic chemotherapy and with much better tolerability. A number of additional therapies including immune therapies, MDM2-inhibitors, and E-selectin inhibitors may also improve AML therapeutics. “I anticipate that in the next 10 years, we will see very high cure rates in the range of 70% to 80% for all patients with AML, so there is much to look forward to and be hopeful [about] for patients with AML,” said Dr Daver.
Hypomethylating agents currently under investigation as maintenance therapies include guadecitabine and CC-486, an oral formulation of azacitidine. Researchers found that CR rates ranged from 50% to 59% with guadecitabine in treatment-naive patients with AML aged 65 years or older in a randomized, open label, phase 1/2 study. Currently, a phase 2 clinical trial is examining maintenance therapy (up to 24 months) with guadecitabine with or without idarubicin in previously untreated patients aged at least 70 years (ClinicalTrials.gov Identifier: NCT02096055). In addition, a randomized, double blind, placebo-controlled phase 3 trial in patients aged 55 years or older is underway investigating CC-486 as maintenance therapy (ClinicalTrials.gov Identifier: NCT01757535).
John Mascarenhas, MD, director of the Adult Leukemia Program at the Mount Sinai Health System in New York, New York, said the improved understanding of the molecular pathogenesis of AML has led to clinically meaningful therapeutic advances. He added that the recent approval of a number of novel agents that can be administered alone or combined with conventional cytotoxic chemotherapy or epigenetic therapy could extend relapse-free and disease-free survival. “Many of the newly approved AML therapies can be administered as oral ambulatory regimens, which has the added benefit of maintaining quality of life and limiting the need for prolonged hospital admissions,” Dr Mascarenhas told Hematology Advisor.