The treatment of acute myeloid leukemia (AML) has entered a new era, with the use of more potent therapies, such as targeted agents and venetoclax (Venclexta). The advent of these newer therapies raises important issues that are yet to be clarified, said Daniel A. Pollyea, MD, MS, Clinical Director, Leukemia Services; Robert H Allen, MD Chair in Hematology Research; and Professor, Hematology, University of Colorado Blood Disorders and Cell Therapies Center, Anschutz, during a session on evolving concepts and management strategies for AML at the National Comprehensive Cancer Network (NCCN) 2022 Annual Congress: Hematologic Malignancies.
Defining Disease
The definition of AML is shifting, and there are now 2 approaches to diagnosing patients. One approach is to define the disease by the presence of cytogenetic abnormalities or gene mutations regardless of the percentage of blasts. The other is based on the degree of differentiation for patients who do not have cytogenetic or molecular abnormalities.
“In the past, you needed 22% blasts to make the diagnosis of AML, but this has changed,” Dr Pollyea noted.
Both the World Health Organization and the International Consensus Classification (ICC; formerly European Leukemia Network [ELN]) recently updated their guidelines for diagnosing patients with AML, with some subtle and not-so-subtle differences between them.
“The ICC classification states that patients with more than 10% blasts are considered to have AML if they have particular cytogenetic abnormalities or gene mutations. However, if patients have 20% or more blasts in the bone marrow or peripheral blood plus another abnormality—the TP53 mutation or specific cytogenetic abnormalities associated with myelodysplasia—they are diagnosed as AML/myelodysplastic syndrome [MDS],” Dr Pollyea explained.
“The difference between AML/MDS is minimal. This is really the same disease, and we are trying to recognize this with our diagnostic systems,” he added. “The two sets of diagnostic criteria create the potential for confusion, and patients can fall into grey areas in between these two systems.”
According to Dr Pollyea, the new understanding of the disease will affect enrollment in clinical trials that evaluate drugs approved for MDS or AML, “specifically for MDS patients where it has been difficult to enroll patients. In the future, these two systems might align once the nuances and differences between them are understood,” he stated.
Changes in Prognostic Categories
The identification of genetic mutations and abnormalities associated with AML and therapies targeted to those abnormalities has shifted prognostic categories in the ELN guidelines. The genetic categories in favorable risk remain similar, but now the presence of FLT3-ITD puts a patient in the intermediate risk category. Patients with FLT3-ITD were formerly considered adverse risk, with more proliferative disease and worse outcomes.
“But now that we can target FLT3, having this mutation moves patients into the intermediate-risk category,” Dr Pollyea asserted. “We use midostaurin [Rydapt] for upfront therapy, or gilteritinib [Xospata] for relapsed/refractory FLT3-positive patients. Other FLT3 inhibitors in development show promise.”
“An expanded list of adverse risk genetic abnormalities can move a patient into the unfavorable group,” he added.
The ELN system has inherent bias, based on treatment with intensive chemotherapy and mostly younger patients. With new treatments that can be used in older patients, the relevant prognostic factors can change.
As an example, venetoclax plus azacitidine (Onureg) is now commonly used to treat patients with newly diagnosed AML, but when this regimen was first introduced, it was unknown whether it could overcome adverse risk factors. A recent study by Dr Pollyea and colleagues showed that patients with the TP53 mutation and other poor-risk cytogenetics achieved more than 2-times higher rates of complete remission or complete remission with incomplete hematologic recovery on venetoclax plus azacitidine compared with azacitidine alone: 40.8% versus 16.7%, respectively, for those with the TP53 mutation, and 70% versus 22.7%, respectively, for those with poor-risk cytogenetics.1
“With new therapies, we need new prognostic factors. We don’t have to consider poor-risk cytogenetics as poor risk if we give venetoclax. This points out the need to study every new therapy that we give. There are no adverse risk factors that are universal,” Dr Pollyea stated.
Treatment Choices
Dr Pollyea explained that in the United States, patients with newly diagnosed AML are currently treated with either venetoclax plus azacitidine or intensive chemotherapy plus the 7 + 3 regimen.
“In the past, when intensive chemotherapy was our only option, it was easier to decide between intensive chemotherapy or no therapy. Now, we have several good options, and selection criteria for candidates for intensive chemotherapy versus newer therapies is an evolving concept,” he said. “In the current era, there are patients who are good candidates for either therapy—venetoclax plus azacitidine or intensive chemotherapy. We need to use information to make decisions, and this is reflected in NCCN guidelines. It hasn’t been pinned down yet.”
Patient selection for current induction regimens is being studied. One group of investigators have developed a propensity score matching for certain risk factors with outcomes on venetoclax plus azacitidine versus intensive chemotherapy plus the 7 + 3 regimen. They found that age >65 years, the presence of RUNX1 mutation, and secondary AML (ie, adverse risk on intensive chemotherapy) were associated with improved progression-free survival and response rates for patients treated with venetoclax plus azacitidine. On the other hand, a French-American-British subtype M5 mutation and a FLT3 mutation favored intensive chemotherapy with 7 + 3, the historical standard of care, for intermediate-risk AML.
“This is still a work in progress. You need to have molecular results before you select a regimen. We know that RUNX1 is associated with poor risk on intensive chemotherapy, but this may not be the case for venetoclax,” Dr Pollyea said.
Reference
- Pollyea DA, Pratz KW, Wei AH, et al. Outcomes in patients with poor-risk cytogenetics with or without TP53 mutations treated with venetoclax and azacitidine. Clin Cancer Res. 2022 Aug 25. Epub ahead of print.