clinical topic updates

Genomic Landscape of MDS and AML: Current Perspectives

by Harry Paul Erba, MD, PhD


Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are part of a disease spectrum that is beginning to enter into the precision medicine era. In addition to the development of targeted therapies such as midostaurin and gilteritinib, immune-modulating agents that may restore antitumor activity are being actively explored in clinical trials.

Expert Commentary

Harry Paul Erba, MD, PhD

Director, Leukemia Program
Medical Director, Hematologic Malignancies Inpatient Service
Division of Hematologic Malignancies and Cellular Therapy
Department of Medicine
Duke Cancer Institute
Duke University School of Medicine
Durham, NC

It is not just the behavior of leukemic blasts and their driver mutations but also their microenvironment that may be important in progression and in determining prognosis.”

Harry Paul Erba, MD, PhD

Patients with MDS and AML have mutations that have been acquired over time. A small set of stem cells that is present from the time of birth is responsible for faithfully replicating the genomic DNA, to continuously populate the bone marrow through 8 or 9 decades of life or longer. In leukemogenesis, mistakes occur along the way, some of which may affect myeloid progenitor proliferation and differentiation. These mutations can be seen in otherwise normal individuals but are seen more frequently in those who develop MDS and AML.

Obtaining mutational data helps to determine the prognosis, with both the specific mutations and the number of mutations present offering prognostic information. We have learned that certain mutations (eg, in TP53, in chromatin modifiers such as ASXL1, and in transcription factors such as RUNX1) are associated with a more rapid progression of bone marrow failure and shorter survival. Thus, allogeneic hematopoietic stem cell transplantation is strongly considered for eligible patients with these and certain other high-risk genetic features.

Some of these molecular alterations have become actionable targets for therapeutic intervention. For instance, FLT3 mutations occur in approximately 30% of patients with AML, resulting in constitutive activation of the FLT3 receptor tyrosine kinase and proliferation and differentiation of the myeloid cells. Further, FLT3 mutation with internal tandem duplication conveys a poor prognosis in AML. For those individuals with FLT3-mutated AML, treatments have been developed that silence or inactivate this overactive tyrosine kinase (ie, midostaurin in the treatment-naïve setting and gilteritinib in the relapsed/refractory setting). Allogeneic hematopoietic stem cell transplantation should be strongly considered for these patients once remission is achieved with chemotherapy and/or FLT3 inhibitors. The availability of such therapy underscores the importance of obtaining molecular assays for FLT3 mutations—both at the time of initial diagnosis and at the time of relapse or the demonstration of chemotherapy-refractory disease.

Another group of mutations that are now targeted are the IDH mutations. Approximately 20% of patients with AML (and somewhat fewer individuals with MDS) will have missense mutations in various hotspots in the IDH1 or IDH2 gene. These mutations essentially impart a block in the differentiation of myeloid stem cells into normal white blood cells, red blood cells, and platelets. And there are now specific inhibitors of the mutant forms of IDH1 and IDH2. The IDH1 mutant inhibitor is ivosidenib and the IDH2 mutant inhibitor is enasidenib. Neither agent has been compared with chemotherapy alone, but both are US Food and Drug Administration approved for adults with AML in certain settings, as they are oral agents that can lead to a remission. A significant toxicity in this class, differentiation syndrome, is attributed to the mechanism of action.

While we have known for decades that not all patients with high-risk-MDS or AML will have an optimal response to intensive chemotherapy, we are still trying to understand markers that correlate with chemotherapy resistance. Many studies that used gene expression profiling to identify genes that are either upregulated or downregulated in patients with refractory disease found that an immunomodulatory signal was present. In other words, it is not just the behavior of leukemic blasts and their driver mutations but also their microenvironment that may be important in progression and in determining prognosis. Knowing that immune dysregulation is implicated in the pathogenesis of MDS and AML, we may be able to modulate the immune environment in chemotherapy-refractory patients with specific mutational profiles. CD47 and TIM-3 are examples of cell surface molecules that affect the immune response to normal and neoplastic cells. Ultimately, as time goes on, we might move away from intensive chemotherapy in MDS and AML and move toward a combination of targeted therapies and agents to affect the immune environment.


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