Hematology Advisor interviewed Courtney D. DiNardo, MD, MSCE, associate professor, and Ghayas C. Issa, MD, assistant professor, of the department of leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, to learn more about the current state of treatment and remaining needs pertaining to patients with acute myeloid leukemia (AML).
Hematology Advisor: What are the top challenges associated with treating relapsed or refractory AML?
Dr DiNardo & Dr Issa: The median age of patients diagnosed with acute myeloid leukemia is close to 70 years. This represents a challenge at all treatment stages — and all the more in relapse — because of all the age-related comorbidities and inherent and secondary resistance mechanisms. Several novel therapies including venetoclax combinations are now available, providing more effective treatment options compared to the previous standard of care in the newly diagnosed setting. However, relapse following these combinations is difficult to treat with limited therapeutic options available.
Certain subtypes of AML remain particularly challenging to treat with inherent treatment resistance, such as AML with mutations in the TP53 gene and chromosomal abnormalities involving 3q26 where the MECOM gene is located. Importantly, the advent of targeted therapies for AML with FLT3 or IDH mutations has improved outcomes for these subsets, however resistance still occurs through multiple mechanisms of escape. Another challenge is to prevent or circumvent these mechanisms of resistance through combination strategies.
Hematology Advisor: How are novel diagnostic techniques and therapies affecting the state of treatment for patients with AML — and how might they impact treatment in the near future?
Dr DiNardo & Dr Issa: After a long period where the standard of care for AML treatment had not changed in decades, multiple new therapies have been approved in recent years. This was mostly due to an improved understanding of the genomic and molecular underpinnings of AML. Next generation sequencing is now critical in determining the best treatment for patients with AML, through incorporation of targeted therapies or through an improved prognostication to guide, which patients would most likely benefit from an allogeneic stem cell transplant.
Minimal or measurable residual disease denotes the cancer cell reservoir remaining posttreatment, which leads to relapse. Advances in detection of minimal/measurable residual disease (MRD) have led to an improved understanding of response and resistance to treatment, therefore influencing treatment strategies aimed at eradicating MRD. Currently, sensitive MRD detection methods rely on flow cytometry analysis, next generation sequencing, or detection of leukemia-specific aberrations using [polymerase chain reaction] methods. These precision method tools, in addition to other investigational approaches such as transcriptomic or epigenetic analyses, will certainly lead to patient-specific tailored treatments and discovery of novel therapeutic targets and biomarkers in the future.
Hematology Advisor: What are other key treatment considerations for clinicians treating this population?
Dr DiNardo & Dr Issa: There are currently numerous therapeutic tools for AML with rapidly evolving combination strategies. Selection of the best treatment can be difficult for non-specialized physicians. In addition, despite all the advances made recently in the AML field, there is a lot of room for improvement. That is why we strongly recommend considering clinical trials for all patients with AML.
Hematology Advisor: What are the most pressing remaining research needs in this area?
Dr DiNardo & Dr Issa: There is a desperate need to improve efficacy and safety of treatment for all patients with AML. Current short-term efforts are focused on incorporating recent advances such as anti-apoptosis or targeted therapies in combination strategies in order to achieve longer remissions for patients with untreated AML and those with relapsed or refractory disease. The most pressing need is to circumvent resistance mechanisms and provide cures. This requires innovative research on adaptive treatment strategies — such as immunotherapy, for example — and rapid adaptation in the clinical setting.