Combination Therapy for Acute Myeloid Leukemia

Overview of Acute Myeloid Leukemia

A recent study published in *Cancer Discovery* has shed light on a promising treatment approach for acute myeloid leukemia (AML) through the combination of chemotherapy and immunotherapy. AML is a cancer that begins in the bone marrow, where blood cells are produced. This type of cancer arises due to abnormal changes in myeloid cells, which typically serve as precursors for white blood cells. In AML, myeloid cells proliferate uncontrollably, potentially spreading to distant organs, including lymph nodes, the spleen, and the central nervous system.

Prevalence of Acute Myeloid Leukemia

While AML is less common than other forms of cancer, more than 19,000 cases are diagnosed annually in the United States. Although some patients may achieve remission through chemotherapy, there is a risk of relapse, leading to relapsed or refractory AML.

Research Findings on Combined Treatment

Study Overview

Researchers from The University of Texas MD Anderson Cancer Center recently conducted a phase-2 clinical trial that demonstrated the effectiveness of combining Nivolumab (an immunotherapy agent) with Azacytidine (a chemotherapy drug). The study, which included 70 patients, reported a 33% overall response rate in those treated with this combination.

Mechanisms of Action

Nivolumab functions as a monoclonal antibody that targets programmed cell death-ligand 1 (PD-L1). In a healthy immune system, T cells play a crucial role in identifying and destroying cancer cells. However, some cancer cells exploit a mechanism involving PD-L1 to inhibit T cell activity, allowing them to proliferate unchecked.

In contrast, Azacytidine, approved in 2004, is primarily used for myelodysplastic syndromes and works by reactivating tumor suppressor genes and exerting direct cytotoxic effects on cancer cells. It inhibits DNA methyltransferases, which are responsible for silencing these important genes, thereby restoring their function and preventing uncontrolled cell division. Additionally, Azacytidine has been shown to enhance the efficacy of immunotherapy by increasing PD-1 and PD-L1 expression.

Response Rates and Outcomes

Among patients receiving the combination therapy, those with no prior exposure to Azacytidine showed significantly better outcomes, achieving an overall response rate of 55%. Notably, 22% of these patients reached complete remission. The median overall survival for all patients was 6.3 months, while those with relapsed AML experienced a survival duration of 10.6 months. These findings are particularly noteworthy given that survival rates for patients treated with Azacytidine alone are typically lower in relapsed cases.

While the study showcased remarkable results, it also noted that 11% of patients experienced life-threatening complications. A significant diagnostic finding was that patients with higher expressions of CD3 and CD8 prior to treatment were more likely to respond favorably to the combined therapy.

Future Directions

The encouraging results of this study have led to the approval of a phase-3 trial, with anticipation for further insights into the effectiveness of this combination therapy in treating AML.

Reference

Daver, N., Garcia-Manero, G., Basu, S., Boddu, P. C., Alfayez, M., Cortes, J. E., . . . Kantarjian, H. (2018). Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Non-randomized, Open-label, Phase 2 Study. *Cancer Discovery*. doi:10.1158/2159-8290.cd-18-0774