Chromosomal Abnormality May Hold Promise in Treating AML

The novel agent lurbinectedin (PM01183) does not appear to demonstrate promise in treating acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)-but the presence of a certain chromosomal abnormality may hold promise in treating the disease. These are the findings of a research article published in Hematological Oncology.

“[While] it is a negative study, it points in the direction of leukemias that have certain chromosomal abnormalities,” said lead study author Christopher Benton, MD, assistant professor in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.

Trabectedin is a marine-derived, antitumor agent that is approved by the US Food and Drug Administration for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma. Lurbinectedin, a next-generation agent from the same medication class as trabectedin, had demonstrated preclinical activity against myeloid leukemia cells.

Benton and colleagues conducted a dose-finding, phase I study to further assess the safety and tolerability of lurbinectedin in patients with AML or MDS. They found that 79% of patients (33 of 42) experienced a reduction in blasts in peripheral blood or bone marrow. However, only 1 patient achieved a partial response, and just 2 patients achieved a morphologic leukemia‐free state. In addition, 71% of patients (30 of 42) discontinued lurbinectedin due to progressive disease.

However, the researchers found that 4 patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without the abnormality. The authors theorize that agents from this class of medication may be leukemia-suppressive for some patients. “It was quite interesting [to see] how the drug works,” Benton said in an interview with Cancer Network. “This is a good example of [a] drug that didn’t work, but we picked up a signal [anyway].”

Benton said this class of agents may be used for more than just sarcomas; however, it looks most promising for solid tumors. AML is particularly challenging to treat, he added.

Eunice S. Wang, MD, chief of the leukemia service and a professor of oncology at Roswell Park Comprehensive Cancer Center in Buffalo, New York, said that five agents have been approved for AML therapy since April 2017, and at least 3 others are currently undergoing FDA review. She said these newly-approved agents have significantly changed the landscape of treatment for AML. However, she added, there is a need for a much greater understanding of the chromosomal pathways involved in the development of AML in various subsets of patients.

“We have made tremendous strides forward, but still have our work cut out for us,” Wang told Cancer Network. She noted that clinicians are now required to obtain cytogenetic and molecular information on patients' tumor cells in a very short time frame to select the most appropriate therapy. Dr. Wang noted that 3 agents have validated the efficacy of targeted therapy for AML by improving outcomes only in specific molecular subtypes of AML (FLT3, IDH1, and IDH2-mutant).

“Although each approved agent represents a significant improvement over standard therapy, the actual increment of improvement remains small. For instance, ivosidenib and enasidenib can significantly prolong the survival of IDH1 and IDH2 mutant relapsed/refractory AML patients, respectively, without the need for IV or intensive chemotherapy,” said Wang.  However, she noted that responses occur in only 40% of IDH-mutant patients, and the median overall survival benefit is only 10 months.