Acute myeloid leukemia (AML) occurs mainly among older patients. Compared to younger patients with the disease, older patients tend to have worse outcomes, with a 3-year survival rate of just 5% to 15%. Moreover, in about half of the cases involving older patients, it is difficult for clinicians to determine the safest, most effective treatment.
But a recent study published online in the Proceedings of the National Academy of Sciences offers a possible new path for improving the treatment of these older patients. Led by researchers at the Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC–James), the study describes a novel marker that may help doctors choose the least toxic, most effective treatment for many older patients with AML.
The researchers investigated patterns of molecules called long noncoding RNAs (lncRNAs), a class of RNA molecules more than 200 nucleotide units long that are involved in regulating genes. The researchers examined the abundance, or expression, of lncRNAs in patients who were 60 years of age and older, and who had cytogenetically normal (CN) AML.
Ramiro Garzon, MD
“We have identified a pattern of 48 lncRNAs that predicted both response to standard chemotherapy and overall survival in older CN-AML patients,” says first author Ramiro Garzon, MD, associate professor of internal medicine at Ohio State.
“Patients in the favorable group had a high probability of responding to standard chemotherapy, while those in the unfavorable group generally responded poorly to the treatment and had worse overall survival,” he says.
The study findings are important for several reasons, says principal investigator Clara D. Bloomfield, MD, distinguished university professor, Ohio State University cancer scholar, and holder of the William Greenville Pace III endowed chair in cancer research.
Clara D. Bloomfield, MD
“First, they strongly suggest that lncRNA expression profiles can predict which patients will respond to standard therapy. That’s important because it would spare these patients from the toxic side effects of experimental therapies.
“Patients who are classified in the unfavorable group would receive a different therapy, stem cell transplant, or a clinical trial using new therapeutic approaches. Thus, this research will help to tailor leukemia therapy to each individual.”
In addition, she says, this study identified many novel targets for the development of new therapies.
Garzon, Bloomfield, and colleagues developed the prognostic scoring system using bone marrow samples from 148 older patients with CN-AML treated on cancer and leukemia group B clinical trials. All had received similar chemotherapy regimens.
The researchers first identified 48 lncRNAs that were most associated with survival. Using these 48 lncRNAs, the researchers divided patients into two groups, those with a favorable outcome score and those with an unfavorable outcome score. The researchers then validated the outcome scores in an independent matched set of 71 similarly treated CN-AML patients.
Comparing patients with an unfavorable score to those with a favorable score revealed the following:
- Patients with an unfavorable score had a lower complete response (CR) rate (54% versus 89%, respectively);
- At 3 years after CR, only 7% of patients with an unfavorable score were disease free compared with 39% of patients with a favorable score.
- Overall survival at 3 years for those with an unfavorable score was 10% versus 43% for patients with a favorable score.
- Distinct lncRNA profiles were associated with six clinically important CN-AML mutations.
In summary, the researchers showed that lncRNA expression profiles were associated with recurrent mutations, clinical features, and outcome in AML. A fraction of these lncRNAs may have a functional role in leukemogenesis. Furthermore, lncRNAs could be used as biomarkers for outcome in AML.
The research was supported by funding from the National Cancer Institute, Brigham and Women’s Hospital, the Coleman Leukemia Research Foundation, the Pelotonia Fellowship Program, the Associazione Italiana Ricerca sul Cancro AIRC, and Ministero della Istruzione Università e Ricerca supported this research.
REFERENCE
Garzon R, Volinia S, Papaioannou D, et al. Expression and prognostic impact of lncRNAs in acute myeloid leukemia. PNAS. 2014;111(52):18679–18684; doi: 10.1073/pnas.1422050112.
