"Patients with the most lethal form of acute myeloid leukemia AML  based on genetic profiles of their cancers  typically survive for only four to six months after diagnosis even with aggressive chemotherapy. But new research indicates that such patients paradoxically may live longer if they receive a milder chemotherapy drug. Treatment with the less intensive drug decitabine is not a cure. But surprisingly AML patients whose leukemia cells carried mutations in a nefarious cancer gene called TP consistently achieved remission after treatment with decitabine. Their median survival was just over a year. The study by a team of scientists at Washington University School of Medicine in St. Louis is published Nov.  in The New England Journal of Medicine. In AML treatment involves intensive chemotherapy to try to kill the patients leukemia cells and put the cancer into remission. If successful a followup bonemarrow transplant can offer a possible cure but this course of treatment is recommended only for patients with a high risk of relapse because the procedure can cause severe complications even death. Whats really unique here is that all the patients in the study with TP mutations had a response to decitabine and achieved an initial remission said the studys senior author Timothy J. Ley MD the Lewis T. and Rosalind B. Apple Professor of Medicine noting that in AML TP mutations have been correlated with an extremely poor prognosis. With standard aggressive chemotherapy we only see about  to  percent of these patients achieving remission which is the critical first step to have a chance to cure patients with additional therapies. The findings need to be validated in a larger trial Ley added but they do suggest that TP mutations can reliably predict responses to decitabine potentially prolonging survival in this ultra highrisk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates. In an accompanying editorial Elihu Estey MD an AML expert at the University of Washington Medical Center and Fred Hutchinson Cancer Research Center in Seattle noted that AML is not one disease but many each driven by different genetic mutations. The results of the current trial he said point to the inevitable need to replace large cancer clinical trials evaluating homogeneous drug treatments with smaller trials that involve subgroups of patients with treatments targeted to their specific mutations. The current study involved  patients treated with decitabine at the Siteman Cancer Center at Washington University School of Medicine and BarnesJewish Hospital and at the University of Chicago. The patients either had AML  a cancer of the bone marrow  or myelodysplastic syndrome MDS a group of blood cancers that often progresses to AML. This year an estimated  people living in the U.S. will be diagnosed with AML and at least  deaths will be attributed to the disease. Decitabine often is given to older patients with AML or MDS because it is less toxic than standard chemotherapies. But fewer than half of patients who get the drug achieve an initial remission so the researchers wanted to determine whether specific mutations in the patients cancer cells could predict their responses to treatment. To find out they sequenced all the genes in patients cancer cells or analyzed select cancer genes. They also conducted standard tests to look for broken missing or rearranged chromosomes. Then the researchers correlated these molecular markers with treatment response to identify subgroups of patients likely to benefit from decitabine. Among the patients in the study  percent achieved a remission with decitabine. But remarkably all  patients whose leukemia cells carried TP mutations went into remission. Patients also were likely to respond to decitabine if they were deemed to have an unfavorable risk prognosis based on extensive chromosomal rearrangements in their cancer cells many of these patients also had TP mutations. Indeed  percent of patients with an unfavorable risk achieved remission compared with  percent of patients who had more favorable prognoses. The challenge with using decitabine has been knowing which patients are most likely to respond said coauthor Amanda Cashen MD an associate professor of medicine who led an earlier clinical trial of decitabine in older patients with AML. The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients but also younger patients who carry TP mutations. First author John Welch MD PhD an assistant professor of medicine added Its important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis which is encouraging. We dont yet understand why patients with TP mutations consistently respond to decitabine and more work is needed to understand that phenomenon. Responses to decitabine are usually shortlived however with remissions typically lasting for about a year. Decitabine does not completely clear all the leukemia cells that carry TP mutations and these cells invariably become resistant to the drug leading to relapse. Remissions with decitabine typically dont last long and no one was cured with this drug Ley explained. But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy and that can mean something. Some people live a year or two and with a good quality of life because the chemotherapy is not too toxic. Roughly  percent of AML patients carry TP mutations in their leukemia cells. Among patients in the study with such mutations median survival was . months  which is not significantly different from the . months survival seen in patients without the mutations  and is longer than the typical four to sixmonth survival observed in such patients treated with more aggressive therapies. Decitabine was approved by the FDA in  as a treatment for MDS but oncologists often prescribe it offlabel as a treatment for AML particularly in older patients. AML typically strikes in a persons mids the average age of people in the current study was . Were now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP mutations Welch said. Its exciting to think we may have a therapy that has the potential to improve response rates in this group of highrisk patients. The research is supported by an AMLSPORE grant and the Genomics of AML Program Project grant both from the National Cancer Institute at the National Institutes of Health NIH grant numbers P CA and P CA. Welch J Petti A Miller C Fronick C OLaughlin M Fulton R Wilson R Baty J Duncavage E Tandon B Lee YS Wartman L Uy G Ghobadi A Tomasson M Pusic I Romee R Fehniger T StockerlGoldstein K Vig R Oh S Abboud C Cashen A Schroeder M Jacoby M Heath S Luber K Janke M Hantel A Khan N Sukanova M Knoebel R Stock W Graubert T Walter M Westervelt P Link D DiPersio J and Ley T. TP and decitabine in acute myeloid leukemia and myelodysplastic syndromes. The New England Journal of Medicine. Nov.  . Washington University School of Medicines  employed and volunteer faculty physicians also are the medical staff of BarnesJewish and St. Louis Childrens hospitals. The School of Medicine is one of the leading medical research teaching and patientcare institutions in the nation currently ranked sixth in the nation by U.S. News  World Report. Through its affiliations with BarnesJewish and St. Louis Childrens hospitals the School of Medicine is linked to BJC HealthCare. Siteman Cancer Center ranked among the top cancer treatment centers by U.S. News  World Report also is one of only a few cancer centers in the U.S. to receive the highest rating of the National Cancer Institute NCI. Comprising the cancer research prevention and treatment programs of BarnesJewish Hospital and Washington University School of Medicine in St. Louis Siteman is Missouris only NCIdesignated Comprehensive Cancer Center and the states only member of the National Comprehensive Cancer Network."