The ongoing clinical trial, called AML02, also found that almost 77 percent of survivors were free of leukemia one year from diagnosis. AML02 was the first to use minimal residual disease (MRD) measurements in a study of AML treatments to make accurate assessments of treatment response for each child, and to adjust treatment accordingly, the researchers reported.
MRD is the tiny but still potentially troublesome population of leukemic cells remaining after the initial phase of chemotherapy (induction therapy) is completed. These cells can replenish the population of leukemic cells and thwart the treatment. Using flow cytometry, researchers identified abnormal combinations of proteins that appear only on the surface of leukemic cells. This allowed the investigators to quickly and accurately determine the percentage of such cells in bone marrow samples. Doctors used MRD measurements made after induction to determine if the treatment was eliminating enough leukemic cells to ensure a high probability of success. Based on that information, the doctors modified the intensity of treatment to avoid unnecessary therapy.
Until now, researchers had to rely on the less-accurate technique of microscopic examination to determine which cells in a child's blood sample were leukemic.
A report on these findings was presented at the 47th annual conference of the American Society of Hematology on December 12 in Atlanta, Georgia, by Jeffrey Rubnitz, M.D., Ph.D., an associate member of the St. Jude Department of Hematology-Oncology. AML02 is the first multi-institutional study of a specific St. Jude investigational protocol, according to Rubnitz.
"The future will show if there is a long-term benefit to our being able to identify slow responders and the effect of intensifying therapy for such patients," he said. "But the results of this study are very encouraging because MRD helped us to more accurately assess and re-design therapy for individual children. And the high rate of remission we achieved at one year reflects that achievement."
The multi-center AML02 trial randomly assigns patients to receive either high- or low-dose treatment with cytarabine (A), daunorubicin (D), and etoposide (E) as induction therapy. After treatment with either high- or low-dose cytarabine, the researchers measured the drug's level to determine its fate in the body. Such information might help doctors optimize their use of cytarabine to treat AML in the future. In addition, the researchers identified the patterns of gene activities linked to either success or failure of treatment in each child. This helped them identify children whose leukemic cells carried mutations that put them at high or low risk of failure, or who could be considered at "standard" risk--information that guided the researchers in determining how aggressively to treat each child.
Patients found to have no response to ADE during induction therapy were subsequently treated with low-dose ADE plus gemtuzumab ozogamicin (GO), while all others received just ADE during the second stage of treatment. Before receiving the final phase of chemotherapy (consolidation therapy) or being given a stem cell transplant, patients were given GO as a single agent if MRD found that 0.1 percent of their bone marrow samples were leukemic. MRD was able to identify with a significant level of accuracy whether treatment would succeed or fail, allowing the doctors to modify treatment to increase the chance of success.
Among the 112 patients enrolled since October 2002, four died from infections that occurred during or after completion of chemotherapy.
"Overall, the MRD and other laboratory studies gave us a extremely helpful insights into how well the course of therapy was helping each individual child," Rubnitz said. "These tools were key to the high overall remission rate and low treatment-related mortality."
The other researchers involved in this study include Bassem Razzouk, Stanley Pounds, Raul Ribeiro, Ching-Hon Pui, Elaine Coustan-Smith, Dario Campana and Shelly Lensing (St. Jude); Paul Bowman (Cook Children's Medical Center, Forth Worth, TX); Gary Dahl and Norman Lacayo (Stanford University Medical Center, Palo Alto, CA); Jeffrey Taub and Yaddanapudi Ravindranath (Children's Hospital of Michigan-Detroit); Soheil Meshinchi (Children's Hospital, Seattle, WA); and Gladstone Airewele (Texas Children's Cancer Center, Houston, TX).
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit www.stjude.org.