Improved risk classification for patients with acute lymphoblastic leukemia offers hope for eliminating irradiation

Improved risk classification for patients with acute lymphoblastic leukemia (ALL), coupled with more intensive intrathecal chemotherapy for high risk patients and the use of a drug called dexamethasone, could one day permit physicians to omit irradiation as a part of routine treatment.

These findings emerged from a clinical trial conducted by investigators at St. Jude Children's Research Hospital. For intrathecal chemotherapy the drugs are injected into the cerebrospinal fluid-filled spaces between the thin membranes covering the spinal cord.

The researchers base their conclusion on results of a study of ALL treatment at St. Jude called Total Therapy Study XIIIB, which are reported in the Nov. 1 issue of the journal Blood. The overall five-year event-free survival rate of the children in Study XIIIB was just above 80 percent, and the overall survival rate was about 86 percent, according to the researchers. Event-free survival means that patients do not experience a recurrence of symptoms or other complications related to the disease or its treatment.

The researchers substituted dexamethasone for the routinely used drug prednisone to achieve greater antileukemic effects in both the central nervous system (brain and spinal cord) and the blood stream. The investigators also used more precise criteria to identify those children who should get more intensive intrathecal and intravenous therapy because they were at high risk for treatment failure.

Success of the modified chemotherapy treatment of XIIIB is significant because it established the importance of intensifying intrathecal chemotherapy early in treatment, and also set the stage for the current St. Jude clinical trial that omits the use of cranial irradiation in all patients, according to Ching-Hon Pui, M.D., director of the St. Jude Leukemia/Lymphoma Division, and American Cancer Society F.M. Kirby Clinical Research Professor. Pui is the first author of the Blood article.

"The ability to omit cranial irradiation while still achieving a high cure rate for ALL would be an important breakthrough," Pui said. "Radiation in children often leads to long-term side effects, such as second cancer and disruption of intellectual development, academic performance and growth. We'd like to spare our children those problems and give them a better quality of life as adults."

Currently, clinicians commonly use cranial radiation to treat patients at high risk of developing a relapse of ALL in the central nervous system. The new, stricter criteria allowed the St. Jude clinicians to limit cranial irradiation to 12 percent of patients in Study XIIIB, compared to 22 percent of those in a previous clinical trial, Total Therapy Study XIIIA.

Total Therapy Study XIIIB included 247 patients 18 years old and younger who underwent treatment for ALL and were followed for up to nine years to determine the treatment effectiveness and to monitor therapy side effects. A total of 117 patients were classified as having low-risk ALL, while 130 were classified as high risk.

Lower-risk patients were identified according to a variety of specific characteristics. For example, those who did not have a form of leukemia called T-cell ALL, or a certain genetic mutation in their leukemic cells called the Philadelphia chromosome were considered lower risk.

The classification system used in Study XIIIB, a revision of the one used in Study XIIIA, improved investigators' ability to identify patients who should get more intensive post-remission treatment to increase the chance of event-free survival. Post-remission therapy is given after the initial treatment to kill leukemic cells remaining after the initial, or induction, therapy. High-risk patients received more intensive chemotherapy than did low-risk patients.

In addition, while all patients received initial intrathecal chemotherapy, high-risk patients received more doses over time than did low-risk patients. Patients considered at high risk for relapse were those who had T-cell ALL and especially high white blood cell counts, or patients with evidence of leukemia in the central nervous systems.

The overall event-free-survival rate of low-risk patients in Study XIIIB was about 89 percent, while the rate for high-risk patients was about 74 percent. Only 1 percent of patients experienced a relapse where leukemic cells appeared in their central nervous systems.

"Our ultimate goal is to cure all patients with ALL," said William E. Evans, Pharm.D., St. Jude hospital director and a senior author of the paper. "To do this, we will have to continue to improve our ability to target therapy more effectively in patients with genetic abnormalities that identify them as being at high risk for treatment failure. For example, we are already testing a new treatment for high-risk patients with ALL carrying the Philadelphia chromosome."