Personalizing chemo for childhood leukemia avoids cranial radiation
Pediatric acute lymphoblastic leukemia (ALL) is curable without preventive cranial radiation by personalizing chemotherapy, which can improve the cure rate and avoid the use of radiation in acute lymphoblastic leukemia treatment, according to findings in the June 25 issue of the New England Journal of Medicine.
Cranial radiation was once a standard childhood ALL treatment to prevent recurrence of the leukemia in the central nervous system (CNS), according to researchers at St. Jude Children's Research Hospital in Memphis, Tenn. Despite radiation's success in treating ALL, the authors said that it produces side effects that include second cancers, stunted growth, hormone imbalances and cognitive deficits.
The investigators reported that optimized use of anticancer drugs, especially those instilled directly into the spinal fluid, have enabled clinicians to reduce radiation use, and only patients at highest risk for relapse have received cranial radiation.
"Cranial radiation was an invaluable treatment when it was introduced by St. Jude oncologists in the mid-1960s," said the study's lead author Ching-Hon Pui, MD, chair of the St. Jude's department of oncology and an American Cancer Society (ACS) professor. "It controlled CNS leukemia and boosted the cure rate for ALL from only 4 percent to 50 percent. But radiation's side effects led to the steady reduction of dosages and limited use to the highest-risk patients."
The study involved 498 patients treated for ALL at St. Jude and Cook Children's Medical Center in Fort Worth, Texas, between 2000 and 2007. The risk of relapse was determined by measurement of residual leukemia cells that were present after remission induction treatment. The measurement of minimal residual disease was used to modify therapy based on the level of disease detected.
This measurement is the most important prognostic indicator, according to a study's co-author Dario Campana, MD, PhD, vice chair for laboratory research in the St. Jude's department of oncology. "The combined use of immunological and molecular methods allows us to study 100 percent of the patients for levels of minimal residual disease, an unprecedented rate of success," he said.
The investigators applied personalized therapy based on molecular genetics of ALL, pharmacogenetic traits of patients and pharmacodynamic principles. "We prospectively determined the activity of drug-metabolizing enzymes of each patient and adjusted the dosage of chemotherapy accordingly," said the study's senior author Mary Relling, PharmD, chair of the St. Jude's department of pharmaceutical sciences. "Personalized therapy that we use avoids over- or under-treatment to maximize the cure rate while preventing excessive toxicity."
Pui and colleagues reported that this therapy produced a projected cure rate of 90 percent for all the patients. To assess whether cranial irradiation would have made a difference in CNS relapse, they compared the outcomes of 71 patients whose leukemias would have qualified them for irradiation with the outcomes of 56 patients who had received such irradiation in the past. The researchers found that the 71 patients, in fact, had significantly better complete remission than the 56 patients who had been irradiated.
"The bottom line is that not only did we get outstanding treatment responses in these patients, many of whom would have otherwise received irradiation, but they will have a better quality of life because of the absence of its side effects," Pui said.
According to Pui, about 20 percent of the approximately 3,400 cases of childhood ALL diagnosed in the United States each year are still treated with radiation. In some developing countries, radiation continues to be used in the majority of children with ALL.
Cranial radiation was once a standard childhood ALL treatment to prevent recurrence of the leukemia in the central nervous system (CNS), according to researchers at St. Jude Children's Research Hospital in Memphis, Tenn. Despite radiation's success in treating ALL, the authors said that it produces side effects that include second cancers, stunted growth, hormone imbalances and cognitive deficits.
The investigators reported that optimized use of anticancer drugs, especially those instilled directly into the spinal fluid, have enabled clinicians to reduce radiation use, and only patients at highest risk for relapse have received cranial radiation.
"Cranial radiation was an invaluable treatment when it was introduced by St. Jude oncologists in the mid-1960s," said the study's lead author Ching-Hon Pui, MD, chair of the St. Jude's department of oncology and an American Cancer Society (ACS) professor. "It controlled CNS leukemia and boosted the cure rate for ALL from only 4 percent to 50 percent. But radiation's side effects led to the steady reduction of dosages and limited use to the highest-risk patients."
The study involved 498 patients treated for ALL at St. Jude and Cook Children's Medical Center in Fort Worth, Texas, between 2000 and 2007. The risk of relapse was determined by measurement of residual leukemia cells that were present after remission induction treatment. The measurement of minimal residual disease was used to modify therapy based on the level of disease detected.
This measurement is the most important prognostic indicator, according to a study's co-author Dario Campana, MD, PhD, vice chair for laboratory research in the St. Jude's department of oncology. "The combined use of immunological and molecular methods allows us to study 100 percent of the patients for levels of minimal residual disease, an unprecedented rate of success," he said.
The investigators applied personalized therapy based on molecular genetics of ALL, pharmacogenetic traits of patients and pharmacodynamic principles. "We prospectively determined the activity of drug-metabolizing enzymes of each patient and adjusted the dosage of chemotherapy accordingly," said the study's senior author Mary Relling, PharmD, chair of the St. Jude's department of pharmaceutical sciences. "Personalized therapy that we use avoids over- or under-treatment to maximize the cure rate while preventing excessive toxicity."
Pui and colleagues reported that this therapy produced a projected cure rate of 90 percent for all the patients. To assess whether cranial irradiation would have made a difference in CNS relapse, they compared the outcomes of 71 patients whose leukemias would have qualified them for irradiation with the outcomes of 56 patients who had received such irradiation in the past. The researchers found that the 71 patients, in fact, had significantly better complete remission than the 56 patients who had been irradiated.
"The bottom line is that not only did we get outstanding treatment responses in these patients, many of whom would have otherwise received irradiation, but they will have a better quality of life because of the absence of its side effects," Pui said.
According to Pui, about 20 percent of the approximately 3,400 cases of childhood ALL diagnosed in the United States each year are still treated with radiation. In some developing countries, radiation continues to be used in the majority of children with ALL.