Prophylactic Cranial Irradiation May Not Be Needed in Children With ALL

By Marilynn Larkin

November 12, 2019

NEW YORK (Reuters Health) - In children with acute lymphoblastic leukemia (ALL) at risk for central nervous system (CNS) relapse, a higher dose of chemotherapy plus two extra doses of intrathecal therapy during early induction can obviate the need for prophylactic cranial irradiation, researchers say.

"With optimal systemic and intrathecal therapy, prophylactic cranial irradiation can be safely omitted in all children with ALL, regardless of their presenting clinical and biologic features," Dr. Ching-Hon Pui of St Jude Children's Research Hospital in Memphis told Reuters Health by email. "Our treatment not only resulted in a negligible rate of CNS relapse but also outstanding cure rate and good quality of life."

"Moreover, CNS relapse in patients who never received cranial irradiation is highly curable," he noted. "With the recent advent of CAR T-cell therapy, most patients with CNS relapse can also be cured without CNS irradiation."

Dr. Pui and colleagues analyzed data from 598 consecutive children up to age 18 (including 12 infants) who received risk-directed chemotherapy without prophylactic cranial irradiation in the St Jude Total Therapy Study 16 (2007-2017). Patients were randomly assigned to receive PEG-asparaginase 3,500 U/m2 versus the conventional 2,500 U/m2. Those with features associated with increased risk of CNS relapse received two extra doses of intrathecal therapy during the first two weeks of remission induction.

As reported online October 28 in the Journal of Clinical Oncology, 98.66% of patients entered complete morphologic remission (low risk, 99.62%; standard risk, 99.64%; high risk, 89.66%).

Eight induction failures - four from fatal infections and four from refractory leukemia – occurred; two patients were alive and in remission 2.2 and 4.5 years later, the latter after undergoing transplantation.

Twenty-four patients underwent allogeneic transplantation at a median of 4.46 months after remission induction; 16 were alive and in remission. Thirty-six relapses occurred: 26 hematologic, seven isolated CNS, one isolated testicular, one combined CNS and ocular, and one combined hematologic and testicular. Six patients developed secondary malignancies.

There were 17 deaths in remission.

Further analysis showed the five-year event-free survival and overall survival rates for the 598 included patients were 88.2% and 94.1%, respectively. The cumulative risk of any CNS relapse - isolated or combined - was 1.5%.

Higher doses of PEG-asparaginase did not affect treatment outcome. T-cell phenotype was the only independent risk factor for any CNS relapse (hazard ratio, 5.15).

No significant differences were observed in the cumulative risk of seizure or infection during induction between patients who did or did not receive the two extra doses of intrathecal treatment.

Dr. Pui said, "We are now working on targeted therapy with molecular therapeutics and novel immuno- and cellular-therapy to replace toxic chemotherapy. We want to further improve the cure rate and quality life of our patients. In fact, we hope that we will eventually eliminate the use of continuation chemotherapy."

Dr. Keith August, Director of the Leukemia and Lymphoma Program at Children's Mercy Kansas City Cancer Center, told Reuters Health, "Most pediatric study groups are moving away from the use of CNS-directed radiation due to the high rates of side effects seen in children, including developmental delays and secondary malignancies."

"The results of this study highlight the fact that intensified chemotherapy treatment of the CNS is an effective and less toxic method of treatment in children with ALL at high risk of CNS relapse, and reinforces the concept that CNS radiation therapy should have a very limited role in the treatment of children with ALL," he said by email.

Nonetheless, he added, "These findings should be validated in follow-up studies before being incorporated into routine clinical practice."


J Clin Oncol 2019.