Intensified CNS-Directed Therapy Worsens Neurocognitive Function in Pediatric Patients With Acute Lymphoblastic Leukemia


Patients who receive high cumulative doses of triple intrathecal therapy may be at an increased risk of neurocognitive problems.

Lisa M. Jacola, PhD

Lisa M. Jacola, PhD

Pediatric patients who receive central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia (ALL) may be at an increased risk of neurocognitive problems as survivors, according to findings published in the Journal of Clinical Oncology. Specifically, patients at high-risk of developing CNS involvement and receive high cumulative doses of triple intrathecal therapy (ITT) experience worse cognitive decline than those who receive a low-risk ITT treatment.

Overall, patients who received CNS-directed therapy demonstrated significantly inferior intelligence (P < .0001), attention (P = .0051), working memory (P = .0001), processing speed (P = .0002), fine motor speed (P = .0001), and math skills (P = .0087) compared with age-normative expectations. No significant differences in neurocognitive function were observed among patients who did or did not receive intensified ITT in the low-risk treatment group. However, in the standard-to-high risk treatment group, treatment with intensified ITT was associated with poorer working memory (P = .0328) and fine motor speed (P = .0403), as well as elevated ratings of inattention (P = .0189) and executive dysfunction (P = .0245) compared with age-normative expectations.

“We found that 3 years after diagnosis, a significant proportion of the overall group of survivors showed elevated risk for problems in attention, working memory, learning and memory, and fine motor coordination,” wrote Lisa M. Jacola, PhD, Department of Psychology, St Jude Children’s Research Hospital, and co-investigators, in the study. “The results from caregiver ratings showed elevated risk for problems with attention, executive function, and adaptive independence. Regardless of treatment approach, survivors of childhood ALL treated with chemotherapy only have elevated risk for neurocognitive problems. These findings also highlight the complexity of neurocognitive outcomes and the need for research into non–treatment-related neurocognitive risk factors.”

The authors noted that findings may be used as a tool to “inform risk-directed neurocognitive screening and intervention that is feasible across settings,” and that the Psychosocial Standards of Care Project for Childhood Cancer guidelines recommend neurocognitive monitoring start at the time of therapy through survivorship.

ALL is the most common childhood malignancy and represents 25% of pediatric cancers. Treatment approaches, including replacing cranial radiation therapy with intrathecal chemotherapy for CNS prophylaxis, have yielded relatively positive global cognitive function with survivors.

The St Jude Total Therapy 16 clinical trial (Total 16) showed that a higher dose of PEG-asparaginase and early intensification of ITT— methotrexate, hydrocortisone, and cytarabine—helped improve CNS control in children with newly diagnosed ALL. Patients who received this treatment experienced a significantly lower 5-year rate of CNS relapse compared with a control group from the St Jude Total Therapy 15 study (1.8% vs 5.7%, respectively). In an extended analysis, investigators reported on the impact of intensified ITT on neurocognitive outcomes.

The study included 400 patients with ALL who were categorized as either low risk, standard risk, or high risk. Remission treatment was a combination of prednisone, vincristine, daunorubicin, and PEG-asparaginase, followed by cyclophosphamide, cytarabine, and a thiopurine. Patients in all groups were treated with 4 courses of high-dose methotrexate and mercaptopurine, followed by antimetabolite-based continuation therapy—which included 2 cycles of reinduction therapy.

On the first day of continuation treatment, all patients were randomly assigned to receive either PEG-asparaginase at 3500 U/m2 or the conventional 2500 U/m2. All patients were administered pulses of dexamethasone and vincristine every 4 weeks as part of continuation therapy (low-risk, 8 mg/m2 per day: standard-to-high risk 12 mg/m2 per day). In addition, patients were classified as having standard-to-high risk therapy also received PEG-asparaginase every 2 weeks. This was interrupted with pulses of doxorubicin for the first 20 weeks of continuation treatment and was followed by 3 rotation drug pairs.

Overall, patients received 120 weeks of continuation therapy. No patients on the study received prophylactic cranial radiation therapy.

The number of ITT doses that a patient received was dependent on their CNS-risk status, as well as their age, and other presenting characteristics. Patients with low CNS-risk status were prescribed 13, 19, or 21 doses. However, patients with standard-to-high-risk status received 16, 25, or 27 doses. In each arm, patients who were at greatest risk for CNS relapse were prescribed the highest dose level available for their arm.

Patients completed a neurocognitive assessment when they completed 120 weeks of continuous treatment, which was typically about 3 years post-diagnosis.

Compared with normative expectations, caregivers reported that their children had greater problems with attention (P = .0173) and executive function (P = .001). They also reported less independence with activities of daily living (P = .001).

Patients who were standard-to-high risk not only experienced worse neurocognitive function than the general population but demonstrated worse performance in working memory (P = .0070), processing speed (P = .0040), and math skills (P = .0465) than patients who were low-risk.

In the low-risk group, male patients performed worse on global intelligence processing speed (P = .0016), executive function (P = .0067), and fine motor speed (P = .0117). These patients also had higher rates of executive dysfunction (P = .0089) as well as adaptive independence (P < .0001). Similarly, patients with public insurance or no insurance, had lower global intelligence (P = .0012), processing speed (P = .0250), math achievement (P = .0084), and higher rates of inattention (P = .0026), and executive dysfunction (P = .0025).

In the high-risk group, males also had scored lower in working memory (P = .0026) and processing speed, as did patients with public or no insurance in the following domains: processing speed (P = .0204) and math categories (P = .0029).

Notably, in the standard-to-high-risk patients, treatment with greater than 27 ITT doses yielded lower working memory, (P = .0328), fine motor speed (P = .0403), and attention scores (P = .0328), and greater executive dysfunction (P = .0245), compared with 26 or fewer doses. In this patient subgroup, the most prominent deficiencies included working memory (43.1%), fine motor skills (52.5%), and learning or memory skills (29.7%).

“Patients in the standard-to-high risk arm treated with greater-intensity CNS-directed therapy additionally had elevated risk for inattention and executive dysfunction according to caregiver ratings, illustrating the functional impact of these difficulties in daily life,” study authors concluded. “By contrast, no impact of intensified CNS-directed therapy was evident among patients treated on the low-risk arm. This may suggest a threshold for ITT, with/without systemic therapy, affecting neurocognitive function.”


Jacola LM, Conklin HM, Krull KR, et al. The impact of intensified CNS-directed therapy on neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated without cranial irradiation. J Clin Oncol. Published Online November 2, 2022. doi:10.1200/JCO.22.00263

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