Long-Term Brain Status and Cognitive Functioning In Children With Acute Lymphoblastic Leukemia Treated According To ALL IC-BFM 2002
Authors: Zajac-Spychala Olga , Pawlak Mikolaj , Karmelita-Katulska Katarzyna , Pilarczyk Jakub , Derwich Katarzyna , Wachowiak Jacek 
Published: October 2019

Abstract

Background
Acute lymphoblastic leukemia (ALL) comprises about 85% of all leukemias in children and is the most frequent malignancy of childhood. Long-term side effects of applied therapy according to ALL IC-BFM 2002 (with prophylactic CNS radiotherapy dose reduced to 12 Gy given in combination with high-dose methotrexate intra venous and methotrexate alone or in combination with cytarabine and prednisolone intra thecally) are still unknown.

Aim
The aim of this cross-sectional study is to assess the long-term side effects of central nervous system (CNS) prophylaxis (high-dose chemotherapy i.v. alone vs. high dose chemotherapy i.v. combined with prophylactic CNS radiotherapy) according to ALL IC-BFM 2002 by the whole brain magnetic resonance and assessment the neuropsychological functioning.

Patients and Methods
Out of 150 children treated in 2002-2010 because of ALL, 58 children (23 girls and 35 boys) aged 6.4 - 19.9 years (median: 14.4) have been previously studied, including 26 children treated with chemotherapy alone, 21 - treated with chemo- and radiotherapy, and 11 - before treatment (control group). The structural assessment included evaluation of the segmentation of brain and calculation of the volume of white and gray matter as well as segmentation of subcortical structures. The neuropsychological assessment included the Wechsler Intelligence Test for Children (WISC-R; IQ assessment and long-term memory), Rey Auditory Verbal Learning Test (RAVLT; evaluation of short term memory), Benton Visual Retention Test (evaluation of visual memory), Verbal Fluency Test (evaluation of verbal memory), the Stroop test (evaluation of reaction time and executive) and Wisconsin Card Sorting Test (WSCT; evaluation of executive functions).

Results
Patients treated with high-dose chemotherapy and CNS radiotherapy had a lower volume of the hippocampus (6.7 cm³) and basal ganglia (29 cm³) compared to the group treated with chemotherapy alone (8 cm³ and 31 cm³, respectively) and the control group (8 cm³ and 32 cm³). All patients treated due to ALL had smaller total volume of brain ventricles (12 cm³ in the group treated with chemo-and radiotherapy, and 13 cm³ in the group treated with chemotherapy alone), compared to the control group (18 cm³).
In patients, who that received chemo-and radiotherapy the average intelligence quotient was lower (IQ - 101), visual-spatial memory was worse (Benton test – 6 correct reproductions), auditory-verbal memory was worse (6, 7, 9, 9, 11) and lower verbal fluency (10 for phonemic category and 13 for semantic one) as compared to patients treated with chemotherapy alone (respectively: IQ - 116, Benton test - 7; RAVLT -7, 7, 10, 12, 13; verbal fluency – 12 and 16) and to patients in the control group (IQ - 116, Benton test - 9; RAVLT - 9, 11 , 13, 13, 14; verbal fluency – 15 and 19). The group treated with chemo-and radiotherapy (WSCT - 3.2 classified category, the rate of correct answers - 0.48, Stroop test - 3.2) and the group treated with chemotherapy alone (WSCT - 4.1 category, the rate of correct answers - 0.59; Stroop test - 2.9) performed significantly worse on measures of executive functioning in comparison to the control group (WSCT - 5.2 category, the rate of correct answers - 0.71; Stroop test - 2.5).

Conclusions
In children treated for ALL according to the ALL IC-BFM 2002 both CNS structural changes and cognitive impairment may be observed. These abnormalities are even more pronounced in children who received chemotherapy in combination with CNS radiotherapy.
This work was supported by grant from the National Science Centre (DEC-2012/05/N/NZ5/00879).

Disclosures:
No relevant conflicts of interest to declare.