Initial Cerebrospinal Fluid Blast Clearance Rate in Pediatric B-Lymphoblastic Leukemia Is Associated with Overall Survival

Among children, B-lymphoblastic acute leukemia (B-ALL) is one of the most prevalent cancers, accounting for roughly a quarter of pediatric cancer cases. Children with disease in the central nervous system (CNS) at B-ALL diagnosis have higher risk clinical features and greater rates of relapse. At diagnosis, lumbar punctures (LP) collect cerebrospinal fluid (CSF) samples to allow for patient stratification based on CNS involvement: CNS1 = no blasts, CNS2 = blasts amid >5 total white blood cells (WBC)/mm³, and CNS3 = blasts amid WBC ≥5/mm³ or grossly traumatic tap. Once diagnosis is confirmed and treatment has begun, subsequent LPs are performed roughly every 5-7 days during induction chemotherapy to monitor for CSF clearance of blasts. It is not yet understood how the clearance rate of CSF blasts during initial B-ALL treatment affects clinical outcomes. This study sought to elucidate the relationship between CSF clearance with overall survival (OS) and relapse rates. We hypothesized that among patients with CNS+ disease at diagnosis, patients with slower CSF blast clearance rates would have overall poorer clinical outcomes with higher rate of relapse, shorter time to relapse, and lower OS than patients who cleared the CSF more rapidly.

Electronic records from patients diagnosed with B-ALL at Children’s Hospital Los Angeles from Sept. 2008 to Dec. 2019 were reviewed. Patients were stratified by CNS status at diagnosis. WBC count and morphologic blast % in all subsequent positive CSFs were collected through the first negative sample. Time (days) from first LP at diagnosis to LP with CSF cleared was used to stratify patients into 3 clearance groups: fast clearers (1-7 days), intermediate clearers (8-15 days), and slow clearers (15+ days). Differences between the 3 cohorts were analyzed with Fisher’s exact test and Kruskal-Wallis rank sum test; overall survival was assessed via log-rank test and Cox regression. P < 0.05 was considered statistically significant.

Of 246 new B-ALL patients, 69 (28%) were CSF+ [60 (87%) CNS2 and 9 (13%) CNS3]. About half (52%) of the cohort were female and the majority (83%) of the cohort were Hispanic. There were 38 (55%) fast clearers, 24 (35%) intermediate clearers, and 7 (10%) slow clearers. Intermediate clearers have the lowest median (IQR) age at diagnosis of 4.9 years (2.9, 12.8) compared to fast (9.4 [3.3, 15.5]) and slow (11.1 [6.0, 16.5]); however, this difference was not significant (p = 0.4). Significant associations with CSF clearance rate included patient ethnicity (fast: 92% Hispanic vs. intermediate: 75% Hispanic vs. slow: 57% Hispanic; p=0.03) and death by any cause (overall: 9 [13%], fast: 5 [13%] vs. intermediate: 1 [4.2%] vs. slow: 3 [43%]; p=0.04). Differences in OS between clearance groups were significant via log-rank test (p = 0.02). The hazard ratio for OS was 4.8 (95% CI: 1.1, 21.8, p=0.043) times higher in slow clearers compared to fast clearers, and 12.0 times higher compared to intermediate clearers (95% CI: 1.2, 120, p = 0.035). There were no significant differences in NCI Risk (p = 0.3) or relapse rates (p = 0.5).

These data suggest that among pediatric patients with CNS+ B-ALL disease at diagnosis, those who cleared the CSF faster had better OS compared to patients who were slower at clearing the CSF of blasts. Although there were no significant differences in relapse rates between the clearance groups, this result could be a function of the small number of relapses in this study cohort and the small sample size. Future directions include examination of incidence of treatment-related toxicities relative to CSF clearance rate. These data could be applied to future prospective studies to determine if protocols can be adjusted based on patients being slow or fast CSF clearers, with the goal of minimizing excess toxicity to patients who clear the CSF faster, or to individualize care for those who clear the CSF more slowly.

H. Hultquist and A. Rodriguez contributed equally.