The Impacts of Circulating Lymphoblasts and the Day of the First Triple Intrathecal Therapy on the CNS Outcomes of Childhood ALL: The Report of Taiwan Pediatric Oncology Group (TPOG)-ALL-2013

The CNS-directed therapy of Taiwan Pediatric Oncology Group (TPOG)-ALL-2013 protocol (TPOG-2013), following our previous report (Yeh et al., Cancer 2018), omitted cranial radiation for all newly diagnosed ALL patients and delayed the diagnostic lumbar puncture and the first triple intrathecal therapy (TIT) injection until circulating lymphoblasts disappeared from the peripheral blood (PB). These procedures are recommended to be performed within 10 days of initiating induction therapy. The study was aimed to evaluate the impacts of circulating blasts and the day of the first TIT on the CNS outcomes. The TPOG-2013 protocol was open from January 1, 2013 to December 31, 2020. A total of 899 children with a newly diagnosed ALL were enrolled in the study. As of Oct. 31, 2023, the 5-year event-free survival and overall survival were 85.6±1.2% and 90.1±1.0%. And the 5-year cumulative incidence of isolated CNS relapse and any CNS (isolated plus combined) relapse were 1.3±0.4% and 2.5±0.6%, respectively. Given that weekends might be excluded for routinely performing the diagnostic lumbar puncture and the first TIT, they are advised to be administered within 12 (10 plus 2) days of induction (Day12) if circulating blasts decrease to ≦3%. Five of 11 isolated CNS relapses and 7 of 20 any CNS relapses occurred in the 170 patients (19%) who received the first TIT after Day12. Using Cox proportional hazard regression, the presence of circulating blasts and the TIT after Day12 showed higher cumulative incidence of relapse (CIR) of any CNS events with hazard ratio (HR) 3.27 (P=0.01) and 2.60 (P=0.043) (model 1), respectively. When CNS status was introduced (model 2), only CNS-3 (vs CNS-1/CNS-2) was an independent predictor of a higher CIR of any CNS event (HR: 21.23, P<0.0001). Further, when age, WBC at diagnosis, NCI risk-group and final risk-group were added (model 3), CNS-3 (HR:14.25, P<0.0001) and WBC ≧100×109/L (HR: 6.35, P=0.027) exhibited adverse prognostic impacts on any CNS relapse. The blocks of models were also used to analyze the impacts on isolated CNS relapse. In model 1, only the TIT after Day12 was associated with a higher CIR of isolated CNS event (HR: 4.10, P=0.02). In model 2, CNS-3 predicted a higher CIR of isolated CNS event (HR: 23.88, P<0.0001) and the TIT after Day12 showed a trend to be an inferior predictor (HR: 3.23, P=0.057). In model 3, only CNS-3 (HR: 13.09, P=0.003) and WBC ≧100×109/L (HR: 17.01, P=0.044) were the significant predictors of a higher CIR of isolated CNS events. In patients receiving diagnostic lumbar puncture and first TIT before Day12 (N=729), Cox proportional hazard regression demonstrated that CNS-3 (HR:11.29, P=0.003) was a predictor of a higher CIR of any CNS event and a PB blast >3% showed a trend towards predicting a higher CIR (HR: 3.15, P=0.051) (model 3). When age, WBC at diagnosis, NCI risk-group, lineage and final risk-group were included (model 4), CNS-3 was the sole independent predictor of a higher CIR of any CNS event (HR: 20.37, P=0.002). In terms of CIR of isolated CNS event, only WBC at diagnosis was associated with an inferior outcome (P=0.014). For those who had the first TIT after Day12 (N=170), only CNS-3 was identified as a predictor of a higher CIR of any CNS event in models 3 (HR: 42.75, p<0.0001) and 4 (HR: 11.36, P=0.02). Similarly, when examining the isolated CNS relapse, CNS-3 was the only predictor of a higher CIR in both models 3 and 4 (P<0.001 and P=0.006, respectively). Furthermore, the CIR of isolated CNS event in patients receiving the first TIT after Day12 was significantly higher than in those receiving it before Day12 (75.0±21.7% vs. 0%, P=0.012). The CIR of any CNS events did not reach statistical significance between patients receiving the first TIT before and after Day12 (25.0±15.4 % vs. 75.0±21.7%, P=0.21). In conclusion, the delay of the first TIT until the clearance of circulating blasts from PB and the total omission of cranial radiation did not compromise survival or CNS control in patients with childhood ALL. We further demonstrated that the presence of circulating blasts >3% and delaying the first TIT beyond 12 days of induction negatively impacted CNS outcomes. The outcome of CNS-3 status would be aggravated if the first TIT was performed after the day 12 of induction.