In recent years, high-dose and multi-agent chemotherapy regimens have improved the outcomes of childhood T-ALL. The 5-year OS and EFS of 74 enrolled patients were 70.2%±6.0% and 67.8%±6.0%, respectively, which is comparable to reports by other centers(Asselin, et al 2011, Hofmans, et al 2019, Karrman and Johansson 2017, Raetz and Teachey 2016, Teachey and Pui 2019, Winter, et al 2018).
The rate of CR after induction chemotherapy was 89.2%, and ETP was a risk factor related to CR after induction chemotherapy (P = 0.000). The AIEOP centers’ study confirmed that ETP-ALL had poor early treatment response and ETP-ALL patients obtained favourable outcome due to application of cyclophosphamide, 6-mercaptopurine, and ara-C(Conter, et al 2016). In the COG AALL0434 study, 1144 patients were included and divided into three groups (ETP, near-ETP, and non-ETP). There are no statistical difference of 5-year OS and EFS among the three groups which showed a lack of significance of the ETP immunophenotype in pediatric T-ALL(Hefazi and Litzow 2018).
The prognosis of HR T-ALL remains unsatisfactory(Dunsmore, et al 2012, Schrappe, et al 2011, Schrauder, et al 2006, Willemse, et al 2002). A risk-stratified approach to treat childhood T-ALL is warranted. In childhood ALL, age, WBC, and response to treatment are independent risk factors. However, the prognostic factors are different between B-ALL and T-ALL(Patrick and Vora 2015). Herein, according to existing literature, we considered CR after induction therapy, MRD at 3 months, MRD re-emergence, or age ≥ 10 years as the hierarchical criteria(Hefazi and Litzow 2018, Merli, et al 2019, Patrick and Vora 2015, Schrappe, et al 2012, Schrappe, et al 2011, Teachey and O'Connor 2020, Teachey and Pui 2019).
Patients with BM leukemic blasts > 25% after induction chemotherapy, those older than 10 years, or those with T-ALL were considered to be at particular risk(Merli, et al 2019). Failure of induction therapy is rare in pediatric ALL (< 2% of patients), but may have a worse outcome(Merli, et al 2019, Schrappe, et al 2012). In our study, eight patients did not achieve CR at the end of induction chemotherapy, and four patients eventually died (three patients died of relapse and one died of intracranial hemorrhage).
Children with T-ALL have poorer tolerance to chemotherapy and have increased extramedullary relapse as a result of that they are generally older than children with B-ALL. This indicates that older age at presentation may lead a worse prognosis for patients with T-ALL(Teachey and Pui 2019). In this study, age ≥ 10 years was an independent risk factor affecting 5-year OS and EFS, indicating that children older than 10 years of age have worse prognosis and are more likely to experience relapse. In the univariate analysis, the P value of age ≥ 10 years for EFS showed a downward trend that was not statistically significant, indicating that patients over 10 years of age may have poorer tolerance to chemotherapy and are more likely to experience treatment complications.
Initial WBC count is an important factor affecting ALL prognosis. In successive EORTC-CLG 58881 and 58951 trials, high-risk T-ALL patients were identified based on WBC count at presentation, CNS-positivity, and treatment response(Hofmans, et al 2019). However in the UK trial, UKALL 2003, EFS was inversely related to WBC for B-ALL (P < 0.001) but not for T-ALL(Vaitkevičienė, et al 2011). The Nordic Society of Pediatric Hematology and Oncology(Vaitkevičienė, et al 2011) and COG(Hastings, et al 2015) also reported that initial WBC count was not a risk factor for T-ALL patients. In this study, high initial WBC count (WBC ≥ 100×109/L) was an independent risk factor affecting the 5-year EFS and CIR, indicating that children with a high initial WBC count may be at greater risk of relapse. The 5-year OS was unaffected by this factor, possibly owing to the application of intensive combination chemotherapy and bone marrow transplantation.
In childhood T-ALL, genetic subtypes such as SIL/TAL1 and t(v; 11q23)/MLL-rearranged are not meaningful, but MRD is a significant factor related to long-term outcomes in most cooperative group studies(Teachey and O'Connor 2020, Teachey and Pui 2019). Improved risk stratification eliminated the previous independent prognostic significance of gender and CNSL, whereas MRD level after induction therapy emerged as a risk stratifying feature(Schmiegelow, et al 2010). A large percentage of childhood T-ALL patients have detectable MRD after induction chemotherapy, however, they could have a favourable outcomes if MRD converts to negative at post-consolidation(Schrappe, et al 2011). In the AIEOP-BFM 2000 trial, the 7-year EFS of childhood T-ALL patients with positive MRD after induction and MRD converting to negative at day 78 was 81%. Conversely, T-ALL patients who were MRD-positive at day 78 had a relatively high 7-year CIR of 45% and were considered for HSCT at CR1(Hefazi and Litzow 2018, Patrick and Vora 2015, Schrappe, et al 2011, Teachey and O'Connor 2020). In this study, MRD positivity at 3 months was not an independent risk factor possibly due to the small sample size and the application of HSCT. Furthermore, 10 patients had detected MRD at 3 months. Four patients chose chemotherapy, but three eventually died of relapse. Six patients chose HSCT, but only one died of multiple organ dysfunction failure (MODF). MRD re-emergence was an independent risk factor affecting 5-year OS, EFS, and CIR, indicating that patients with MRD re-emergence during treatment had a relatively high relapse risk which seriously affected the prognosis.
Although intensive combination chemotherapy regimens are now widely used, HSCT is still valuable for treatment of pediatric T-ALL. HSCT should be strongly recommended for childhood T-ALL patients with positive MRD after consolidation(Teachey and O'Connor 2020). It is suggested for patients to undergo HSCT in condition of continuous CR and low-level MRD (United States༜0.1%, United Kingdom༜0.01%)(O’Connor, et al 2017, Schrappe, et al 2011, Teachey and O'Connor 2020). In a study, childhood T-ALL patients older than 6 years who received HSCT had a favourable survival compared to those received chemotherapy (5-year EFS of 40–45% vs. 26%)(Schrappe, et al 2012). The German ALL-BFM 90 and 95 studies reported that 5-year DFS was 67% in the HSCT group compared to 42% in the chemotherapy group(Schrauder, et al 2006). In the AIEOP ALL 2000 study, children with T-ALL seemingly benefitted from HSCT with a 5-year DFS of 59.7%(Conter, et al 2014). A prospective study showed that the 5-year DFS rate was 62.2% in childhood T-ALL patients that were assigned related donor transplantation(Balduzzi, et al 2005). In a previous study at our institution, 35 HR childhood T-ALL patients received haplo-HSCT in CR1, and the 3-year LFS and CIR was 65.7% and 19.8% respectively(Xu, et al 2016). Only a portion of T-ALL patients required HSCT for cure. In this study, the 5-year OS, EFS, and CIR of the low-risk chemotherapy cohort were 100%, 93.8%±6.1%, and 6.3%±0.4% respectively, with the therapeutic effect exceeding the international level. Patients in high-risk chemotherapy cohort had a significantly worse outcomes that the 5-year OS, EFS, and CIR were 51.2%±10%, 48.4%±9.8%, and 45.5%±0.8%. The P values were 0.003, 0.01, and 0.043 respectively when compared to the low-risk chemotherapy cohort. This demonstrated good risk stratification of patients in this cohort. More importantly, the 5-year OS, EFS, and CIR were 77.0%±8.3%, 77.0%±8.3%, and 11.9%±0.4% respectively, for the high-risk transplant cohort. The therapeutic effect exceeded the level of our previous institutional study, which may be due to the improvement of transplantation technology. When compared to the high-risk chemotherapy cohort, the P values were 0.084, 0.041, and 0.011 respectively, validating that HSCT was an effective strategy to reduce relapse and had the tendency to improve long-term survival in childhood HR T-ALL in CR1. We also compared the prognosis of 24 patients in the high-risk transplant cohort who were CR1 and MRD-negative before HSCT versus the high-risk chemotherapy cohort. Patients in the high-risk group in CR1 with undetectable MRD before HSCT had better outcomes compared to patients with detectable MRD before HSCT. When the prognosis of haplo-HSCT recipients who were CR1 and MRD-negative before HSCT in the high-risk transplant cohort was compared to the high-risk chemotherapy cohort, haplo-HSCT tended to improve long-term survival and reduce relapse.
In previous international studies, conditioning regimen was usually based on TBI(Balduzzi, et al 2005, Conter, et al 2014, Schrauder, et al 2006). However, the associated side effects were significant. Recently, HSCT without TBI has been proven effective for childhood ALL(Hamidieh, et al 2017). It has been demonstrated that central nervous system relapse of childhood ALL could be effectively prevented by risk-adjusted chemotherapy without cranial radiotherapy(Patrick and Vora 2015, Pui, et al 2009). Here, patients receiving HSCT with a TBI-free, Bu-based conditioning regimen had a excellent outcomes with a 5-year OS of 77.0%±8.3% and a low 5-year CIR rate of 11.9%±0.4%.
In conclusion, HSCT (especially haplo-HSCT) without TBI may improve long-term prognosis for children with high-risk T-ALL in CR1. However, this study is limited because it is a nonrandomized retrospective study with a small sample size in a single-center. In addition, two different chemotherapy regimens were applied to patients which may cause bias, however, there were no statistical difference for long-term survival between patients with those two regimens. The results should be further confirmed by prospective, multicentre, randomized controlled clinical trials.