The Monitoring And Clinical Significance Of Minimal Residual Disease In Children With Acute T Lymphoblastic Leukemia

Background and objective:With the advances of study on leukemogenesis and effective therapies, the cure rate of childhood leukemia has been significantly improved, with more than 80% of cure rate in some developed countries. However, relapse is still the leading cause of death in children with leukemia currently. It is now known that the minimal residual disease (MRD) is the main cause of disease recurrence, therefore it is crucial to detect the MRD in children with leukemia. Recently, MRD has become a new clinical index to evaluate the therapeutic results and prognosis. Although there have been some studies to investigate the relationship between MRD monitoring and clinical prognosis in children with acute lymphoblastic leukemia, mostly focusing on patients with acute B lymphoblastic leukemia (B lineage ALL), whereas there are only a few studies focusing on patients with acute T lymphoblastic leukemia (T-ALL). The TDT/D3 or CyCD3 had been commonly used to detect T-ALL MRD in domestic and foreign studies. However, we found that TDT/CD3 or CyCD3 had low expression rate, whereas CD2 had high expression rate in the marrow of childhood T-ALL patients. In this study, we monitored MRD in T-ALL patients by CD2+CD56-CD45+CD3-immunophenotype, investigate its validity, sensitivity and specificity, and evaluate the corresponding clinical values.Methods:From Jan 2002 through Dec 2009,67 childhood T-ALL cases were enrolled into the study. A T-ALL associated immunophenotype including CD2+CD56-CD45+ CD3-was tested for its effectiveness on monitoring the minimal residual diseases (MRD) in childhood T-ALL using four-color flow cytometry. MRD in T-ALL patients was monitored on six timepoints including 3 weeks,5 weeks,3 months,6 months and 12 months after treatment.54 patients were received long term follow-up with average follow-up time of 17.5 months (3-76 month). We compared the 3-year DFS rate in groups with different levels of MRD in 22 T-ALL patients by analyzing the survival and prognosis of patients. Given the values of CD2+CD56-CD45+CD3-measured in the bone marrow samples taken from 31 B-ALL patients as the baseline control, we investigate the sensitivity and specificity of CD2+CD56-CD45+CD3-immunophenotype in the monitoring of MRD in T-ALL patients.Results:Of the 67 patients treated,63 (94.02%) achieved complete remission(CR) at the end of induction chemotherapy. Kaplan Meier studies showed the 3 year OS rate of 48.2±7.3%and the 3 year DFS rate of 45.9±7.6%, respectively. Of the 67 patients 22 were monitored the minimal residual diseases (MRD)by the CD2+ CD3-CD56-CD4.5+immunophenotype,5 weeks after treatment,3-year DFS rate (33.3±25.5%, n=16) in patients with MRD levels greater than 10-3 was significantly lower than that (53.1±14.1%, n=6) with MRD less than 10'3 (P=0.05).5 weeks after treatment, the 3-year DFS rate(40.5±12.7%) in patients (n=20) with MRD levels greater than 10-4 was also significantly lower than those (50±35.4%,n=2) with MRD less than 10-4 (P=0.016).12 months after treatment,3-year DFS rate in patients (0%,n=4) with MRD levels greater than 10-2 was significantly lower than that (63±17.7%,n=10) with MRD less than 10-2 (P=0.018). No significant difference in 3-year DFS rates between groups with different MRD levels in other follow-up time points. The events detected in patients with T-ALL[median:182x10-5 (range:20～47490 X 10"5), (n=79)] were significantly higher than those[median:98x 10-5 (range:6～995 X10-5) (n=31)] detected in patients with B lineage ALL (p=0.03). When CD2+CD56-CD45+CD3- employed as antibody combination to monitor MRD, the results show the sensitivity of 46.8% and the specificity of 90.3% when the value of MRD is 250×10-5.Conclusion:(1) 5-year OS rate is 48.2±7.3%,5-year DFS rate is 45.9±7.63%in T-ALL patients.(2) When CD2+CD56-CD45+CD3-employed as antibody combination to monitor MRD 3-year DFS rates in patients with MRD greater than 10-3 are significantly lower than those with MRD less than 10"3 on the 5th week after treatment.3-year DFS rates in patients with MRD greater than 10-2 are significantly lower than those with MRD less than 10-2 on the 12nd month after treatment.(3) CD2+CD56-CD45+CD3-is an effective antibody combination to monitor MRD in T-ALL patients. T leukemia cell should be considered when the value of MRD is greater than 250 x 10-5 in T-ALL patients.