Abstract

Slow early response indicates poor prognosis in childhood ALL. We aimed to evaluate if post-induction MRD levels had different prognostic impact in precursor B-cell (pB) or T-cell ALL. From 07/2000 to 06/2006, 4730 pts with ALL were enrolled in trial AIEOP-BFM ALL 2000. MRD levels were centrally measured by real-time quantitative polymerase chain reaction using the identification of clone-specific T-cell receptor and immunoglobulin gene rearrangements. MRD study time-points (TP) were treatment day 33 (TP1, end of induction) and day 78 (TP2, after consolidation). To define MRD negativity, two markers with a sensitivity of at least 10−4 were required. Patients were treated with BFM induction (protocol I-A), consolidation (I-B), extra-compartment/intensified consolidation (HD-MTX in non-high-risk patients, pulses in high-risk patients), reinduction, and maintenance. MRD analysis at one or two time points suceeded in 3707 pts; the immunophenotype was available from 3636 pts. MRD levels and corresponding estimated 5-year event-free survival (5y-pEFS) comparing pB- and T-ALL are shown in Table 1 (3yrs median follow-up). MRD response in T-ALL was slower than in pB-ALL resulting in a higher percentage of pts with high MRD load in T-ALL. In pB-ALL as well as T-ALL, high MRD levels at TP2 were well predictive to identify pts with poor prognosis. For prediction of good prognostic subgroups, TP1 was more appropriate identifying a subgroup with excellent 5y-pEFS of >90% in case of MRD negativity. Specificity of TP1 was poor in T-ALL if the pB-ALL criteria of MRD negativity were applied. If MRD low positive and MRD negative T-ALL pts were combined, the discrimination was as good as in pB-ALL. The optimal choice of MRD evaluation time points depends on biological factors and treatment, and is most relevant for MRD-based risk stratification.

Table 1
pB-ALLT-ALL
n%5y-pEFS % (SE)n%5y-pEFS % (SE)
all 3177 100% 82.3 (1.0) 459 100% 77.2 (2.2) 
MRD TP1        
    neg 1399 44.1 92.5 (1.0) 75 16.4 94.3 (2.8) 
    10E-4/−5 1122 35.4 81.9 (1.7) 116 25.4 91.2 (2.8) 
    10E-3 393 12.4 66.4 (3.5) 110 24.1 75.3 (4.6) 
    ≥10E-2 256 8.1 53.2 (4.3) 156 34.1 59.8 (4.5) 
MRD TP2        
    neg 2464 77.6 87.7 (1.0) 220 47.9 91.9 (2.0) 
    10E-4/−5 523 16.5 68.9 (2.9) 143 31.2 76.6 (3.9) 
    10E-3 107 3.4 56.3 (6.5) 58 12.6 50.2 (8.1) 
    ≥10E-2 82 2.6 38.0 (7.3) 38 8.3 33.2 (8.3) 
pB-ALLT-ALL
n%5y-pEFS % (SE)n%5y-pEFS % (SE)
all 3177 100% 82.3 (1.0) 459 100% 77.2 (2.2) 
MRD TP1        
    neg 1399 44.1 92.5 (1.0) 75 16.4 94.3 (2.8) 
    10E-4/−5 1122 35.4 81.9 (1.7) 116 25.4 91.2 (2.8) 
    10E-3 393 12.4 66.4 (3.5) 110 24.1 75.3 (4.6) 
    ≥10E-2 256 8.1 53.2 (4.3) 156 34.1 59.8 (4.5) 
MRD TP2        
    neg 2464 77.6 87.7 (1.0) 220 47.9 91.9 (2.0) 
    10E-4/−5 523 16.5 68.9 (2.9) 143 31.2 76.6 (3.9) 
    10E-3 107 3.4 56.3 (6.5) 58 12.6 50.2 (8.1) 
    ≥10E-2 82 2.6 38.0 (7.3) 38 8.3 33.2 (8.3) 

Author notes

Disclosure:Research Funding: This work was supported by the Deutsche Krebshilfe, Bonn.