Minimal Residual Disease (MRD) at the End of Induction (EOI) after a Three or Four-Drug Induction Regimen for Childhood Standard-Risk B-Cell Precursor Acute Lymphoblastic Leukemia (SR-BCP-ALL): Interim Results of the FRALLE 2000-A Protocol.

From Dec 2000 to Dec 2003, 390 children with SR-BCP-ALL (age: 1–9, WBC<50 G/L, CNS-, no MLL-R, no BCR-ABL) were included in the FRALLE 2000 -A protocol. Induction regimen is: prednisone prephase for 7 days (60 mg/m2/d) +IT MTX, dexamethasone 6 mg/m2 (D8–D28), vincristine 1.5mg/m2(D8, D15, D22, D29), L-asparaginase 6000 U/m2 (9 infusions). Good marrow responders at D21(M1 pts) are randomized to receive or not daunorubicin (DNR) 40 mg /m2 at D22 and D29. D21 M2/M3 pts are not randomized and given DNR. MRD at EOI is determined by DNA-based PCR for Ig/TCR rearrangements. Two methods are used for quantification (competitive PCR with GeneScan analysis -sensitivity: 0.5x 10-3-, RQ-PCR with clone-specific probes- sensitivity range: 10-3-10-5). EOI MRD data are evaluable for 343 pts with D21 M1 response (DNR+= 169/ DNR−= 173/ not randomized = 1) and for 20 pts M2M3 ; two pts died during induction and thus are NE. MFU of these 365pts is 22m (3–39). Median age is 4.1y(1.1–9.9), median WBC is 7.47 G/L (.9–47). MRD results are classified for analysis either in three categories (negative, weakly +ve if < 10−3, highly positive if > 10−3, or according to the exact level of positivity.

Results: 1) 15% (51/336 pts) of the SR-BCP ALL have a detectable MRD at EOI 2) As expected, whatever the threshold, pts with D21 M2/M3 marrow are more likely to have a detectable MRD (p=.0017). But 43/316 M1 pts (14%) have a highly +ve (n=19;6%) or weakly +ve MRD (n=24 ; 8%). Surprisingly, only 1 out 20 M2M3 pts had a MRD > 10−2 while it is the case for 8 out 316 M1 pts (p=NS). If only pts receiving DNR are considered (DNR+ M1 pts and all M2/M3 pts), again pts with D21 M2/M3 marrow are more likely to have a detectable MRD (p=.0015). 3) If we compare the MRD levels in the 2 arms (DNR+ve or neg) in the 315/343 M1 pts evaluable for MRD: 136 pts in each arm had no detectable MRD; 16 and 8 have a weak positivity in the DNR− and DNR+ arm respectively while 10 and 9 have a weak positivity in the DNR− and DNR+ arm respectively: p= .29). If the exact level is considered, this absence of difference remains at all levels considered.

Conclusions: 15% of the SR-BCP ALL have a detectable MRD at EOI after a three or four-drug induction. D21 M2/M3 pts are more likely than M1 pts to have a detectable MRD at EOI but 14% of the D21 M1 pts have a high (> 10−3) or very high MRD (> 10−2) which confirms the added value of MRD detection to classical morphology. The MRD level at EOI is not different in SR-BCP-ALL after a three or four-drug induction regimen. This is of paramount importance since EOI MRD is a surrogate marker for probability of relapse.