Minimal Residual Disease in High and Very High Risk ALL (HR/VHR-ALL) at the End of Induction (EOI) in FRALLE 2000 B and T Protocols.

Abstract

From January 2000 to July 2006, 580 BCR-ABL negative patients with HR/VHR-ALL (200 T-ALL and 380 BCP-ALL (age≥10 or WBC≥50 or CNS+ or MLL-R) were included in the FRALLE 2000-BT trials. Induction regimen is prednisone (PRED) prephase + IT MTX, VCR, L-Aspa, DNR 120mg/m2 cumulated dose or DNR 160mg/m2 + cyclophosphamide 1g/m2 (T-ALL and D21 M2M3 marrow or MLL-R BCP-ALL). MRD at EOI is quantitatively determined by DNA-based PCR for Ig/TCR rearrangements either competitive PCR with GeneScan analysis or RQ-PCR with clone specific primers (sensitivity ranges 0.5×10−3–10−3, and 10−3–10−5, respectively). MRD status at EOI are available for 425 out of 552 CR (77%). MRD results are reported as negative, positive <10−3, highly positive (10−3≤MRD<10−2), very highly positive (≥10−2). Patients with EOI MRD ≥10−2 were to receive an intensified treatment.Results:1.30% (89/293) of HR/VHR BCP-ALL and 34% (45/132) T-ALL have detectable MRD at EOI, NS. A high or very high MRD is encountered in 16% (47/293) of BCP-ALL and 21% (27/132) of T-ALL (NS).2.Surprisingly 57% (20/35) of the pts with BCP-ALL and D8 poor PRED response (PPR) and 71% (36/51) of the pts with D8 PPR T-ALL have a negative or slightly positive MRD (<10−3) at EOI, NS. 30% (7/23) of the pts with D21 M2M3 BCP-ALL and 46% (6/13) of the pts with D21 M2M3 T-ALL have also a negative or slightly positive MRD (<10−3) at EOI. By contrast, 11% of good early responders (D8 good PRED response and D21 M1) with BCP-ALL or T-ALL (27/245 and 11/74, respectively) have a high or very high positive MRD.3.Overall, 20 out of 449 (4.5%) HR/VHR pts in CR have received an intensified treatment due to a very high MRD only.4.3y DFS for pts with a highly positive or very highly positive MRD are 65±7% (BCP-ALL) and 64±9% (T-ALL), NS. 3y DFS for pts with a negative or slightly positive MRD (<10−3) are 94±2% (BCP-ALL) and 87±4% (T-ALL), p=.04.5.There is a statistically significant difference in term of DFS between pts with MRD≥10−3 and MRD < 10−3, p=.001 and p =.05 for BCP- and T-ALL, respectively.Conclusions:1.the incidence of high and very high MRD at EOI is identical in children with HR/VHR-BCP- and T-ALL.2.High and very high MRD levels are found in good early responders defined by morphology. Conversely, excellent molecular responses can be found in bad early responders.3.High or very high MRD values are associated to a comparable prognosis between BCP- and T-ALLs.