Improved Prognosis of Children and Adolescents with Acute Lymphoblastic Leukemia (ALL) and Very-High Minimal Residual Disease (MRD) and the End of Induction therapy (EOI)? Preliminary Results of the FRALLE 2000 Protocol

MRD at EOI is a powerful prognostic indicator in childhood ALL. Cave et al (N Engl J Med 1998) and van Dongen et al (Lancet 1998) have shown that a very high EOI-MRD (≥ 10⁻²) is associated to a dismal prognosis (5y EFS: 15–20%). From December 2000 to July 2007 1496 children and adolescents (1–20 years, no Ph+) have been included in the ongoing FRALLE 2000 protocol. EOI-MRD at D35–42 was measured by competitive PCR of Ig/TCR markers and Gene Scan analysis and was decisional for further treatment intensification if ≥ 10⁻². 1017 pts are fully evaluable (monitored data, no induction failure, evaluable EOI-MRD, outcome). MFU is 36 months. Three risk-groups have been defined. A (n=620): NCI standard risk BCP-ALL, B (n=265): NCI high risk-ALL, T (n=132): T-cell ALL. Fifty-eight pts (5.7%) have a very high EOI-MRD, 2.6% in group A, 9% in group B, 14% in group T. These pts were more likely than pts with lower MRD (< 10⁻²) to have a D8 poor prednisone response (PPR) (31% vs 10%, p <.001), a slow marrow response (D21M2 or M3, 24% vs 5%, p <.001) or both (22% vs 1.5%, p <.001). A very high MRD only (no high-risk cytogenetic features, no D8 PPR, no D21 M2/M3 marrow) was found in 33 out the 58 pts (57%), i.e. 3% of all pts. A group pts (n=16) with very high EOI-MRD received a 3 block-consolidation plus a double delayed intensification (DDI) while B or T group pts received a 3 block-consolidation plus DDI (24 pts) or HSCT (18 pts). 5y EFS and OS where 50±10% and 74±7% respectively for the 58 pts. A similar 5 y EFS was found for pts with BCP-ALL or T-cell ALL with very high MRD (50±12% and 48±12%, respectively). There is a trend for a better EFS for pts with very high EOI-MRD only compared to those with other associated high-risk features (60±11% vs 39±11%, p=.10).

Conclusion: these results compare favourably with published results suggesting that intensification of therapy may improve the outcome of pts with bad early response to initial chemotherapy.