Prognostic Impact of MRD in the Bone Marrow of Children at First Isolated Extramedullary Relapse of ALL.

Sensitive quantification of minimal residual disease (MRD) is an established method to assess treatment response in patients with bone marrow (BM) relapse of acute lymphoblastic leukemia (ALL). We have investigated, whether MRD can also determine the tumor load in the BM at cytologically isolated extramedullary (IEM) relapse and can consequently be associated with prognosis in this subgroup.

The extent of sub-cytological BM involvement at relapse diagnosis has been quantified in 53 patients with first relapse in the central nervous system (n=36), and in the testes (n=17) treated in Germany (n=33; 09′94 - 12′03) and Czech Republic (n=9; 10′01 - 04′04), or in France (n=11; 12′90 - 11′03) according to protocols ALL-REZ BFM, or to COOPRALL, respectively. MRD has been sensitively assessed by real-time-quantitative PCR using T-cell-receptor and immunoglobulin gene-rearrangements detected in the extramedullary or initial BM material. Stability of initial clonal markers was confirmed. A MRD-level of <10⁻⁴ was measured in 22 patients. Thirty-one patients showed a positive MRD-status: <10⁻³ - =/>10⁻⁴: n=9; <10⁻² - =/>10⁻³: n=12; and >10⁻²: n=10. MRD-status was not associated with the relevant prognostic parameters sex, time-point of relapse, immunophenotype, and site, whereas it was associated with age at initial diagnosis (p=.057), and BCR/ABL translocation (p=.011). The probability of event-free survival (EFS) at 5 years was .55+/−.15 and the rate of subsequent relapses was 18% in patients without MRD detection at a level of 10⁻⁴ compared to .16+/−.10 and 52% in those with =/>10⁻⁴ (p(log-rank)=.16 and p=.028 respectively).

Our study reveals a large range of subcytological BM involvement in patients with IEM relapses of ALL. A relation to single prognostic factors and to the relapse rate can be found, but not to EFS.

The study was kindly supported by ‘Deutsche Kinderkrebsstiftung’, Germany, by ‘Kompetenznetz der Paediatrischen Onkologie’, BMBF, Germany; by ‘programme hospitalier de recherche clinique’ (PHRC 2002), France and by GAUK 62/2004, Czech Republic.