Treatment of High-Risk (HR) Philadelphia Chromosome-Negative (Ph-) Adult Acute Lymphoblastic Leukemia (ALL) According to Classical Risk Factors and Minimal Residual Disease (MRD). Interim Results of the PETHEMA ALL-AR-03 Trial.

Current therapeutic protocols for adult ALL consider MRD together with the classical risk factors (age, WBC count, immunophenotype, cytogenetics and speed in response to therapy) for treatment decisions. The aim of the prospective study ALL-AR-03 from the Spanish PETHEMA Group was to evaluate the feasibility of sequential MRD detection and the response to a differentiated therapy according to MRD levels (assessed by cytofluorometry at the end of induction and consolidation therapy) in HR Ph- adult ALL pts. HR ALL included one or more of the following: age 30–60 yr, WBC count >25×10⁹/L and 11q23 or MLL rearrangements. Induction therapy included VCR, DNR and PDN for 4 wk. In pts with slow cytologic response (≥ 10% blasts in BM assessed on d14) intensified induction with HD-ARA-C and mitoxantrone was administered. Early consolidation therapy included 3 cycles with rotating cytotoxic drugs including HD-MTX, HD-ARA-C and HD-ASP. Pts. with slow cytologic response on d14 or MRD level >0.05% after consolidation were assigned to allogeneic SCT (related or unrelated) and those with standard cytologic response on d14 and MRD level <0.05% after consolidation received 3 additional cycles of delayed consolidation (identical to those of early consolidation) followed by maintenance therapy up to 2yr in CR.

On May 2006,119 patients were evaluable (mean (SD) age 37(14) yr, 64 males, 75 precursor B-ALL, 44 T-ALL, WBC 67(87) ×10⁹/L). Induction death 7(%), resistance 20 (%), CR 93 (78%) and MRD<0.1% in 64% were observed. Early consolidation was completed in 63 patients. MRD<0.05% was observed in 77% at the end of consolidation. Allo-SCT was performed in 20 pts (TRM 6, relapse 1, CCR 13) and delayed consolidation and maintenance in 38 (toxic death 2, relapse 7, CCR 29). Two-yr DFS for the whole series was 35±13%. No significant differences were observed between pts receiving chemotherapy or SCT. Slow cytologic response was associated with a lower CR. No initial variable was associated with a higher probability of MRD negativity after induction or consolidation. Neither the negativity of MRD nor the pattern of clearance of MRD were associated with a better DFS. These preliminary results suggest that in HR adult ALL pts with adequate response to induction and adequate clearance of MDR the results of late consolidation and maintenance are not hampered by avoiding allo-SCT.