Minimal Residual Disease (MRD) and Risk-Oriented Therapy in Adult Acute Lymphoblastic Leukemia (ALL).

In adult ALL standard prognostic models do not predict relapse with great accuracy, which implies under-/over-exposure to a given therapy, especially transplants. A study is exploiting MRD as “best” predictive factor and decisional aid for therapy in unselected patients. Adults with ALL underwent induction-consolidation with IDR/V/ASP/P/CY (cycles 1–3,5,6,8), HD-MTX/Ara-C (cycles 4,7), and CNS prophylaxis. Imatinib was added in Ph+ ALL. For MRD, 3 marrow samples were taken before cycles 4, 6, 8, to be analyzed by PCR/RQ-PCR with case-specific probe(s) targeting fusion genes or Ig-H/TCR rearrangements. MRD negativity was defined as negative/low-positive ( 100 and adverse cytogenetics predicted to some extent an MRD+ result (P=0.05), while MRD negativity was always confirmed as early as TP1 (week 10). Only 6 MRD− cases relapsed (17%), 1 with a new clone and 4 with suboptimal MRD study, compared to 20/44 (45.5%) MRD+ (P=0.000). DFS at 4 years was 76% in MRD− vs. 24% in MRD+ vs. 54% in the unknown MRD group. In multivariate analysis MRD was stronly predictive for relapse (RR 5.51, P=0.000) followed by a WBC count >30 (RR 3.64, P=0.001), the latter effect being almost exclusively seen in MRD+ patients. As regards MRD monitoring, conversion rate from MRD+ to MRD− was similar after SCT and “hypercycles” in the few cases evaluable (4/6 in each group), with a strong correlation in every prognostic/treatment group between overt relapse and prior positive MRD test (2/35 MRD− vs. 9/20 MRD+; P=0.000). MRD is an invaluable prognostic tool for risk-oriented trials. Both an early analysis and monitoring support optimal therapeutic choices (with some reported exceptions), identify patients at greatest risk of relapse, and could allow comparative trials testing specific treatment elements in different ALL subsets.