In Adult Acute Lymphoblastic Leukemia (ALL) Different Minimal Residual Disease (MRD) Levels Predict Clinical Outcome in All Patients and Response to Allogeneic/Autologous Transplantation in MRD-Positive Patients.

Abstract 2493

MRD is a powerful prognostic tool, increasingly adopted in adult ALL for a risk-oriented application of stem cell transplantation (SCT) in MRD-positive (MRD^pos) patients. This policy gives the opportunity to assess the therapeutic value of allogeneic (or autologous) SCT in MRD^pos patients, who are very unlikely to be cured by chemotherapy. In this study we reanalyze the long-term results of a prospective Northern Italy Leukemia Group trial (Bassan et al, Blood 2009;113:4153), aiming to determine which MRD levels were predictive of a better SCT outcome in MRD^pospatients after induction/consolidation therapy.

MRD was evaluated molecularly using one or two patient-specific probe(s) with sensitivity of at least 10⁻⁴. In remission patients, bone marrow MRD was assessed after chemotherapy courses no. 3 (week 10), 4 (week 16) and 6 (week 22). In the original risk model, MRD^pos was defined by a level of 10⁻⁴ or greater at week 16 and/or any positivity at week 22. For this analysis, MRD results from all three time-points were pooled, and the highest value registered in individual patients was used to identify the MRD-negative group (always MRD^neg) and three other subsets characterized by increasing levels of residual leukemia (less than 10⁻⁴ [MRD^pos1], 10⁻⁴ and greater but less than 10⁻³ [MRD^pos2], 10⁻³ and greater [MRD^pos3]. Survival, disease-free survival (DFS), and relapse incidence were assessed and compared among these MRD groups, as well as outcome following SCT in MRD^possubsets, and this in accordance with protocol design i.e. in patients having SCT at end of consolidation phase after completion of the MRD study.

Three-hundred and four patients with Ph- ALL were treated between 2000–2006 (median age 35 years, range 16–68; male gender 57%), of whom 258 (85%) entered complete remission. One or more sensitive probe(s)were available for 200 responsive patients (77.5%), of whom 141 completed consolidation and 59 did not because of elective early SCT in t(4;11)+ ALL (n=13), relapse (n=41) and toxicity (n=5). Of 141 evaluable patients, 136 completed the MRD study through weeks 10–22 (standard risk: 61 B-lineage and 14 T-lineage; high-risk: 41 B and 17 T; unspecified 3). Altogether, 64 patients were reclassified MRD^neg (47%), 21 MRD^pos1 (15.5%), 17 MRD^pos2 (12.5%) and 34 MRD^pos3 (25%). With a minimum observation time of 4 years and a maximum close to 12 years, estimated 6-year survival, DFS and relapse rates were 72.5%, 64% and 36% in MRD^neg, 56%, 57% and 32% in MRD^pos1, 48.5%, 46% and 50% in MRD^pos2 and 23.5%, 15% and 76% in MRD^pos3 cohorts, respectively (all P values <0.0001). Of 72 MRD^pos patients, 44 (61%) underwent SCT as per protocol design (allogeneic 26, autologous 18). Although 6-year DFS rate was improved after allogeneic SCT (42% vs 20% with autologous SCT, P=0.09), the most influential factor for posttransplantation outcome was MRD level (DFS 48% in MRD^pos1–2 group [n=25] vs 16% in MRD^pos3 group [n19], P=0.025), and the best overall result was obtained with allogeneic SCT in MRD^pos1–2 group (DFS 60% [n=15] vs 18% in MRD^pos3 group [n=11], P=0.08).

In this study different MRD levels measured at weeks 10–22 were associated with a progressively worse outcome in the four patient subsets defined by the highest individual value at three study time-points. However, about one half of MRD^pos1–2 patients could be salvaged by SCT, and even more with allogeneic rather than autologous SCT. Because of the very poor SCT results in MRD^pos3 group, patients with MRD levels of 10⁻³ and greater should receive further therapy and not proceed to SCT until the MRD signal is below the 10⁻³ cutoff.