Different molecular levels of post-induction minimal residual disease may predict hematopoietic stem cell transplantation outcome in adult Philadelphia-negative acute lymphoblastic leukemia

Minimal residual disease (MRD) is a powerful indicator of the risk of relapse in adult acute lymphoblastic leukemia (ALL), used for the risk-oriented application of allogeneic stem cell transplantation (allo-SCT) in patients who remain MRD-positive (MRDþ ) following induction and consolidation chemotherapy. Although allo-SCT is less effective in MRDþ state, correlations between post-induction quantitative MRD ranges and SCT outcome have not been clearly defined. This would allow an early identification of MRDþ patients at higher risk of posttransplantation failure, for whom a closer MRD monitoring and other therapies could be recommended before and after alloSCT. The quantitative MRD to SCT relationship is examined in the final update of a prospective Northern Italy Leukemia Group (NILG) trial. In this study, post-induction MRD positivity was the sole decisive factor for the allocation to allo-SCT of adult patients with Philadelphia chromosome-negative (Ph ) ALL. NILG trial ALL 09/00 was conducted between 2000 and 2006 (Supplementary Figure S1). Details of molecular MRD analysis, risk classification and application of risk/MRD-oriented therapy in the first 280 patients (192 with Ph ALL) were published. For MRD analysis, one or two patient-specific molecular probe(s) were used, with a sensitivity of at least 10 , and the bone marrow was examined at weeks 10, 16 and 22, that is, after 3, 5 and 7 treatment blocks, respectively. Patients with MRD X10 4 at time point 2 (TP2, week 16) and/or with any detectable positivity at TP3 (week 22) constituted the MRDþ group and were eligible for alloSCT from human leukocyte antigen-matched related or unrelated donors. To avoid treatment delay, the donor search was initiated at complete remission (CR). No specific conditioning regimen was recommended. MRDþ patients without donor received highdose treatment (‘hypercycles’) with autologous stem cell rescue (auto-SCT), followed by maintenance. MRD-negative (MRD ) patients were to receive standard maintenance therapy. The only exception to this design was t(4;11)þ ALL, always eligible for alloSCT. The primary objective of the current analysis was to determine whether different post-induction MRD levels were predictive of posttransplantation outcome in MRDþ patients. To this end the highest quantitative MRD value from all three study TPs qualified individual patients for inclusion into a given MRD subset. Patients with all negative MRD determinations were assigned to the complete molecular remission (CMR) group. The remaining patients formed the molecularly responsive (MR) subset, with all MRD signals below 10 , and two molecularly resistant groups with one or more MRD determinations ranging from 10 4 to o10 3 (MR1) and X10 3 (MR2). Survival, disease-free survival (DFS) and relapse incidence (RI) were compared by MRD category in unselected patients and in those allocated to SCT in keeping with study design. Kaplan–Meier graphs, the log-rank and two-tailed chi-squared tests were used as appropriate for data reporting and comparative analyses among patient groups. The study enrolled 304 patients with Ph ALL (Table 1). Twohundred fifty-eight entered CR (85%). Sensitive molecular probe(s) were available for 200 CR patients (77.5%). Of these, 141 completed consolidation (70.5%) and 59 did not because of early SCT (n1⁄4 13), relapse (n1⁄4 41) and treatment toxicity (n1⁄4 5). Onehundred thirty-six of 141 evaluable patients completed the MRD study: 76 were classified MRD (56%) and 60 MRDþ (44%) (Supplementary Figure S2). Forty-three of the 60 MRDþ patients (71.6%) underwent SCT as per protocol design (26 allo-SCT, 17 ‘hypercycles’ with auto-SCT) after a median of 2.2 months from the last consolidation cycle (range 0.5–15.4 months). Allo-SCT was from unrelated and sibling donors in 14 and 12 patients; and the stem cell source was bone marrow in 11, peripheral blood in 13 and cord blood in 2 patients, respectively. Long-term study results are available in Supplementary Figure S3, including outcomes according to clinical risk class. According to the current analysis, there were 64 CMR patients (47%), 21 MR patients (15.5%), 17MR1 patients (12.5%) and 34 MR2 patients (25%). Notably, these were all distinct subjects, summing up to the total of 136 MRDevaluable cases, with no overlapping across different MRD subgroups. Therefore, all CMR-negative patients were MRD at all evaluable TPs, and as such were excluded from allo-SCT by design (Table 1). Apart from that, a proportion of the remaining patients could express lower MRD levels at some TP, a finding that was progressively less frequent from MR1 to MR2 patients (o10% CMR and 20% MR at another TP) and affected mainly different individuals, suggesting consistency of the MRD risk reclassification, as already indicated in this clinical study by the strong statistical correlation between MRD TP1 and TP2/3 results. After a minimum observation of 4 years and a maximum close to 13.5 years, estimated 6-year survival and DFS rates ranged from 73% and 64% in CMR patients to 24% and 15% in MR2 patients, respectively, mostly in relation with an increasing RI (Figures 1a–c, all Ps o0.0001), except for CMR and MR groups. Although 6-year DFS was improved following allo-SCT in MRDþ patients (42% versus 18% with auto-SCT, P1⁄4 0.035; Supplementary Figure S4), posttransplantation outcome was sensibly affected by postinduction MRD level (Figures 1d–f). Notably, SCT results were superimposable in MR and MR1 groups (not shown), with a cumulative survival and DFS rate of 46% and 50% (n1⁄4 24) compared with 16% and 26% in MR2 patients (n1⁄4 19) (P1⁄4 0.02 and P1⁄4 0.03), respectively. RI was 43% compared with 69% (P1⁄4 0.16). The best overall results were observed after allo-SCT in MR/MR1 patients, with cumulative survival and DFS rates of 60% (n1⁄4 15) compared with 27 and 18% in MR2 subset (n1⁄4 11) (P1⁄4 0.08 and 0.05), and a RI of 23% compared with 64% (P1⁄4 0.09) (Figures 1g–i). This very long-term update of a prospective trial included 136 MRD-evaluable patients with Ph ALL, extending our prior observation on 112 patients with both Ph and Phþ disease. The dominant prognostic role of MRD was confirmed even after Citation: Blood Cancer Journal (2014) 4, e225; doi:10.1038/bcj.2014.48 & 2014 Macmillan Publishers Limited All rights reserved 2044-5385/14