title: Minimal residual disease before and after transplantation for childhood acute lymphoblastic leukaemia: is there any room for intervention?
abstract: Eighty-two children and adolescents who underwent allogeneic transplantation for acute lymphoblastic leukaemia in remission (period 2001-2011, median follow-up 4·9 years) had been assessed for minimal residual disease (MRD) by real-time quantitative polymerase chain reaction before and at 1, 3, 6, 9 and 12 months after transplantation. Five-year event-free survival (EFS) and cumulative incidence of relapse were 77·7% [standard error (SE) 5·7] and 11·4% (SE 4·4), respectively, for patients with pre-transplant MRD <1 × 10(-4) (68%), versus 30·8% (SE 9·1; P < 0·001) and 61·5% (SE 9·5; P < 0·001), respectively, for those with MRD ≥1 × 10(-4) (32%). Pre-transplant MRD ≥1 × 10(-4) was associated with a 9·2-fold risk of relapse [95% confidence interval (CI) 3·54-23·88; P < 0·001] compared with patients with MRD <1 × 10(-4). Patients who received additional chemotherapy pre-transplant to reduce MRD had a fivefold reduction of risk of failure (hazard ratio 0·19, CI 0·05-0·70, P = 0·01). Patients who experienced MRD positivity post-transplant did not necessarily relapse (5-year EFS 40·3%, SE 9·3), but had a 2·5-fold risk of failure (CI 1·05-5·75; P = 0·04) if any MRD was detected in the first 100 d, which increased to 7·8-fold (CI 2·2-27·78; P = 0·002) if detected after 6 months. Anticipated immunosuppression-tapering according to MRD may have improved outcome, nevertheless all patients with post-transplant MRD ≥1 × 10(-3) ultimately relapsed, regardless of immunosuppression discontinuation or donor-lymphocyte-infusion. In conclusion, MRD before transplantation had the strongest impact on relapse and MRD positivity after transplantation, mostly if detected early and at low levels, did not necessarily imply relapse. Additional intensified chemotherapy and modulation of immunosuppression may reduce relapse risk and improve ultimate outcome.
authors.affiliation: Clinica Pediatrica, Università degli Studi di Milano-Bicocca, Ospedale San Gerardo, Monza, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Balduzzi
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Maio
authors.forename: Daniela
authors.initials: D
authors.lastname: Silvestri
authors.forename: Simona
authors.initials: S
authors.lastname: Songia
authors.forename: Sonia
authors.initials: S
authors.lastname: Bonanomi
authors.forename: Attilio
authors.initials: A
authors.lastname: Rovelli
authors.forename: Valentino
authors.initials: V
authors.lastname: Conter
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: Maria G
authors.initials: MG
authors.lastname: Valsecchi
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007223:Infant; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology* / Q000601:surgery*; D011379:Prognosis; D016896:Treatment Outcome
keywords: acute lymphoblastic leukaemia; allogeneic transplantation; childhood; minimal residual disease; relapse