Minimal residual disease before and after transplantation for childhood acute lymphoblastic leukaemia: is there any room for intervention?

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.     

Relationship between HLA‐DP supertype and survival in childhood acute lymphoblastic leukaemia: evidence for selective loss of immunological control of residual disease?

We recently reported that two of six HLA-DP supertypes (DP1–4, 6, 8) were associated with susceptibility (DP2) and resistance (DP1) to childhood acute lymphoblastic leukaemia (ALL). To determine whether DP supertypes are associated with childhood ALL prognosis, we compared treatment outcomes in a cohort ( n  = 798) of DPB1 -typed ALL cases in the UK Medical Research Council UKALL XI trial. No differences in clinical characteristics and outcome between DPB1 -typed and untyped ( n  = 1292) cases suggest no selection bias. Event-free survival (EFS) rates in patients with DP1 and DP3 supertypes were significantly worse than in patients with DP2, DP4, DP6 and DP8 [10-year EFS: 55%; 95% confidence interval (CI) = 49–61%; compared with 64% (61–68%), P  = 0·006]. Ten-year EFS in DP1/DP3 heterozygous patients [30% (2–58%)] was significantly worse than in patients with DP1, DP3 or neither allele [56% (50–62%); P  = 0·02]. Lack of evidence that DP1 or DP3 are associated with known prognostic factors leads us to suggest that these two supertypes exert an independent effect on prognosis. This may involve abrogation of DP1/3-restricted T-cell control of residual disease due to selective effects of chemotherapy. Further studies of HLA supertypes in relation to outcome in recent childhood ALL trials may resolve this question.     

High prevalence of Plamodium malariae infections in a Brazilian Amazon endemic area (Apiacás-Mato Grosso State) as detected by polymerase chain reaction

Plasmodium malariae is commonly confounded with Plasmodium vivax at the microscopic examination of thick blood smear. In the present study, we used a nested PCR assay to amplify a species-specific sequence of the 18S SSU rRNA gene of Plasmodium in blood samples of 497 individuals living in an endemic region of the Brazilian Amazon basin. We have found that, while the microscopic examination of thick blood smears showed a P. malariae prevalence of 1.2% (6 out of 497), the nested PCR revealed 11.9% (59 out of 497) of positive cases for this specie. These results point to the need of the development or use of a more accurate diagnosis method to distinguish between P. malariae and P. vivax, which is particularly important in view of the fact that the choice of drug for the antimalarial therapy depends on the parasite species.     

Predictive role of minimal residual disease and log clearance in acute myeloid leukemia: a comparison between multiparameter flow cytometry and Wilm’s tumor 1 levels

In acute myeloid leukemia (AML), the detection of minimal residual disease (MRD) as well as the degree of log clearance similarly identifies patients with poor prognosis. No comparison was provided between the two approaches in order to identify the best one to monitor follow-up patients. In this study, MRD and clearance were assessed by both multiparameter flow cytometry (MFC) and WT1 expression at different time points on 45 AML patients achieving complete remission. Our results by WT1 expression showed that log clearance lower than 1.96 after induction predicted the recurrence better than MRD higher than 77.0 copies WT1/10⁴ ABL. Conversely, on MFC, MRD higher than 0.2 % after consolidation was more predictive than log clearance below 2.64. At univariate and multivariate analysis, positive MRD values and log clearance below the optimal cutoffs were associated with a shorter disease-free survival (DFS). At the univariate analysis, positive MRD values were also associated with overall survival (OS). Therefore, post-induction log clearance by WT1 and post-consolidation MRD by MFC represented the most informative approaches to identify the relapse. At the optimal timing of assessment, positive MRD and log-clearance values lower than calculated thresholds similarly predicted an adverse prognosis in AML.