More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling

Abstract

Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.

Graphical abstract

Figure 1.

Influence on relapse of MRD_pre-HCTand MRD_post-HCT. HRs for relapse from a Cox regression model (A) considering only pre-HCT MRD or considering only post-HCT MRD treated as time-dependent covariate (B) with both variables MRD_pre-HCT as a fixed covariate and MRD_post-HCT as a time-dependent covariate. Cumulative hazard of relapse from children with ALL who were MRD positive before HCT low (C), high (D), and very high (E). The MRD values after transplant are MRD negative (neg; solid red line), MRD low positive (dashed light green line), MRD high positive (solid blue line), and MRD very high positive (dashed purple line); the values were treated as time-dependent covariates. The vertical line represents an HR of 1 for reference.

Figure 2.

Predicted EFS and CIR in patients with MRD post-HCT according to their pre-HCT MRD level. (A-C) Model-based EFS. (D-F) A model-based CIR. The model is presented in Figure 1B. The lines represented the predicted outcome for reference children with MRD assessed on day +30 after HCT. The red solid lines represent the outcome for reference children whose MRD was negative. The dashed light green lines show the predicted outcome for reference children whose MRD was low. Analogously, the blue solid lines illustrate the reference children whose MRD measurements were high, and the dashed purple lines represent the predicted outcome for reference children with MRD very high. In addition, panels A and D are the prediction considering MRD before HCT = low, panels B and E are the prediction considering MRD before HCT = high, and panels C and F are the prediction considering MRD before HCT = very high.

Figure 3.

Influence of MRD and aGVHD early after HCT (day +30 time point) on relapse. Cumulative hazard estimates for relapse in children with ALL during the first 2 years after HCT for patients remaining MRD negative post-HCT at the first month after HCT (A) and patients with MRD detected at any level post-HCT (B). The estimates are from a Cox proportional hazards regression model with all MRD (MRD negative, MRD positive) measurements after transplant and aGVHD both as time-dependent covariates. (C) EFS and CIR curves for patients who were MRD positive during the landmark day +30 time point interval and did or did not experience aGVHD.

Figure 4.

CIR by the integrated score before HCT. Values are given for the derivation cohort (A) and the validation cohort (B).