Figure 3.
Early prediction of relapse through assessment of clonal involvement of distinct stem and progenitor cells. (A) Number of months by which mutational MRD-positivity in BM MNCs and HSPCs preceded diagnosis of relapse. Individual values (circles) for all patients in relapse and mean (± SEM) are shown. The paired MNC and HSPC sample for each patient are connected by gray dashed lines. P value; the Wilcoxon paired test. (B) Fold changes in %VAF in HSPCs relative to BM MNCs in patients who later relapsed, for all remission BM samples in which MNCs and/or HSPCs were MRD-positive (15 patients, 25 remission time points indicated by blue circles). VAF of mutations with the highest VAF within the highest clonally involved HSPC population was compared with the VAF of MNCs in the same BM remission sample. For mutations in which MNC VAFs were below the LOD, the LOD value was used instead of the actual VAF. The paired MNC and HSPC samples for each patient are connected by gray dashed lines. Mean (± SEM) values are also shown. P value; a binomial test. (C) Kinetic assessment of MRD in purified HSPCs after allo-HSCT, as assessed by ddPCR analysis for patient-specific mutations in patients in whom MRD positivity of HSPCs preceded MRD positivity of BM MNCs for at least 2 consecutive remission time points. Arrowheads indicate time of diagnosis of clinical relapse from the time of transplantation (0), and the length of the arrows indicates months from detection of molecular MRD to time of clinical diagnosis of relapse. MNC MRD+; at least 1 mutation confidently detected in BM MNCs by ddPCR; MNC MRD−, no mutation confidently detected in BM MNCs by ddPCR; HSPC MRD+, at least 1 mutation confidently detected in ≥1 stem and progenitor cell populations by ddPCR; HSPC MRD−, no mutation confidently detected by ddPCR in any investigated stem and progenitor cell populations (see “Methods” and supplemental Methods). (D) ddPCR-based VAFs for patient-specific mutations in BM MNCs and purified HSPCs in consecutive remission samples for patients who later relapsed. Error bars represent the 95% confidence interval of VAFs calculated according to Poisson distribution as further specified in “Methods.” Blue color indicates highly confident clonal involvement, red indicates negative, and green inconclusive, as described in supplemental Methods. Only HSPC populations with highly confident clonal involvement for at least 1 time point are shown. Raw data can be found in source data file 1.

Early prediction of relapse through assessment of clonal involvement of distinct stem and progenitor cells. (A) Number of months by which mutational MRD-positivity in BM MNCs and HSPCs preceded diagnosis of relapse. Individual values (circles) for all patients in relapse and mean (± SEM) are shown. The paired MNC and HSPC sample for each patient are connected by gray dashed lines. P value; the Wilcoxon paired test. (B) Fold changes in %VAF in HSPCs relative to BM MNCs in patients who later relapsed, for all remission BM samples in which MNCs and/or HSPCs were MRD-positive (15 patients, 25 remission time points indicated by blue circles). VAF of mutations with the highest VAF within the highest clonally involved HSPC population was compared with the VAF of MNCs in the same BM remission sample. For mutations in which MNC VAFs were below the LOD, the LOD value was used instead of the actual VAF. The paired MNC and HSPC samples for each patient are connected by gray dashed lines. Mean (± SEM) values are also shown. P value; a binomial test. (C) Kinetic assessment of MRD in purified HSPCs after allo-HSCT, as assessed by ddPCR analysis for patient-specific mutations in patients in whom MRD positivity of HSPCs preceded MRD positivity of BM MNCs for at least 2 consecutive remission time points. Arrowheads indicate time of diagnosis of clinical relapse from the time of transplantation (0), and the length of the arrows indicates months from detection of molecular MRD to time of clinical diagnosis of relapse. MNC MRD+; at least 1 mutation confidently detected in BM MNCs by ddPCR; MNC MRD−, no mutation confidently detected in BM MNCs by ddPCR; HSPC MRD+, at least 1 mutation confidently detected in ≥1 stem and progenitor cell populations by ddPCR; HSPC MRD−, no mutation confidently detected by ddPCR in any investigated stem and progenitor cell populations (see “Methods” and supplemental Methods). (D) ddPCR-based VAFs for patient-specific mutations in BM MNCs and purified HSPCs in consecutive remission samples for patients who later relapsed. Error bars represent the 95% confidence interval of VAFs calculated according to Poisson distribution as further specified in “Methods.” Blue color indicates highly confident clonal involvement, red indicates negative, and green inconclusive, as described in supplemental Methods. Only HSPC populations with highly confident clonal involvement for at least 1 time point are shown. Raw data can be found in source data file 1.

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