Figure 3.
Evidence of preexisting and later-appearing resistant clones. Panels A and B include B-ALL samples; panels C through E include both B- and T-ALL samples. (A) Histogram (top) indicates the distribution of relapse times across B-ALL samples in the cohort (50-day bins) together with kernel density estimation (gray line). Arrows indicate predicted relapse time of 95% of the B-ALL cohort given a single preexisting resistant cell and a doubling time of 5, 6, 7, 8, or 9 days. Purple indicates very early relapses (<9 months from diagnosis), likely relapsing due to a preexisting resistant clone (schematic at bottom). Yellow represents early relapses (9-36 months), which appear at times consistent with postdiagnosis appearance of the resistant clone from a persister clone that survives initial treatment (bottom), or delayed growth (≥9-day doubling time) of a preexisting clone. Blue represents late relapses (>36 months) appearing after the time treatment had ended on all protocols (3 years, “treatment end” bar). These clones may have survived treatment without outright resistance and relapse at times consistent with resumption of proliferation at treatment cessation. “Survival” (blue circles) and “resistance” (red circles) represent mutations conferring these phenotypes. (B) Percentage of very early, early, or late B-ALL relapses consistent only with the preexisting resistant subclone scheme. The percentages are calculated based on projected relapse times when the doubling time of the resistant clone is 5, 6, 7, 8, or 9 days (shown in arrows in panel A at top); if a sample relapsed before that projected time, it was considered preexisting. (C) Distribution of relapse-enriched variants in the 3 patient groups with very early (<9 months), early (9-36 months), and late (>36 months) relapse. D indicates diagnosis-specific variants, R indicates relapse-specific, and D+R indicates shared. Also shown are the mutation burden (panel D) and number of SVs (panel E) at diagnosis (D) and relapse (R) in the 3 groups along with P values from the 2-sided Wilcoxon rank sum test for D vs R. Variants at D or R in panels D and E included shared variants.

Evidence of preexisting and later-appearing resistant clones. Panels A and B include B-ALL samples; panels C through E include both B- and T-ALL samples. (A) Histogram (top) indicates the distribution of relapse times across B-ALL samples in the cohort (50-day bins) together with kernel density estimation (gray line). Arrows indicate predicted relapse time of 95% of the B-ALL cohort given a single preexisting resistant cell and a doubling time of 5, 6, 7, 8, or 9 days. Purple indicates very early relapses (<9 months from diagnosis), likely relapsing due to a preexisting resistant clone (schematic at bottom). Yellow represents early relapses (9-36 months), which appear at times consistent with postdiagnosis appearance of the resistant clone from a persister clone that survives initial treatment (bottom), or delayed growth (≥9-day doubling time) of a preexisting clone. Blue represents late relapses (>36 months) appearing after the time treatment had ended on all protocols (3 years, “treatment end” bar). These clones may have survived treatment without outright resistance and relapse at times consistent with resumption of proliferation at treatment cessation. “Survival” (blue circles) and “resistance” (red circles) represent mutations conferring these phenotypes. (B) Percentage of very early, early, or late B-ALL relapses consistent only with the preexisting resistant subclone scheme. The percentages are calculated based on projected relapse times when the doubling time of the resistant clone is 5, 6, 7, 8, or 9 days (shown in arrows in panel A at top); if a sample relapsed before that projected time, it was considered preexisting. (C) Distribution of relapse-enriched variants in the 3 patient groups with very early (<9 months), early (9-36 months), and late (>36 months) relapse. D indicates diagnosis-specific variants, R indicates relapse-specific, and D+R indicates shared. Also shown are the mutation burden (panel D) and number of SVs (panel E) at diagnosis (D) and relapse (R) in the 3 groups along with P values from the 2-sided Wilcoxon rank sum test for D vs R. Variants at D or R in panels D and E included shared variants.

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