Figure 3.
Figure 3. Clinical response to mIDH2 inhibition is associated with induction of myeloid differentiation. (A) Representative immunophenotypic analyses by flow cytometry on sequential bone marrow samples. Cell-surface markers studied are shown. Data from a responding patient (pretreatment to CR to relapse) (left). Data from a nonresponding patient (pretreatment to progressive disease) who remained in stable disease during treatment (right). Numbers in FACS plots refer to the size of the population as a percentage of lineage-negative bone marrow mononuclear cells. For normal bone marrow (n = 12), the standard deviation is ±2.7% for immature progenitor, ±9.6% for immature precursors, and ±9.7% for mature myeloid cells. (B) Graph showing ratio of immature to mature cell populations by flow cytometry from bone marrow over time (top): the average ratios of myeloid progenitor or myeloid precursors to mature myeloid cells in bone marrow from normal donors (n = 12) and 5 patients who had either a CR or a PR with enasidenib are shown. In patient 201-010, the changing size of myeloid precursor (red) cell populations in relation to mature myeloid cells is shown. In the remaining 3 patients, the changing size of myeloid progenitor (blue) populations to mature cells is shown. Colored bars represent the 95% confidence intervals in normal controls. The mIDH2 VAF in each patient at different time points in all bone marrow mononuclear cells (VAF total) and in FACS-sorted mature myeloid cells (CD34−CD117−) are shown (bottom). (C) mIDH2 VAF in bone marrow mononuclear cells prior to treatment (blue) and in sorted peripheral blood neutrophils at time of best response (red) in 7 patients achieving CR (top). VAF of indicated mutation in bone marrow mononuclear cells prior to treatment and in sorted peripheral blood neutrophils at time of best response in 2 patients achieving CR (middle and bottom). (D) Histogram of the percentages of functional neutrophils observed in ex vivo enasidenib-treated patient samples (left) and representative images (right) assessed by phagocytic assay quantifying neutrophils (blue) that contained latex beads (green). The percentage of neutrophils containing beads was measured by scoring 5 different fields of view per sample. BRCA2, breast cancer type 2; Gran, granulocyte; PD, progressive disease; Post, time of best response; Pre, prior to treatment; TNC, total nucleated cell count.

Clinical response to mIDH2 inhibition is associated with induction of myeloid differentiation. (A) Representative immunophenotypic analyses by flow cytometry on sequential bone marrow samples. Cell-surface markers studied are shown. Data from a responding patient (pretreatment to CR to relapse) (left). Data from a nonresponding patient (pretreatment to progressive disease) who remained in stable disease during treatment (right). Numbers in FACS plots refer to the size of the population as a percentage of lineage-negative bone marrow mononuclear cells. For normal bone marrow (n = 12), the standard deviation is ±2.7% for immature progenitor, ±9.6% for immature precursors, and ±9.7% for mature myeloid cells. (B) Graph showing ratio of immature to mature cell populations by flow cytometry from bone marrow over time (top): the average ratios of myeloid progenitor or myeloid precursors to mature myeloid cells in bone marrow from normal donors (n = 12) and 5 patients who had either a CR or a PR with enasidenib are shown. In patient 201-010, the changing size of myeloid precursor (red) cell populations in relation to mature myeloid cells is shown. In the remaining 3 patients, the changing size of myeloid progenitor (blue) populations to mature cells is shown. Colored bars represent the 95% confidence intervals in normal controls. The mIDH2 VAF in each patient at different time points in all bone marrow mononuclear cells (VAF total) and in FACS-sorted mature myeloid cells (CD34−CD117−) are shown (bottom). (C) mIDH2 VAF in bone marrow mononuclear cells prior to treatment (blue) and in sorted peripheral blood neutrophils at time of best response (red) in 7 patients achieving CR (top). VAF of indicated mutation in bone marrow mononuclear cells prior to treatment and in sorted peripheral blood neutrophils at time of best response in 2 patients achieving CR (middle and bottom). (D) Histogram of the percentages of functional neutrophils observed in ex vivo enasidenib-treated patient samples (left) and representative images (right) assessed by phagocytic assay quantifying neutrophils (blue) that contained latex beads (green). The percentage of neutrophils containing beads was measured by scoring 5 different fields of view per sample. BRCA2, breast cancer type 2; Gran, granulocyte; PD, progressive disease; Post, time of best response; Pre, prior to treatment; TNC, total nucleated cell count.

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