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. 2022 Mar 3;107(8):1994–1998. doi: 10.3324/haematol.2021.280393

Figure 1.

Figure 1.

Ixazomib citrate is effective against chronic lymphocytic leukemia ex vivo and in vivo. (A) Graphical illustration of the index patient’s treatment history, shown as years since diagnosis. Peripheral blood mononuclear cells (PBMC) were collected at the indicated time points T1-T7. The figure was created with BioRender.com. (B) PBMC collected from 3 treatment-naïve chronic lymphocytic leukemia (CLL) patients, as well as at T1 and T6 from the index patient, were co-cultured with CD40L+, BAFF+, and APRIL+ L cells (ratio 1:1:1) for 24 hours (h) prior to initiation of the experiment to mimic the tumor microenvironment. The L cells were then removed and the CLL cells were treated with the indicated 93 single agents at 5 different concentrations (1–10,000 nM) for 72 h. Cell viability was assessed with the CellTiter-Glo luminescent assay. The response readouts were normalized to the negative (0.1% DMSO) and positive (100 µM benzethonium chloride) controls. The heatmap was created using ClustVis (https://biit.cs.us.ee/clustvis/) and illustrates the calculated DSS on a scale from 0-100 (see key, right). Rows are clustered using Manhattan distance and Ward (unsquared distances) linkage. (C) Relative cell viability of PBMC collected at T1 or T6 in response to venetoclax, bortezomib or ixazomib citrate exposure. The experiment is described in (B). The solid, vertical line indicates the maximum plasma concentration of venetoclax reported for patients treated with 400 mg/day. The dashed, vertical line indicates the maximum plasma concentration of ixazomib citrate for patients treated with 4 mg/day. (D) Blood counts of the index patient in response to treatment with ixazomib citrate + dexamethasone. (E) Anti-Pax-5- and hematoxylin and eosin (H&E)-stained sections of bone marrow from T6 and T7, at 2x magnification. Pax-5-positive cells are shown in brown. CLL cells were reduced from 90% (T6) to 65% (T7) of the bone marrow cellularity. AE: adverse event; CR: complete remission; NR: no response; SD: stable disease; UM-CLL: IGVH unmutated CLL; uMRD: undetectable minimal residual disease.