Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia

Abstract

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been shown to be highly effective in patients with chronic lymphocytic leukemia (CLL) and is approved for CLL treatment. Unfortunately, resistance and intolerance to ibrutinib has been observed in several studies, opening the door for more specific BTK inhibitors. CC‐292 (spebrutinib) is a BTK inhibitor with increased specificity for BTK and less inhibition of other kinases. Our in vitro studies showed that CC‐292 potently inhibited B‐cell receptor signaling, activation, proliferation and chemotaxis of CLL cells. In in vivo studies using the adoptive transfer TCL1 mouse model of CLL, CC‐292 reduced tumor load and normalized tumor‐associated expansion of T cells and monocytes, while not affecting T cell function. Importantly, the combination of CC‐292 and bendamustine impaired CLL cell proliferation in vivo and enhanced the control of CLL progression. Our results demonstrate that CC‐292 is a specific BTK inhibitor with promising performance in combination with bendamustine in CLL. Further clinical trials are warranted to investigate the therapeutic efficacy of this combination regimen.

Network-Based Drug Discovery Identifies Statins as a Repurposing Agent to Improve Activity of Current Therapies in Chronic Lymphocytic Leukemia.

“…In vitro CLL proliferation assay CLL primary cells (10 7 cells) were labeled with 0.5 µM carboxy uoresceinsuccinimidyl ester (CFSE; Life Technologies) as reported previously [13,14]. Brie y, 10 5 cells/200 μL were cultured for 6 days in an enriched RPMI-1640 supplemented with 15 ng/mL recombinant human IL-15 (R&D systems, Minneapolis, MN) to sustain survival and with 0.2 μM CpG DNA TLR-9 ligand (ODN-2006; Invivogen, San Diego, CA) to induce cell proliferation [15].…”

Synthesis of a potential bendamustine deschloro dimer impurity

“…The resultant clear solution was further stirred overnight. After removal of the white precipitate by filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by flash chromatography to afford compound 7 (1.8 g, 64.5%); 1…”

“…It features an active nitrogen mustard moiety (mechlorethamine unit) together with a benzimidazole ring and a butanoic acid residue. [1][2][3][4] Its mechlorethamine moiety Bendamustine deschloro dimer, a potential impurity of bendamustine hydrochloride, has been efficiently synthesized from compound 1 in nine steps which involve two key intermediate compounds 4 and 6.…”

“…The organic extracts were combined, washed with saturated brine and dried over anhydrous Na 2 SO 4. Compound 2 was obtained as off-white solid (6.5 g, 87% yield in two steps);1 H NMR (300 MHz, CDCl3) δ 7.22 (m, 6H), 7.08 (s, 1H), 7.11 (s, 1H), 6.89 (m, 1H), 4.55 (s, 2H), 4.11 (m, 2H), 3.79 (t, 2H, J = 5.52 Hz), 3.67 (s, 3H), 3.54 (t, 3H, J = 5.61 Hz), 2.89 (t, 2H, J = 7.59 Hz), 2.47 (t, 2H, J = 6.93 Hz), 2.17 (m, 3H),1.24 (t, 3H, J = 7.14 Hz); MS ESI m/z calcd for C 23 H 30 N 3 O 3 + [M + H] + : 396.2; found 396.2.…”

Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies

“…Zanubrutinib was efficacious in clinical trials of patients with MCL and CLL/SLL, was recently FDA approved for MCL treatment (32), and is being investigated in patients with WM (33)(34)(35)(36). Another BTK inhibitor, spebrutinib (CC-292), impaired CLL cell proliferation and improved control of CLL progression when given concurrent with bendamustine in preclinical models (37). However, in a phase 1 study, spebrutinib monotherapy had a shorter duration of response than those reported for ibrutinib or acalabrutinib, although it was well tolerated (38)(39)(40).…”