New Study Highlights Venetoclax Combo Efficacy in ALL

Researchers have found that combination treatment with venetoclax and bendamustine on T-cell acute lymphoblastic leukemia (T-ALL) cell lines demonstrated the greatest synergistic effect, according to a recent study published in In Vivo. This study evaluated the efficacy of various monotherapies and combination therapies, particularly focusing on the combination of venetoclax with other anticancer drugs.¹

T-ALL, accounting for approximately 25% of all adult ALL cases, is a rare hematologic malignancy with a high tumor burden and poor long-term outcomes.² Early T-cell precursor ALL (ETP-ALL), a novel subgroup of T-ALL characterized as CD8 negative, CD1a negative, and CD5 weak, has shown even poorer outcomes compared with non–ETP-ALL subgroups. The study examined 3 T-ALL cell lines: Loucy, Jurkat, and CCRF-CEM. Loucy is an ETP-ALL cell line characterized by an immature phenotype, while Jurkat and CCRF-CEM are late T-cell progenitor ALL (LTP-ALL) cell lines. Researchers conducted monotherapy trials using venetoclax, cytarabine, bendamustine, and azacytidine, while combination therapies were tested using venetoclax with cytarabine, bendamustine, or azacytidine.

The monotherapy trials found that Loucy cells exhibited greater sensitivity to venetoclax, with a mean (SD) half maximal inhibitory concentration (IC50) of 0.15 (0.02) µM compared with IC50 values observed in Jurkat (5.82 [0.85] µM) and CCRF-CEM (3.37 [0.25] µM) cells. For other monotherapies, Jurkat and CCRF-CEM cells showed greater sensitivity to cytarabine, bendamustine, and azacytidine compared with Loucy cells. For cytarabine, the IC50 values were 0.58 (0.03) µM in Jurkat cells, 0.4 (0.02) µM in CCRF-CEM cells, and 2.25 (0.36) µM in Loucy cells. Bendamustine showed IC50 values of 7.36 (0.57) µM in Jurkat cells, 11.00 (0.5) µM in CCRF-CEM cells, and 22.09 (1.62) µM in Loucy cells. Azacitidine had IC50 values of 5.47 (0.39) µM in Jurkat cells, 3.72 (0.23) µM in CCRF-CEM cells, and 44.49 (3.53) µM in Loucy cells.

To ensure the reliability of their results, the authors of this study utilized a novel synergy scoring method, Bliss/Loewe consensus, to evaluate potential drug combinations. | Image Credit: GoodIdeas-stock.adobe.com

Combining venetoclax with cytarabine, bendamustine, or azacitidine generally demonstrated higher efficacy than monotherapies across the cell lines. For non–ETP-like phenotype cell lines, Jurkat and CCRF-CEM, the combination of venetoclax and cytarabine showed an additive effect, with Loewe synergic scores ranging from –10 to 10. Specifically, the Loewe score was 6.06 for Jurkat and 3.22 for CCRF-CEM. In the ETP-like Loucy cell line,the combination had a Loewe synergic score of 5.82, also indicating an additive effect. The combination of venetoclax and azacitidine also showed an additive effect in Jurkat (Loewe score: 5.00) and CCRF-CEM (Loewe score: 7.97) cells. In Loucy cells, the combination exhibited a synergistic effect with a Loewe score of 13.54.

The most significant results were observed with the combination of venetoclax and bendamustine in Loucy cells, with the combination exhibiting a strong synergistic effect with a Loewe score of 16.6. For Jurkat and CCRF-CEM cell lines, the Loewe scores were 4.38 and 8.48, respectively, indicating an additive to moderately synergistic effect.

To ensure the reliability of the results, a novel synergy scoring method, Bliss/Loewe consensus, was used to evaluate potential drug combinations. This method eliminates false-positive outcomes through a comprehensive assessment of drug combination effects. The mean Bliss/Loewe consensus score of 13.832 (0.55) confirmed the strong synergy of the venetoclax and bendamustine combination in inhibiting ETP-ALL cell proliferation.

“The combination of venetoclax and bendamustine demonstrated the greatest synergistic effect in suppressing ETP-ALL cell proliferation,” the authors concluded. “Although these findings cannot be extrapolated to all patients with primary T-ALL, one advantage emerging from these findings is that synergy analysis in ETP-ALL cell lines can provide insights that could help discover robust optimal chemotherapeutic combinations for the treatment of high-risk T-ALL before proceeding with clinical trials.”

References

1. Nguyen HDT, LE TM, Lee D, et al. Synergistic effect of venetoclax and bendamustine in early T-cell precursor acute lymphoblastic leukemia. In Vivo. 2024;38(4):1740-1749. doi:10.21873/invivo.13624

2. Marks DI, Rowntree C. Management of adults with T-cell lymphoblastic leukemia. Blood. 2017;129(9):1134-1142. doi:10.1182/blood-2017-03-772350