Mechanistic Investigation Of Neutropenia Associated With Palbociclib

Bone marrow suppression, especially neutropenia, has been identified as one of the main dose-limiting toxicities for the selective CDK4/6 inhibitor, palbociclib, in the clinic. However, compared to chemotherapy-induced myelotoxicity, palbociclib-induced neutropenia is quickly reversible, uncomplicated and is proactively managed by a short duration treatment-free period between cycles, or reactively by dose delay or reduction. To aid in understanding the mechanism by which neutropenia occurs and to further differentiate it from chemotherapy- induced myelotoxicity, an in vitro bone marrow toxicity assay was utilized to evaluate the cellular mechanism and the reversibility of bone marrow suppression induced by palbociclib as a single agent or in combination with anti-estrogens. This investigation has demonstrated that palbociclib-induced bone marrow suppression manifested through cell cycle arrest without apoptosis; by contrast, chemotherapeutic agents, including paclitaxel, doxorubicin, and carboplatin, primarily caused apoptotic cell death in the bone marrow. Following palbociclib treatment withdrawal in vitro, bone marrow cells resumed proliferation in the presence or absence of the anti-estrogen (fulvestrant); while breast cancer cells (MCF-7) remained arrested in the presence of fulvestrant. Bone marrow cells did not resume proliferation following chemotherapy treatment withdrawal. To further investigate the mechanism of reversibility, we evaluated the involvement of cellular senescence. Bone marrow cells did not enter senescence following treatment with palbociclib, anti-estrogen, or a combination of both agents. MCF-7 cells, on the other hand, became senescent following palbociclib or anti-estrogen treatment, and this effect was larger in the presence of both agents. In summary, the current investigative work shed light on the mechanism of palbociclib- induced bone marrow suppression and clearly differentiated it from that induced by chemotherapeutic agents. These results potentially explain the quick reversibility of palbociclib-induced myelosuppression and its uncomplicated nature when compared to traditional cytotoxic agents. Moreover, the data supports the current dosing regimen in the clinic, which provides time for bone marrow cells to recover during the 1 week treatment-free period without impacting tumor efficacy. This investigative work provides valuable information to the clinicians in managing the neutropenia risk associated with breast cancer treatment. This research was funded by Pfizer, Inc. Citation Format: Wenyue Hu, Tae Sung, Bart Jessen, Aida Sacaan. Mechanistic investigation of neutropenia associated with palbociclib. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1635. doi:10.1158/1538-7445.AM2015-1635