Palbociclib/Ruxolitinib Combo Shows Preclinical Promise in Myelofibrosis

Golam Mohi, PhD

Palbociclib (Ibrance) plus ruxolitinib (Jakafi) led to normalized blood leukocyte counts, reduced splenomegaly, and significantly improved bone marrow fibrosis in JAK2 V617F and MPLW515L mouse models of myelofibrosis, suggesting that the combination could provide therapeutic benefit to patients with the malignancy, according to findings from a study published in Cancer Research.^1,2

“We have identified CDK6, a regulator of cell cycle, as a new therapeutic target in myelofibrosis. We demonstrate that CDK4/6 inhibitor palbociclib, in combination with ruxolitinib, markedly inhibits myelofibrosis, suggesting this drug combination could be an effective therapeutic strategy against this devastating blood disorder,” said senior study author Golam Mohi, PhD, a professor in biochemistry and molecular genetics at the University of Virginia School of Medicine.

Myelofibrosis is the most aggressive type of myeloproliferative neoplasm, with a median survival of 16 to 35 months in intermediate- and high-risk cases. Ruxolitinib, although approved for the treatment of patients with myelofibrosis, primarily provides symptom relief rather than antitumor activity, and prolonged exposure to the agent can lead to dampened or lost response.

“Current therapies only provide symptomatic relief without offering significant improvement of bone marrow fibrosis. So, there is a critical need to develop more effective therapy for myelofibrosis,” said Mohi.

CDK6 is overexpressed in hematopoietic progenitors of JAK2 V617F knock-in mice and patients with myelofibrosis, making the gene a potential target for treatment.

In the study, the mice were randomized to receive treatment with vehicle (placebo), 50 mg/kg of palbociclib, 60 mg/kg of ruxolitinib, or 50 mg/kg of palbociclib plus 60 mg/kg of ruxolitinib by oral gavage once daily for 6 weeks. MPLW515L bone marrow transplant mice were treated with the drugs for 3 weeks.

The results showed that palbociclib alone and in combination with ruxolitinib led to a significant reduction in white blood cell and neutrophil counts vs vehicle treatment.

Additionally, using flow cytometry, investigators showed a significant reduction in myeloid precursors (Gr-1+/Mac-1+) in the bone marrow of JAK2VF/VF mice that received palbociclib alone or in combination with ruxolitinib.

Furthermore, the JAK2VF/VF mice experienced a significant reduction in spleen size and weight following treatment with ruxolitinib alone, palbociclib alone, or the combination thereof (P < .05; P <.005; and P <.0005).

Histopathologic analyzes also showed extensive bone marrow fibrosis in vehicle-treated JAK2VF/VF mice. Treatment with palbociclib alone led to a significant reduction of bone marrow fibrosis in the JAK2VF/VF mice that was almost completely eradicated with the addition of ruxolitinib.

“A combinatorial therapeutic approach involving palbociclib and ruxolitinib will enable lowering the doses of each of the inhibitors and thus reducing toxicities while enhancing the therapeutic efficacy. Results from our study support the clinical investigation of the palbociclib and ruxolitinib combination in patients with myelofibrosis,” concluded lead study author Avik Dutta, PhD, a postdoctoral research fellow at the National Institutes of Health, and coauthors in the study publication.¹

References

1. Dutta A, Nath D, Yang Y, et al. CDK6 is a therapeutic target in myelofibrosis. Cancer Res. [Online ahead of print June 18, 2021]. doi:10.1158/0008-5472.CAN-21-0590
2. UVA discovery suggests potential new treatment for deadly blood cancer. News release. University of Virginia. August 11, 2021. Accessed August 13, 2021. https://bit.ly/3AC2TNa