Novel, orally available inhibitor of BCL-XL/BCL-2

Patients being treated with first-line JAK inhibitor monotherapy often relapse [1]. Dr Naveen Pemmaraju (MD Anderson Cancer Center, Texas, USA) presented promising data of an ongoing phase 2 study evaluating navitoclax, a novel, orally available inhibitor of primarily BCL-X_L and BCL-2, which are anti-apoptotic members of the BCL-2 family.

Myelofibrosis is primarily driven by constitutive activation of the JAK/STAT signalling pathway. This results in increased transcription of growth factors, inflammatory cytokines, and anti-apoptotic proteins such as BCL-X_L [2]. Patients with myelofibrosis who have high-molecular-risk mutations, such as those in ASXL1, SRSF2, EZH2, U2AF1, and IDH1/2, at diagnosis will have shorter overall survival (OS) and increased risk of leukaemic transformation [3]. However, there are limited therapeutic options for patients with myelofibrosis who lose response to ruxolitinib. Preclinical studies have demonstrated that dual inhibition of both JAK2 and BCL-2/BCL-X_L can enhance malignant cell death over JAK2 inhibition alone. Additionally, JAK2 plus BCL-2/BCL-X_L inhibition could overcome acquired resistance to single-agent JAK inhibitor treatment [4].

An ongoing phase 2 study demonstrated that the combination of navitoclax plus ruxolitinib induced clinically meaningful spleen volume responses, improvement in Total Symptom Score, and reduction in bone marrow fibrosis grading in patients with myelofibrosis and suboptimal or failed responses to ruxolitinib alone [5]. Patients with myelofibrosis previously treated with ruxolitinib alone who then received navitoclax plus ruxolitinib achieved clinically meaningful improvements in spleen volume and symptom burden. “Notably, these improvements were independent of the presence of high-risk molecular mutations or high numbers of total gene mutations at baseline,” Dr Pemmaraju mentioned.

Additionally, preliminary results from ongoing cytokine analyses suggested that dual therapy with navitoclax and ruxolitinib can help modulate key cytokines previously implicated in myeloproliferative neoplasm symptom improvement in patients with myelofibrosis with suboptimal response to ruxolitinib alone. The modulation of these disease-relevant proinflammatory cytokines correlated with reductions in spleen volume.

1. Scherber RM & Mesa RA. Blood Rev. 2020;42:100716.
2. Byrne M, et al. Ther Adv Hematol. 2018;9:251-9.
3. Tse C, et al. Cancer Res. 2008;68:3421-8.
4. Waibel M, et al. Cell Rep. 2013;5:1047-59.
5. Pemmaraju N, et al. The Addition of Navitoclax to Ruxolitinib Demonstrates Efficacy within Different High-Risk Populations in Patients with Relapsed/Refractory Myelofibrosis. 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract 52.

Posted on 18 February 202118 February 2021