2022
DOI: 10.1016/s2352-3026(22)00116-8
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Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study

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Cited by 33 publications
(39 citation statements)
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“… 84 An exploratory study provided preliminary evidence for BM fibrosis grade reduction in approximately one-third of patients with MF that received combination navitoclax and ruxolitinib, regardless of high-molecular risk mutation status, and reduction of ≥20% in driver VAF, suggesting disease modifying benefits as these treatment-induced biological changes were associated with increased survival. 100 Results from the ongoing phase 3 trials in the upfront (TRANSFORM-1) and relapsed/refractory (TRANSFORM-2) settings are awaited.…”
Section: Non-jak2 Targets In Mpnsmentioning
confidence: 99%
“… 84 An exploratory study provided preliminary evidence for BM fibrosis grade reduction in approximately one-third of patients with MF that received combination navitoclax and ruxolitinib, regardless of high-molecular risk mutation status, and reduction of ≥20% in driver VAF, suggesting disease modifying benefits as these treatment-induced biological changes were associated with increased survival. 100 Results from the ongoing phase 3 trials in the upfront (TRANSFORM-1) and relapsed/refractory (TRANSFORM-2) settings are awaited.…”
Section: Non-jak2 Targets In Mpnsmentioning
confidence: 99%
“…All JAK2 inhibitors resulted in downregulation of BCL2 and BCL2L1 (BCL‐xL), with ruxolitinib sustaining inhibition at 48 hours. Similarly, inhibitors augmenting pro‐apoptotic pathways through inhibition of BCL2 and BCL‐xL have demonstrated efficacy across MPN models and are under evaluation in MF as well as accelerated/blast phase MPNs 21–24 . We also observed that immune checkpoint protein PD‐L1 ( CD274 ) was only suppressed by ruxolitinib at both timepoints, despite its well‐established regulation by STAT3.…”
Section: Resultsmentioning
confidence: 79%
“…The development of navitoclax faces obstacles due to a high incidence of on-target thrombocytopenia related to the inhibition of BCL-XL in platelets (47). However, combinations of navitoclax and various molecularly targeted drugs continue to be explored in patients, with constantly improving therapeutic indices (17) and initial evidence of clinical benefit; for example, addition of navitoclax to the JAK1/2 inhibitor ruxolitinib improved survival in patients with myelofibrosis who had disease progression or suboptimal response to ruxolitinib monotherapy (48,49). Furthermore, our observation that cetuximab imparts a unique dependency on BCL-XL provides a rationale for the prospective use of more specific and less toxic BCL-XL inhibitors, such as BCL-XL proteolysis-targeting chimeras that direct BCL-XL to ubiquitin ligases abundant in cancer cells but poorly expressed in platelets (50).…”
Section: Discussionmentioning
confidence: 99%