Navitoclax/Ruxolitinib Combo Benefited Myelofibrosis Patients, Despite Molecular Risk

A post-hoc biomarker analysis of the REFINE trial indicated that the clinically meaningful splenic responses seen in patients with myelofibrosis (MF) who were no longer benefitting from ruxolitinib monotherapy treated with navitoclax plus ruxolitinib occurred independently of high molecular risk mutation status.

“The current analyses assessed all biomarker-evaluable patients for a mutational profile with a panel of driver genes and genes that are thought to be prognostic,” study researchers explained. “No significant differences in ≥35% spleen volume reduction (SVR₃₅), duration of SVR₃₅, and overall survival (OS) were detected in the high molecular risk and non-high molecular risk groups.”

REFINE was a phase II, open-label trial assessing navitoclax alone or in combination with ruxolitinib in patients with primary or secondary MF. Cohort 1a of the study included patients with disease progression or suboptimal response on stable ruxolitinib monotherapy. These patients continued their ruxolitinib dose and added navitoclax 50 mg per day with the dose escalated weekly to a maximum of 300 mg per day.

Results of this study showed that the addition of navitoclax to ruxolitinib resulted in SVR₃₅ and reduced symptoms.

The researchers conducted a post-hoc biomarker analyses of patients in this cohort to evaluate potential prognostic biomarkers of benefit of the combination therapy.

In Cohort 1a, 34 patients received at least one dose of navitoclax plus ruxolitinib. Thirty-three of these patients were evaluable for biomarker analyses; 58% had high molecular risk mutations.

Nearly a third (31%) of patients in the high molecular risk group had SVR₃₅ at week 24 compared with 25% of the non-high molecular risk group. In addition, 39% of patients in the high molecular risk group had improvement in fibrosis by at least one grade compared with 36% in the non-high molecular risk group. Reductions in variant allele frequency of 20% or greater occurred in 28% of high molecular risk patients compared with 17% of non-high molecular risk patients.

Patients who had improvement in fibrosis of one grade or more and a reduction of 20% or more of variant allele frequency had improved OS compared with those who did not achieve fibrosis improvement of reduction in variant allele frequency (not reached vs 28.5 months).

“The observed improvements in bone marrow fibrosis, reductions in variant allele frequency, and the association with an OS benefit suggest a disease-modifying effect of navitoclax plus ruxolitinib for patients with MF,” the researchers wrote. “These results are, to the best of our knowledge, among the first to show a survival benefit associated with treatment-induced disease modification.”

Pemmaraju N, Garcia JS, Potluri J, et al. Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study. Lancet Haematol. 2022. doi:10.1016/S2352-3026(22)00116-8