Predicting Ruxolitinib Treatment Outcomes in Myelofibrosis

A new prognostic model identified risk factors for reduced survival in patients with myelofibrosis (MF) who received ruxolitinib for at least six months and may inform treatment strategies these patients.

Margherita Maffioli, MD, of the Circolo Hospital and Macchi Foundation in Varese, Italy, and colleagues conducted the research and published their findings in Blood Advances.

Ruxolitinib, a JAK inhibitor, is a common treatment for patients with MF. However, “despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival,” Dr. Maffioli and colleagues wrote.

The researchers created the prognostic model because the lack of criteria to predict overall survival (OS) in ruxolitinib-treated patients with MF can lead to “uncertainty regarding the switch to second-line treatments,” they wrote.

The researchers investigated survival predictors in 209 patients with MF who received at least six months of ruxolitinib treatment. All patients were participating in the real-world ambispective, observational RUXOREL-MF study. The median follow-up from the initiation of ruxolitinib treatment was 30.5 months, and the median time on treatment was 28.2 months.

The researchers used a multivariable analysis to identify several risk factors for reduced OS. Receiving a dose of ruxolitinib <20 mg twice daily at baseline, month three, and month six significantly increased the risk of reduced OS (hazard ratio [HR], 1.79; 95% CI, 1.07-3.00; P=.03).

“Of note, our data suggest that starting with a suboptimal dose of [ruxolitinib] (ie, lower than expected on the basis of the platelet count) frequently precludes the possibility of reaching the prognostically relevant dose of 20 mg twice daily at subsequent time points, thus indicating that optimal [ruxolitinib] dosing from the beginning, whenever clinically feasible, bears great prognostic relevance,” Dr. Maffioli and colleagues wrote.

A palpable spleen length reduction of ≤30% from baseline at months three and six (HR, 2.26; 95% CI, 1.40-3.65; P=.0009) was also significantly associated with a risk of reduced OS. A need for a red blood cell (RBC) transfusion at month three and/or month six (HR, 1.66; 95% CI, 0.95-2.88; P=.07) was also associated with a significantly increased risk of reduced OS, as was a need for RBC transfusion at all time points, which more than doubled the risk of reduced OS (HR, 2.32; 95% CI, 1.19-4.54; P=.02).

The researchers developed a prognostic model called Response to Ruxolitinib After 6 Months (RR6) based on this data. The model included a low-risk category (median OS, not reached), an intermediate-risk category (median OS, 61 months), and a high-risk category, (median OS, 33 months). Researchers validated and confirmed the RR6 model in an external cohort of 40 patients with MF.

“The RR6 model can aid decision-making, recognizing patients with a high probability of fatality. Based on this model, treating physicians can propose [hematopoietic stem cell transplantation] earlier, avoiding deferring the decision after [ruxolitinib] discontinuation due to exhausted activity, a setting associated with a limited likelihood of good outcome post-[transplant],” Dr. Maffioli and colleagues concluded. “Furthermore, given the prognostic relevance of dose intensity and spleen response on the one hand, and of avoiding RBC transfusion requirement on the other, the frontline use of add-on agents mitigating the risk of developing RBC transfusion necessity in the context of [ruxolitinib]-treated MF, such as the BET-inhibitor pelabresib, may prove particularly beneficial.”

Reference

Maffioli M, Mora B, Ball S, et al. A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis. Blood Adv. 2022;6(6):1855-1864.