Model Can Predict Overall Survival in Myelofibrosis After Ruxolitinib Treatment

Evaluating ruxolitinib dose, spleen response, and transfusion requirement after 6 months of treatment can predict overall survival (OS) in myelofibrosis (MF), according to a study published in Blood Advances.

Ruxolitinib is being used extensively in MF because of its early efficacy within the first 6 months of treatment, but patients who lose response over time and discontinue have a worse OS, the authors explained.

“In the real world, the definition of the optimal timing for a treatment shift or for stem cell transplant (SCT) after [ruxolitinib] is a recognized unmet medical need,” they wrote.

The purpose of their study was to identify the early predictors of inferior survival. This study was conducted in Italy, which has a regionally based health service characterized by universal coverage.

A total of 209 patients with MF who were regularly followed at 17 centers were evaluated, and there was a validation cohort of 91 patients with MF treated with ruxolitinib at Moffitt Cancer Center. The median follow-up for the study cohort was 30.5 months (interquartile range, 9.7-50.0) from the start of ruxolitinib, and the median time on the therapy was 28.2 months (IQR, 14.3-44.6).

Overall, 75 patients (35.8%) discontinued ruxolitinib, all after completing their 6-month visit. The most common reasons for discontinuation were SCT (26.7%), spleen response/progression of splenomegaly (22.7%), hematologic toxicity (12.0%), leukemic transformation (10.7%), and infection (10.7%). Eleven percent of patients underwent SCT a median of 14 months (9.5-40.5) after starting ruxolitinib.

About one-third (34.0%) of patients died, with the most common causes of death being blast phase (29.6%), MF progression (23.9%), and infection (22.5%). The estimated median OS was 145.0 months from diagnosis and 59.4 months from ruxolitinib start.

More than one-third (35%) of patients who were in lower-risk categories at baseline shifted to higher-risk categories at 6 months. The authors used a multivariable Cox proportional hazard regression and identified risk factors associated with shorter survival. In the Response to Ruxolitinib after 6 months (RR6) model that was created, the researchers assigned a weight to each risk factor based on hazard ratio:

• Ruxolitinib treatment at baseline, month 3, and month 6 that was below 20-mg twice daily—1 point
• Palpable spleen reduction at months 3 and 6 that was ≤ 30% from baseline—1.5 points
• The need for red blood cell transfusions at month 3 and/or 6—1 point
• The need for red blood cell transfusions at all time points—1.5 points

Using the scores, the researchers created 3 prognostic groups:

1. Low risk (score 0): no poor prognostic factor, which included 19.1% of patients who had a median OS that was not reached
2. Intermediate risk (score 1 to 2): 45.2% of patients with a median OS of 61 months
3. High risk (score 2.5 or more): 35.6% of patients with a median OS of 33 months

The RR6 model was applied to the validation cohort, which confirmed its predictive ability.

The authors concluded that the model can be applied to patients with myelofibrosis after 6 months of ruxolitinib treatment to identify patients who are a candidate for an approved second-line treatment, a candidate for SCT, or need investigative second-line interventional trials because they have such limited survival.

“While developing the RR6 model, the choice of the 6-month time point to perform our analysis was arbitrary, although based on clinical experience and current recommendations,” they wrote. “It is nonetheless quite plausible that—given the availability of an effective second-line treatment—the early identification of inadequate responders to [ruxolitinib] may have prognostic value, considering that risk factors acquired over time, such as the occurrence of thrombocytopenia, clonal evolution, or blast phase transformation, negatively impact patient outcomes.”

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. Published online February 7, 2022. doi:10.1182/bloodadvances.2021006889