A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis

Abstract

Ruxolitinib (RUX) is extensively used in myelofibrosis (MF). Despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival (OS). Currently, response criteria able to predict OS in RUX-treated patients are lacking, leading to uncertainty regarding the switch to second-line treatments. In this study, we investigated predictors of survival collected after six months of RUX in 209 MF patients participating in the real-world ambispective observational RUXOREL-MF study (NCT03959371). Multivariable analysis identified the following risk factors: (i) RUX dose <20 mg twice daily at baseline, month 3, and 6 (hazard ratio, HR, 1.79, 95% confidence interval, CI, 1.07-3.00, p=0.03), (ii) palpable spleen length reduction from baseline ≤30% at month 3 and 6 (HR 2.26, 95% CI 1.40-3.65, p=0.0009), (iii) red blood cell (RBC) transfusion need at month 3 and/or 6 (HR 1.66, 95% CI 0.95-2.88, p=0.07), and (iv) RBC transfusion need at all time points, i.e. baseline and months 3 and 6 (HR 2.32, 95% CI 1.19-4.54, p=0.02). Hence, we developed a prognostic model, named Response to Ruxolitinib after 6 months (RR6), dissecting three risk categories: low (median OS not reached), intermediate (median OS 61 months, 95% CI 43-80), and high (median OS 33 months, 95% CI 21-50). The RR6 model was validated and confirmed in an external cohort comprised of 40 MF patients. In conclusion, the RR6 prognostic model allows for the early identification of RUX-treated MF patients with impaired survival who might benefit from a prompt treatment shift.

Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis

“…As of note, OS was not different between RUX-treated patients who were TI and not TI at week 24 in long-term pooled analyses from the COMFORT-I and COMFORT-II phase 3 trials [ 13 ]. However, transfusion need at several timepoints following treatment with RUX was associated with shortened survival in a real-world observational study in MF, and was subsequently incorporated into the Response to Ruxolitinib After 6 Months (RR6) prognostic model that may help to predict which patients will benefit from a prompt treatment switch from RUX [ 15 ].…”

“…OS was not significantly different between RUX-treated patients who were transfusion independent and not transfusion independent at week 24 [ 13 ], whereas a significant prognostic improvement was demonstrated in RUX-treated patients who experienced spleen volume reduction at week 24 compared to those who did not [ 14 ]. In an observational study of RUX-treated patients with MF, red blood cell transfusion need at baseline, 3 months, and 6 months of treatment was negatively correlated with OS [ 15 ]. Further, a real-world study of intermediate- to high-risk MF patients demonstrated that OS was significantly improved in the five years following RUX approval compared with the two years prior; notably, in the RUX post-approval time frame, OS was greater for those who received RUX versus those who did not [ 16 ].…”

Quality of life independently predicts overall survival in myelofibrosis: Key insights from the COntrolled MyeloFibrosis Study with ORal Janus kinase inhibitor Treatment (COMFORT)‐I study

“…Other contemporary investigations have examined multiparameter flow cytometry as a substitute for blast count and response to ruxolitinib treatment after 6 months as potential predictors of survival. 10,11 Improved survival seen with ruxolitinib use has been further validated on other real-world datasets, with the mechanism of improvement likely multifactorial including less debilitation, slower rates of leukaemic transformation, and fewer disease-associated complications. 12 Higher baseline QOL might also be associated with less diseaserelated debilitation, decreased hospitalisations, and fewer life-threatening complications.…”

Management of Myelofibrosis during Treatment with Ruxolitinib: A Real-World Perspective in Case of Resistance and/or Intolerance

“…Most of the physicians in this study considered treatment failure as the lack of SVR35% at 6 months, a suboptimal response as the lack of a minimal clinical benefit within 6 months, and progression as a >25% increase in SV from baseline or nadir or an increased WBC count together with decreased platelet counts and worsening of anemia. More recently, a prognostic model has been proposed to predict survival after 6 months of ruxolitinib in patients with MF [ 16 ].…”