Cytopenias and Failure to Use Innovative Therapy Are Main Drivers of Worse Outcome after Discontinuation of Ruxolitinib in Myelofibrosis
Authors: Palandri Francesca , Breccia Massimo , Morsia Erika , Benevolo Giulia , Tiribelli Mario , Beggiato Eloise , Farina Mirko , Martino Bruno , Caocci Giovanni , Pugliese Novella , Tieghi Alessia , Crugnola Monica , Binotto Gianni , Cavazzini Francesco , Abruzzese Elisabetta , Isidori Alessandro , Dedola Alessandra , Scalzulli Emilia , Moioli Alessia , Guglielmana Veronica , Caserta Santino , Duminuco Andrea , Lemoli Roberto Massimo , Cilloni Daniela , Bocchia Monica , Pane Fabrizio , Heidel Florian , Elli Elena Maria , Bonifacio Massimiliano , Palumbo Giuseppe Alberto , Branzanti Filippo 
Published: December 2024

Introduction
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by marrow fibrosis, and progressive splenomegaly, symptoms and cytopenias. Ruxolitinib (RUX) is a JAK1/2 inhibitor that can reduce spleen size and symptom burden and improve overall survival (OS). However, the prognosis after RUX discontinuation is poor, particularly in patients (pts) with clonal evolution and/or leukemic transformation (LT) (Newberry et al, Blood 2017). Limited data are available on clinical outcomes of pts discontinuing RUX while in chronic phase.
Aims
To evaluate the outcomes after RUX discontinuation of chronic phase MF pts, focusing on the impact of disease phenotype and subsequent treatment strategies on OS.
Methods
After IRB approval (approval file number: 048/2022/Oss/AOUBo), the “RUX-MF” retrospective multicenter study collected 1055 MF pts who received RUX outside clinical trials.
Survival analyses were performed using Kaplan-Meier curves, and differences were evaluated using the log-rank test. OS was calculated from the date of ruxolitinib discontinuation to death, allogeneic transplant (ASCT), last contact or from the date of 2nd line therapy start, to either death, or last contact. Cox regression models and delay entry were used to perform estimated survival plots.
Results
Among 1055 pts included in the RUX-MF study, 718 (68.1%) pts discontinued RUX; 397 pts were alive and in chronic phase at RUX discontinuation and were included in this analysis. Median OS of these 397 pts from RUX stop was 27.6 months (1.2 - 181.2).
At RUX discontinuation, 208 (52.4%) pts had a cytopenic phenotype, including 122 pts with only platelet (PLT) ≤100 x109/L, 35 pts with only hemoglobin (Hb) ≤8 g/dL, and 51 pts having both low PLT and Hb values. Among the remaining 189 pts, 55 had a fully proliferative phenotype (Hb&gt;10 g/dL, PLT&gt;100 x109/L and spleen palpable ≥5 cm below costal margin, BCM) and 134 had a mild anemia (Hb between 8 and 10 g/dL) with or without palpable splenomegaly.
OS at 3 years was 33.4% in cytopenic and 54.4% in non-cytopenic pts (median OS: 3.9 vs 1.5 years, p&lt;0.001), with no differences between pts with fully proliferative or mildly anemic myelofibrosis (p=0.73). After DIPSS adjustment, the difference in OS remained significant (p=0.002).
At RUX discontinuation, 175 pts (44.1%) had a large spleen (palpable ≥10 cm BCM). OS at 3 years was 33.5% and 51.6% in pts with and without large splenomegaly (median OS: 2.1 vs 3.3 years, p=0.01), confirmed after DIPSS adjustment (p=0.04). Notably, large splenomegaly was associated with poorer OS only in non-cytopenic pts (44.5% vs 60.7% without large spleen, p=0.05). In the cytopenic cohort, the presence of a large spleen did not significantly affect OS (p=0.26).
Within 1 year from RUX stop, 272 pts received a 2nd line therapy: conventional therapy (CT: including hydroxyurea, steroids, danazol, busulfan, RUX rechallenge, splenectomy, interferon and RBC/PLT transfusions; n.119), novel therapy (NT: experimental drugs and novel JAK2 inhibitors; n.71) and ASCT (n.82).
Compared to pts receiving NT and ASCT, pts treated with CT had higher DIPSS risk and larger spleen (both p&lt;0.001), lower PLT and Hb values (both p=0.02). The other clinical/laboratory features including driver and additional mutations were comparable.
OS at 3 years was 22.8%, 49.1% and 62.5% in CT, NT and ASCT pts, respectively (p&lt;0.001). This was confirmed after adjustment for DIPSS, PLT and spleen length (p&lt;0.001). The same OS distribution was observed in separate analysis including only pts with/without large splenomegaly and pts with/without cytopenic phenotype (all p&lt;0.001).
In multivariable Cox analysis including cytopenic phenotype, CT (vs NT) and large splenomegaly, only cytopenic phenotype (HR: 1.57, 95% CI: 1.10 - 2.28; p&lt;0.001) and CT (HR: 1.82, 95% CI: 1.20 - 2.77; p=0.005) remained significantly associated with worse OS.
Conclusions
In chronic phase MF pts, OS after RUX discontinuation ranges around 2.5 yrs, suggesting a significant unmet clinical need. Large spleen in myeloproliferative MF and cytopenic phenotype are key determinants of prognosis after RUX discontinuation. ASCT and NT represent superior approaches compared to CT regardless of disease phenotype and should be prioritized whenever possible to improve pts outcomes. Personalized treatment strategies targeting these specific phenotypes are warranted to improve OS after ruxolitinib discontinuation.