A Population-Based Study on Survival of Higher Risks Myelofibrosis Patients Treated with Ruxolitinib in the Italian Lombardy Region

Introduction Myelofibrosis (MF) is a severe disease, and patients in the higher prognostic risk categories have a median overall survival (OS) between two and four years after diagnosis. Ruxolitinib (RUX) is the first approved drug for MF, with efficacy in terms of reduction of spleen and symptoms. An improvement of OS with RUX has been reported in different studies, such as a post-hoc analysis of the registration trials (Verstovsek et al, 2017) and in the real-world setting (Guglielmelli et al, 2022).

In Italy, RUX is available since October 2014 for intermediate-2 (INT-2) and high risk (HR) and since January 2018 for intermediate-1 MF cases. High-cost drugs are delivered and monitored by each regional health authority. In this study, we analyzed the outcome of INT-2 and HR MF patients treated with RUX in Lombardy, a region of roughly 10 million individuals.

Methods This is a population-based retrospective cohort study based on healthcare utilization databases of Lombardy region, including data on hospital admissions, drug prescriptions, outpatient's health services and demographics.

The study cohort included all beneficiaries of the Regional Health Service who started RUX between October 2014 and December 2017 (to include only INT-2 and HR MF patients) and followed-up until 31st July 2021 (minimum observation period of the study: 3.5 years).

The primary outcome of the study was OS, defined as the time between RUX start and death for any cause or censoring due to migration or to end of data availability. The secondary outcome was time-to-treatment failure (TTF), defined as the time between RUX start and interruption for any reason, including allogenic stem cells transplant (allo-SCT) or death, or censoring. OS and TTF were estimated by the Kaplan-Meier method and 95% confidence interval (95%CI) was calculated.

The incidence of adverse events (AEs) and secondary malignancies (included blast phase, BP, or post MF-myelodysplastic syndromes, MDS) that required hospital admission and occurring during follow-up was assessed and expressed as incidence rate (IR) x100 person-years (p-y). Infections, bleedings, and major thrombotic events were considered if they occurred within 90 days from the last RUX prescription and before evolution into BP/MDS.

Results During study period, 315 MF patients started RUX. Median age at first administration was 70 years (range, 24-92) and 57% were females. Within the three months preceding RUX start (from now on, referred to as "baseline"), 76 (24%) subjects received at least one red blood cells (RBC) transfusion unit and, among those, 18 (24%) could be classified as RBC transfusion-dependent (TD- Gale et al, 2011).

RUX initial dose was <20 mg bid in 216 (69%) subjects and, within this subgroup, 93 (43%) started with only 5 mg bid. As for the 284 (90%) patients with at least six months of RUX exposure, modification of RBC transfusions needs compared to baseline is reported in Table 1.

Median study follow-up was 40.5 months (range, 1-82). Overall, 173 (55%) deaths were observed. Median OS was 46.3 months (95%CI: 41.6-56.0), as reported in Figure 1. Treatment failure was observed in 144 (46%) patients, and the median TTF was 25.3 months (95%CI: 19.6-33.9). Among those subjects, median treatment duration was 12 months (range, 0.9-75.5). Allo-SCT was performed in 36 (11.4%) subjects at a median time of 8.7 months (range, 1.4-66.7) after RUX start.

The most frequent AEs were infections (IR: 13.5 x100 p-y), bleeding events (4.2 x100 p-y) and thrombosis (1.8 x100 p-y). Secondary solid tumours had an IR of 4.5 x100 p-y, while the latter was 1.2 x100 p-y for lymphoproliferative disorders. Evolution into BP/MDS was reported in 58 (18%) of the cohort, with an IR of 5.8 x100 p-y.

Conclusions This study provided a real-world description of RUX treatment outcomes in an unselected population-based cohort of patients with higher risks MF, reflecting the daily clinical practice in Lombardy, the most populated Italian region.

In this cohort of 315 long observed INT-2 and HR MF patients, RUX demonstrated to have a robust effect on survival. Among patients without baseline transfusions needs, 21% started receiving RBC units during the first six months of exposure to RUX. In the same period, 77% of subjects that transfused at baseline continued receiving RBC units. MF progression rate into BP/MDS after RUX start was comparable to data of the pre-RUX era, confirming this still remains an unmet clinical need in the field.

Mora:Novartis: Speakers Bureau. Guglielmelli:Novartis, Abbvie: Other: Other member of advisory board, speaker at meeting. Voso:Astellas: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; jazz: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau. Vannucchi:Morphosys: Membership on an entity's Board of Directors or advisory committees; AOP Orphans Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BluePrint: Membership on an entity's Board of Directors or advisory committees, Other: NA; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Other: NA; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Passamonti:Novartis, Celgene, BMS, Abbvie, Janssen, Roche, AOP Orphan, Karyopharma, KYOWA KIRIN, Mei: Consultancy, Honoraria, Speakers Bureau; BMS: Research Funding.