Overall and cause specific changes in mortality of patients with myelofibrosis over the last 3 decades

ABSTRACT

Background: Patients with myelofibrosis (MF) have decreased overall survival with a median of 5 years. Leading causes of death are believed to be directly or indirectly related to MF progression or complications, including transformation to acute leukemia (AML) and infections. Aims: We aimed to compare survival, mortality rate and causes of death of MF patients referred to our institution before (≤) and after the years of 2010. Methods: This retrospective study included patients with MF diagnosed within one year prior to their presentation to our institution (between January 1990 and February 2020, 4% presented < year 2000). Patients with unknown cause of death or loss to follow-up were excluded (final cohort, n = 995). Causes of death were divided into groups i) MF progression;ii) AML (≥ 20% blasts);iii) sudden multi-organ failure or vascular event (possibly related to MF, Vasc/MOF);iii) infections (MF had to be controlled or in remission);iv) other (unrelated medical conditions). We calculated crude mortality rate per 1000 person - years of observation (comparison by Poisson's regression) and overall survival (by Kaplan Meier method with log rank test). To account for variations in age groups (< 49;50-59;60-69;and 70+ years), we assessed age-adjusted mortality rates per 1000 person-years standardized for the entire cohort. Results: The study included 378 and 617 patients ≤ and > 2010, respectively, 59% of which were males. Sixty-five percent of patients were ≥60 years. Distribution of age groups between periods was comparable, except for higher proportion of 70+ year old patients > 2010, counterbalanced by lower proportion of < 60 years. Over the observation time of 1942 and 1608 person-years for ≤ and > 2010, 206 (55%) and 100 (16%) of patients died, respectively (p < 0.001, RR 0.54, CI 0.48-0.63). Crude, age-adjusted and cause-specific mortality per 1000 person-years in both periods is outlined in Table. Overall mortality, both crude and age-adjusted, was significantly higher ≤ 2010 irrespectively of gender and age. As expected, crude mortality steadily increased with age in both periods. For each of the respective age groups, more patients died ≤ 2010 than > 2010. In both periods, males COVID-19 (n= 30 PV, n= 30 ET, n= 30 PMF) (45 men, 45 women, mean age 50 years, range 30-60). All patients gave written informed consent for study enrollment. The mean duration of disease was 12 years. All patients were on ASA 100 mg once daily. Concerning presentation and therapy, our MPNs patients with COVID-19 and without COVID-19 had not comorbidities and drug treatment was consistent with therapeutic standards (hydroxyurea, interferon, anagrelide, ruxolitinib). All patients were on ASA 100 mg once daily. IL-6 was measured by multiplex bead array (Millipore Sigma), TF and DD, and TAT by ELISA and Fib by Clauss method. PF4 was determined by ELISA. Whole blood viscoelastic analysis including clotting time (CT), and clot formation time (CFT) were measured by thomboelastometry method. Results: MPNs with COVID-19 had high IL-6 and TF (50±12pg/ml and 1950±500 pg/ml) compared with MPNs without COVID-19 (3±2pg/ml and 19±2 pg/ml), as well as DD, TAT and Fib (549±100 □g/l, 69±10 □g/l and 590±20mg/dl) compared with MPNs without COVID-19 (59±5□g/l, 2±1□g/l and 149±10 mg/l). PF4 was elevated (150.1□62.7 IU/ml) in MPNs with COVID-19 compared with MPNs without COVID-19 (2□1 UI/ml). A positive correlation was found between inflammatory, endothelial and coagulation mediators. A p-value of <.05 was considered statistically significant. Shortened CT (CT, unit s. n.v. 100-240 s) (40±20 s) and shortened CFT (CFT, unit s, n.v. 30-160 s (14±10 s) there were in MPNs with COVID-19 compared with MPNs without COVID-19 (CT 99±10 s and CFT 39±5 s). Summary/Conclusion: These data suggest that COVID-19 infection in MPNs patients may increase the thrombotic risk and get worse prognosis. In our opinion, this study can serve as a baseline study of COVID-19 thrombotic risk in MPNs and it is worthy of dissemina ion amongst patients and clinician communities.