CALR mutation burden in essential thrombocythemia and disease outcome.

ABSTRACT: Among 281 patients with essential thrombocythemia and calreticulin (CALR) mutation, we found a variant allele frequency of ≥60% to be associated with significantly shortened myelofibrosis-free survival, mostly apparent with CALR type-1 and CALR type-indeterminate mutations.

One thousand patients with essential thrombocythemia: the Florence-CRIMM experience.

We describe 1000 patients with essential thrombocythemia seen at the Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM), Florence, Italy, between 1980 and 2023: median age 59 years (18-95), females 65%, JAK2/CALR/MPL-mutated 66%/19%/4%, triple-negative (TN) 11%. Extreme thrombocytosis (ExT, platelets ≥1000 × 109/L) in 16%, leukocytosis (leukocytes >11 × 109/L) in 16%, and at least one cardiovascular risk factor in 52% of cases. JAK2-mutated patients were older (median 62 years) and CALR-mutated and TN (53 years for both) younger (p < 0.001). Female gender clustered with TN (76%) and JAK2 (67%) vs CALR (46%) mutations (p < 0.001). ExT clustered with CALR (type-2 more than type-1), TN and MPL, and leukocytosis with JAK2 mutation (p < 0.001). In multivariable analysis, risk factors for arterial thrombosis-free survival were age ≥60 years (HR 2.0; p < 0.001) and JAK2 mutation (HR 1.3; p = 0.02) with borderline significance for male gender (p = 0.08) and cardiovascular risk factors (p = 0.08); for venous thrombosis-free survival, JAK2 mutation (HR 1.9; p = 0.03) with borderline significance for venous thrombosis history (p = 0.07); for overall survival, older age (p < 0.001), male gender (HR 1.9; p < 0.001), absolute neutrophil count (ANC) ≥ 8 × 109/L (HR 1.8; p = 0.01), absolute lymphocyte count (ALC) < 1.7 × 109/L (HR 1.2; p = 0.03); for myelofibrosis-free survival, CALR mutation (HR 2.7; p < 0.001, particularly for CALR type 1/1-like, HR 3.3) and MPL mutation (HR 3.9; p = 0.001); for leukemia-free survival, older age (p = 0.03). Cytoreductive therapy appeared to mitigate both venous (HR 0.3; p = 0.01) and arterial thrombosis (HR 4; p = 0.04); there was a trend for aspirin in preventing arterial thrombosis recurrence. The current study provides real-world observations in essential thrombocythemia, representing a valid source document for interpreting current literature and planning future studies.

Compassionate use of JAK1/2 inhibitor ruxolitinib for severe COVID-19: a prospective observational study.

Overwhelming inflammatory reactions contribute to respiratory distress in patients with COVID-19. Ruxolitinib is a JAK1/JAK2 inhibitor with potent anti-inflammatory properties. We report on a prospective, observational study in 34 patients with COVID-19 who received ruxolitinib on a compassionate-use protocol. Patients had severe pulmonary disease defined by pulmonary infiltrates on imaging and an oxygen saturation ≤ 93% in air and/or PaO2/FiO2 ratio ≤ 300 mmHg. Median age was 80.5 years, and 85.3% had ≥ 2 comorbidities. Median exposure time to ruxolitinib was 13 days, median dose intensity was 20 mg/day. Overall survival by day 28 was 94.1%. Cumulative incidence of clinical improvement of ≥2 points in the ordinal scale was 82.4% (95% confidence interval, 71-93). Clinical improvement was not affected by low-flow versus high-flow oxygen support but was less frequent in patients with PaO2/FiO2 < 200 mmHg. The most frequent adverse events were anemia, urinary tract infections, and thrombocytopenia. Improvement of inflammatory cytokine profile and activated lymphocyte subsets was observed at day 14. In this prospective cohort of aged and high-risk comorbidity patients with severe COVID-19, compassionate-use ruxolitinib was safe and was associated with improvement of pulmonary function and discharge home in 85.3%. Controlled clinical trials are necessary to establish efficacy of ruxolitinib in COVID-19.