Abstract Once-daily (od), low-dose aspirin (75–100 mg) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia (ET). This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera, with the assumption of similar aspirin pharmacodynamics in the two settings. However, the pharmacodynamics of low-dose aspirin is impaired in ET, reflecting accelerated renewal of platelet cyclooxygenase (COX)-1. ARES is a parallel-arm, placebo-controlled, randomized, dose-finding, phase II trial enrolling 300 ET patients to address two main questions. First, whether twice or three times 100 mg aspirin daily dosing is superior to the standard od regimen in inhibiting platelet thromboxane (TX)A 2 production, without inhibiting vascular prostacyclin biosynthesis. Second, whether long-term persistence of superior biochemical efficacy can be safely maintained with multiple vs. single dosing aspirin regimen. Considering that the primary study end point is serum TXB 2 , a surrogate biomarker of clinical efficacy, a preliminary exercise of reproducibility and validation of this biomarker across all the 11 participating centers was implemented. The results of this preliminary phase demonstrate the importance of controlling reproducibility of biomarkers in multicenter trials and the feasibility of using serum TXB 2 as a reliable end point for dose-finding studies of novel aspirin regimens.
Abstract Background Patients with cytopenic myelofibrosis (MF) have more limited therapeutic options and poorer prognoses compared with patients with the myeloproliferative phenotype. Aims and Methods Prognostic correlates of cytopenic phenotype were explored in 886 ruxolitinib‐treated patients with primary/secondary MF (PMF/SMF) included in the RUX‐MF retrospective study. Cytopenia was defined as: leukocyte count <4 × 10 9 /L and/or hemoglobin <11/<10 g/dL (males/females) and/or platelets <100 × 10 9 /L. Results Overall, 407 (45.9%) patients had a cytopenic MF, including 249 (52.4%) with PMF. In multivariable analysis, high molecular risk mutations ( p = .04), intermediate 2/high Dynamic International Prognostic Score System ( p < .001) and intermediate 2/high Myelofibrosis Secondary to Polycythemia Vera and Essential Thrombocythemia Prognostic Model ( p < .001) remained associated with cytopenic MF in the overall cohort, PMF, and SMF, respectively. Patients with cytopenia received lower average ruxolitinib at the starting (25.2 mg/day vs. 30.2 mg/day, p < .001) and overall doses (23.6 mg/day vs. 26.8 mg/day, p < .001) and achieved lower rates of spleen (26.5% vs. 34.1%, p = .04) and symptom (59.8% vs. 68.8%, p = .008) responses at 6 months compared with patients with the proliferative phenotype. Patients with cytopenia also had higher rates of thrombocytopenia at 3 months (31.1% vs. 18.8%, p < .001) but lower rates of anemia (65.6% vs. 57.7%, p = .02 at 3 months and 56.6% vs. 23.9% at 6 months, p < .001). After competing risk analysis, the cumulative incidence of ruxolitinib discontinuation at 5 years was 57% and 38% in patients with cytopenia and the proliferative phenotype ( p < .001), whereas cumulative incidence of leukemic transformation was similar ( p = .06). In Cox regression analysis adjusted for Dynamic International Prognostic Score System score, survival was significantly shorter in patients with cytopenia ( p < .001). Conclusions Cytopenic MF has a lower probability of therapeutic success with ruxolitinib as monotherapy and worse outcome. These patients should be considered for alternative therapeutic strategies.
Topic: 10. Myelodysplastic syndromes - Clinical Background: Chronic Myelomonocytic Leukemia (CMML) is a rare hematologic malignancy at risk to progress to secondary acute myeloid leukemia (AML). Few patients are reported in the literature to have both CMML and plasma cell disease, mostly Multiple Myeloma; furthermore, no data about concomitant detection and significance of monoclonal gammopathy of undefined significance (MGUS) are available. Aims: We retrospectively conducted an analysis of patients affected by CMML, prospectively diagnosed at three hematological centres to study the incidence and characteristics of MGUS, and the correlation with outcomes. Methods: Data from 84 consecutive CMML patients, diagnosed according to the WHO 2016 criteria between 1995 and 2022, were evaluated. Data about clinical, morphological and hematological features of CMML patients and type of treatment were collected retrospectively. The CMML-specific prognostic score system (CPSS) was used to define the prognosis of all patients. Time to progression in AML and overall survival (OS) were determined from CMML diagnosis to the LAM evolution and to death or last contact, respectively. Results: The median age at diagnosis was 73 years (range 19 - 90), 57 patients were males (68%) and 27 females (32%). According to WHO 2016 classification we identified 35 (42%) myelodysplastic CMML and 49 (58%) myeloproliferative CMML; 39 (46.4%) patients were classified as CMML-0, 29 (34.6%) as CMML-1 and 16 as (19.1%) CMML-2. CPSS risk score was low in 24 (28.6%), intermediate-1 in 26 (30.9%), intermediate-2 in 25 (29.8%), and high in 8 (9.5%) patients, respectively. Most cases (n= 68, 80.9%) were oligoblastic forms (blasts < 5% in peripheral blood and < 10% in bone marrow). According to treatment, 10 (11.9%) patients received hypomethylating agents (5-azacitidine), 19 (22.6%) hydroxyurea, 17 (20.2%) allogeneic haematopoietic stem cell transplantation as upfront or consolidation therapy, 32 (38.1%) patients did not receive any treatment. Progression to AML occurred in 23 (27.4%) cases. At last follow up, 36 (42.9%) patients were alive; the median overall survival of the entire cohort was 20 months (range 0.8 – 329). Concomitant MGUS was detected in 18 (21.4%) of 82 evaluable patients: 11 (61.1%) were males, 7 (38.9%) females; all patients were older than 60. 9 patients (50%) were CMML-0, 4 (22.2%) CMML-1 and 5 (27.8%) CMML-2, with a prevalence of oligoblastic forms in 72.2% of cases; CPSS was low/intermediate-1 in 11 (61.1%) and intermediate-2/high in 7 (38.9%) cases respectively. Summary/Conclusion: In our cohort of CMML patients, concomitant MGUS was detected in one-fifth of patients, with about two-third of cases occurring in oligoblastic forms and lower CPSS risk classes. No difference in terms of AML progression or impact on survival was evidenced. Our data suggest that MGUS may occur frequently in patients with lower risk CMML without impact on disease outcome; further analyses will be needed to confirm this observation.Keywords: CMML, Myeloid malignancies, MGUS, Chronic myelomonocytic leukemia
In polycythemia vera (PV), the prognostic relevance of an ELN-defined complete response (CR) to hydroxyurea (HU), the predictors of response, and patients' triggers for switching to ruxolitinib are uncertain. In a real-world analysis, we evaluated the predictors of response, their impact on the clinical outcomes of CR to HU, and the correlations between partial or no response (PR/NR) and a patient switching to ruxolitinib. Among 563 PV patients receiving HU for ≥12 months, 166 (29.5%) achieved CR, 264 achieved PR, and 133 achieved NR. In a multivariate analysis, the absence of splenomegaly (p = 0.03), pruritus (p = 0.002), and a median HU dose of ≥1 g/day (p < 0.001) remained associated with CR. Adverse events were more frequent with a median HU dose of ≥1 g/day. Overall, 283 PR/NR patients (71.3%) continued HU, and 114 switched to ruxolitinib. In the 449 patients receiving only HU, rates of thrombosis, hemorrhages, progression, and overall survival were comparable among the CR, PR, and NR groups. Many PV patients received underdosed HU, leading to lower CR and toxicity rates. In addition, many patients continued HU despite a PR/NR; however, splenomegaly and other symptoms were the main drivers of an early switch. Better HU management, standardization of the criteria for and timing of responses to HU, and adequate intervention in poor responders should be advised.
