ABSTRACT:Secondary myelofibrosis (SMF) represents a late stage of polycythemia vera (PV) and essential thrombocythemia (ET), with overall survival (OS) currently defined by the myelofibrosis secondary to PV and ET prognostic model (MYSEC-PM). To identify additional myeloid neoplasm-associated cancer gene variants (CGVs) associated with SMF outcome, we evaluated next-generation sequencing panel testing in 644 patients within the MYSEC cohort. Overall, 429 (66.6%) patients reported at least 1 CGV, with ASXL1, TET2, and DNMT3A being the most frequently involved. Specific molecular profiles affected OS (P< .001): U2AF1, TP53, or SRSF2 variants (UTS; 9.3%; median OS, 4.1 years) and ASXL1 without UTS (25.3%; median OS, 8.4 years). By integrating these genetic signatures within the MYSEC-PM through penalized Cox regressions, we identified the following independent predictors (P< .0001 to .02): hemoglobin level <11 g/dL (1 point), circulating blasts ≥3% (2 points), platelet count <150 × 109/L (2 points), age (0.21 points/y), ASXL1 without UTS mutations (1 point), and any UTS mutations (3 points). Finally, we developed the MYSEC-molecular prognostic model (MYSEC-mPM) allocating 582 patients with SMF into 4 categories with different OS (P < .001): low (median OS, 18.0 years; score <14), intermediate-1 (8.8. years; score, 14-16), intermediate-2 (4.6 years; score, 17-18), and high risk (1.9 years; score ≥19). Additionally, in 381 patients with SMF and available cytogenetics, the MYSEC-mPM was implemented with complex/monosomal karyotype, generating the karyotype-enhanced MYSEC-kmPM. Our study shows that genomic and cytogenetic profiling improves survival prediction in SMF, outperforming the MYSEC-PM.
BACKGROUND:Current society guidelines recommend physiological assessment of intermediate coronary lesions to guide revascularization. Data regarding revascularization guided by vessel fractional flow reserve (vFFR), derived from three-dimensional quantitative coronary angiography without the need for a pressure wire or hyperemic agent, as compared with pressure-wire-based fractional flow reserve (FFR), are lacking. METHODS:We conducted an international, open-label, randomized, noninferiority trial at 37 sites in Europe. Patients with intermediate coronary-artery lesions (diameter stenosis of 30 to 80%) who presented with chronic or acute coronary syndromes were randomly assigned in a 1:1 ratio to undergo either vFFR-guided or FFR-guided revascularization of the intermediate coronary-artery lesions. The primary end point was a composite of death from any cause, any myocardial infarction, or any revascularization at 1 year. The noninferiority margin was 3.0 percentage points. RESULTS:The primary end point was assessed in 1116 patients in the vFFR group and 1095 in the FFR group. The mean age of the patients was 67 years, 24.3% were women, 18.7% presented with an acute coronary syndrome, and 26.6% had diabetes mellitus. At 1 year, a primary end-point event had occurred in 80 patients (Kaplan-Meier estimate, 7.5%) in the vFFR group and in 79 patients (Kaplan-Meier estimate, 7.5%) in the FFR group (risk difference, -0.02 percentage points; 95% confidence interval, -2.25 to 2.21; P = 0.004 for noninferiority). The incidence of serious adverse events appeared to be similar in the two groups. CONCLUSIONS:Among patients with intermediate coronary lesions, vFFR-guided revascularization was noninferior to FFR-guided revascularization with respect to a composite of death, myocardial infarction, or revascularization at 1 year. (Funded by Pie Medical Imaging and Siemens Healthineers; FAST III ClinicalTrials.gov number, NCT04931771.).
B-cell receptor inhibitors (BCRi) and B-cell lymphoma-2 inhibitor (BCL2i) improved outcomes of patients with chronic lymphocytic leukemia (CLL), but relapsing after two inhibitors still represent an unmet clinical need. This multicenter real-world study analyzes outcomes of a cohort treated in Italy between May 2017 and September 2023 following prior exposure to both BCRi and BCL2i. The median follow-up after venetoclax initiation was 47 months (IQR 28-56). Of 153 double-exposed patients, 104 (68%) discontinued venetoclax and 53 of them (51%) received a subsequent treatment. Venetoclax was discontinued due to progressive disease (PD) in 51/104 cases (49.0%), with nine deaths occurring rapidly after PD without the administration of any further treatment. Fifty-three patients received treatment after venetoclax: 29/53 (54.7%) received inhibitors (13 cBTKi, 11 idelalisib, 2 BCL2i, 3 non-covalent BTKi), 19/53 (35.8%) received chemoimmunotherapy (CT: 16 intensive, 3 palliative), 5/53 (9.4%) received hematopoietic stem cell transplantation (HSCT). Overall response rate was 50%; median event free survival (EFS) in the groups of inhibitors, CT and HSCT was 11, 2, and 10 months, respectively (p < 0.0001); median overall survival (OS) was 12, 5, and 10 months, respectively (p = 0.020). Disease progression during venetoclax treatment was associated with shorter subsequent EFS compared to discontinuation for other reasons, even if the finding did not reach statistical significance (median EFS 4 vs. 10 months; p = 0.11). No decrease in EFS was associated with del17p and/or TP53 mutations, the use of venetoclax monotherapy or a previous treatment with one versus multiple BCRi. Despite its limitations, this real-world study provides additional insights into double-exposed patients, who still pose a clinical challenge, demonstrating the superior efficacy of inhibitors over alternative treatment options. Enrollment in clinical trial and treatments with novel molecules, if available, may help address this unmet clinical need.
Minimal residual disease (MRD) is the strongest prognostic factor in acute lymphoblastic leukemia (ALL). According to the European Guidelines, MRD monitoring is based mainly on real-time quantitative PCR (RQ-PCR) of IG/TCR rearrangements. However, RQ-PCR has some limitations, including the need for standard curves and the occurrence of positive non-quantifiable (PNQ) results, particularly at low disease levels. Digital droplet PCR (ddPCR) enables absolute quantification and may improve MRD resolution. We investigated whether MRD assessment by ddPCR could refine prognosis better than RQ-PCR in a cohort of adult Ph negative BCP and TALL enrolled into a clinical trial (NILG 10/07 NCT 00795756). Overall, 101 patients were analyzed. Concordance between RQ-PCR and ddPCR was found in 73 patients (71%), while ddPCR reclassified as positive 28/101 patients (29%) defined as negative or PNQ by RQ-PCR. This molecular reclassification identified a subgroup with a significantly higher cumulative risk of relapse at 5-year (CIR, 43% vs 18%, p=0.02). In BCP-ALL, RQ-PCRneg/ddPCRpos patients showed a relapse risk comparable to RQ-PCR-positive cases and had inferior RFS and OS compared with RQ-PCRneg/ddPCRneg patients. In TALL , ddPCR improved MRD resolution, although outcome differences were less pronounced. The findings suggest that ddPCR MRD can refine MRD risk stratification in adult ALL, particularly among patients with RQ-PCR-negative or PNQ results. Given the increasing adoption of NGS-based MRD assessmentour results also support a potential hybrid strategy in which NGS is used upfront for clonotype identification, and ddPCR is subsequently applied for sensitive, rapid, and cost-effective longitudinal MRD monitoring. Prospective validation is warranted.
