News of the Week

Highlights:

• Missense mutations in EZH2, present in 20%–25% of patients with follicular lymphoma (FL), impair transcriptional programs regulating cell cycle and plasma‐cell differentiation, promoting oncogenic transformation.
• EZH2 mutations are associated with a more favorable prognosis in patients receiving chemoimmunotherapy.
• A previous retrospective single‐center study suggested that EZH2 status may influence treatment response and guide regimen selection: patients with EZH2‐mutated FL achieved improved progression‐free survival (PFS) and overall survival when treated with R‐CHOP compared to R‐bendamustine, whereas patients with wild‐type EZH2 could obtain a greater benefit from R‐bendamustine.
• In this study, EZH2 mutations were associated with inferior PFS in patients treated with R‐bendamustine. These findings are consistent with the biological role of EZH2 in FL, where gain‐of‐function mutations promote aberrant germinal center maintenance and treatment resistance.

Data from 324 patients diagnosed with FL between 2002 and 2020 at six Spanish academic hospitals were analysed. Only patients who completed or were planned to receive six full‐dose cycles of R‐CHOP or R‐bendamustine were included. All included patients had newly diagnosed, previously untreated FL. Those who had prior systemic therapy for FL were excluded. In total, 82 patients (25%) presented EZH2 variants: 14/70 in the R‐bendamustine group (20%) and 68/254 in the R‐CHOP group (27%) (P=0.28). In patients with mutated EZH2 (n=82), 6‐year PFS was significantly worse when treated with R‐bendamustine compared with R‐CHOP (37% vs. 60%; P=0.026).

Highlights:

• High-dose methotrexate (HD-MTX)-based immunochemotherapy remains the standard for primary CNS lymphoma (PCNSL), yet relapse rates are high and outcomes suboptimal.
• While Bruton’s tyrosine kinase inhibitors (BTKi) demonstrate efficacy in trials, their comparative benefit against conventional regimens in heterogeneous real-world populations remains undefined.
• These study findings suggest that integrating BTKi into frontline regimens is associated with a favorable progression-free survival (PFS) profile and improved response in newly diagnosed PCNSL. Definitive overall survival (OS) conclusions cannot be drawn.

131 newly diagnosed patients were stratified by frontline induction therapy (BTKi-based, n=85; conventional, n=46). BTKi-based therapy was associated with improved PFS (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.32–1.00; P=0.048) and a higher complete response rate (odds ratio [OR] 5.50, 95% CI 2.25–13.47; P<0.001). The objective response rate was also higher (OR 2.59, 95% CI 1.05–6.36; P=0.038). The OS difference was not statistically significant (HR 0.65, 95% CI 0.31–1.38; P=0.263) which may reflect multifactorial confounding inherent in this retrospective comparison.

Key points:

• Autoimmune neutropenia (AiN) in adults is rare when compared with children. It occurs predominantly in female patients and in individuals with other autoimmune conditions. See Figure 2 in original paper.
• It is important to distinguish AiN from congenital isolated neutropenia disorders, for which genetic testing can be helpful, and from a low absolute neutrophil count (ANC) due to lack of the Duffy antigen. Duffy-null–associated neutrophil count is entirely benign and found in ~80% of individuals of sub-Saharan African ancestry, as well as people of Middle Eastern descent, with at a lower frequency in other populations.
• AiN can be primary (eg, occurring in the absence of a clear trigger) or secondary (eg, developing in the setting of an underlying autoimmune condition, lymphoproliferative disorder, or infection).
• AiN can also occur in concert with other autoimmune cytopenias, such as autoimmune hemolytic anemia and/or immune thrombocytopenia.
• Anti-neutrophil antibodies are detected in ~50% of patients with AiN, and it is not clear whether this reflects testing limitations or cell-mediated (rather than antibody-mediated) mechanisms of neutrophil destruction.
• Unlike the commonly self-limited pediatric disease, adult AiN is generally chronic. The degree of neutropenia and clinical severity is highly variable, and most patients remain asymptomatic and free of infection despite ANCs persistently lower than 500/μL.
• Because most patients do well despite their neutropenia, observation and supportive care are generally preferred over active treatment.
• Therapy focuses on boosting endogenous neutrophil production, reducing immune-mediated destruction, or eliminating pathogenic autoantibodies. See Figure 4 in original paper.
• For patients with AiN who present with infections, granulocyte colony-stimulating factor (G-CSF) in addition to empiric antibiotic therapy is the mainstay of initial management.
• The authors typically administer G-CSF daily until the ANC is >1000/μL for 2 consecutive days. Some patients with AiN never achieve an ANC of >1000/μL, and therefore, this recommendation must be tailored to each individual patient (eg, G-CSF until afebrile × 72 hours).
• Some patients with AiN can have a rapid and robust rise in ANC and therefore, the authors tend to avoid the longer-acting pegylated forms of G-CSF in lieu of the short-acting formulation.
• In the outpatient setting, the frequency of G-CSF administration should be adjusted to maintain adequate neutrophil support while avoiding potential side effects (eg, bony pain) and undue burden for the patient and caregivers.
• For long-term or chronic administration, most patients do well with G-CSF administered twice weekly or 3 times weekly.
• Clinical response is highly variable, and second-line therapies, including T cell-directed approaches, can be effective, supporting a role for cell-mediated mechanisms of neutrophil destruction in a subset of patients.
• The authors propose that treatment response criteria focus first on clinical well-being (including the absence of recurrent infections) and then, possibly, on a percentage change in ANC from the patient’s personal baseline.

This comprehensive Review provides essential background information and illustrations summarising relevant hereditary haemorrhagic telangiectasia (HHT) pathophysiology, followed by focused, detailed discussions of each of the novel agents in development, including the mechanisms, therapeutic rationale, clinical trial programmes, and potential therapeutic effects

Key points:

• HHT is the second most common heritable bleeding disorder worldwide, with a prevalence more than twice that of haemophilia, and is the most morbid inherited bleeding disorder of women.
• As an autosomal dominant vasculopathy due to dysregulated angiogenic signalling, patients with HHT develop telangiectasias and arteriovenous malformations which cause numerous complications.
• These complications include moderate-to-severe chronic epistaxis, gastrointestinal bleeding, iron deficiency anemia, and requirement for intravenous iron or red cell transfusion. Additionally, incidence of intracranial haemorrhage is high and morbid non-bleeding complications, such as venous thromboembolism, stroke, and liver disease, are common.
• Many novel, investigational agents targeting vascular and haemostatic systems are now rapidly undergoing formal development: See Table in original paper. These agents include:
• The selective activin receptor-like protein kinase AKT1/AKT2 inhibitor (engasertib)
• AKT1-selective inhibitors (ATV-1601 and TER-4480)
• Plasminogen siRNA agent (ALN-6400)
• Activin receptor-like kinase 1–bone morphogenetic protein receptor type II bispecific clustering antibody (DIAG723)
• Apelin receptor antagonist antibody (TX2100)

Key points:

• Janus kinase inhibitors are the cornerstone of treatment for myelofibrosis, but have limited disease-modifying activity.
• Combinations of ruxolitinib with pelabresib, navitoclax, or selinexor improve spleen responses, although benefits for symptoms and anemia are less consistent, and toxicity may increase. Such approaches may optimize splenomegaly before transplantation.
• Emerging calreticulin (CALR)-directed therapies, particularly INCA033989, offer potential for selective suppression of the malignant clone while improving spleen, anemia, and symptom outcomes.
• Anemia-directed agents targeting TGF-β/BMP-SMAD signaling, including luspatercept, elritercept, and selcodebart, may reduce transfusion burden.
• Future strategies should align treatment with therapeutic intent and prioritize transplantation, molecular response, progression-free survival, and overall survival endpoints.