News of the Week

Keypoints:

• VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic) syndrome is a clonal hematoinflammatory disorder affecting older, predominantly male patients, characterized by systemic inflammation and progressive bone marrow failure.
• It is caused by somatic mutations in ubiquitin-activating enzyme E1 (UBA1), an X-linked gene, essential for initiating cellular ubiquitination. Loss-of-function mutations, most commonly M41 missense variants, lead to decreased expression of the cytoplasmic isoform, UBA1b, resulting in accumulation of misfolded proteins and activation of the endoplasmic reticulum stress pathway.
• Patients classically present with systemic and often refractory inflammation, requiring chronic glucocorticoid treatment and targeted immunosuppressive therapies.
• A central hallmark of this syndrome is progressive bone marrow failure and associated cytopenia, with a diagnosis of myelodysplastic syndromes (MDS) being reported in ~30% to 50% of patients, whereas only 1% of unselected patients with MDS have UBA1
• Important diagnostic MDS criteria include persistent and unexplained cytopenia in ≥1 peripheral blood lineages, morphologic dysplasia in ≥1 bone marrow (BM) cell lineages (comprising >10% of cells in the involved lineage[s]), an increase in peripheral blood/BM blasts, and presence of somatic mutations and/or cytogenetic abnormalities. Although somatic mutations can be seen in almost all patients with MDS, cytogenetic abnormalities are seen in only half of cases.
• In VEXAS syndrome, apart from the disease-defining UBA1 mutation, somatic mutations can be seen in ~60% of patients, with the clonal hematopoiesis landscape being dominated by DNMT3A and TET2 mutations, even in patients with an MDS diagnosis.
• Another feature of MDS in VEXAS syndrome is the very low risk of acute myeloid leukemia transformation, with only few cases having been reported thus far.
• Given the high degree of baseline dyspoiesis in VEXAS syndrome that may overlap with morphologic dysplasia, caution is warranted in rendering a diagnosis of MDS without characteristic genomic aberrations or increased blasts, and close attention to the clinical setting is imperative.
• Sustained and progressive cytopenia, especially requiring transfusions, with overt dysplasia, often multilineage, is highly suggestive of a diagnosis of MDS in VEXAS syndrome.
• Except for hematopoietic stem cell transplantation, hypomethylating agents are the only therapy that have demonstrated molecular responses and long-term remissions.
• In the absence of standardized clinical response criteria, it is difficult to know the exact rates of responses; however, in 2 major trials reported in the French cohorts (retrospective assessment for UBA1 mutation status), hematologic responses were approximated at 60% to 70%, whereas overall inflammatory responses were in the 50% to 60% range.
• Toxicities, particularly infection and early deaths within the first 6 cycles are notable with azacitidine treatment in VEXAS syndrome.
• Although MDS is the most commonly associated hematologic malignancy in VEXAS syndrome with canonical UBA1 mutations, plasma cell dyscrasias have been described in many small case series.
• For a disease described merely 6 years ago, there have been tremendous scientific advances to expand our knowledge of biology as well as clinical phenotypes owing to collaborative international efforts.

Recommendations emphasize prioritizing hematopoietic cell transplantation (HCT) for younger individuals with an available matched sibling or unrelated donor and as a second-line option after failure of immunosuppressive therapy (IST). The panel also recommended adding eltrombopag to immunosuppressive regimens and using antibiotic and antifungal prophylaxis for patients with neutropenia.

Keypoints:

• For patients aged <20 years and those aged 20 to 40 years, with severe or very severe aplastic anemia (AA) who have a matched sibling donor available, the American Society of Hematology (ASH) guideline panel suggests an HCT over IST.
• For patients aged >40 years with severe or very severe AA who have a matched sibling donor available, the ASH guideline panel suggests IST over HCT.
• For patients aged <20 years and those aged 20 to 40 years, with severe or very severe AA, the ASH guideline panel suggests either matched unrelated HCT or IST.
• For patients with severe or very severe AA, the ASH guideline panel suggests IST over haploidentical HCT.
• For adults and children with severe or very severe AA undergoing IST, the ASH guideline panel suggests the addition of eltrombopag to antithymocyte globulin (ATG) and cyclosporine.
• For patients aged >60 years with severe or very severe AA and no response to an initial course of IST, the ASH guideline panel suggests either HCT or a second ATG-based therapy.
• For patients aged <40 years and those aged 40 to 60 years, with severe or very severe AA who respond to a first course of IST but subsequently experience disease relapse, the ASH guideline panel suggests either HCT or a second ATG-based therapy.
• For patients with severe and very severe AA who do not respond to IST, the ASH guideline panel suggests initiating a second-line treatment no later than 6 months after ATG administration.
• Although some individuals with very severe AA (neutrophil count <0.2 × 10⁹/L) may respond to IST after 3 months, the severity of cytopenias and increased risk of adverse outcomes in this population may warrant an earlier decision to initiate second-line treatment.
• For patients with severe and very severe AA with a neutrophil count of <0.5 × 10⁹/L, the ASH guideline panel suggests mold-active antifungal prophylaxis.
• For patients with severe and very severe AA with a neutrophil count of <0.5 × 10⁹/L, the ASH guideline panel suggests antibiotic prophylaxis.

Key points: See Figure 1 in original paper.

Caring for pediatric hematology-oncology patients from families identifying as Jehovah’s Witnesses presents opportunities to align clinical and ethical care considerations, particularly regarding blood transfusion refusal. See Table 1 in original paper. Although transfusion avoidance is presumed, patient and family preferences are heterogenous and influenced by individual conscience, cultural context, and interpretation of religious guidance.

Position:

• Generally prohibited: Allogeneic whole blood; red blood cells; white blood cells; platelets; plasma.
• Personal discretion: Blood fractions (e.g., fibrinogen, albumin, immunoglobulins, clotting factors, cryoprecipitate); hemoglobin‐based products; cell salvage with continuous circuit (varies); epidural blood patch; fibrin sealant; cardiopulmonary bypass (if not primed with allogeneic blood).
• Generally accepted: Non-blood volume expanders (crystalloids, colloids); erythropoiesis-stimulating agents; iron; tranexamic acid; desmopressin; recombinant clotting factors; procoagulant medications; autologous blood transplantation; hemoglobin-based oxygen carriers.
• Although transfusion avoidance is often presumed, patient and family preferences are heterogeneous and influenced by individual conscience, cultural context, and interpretation of religious guidance.
• See Table 2 in original paper for management of transfusion-free hematopoietic cell transplant.

Highlights:

• This investigation identified dermal absorption of the gasoline additive N-methylaniline from fuel-contaminated seawater as the likely cause of recurrent, life-threatening methemoglobinemia associated with maritime migration.
• These findings underscore the importance of methylene blue availability, and frontline diagnostic capacity, including pulse CO-oximetry and rapid point-of-care Glucose-6-phosphate dehydrogenase testing. Such things are essential to improve outcomes in prehospital and maritime rescue settings where similar exposure conditions may occur.

Migrants crossing the Central Mediterranean sea route travel in overcrowded vessels, where fuel may leak and contaminate seawater accumulating on the vessel floor, resulting in prolonged dermal exposure and fuel-related skin injuries. Since March 2024, clusters of cases of severe acquired methemoglobinemia with no apparent cause have been identified by clinicians in Lampedusa at disembarkation among migrants arriving in Italy.
The authors conducted a coordinated clinical and toxicological investigation to characterize these cases and identify the cause. Between March 2024 and December 2025, a total of 82 patients with severe acquired methemoglobinemia were identified, 90% of whom were male; the median age of the patients was 22.5 years (interquartile range [IQR], 19.5 to 28.0). The median methemoglobin level at presentation was 44.6% (IQR, 32.0 to 55.7), with 43% of the patients having a level of ≥50%. Methylene blue therapy was used in 90% of the patients, often in repeated doses. Hemolytic anemia occurred as a delayed complication in 38 patients, frequently leading to blood transfusion. Two patients died. Toxicologic analysis identified N-methylaniline (a gasoline additive) or its metabolites in 37 of 39 tested patients (95%) and N-methylaniline at a concentration of 1.1% in the fuel sample from the vessel.

Highlights:
When fat pad and bone marrow sampling are combined, the pooled sensitivity rises to 89%, meaning only 11% of patients would ultimately require an organ biopsy for diagnosis.

The authors aimed to assess the diagnostic test accuracy of abdominal fat pad sampling and bone marrow biopsy for immunoglobulin light-chain amyloidosis using organ biopsy as the reference standard. After deduplication, 29,237 records were screened, and 31 studies were included. Twenty-five studies (n=4,649) reported on fat pad sampling, with a pooled sensitivity of 0.77 (95% CI 0.72–0.81), while twenty studies (n=2,771) reported on bone marrow biopsy, with a pooled sensitivity of 0.55 (0.46–0.63). All studies enrolled patients with confirmed disease, specificity was not reported in the included studies. Fat pad aspiration (15 studies, n=1,590) and surgical or punch biopsy (4 studies, n=222) showed similar sensitivities of 0.80 (0.76–0.83) and 0.77 (0.61–0.88), respectively. In a single study (n=612), performing both tests together yielded a sensitivity of 0.89.  Certainty of evidence (GRADE approach) was judged to be Moderate for fat pad sampling and Low for bone marrow biopsy.