Integration of torque teno mini virus (TTMV) generating the TTMV::RARA (retinoic acid receptor α) fusion represents a newly recognized subtype of acute promyelocytic leukemia (APL) that merits detailed investigation. We present, to our knowledge, the first comprehensive characterization of its epidemiologic profile, clinical presentation, virologic characteristics, and underlying molecular mechanisms. Our findings indicate that TTMV::RARA is more prevalent in pediatric patients and represents the second most common retinoic acid receptor fusion after PML::RARA. Affected patients exhibit a high incidence of extramedullary involvement, particularly myeloid sarcoma. Cytogenetic abnormalities involving i(17)(q10) or 7q22 were identified in 52.0% of cases, largely in a mutually exclusive manner. Co-occurring mutations in epigenetic regulators were present in 76.9% of patients. Although most patients achieved initial remission, relapse was common and associated with rapid acquisition of all-trans retinoic acid (ATRA)-resistant mutation and secondary chemoresistance. Venetoclax-containing regimens demonstrated encouraging clinical efficacy. Phylogenetic analysis indicated that patient-derived TTMV strains clustered into a distinct clade. TTMV integration consistently occurred within RARA intron 2, involving a consensus fragment of 510 to 610 base pairs encompassing the viral promoter and open reading frame 2 (ORF2) N terminus, likely mediated by microhomology-driven recombination. Tandem RUNX1-binding motifs within the integrated viral promoter may underlie the myelotropism of these TTMV strains and facilitate transcriptional activation of TTMV::RARA. The chimeric protein retains at least the first 56 N-terminal residues of ORF2 and remains transcriptionally responsive to pharmacological concentrations of ATRA. These findings establish TTMV::RARA-APL as a distinct leukemia entity, laying the foundation for future studies on virus-mediated leukemogenesis and therapeutic strategies.

Asparaginase-associated pancreatitis (AAP) is a significant complication in pediatric acute lymphoblastic leukemia (ALL) therapy, often leading to treatment delays or discontinuation. This study aimed to identify AAP risk factors, assess outcomes after first and second episodes, and evaluate the impact of asparaginase rechallenge. We retrospectively analyzed 7640 patients (aged 1 month to 18 years) treated under the Chinese Children Cancer Group ALL 2015 protocol. Patients were stratified as low risk (LR), intermediate risk (IR), or high risk (HR) based on clinical features and measurable residual disease (MRD). AAP was categorized as early or late onset depending on treatment phase. Older age and IR/HR status were independent risk factors for AAP. The cumulative AAP incidence was 2.2% in LR and 5.8% in IR/HR groups. Among 298 patients who developed AAP, 92 were rechallenged with asparaginase; second episodes occurred in 20.8% of LR and 33.8% of IR/HR patients, with no increase in severity. Lack of rechallenge and day 46 MRD of ≥0.01% were independently associated with inferior event-free survival (EFS). Among patients with early-onset AAP, those who were rechallenged had superior 5-year EFS than those who were not rechallenged (80.1% vs 60.2%; P = .003). Similarly, among IR/HR group, those who were rechallenged had better 5-year EFS than those who were not rechallenged (82.4% vs 60.6%; P = .004). IR/HR patients with early-onset AAP who were not rechallenged had especially poor outcomes (5-year EFS, 53.3%). These findings support considering asparaginase rechallenge in IR/HR patients with early-onset AAP when alternative therapies are limited. This trial was registered at www.chictr.org.cn as #ChiCTR2000032211.

The US Food and Drug Administration recently licensed 14-day cold-stored platelets for bleeding patients. This policy change represents a reversal from the 1970s when cold-stored platelets were discontinued because of their short circulation time in healthy humans. This change will increase their availability in US hospitals with large trauma populations and in remote and rural settings in the United States. In some of these hospitals, cold-stored platelets will be the only platelets available. It is currently unclear whether patients with hypoproliferative thrombocytopenia who need platelet transfusion for prophylaxis benefit from cold-stored platelets. However, it is noteworthy that in recent clinical trials using room temperature-stored platelets, the transfusion interval in patients with hematologic and oncologic conditions can be as short as 1 transfusion per day, very similar to what one would expect to achieve with cold-stored platelets. Furthermore, the emphasis on the posttransfusion count increment and the platelet count as a transfusion trigger per se is questionable. In the PLADO trial, there was only a poor correlation between the morning platelet count and bleeding events, implicating other factors, such as red blood cells, coagulation factors, and vascular health, as possible culprits. In this perspective article, we review the history of cold platelets and the reason for their discontinuation, focus on recent clinical trial data using room temperature-stored platelets, and review the platelet count as a transfusion trigger. Overall, using cold platelets for prophylaxis may seem counterintuitive, but a closer look at the available data suggests that the indication expansion may hold more promise.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare but life-threatening condition in which maternal alloantibodies, generated during pregnancy, target human platelet antigens (HPAs), leading to thrombocytopenia and increased risk of bleedings in the fetus or neonate. The most clinically relevant antigen in people of European descent is HPA-1a, located on the integrin β3 subunit. The β3 integrins are conformationally regulated heterodimeric receptors including platelet integrin αIIbβ3 but also αvβ3, expressed strongly on endothelial cells. FNAIT is clinically highly heterogeneous, with symptoms ranging from mild thrombocytopenia to intracranial hemorrhage (ICH), which can cause lifelong disabilities or perinatal death. It has been suggested that anti-HPA-1a antibodies that exclusively react with αvβ3 cause ICH, due to induction of endothelial cell damage and/or defects in angiogenesis. Here, we analyzed a large cohort of retrospectively and prospectively collected maternal sera from severe and mild FNAIT cases. Disease severity was associated with the extent of thrombocytopenia, and with high anti-HPA-1a antibody reactivity toward both αIIbβ3 and αvβ3. Exclusive anti-HPA-1a reactivity with αvβ3 or endothelial cells was not found. In contrast, all anti-HPA-1a antibodies reacted with platelets and endothelial cells, and with αvβ3- and αIIbβ3-transduced cells, but reacted generally more with the αIIbβ3 integrin. Furthermore, HPA-1a epitope accessibility and antibody binding is influenced by integrin conformation and activation status. Higher reactivity of anti-HPA-1a antibodies with αIIbβ3 over αvβ3 diminishes upon integrin conformational activation. Together, these data emphasize the need for further investigation into the relation between endothelial properties of anti-HPA-1a antibodies and disease outcome in FNAIT.