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.

We analyzed 217 patients with KMT2A-rearranged acute myeloid leukemia (AML) in 2 large sequential randomized trials. Those randomized to FLAG-Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubucin) had markedly lower rates of relapse than other chemotherapy regimens. Molecular measurable residual disease assessment after cycle 2 was strongly prognostic for relapse and death. The trials were registered at the ISRCTN Registry as AML17 ISRCTN55675535 and AML19 ISRCTN78449203.

In 1974, Van den Berghe et al described a distinct hematologic disorder associated with acquired, interstitial deletion of part of the long arm of chromosome 5. This condition is now classified as myelodysplastic syndrome (MDS) with isolated deletion 5q, or MDS-del(5q). The common deletion region 5q32-5q33 contains several genes and microRNAs whose expression levels are reduced in hematopoietic cells, consistent with the loss of 1 allele. Haploinsufficiency production of multiple gene transcripts, primarily involving CSNK1A1, RPS14, MIR145, and MIR146A, results in myelodysplastic hematopoiesis. Lenalidomide can selectively suppress the del(5q)-mutant clone by promoting proteasomal degradation of casein kinase 1A1 and inducing mutant stem cell failure. However, lenalidomide is not a curative treatment, as almost all patients relapse. Molecular profiling studies have significantly improved our understanding of MDS-del(5q). Only a minority of patients have interstitial deletion 5q as their sole genetic lesion, a condition that is associated with an indolent clinical course. Most patients have co-occurring somatic mutations in myeloid genes, including DNMT3A, TET2, ASXL1, SF3B1, TP53, RUNX1, and CSNK1A1. These comutations have independent effects on leukemic transformation and survival, so genomic profiling is required for implementing a precision management approach to MDS-del(5q) in a clinical setting. Accurate assessment of the TP53 allelic state is crucial for distinguishing MDS-del(5q) from TP53-mutant MDS, a myeloid malignancy characterized by TP53 multihit state and very aggressive clinical course. Genomic profiling is also critical for therapeutic decision-making in patients with MDS-del(5q), particularly for assessing a patient's eligibility for allogeneic transplantation, which remains the only curative treatment.

Understanding the roles of myeloid cells in the tumor microenvironment (TME) has emerged as a promising strategy to identify novel targets to counteract the immunosuppressive barriers protecting multiple myeloma (MM). Neutrophils are a new cancer research focus due to their potential to reduce the efficacy of immune-based therapies. This study aimed to deepen understanding of neutrophil function in MM by analyzing freshly isolated myeloid cells from paired focal lesions (FLs) and bone marrow using single-cell RNA sequencing, immunofluorescence imaging, and functional assays. We describe 3 distinct CXCR2+ mature neutrophil subsets: TREM1+CD10+, RETN+LCN2+, and TNFAIP3+CXCL8+, each exhibiting unique phenotypes within the TME. Notably, the TREM1+CD10+ subset was highly prevalent, particularly in FLs, demonstrating potent immunosuppressive effects on T cells. This subset's gene signature was correlated with shorter overall survival (OS) in a large data set of patients with MM, underscoring its clinical significance. Targeted inhibition of neutrophil activity through CXCR2 blockade, alone or combined with standard anti-MM therapies, significantly reduced tumor burden, improving OS in preclinical MM models. These insights into neutrophil-mediated immunosuppression in MM provide valuable knowledge regarding mechanisms driving immune evasion, and reveal new therapeutic approaches to enhance the efficacy of MM treatment.

Chronic myeloid leukemia (CML) represents a paradigm of success in targeted therapy, with tyrosine kinase inhibitors (TKIs) revolutionizing patient outcomes. This progress has extended to the management of pregnancy in women with CML, a complex scenario requiring a balance between disease control and fetal safety. Because TKIs are contraindicated during the first trimester due to their teratogenic potential, treatment must be stopped as soon as pregnancy is confirmed, necessitating careful preconception planning and alternative management strategies. This article uses illustrative clinical cases to explore key aspects of CML pregnancy management, including the timing of TKI discontinuation, the feasibility of treatment-free remission, and the role of alternative therapies such as interferon alfa. Additionally, we discuss the challenges of restarting treatment during pregnancy, the TKI selection in subsequent trimesters, and postpartum disease management, including breastfeeding considerations. Through the analysis of real-world cases, we provide insights into the evolving landscape of CML and pregnancy, offering practical guidance on optimizing maternal and fetal outcomes in this unique setting.

Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), 2 B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma; however, the 6 to 8 weeks manufacturing time risks disease progression or death in up to 10% of patients. Talquetamab, a G-protein-coupled receptor, family C, group 5, member D (GPRC5D)-targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 United States, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel. Among 134 patients receiving talquetamab, 119 proceeded to CAR-T (n = 98 cilta-cel, n = 21 ide-cel). Reasons for not proceeding (n = 15) included progression (n = 7), manufacturing failure (n = 6), or patient decision (n = 2). Median age was 65 years and had median 5 prior lines of therapy. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days. Toxicity was manageable: no grade ≥3 cytokine release syndrome (CRS), 2% grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) and grade 1 to 2 talquetamab unique toxicities (70% oral, 38% skin, and 17% nail; 60% resolved). Talquetamab achieved 71% response rate. After CAR-T, 88% responded (54% complete response), with low-grade toxicities (2 grade ≥3 CRS, 1 grade 3 ICANS, and 5% grade ≥3 infections). Two cases of facial palsy and 1 acute myeloid leukemia occurred. Talquetamab correlated with sustained soluble BCMA decline and peak CAR-T expansion around day 14. Talquetamab bridging appears safe, enabling the majority of difficult-to-treat patients to successfully proceed to BCMA CAR-T therapy.

Hematopoietic stem cells (HSCs) exhibit a distinctive antioxidant profile during steady-state and stress hematopoiesis. HSCs and multipotential progenitors (MPPs) are metabolically coupled to bone marrow mesenchymal stromal cells through mitochondrial transfer, a process dependent on hematopoietic connexin 43 (Cx43) and low adenosine monophosphate-activated protein kinase (AMPK) activity. However, the mechanism by which Cx43 preserves mitochondrial functionality in HSCs remains elusive. Here, through integrated transcriptomic, proteomic, metabolomic, phenotypic, and functional analyses of HSCs and their isolated mitochondria, we identified that Cx43 is present on the inner and outer mitochondrial membranes of HSCs/MPPs, in which it primarily regulates mitochondrial metabolism and adenosine triphosphate synthesis by preserving the mitochondrial cristae, activation of mitochondrial AMPK, and 2-oxoglutarate dehydrogenase, a rate-liming enzyme in tricarboxylic acid cycle and electron transfer chain. During replicative stress, Cx43-deficient HSCs/MPPs fail to adapt metabolically and accumulate mitochondrial Ca2+, leading to increased mitochondrial AMPK activity, mitochondrial fission, mitophagy, and production of reactive oxygen species, thereby limiting HSC/MPP regeneration potential. Disruption of hyperfragmentation of mitochondria and mitophagy by Drp1 dominant-negative mutant (Drp1K38A) or restoration of mitochondrial function through ex vivo heteroplasmy prevents the harmful effects of Cx43 deficiency on mitochondrial metabolism and restore HSC activity in serial transplantation experiments. Re-expression analysis of Cx43 structure-function mutants indicates that Cx43 hemichannels are sufficient to reset HSC mitochondrial metabolism, dynamics, Ca2+ levels, and regeneration capacity. This report defines the cell-autonomous mechanism of action behind the role of Cx43 in HSC activity and opens a venue to translational applications in transplantation.

The current approach to minimize transplant-associated complications, including graft-versus-host disease (GVHD) includes long-term pharmacological immune suppression frequently accompanied by unwanted side effects. Advances in targeted immunotherapies regulating alloantigen responses in the recipient continue to reduce the need for pan-immunosuppression. Here, in vivo targeting of the tumor necrosis factor superfamily receptor TNFRSF25 (also known as DR3) and the high-affinity interleukin-2 (IL-2) receptor with a TL1A-immunoglobulin (TL1A-Ig) fusion protein and low-dose IL-2, respectively, was used to pretreat recipient mice before allogeneic hematopoietic stem cell transplantation (aHSCT). Pretreatment induced regulatory T cell (Treg) expansion persisting 1 to 2 weeks after HSCT, leading to diminished GVHD and improved transplant outcomes. Expansion was accompanied by an increase in the frequency of stable and active Tregs, creating a suppressive tissue environment in the colon, liver, and eye. Importantly, pretreatment supported epithelial cell function/integrity, a diverse microbiome including reduction of pathologic bacteria outgrowth, and promotion of butyrate producing bacteria, while maintaining physiologic levels of obligate/facultative anaerobes. Notably, using a sphingosine 1-phosphate receptor agonist to sequester T cells in lymphoid tissues, it was found that the increased tissue Treg frequency included resident CD69+CD103+FoxP3+ hepatic Tregs. In contrast to infusion of donor Tregs, the strategy developed here resulted in the presence of immunosuppressive target tissue environments in the recipient before the receipt of donor allogeneic-reactive T cells and successful perseveration of graft-versus-leukemia responses. We posit strategies that circumvent the need of producing large numbers of ex vivo manipulated Tregs may be accomplished through in vivo recipient Treg expansion, providing translational approaches to improve aHSCT outcomes.