Maternal alloantibodies directed to HPA-1a on fetal platelets can induce fetal-neonatal alloimmune thrombocytopenia (FNAIT) which causes intracranial hemorrhage in 10-20% of fetuses/newborns. Presentation is usually unexpected and identified by neonatal bleeding, with implications for future pregnancies. This review synthesizes advances in diagnosis, pathophysiology, and management that reshape understanding of anti-HPA-1a-mediated FNAIT. Genomic and serologic testing, together with cell-free fetal DNA for fetal HPA typing, allow accurate identification of at-risk pregnancies. Among HPA-1bb women, those who carry DRB3*01:01 are at greatest risk of forming clinically-significant anti-HPA-1a. Not only anti-HPA-1a levels but also structural features, particularly decreased Fc-fucosylation enhancing FcγR-mediated effector functions, more accurately determine disease severity. Furthermore, increased Fc-galactosylation may contribute by enhancing complement activation. Fab-mediated effects impact platelets, megakaryocytes, trophoblasts, and endothelial cells. Taken together, this explains why anti-HPA-1a levels and neonatal platelet counts alone do not reliably predict bleeding including intracranial hemorrhage. Anti-HPA-1a also induces placental inflammation increasing risks of fetal growth restriction and long-term neurodevelopmental impairment, e.g. autism. Neonatal management involves random donor and matched platelet transfusions, and also IVIG if needed. Antenatal IVIG, with/without prednisone administered in an affected pregnancy typically increases fetal platelet counts with management strategies varying internationally. Blocking FcRn has emerged as an alternative approach to both reduce maternal anti-HPAa-1a levels and inhibit its transplacental transfer. Whether antenatal treatment reduces placental inflammation requires further study. These developments support the importance of identifying predictive biomarkers of fetal risk to guide antenatal management and of preventing affected pregnancies ideally by screening all pregnancies followed by prophylaxis.

Breakthroughs in cancer immunotherapy have redefined patient care, ushering in a new era of therapeutic modalities including checkpoint inhibitors, chimeric antigen receptor (CAR) T-cells, and bispecific T-cell engagers, amongst others. However, their distinct toxicity profiles have required clinicians across all specialties to rapidly adopt an immunologic perspective in management. Among them, therapy related hemophagocytic lymphohistiocytosis (HLH)-like toxicities are increasingly recognized as part of a broader category of hyperinflammatory syndromes. The recently defined Immune effector cell-associated HLH-like syndrome (IEC-HS), characterized by hallmark clinical and biochemical features of secondary HLH, is both clinically and temporally distinct from cytokine release syndrome (CRS), typically emerging as CRS subsides or after it has resolved. In contrast, in CRS with multiorgan dysfunction (CRS-MOD), HLH-like manifestations often appear with worsening CRS and progress through standard CRS-directed therapy. Importantly, CRS-MOD is to be differentiated from the acute hyperferritinemia and transient organ toxicities seen with CRS, which often responds to standard CRS management. Clinically differentiating these HLH-like syndromes remains challenging; however, their shared pathophysiology has contributed to an evolving landscape of therapeutic strategies. Given the association of HLH-like toxicities with poor outcomes, enhanced recognition, comprehensive diagnostic approaches and early intervention strategies may improve outcomes-preserving the potential benefit of the therapies patients are receiving. In this "How I Treat," we highlight our collective approach in managing two recognized CAR-associated HLH-like toxicity syndromes, CRS-MOD and IEC-HS, and provide an overview of the current treatment landscape.

Myeloid/Lymphoid neoplasms with FGFR1 rearrangement (M/LN-FGFR1) are rare, heterogenous diseases due to fusion transcripts originated by translocations of FGFR1 with different partners, resulting in constitutive FGFR1-mediated signaling. Presentation varies from chronic myeloid neoplasms to acute leukemia or lymphoma and extramedullary localizations are common. Outside allogeneic stem cell transplantation (ASCT), survival with conventional therapy is dismal, representing an unmet clinical need. We summarize here the data that led to approval of pemigatinib, a FGFR1 inhibitor, showing unprecedented efficacy in M/LN-FGFR1.

The therapeutic landscape for systemic immunoglobulin light chain (AL) amyloidosis has been revolutionized by daratumumab-based regimens, achieving 76% five-year overall survival in the landmark ANDROMEDA trial. However, the current prognostic models were developed using patient populations treated with now-suboptimal therapies, creating a critical gap between risk stratification models and contemporary outcomes. This comprehensive review analyses prognostic factors and progression biomarkers in AL, categorizing them into disease-specific (clone-related and organ-related) and patient-specific factors. Notably, traditional baseline biomarkers including difference between involved and uninvolved free light chains (dFLC) and bone marrow plasma cell burden are losing prognostic significance with effective clone-directed therapies. Emerging approaches show promise, including dynamic markers such as minimal residual disease by free light chain mass spectrometry, cardiac imaging parameters such as global longitudinal strain, and functional measures. There is an urgent need for validation studies and prognostic model refinement to identify high-risk patients who may benefit from interventions beyond anti-plasma cell therapy.

This study assessed real-world effectiveness and safety of lisocabtagene maraleucel (liso-cel) in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), including those with high-risk disease, secondary central nervous system (sCNS) involvement, comorbidities, and poor fitness, using data in the Center for International Blood and Marrow Transplant Research Registry from 5 Feb 2021 to 4 Feb 2025. Eligible patients (N=1116) received liso-cel and had ≥1 effectiveness and safety assessment after infusion, including 195 in the second-line setting, 71 with sCNS, and 257 with transformed LBCL. Median age was 71.1 years (range, 21.5‒91.2), with 72.3% ≥65 years. Within the overall population, 6.6% had Eastern Cooperative Oncology Group performance status of ≥2, 53.4% had ≥1 comorbidity, and median number of prior lines of therapy was 3 (range, 1‒16). Median study follow-up was 12.6 months (95% confidence interval [CI], 12.5‒12.8). Among effectiveness-evaluable patients (n=1109), objective response rate was 81.2% and complete response rate was 71.3%. Duration of response, progression-free survival, and overall survival rates (95% CI) at 12 months were 60.2% (56.4‒63.9), 51.2% (48.0‒54.4), and 67.6% (64.5‒70.6), respectively. Cytokine release syndrome was reported in 51.0% of patients, with grade ≥3 events in 2.5%. Immune effector cell-associated neurotoxicity syndrome was reported in 26.6% of patients, with grade ≥3 events in 9.2%. The 12-month nonrelapse mortality rate was 6.1% (95% CI, 4.6‒7.8). These real-world data reinforce the effectiveness and safety of liso-cel in this broad population of patients with R/R LBCL, including younger patients and those with high-risk disease features.

The contribution of immune cells to thrombus architecture and mechanical properties in acute ischemic stroke (AIS) remains poorly understood. Using 3D imaging and multiplex staining, we mapped immune cells in human stroke thrombi and identified neutrophils as the dominant population. Analysis of 19 thrombi confirmed their positive correlation with collagen, increased stiffness, and poorer clinical outcomes. To preserve the spatial context, we developed a laser capture-based proteomic workflow and analyzed thrombus neutrophils from 34 patients with AIS stratified by 90-day outcomes, followed by validation in an independent cohort of 22 patients. Proteomic analysis revealed SERPINB3 as a neutrophil-enriched protein strongly correlated with poor prognosis. In murine models of FeCl₃-induced carotid artery thrombosis and middle cerebral artery occlusion, experiments using wild-type, neutrophil-depleted, and Serpinb3a knockout mice demonstrated that neutrophil-derived SERPINB3 promotes early thrombus formation, enhances collagen deposition, and contributes to progressive thrombus stiffening. Mechanistically, SERPINB3 secreted by neutrophils amplifies thrombus stiffness through upregulation of TGFβ1, neutrophil extracellular traps, and COL1A1. Targeted SERPINB3 knockdown delayed vascular occlusion, improved thrombolysis efficiency, and resulted in better neurological recovery. Collectively, these findings identify a neutrophil-driven mechanism underlying thrombus stiffening and establish SERPINB3 as both a prognostic biomarker and a promising therapeutic target in AIS. This project has been registered with the Chinese Clinical Trial Registration Platform (https://www.chictr.org.cn/index.html) and has successfully passed the review process (Registration Number: ChiCTR2300077911).

The TCF3::HLF fusion protein defines a highly aggressive and incurable subtype of B cell acute lymphoblastic leukemia (B-ALL). Using a newly established mouse model that faithfully recapitulates human TCF3::HLF B-ALL, including osteolytic bone lesions, we identified self-reinforcing IL-1β signaling networks as a central driver of disease progression. TCF3::HLF B-ALL cells displayed marked upregulation of inflammatory cytokines such as IL1B, IL6, and IFNG. Genetic deletion of IL1B or its receptor IL1R1 suppressed leukemic growth, reduced RANKL expression, and ameliorated bone destruction in vivo. Epigenetic profiling revealed a previously unrecognized intronic regulatory element within the IL1B locus bound directly by TCF3::HLF. Importantly, single-cell RNA-seq of patient samples demonstrated strong IL1B induction at relapse compared with diagnosis, underscoring its clinical relevance. Collectively, these findings establish the TCF3::HLF-IL-1β axis as a critical determinant of leukemic propagation and bone pathology, and highlight IL-1β blockade as a potential therapeutic strategy for this otherwise incurable leukemia.

Autologous second-generation CD7-directed CAR T-cells, expressing an anti-CD7 protein expression blocker to prevent self-killing fratricide, were infused in three pediatric/young adult patients with relapsed/refractory CD7+ acute myeloid leukemia resulting in measurable residual disease negativity. The safety profile was favorable.

CD4+CD25+Foxp3+ regulatory T cells (Tregs) are pivotal negative regulators of the adaptive immune system. Abnormalities in the number and/or function of Tregs contribute to the pathogenesis of primary immune thrombocytopenia (ITP). Strategies aimed at modulating Tregs offer potential therapeutic opportunities for ITP management. In this study, we demonstrated that inhibition of cyclin-dependent kinase 8 (CDK8) and CDK19 activity by the small-molecule inhibitor AS2863619 (AS) robustly promoted the conversion of CD4+CD25- effector T cells (Teffs) into CD4+CD25+Foxp3+ Tregs, endowing the converted Tregs with lineage stability and potent suppressive capacity. Mechanistically, AS rapidly augmented STAT5 phosphorylation and subsequent Foxp3 induction. STAT5 blockade completely abrogated this effect, confirming that the Treg-promoting activity of AS was critically dependent on STAT5 signaling. In parallel, AS suppressed STAT3 phosphorylation under IL-6-driven conditions, thereby attenuating Th17 polarization. These mechanistic findings were supported by global transcriptomic analysis, which revealed a profound transcriptional shift by broadly suppressing gene programs of Teff differentiation and function while simultaneously upregulating a robust signature characteristic of stable Tregs. Crucially, unbiased upstream analysis of these changes pinpointed STAT5, STAT3, and FOXP3 as the core transcription factors mediating the drug's effect. Functional metabolic analysis further revealed that AS mediated metabolic reprogramming in T cells by suppressing glycolysis, thereby providing the necessary metabolic adaptations for Treg conversion. In a murine model of active ITP, CDK8/CDK19 inhibition elevated Treg frequencies and ameliorated thrombocytopenia in a STAT5-dependent manner. Collectively, our study highlighted the therapeutic potential of CDK8/CDK19 inhibition in restoring immune homeostasis and managing ITP.

Chronic graft-versus-host disease (cGVHD) significantly contributes to late mortality after allogeneic stem cell transplantation, with bronchiolitis obliterans syndrome (BOS) being a particularly lethal and treatment-resistant complication despite available therapies. Bromodomain and Extra terminal (BET) proteins are epigenetic readers driving inflammatory transcriptional programs across multiple cell types. We hypothesized that BET inhibition would suppress inflammatory T and B cells while also decreasing macrophage polarization to a profibrotic phenotype, alleviating disease. In an established BOS cGVHD model, BET inhibition reduced germinal center formation and response through a reduction of the CXCL13:CXCR5 axis, inflammatory Tfh/GC B cells in the spleen along with a reduction in plasma cell infiltration within the lung. Mice with cGVHD had elevated pathogenic IgG1 and IgM, both in circulation and deposited on lung tissue, which was attenuated under BET inhibition. Single-cell RNA sequencing analysis revealed distinct cell states in the BOS lung vs. control. In cGVHD mice, GSEA analysis revealed upregulation of profibrotic Arginase1 and Tgfb1 expression in alveolar macrophages (AM) and interstitial macrophages (IM), which was significantly reduced with BET inhibition. Furthermore, BET inhibition targeted lung-infiltrating M2 macrophages, through selective depletion of CD206+FcgR+ IMs and AMs, ultimately resulting in reduced collagen deposition and improved lung function. Our findings reveal a previously unrecognized mechanistic axis of BET regulation during cGVHD fibrosis and highlight BET inhibition as a promising therapeutic strategy.

The phase 3 CRISTALLO trial (NCT04285567) compared first-line fixed-duration venetoclax-obinutuzumab (VenO) vs fludarabine, cyclophosphamide, and rituximab (FCR)/bendamustine-rituximab (BR) in patients with chronic lymphocytic leukemia, using undetectable minimal residual disease (uMRD) as the sole primary endpoint. Previously untreated patients with a cumulative illness rating scale score ≤6, creatinine clearance ≥70 mL/min, without del(17p)/TP53 mutations were randomized 1:1 to VenO or FCR/BR. The primary endpoint was uMRD (<10-4) in peripheral blood (PB) using next-generation sequencing at month 15. Key secondary endpoints included uMRD (<10-4) in PB and bone marrow (BM) at end of treatment (EOT), and progression-free survival (PFS). uMRD at deeper cutoffs were explored. At data cutoff (March 19, 2024), 80 patients received VenO and 86 received FCR/BR. Baseline characteristics were generally balanced across arms. The primary endpoint was met: 81.3% (VenO) and 54.7% (FCR/BR) achieved uMRD (<10-4) in PB at month 15 (P = .0004). uMRD (<10-4) in PB and BM at EOT was also higher with VenO vs FCR/BR. Short follow-up precluded evaluation of PFS at the first planned interim analysis; however, fewer patients progressed/died with VenO vs FCR/BR (7 vs 13). At month 15, 65.0% (VenO) and 25.6% (FCR/BR) achieved uMRD (<10-6) in PB. The overall safety profile was consistent with the known safety profile of each drug. No patient in the VenO arm was deemed high-risk for tumor lysis syndrome following obinutuzumab debulking; no clinical TLS occurred. These results confirm and extend the findings from the GAIA-CLL13 trial, validating increased depth of response with VenO vs chemoimmunotherapies.

T cell-based therapies have shown remarkable efficacy in multiple myeloma (MM), yet the disease remains largely incurable. Here, we investigated the constant domains of the immunoglobulin heavy chain (IgH) as novel targets for therapeutic T cell receptors (TCRs), after confirming high and homogeneous IGH expression in >95% of MM patients. MM cells secrete excessive monoclonal immunoglobulins (M-proteins) that drive complications but are inaccessible to CAR T-cell or antibody targeting. Peptides from IgA and IgG constant regions were eluted from HLA-A*02:01, and reactive TCRs were isolated from healthy donors using allo-HLA-A*02:01 presentation to circumvent self-tolerance. T cells engineered with two TCRs specific for IgA or IgG passed a stringent multi-tier safety screen and selectively eliminated MM cells from 20 HLA-A*02:01+ patients secreting the relevant IgH in vitro. In vivo, IgA-TCR T cells eradicated IgA+HLA-A*02:01+ MM cells in xenograft models and reduced circulating IgA in humanized mice. These findings establish immunoglobulin constant domains as viable TCR targets in MM, potentially making ~40% of patients of European descent eligible for TCR T cell therapy, and extension to additional HLA alleles could further broaden eligibility. The approach may also be applicable to lymphoma and antibody-mediated autoimmune diseases.

VEXAS syndrome is a severe adult-onset autoinflammatory disease caused by somatic mutations in the UBA1 gene, disrupting cytoplasmic ubiquitin-activating enzyme E1 function in hematopoietic progenitors. Its pathogenesis remains poorly understood, particularly the mechanisms by which UBA1 mutations disrupt myeloid cell function in the context of inflammatory stimuli. Here, we combine a genetically engineered THP-1 monocytic model with ex vivo analyses of blood and tissue samples from VEXAS patients to investigate the consequences of the canonical UBA1M41V mutation. We show that UBA1-mutated monocytes exhibit TNF-α-induced cell death, characterized by RIPK1 phosphorylation, and MLKL- and caspase-8-mediated cell death. Importantly, we extend these findings to patient-derived CD14⁺ sorted cells, confirming that these cells undergo aberrant apoptotic and necroptotic cell death. Mechanistically, activation of these cell death pathways appears to be promoted by defective NF-κB-dependent transcriptional responses and reduced cFLIP(L) expression following TNF-α stimulation. UBA1-mutated monocytes also display blunted cytokine responses to Toll-like receptor (TLR) agonists despite preserved TLR expression, linked to an impaired NF-κB response. UBA1M41V-derived macrophages exhibit a pro-inflammatory transcriptional profile with increased chemokine secretion that promotes monocyte recruitment. In addition, these UBA1-mutated macrophages display impaired efferocytosis due to lysosomal dysfunction. Together, these findings reveal a pathogenic axis in VEXAS syndrome linking UBA1 loss of function and defective ubiquitination to RIPK1-mediated inflammatory cell death, impaired antimicrobial signaling, and defective resolution mechanisms. Our study provides novel mechanistic insights into the myeloid dysfunction underlying inflammation and cytopenia in VEXAS and supports the therapeutic targeting of inflammatory cell death pathways.

Autologous stem cell transplantation (ASCT) with maintenance lenalidomide remains the mainstay of consolidation therapy for eligible multiple myeloma (MM) patients but preventing disease relapse remains a critical unmet need. Here we investigated whether immunosuppressive myeloid populations in bone marrow (BM) correlated with ASCT outcomes. We identified a subset of CD64+CD169+CD163+ macrophages that expressed CSF-1R, PD-L1, and CD155, and were expanded in patients who relapsed post-ASCT. Using a preclinical ASCT model with suboptimal endogenous anti-myeloma activity, we demonstrated that while neither CSF-1R inhibition nor lenalidomide monotherapy significantly improved outcomes, their combination synergistically attenuated disease progression and prolonged survival. Single-cell RNA sequencing revealed that lenalidomide expanded NK-like CD8+ T-cells but paradoxically also increased the frequency of Csf1r+ macrophages. Cell-cell communication analyses identified Csf1r+ macrophages as suppressors of these NK-like and effector-like exhausted (Tphex) CD8 T-cell populations through CD94/NKG2A and PD-L1/PD-1, respectively. CSF-1R blockade depleted these immunosuppressive macrophages, which correlated with decreased expression of inhibitory receptors and enhanced expression of activation markers in Tphex. Given the FDA approval of axatilimab for chronic GVHD, combining CSF-1R blockade with lenalidomide maintenance represents a readily testable strategy to improve progression-free survival after ASCT.

Thrombotic Thrombocytopenic Purpura (TTP) was first described just over a century ago and it is now 25 years since the identification of ADAMTS13 as the enzyme deficient in both antibody-mediated immune TTP and congenital TTP. The discovery of ADAMTS13 has been fundamental to the vast improvement seen in TTP outcomes. Understanding the interaction between ADAMTS13, platelets and vWF led to development of clinical ADAMTS13 assays and therefore quicker and accurate diagnosis, but also, critically, to novel therapies and monitoring of treatment. Landmark additions to immune TTP therapy have included anti-CD20 treatment with rituximab, in both the acute and elective setting and the use of the nanobody caplacizumab in acute TTP. In congenital TTP, the use of ADAMTS13 replacement is playing a role in reducing end-organ damage and morbidity, with recombinant ADAMTS13 now representing the gold standard for cTTP. The ability to measure response to treatment by monitoring ADAMTS13 activity has underpinned these treatment advances and allowed clinicians to tailor immunosuppressive treatment for iTTP and rADAMTS13 dosing in cTTP. Looking forward, there are many avenues for future development with potential expansion of recombinant ADAMTS13 to treat immune TTP, new, quicker assays to improve diagnosis, monitoring and immunomodulatory therapeutic advancement, all underpinned by ADAMTS13. Future endeavors for the role of ADAMTS13 in other thrombotic indications opens further exciting opportunities.

Bone marrow failure (BMF) syndromes are heterogenous diseases characterized by impaired hematopoiesis and risk of evolution to myelodysplastic syndrome (MDS) and leukemia. We report 6 unrelated individuals with variable BMF phenotypes and hypocellular MDS presenting at a median age of 10 years (4 weeks - 53 years). Genomic analysis revealed germline heterozygous variants in MDM4, including 4 null (frameshift, nonsense, and splice-site resulting in premature truncation confirmed by RNA sequencing) and 2 missense variants, of which one had previously been associated with a familial BMF syndrome. Mechanistically, MDM4 mutations are loss-of-function leading to enhanced p53 activation. We used CRISPR/Cas9 to delete MDM4 in healthy donor hematopoietic stem and progenitor cells (HSPCs). The resulting MDM4-haploinsufficient HSPCs exhibited increased p53 activity, impaired colony-forming capacity, and reduced engraftment potential in immunodeficient mice. Complementation studies revealed both p53-binding and RING-finger domains as necessary for MDM4-mediated hematopoietic regulation. To study variant effect in a confounder-free genetic background, we introduced patient-specific MDM4 variants into induced pluripotent stem cells (iPSCs). MDM4-mutant iPSCs yielded significantly reduced erythroid and myeloid cells and exhibited increased p53 activity, as evidenced by elevated p21 expression, confirming the role of MDM4 regulating hematopoiesis through p53. Transcriptome analysis of iPSC-derived hematopoietic cells revealed upregulation of p53 pathway. Importantly, one patient with MDS acquired loss-of-function TP53 mutations, suggesting maladaptive somatic rescue.Our findings establish MDM4 deficiency as a TP53 activating syndrome with features of BMF and variable hematopoietic manifestations. This study also highlights the critical role of the MDM4-p53 axis in maintaining hematopoietic homeostasis.