Erythropoiesis, the process of red blood cell production, is highly dependent on iron uptake via transferrin and its receptor, transferrin receptor 1 (TfR1), but the mechanisms governing the proper recycling of TfR1 in relation to cellular iron demands remain elusive. Here, we identify human TMEM187, a Golgi transmembrane protein of unknown function, as a novel negative regulator of erythropoiesis. Lack of TMEM187 in a cell model initiates erythropoiesis without the normal induction protocol and accelerates iron uptake. Following the induction protocol, TMEM187 ablation leads to premature erythroid maturation, resulting in early phosphatidylserine ectopia and cell membrane fragility, hallmarks of cellular senescence that renders the cells susceptible to macrophage recognition and phagocytosis. In zebrafish embryos, tmem187 deletion leads to enhanced early erythropoiesis, although the phenotype is later compensated, whereas hematopoietic stem-cell expression of human TMEM187 in mice, which lack endogenously a homologous gene, resulted in compromised erythropoiesis and moderate anemia. Mechanistically, we demonstrate that TMEM187 interacts with RAB11 to restrain endosomal recycling, interfering with RAB11-GRAB association that activates RAB11. Consequently, TMEM187 modulates TfR1 recycling to the cell membrane to fine-tune iron uptake efficiency for erythropoiesis. Our findings reveal a novel modulatory pathway in which TMEM187 plays a crucial role in regulating erythroid differentiation, maturation, and senescence, providing a previously unexplored perspective of TMEM187's physiological function.

Mice lacking Tissue Factor Pathway Inhibitor (Tfpi-/-) succumb to embryonic lethality from excess thrombin production and associated cerebrovascular defects called glomeruloid bodies. A transgene producing hyperactivatable mouse protein C (hMPC) was bred into Tfpi+/- mice to determine if excess activated PC (aPC) would correct the cerebrovascular defects in Tfpi-/- embryos. Tfpi-/-/hMPC+ embryos survived to adulthood. Despite the rescue of embryonic lethality, hMPC reduced glomeruloid body numbers by only 36% and did not prevent fibrin deposition or disruption of the blood-brain barrier within glomeruloid bodies. However, there was decreased hypoxia and cellular death in Tfpi-/-/hMPC+ brains suggesting that cytoprotective effects of hMPC contributed to Tfpi-/- rescue. The glomeruloid bodies were completely resolved in Tfpi-/-/hMPC+ P10 pups revealing a distinct temporal effect of TFPI on embryonic cerebrovascular development. Bulk RNAseq of E15.5 brain tissue identified increased angiogenesis as the overwhelming biological process altered in Tfpi-/- brain. This included changes in genes encoding apelin, adrenomedulin, and UNC5b, which was consistent with abundant endothelial tip cells within glomeruloid bodies. The increased expression of these angiogenic genes was reversed by the hMPC transgene. These findings define TFPI as an essential inhibitor of thrombin generation during embryonic angiogenesis that acts temporally within or around developing cerebral vasculature in a manner that is not compensated for by other anticoagulant proteins. The findings emphasize the importance of blood coagulation proteases and regulation of their activity in diverse biological processes.

Radiotherapy is an established treatment for low-grade primary cutaneous B-cell lymphoma. Recommendations on its use differ internationally, which prompted our group to conduct the present analysis. Twenty-two institutions participated in this international study. Patient eligibility required a diagnosis of limited (T1/T2) primary cutaneous marginal zone or follicle center lymphoma treated with radiotherapy between 1995 and 2023. Data were collected retrospectively until February 2024 in the framework of the International Lymphoma Radiation Oncology Group. Overall, 535 patients were analyzed. Predominant locations were the head (40%) and trunk (36%). Radiotherapy had a median dose of 24 Gy in fractions of 2 Gy. Complete responses were seen in 91% at a median time of 3.6 months following radiotherapy. There was no statistically significant difference between treatments ≤4 Gy or >4 Gy for complete or overall response rates (p=0.077 and p=0.056). However, there was an inferior duration of local control with ≤4 Gy (5-year local control 73% ± 12% vs. 96% ± 2%; p<0.001). Radiation dose was the main prognostic factor in the univariate and multivariate Cox analysis; however, higher doses did not translate into an overall survival benefit. Toxicities rarely exceeded grade 2 but were more frequent in the >4 Gy group. Radiotherapy remains an effective treatment option for indolent skin lymphoma with low toxicities. High response rates are observed with low doses ≤4 Gy. In comparison to conventional doses, these treatments have a shorter duration of local control but a favorable toxicity profile.

Intensive chemotherapy is standard for AML but carries high risks of life-threatening complications, particularly in vulnerable patients. We aimed to compare the efficacy and safety of a low-dose chemotherapy (LDC) regimen for induction of AML. A randomized, multicenter, noninferiority trial was conducted in patients aged <18 years with AML. Patients received low-dose cytarabine, mitoxantrone or idarubicin, and G-CSF (LDC) or standard-dose induction chemotherapy (SDC) (cytarabine, daunomycin, and etoposide). All patients received post-remission consolidation with standard chemotherapy and/ or hematopoietic stem cell transplantation. The primary endpoint was to compare response rates between treatments. The secondary endpoints were to compare the outcomes, toxicity, and safety of the LDC and SDC regimens. The two treatment arms showed no significant differences in outcomes. Complete remission (CR/CRi) rates after induction were 95.1% and 95.3% in the LDC and SDC arms, respectively. Measurable residual disease < 0.1% after induction II was observed in 87.4% and 87.1% of patients in the LDC and SDC arms, respectively. Median time to neutrophil and platelet recovery was significantly shorter among patients receiving the LDC regimen. Patients in the LDC arm had a 4-year overall survival (OS) of 81.3% vs. 83.6% (P = .611) and a 4-year event-free survival (EFS) of 61.5% vs. 63.1% (P = .832). In conclusion, the LDC regimen was well tolerated and was associated with CR, EFS, and OS rates that were not inferior to those of patients treated with the SDC regimen. The trial was registered at Chinese Clinical Trial Registry (ChiCTR1800015883).

Transposable elements (TEs) are emerging regulators of hematopoiesis and leukemia, creating vulnerabilities exploitable for therapy. Recent evidence shows that TE reactivation induces innate immune signalling, DNA damage responses and dependence on Poly(ADP-ribose) polymerase (PARP)-mediated protection, enabling synthetic lethality with PARP inhibition even in homologous-recombination-proficient leukemias with epigenetic gene mutations. In this article, we highlight the biology underpinning this novel TE-PARP axis, its therapeutic implications and strategies to expand beyond HR-deficient cancers through rational combinations with immunotherapy and refined patient stratification.

Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a bleeding disorder in which maternal antibodies target fetal and neonatal platelet alloantigens, most commonly human platelet alloantigen-1a (HPA-1a), resulting in fetal and neonatal thrombocytopenia severe enough to cause life-threatening organ bleeds, such as intracranial hemorrhage. Hemolytic disease of the fetus and newborn (HDFN) is an analogous disease caused by maternal exposure to fetal red blood cell (RBC) alloantigens, most commonly because of postpartum fetal maternal hemorrhage (FMH), that can be prevented by prophylactic administration of fetal RBC-specific antibodies. Unlike HDFN, the events that trigger FNAIT are unknown and can occur during first pregnancies, making FNAIT difficult to predict and prevent. Herein, we investigated the ability of in utero FMH to induce maternal alloimmunization to HPA-1a and cause FNAIT in a preclinical model. Transfusion of HPA-1a-positive platelets into wild-type (WT) mice in numbers representing moderate and severe FMH in humans induced production of equivalent levels of HPA-1a-specific antibodies in non-pregnant mice and mice pregnant with WT or HPA-1a-positive fetuses, causing FNAIT in the latter. Administration to pregnant females of the HPA-1a-specific monoclonal antibody RLYB212/mAb 26.4 prevented FMH-induced maternal alloimmunization to HPA-1a and FNAIT in genetically susceptible pups. In mice pregnant with HPA-1a-positive fetuses but not exposed to FMH, administration of RLYB212/mAb 26.4 did not cause FNAIT. Together, these findings identify in utero FMH as a potential trigger for maternal alloimmunization to fetal HPA-1a and provide proof of concept that prophylactic administration of HPA-1a-specific antibodies may safely and effectively prevent FMH-induced FNAIT in at-risk pregnancies.

The terms clonal monocytosis of undetermined significance (CMUS) and clonal cytopenia and monocytosis of undetermined significance (CCMUS) were introduced by the International Consensus Classification of Myeloid Neoplasms (ICC) to describe cases of clonal hematopoiesis (CH) and a concurrent monocytosis, that did not meet the diagnostic criteria of chronic myelomonocytic leukemia (CMML). To date, their practical relevance as clinicopathological entities at a population level has not been assessed. Here, we assess the prevalence, significance and natural history of CMUS and CCMUS amongst 431,531 UK Biobank participants through analysis of clinical, genomic and health outcome data. We find that CMUS with an absolute monocytosis and CCMUS are high-risk entities strongly associated with incident myeloid neoplasia (MN), cardiovascular and renal disease. Noting the overall higher monocyte counts in men and the low rate of progression of DNMT3A-CMUS, we show that amending the definition of CMUS/CCMUS to incorporate sex-specific monocyte thresholds and the exclusion of isolated DNMT3A mutations from the definition significantly strengthens the association with incident MN. Finally, given their association with poor outcomes, we develop MoSAIC, a machine learning classifier to infer the presence of SRSF2 mutations (associated with high MN risk) amongst individuals with monocytosis, based on complete blood count indices alone. We corroborate our findings in an independent cohort of 625,328 Danish primary care patients. Our findings underscore the clinical relevance of CMUS and CCMUS as distinct high-risk states within the spectrum of clonal hematopoiesis, and establish an evidence base to refine their diagnostic definition.

Immunotherapies, such as allogeneic hematopoietic cell transplantation and infusion of chimeric antigen receptor T (CAR-T) cells have significantly extended our therapeutic armamentarium against several hematological malignancies. Blocking negative regulators of immunity with immune checkpoint inhibitors has significantly improved the survival of patients with mainly solid tumors. Despite their beneficial effects, these therapies are also associated with severe, immune-mediated side effects. Here, we discuss biological similarities and differences of acute graft-versus-host disease (GVHD), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hemophagocytic lymphohistiocytosis like syndrome (IEC-HS), immune effector cell-associated hematotoxicity (ICAHT), local immune effector cell-associated toxicity syndrome (LICATS), and immune-related adverse events after immune checkpoint inhibition (irAEs). Recent data have led to a better understanding of the role of myeloid cells and T-cells, including tissue-resident T-cells, in the pathophysiology of GVHD, CAR-T-cell associated immunotoxicities and irAEs. Further, we summarize approved, currently evaluated and potential future therapies for immune-mediated toxicities of cancer immunotherapies. This review will help to understand how therapeutic strategies target communalities of different side effects to overcome immune-mediated side effects of cancer immunotherapies.

Despite great progress in understanding the genomic basis of immature T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL) and acute leukemias of ambiguous lineage (ALAL), there are still cases that lack defining genetic markers, complicating risk stratification and limiting targeted therapeutic options. Recent studies have shown that enhancer hijacking drives oncogene activation in approximately half of T-ALL cases, with the BCL11B enhancer frequently involved. Here, we describe a subtype of leukemia with a distinct gene expression signature, and immunophenotype characterized by positivity for immature (CD38), myeloid (CD13), T-lymphoid (cytoplasmic (c)CD3, CD7), and B-lymphoid markers (CD19, CD79a, CD10). This subtype is defined by the t(14;16)(q32;q24) translocation, which places the FOXF1 gene and its antisense long noncoding RNA gene FENDRR under the regulatory control of the BCL11B enhancer, leading to their ectopic transcriptional activation. Common concomitant genetic lesions are loss-of-function alterations of GATA3, CDKN2A/CDKN2B deletion and activating JAK/STAT and NOTCH1 pathway mutations. Patients were predominantly children and adolescents/young adults (AYA) and experienced poor treatment outcome. High-throughput drug screening of 176 compounds demonstrated efficacy of combined BCL2-family proteins and JAK/STAT signaling inhibitors. Additionally, the clinical use of tyrosine kinase inhibitors in some of these cases showed therapeutic efficacy. Collectively, these findings identify BCL11B-enhancer mediated deregulation of FOXF1/FENDRR as a hallmark of a subtype of high-risk lineage ambiguous leukemia that is potentially amenable to targeted therapeutic intervention.

Hypofibrinogenemia reduces experimental venous thrombosis, but the impact on arterial thrombosis remains unknown. In a cohort of patients with congenital fibrinogen disorders, 19/264 (~7%) patients developed arterial thrombosis, including 4/41 (~10%) patients with hypofibrinogenemia. However, 0/8 patients with fibrinogen aC-region truncation mutations reported arterial thrombosis over 286 patient-years. To analyze the impact of hypofibrinogenemia and the fibrinogen aC-region on arterial thrombosis, two mouse models were employed: 1) wildtype mice treated with lipid nanoparticles encapsulating siRNA against fibrinogen (siFga) and 2) Fga270/270 hypofibrinogenemic mice expressing fibrinogen with a truncated aC-region. While siFga-treated hypofibrinogenemic mice developed occlusive carotid artery thrombi similarly to controls, Fga270/270 mice displayed suppressed carotid thrombosis following FeCl3 challenge, indicating loss of the aC-region but not hypofibrinogenemia alone reduces arterial thrombosis. To determine if protection from arterial thrombosis in Fga270/270 mice was linked to loss of aC-region-platelet glycoprotein VI receptor (GPVI) interaction, platelet GPVI was depleted by JAQ1 antibody administration. JAQ1-treated wildtype mice were protected from arterial thrombosis following 5% FeCl3 but not 10% FeCl3 challenge. Interestingly, JAQ administration suppressed arterial thrombosis in siFga-treated mice but did not enhance protection in Fga270/270 mice following 10% FeCl3 challenge. Our studies suggest the fibrinogen aC-region promotes arterial thrombosis in hypofibrinogenemic conditions.

B cell receptor (BCR) signaling is a key determinant of chronic lymphocytic leukemia (CLL) pathophysiology. CD49d, the alpha4 subunit of the very late antigen-4 (VLA-4) integrin, can be activated by BCR signals; however, its role in modulating BCR functionality remains unknown. We used knockout mouse models and primary human CLL stratified by CD49d expression to address this aspect. CD49d was required for bone marrow infiltration and shaped bone marrow infiltration patterns and patient outcomes in human CLL. In TCL1 transplantation models, loss of CD49d abrogated bone marrow homing and leukemic cell positioning within splenic niches. At the cellular level, CD49d-deficient murine TCL1 transgenic cells and human CD49d-low CLL cells failed to form efficient immune synapses with antigen-presenting membranes. Transcriptome analyses identified CD49d-dependent regulation of actin-associated pathways and distinct signatures of BCR responsiveness in human and mouse. Consistently, CD49d-low human CLL cells displayed aberrant actin remodeling following BCR stimulation, and a second aggressive murine CLL model reproduced the actin and engraftment defects. Kinome profiling linked impaired antigen-induced BCR responses in CD49d-deficient murine cells to altered kinase activity, and pharmacological actin perturbation phenocopied CD49d loss. In human CD49d-low CLL cells, a desynchronization of BCR-related downstream Syk and PLCɣ activation was found. Mechanistically, the CD49d-BCR interplay involved their co-localization, and CD49d converged with BCR signaling on a focal adhesion kinase-actin axis. In summary, our findings establish CD49d as a key regulator of BCR functionality in CLL, linking integrins to cytoskeletal dynamics and antigen responsiveness.

The molecular classification of T-cell acute lymphoblastic leukemia (T-ALL) remains incomplete, limiting risk stratification and the development of targeted therapies. Enhancer hijacking is a critical oncogenic mechanism that deregulates proto-oncogenes by repositioning cis-regulatory regions via structural variants. Here, we performed an integrated analysis of pediatric and adult T-ALL and mixed phenotype acute leukemias (MPALs), using whole-genome and whole-transcriptome sequencing. This analysis identified a group of 14 patients with predominantly T-lineage neoplasms driven by a t(14;16)(q32;q24) translocation, harboring universal GATA3 mutations and CDKN2A/B deletions. Mechanistically, this translocation repositions the ThymoD locus downstream of BCL11B, causing monoallelic, ectopic overexpression of FENDRR and mesenchymal transcription factor genes FOXF1 and FOXC2, activating epithelial-mesenchymal transition (EMT) transcription signatures. Immunophenotypic and single-cell RNA-seq analyses revealed marked lineage ambiguity with myeloid and B-cell differentiation potentials specific to this subtype. Furthermore, functional analyses in CD34-positive cord blood cells demonstrated that FOXF1 overexpression promotes myeloid differentiation while suppressing T-cell differentiation, serving as a key factor for lineage specification. Clinically, this subtype was detected in 0.15-4.0% of T-ALL/MPAL cases depending on the cohort, showing a median age of 15 years and enrichment in adolescents and young adults (AYA). Importantly, patients with t(14;16)(q32;q24) have an extremely poor prognosis, showing a trend toward worse outcomes than high-risk groups such as KMT2A-rearranged early T-cell progenitor (ETP)-like, SPI1-rearranged, and LMO2 γδ-like T-ALLs. The unique molecular landscape and poor prognosis of patients with the t(14;16)(q32;q24) translocation underscore the need for the development of novel subtype-specific therapeutic approaches.

Briquilimab is a monoclonal antibody inhibiting stem cell factor (SCF) binding to CD117 (c-Kit). Based on preclinical data demonstrating the antibody clears hematopoietic stem and progenitor cells (HSPC) and myeloid malignant cells, we conducted a phase 1 trial examining briquilimab plus non-myeloablative fludarabine (flu) and total body irradiation (TBI) as conditioning for older adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing matched donor allogeneic hematopoietic cell transplantation (HCT). Briquilimab was infused 10-14 days before transplant day (TD) 0; fludarabine 30mg/m2 and TBI 2-3 Gy were administered on TD -4 to -2 and TD0, respectively. Graft-versus-host disease prophylaxis consisted of tacrolimus, sirolimus, and mycophenolate mofetil. Thirty-two patients enrolled (n=13 AML in complete remission [CR], n=3 AML in relapse, n=16 MDS). Median age was 70 years and most had detectable measurable residual disease at screening. There were no briquilimab infusion reactions, dose limiting toxicities, or primary graft failure events; briquilimab clearance was predictable across patients. Among the AML in CR cohort, 1-year EFS was 69.2% (95% CI, 37.3, 87.2); 1-year OS was 75% (95% CI, 40.8, 91.2). Among the MDS cohort, 1-year EFS was 53.8% (26.8, 74.8); 1-year OS was 76.4% (42.7, 91.8). One of 3 AML patients in relapse experienced a transient response. Marrow samples obtained before and after briquilimab and prior to flu/TBI demonstrated AML/MDS HSPC depletion (mean 62.4±22.7%) with resultant 3-fold increase in serum SCF. In summary, we demonstrate the feasibility, safety, and proof of concept of CD117 targeting with briquilimab as HCT conditioning for AML/MDS. The trial is registered at clinicaltrials.gov; using identifier: NCT04429191.

Secondary myelofibrosis (SMF) represents a late stage of polycythemia vera and essential thrombocythemia, with overall survival (OS) currently defined by the MYelofibrosis SECondary to PV and ET (MYSEC) Prognostic Model (MYSEC-PM). To identify additional myeloid neoplasm-associated cancer gene variants (CGVs) associated with SMF outcome, we evaluated next-generation sequencing panel testing in 644 patients within the MYSEC cohort. Overall, 429 (66.6%) subjects reported at least one CGV, with ASXL1, TET2 and DNMT3A being the most frequently involved. Specific molecular profiles affected OS (p < .001): U2AF1, TP53 or SRSF2 variants (UTS, 9.3% of cases, median OS 4.1 years) and ASXL1 without UTS (25.3%, median OS 8.4 years). By integrating these genetic signatures within the MYSEC-PM through penalized Cox regressions, we identified the following independent predictors (p from < .0001 to .02) and weighted: hemoglobin <11 g/dl (1 point), circulating blasts ⩾3% (2), platelets <150 × 109/l (2), age (0.21 points/year), ASXL1 without UTS mutations (1) and any UTS mutations (3). Finally, we developed the MYSEC-molecular prognostic model (MYSEC-mPM) allocating 582 SMF patients into four categories with different OS (p < .001): low (median OS 18.0 years, 95%CI: 14.2-not reached; score <14), intermediate-1 (8.8. years, 95%CI: 7.7-9.7; score 14-16), intermediate-2 (4.6 years, 95%CI: 3.1-7.2; score 17-18), and high risk (1.9 years, 95%CI: 1.2-2.5; score ⩾19). Additionally, in 381 SMF with available cytogenetics, the MYSEC-mPM was implemented with complex/monosomal karyotype, generating the karyotype-enhanced MYSEC-kmPM. Our study shows that genomic and cytogenetic profiling improve survival prediction in SMF, outperforming the MYSEC-PM.

Protein disulfide isomerase (PDI) functions in thrombus formation in vivo and represents a viable target for antithrombotic therapy. PDI is a redox sensor that can either reduce or oxidize substrates depending on the redox environment. Yet whether PDI functions primarily as a reductase or an oxidase in the context of thrombus formation is unknown. We have used pharmacological approaches and PDI mutants to determine how the redox state of PDI affects thrombus formation. LOC14, which inhibits PDI reductase activity and induces PDI oxidation, promoted thrombus formation in arteries exposed to FeCl3 and enhanced injury-induced platelet accumulation and fibrin formation in cremaster arterioles. Substitution of a single sulfur atom with oxygen in LOC14 reversed these prothrombotic effects. Blocking antibodies targeting PDI also reversed the effect of LOC14. Evaluation of sulfenylation-mediated PDI oxidation using C53A, C56A, R120D and T101A PDI mutants showed that the sulfenylation mechanism of PDI resembles that of H2O2 reduction by peroxiredoxins. These studies identified PDI mutants that failed to undergo H2O2-mediated oxidation, but showed normal reductase activity. When tested in vivo, either wild-type PDI or the R120D mutant fully restored normal thrombus formation following morphilino-induced knockdown of PDI. In contrast, the R120D mutant PDI was unable to fully restore thrombus formation in the setting of oxidative stress induced in mice with genetic deletion of glutathione peroxidase 3 null (GPx3-/-). These studies show that PDI-catalyzed oxidization drives thrombus formation in vivo and demonstrate a mechanism of peroxide-mediated oxidation of PDI that contributes to the prothrombotic response of oxidative stress.

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.