Chemotherapy-induced thrombocytopenia (CIT) is a common complication of cancer therapy that may result in major bleeding events and reduction of chemotherapy relative dose intensity. While there remain no widely available licensed therapies to manage CIT, major studies-including global pivotal phase 3 clinical trials of the thrombopoietin receptor agonists (TPO-RAs) romiplostim and avatrombopag in CIT- have been completed, along with additional supporting evidence from other clinical trials and observational studies. Like patients with chemotherapy-induced neutropenia, not all patients with CIT require treatment-but for those who do, it can have a major impact on a patient's oncologic care and outcomes. Proper management of CIT requires an understanding of the two clinical subtypes of CIT (persistent and nadir), the limited role of platelet transfusions and antifibrinolytics, and when and how to appropriately use TPO-RA support. In this article, 4 patient cases of CIT are used to illustrate common and challenging scenarios occurring in clinical practice. Built on a framework of published studies and supported by extensive clinical experience, appropriate treatment strategies for CIT are described in detail, with emphasis on proper patient selection, dosing, titration, and monitoring for the use of TPO-RAs in CIT.

After five decades of CHOP-based therapy, the treatment landscape for patients with newly diagnosed large B-cell lymphoma (LBCL) is rapidly evolving. Novel agents, including antibody-drug conjugates, bispecific antibodies, targeted therapies, and chimeric antigen receptor (CAR) T-cell therapies, have demonstrated significant activity, raising the potential for improved outcomes from first-line treatment. However, this progress has introduced substantial complexity without a clear framework for clinical decision-making. Ongoing phase 3 trials employ heterogeneous designs, including differing control arms, eligibility criteria, and endpoints, yet share a common limitation: the inconsistent incorporation of biomarker-driven patient selection. As a result, cross-trial comparisons are challenging, and identifying the optimal regimen for an individual patient remains difficult. Although the POLARIX trial established polatuzumab-based therapy (R-CHP-pola) as superior to R-CHOP, many ongoing studies continue to use R-CHOP as the comparator, further complicating interpretation. Moreover, "R-CHOP + X" strategies evaluated in clinically defined populations without biologic stratification may yield modest benefits across heterogeneous groups, limiting their applicability to individual patients. These trends risk producing a fragmented landscape of effective yet non-comparable regimens without a principled framework for patient selection. We thus propose a harmonized, data-driven strategy to shape the next era of LBCL therapy: (1) pooled patient-level analyses; (2) standardized biomarker and minimal residual disease platforms; (3) AI-enabled predictive modeling integrating trial and real-world data; and (4) regulatory approaches promoting collaborative trial design and shared biomarker analyses. Ultimately, progress in LBCL will depend on aligning data, biology, and clinical decision-making to deliver precise, equitable, and effective care.

Transfusion medicine has practiced a form of precision medicine for decades through compatibility testing, infectious disease screening, component manufacturing, traceability, and hemovigilance. Yet blood is still often treated primarily as a commodity, collected, processed, stored, and transfused, rather than as a dynamic biologic product rich in molecular information. This Perspective argues that the field is uniquely positioned to extend its longstanding precision framework into a more molecular, longitudinal, and predictive era. Omics approaches, especially genomics and repeated metabolomic or proteomic profiling, can help define stable donor traits, track physiologic changes across the donation career, and connect donor biology to storage quality, post-transfusion performance, and recipient outcomes. Clinical metabolomics may eventually extend this framework to recipients, enabling deeper phenotyping across the full vein-to-vein continuum. This vision supports the emergence of the "blood unit+", a blood product enriched not only by compatibility and availability, but also by biologic context that may inform quality, resilience, and transfusion efficacy. At population scale, longitudinal donor testing could transform blood systems into distributed observatories of public health, or health weather stations, enabling molecular epidemiology, digital donor twins, and more meaningful reciprocity with donors. Integrated with artificial intelligence, these data could help strengthen donor recruitment and retention, by engaging a new generation of increasingly health-conscious donors, while supporting the resilience of blood systems facing demographic aging and shifting patterns of donor behavior, while linking donor biology, product behavior, and recipient response in ways no other field can presently match.

Bone marrow (BM) fibrosis in primary and post-polycythemia vera/essential thrombocythemia myelofibrosis (MF) has traditionally been considered a reactive process driven by cytokines, such as transforming growth factor (TGF)-β1, primarily produced by neoplastic megakaryocytes and platelets. These cytokines promote the differentiation of wild-type mesenchymal stromal cells into collagen- and fibronectin-producing myofibroblasts, thereby inducing BM fibrosis. However, hematopoietic-derived collagen-producing cells of monocyte lineage, termed fibrocytes, have also been implicated in this process. Here, we demonstrate that fibrocytes constitute a major collagen-producing cell population in the BM of patients with JAK2V617F-mutated MF, with additional contributions from myofibroblasts. Analysis of BM samples from patients with JAK2V617F-mutated myeloproliferative neoplasms (MPNs) revealed that fibrocytes accounted for nearly two-thirds of collagen-producing cells, whereas myofibroblasts represented a smaller subset. Using BM-derived fibrocytes from Jak2V617F transgenic mice (Jak2V617F mice), we performed a high-throughput drug screen and identified statins as inhibitors of fibrocyte proliferation in vitro. In vivo, pitavastatin treatment reduced fibrocyte numbers, ameliorated BM fibrosis, and improved anemia in Jak2V617F mice. Pitavastatin also decreased TGF-β1 production by neoplastic fibrocytes, resulting in reduced myofibroblast expansion. Peripheral blood-derived fibrocytes from patients with JAK2V617F-mutated MPNs were similarly sensitive to pitavastatin in vitro. Together, these findings suggest that fibrocytes substantially contribute to BM fibrosis in JAK2V617F-mutated MF and support further investigation of pitavastatin as a potential antifibrotic strategy in this molecular subset.

Leukemia stem cells (LSCs) drive acute myeloid leukemia (AML) initiation, relapse, and chemoresistance, yet the core post-translational events sustaining LSC maintenance remain poorly defined. Here, through phosphoproteomic profiling of normal hematopoietic stem and progenitor cells (HSPCs) versus LSC-enriched populations, we identify DEK phosphorylation as a critical modification during leukemogenesis. Functional studies in MLL-AF9- and HOXA9/MEIS1-driven AML mouse models, as well as patient-derived xenografts (PDXs), demonstrate that DEK deficiency impairs LSC maintenance and AML progression. Moreover, DEK deletion enhances LSC chemosensitivity to the standard-of-care combination of azacitidine and venetoclax (Aza/Ven), whereas DEK overexpression confers robust chemoresistance. Mechanistically, DEK recruits the transcription factor GABPA to upregulate the transcriptional cofactor PBX3, a key oncogenic driver in AML, thereby sustaining the leukemogenic transcriptional program. This DEK-GABPA interaction strictly depends on DEK phosphorylation at Ser301/303/306/307 (the 4S sites), which stabilizes the conformation of the DEK-GABPA complex. We identify casein kinase 2 (CK2) as the upstream kinase that directly phosphorylates DEK-4S sites. Importantly, blockade of DEK phosphorylation via 4S site mutagenesis or treatment with the clinical-stage CK2 inhibitor CX-4945 selectively depletes LSCs while sparing normal HSPCs. Furthermore, combining CX-4945 with venetoclax promotes LSC apoptosis and represses the PBX3-driven leukemogenic transcriptional program, exhibiting synergistic anti-AML effects both in vitro and in vivo. Collectively, our findings uncover a previously unrecognized phosphorylation event (DEK-4S phosphorylation) that sustains LSCs and establish the CK2-DEK axis as a promising LSC-specific therapeutic strategy for AML.

Primary cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal non-Hodgkin lymphomas. Outcomes for patients with advanced-stage disease are suboptimal, as few complete and durable responses are achieved with currently available therapeutic agents. However, improved understanding of oncogenic transcriptional programs in malignant T cells and their engagement with the tumor microenvironment (TME) may unveil therapeutic vulnerabilities. Therefore, we have compiled the largest available scRNA-seq CTCL atlas that includes >2 million skin and blood cells from 116 individual patients. We identified recurrent transcriptional programs in malignant T cells, a subset of which are associated with GATA-3 dependent transcriptional programs, especially in the setting of large cell transformation and advanced-stage disease. Many of the transcriptional programs identified are therapeutically targetable with clinically available agents, including HDAC, XPO1, CDK9, JAK/CSF1R, and IKZF1/IKZF3 antagonists. The CTCL TME is dominated by infiltrating and exhausted effector and cytotoxic T cells that are restrained by a robust infiltrate of regulatory T cells, transcriptionally polarized monocytes/macrophages, and cancer-associated fibroblasts. Collectively, these findings have significant implications for the rationale design of combinatorial strategies targeting immune checkpoints, including PD-1. We have identified transcriptional programs, driven by oncogenic transcription factors, and constituents of the TME as therapeutic vulnerabilities in CTCL, and hope that the CTCL atlas constructed will provide a valuable resource for future studies exploiting these therapeutic vulnerabilities.

The Phase 3 TRANSFORM-1 study (NCT04472598) evaluated ruxolitinib (RUX) in combination with navitoclax (NAV) or placebo (PBO) in Janus-kinase-inhibitor-naïve adults with intermediate-2 or high-risk myelofibrosis and Eastern Cooperative Oncology Group performance status ≤2. Patients were randomized 1:1 to NAV (200 mg/day starting dose or 100 mg escalated to 200 mg/day) or PBO, with RUX dosed per label. The primary endpoint was ≥35% spleen volume reduction (SVR) at Week 24 (SVR35W24). Secondary endpoints included change from baseline in Total Symptom Score (TSS) at Week 24 and SVR35 at any time. A total of 252 patients (NAV+RUX, n=125; PBO+RUX, n=127; median follow-up 20.3 months) were randomized; >80% had intermediate-2 risk and nearly 50% were high-molecular risk (HMR). SVR35W24 was achieved by 63.2% with NAV+RUX versus 31.5% with PBO+RUX (P<0.0001). Mean change in TSS at Week 24 was not significantly different between NAV+RUX and PBO+RUX (-10.2 vs -11.6; P=0.2852). SVR35 at any time was achieved in 76.8% with NAV+RUX versus 44.1% with PBO+RUX (nominal P<0.0001). A ≥20% variant allele frequency reduction (exploratory endpoint) occurred in 58.5% (95% CI: 49.0-67.5) with NAV+RUX and 45.5% (95% CI: 36.4-54.8) with PBO+RUX. NAV+RUX showed higher hematologic toxicity versus PBO+RUX (Grade 3/4 thrombocytopenia: 54.0% vs 19.2%; Grade 3/4 neutropenia: 40.3% vs 8.8%); diarrhea (any grade: 41.9% vs 16.8%) was also more common. Cytopenias were generally manageable and reversible with dose adjustments.

Antiphospholipid syndrome (APS) is an immunothrombotic disorder, frequently attributed to autoantibodies that bind β2-glycoprotein I (β2GPI). A study showed that the platelet-specific chemokine, platelet factor 4 (PF4), binds to β2GPI, enhancing recognition of β2GPI by APS antibodies. APS antibodies induce the release of neutrophil extracellular traps (NETs), webs of decondensed chromatin that bind both PF4 and b2GPI. We propose that PF4 bridges β2GPI to NETs (and other PF4-targeted polyanions), leading to the formation of prothrombotic PF4:b2GPI:NET immunotargets in APS. Dynamic light-scattering studies of isolated IgGs from four patients with triple-positive APS show formation of PF4:β2GPI:NET complexes that bind APS antibodies. NETs released in a microfluidic system bound b2GPI, but only in the presence of PF4, forming a multimolecular APS antigenic target. Whole blood infused through a photochemically-injured, endothelium-lined microfluidic channel formed platelet-, fibrin-, and complement- rich thrombi that bound APS antibody only in the presence of PF4. Thrombi were reduced in size if either ADAMTS13 or DNase1 was infused. In a murine APS model, wildtype and transgenic mice expressing platelet human PF4 ± FcgRIIA developed more intense neutrophil rolling along veins, and more extensive thrombus formation following laser injury to cremaster arterioles and venules, whereas mice lacking PF4 did not. Three antigenically distinct anti-hPF4 monoclonal antibodies blocked thrombosis in vitro, and neutrophil rolling and thrombosis in vivo. Our studies provide new insights into the basis of APS that has mechanistic parallels to other known PF4 immunothrombotic disorders and offer potential diagnostic and non-anticoagulant therapeutic strategies for clinical management.

Allogeneic hematopoietic cell transplantation (HCT) has benefited many patients with hematological malignancies and bone marrow failure states. However, graft vs host disease (GVHD) and immune incompetence remain significant challenges that limit the field to the treatment of patients with life threatening, high-risk disorders due to the significant non-relapse mortality (NRM) associated with the treatment. With a greater understanding of the pathophysiology of GVHD it has become apparent that this disorder represents a dysregulated immune reaction resulting in immune dysfunction further exacerbated by the treatment with immunosuppressive medications and injury to lymphoid tissues where immune recovery and tolerance develop. The emergence of fundamental mechanisms of immune regulation, whose pioneers received the 2025 Nobel Prize in Physiology and Medicine, have resulted in new concepts for improving outcomes for patients and the hope that with reduction in transplant related risk HCT can be offered to more patients with a broader range of immune mediated disorders. In this review the history, preclinical studies and successful translation of CD4+CD25+FoxP3+ regulatory T cells (Treg) in the context of allogeneic HCT will be discussed.