Type 1 plasminogen deficiency (PLGD), an ultrarare disorder caused by PLG pathogenic variants, results in decreased levels of immunoreactive and functional plasminogen. PLGD can cause fibrin-rich pseudomembranes on mucosa that impair tissue/organ function, affect quality of life, and are potentially life threatening. Lesion regression/resolution is facilitated by IV administration of human plasma-derived Glu-plasminogen (IV PLG concentrate), the first and only US Food and Drug Administration-approved specific treatment, licensed in 2021. The diagnosis of PLGD is frequently delayed because of its rarity (1.6 per million) and the variability of the initial medical specialty contact determined by the affected systems. Symptoms are often attributed to more common conditions, such as conjunctivitis, recurrent otitis media, reactive airway disease, etc. This article presents clinical vignettes highlighting strategies for PLGD diagnosis and treatment. Initial evaluation includes a detailed history, laboratory assays, and, at times, radiologic or other procedures. Genetic testing can confirm the diagnosis. Consistent, knowledgeable management is required to promptly identify and treat lesions, even in initially asymptomatic individuals. Personalized treatment may include continuous prophylaxis or intermittent treatment with IV PLG concentrate, dependent on disease severity and clinical course. Specialized facilities such as hemophilia treatment centers offering multidisciplinary care represent medical homes for this ultrarare disorder.

Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder. There are 2 components to the pathogenesis of PNH: (1) a mutant stem cell and (2) expansion of the mutant clone. Component 1 is straightforward: there is almost always an inactivating somatic mutation of the X-linked gene PIGA. As for component 2, different mechanisms may be involved. In rare cases, expansion may be driven by independently arisen mutations (eg, in JAK2); however, in most patients with PNH, such mutations are not found. Instead, clonal expansion may result from the escape of glycosylphosphatidylinositol (GPI)-negative (PIGA-mutant) stem cells from a T-cell-mediated autoimmune attack on nonmutant stem cells. Several lines of evidence support this mechanism. (1) PNH is closely related to aplastic anemia (AA). (2) PIGA-mutant microclones exist in normal people but they do not expand. (3) In patients with PNH receiving syngeneic bone marrow transplantation, PNH remission has occurred only when immunosuppressive conditioning was applied. (4) After targeted inactivation of piga in mice, large populations of GPI-negative blood cells are produced, but they gradually disappear rather than expand. (5) There is evidence that cytotoxic T cells may spare GPI-negative stem cells, and CD1d-restricted GPI-specific T cells have been demonstrated in patients with PNH and with AA. Thus, the pathogenesis of PNH conforms to a Darwinian model within somatic cell populations: it results from a somatic mutation and a specific selective environment. The findings in PNH are also highly relevant to the pathogenesis of AA.

The critical role of leukemia-initiating cells as a therapy-resistant population in myeloid leukemia is well established. However, the molecular signatures of such cells in acute lymphoblastic leukemia remain underexplored. Moreover, their role in therapy response and patient prognosis is yet to be systematically investigated across various types of acute leukemia. We used single-cell multiomics to analyze diagnostic specimens from 96 pediatric patients with acute lymphoblastic, myeloid, and lineage-ambiguous leukemias. Through the integration of single-cell multiomics with extensive bulk RNA sequencing and clinical data sets, we uncovered a prevalent, chemotherapy-resistant subpopulation that resembles hematopoietic stem and progenitor cells (HSPC-like) and is associated with poor clinical outcomes across all subtypes investigated. We identified a core transcriptional regulatory network (TRN) in HSPC-like blasts that is combinatorially controlled by HOXA/AP1/CEBPA. This TRN signature can predict chemotherapy response and long-term clinical outcomes. We identified shared potential therapeutic targets against HSPC-like blasts, including FLT3, BCL2, and the PI3K pathway. Our study provides a framework for linking intratumoral heterogeneity with therapy response, patient outcomes, and the discovery of new therapeutic targets for pediatric acute leukemias.

Recurrent ischemic priapism is a common complication of sickle cell anemia (SCA) and is associated with devastating physical and psychosocial consequences. All previous trials for priapism prevention have failed to demonstrate clear efficacy. We conducted a randomized, controlled, double-blind phase 2 feasibility trial comparing fixed moderate-dose hydroxyurea plus placebo (usual-care arm) with fixed moderate-dose hydroxyurea plus tadalafil (experimental arm) in 64 males (aged 18-40 years) with at least 3 episodes of SCA-related priapism in the past 12 months. Priapism data were obtained via daily text messages to the participants. The trial's primary outcome measures were 100% recruitment, 98.4% retention, and 93.5% adherence rates. Over a median of 10 months (interquartile range, 3-12), 2.5 and 3.02 priapism events per participant-month were recorded in the usual-care and the experimental arms, with an incidence rate ratio of 0.8 (95% confidence interval [CI], 0.3-1.9; P = .654). The rates of serious adverse events (P = .999) and hospitalization (P = .289) were similar in the 2 arms. Sperm concentration, motility, and normal morphology significantly decreased on hydroxyurea therapy but recovered to prehydroxyurea levels 3 months after therapy cessation. Post hoc, single-arm, pre-post analysis showed a 58.3% priapism incidence rate reduction in the usual-care arm (5.9-2.5 events per month; difference, 3.4; 95% CI, 1.1-5.8; P = .005) and a 66.3% priapism reduction in the experimental arm (8.9-3.02 events per month; difference, 5.9; 95% CI, 3.4-8.5; P < .001) compared with the prerandomization rates. A randomized controlled trial for priapism prevention is feasible in men with SCA. This trial was registered at www.clinicaltrials.gov as #NCT05142254.

This study aimed to assess the efficacy and safety of combining cemiplimab, an anti-programmed cell death protein 1 (PD-1) antibody, with isatuximab, an anti-CD38 antibody, in relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL). The hypothesis was that CD38 blockade could enhance the antitumor activity of PD-1 inhibitors. Eligible patients received cemiplimab (250 mg on days 1 and 15) and isatuximab (10 mg/kg on days 2 and 16) IV every 4 weeks for 6 cycles. Responders then received cemiplimab (350 mg) and isatuximab (10 mg/kg) every 3 weeks for up to 24 months. The primary end point was the complete response (CR) rate based on the best response. Of 37 patients enrolled, the CR rate was 51% (19/37), exceeding the primary end point of 40%, and the objective response rate was 65% (24/37). After a median follow-up of 30.2 months (95% confidence interval [CI], 25.6-34.8 months), the median progression-free survival was 9.5 months (95% CI, 1.4-17.6 months), whereas the median overall survival had not yet been reached. Patients achieving CR received a median of 28 cycles (range, 4-33 cycles), and the median duration of response for responders (n = 24) was 29.4 months (95% CI, 15.4-43.4 months). Structural variations disrupting the 3'-untranslated region of PD-L1 and high programmed death ligand 1 (PD-L1) expression were observed in responders. Most adverse events were mild (grade 1-2), with grade ≥3 events (32%) and no treatment-related deaths. The combination of isatuximab and cemiplimab demonstrated sustained antitumor activity and a manageable safety profile in R/R ENKTL. This phase 2 trial is registered at www.clinicaltrials.gov as number NCT04763616.

The development of targeted therapy for patients with multiple myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chromosome 1q (1q+) is the most frequent arm-level copy number gain in patients with MM and is associated with higher risk of progression and death despite recent therapeutic advances. Thus, developing targeted therapy for patients with MM with 1q+ stands to benefit a large portion of patients in need of more effective management. Here, we used large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with 1q+ and displayed increased sensitivity to myeloid cell leukemia-1 (MCL1) and phosphatidyl inositol 3-kinase (PI3K) inhibitors. Using single-cell RNA sequencing, we compared subclones with and without 1q+ within the same patient tumors and demonstrated that 1q+ is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number profiles for part of the chromosome 1q arm, we observed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with 1q+, uncovering a cytostatic effect. In conclusion, this study highlights that MM with 1q+ may present enhanced sensitivity to MCL1 and PI3K inhibitors, enabling their use at lower doses without sacrificing efficacy, and may thus accelerate the development of targeted therapy for patients with MM and 1q+.

Whether allogeneic hematopoietic cell transplant (allo-HCT) to treat acute myeloid leukemia (AML) is equitably accessible regardless of social determinants of health (SDOH) remains unknown. We examined associations of SDOH with access to allo-HCT and other outcomes. Patients presenting for treatment (n = 692) at 13 AML treatment centers were prospectively recruited to a registered clinical trial (number NCT01929408). Various patient-, AML-, and SDOH-specific variables were collected. Outcomes included mortality without allo-HCT, receipt of allo-HCT, and mortality after allo-HCT. Individual multivariable models (Fine-Gray for the first 2 outcomes, Cox regression for the third) were fit for each SDOH variable, adjusting for relevant patient- and AML-specific variables. Allo-HCT was used to treat 46% of patients. A 10% increase in the proportion with less than a high school education, in households receiving Supplemental Nutrition Assistance Program, receiving Supplemental Security Income, or in poverty led to modeled adjusted hazard ratios (aHRs) of 1.21 (0.99-1.46), 1.13 (0.97-1.31), 1.41 (1.01-1.97), and 1.16 (0.96-1.39) for death without allo-HCT. The aHRs were 0.67 (0.55-0.83), 0.88 (0.76-1.01), 0.71 (0.48-1.05), and 0.91 (0.75-1.09) for lessened receipt of allo-HCT. Among those who received allo-HCT, aHRs for mortality were 1.18 (0.87-1.60), 1.13 (0.92-1.38), 1.21 (0.81-1.82), and 1.04 (0.79-1.36). Results highlight increased mortality without allo-HCT and decreased access to allo-HCT, but lesser magnitude of increased mortality after allo-HCT, among patients from lower resourced areas due to limited education and/or increased poverty. Targeted interventions and policy changes are needed to ensure that marginalized patient populations have equitable chances for AML cure compared with others.

Donor blood saves lives, yet the potential impact of recurrent large-volume phlebotomy on donor health and hematopoietic stem cells (HSCs) remains largely unexplored. In our study, we conducted a comprehensive screening of 217 older male volunteer donors with a history of extensive blood donation (>100 lifetime donations) to investigate the phenomenon of clonal hematopoiesis (CH). No significant difference in the overall incidence of CH was found in frequent donors (FDs) compared with sporadic donors (<10 lifetime donations; 212 donors). However, upon deeper analysis of mutations in DNMT3A, the most commonly affected gene in CH, we observed distinct mutational patterns between the FD and age/sex-matched control donor cohorts. Functional analysis of FD-enriched DNMT3A variants examined in CRISPR-edited human HSCs demonstrated their competitive outgrowth potential upon stimulation with erythropoietin (EPO), a hormone that increases in response to blood loss. In contrast, clones harboring leukemogenic DNMT3A R882 mutations increase upon stimulation with interferon gamma. Through concurrent mutational and immunophenotypic profiling of primary samples at single-cell resolution, a myeloid bias of premalignant R882 mutant HSCs was found, whereas no significant lineage bias was observed in HSCs harboring EPO-responsive DNMT3A variants. The latter exhibited preferential erythroid differentiation when persistent erythropoietic stress was applied to CRISPR-edited human HSC xenografts. Our data demonstrate a nuanced, ongoing Darwinian evolution at the somatic stem cell level, with EPO identified as a novel environmental factor that favors HSCs carrying certain DNMT3A mutations.

Among 64 patients with Erdheim-Chester disease treated with a BRAF inhibitor (median follow-up 4 years), we found high response rates (85%) but frequent discontinuations (61%), primarily because of adverse events. Additionally, patients experienced poor health-related quality of life and high symptom burden.

Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, lowers antithrombin (AT) to increase thrombin generation and rebalance hemostasis in people with hemophilia. This phase 3 open-label extension study (ATLAS-OLE) evaluated safety and efficacy of an AT-based dose regimen (AT-DR) in males aged ≥12 years with severe hemophilia A/B, with/without inhibitors. The original dose regimen (ODR) of 80 mg monthly was optimized to AT-DR targeting AT activity levels 15% to 35% to mitigate thrombotic risk (starting dose of 50 mg once every 2 months, individually adjusted to 20 mg once every 2 months, or 20/50/80 mg monthly as needed). Primary and secondary end points were safety and efficacy, respectively. Integrated safety analyses assessed safety of AT-DR and ODR across all fitusiran studies and integrated efficacy analyses compared efficacy of AT-DR in ATLAS-OLE with phase 3 parent study control groups. At interim data cutoff, 213 participants were enrolled on AT-DR (78% on regimens of once every 2 months). Integrated safety analyses of participants receiving AT-DR (n = 286) demonstrated that AT-DR was well tolerated. In ATLAS-OLE, median observed annualized bleeding rate (ABR) with AT-DR was 3.7 (interquartile range, 0.0-7.5). Integrated efficacy analyses demonstrated superiority of AT-DR over on-demand clotting factor concentrates (CFCs; 71% mean ABR reduction; P < .0001), and on-demand bypassing agents (BPAs; 73% mean ABR reduction; P = .0006); improvement over BPA prophylaxis (70% mean ABR reduction); and ABR comparable with that observed with CFC prophylaxis. Fitusiran AT-DR was well tolerated and maintained bleed protection with as few as 6 injections per year. This trial was registered at www.ClinicalTrials.gov as #NCT03754790.