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) versus fixed moderate-dose hydroxyurea plus tadalafil (experimental arm) in 64 men (18- 40 years) with at least three 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 (IQR: 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% CI: 0.3 -1.9; p= 0.654. Serious adverse events (p=0.999) and hospitalizations (p=0.289) were similar in both arms. Sperm concentration, motility, and normal morphology significantly decreased on hydroxyurea therapy but recovered to pre-hydroxyurea levels three months after therapy cessation. Post-hoc, single-arm, pre- and post-analysis comparing the priapism rate in the treatment phase to pre-randomization showed a 58.3% priapism incidence rate reduction in the usual care arm (5.9 to 2.5 events per month; difference 3.4, 95% CI: 1.1 - 5.8; p=0.005]) and 66.3% priapism reduction in the experimental arm (8.9 to 3.02 events per month; difference 5.9; 95% CI: 3.4 - 8.5; p<0.001]). A randomized controlled trial for priapism prevention is feasible in men with SCA. (NCT05142254).

This study aimed to assess the efficacy and safety of combining cemiplimab, an anti-PD1 antibody, with isatuximab, an anti-CD38 antibody, in relapsed or refractory extranodal NK/T-cell lymphoma (R/R ENKTL). The hypothesis was that CD38 blockade could enhance the antitumor activity of PD1 inhibitors. Eligible patients received cemiplimab (250 mg on days 1 and 15) and isatuximab (10 mg/kg on days 2 and 16) intravenously every four weeks for six cycles. Responders then received cemiplimab (350 mg) and isatuximab (10 mg/kg) every three weeks for up to 24 months. The primary endpoint was the complete response (CR) rate based on the best response. Out of 37 patients enrolled, the CR rate was 51% (19/37), exceeding the primary endpoint of 40%, and the objective response rate was 65% (24/37). After a median follow-up of 30.2 months (95% CI: 25.6-34.8 months), the median progression-free survival was 9.5 months (95% CI: 1.4-17.6 months), while the median overall survival had not yet been reached. Patients achieving CR received a median of 28 cycles (range: 4-33), 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'-UTR of PD-L1 and high 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 II trial is registered at www.clinicaltrials.gov as #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 MM patients with 1q+ stands to benefit a large portion of patients in need of more effective management. Here, we employed large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with 1q+ and displayed increased sensitivity to MCL1 and 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 (#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 two 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 to 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 life-time donations) to investigate the phenomenon of clonal hematopoiesis (CH). No significant difference in the overall incidence of CH was found in frequent donors (FD) compared to sporadic donors (<10 life-time 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 (CD) 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 which increases in response to blood loss. In contrast, clones harboring leukemogenic DNMT3A R882 mutations increase upon stimulation with IFNy. Through concurrent mutational and immunophenotypic profiling of primary samples at single cell resolution, a myeloid bias of premalignant R882 mutant HSCs was found, while 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 siRNA therapeutic, lowers antithrombin (AT) to increase thrombin generation and rebalance hemostasis in people with hemophilia. This phase 3 open-label extension study (ATLAS‑OLE, NCT03754790) evaluated safety and efficacy of antithrombin-based dose regimen (AT-DR) in males ≥ 12 years with severe hemophilia A/B, with/without inhibitors. The original 80 mg monthly (QM) dose regimen (ODR) was optimized to AT-DR targeting AT activity levels 15-35% to mitigate thrombotic risk (starting dose 50 mg once every 2 months [Q2M], individually adjusted to 20 mg Q2M or 20/50/80 mg QM as needed). Primary and secondary endpoints 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 cut-off, 213 participants were enrolled on AT-DR (78% on Q2M regimens). Integrated safety analyses of participants receiving AT-DR (n = 286) demonstrated that AT-DR was well tolerated. In ATLAS-OLE, median (interquartile range) observed annualized bleeding rate (ABR) with AT-DR was 3.7 (0.0, 7.5). Integrated efficacy analyses demonstrated superiority of AT-DR over on-demand clotting factor concentrates (CFCs) (71% mean ABR reduction, P < 0.0001), and on-demand bypassing agents (BPAs) (73% mean ABR reduction, P = 0.0006); improvement over BPA prophylaxis (70% mean ABR reduction); and comparable ABR to 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.