Blood advances最新文献

Emerging long-term data indicates relapse rates of over 50% after CD19 redirected chimeric antigen receptor (CAR) T cell therapy in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). To reduce selective pressure on the CD19 antigen we conducted a first-in-human phase I clinical trial of zamtocabtagene autoleucel (zamto-cel) - a non-cryopreserved tandem CD20-CD19-directed CAR-T cell therapy. Two predefined dose levels (DL1=1x106 and DL2=2.5x106 CAR+ T cells/kg body) were applied. The primary endpoint (EP) was the maximum tolerated dose (MTD). Secondary EPs included adverse events (AEs), best overall response (BOR) and biomarker assessments. A total of 12 patients, 6 per dose level were treated. No DLT and no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) grade ≥3 were observed. Thus, MTD was not reached. The BOR by investigator assessment was 75% with 5/12 patients (42%) achieving complete remission (CR) until month 12 with no relapse in clinical evaluation up to 5 years after infusion. CR was associated with higher mean Cmax and detection of zamto-cel beyond month 6. Additional product characterization revealed increased expression of CD27 and CD127 along with increased expansion of CAR+ TCM cells in patients with CR, thus facilitating persistence and improved outcomes in r/r B-NHL treated with zamto-cel. Based on the promising risk-to-benefit ratio, evaluation of zamto-cel at DL2 is ongoing in pivotal Phase II clinical trials for patients with r/r aggressive B-NHL. This trial was registered at www.clinicaltrials.gov as #NCT03870945.

Iron deficiency anemia (IDA) affects nearly one-third of women globally, with heavy menstrual bleeding (HMB) being a significant risk factor among those of reproductive age. Despite the substantial burden of HMB-related IDA, patients often face delays in receiving effective treatment. Oral iron is typically used as first-line therapy, despite frequent gastrointestinal side effects and challenges in treatment adherence. This study evaluated the reproductive lifespan cost-effectiveness of first-line intravenous (IV) versus oral iron therapy for women with HMB and IDA. We developed a Markov model simulating a cohort of women from age 18 to 51, comparing first-line treatment with IV iron dextran, IV ferumoxytol, IV iron sucrose, or oral ferrous sulfate. Costs and quality-adjusted life years (QALYs) were estimated from the societal perspective. IV iron dextran was the cost-effective treatment, yielding 19.26 QALYs at a cost of $157,500, compared with 19.10 QALYs at $152,900 for oral ferrous sulfate. The incremental cost-effectiveness ratio for IV iron dextran was $28,600 per QALY. Treatment with IV ferumoxytol and iron sucrose cost $158,300 and $163,500 respectively and did not provide additional QALY benefit compared with IV iron dextran, which remained the cost-effective treatment across a range of scenarios and sensitivity analyses. Our findings indicate that first-line treatment with IV iron dextran is the cost-effective strategy for managing IDA in women with HMB at commonly accepted willingness-to-pay thresholds. These results support expanding access to IV iron as a first-line option and highlight the need to reduce treatment delays and insurance-related barriers.

Bruton tyrosine kinase inhibitors (BTKis) have dramatically changed the therapeutic landscape of chronic lymphocytic leukemia (CLL), with ibrutinib, first-in-class, demonstrating durable efficacy even in high-risk patients. However, off-target adverse events (AEs) have raised concerns, prompting the development of more selective second-generation BTKi, as zanubrutinib, designed to improve tolerability while maintaining efficacy. Despite encouraging results from clinical trials, real-world data comparing zanubrutinib with ibrutinib remain limited. In this multicenter, retrospective study, we analyzed 934 CLL patients treated outside clinical trials, including 393 receiving zanubrutinib and 541 receiving ibrutinib. We evaluated time to treatment discontinuation (TTD) and time to next treatment or death (TTNTD) in both the overall cohort and a propensity score-matched population. Zanubrutinib-treated patients experienced lower 12-month discontinuation rates (overall:12.6% versus 21.4%; matched:12.4% versus 20.2%) and higher 12-month TTNTD rates (overall:91.9% versus 83.0%; matched:93.2% versus 83.4%). Multivariable analyses confirmed zanubrutinib as an independent predictor of longer TTD and TTNTD, while high-risk features, including age, relapsed/refractory disease, Binet stage C, TP53 disruption, ECOG 2-3, and congestive heart failure, were consistently associated with poorer outcomes. AEs leading to discontinuation, particularly atrial fibrillation, bleeding, and infections, were less frequent with zanubrutinib, reflecting its favorable safety profile. These findings provide real-world evidence that zanubrutinib offers more durable disease control and improved persistence compared with ibrutinib, reinforcing its clinical value as a preferred second-generation BTKi. Nevertheless, the relatively short follow-up for zanubrutinib warrants cautious interpretation of long-term outcomes and underscores the need for ongoing observation to fully characterize its durability and safety.

TP53 and PPM1D are key regulators of DNA damage response and repair and somatic mutations in these genes often co-occur in hematopoietic cells, expanding under genotoxic stress. Unlike with TP53 mutations, where mechanisms of progression are defined, pathways underlying clonal fitness and transformation in PPM1D mutant cells remain unclear. In collaboration with 5 academic institutions, we analyzed the clinical and molecular landscape of 337 patients with clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance (CCUS) across four genotypes: PPM1Dmt/TP53wt (n= 170 [50%]), PPM1Dmt/TP53mt (n= 25 [7%]), TP53mt/PPM1Dwt (n=17 [5%]), and TP53wt/PPM1Dwt (n= 125 [38%]). All PPM1D variants were truncating, located in exon 6 of the gene, with a median variant allele frequency (VAF) of 6% (0.3-64%). The PPM1Dmt/TP53mt genotype was most frequently encountered in therapy related (t)CH/CCUS (80%, 66.5%, 76.5% and 19%; p= <0.001) and had a shorter time interval to detection from last genotoxic exposure (6.2, 5.9, 11.25, and 24.5 months; p= <0.001), in comparison to PPM1Dmt/TP53wt, TP53mt/PPM1Dwt and TP53wt/PPM1Dwt genotypes, respectively. Acknowledging the short follow-up duration, rates of malignant transformation were lower in PPM1Dmt/TP53wt (2%) and PPM1Dmt/TP53mt (4%) groups, in comparison to PPM1Dwt/TP53wt (12%) and PPM1Dwt/TP53mt (17%) groups (p= <0.001), respectively. In summary, PPM1D mutations are frequently observed in t-CH/CCUS, with low median VAFs and are associated with low rates of progression, even when co-mutated with TP53.

Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), are chronic myeloid neoplasms associated with increased risk of cardiovascular disease (CVD). Statins are a common group of cholesterol-lower medications recommended for the primary and secondary prevention of CVD, including arterial thrombotic events. Emerging evidence suggests that statins may reduce the risk of developing MPNs and their use may be associated with improved survival. However, statins impact on cardiovascular and hematologic outcomes among patients with MPNs remains uncharacterized. We conducted a multicenter retrospective cohort study of patients with MPNs who had at least one transthoracic echocardiogram (TTE) from 2010 to 2024. Inverse-probability treatment weighting (IPTW) competing-risk regression analysis was performed to assess the association between statin use at time of index TTE on major adverse cardiovascular events (MACE), MPN disease progression, and all-cause death. MPN patients were analyzed as a whole and separately by type (ET or PV and MF). A total of 669 patients were included, 43.9% were on statin use, 50.5% were female, 83.9% were White, 78.8% had JAK2 driver mutation, and 72.9% had class I guideline indication for statin therapy. There were 267 (39.9%) PV, 234 (35.0%) ET, and 168 (25.1%) MF patients. After IPTW, statin use was associated with lower risk of MACE (SHR 0.83, 95% CI 0.70 - 0.98) but not MPN disease progression (SHR 0.96, 95% CI 0.72 - 1.29) or all-cause death (HR 1.04, 95% CI 0.87 - 1.24). Among patients with ET or PV, statin use was associated with lower risk of MACE (SHR 0.78, 95% CI 0.64 - 0.95) but not MPN progression (SHR 1.03, 95% CI 0.74 - 1.44) or all-cause death (HR 0.85, 95% CI 0.68 - 1.06). Among patients with MF, there was no difference in MACE, leukemia progression, or all-cause death. Among patients with MPNs who underwent TTE, statin use was associated with lower risk of MACE, particularly among patients with ET or PV. However, there was no association between statin use and all-cause death or MPN disease progression. Statin therapy is underutilized in this patient population. Further studies are needed to explore the utility of statin therapy in patients with MPN and identify patients who would benefit most from statin therapy.

Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody intended for once-daily subcutaneous prophylactic treatment for people with hemophilia A or B with and without inhibitors. Results from the phase 3 explorer7 study confirmed superiority of concizumab prophylaxis over no prophylaxis in reducing the annualized bleeding rate (ABR) in people with hemophilia A or B with inhibitors (HAwI/HBwI). Male patients aged ≥12 years were randomized 1:2 to no prophylaxis (group 1) or concizumab prophylaxis (group 2), or allocated to concizumab prophylaxis (groups 3 and 4). After ≥24 weeks of treatment, patients in group 1 could switch to concizumab prophylaxis. At the 56-week cut‑off (defined as when all patients in groups 2-4 had completed the visit at 56 weeks or permanently discontinued treatment), bleed-related efficacy, pharmacokinetics and pharmacodynamics, and safety were assessed. Of the 133 patients enrolled (HAwI, n=80; HBwI, n=53), 114 received concizumab prophylaxis (groups 2-4) and 19 were randomized to no prophylaxis (group 1). After ≥24 weeks, 13 patients from group 1 switched to concizumab. Median ABR for treated spontaneous and traumatic bleeding episodes in patients receiving concizumab was 0.8 (interquartile range [IQR] 0.0-3.2) at the 56‑week cut-off, consistent with the low bleeding rates (median ABR 0.0, IQR 0.0-3.3) at the 32‑week cut‑off. Concizumab and free TFPI concentration remained stable over time. No new safety concerns were reported. Longer‑term (≥1 year) efficacy and safety results of concizumab prophylaxis for HAwI/HBwI were consistent with the 32-week cut-off results in explorer7. ClinicalTrials.gov; NCT04083781.

Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 and CXCR4 mutations, whose prognostic value in chemoimmunotherapy-treated patients remains unclear. Moreover, the typically prolonged progression-free survival (PFS) correlates inconsistently with overall survival (OS), underscoring the importance of examining other surrogates. Progression of disease within 24 months (POD24), an established early endpoint, delineates functionally high-risk patients in other indolent lymphomas. This international study evaluated 253 patients receiving frontline fixed-duration bendamustine-rituximab (BR), a common chemoimmunotherapy for WM. At median follow-up of 5.9 years, 5-year PFS and OS were 65% and 87%, respectively; 5-year PFS was similar between MYD88L265P (90%) and MYD88wild-type (WT) subcohorts (64% each, p=0.4). Among 89 patients with known CXCR4 status, the subcohort with CXCR4mutation (28%) had shorter PFS (median, 3.3 versus 8.8 years; HR 2.8, p=0.0036) and OS (HR 2.6, p=0.036) compared to CXCR4WT. POD24 occurred in 11.5% of patients who demonstrated inferior subsequent OS (5-year OS: 71% versus 86%; HR 3.1, p=0.005) and higher mortality (SMR 3.7), unlike the non-POD24 group, whose mortality was comparable to the matched general population (SMR 1.1). In conclusion, BR is effective, irrespective of the MYD88 status, but CXCR4 mutations and POD24 portend worse outcomes. Non-POD24 patients represent a cohort with distinctly favorable outcome.

Myeloproliferative neoplasms (MPN) are associated with a high symptom burden and impaired quality of life (QoL), often unaided by available treatments. Physical activity has demonstrated benefits in other cancers; however, its potential has yet to be explored in MPN. This randomized controlled trial aimed to evaluate the feasibility, acceptability, and efficacy of a supervised exercise program in patients with MPN based on longitudinal assessment of symptom burden, QoL, and clinical/inflammatory markers (CRP, ESR, ferritin, LDH, serum cytokines). MPN patients (n=55) were randomized 3:2 to a 12-week home-based exercise intervention (flexibility/resistance/aerobics) supervised by a kinesiologist versus waitlist control. Measures included patient-reported outcome questionnaires, peripheral blood sampling and post-intervention interviews with participants. Forty-seven patients completed the trial (FIT, n=26; control, n=21). Median [range] age was 66 years [27-86]; 60% were female. All feasibility benchmarks were met, with 88% of participants satisfied and 92% with intent to continue an exercise program on a regular basis. A significant reduction in lactate dehydrogenase levels (LDH) was observed in FIT patients compared to controls (-14.5 U/L vs +4.0 U/L; p=0.03). Patients interviewed described positive effects of the intervention on symptoms and would unanimously recommend the program to others with MPN. In this pilot study, supervised exercise was feasible, acceptable, and showed potential benefits on inflammatory/disease markers.