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In hematological malignancies, structural alterations of genes for G1-specific cyclin-dependent kinases inhibitors (CKIs) have been extensively investigated. G1-CKIs might play an important role not only as tumor suppressor genes but also in cellular differentiation. We examined constitutive and differentiation-induced expression and regulation of the four members of the G1-CKI family p16INK4A, p15INK4B, p18INK4C and p19INK4D in acute myeloid leukemia as well as their expression in normal granulocytes and monocytes. p18INK4C and p19INK4D mRNA were expressed constitutively at high levels in seven myeloid cell lines and 16 AML patient samples, whereas expression of p15INK4B mRNA was very low and only detectable by nested RT-PCR analysis. During phorbol ester-induced monocytic differentiation of leukemic HL-60 cells expression of particular G1-CKIs was disparately regulated. This process was associated with growth arrest of the majority of the cells (> or = 80%) in G1/G0, and in parallel p15INK4B were upregulated whereas p18INK4C and p19INK4D expression was downregulated. In contrast, granulocytic differentiation induced by DMSO was accompanied by an increase of p18INK4C and p19INK4D expression only. PMA treatment of blast cells from two AML patients confirmed these cell line results. Disparate regulation of p15INK4B and p18INK4C mRNA was dependent on intermediary protein synthesis and occurred at the post-transcriptional level as shown by nuclear run-on analysis and mRNA half-life studies. In normal granulocytes and monocytes low constitutive p15INK4B and p18INK4C mRNA expression was detectable by RT-PCR only, but p19INK4D transcripts were noted by Northern blotting in both cell types. Disparate expression of G1-specific cell cycle inhibitors indicates complex and divergent roles of particular CKIs during normal and leukemic myeloid hematopoiesis. [ABSTRACT FROM AUTHOR]

• Nonrelapse mortality after prior autologous hematopoietic cell transplantation (HCT) for subsequent allogeneic HCT in the second complete remission • Conditioning toxicity • Consolidation of acute myeloid leukemia in complete remission 1 by autologous HCT After autologous hematopoietic cell transplantation (HCT) in the first complete remission (CR1), patients with acute myeloid leukemia (AML) may relapse and undergo allogeneic HCT in the second complete remission (CR2). The aim of this study was to analyze the outcome of allogeneic HCT performed in CR2 comparing patients with prior consolidation by autologous HCT versus patients with chemotherapy consolidation. Included were 2619 adults with allogeneic HCT in CR2 from 2000 to 2017 with (n = 417) or without (n = 2202) prior autologous HCT. Patient groups were not entirely comparable; patients with prior autologous HCT were younger, had less often a favorable cytogenetic profile, had more commonly donors other than matched siblings, and more often received reduced-intensity conditioning. In multivariate analysis, nonrelapse mortality risks in patients with prior autologous HCT were 1.34 (1.07 to 1.67; P =. 01) after adjustment for age, cytogenetic risk, transplant year, donor, conditioning intensity, sex matching, interval diagnosis-relapse, and relapse-allogeneic HCT as compared with chemotherapy consolidation. Similarly, risks of events in leukemia-free survival and graft-versus-host disease, relapse-free survival were higher with prior autologous HCT, 1.17 (1.01 to 1.35), P =. 03 and 1.18 (1.03 to 1.35), P =. 02, respectively. Risk of death was also higher, 1.13 (0.97 to 1.32), P =.1, but this was not significant. Postremission consolidation with autologous HCT for AML in CR1 increases toxicity of subsequent allogeneic HCT in CR2. [ABSTRACT FROM AUTHOR]

Background: Patients with acute myeloid leukemia (AML) often reach complete remission, but relapse rates remain high. Next-generation sequencing enables the detection of molecular minimal residual disease in virtually every patient, but its clinical value for the prediction of relapse has yet to be established.Methods: We conducted a study involving patients 18 to 65 years of age who had newly diagnosed AML. Targeted next-generation sequencing was carried out at diagnosis and after induction therapy (during complete remission). End points were 4-year rates of relapse, relapse-free survival, and overall survival.Results: At least one mutation was detected in 430 out of 482 patients (89.2%). Mutations persisted in 51.4% of those patients during complete remission and were present at various allele frequencies (range, 0.02 to 47%). The detection of persistent DTA mutations (i.e., mutations in DNMT3A, TET2, and ASXL1), which are often present in persons with age-related clonal hematopoiesis, was not correlated with an increased relapse rate. After the exclusion of persistent DTA mutations, the detection of molecular minimal residual disease was associated with a significantly higher relapse rate than no detection (55.4% vs. 31.9%; hazard ratio, 2.14; P<0.001), as well as with lower rates of relapse-free survival (36.6% vs. 58.1%; hazard ratio for relapse or death, 1.92; P<0.001) and overall survival (41.9% vs. 66.1%; hazard ratio for death, 2.06; P<0.001). Multivariate analysis confirmed that the persistence of non-DTA mutations during complete remission conferred significant independent prognostic value with respect to the rates of relapse (hazard ratio, 1.89; P<0.001), relapse-free survival (hazard ratio for relapse or death, 1.64; P=0.001), and overall survival (hazard ratio for death, 1.64; P=0.003). A comparison of sequencing with flow cytometry for the detection of residual disease showed that sequencing had significant additive prognostic value.Conclusions: Among patients with AML, the detection of molecular minimal residual disease during complete remission had significant independent prognostic value with respect to relapse and survival rates, but the detection of persistent mutations that are associated with clonal hematopoiesis did not have such prognostic value within a 4-year time frame. (Funded by the Queen Wilhelmina Fund Foundation of the Dutch Cancer Society and others.). [ABSTRACT FROM AUTHOR]

Background Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)–positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available. Methods We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD–positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy. Findings With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years. Interpretation Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD–positive AML relapsing after allo-SCT. [ABSTRACT FROM AUTHOR]

The occurrence of varicella zoster virus (VZV) reactivation is increased after allogeneic transplantation, whereas limited data are available for herpes zoster (HZ) after autologous SCT (ASCT). We determined the incidence and the prognostic significance of HZ and its correlation with VZV serology in 191 consecutive myeloma patients undergoing high-dose melphalan chemotherapy with ASCT. We found that VZV reactivation occurred in 57 (30%) patients, in 8.5% during induction and in 21.5% after ASCT peaking at 8 months after ASCT. Disease burden due to HZ was assessed as high or rather high in 70% of the patients. By immune fluorescence and Serion Elisa VZV IgG assessment, 90.8% of all patients had specific anti-VZV antibodies at ASCT. Lower specific antibody titers at transplantation were observed in patients with HZ after ASCT than in those without reactivation (P=0.009). Finally, OS was better in myeloma patients with HZ after ASCT compared with patients without HZ (P=0.007). Our data indicate that VZV reactivation after ASCT is a frequent event carrying a significant disease burden and it is associated with improved survival. Low levels of specific VZV antibodies at ASCT suggest increased vulnerability for VZV reactivation. [ABSTRACT FROM AUTHOR]

Therapeutic resistance remains the principal problem in acute myeloid leukemia (AML). We used area under receiver-operating characteristic curves (AUCs) to quantify our ability to predict therapeutic resistance in individual patients, where AUC=1.0 denotes perfect prediction and AUC=0.5 denotes a coin flip, using data from 4601 patients with newly diagnosed AML given induction therapy with 3+7 or more intense standard regimens in UK Medical Research Council/National Cancer Research Institute, Dutch-Belgian Cooperative Trial Group for Hematology/Oncology/Swiss Group for Clinical Cancer Research, US cooperative group SWOG and MD Anderson Cancer Center studies. Age, performance status, white blood cell count, secondary disease, cytogenetic risk and FLT3-ITD/NPM1 mutation status were each independently associated with failure to achieve complete remission despite no early death ('primary refractoriness'). However, the AUC of a bootstrap-corrected multivariable model predicting this outcome was only 0.78, indicating only fair predictive ability. Removal of FLT3-ITD and NPM1 information only slightly decreased the AUC (0.76). Prediction of resistance, defined as primary refractoriness or short relapse-free survival, was even more difficult. Our limited ability to forecast resistance based on routinely available pretreatment covariates provides a rationale for continued randomization between standard and new therapies and supports further examination of genetic and posttreatment data to optimize resistance prediction in AML. [ABSTRACT FROM AUTHOR]

The majority of patients with acute myeloid leukemia (AML) still die of their disease, and novel therapeutic concepts are needed. Timely expression of the hematopoietic master regulator PU.1 is crucial for normal development of myeloid and lymphoid cells. Targeted disruption of an upstream regulatory element (URE) located several kb upstream in the PU.1 promoter decreases PU.1 expression thereby inducing AML in mice. In addition, suppression of PU.1 has been observed in specific subtypes of human AML. Here, we identified nuclear factor-κB (NF-κB) to activate PU.1 expression through a novel site within the URE. We found sequence variations of this particular NF-κB site in 4 of 120 AML patients. These variant NF-κB sequences failed to mediate activation of PU.1. Moreover, the synergistic activation of PU.1 together with CEBPB through these variant sequences was also lost. Finally, AML patients with such variant sequences had suppressed PU.1 mRNA expression. This study suggests that changes of a single base pair in a distal element critically affect the regulation of the tumor suppressor gene PU.1 thereby contributing to the development of AML. [ABSTRACT FROM AUTHOR]

Summary:The purpose of the present project was to analyse the costs incurred by the implementation of JACIE standards at a University Hospital with 1000 beds, performing some 40 autologous transplants per year. The cost analysis was performed on the basis of a prospective assessment of the time spent by all staff members involved with the implementation over a 14-month period of the quality management system (QMS) required by the JACIE standards. Two physicians worked on JACIE Section A (management=82?h), one physician and two nurses for section Ba (clinical unit adults=125.75?h), two physicians and three nurses for section Bp (clinical unit paediatrics=206?h), one physician, two nurses and one technician for section C (progenitor cell collection facility=105.75?h), and one physician and two technicians for section D (progenitor cell processing facility=426?h). The total time spent on the project amounted to 945.5?h with a total salary cost of \[euro]150?000. We concluded that implementation of the JACIE standards was accomplished within a 14-month period with a financial impact of approximately \[euro]150?000. The impact on quality parameters (eg clinical and laboratory end points, side effects) on HPC transplantation will be assessed in a second report after the first year of practical implementation.Bone Marrow Transplantation (2004) 34, 847-853. doi:10.1038/sj.bmt.1704649 [ABSTRACT FROM AUTHOR]

Introduction: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease, with unique diagnostic challenges and often dismal outcome. There are no widely accepted treatment guidelines available. Lymphoma-like regimens with or without autologous or allogenic transplantation were the cornerstone of most therapeutic concepts. A few years ago, the CD123-directed immunoconjugate tagraxofusp emerged as a new valuable treatment option. The goal of our research was to collect available data on BPDCN-patients treated at large centres in Switzerland and worldwide and to draw conclusions regarding the incidence, clinical presentation, prognostic factors and therapeutic strategies., Methods: We collected data from BPDCN patients from leading Swiss haemato-oncology centres from 2005 to 2022. Furthermore, we reviewed and analysed the published literature (cohorts and case reports in peer-reviewed journals) from 1997 to 2020 (structured review of the literature)., Results: We identified 115 international publications including 600 patients from all over the world. Most of them had very small sample sizes (only ten papers with more than ten patients) and all but one were retrospective or observational respectively. Most included patients were Europeans (n = 385, 64%) and Asians (n = 120, 20%), followed by Americans (n = 90, 15%) and patients from Australia/New Zealand (n = 3) and Africa (n = 2). BPDCN was more common in men with a predominance of 3:1. The median age (n = 414) at diagnosis was 66.5 years ranging from one month to 103 years. Newly diagnosed women were significantly younger than men (median: 62 vs 67 years, mean: 53.4 vs 59.3 years, p = 0.027) and less often had bone marrow infiltration and affected lymph nodes. Upfront allogenic transplantation as well as ALL regimens performed best, with response to first-line therapy clearly associated with better overall survival. The Swiss cohort contained 26 patients (23 males and 3 females) over 18 years (2005-2022). The median age at diagnosis was 68.5 years (range: 20-83). Ten patients underwent upfront stem cell transplantation (seven allogenic and three autologous), at least trending towards a better overall survival than other therapies. With a follow-up of 8 years, the median overall survival was 1.2 years. Eight patients in this cohort were treated with tagraxofusp, which became available in 2020 and was approved by Swissmedic in 2023., Conclusions: Our study confirms that BPDCN is a very rare and difficult-to-treat disease. Underdiagnosis and underreporting in the literature pose further challenges. Symptoms at presentation seem to differ slightly between sexes and reaching a complete remission after first-line treatment remains crucial for a prolonged overall survival. Effective treatment protocols in first line include transplantation regimens (mainly allogenic, potentially also autologous) as well as ALL protocols. In order to understand the significance of tagraxofusp as a bridge to transplant or as a continuous monotherapy in elderly patients, further evaluation with longer follow-up periods is required. In general, analysis of the Swiss patients confirmed the results from the worldwide cohort.

Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM), but direct comparisons are lacking. Leveraging an international multicenter RRMM cohort, we compared the outcome of ide-cel ( n  = 162) versus cilta-cel ( n  = 42). Co-primary efficacy endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). Co-primary safety endpoints were the incidence of cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS). Median turnaround time between apheresis and infusion was 47 days for ide-cel versus 68 days for cilta-cel ( p  < 0.001). Cilta-cel showed significantly higher ORR (93% vs. 79%; p  < 0.001), with complete response at Day 30 of 48% versus 26% ( p  < 0.001). The 10-month PFS and overall survival (OS) was 82% and 90% for cilta-cel versus 47% and 77% ide-cel ( p  < 0.001 and p  = 0.06), and improved outcome for cilta-cel was confirmed after multivariable adjustment. Incidence of CRS and ICANS appeared similar (81% and 19% for cilta-cel versus 85% and 19% for ide-cel), while 10% and 7% in the cilta-cel group versus 4% and 2% in the ide-cel group showed severe CRS and ICANS grade 3-4, with CRS occurring significantly earlier for ide-cel (median, 2 days vs. 4 days; p  < 0.001). Nonrelapse mortality was 5% for cilta-cel versus 3% for ide-cel ( p  = 0.51). Cilta-cel showed later peak of CAR-T expansion at Day 14 versus Day 7 for ide-cel, while cilta-cel expansion was associated with ICANS. Our study provides real-world evidence that cilta-cel was associated with superior outcomes and distinct cellular dynamics versus ide-cel in triple-class exposed RRMM., Competing Interests: Nico Gagelmann: Consulting or Advisory Role: Stemline Therapeutics, MorphoSys Travel, Accommodations, Expenses: Bristol Myers Squibb/Celgene, Janssen. Maximilian Merz: Honoraria: Janssen, BMS GmbH & Co KG, Amgen, AbbVie, Stemline Therapeutics, Takeda, Sanofi, Pfizer Consulting or Advisory Role: Janssen, BMS GmbH & Co KG, Pfizer, Sanofi Research Funding: Janssen, SpringWorks Therapeutics, Roche/Genentech Travel, Accommodations, Expenses: Janssen, Stemline Therapeutics, Pfizer. Aina Oliver‐Caldés: Travel, Accommodations, Expenses: Janssen. Friedrich Stölzel: Honoraria: Medac, Jazz Pharmaceuticals, Consulting or Advisory Role: Glycostem, Travel, Accommodations, Expenses: SERVIER. Anca‐Maria Albici: Honoraria: AbbVie, Travel, Accommodations, Expenses: SERVIER. Natalie Schub: Honoraria: Janssen Oncology, Consulting or Advisory Role: BMS, Travel, Accommodations, Expenses: Kite/Gilead. Soraya Kharboutli: Honoraria: Bristol Myers Squibb GmbH, Travel, Accommodations, Expenses: Janssen, Bristol Myers Squibb, Sobi, Novartis. Fabian Müller: Honoraria: AstraZeneca, Bristol Myers Squibb/Pfizer, Kite/Gilead, Consulting or Advisory Role: Bristol Myers Squibb/Pfizer, Janssen, Kite/Gilead, Kite/Gilead, Novartis, Miltenyi Biomedicine, Research Funding: Kite/Gilead, Travel, Accommodations, Expenses: SOBI, Janssen. Vladan Vucinic: Honoraria: Janssen, BMS GmbH & Co KG, Gilead Sciences, Amgen, Consulting or Advisory Role: Gilead Sciences, Janssen, BMS GmbH & Co KG, Amgen, Travel, Accommodations, Expenses: Sobi, Janssen, Gilead Sciences, Amgen. Uwe Platzbecker: Honoraria: Celgene/Jazz, AbbVie, Curis, Geron, Janssen, Consulting or Advisory Role: Celgene/Jazz, Novartis, BMS GmbH & Co KG, Research Funding: Amgen (Inst), Janssen (Inst), Novartis (Inst), BerGenBio (Inst), Celgene (Inst), Curis (Inst), Patents, Royalties, Other Intellectual Property: Part of a patent for a TFR‐2 antibody (Rauner et al. Nature Metabolics 2019), Travel, Accommodations, Expenses: Celgene. Francis Ayuk: Honoraria: Bristol Myers Squibb/Celgene, Kite/Gilead, Janssen, Miltenyi Biomedicine, Novartis, Takeda, Mallinckrodt/Therakos, medac pharma, Consulting or Advisory Role: Bristol Myers Squibb/Celgene Research Funding: Mallinckrodt/Therakos. Nicolaus Kröger: Honoraria: Novartis, Celgene (Inst), Sanofi, Jazz Pharmaceuticals (Inst), Kite/Gilead, RIEMSER (Inst), AOP Orphan Pharmaceuticals, BMS GmbH & Co KG, Neovii, Alexion Pharmaceuticals, Takeda, Pierre Fabre Consulting or Advisory Role: Neovii, Sanofi, Jazz Pharmaceuticals, Novartis, Celgene, RIEMSER, Gilead Sciences, Speakers' Bureau: AOP Orphan Pharmaceuticals, Research Funding: Neovii (Inst), Novartis (Inst), Celgene (Inst), Riemser (Inst), Travel, Accommodations, Expenses: Neovii, Novartis, Gilead Sciences, Jazz Pharmaceuticals, Sanofi, Celgene. Carlos Fernández de Larrea: Honoraria: Janssen, BeiGene, Bristol Myers Squibb/Celgene, Pfizer, Amgen, GlaxoSmithKline Consulting or Advisory Role: Janssen, Bristol Myers Squibb/Celgene, Amgen, Pfizer, Sanofi, BeiGene Research Funding: Janssen (Inst), Bristol Myers Squibb/Celgene (Inst), Amgen (Inst), GlaxoSmithKline (Inst) Travel, Accommodations, Expenses: Janssen, Amgen, GlaxoSmithKline, Bristol Myers Squibb/Celgene, BeiGene, Pfizer. No other potential conflicts of interest were reported., (© 2025 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Glofitamab, a bispecific antibody targeting CD20 and CD3, is approved for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) after at least two prior treatment lines, but real-world data is scarce. In this retrospective, multicenter, multinational study, we evaluated the outcomes of 70 patients with r/r DLBCL treated with glofitamab as part of the compassionate use patient program in the DACH region (Germany, Austria, Switzerland). The median number of prior treatment lines was four, with 71% of patients having received prior CAR-T therapy, and 71% being refractory to their last treatment. Cytokine release syndrome (CRS) was observed in 40% of patients (grade 3-4 in 2%), immune effector cell-associated neurotoxicity syndrome (ICANS) in 10% (grade 3 in 1%), and infections in 31% (grade 5 in 3%). The overall response rate was 47%, with 27% achieving complete responses (CR) and 20% partial responses (PR). The median progression-free survival (PFS) was 3.6 months, while the median overall survival (OS) was 5.7 months. Notably, 13 patients (19%) were in CR 6 months after initiation of glofitamab and exhibited durable responses. Elevated LDH is the most robust predictor of inferior outcome. Patients pretreated with bendamustine within 6 months prior glofitamab initiation exhibited significantly reduced PFS, suggesting that bendamustine may impair T-cell fitness and hence glofitamab efficacy. In summary, glofitamab demonstrates promising efficacy and a manageable safety profile in heavily pretreated r/r DLBCL patients in the real-world scenario and the optimal sequence of treatments should use T-cell-depleting agents before glofitamab with caution., (Copyright © 2024 American Society of Hematology.)

Abstract: Outcomes are poor in triple-class-exposed (TCE) relapsed and refractory multiple myeloma (R/RMM). In the phase 3 KarMMa-3 trial, patients with TCE R/RMM and 2 to 4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary end point; 13.3 vs 4.4 months; P < .0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median was 41.4 (95% CI, 30.9 to not reached [NR]) vs 37.9 (95% CI, 23.4 to NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI, 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE R/RMM. This trial was registered at www.ClinicalTrials.gov as #NCT03651128., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients (n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab (n = 28), teclistamab (n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies (n = 43), and others (n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome (P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others (P < 0.001). Duration of response, as well as median survival, was significantly improved with bispecific antibodies (P < 0.001, respectively). Bispecific antibodies seemed to overcome the poor prognosis associated with early relapse and EMD, and were independent predictors for improved survival in multivariable analysis. In summary, these results suggest bispecific antibodies as the standard of care for relapse after CAR T-cell therapy for RRMM., Competing Interests: Competing interests: Nico Gagelmann: Consulting or Advisory Role: Stemline Therapeutics, MorphoSys Travel, Accommodations, Expenses: Bristol Myers Squibb/Celgene, Janssen. Maximilian Merz: Honoraria: Janssen, BMS GmbH & Co KG, Amgen, AbbVie, Stemline Therapeutics, Takeda, Sanofi, Pfizer Consulting or Advisory Role: Janssen, BMS GmbH & Co KG, Pfizer, Sanofi Research Funding: Janssen, SpringWorks Therapeutics, Roche/Genentech Travel, Accommodations, Expenses: Janssen, Stemline Therapeutics, Pfizer. Hamza Hashmi: Consulting or Advisory Role: Sanofi, Bristol Myers Squibb/Celgene, Janssen Speakers’ Bureau: Janssen, Karyopharm Therapeutics, Amgen. Nausheen Ahmed: Consulting or Advisory Role: Kite/Gilead, BMS Research Funding: Kite/Gilead (Inst). Aina Oliver-Caldés: Travel, Accommodations, Expenses: Janssen. Friedrich Stölzel: Honoraria: Medac, Jazz Pharmaceuticals, Consulting or Advisory Role: Glycostem, Travel, Accommodations, Expenses: SERVIER. Anca-Maria Albici: Honoraria: AbbVie, Travel, Accommodations, Expenses: SERVIER. Natalie Schub: Honoraria: Janssen Oncology, Consulting or Advisory Role: BMS, Travel, Accommodations, Expenses: Kite/Gilead. Soraya Kharboutli: Honoraria: Bristol Myers Squibb GmbH, Travel, Accommodations, Expenses: Janssen, Bristol Myers Squibb, Sobi, Novartis. Fabian Müller: Honoraria: AstraZeneca, Bristol Myers Squibb/Pfizer, Kite/Gilead, Consulting or Advisory Role: Bristol Myers Squibb/Pfizer, Janssen, Kite/Gilead, Kite/Gilead, Novartis, Miltenyi Biomedicine, Research Funding: Kite/Gilead, Travel, Accommodations, Expenses: SOBI, Janssen. Leyla Shune: Consulting or Advisory Role: Janssen Oncology. Faiz Anwer: Consulting or Advisory Role: Janssen, BMS, Speakers’ Bureau: Bristol Myers Squibb Foundation, Research Funding: Celgene (Inst), Acetylon Pharmaceuticals (Inst), Millennium (Inst), Astellas Pharma (Inst), AbbVie (Inst), Janssen (Inst), Bristol Myers Squibb (Inst), Caribou Biosciences (Inst), Caribou Biosciences, Travel, Accommodations, Expenses: Bristol Myers Squibb, Open Payments Link: https://openpaymentsdata.cms.gov/physician/16726 . Vladan Vucinic: Honoraria: Janssen, BMS GmbH & Co KG, Gilead Sciences, Amgen, Consulting or Advisory Role: Gilead Sciences, Janssen, BMS GmbH & Co KG, Amgen, Travel, Accommodations, Expenses: Sobi, Janssen, Gilead Sciences, Amgen. Uwe Platzbecker: Honoraria: Celgene/Jazz, AbbVie, Curis, Geron, Janssen, Consulting or Advisory Role: Celgene/Jazz, Novartis, BMS GmbH & Co KG, Research Funding: Amgen (Inst), Janssen (Inst), Novartis (Inst), BerGenBio (Inst), Celgene (Inst), Curis (Inst), Patents, Royalties, Other Intellectual Property: Part of a patent for a TFR-2 antibody (Rauner et al. Nature Metabolics 2019), Travel, Accommodations, Expenses: Celgene. Francis Ayuk: Honoraria: Bristol Myers Squibb/Celgene, Kite/Gilead, Janssen, Miltenyi Biomedicine, Novartis, Takeda, Mallinckrodt/Therakos, medac pharma, Consulting or Advisory Role: Bristol Myers Squibb/Celgene Research Funding: Mallinckrodt/Therakos. Nicolaus Kröger: Honoraria: Novartis, Celgene (Inst), Sanofi, Jazz Pharmaceuticals (Inst), Kite/Gilead, RIEMSER (Inst), AOP Orphan Pharmaceuticals, BMS GmbH & Co KG, Neovii, Alexion Pharmaceuticals, Takeda, Pierre Fabre Consulting or Advisory Role: Neovii, Sanofi, Jazz Pharmaceuticals, Novartis, Celgene, RIEMSER, Gilead Sciences, Speakers’ Bureau: AOP Orphan Pharmaceuticals, Research Funding: Neovii (Inst), Novartis (Inst), Celgene (Inst), Riemser (Inst), Travel, Accommodations, Expenses: Neovii, Novartis, Gilead Sciences, Jazz Pharmaceuticals, Sanofi, Celgene. Jack Khouri: Honoraria: GPCR Therapeutics, Consulting or Advisory Role: Janssen Oncology. Joseph McGuirk: Honoraria: Kite, a Gilead company, AlloVir, Magenta Therapeutics, Nektar, Sana Biotechnology Consulting or Advisory Role: Kite, a Gilead company, Juno Therapeutics, Allovir, Magenta Therapeutics, EcoR1 Capital, CRISPR therapeutics, Speakers’ Bureau: Kite/Gilead, Research Funding: Novartis (Inst), Fresenius Biotech (Inst), Astellas Pharma (Inst), Bellicum Pharmaceuticals (Inst), Novartis (Inst), Gamida Cell (Inst), Pluristem Therapeutics (Inst), Kite, a Gilead company (Inst), AlloVir (Inst), Travel, Accommodations, Expenses: Kite, a Gilead company, Syncopation Life Sciences, SITC/ACCC. Al-Ola Abdallah: Research Funding: Celgene (Inst), Seagen (Inst), AbbVie (Inst), Bristol Myers Squibb/Medarex (Inst), Sanofi (Inst), GlaxoSmithKline (Inst), Patents, Royalties, Other Intellectual Property: PSA vaccine patent. Carlos Fernández de Larrea: Honoraria: Janssen, BeiGene, Bristol Myers Squibb/Celgene, Pfizer, Amgen, GlaxoSmithKline Consulting or Advisory Role: Janssen, Bristol Myers Squibb/Celgene, Amgen, Pfizer, Sanofi, BeiGene Research Funding: Janssen (Inst), Bristol Myers Squibb/Celgene (Inst), Amgen (Inst), GlaxoSmithKline (Inst) Travel, Accommodations, Expenses: Janssen, Amgen, GlaxoSmithKline, Bristol Myers Squibb/Celgene, BeiGene, Pfizer. No other potential conflicts of interest were reported., (© 2024. The Author(s).)

Background: Cancer is associated with an increased risk of atrial fibrillation. Whether cancer is also associated with atrial cardiopathy, another atrial pathology associated with heightened ischemic stroke risk, is uncertain., Methods: We conducted a retrospective cross-sectional study among consecutive patients hospitalized with acute ischemic stroke at a quaternary care center in New York, United States from 2011 through 2016. The study exposure was active cancer. The study outcome was atrial cardiopathy, defined as a left atrial volume index ≥35 mL/m 2 on echocardiography. We used multivariable logistic regression, adjusting for baseline characteristics, to evaluate the relationship between cancer (active or historical) and atrial cardiopathy. We performed a subgroup analysis among patients with embolic stroke of undetermined source (ESUS)., Results: The final cohort included 1104 patients with acute ischemic stroke, of whom 10 % had active cancer and 47 % had atrial cardiopathy. Patients with atrial cardiopathy, compared to those without, were older (median age, 77 versus 68 years), and more frequently had hypertension, coronary disease, and atrial fibrillation. Active cancer was present in 9.6 % of patients with atrial cardiopathy (n = 50/520) and 10.4 % of patients without (n = 61/584). There was no association between active cancer and atrial cardiopathy among the overall ischemic stroke cohort (adjusted odds ratio [OR], 0.91; 95 % confidence interval [CI], 0.60-1.37) nor in patients with ESUS (aOR, 0.64; 95 % CI, 0.30-1.36). When the cancer exposure was broadened to include any history of cancer (n = 236, 21.4 %), there still was no significant association with atrial cardiopathy (aOR, 0.93; 95 % CI, 0.68-1.25)., Conclusions: When defining atrial cardiopathy by left atrial volume, we did not find an association between cancer and atrial cardiopathy in patients with ischemic stroke, including among those with ESUS. Future studies, evaluating other atrial cardiopathy biomarkers and settings, are needed to further investigate any potential link between cancer and atrial cardiopathy., Competing Interests: Declaration of competing interest Dr. Beyeler has received research support from the University of Bern, Switzerland. Dr. Navi has received personal fees for serving on an adjudication committee for MindRhythm Inc. Dr. Kamel reports serving as a PI for the ARCADIA trial (NIH/NINDSU01NS095869), which received in-kind study drug from the BMS-Pfizer Alliance for Eliquis® and ancillary study support from Roche Diagnostics; other funding from NIH (R01HL144541, R01NS123576, U01NS106513); serving as Deputy Editor for JAMA Neurology; serving on clinical trial steering/executive committees for Medtronic, Janssen, and Javelin Medical; serving on endpoint adjudication committees for AstraZeneca, Novo Nordisk, and Boehringer Ingelheim; and household ownership interests in TETMedical, Spectrum Plastics Group, and Burke Porter Group. The other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The absence of the susceptibility vessel sign (SVS) in patients treated with mechanical thrombectomy (MT) is associated with poor radiological and clinical outcomes after 3 months. Underlying conditions, such as cancer, are assumed to influence SVS status and could potentially impact the long-term outcome. We aimed to assess SVS status as an independent predictor of long-term outcomes in MT-treated patients., Methods: SVS status was retrospectively determined in consecutive MT-treated patients at a comprehensive stroke center between 2010 and 2018. Predictors of long-term mortality and poor functional outcome (modified Rankin Scale (mRS) ≥3) up to 8 years were identified using multivariable Cox and logistic regression, respectively., Results: Of the 558 patients included, SVS was absent in 13% (n=71) and present in 87% (n=487) on baseline imaging. Patients without SVS were more likely to have active cancer (P = 0.003) and diabetes mellitus (P < 0.001) at the time of stroke. The median long-term follow-up time was 1058 days (IQR 533-1671 days). After adjustment for active cancer and diabetes mellitus, among others, the absence of SVS was associated with long-term mortality (adjusted HR (aHR) 2.11, 95% CI 1.35 to 3.29) and poor functional outcome in the long term (adjusted OR (aOR) 2.90, 95% CI 1.29 to 6.55)., Conclusion: MT-treated patients without SVS have higher long-term mortality rates and poorer long-term functional outcome. It appears that this association cannot be explained by comorbidities alone, and further studies are warranted., Competing Interests: Competing interests: MB reports research support from the Kurt und Senta Hermann-Stiftung. JK reports grants from the Swiss Academy of Medical Sciences/Bangerter Foundation, Swiss Stroke Society, and Clinical Trials Unit Bern during the conduct of the study. UF reports grants during the conduct of the study from Medtronic, Stryker, and CSL Behring, unrelated to the submitted work. JG is a global principal investigator of STAR (Solitaire FR Thrombectomy for Acute Revascularisation), Clinical Event Committee member of the PROMISE study (Prospective, Multicenter, Observational, Single-Arm European Registry on the ACE Reperfusion Catheters and the Penumbra System in the Treatment of Acute Ischemic Stroke; Penumbra), and a principal investigator and consultant for the SWIFT DIRECT study (Solitaire With the Intention for Thrombectomy Plus Intravenous tPA Versus DIRECT Solitaire Stent-Retriever Thrombectomy in Acute Anterior Circulation Stroke; Medtronic) and receives Swiss National Science Foundation grants for magnetic resonance imaging in stroke. MA reports personal fees from Bayer, Bristol-Myers Squibb, Medtronic, Amgen, Daiichi Sankyo, Nestlé Health Sciences, Boehringer Ingelheim, and Covidien during the conduct of the study. TRM reports research support from the Bangerter Rhyner Foundation, Swiss National Foundation, and the Swiss Heart Foundation. SJ reports grants from the Swiss National Science Foundation and the Swiss Heart Foundation. EIIP reports grants from the Swiss National Science Foundation. MRH reports grants from Swiss National Science Foundation, SITEM Research Support Funds and Swiss Heart Foundation, not directly related to this manuscript., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

In fit patients with newly diagnosed myeloma, high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is considered standard of care. For mobilization of CD34+ cells for ASCT, combined cytotoxic chemotherapy and G-CSF is commonly used. However, the importance of cytostatic chemotherapy for reliable mobilization remains unclear. This prospective randomized phase II non-inferiority trial compared G-GSF only (G) compared to standard chemotherapy/G-CSF (CG) for CD34+ mobilization. The primary endpoint was a less than 15% difference in successful stem cell collection ( ≥ 5.0 × 10 6 CD34+ cells/kg b.w. in a single day collection procedure without additional stimulation with plerixafor) with the G regimen. 136 patients were 1:1 randomized. With an 18% difference in favor of the CG therapy, the non-inferiority margin was not maintained (95% CI 1%, 34%, p = 0.04). The median total CD34+ yield was 9.99 × 10 6 /kg b.w. in CG patients and 7.42 × 10 6 /kg b.w. in patients with G-CSF alone (p < 0.001). Ultimately, 130 (96%) patients proceeded to HDCT with ASCT. There were no differences in adverse events, hematologic engraftment, quality of life, or pain perception between the groups. Our data indicate that G-CSF only is inferior to chemotherapy with G-CSF for peripheral CD34+ stem cell mobilization. Trial registration SNCTP #: SNCTP000002952; Trials.gov #: NCT03442673., Competing Interests: Competing interests MD received financial support for attending haematology meetings from Kite Gilead/Novartis and serves as an advisory board member for Novartis. There are no financial disclosures from any of the other authors. Ethics approval and consent to participate We confirm that all methods were performed in accordance with the relevant guidelines and regulations. The study had approval by the local Ethics Committee of Bern, Switzerland, with the decision number 2018-00615. Written informed consent was obtained from all participants., (© 2024. The Author(s).)

Mine waste rock poses significant environmental challenges. Evaluating management and reclamation options is particularly complex because of the wide particle size distribution, the non-uniform distribution of acid-generating and buffering minerals, and the variable contribution of the different particle size fractions to acid mine drainage (AMD) generation. Reactive transport simulations can be useful to complement and overcome the limitations of laboratory and field experiments. However, predicting field-scale and long-term geochemical behavior of waste rock requires a better understanding of numerical parameters scale-up. In this study, three waste rocks, with different mineral composition and particle size distribution, were separated into different fractions and tested in the laboratory. Kinetic tests were used to calibrate numerical models and adjust minerals' effective kinetic rate constants to match measured pH and metal concentrations. Calibrated reactive transport simulations were able to reproduce accurately the effect of particle size on pH and sulfate and calcium production rates. Experimental and numerical results confirmed that waste rock oxidation and neutralization rates tended to decrease with increasing particle sizes. Several models were tested and the weighted geometric mean of the effective kinetic rate constants as a function of the proportion of each fraction provided the most accurate estimation of the whole specimen kinetic rate constants. A novel approach to predict waste rock geochemical behavior from a single laboratory test also showed promising results. Overall, these results should contribute to improving the extrapolation of laboratory kinetic test results to field predictions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The growing body of evidence around sexual and gender dimorphism in medicine, particularly in oncology, has highlighted differences in treatment response, outcomes, and side effects between males and females. Differences in drug metabolism, distribution, and elimination, influenced by factors like body composition and enzyme expression, contribute to these variations., Methods: We retrospectively analyzed data of 112 multiple myeloma (MM) patients treated with first-line high-dose chemotherapy (HDCT) with treosulfan and melphalan (TreoMel) followed by autologous stem cell transplantation (ASCT) at a single academic center between January 2020 and August 2022. We assessed response rate, progression-free survival (PFS), overall survival (OS), and toxicities in relation to gender and treosulfan exposure., Results: Our analysis revealed significant gender-specific differences in treosulfan exposure. Females had higher peak levels (343.8 vs. 309.0 mg/L, p = 0.0011) and area under the curve (AUC) (869.9 vs. 830.5 mg*h/L, p = 0.0427) compared to males. Higher treosulfan exposure was associated with increased mortality in females but not in males. Females with treosulfan AUC > 900 mg*h/L had significantly shorter overall survival, while PFS was unaffected by treosulfan exposure., Conclusion: Our study demonstrates that female patients undergoing TreoMel HDCT have higher treosulfan exposure than males and that females with higher levels are at increased risk for toxicity and adverse outcomes. These data suggest that higher treosulfan doses do not confer a benefit in terms of better outcomes for females. Therefore, exploring lower treosulfan doses for female MM patients undergoing TreoMel HDCT may be warranted to mitigate toxicity and improve outcomes.

Background: Early diagnosis of previously unknown cancer (i.e., occult cancer) after an acute ischemic stroke (AIS) could result in faster initiation of cancer therapy and potentially improve clinical outcomes. Our study aimed to compare mortality rates between AIS patients with occult cancer diagnosed during the index stroke hospitalization versus those diagnosed after hospital discharge., Methods: Among consecutive AIS patients treated at our stroke center from 2015 through 2020, we identified new cancer diagnoses made within the year after the AIS. We used multivariable Cox regression analyses to evaluate the association between the timing of occult cancer diagnosis (during the AIS hospitalization versus after discharge) and long-term survival., Results: Of 3894 AIS patients with available long-term follow-up data, 59 (1.5 %) were diagnosed with a new cancer within one year after index stroke. Of these, 27 (46 %) were diagnosed during the index hospitalization and 32 (54 %) were diagnosed after discharge. During a median follow-up of 406 days (interquartile range, 89-1073), 70 % (n = 19) of patients whose cancer was diagnosed during hospitalization had died, compared to 63 % (n = 20) of patients whose cancer was diagnosed after discharge (p= 0.58). In our main multivariable model, there was no difference in long-term mortality between patient groups (adjusted hazard ratio, 1.16; 95 % confidence interval, 0.53-2.52; p= 0.71)., Conclusions: In this analysis, timing of a new cancer diagnosis after AIS did not seem to influence patients' long-term survival. Given the fairly small number of included patients with previously occult cancer, larger multicenter studies are needed to confirm our results., Competing Interests: Declaration of competing interest Morin Beyeler reports research support from the “Kurt und Senta Hermann-Stiftung”, the Department of Neurology, Inselspital, Bern University Hospital and the University of Bern, Switzerland. None of the other authors report any conflicts of interest in relation with this study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Core-binding factor acute myeloid leukemia (CBF-AML) represents 12-15% of all AML cases. Although CBF positivity infers a survival advantage, overall survival (OS) remains dismal. Treatment is with cytarabine/anthracycline-based chemotherapy induction followed by high-dose cytarabine (HiDAC) consolidation. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is reserved for relapse or for patients having not achieved MRD-negativity at high risk for relapse. The role of SCT in first complete remission (CR1) remains controversial and is considered in high risk conditions. In this retrospective, multi-national, European Society for Blood and Marrow Transplantation (EBMT)-based study, we identified 1901 patients with de novo CBF-AML who received an allo-SCT or autologous transplantation (ASCT) in CR1. 65.5% harbored t(8;21) and 34.4% inv(16). In this group, the majority (77%) were treated with allo-SCT in CR1. In multivariate analysis, treatment with allo-SCT was an independent and significant, negative predictor of NRM and OS (HR 4.26, p < 0.0001 and HR 1.67, p = 0.003) and among patients treated with allo-SCT, those treated with MSD had the best outcomes, comparable to those treated with ASCT. There was no interaction between the type of transplant and MRD status at time of SCT. In both, MRD-negative and MRD-positive groups, NRM was worse in the allo-SCT group (MRD-: 12.9% vs 5.2%, p = 0.007; MRD+: 10.6% vs 0%, p = 0.004). We therefore demonstrated that consolidation in CR1 with allo-SCT results in worse outcomes than ASCT. Whether consolidation with ASCT yields better outcomes than chemotherapy alone or chemotherapy in combination with Gemtuzumab Ozogamicin is yet to be investigated., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)