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Abstract Background Thrombotic Thrombocytopenic Purpura (TTP) is a rare, typically acquired disorder due to an immune-mediated deficiency of ADAMTS13, a metalloprotease responsible for cleaving large multimers of von Willebrand Factor (vWF). In the absence of ADAMTS13 activity, ultra-large vWF multimers accumulate, promoting widespread platelet aggregation and microvascular thrombosis. This consumptive cascade leads to thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological symptoms, and rarely renal dysfunction. Although therapeutic plasma exchange (TPE) has long been the cornerstone of TTP treatment, the FDA approved Caplacizumab as a first-line treatment for TTP in 2019. This drug is a bivalent single-domain antibody that binds to the A1 domain of vWF and prevents its interaction with platelets, thus effectively interrupting the pathogenic cascade, which is associated with a risk of bleeding. Methods We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, comprising data from 152 healthcare organizations. Adults (≥18 years) with a diagnosis of TTP who received Caplacizumab plus TPE were compared to patients with TTP who received TPE alone. 1:1 propensity score matching (PSM) was performed to balance characteristics between cohorts. The primary outcomes assessed were all-cause mortality and major bleeding events over a period of 1 month. Results A total of 4084 patients with TTP were identified, of whom 356 received caplacizumab with TPE and 3728 received TPE. After PSM, 2 balanced cohorts were created: C+P (Caplacizumab + TPE), P only (TPE), each comprising 356 patients. The average age in C+P and P only, after PSM, was 50.4 +/- 16.2 and 50.8 +/- 16.2 years, respectively. Females formed 65.7% of both C+P and P only, and males accounted for 28.4% and 28.7% of C+P and P only, respectively. 2.8% patients in C+P and 7.06% patients in P only had all-cause mortality at the end of 1 month. One-month all-cause mortality was significantly lower in C+P (2.8%) compared to P only (7.06%), with an odds ratio (OR) of 0.385 (95% CI 0.182 to 0.814, p=0.010). Upon assessment of bleeding outcomes, no statistically significant risk difference was noted between the 2 groups, with the odds ratio being 0.974 (95% CI 0.399 to 2.379, p=0.954). Conclusion Our large database study suggests that the addition of caplacizumab to standard TPE therapy is associated with a reduction in one-month all-cause mortality in patients with TTP, without a corresponding increase in major bleeding. However, given the lack of granular clinical data, such as contraindications to caplacizumab use, it is possible that patients who received TPE alone were inherently at a higher risk. As such, while these findings support the potential benefit of early caplacizumab use, they should be interpreted with caution and warrant prospective validation to confirm causality and assess long-term outcomes.

Abstract Background: MyeloMATCH is an NCI-sponsored initiative for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) employing a Master Screening and Reassessment Protocol (MSRP) to assign patients (pts) to a pt and disease biology-specific clinical trial. Several trials evaluating initial therapies are currently open, while subsequent trials dedicated to eradicating measurable residual disease during consolidation and including stem cell transplant are being developed. A pt enrolled at diagnosis may be followed longitudinally and be eligible for trials in sequential tiers throughout the treatment course. We report key data concerning the first cohort of pts enrolled on the MSRP. Methods: After pts with suspected AML or MDS consent for the MSRP, blood and marrow are sent to the myeloMATCH Molecular Diagnostics Network (MDNet) of central CLIA labs operating under a single Investigational Device Exemption to rapidly define molecular, cytogenetic, and immunophenotypic characteristics. These data are catalogued by a bioinformatics team (MATCHBox) and reviewed daily to assign participants to an available trial based on pt and disease features. A Tier Advancement Pathway (TAP) allows standard of care therapy with potential for assignment to subsequent myeloMATCH trials. Since activation in May 2024, 550 patients age≥18 were enrolled on the MSRP from 76 institutions: 48 Academic, 14 NCORP, 11 community, 3 VA. There are currently 4 open randomized AML trials (≥age 60 or unfit with mutant FLT3, ≥age 60 IDH2 mutant AML, fit age<60 ELN 2017 intermediate-risk AML, fit age<60 ELN 2017 adverse risk) and 1 MDS trial(IDH2 mutant). Patients not eligible for an open protocol were assigned to TAP. Results: Of the 550 pts consented, 491 completed screening assays; 49 had no or incomplete samples; 10 withdrew before completed analysis. Median cytogenetic turnaround time (TAT) was 69 hours (91% within 72 hours), and median Next Generation Sequencing (NGS) TAT from receipt was 49 hours (95% within 72 hours). Seventy-six pts (of 491 with assay data) were not assigned due to non-AML or non-MDS diagnoses, the most common being: B-ALL [n=11], MPN [9], benign marrow [9], APML [7], and MPAL [6]. The AML/MDS verified cohort was 415 pts, 366 (89.2%) patients with AML (45% age <60) and 49 (11.8%) with MDS. The median age at screening was 63 years (range:18-95) and 186 (45%) were female. Eighty-two percent identified as White, 7.5% Black, 3% Asian, 7% unknown, and 9% as Hispanic. The most frequent mutations in the AML pts were NPM1 (24.0%), DNMT3A (22.7%), TET2 (19.9%), NRAS (18.0%), FLT3 (18.0% ITD, TKD 7.1%), TP53 (14.5%), and CEBPA (8.7%); IDH1/2 mutation rates were 8.2% and 13.7%, respectively. Co-mutations include FLT3/NPM1 (9.8%), NPM1/IDH2 (4.4%), IDH1/2 and any RAS (3.8%). Karyotypes were normal in 40.4%, complex 20.8%, inv(16) 6.0%, MLL/KMT2A 4.6% and t(8;21) 1.9%. 29% had favorable risk disease, 29% intermediate, and 42% adverse (ELN 2017). In MDS, mutations included: TP53 (36.7%), RUNX1 (20.4%) ASXL1 (20.4%), TET2 (18.4%), spliceosome mutations (SRSF2, SF3B1, U2AF1 and ZRSR2, 28.6%) andIDH1/2 in 4.1% and 6.1%, respectively. Karyotypes were normal in 24.5%; complex in 40.8%. By IPSS-R, 2.4% were low, 73.8% intermediate, 2.4% high, and 21.4% very high risk. 82/415 (20%) pts were assigned to initial therapy protocol, with an increase in assignment rate to 44% in the most recent two months. 71/415 pts (16%) were enrolled in one of the MyeloMATCH studies. Three-hundred forty-four pts (80%) were assigned and enrolled to TAP (296 AML, 48 MDS) for potential assignment to subsequent tier trials. In the TAP AML pts, 99 (33%) have completed initial treatment, including intensive chemotherapy (IC) in 62% of pts and hypomethylating agents/venetoclax (HMA/VEN) in 38%. In pts <60 years of age, 87% received IC v. 13% with HMA/VEN, in >60 34% IC v. 66% HMA/VEN and in age 60-75 42% IC v. 58% HMA/Ven. Conclusion: MyeloMATCH has screened over 500 pts from academic and community sites in the US and Canada in 14 months, meeting the TAT goal of sample acquisition to results of <72 hours. Assignment to treatment protocols has substantially increased recently. As additional trials open (12 in development) we expect the percentage of pts enrolled on MSRP who go on to therapeutic trials will markedly increase, thereby allowing a personalized medicine approach for a broad group of US and Canadian adult pts with AML and MDS.

Abstract Over the past decade, classification systems using high-throughput genetic data have been developed to identify molecular subtypes of DLBCL. Although not a primary goal, these classifiers were also proposed as prognostic factors in their respective publications. To date, however, no study has directly compared these classifiers' ability to predict overall (OS) and event-free survival (EFS) in the same cohort. Herein, we sought to systematically compare predictive performance, benchmarked against the IPI, of several current established molecular classifiers and evaluate if any add significant independent prognostic information beyond the IPI. WES (including paired germline filter) and RNAseq data from newly diagnosed DLBCL patients (N=432; 2018 WHO criteria) in the Mayo Clinic/University of Iowa Lymphoma Molecular Epidemiology Resource (MER) were available for analysis (WES n=112, RNAseq n=40, or both n=280). The number of cases able to be classified (including as unclassified) for each classifier was as follows: IPI (432, 100%), cell-of-origin (COO, by Hans algorithm; 346, 80.1%), refined COO (by gene expression with Dark Zone Signature; 320, 100%), Haematological Malignancy Research Network (HMRN; 349, 89.0%), B-cell state (320, 100%), Lymphoma Ecotype (320, 100%), Lymphoma Microenvironment (LME; 320, 100%), Tumor microenvironment (TME26; 320, 100%), SubLymE (312, 97.5%), LymphGen (358, 91.3%), and DLBclass (223, 58.2%). OS was defined as time from diagnosis to all-cause death while EFS was defined as time from diagnosis to disease progression, initiation of second-line treatment, or all-cause death. We calculated Harrell's c-statistics for each Cox proportional hazards model evaluating the discriminative performance of each classifier in predicting OS/EFS. Using bootstrap validation, we obtained optimism-corrected c-statistics, which we report in the results. We performed likelihood ratio tests (LRT) comparing a univariable Cox model with IPI alone and models including both IPI and a given classifier to assess if a classifier provided independent prognostic information beyond the IPI. All patients were treated with immunochemotherapy (IC) with curative intent, 247 (57%) were male, median age at diagnosis was 65 years (IQR 55-72 years), 390 (96%) were White, 209 (60%) had GCB subtype by Hans, 22 (5.1%) had MYC double-hit by FISH (MYC and BCL2 or BCL6), and 162 (37.9%) had an IPI ≥ 3. The median follow-up was 7.0 years, 167 (39%) experienced an event, and 137 (32%) died. In a univariable Cox model, the c-statistic for IPI predicting OS was 0.66 (95% confidence interval [CI] 0.61-0.70). All other classifiers had c-statistics of ≤0.56. The c-statistic for IPI predicting EFS was 0.64 (95% CI 0.60-0.69), and all other classifiers had c-statistics of ≤0.58. The univariate DLBclass results for OS and EFS were not significantly impacted when restricted to cases with confidence >0.7 (n=136). In Cox models of IPI alone versus IPI plus an individual classifier, the only classifier that provided statistically significant, independent information for OS was TME26 (LRT p=0.02). Adjusting for IPI, patients who were TME26-negative had significantly inferior OS compared to TME26-positive cases (HR 1.63, 95% CI 1.07-2.47; p=0.02). For EFS, DLBclass (restricted to confidence >0.7) added significant prognostic information beyond IPI (LRT p=0.02). This finding was largely driven by C5 subtype; relative to C1 subtype and adjusting for IPI, C5 subtype had significantly inferior EFS (HR 5.53, 95% CI 1.81-17.0; p=0.003). In summary, we compared prognostic performance of multiple DLBCL molecular classifiers with respect to OS and EFS in a single real-world, prospective cohort of newly diagnosed, IC-treated DLBCL. Our data supports two key findings: all classifiers had modest performance for prognosis, and none individually outperformed the IPI in predicting OS nor EFS. Second, only TME26 and DLBclass (confidence >0.7) provided additional prognostic information beyond that captured by the IPI for OS and EFS, respectively. This finding suggests that the tumor immune microenvironment and characteristics of C5 DLBCLs (ABC-subtype, CD79B mutations) can potentially offer significant independent information for predicting survival and response to front-line immunochemotherapy. If replicated, these findings could inform risk-adapted treatment approaches and aid in identifying high-risk patients for enrollment in genomically-informed clinical trials.

Abstract Chimeric antigen receptor T (CART) cell therapy has shown unprecedented success in the treatment of hematological malignancies. However, the immunosuppressive tumor microenvironment of both solid and liquid tumors is a major barrier for CART efficacy. Immunosuppressive myeloid cells inhibit CART efficacy. Colony-stimulating factor 1 receptor (CSF1R) promotes macrophage proliferation, survival, and anti-inflammatory response and is upregulated on myeloid cells in many cancers, making CSF1R an appealing therapeutic target. We aimed to test the interactions between CSF1R, myeloid cells, and CART response, and to study CSF1R targeting in the context of CART cell therapy. We utilized CD19-targeted CART cell therapy (CART19) in lymphoma preclinical models and thyroid-stimulating hormone receptor (TSHR)-targeting CART cell therapy (TSHR-CART) in thyroid cancer models. We first measured CSF1R expression on myeloid cells in vitro. Suppressive myeloid cells, polarized from healthy donor monocytes using an anaplastic thyroid cancer (ATC) cell line, 8505c, or mantle cell lymphoma cell line, JeKo-1, significantly upregulate CSF1R (p=0.0002) compared to media control. After polarization, myeloid cells significantly inhibit TSHR-CART and CART19 antigen-specific proliferation compared to freshly isolated monocytes (p=0.012, p<0.01, respectively) indicating that suppressive myeloid cells contribute to CART failure in multiple tumor types. We then performed single cell RNA sequencing on peripheral blood taken at baseline from patients with mantle cell lymphoma treated with CART19. We found a significant increase of CSF1R on monocyte subsets in CART19 non-responders vs responders (padj=0.0037). Next, we determined the impact of CSF1R blockade on CART cell therapy in vivo. Using lymphoma models, B6 mice were engrafted with the luciferase+ CD19+ murine lymphoma cell line TBL-12 (1x106 cells i.v. 1 day after 250 mg/kg cyclophosphamide). Tumor burden was significantly reduced after 7 days of treatment with low dose CART19 (0.5x106 i.v.) + anti-mouse CSF1R antibody (16mg/kg i.p. twice weekly) vs CART19 + IgG control (p=0.0146). We then tested the impact of CSF1R blockade in mice experiencing tumor relapse. After TBL-12 engraftment, mice were treated with anti-mouse CSF1R or IgG control antibody followed two days later with high dose CART19 (1x106 i.v.) to induce remission. Mice were re-challenged with TBL-12 14 days later. Mice treated with anti-mouse CSF1R antibody showed increased tumor control and significantly higher survival (p=0.0416). Using thyroid cancer models, first we identified high macrophage infiltration in biopsy specimens of patients with ATC compared to normal thyroid tissue and benign thyroid tumors through immunohistochemistry (IHC) of patient samples (p<0.01, p<0.0001, respectively). To test if macrophages are associated with CART failure in ATC, NSG mice were subcutaneously engrafted with 1x106 TSHR+ THJ529 tumors, an ATC cell line derived from patient biopsy samples from the Mayo Clinic thyroid cancer biobank, followed by i.v. treatment with 1x107 TSHR-CART or untransduced T cell control (UTD). IHC staining of tumor tissue collected at experimental endpoints revealed a dose-dependent, significant infiltration of human CD3+ T cells into the tumors which inversely correlated with murine F4/80+ myeloid cell and murine YM-1+ M2 macrophage infiltration. This led us to hypothesize that myeloid cell targeting with CSF1R blockade can improve TSHR-CART efficacy. We utilized the same ATC model described above to test CSF1R targeting. When TSHR+ THJ529 tumors reached approximately 100 mm3, mice were randomized by tumor volume and treated with CSF1R inhibitor PLX5622 (600mg/kg) or vehicle control, followed by either UTD or TSHR-CART cells 5x106 i.v. Mice treated with TSHR-CART + PLX5622 showed significantly improved tumor control vs TSHR-CART + vehicle control (p<0.0001) or UTD + PLX5622 (p<0.0001). Together, our results highlight immunosuppressive myeloid cells which express CSF1R as a major cell type limiting CART efficacy in both solid and liquid tumors. We also identified a strategy to overcome myeloid-mediated suppression of CART cells by targeting CSF1R with antibody or small molecule inhibitors.

Abstract Introduction: CAR T-cell therapy represents a pivotal treatment for individuals with relapsed or refractory (R/R) MM. Currently, two CAR T-cell therapeutics have received regulatory approval: Abecma (idecabtagene vicleucel, ide-cel) and Carvykti (ciltacabtagene autoleucel, cilta-cel). Although direct comparative investigations delineating the efficacy of these modalities are absent, clinical trials have shown significant disparities in response and remission rates between these therapies. Both agents are implicated in the manifestation of CRS and ICANS; however, variations in the frequency and severity of these adverse effects have been observed. We harnessed data from the National Inpatient Sample (NIS) to gain a deeper understanding of the incidence of different adverse events associated with both CAR T products in MM. Method: In this retrospective study, the 2022 NIS database was used to identify hospitalizations with MM and those who received ide-cel or cilta-cel using appropriate ICD-10-CM diagnostic and ICD-10-PCS procedure codes. Data on CRS, ICANS, infections, and adverse cardiac events were extracted using relevant ICD-10-CM codes. These outcomes were compared between the two CAR-T products using Pearson's chi-square analysis. Multivariate logistic regression was also performed, adjusting for demographics, hospital-specific characteristics, and comorbidities. Results: We identified 805 patients with MM who received CAR T-cell therapy, among whom 530 patients (60.4% male; 67% Caucasian, 14.6% African American and 17.5% other ethnicities) received ide-cel and 275 patients (70.9% male; 79.6% Caucasian, 14.3% African American and 6.1% other ethnicities) received cilta-cel. The incidence of CRS was 72.6% for ide-cel and 56.4% for cilta-cel, and the difference was almost statistically significant by chi-square analysis (p = 0.051). This difference was not statistically significant after multivariate analysis [Adjusted Odds ratio (OR) = 0.5, CI 0.2 to 1.3, p=0.154]. The incidence of ICANS was 19.8% for ide-cel and 18.2% for cilta-cel, and it was not statistically significant by chi-square analysis (p = 0.825). Among cardiovascular events, there was no significant difference in the incidence of cardiogenic shock (ide-cel vs cilta-cel, 0.9% vs 0%, p = 0.497), stroke (0.9% vs 1.8%, p = 0.661) and arrhythmias (22.6% vs 21.8%, p = 0.892) between these CAR T-cell therapies. Furthermore, there were no significant differences in the incidence of infectious complications, including pneumonia (1.9% vs 0%, p = 0.334), sepsis (0.9% vs 3.6%, p = 0.247), or septic shock (0.9% vs 0%, p = 0.430) between these CAR T-cell therapies. There was no significant difference in all-cause in-hospital mortality between these therapies (1.9% vs 5.5%, p = 0.181). Conclusion: There was no significant difference in the occurrence of CRS and ICANS between ide-cel and cilta-cel in our study. Both CAR T-cell therapies have the potential to cause infections and cardiovascular issues, necessitating careful monitoring, early detection, and timely treatment. When choosing between these CAR T-cell therapies, several factors should be considered, including the patient's previous treatment history, manufacturing time, cost, availability, and potential short-term and long-term side effects. Our study has some limitations, including its retrospective design, dependence on ICD-10 codes for identifying patients with adverse events, and the lack of long-term longitudinal data on adverse effects. However, this study provides important insights for hematologists regarding the rates of specific adverse events associated with both the CAR T-cell products in a real-world setting.

Abstract Background Teclistamab (Tec) and Talquetamab (Tal) are the two first FDA approved bispecific antibodies (BsAb) for the treatment of patients (pts) with relapsed/refractory multiple myeloma (RRMM). Both Tec and Tal should be initiated with step-up dosing (SUD) in an inpatient (IP) setting to mitigate the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), per US label. However, standard of care practice continues to evolve and more pts receive SUD as an outpatient (OP) to reduce healthcare resource utilization and improve pt convenience. While most real-world evidence has focused on clinical and safety outcomes of pts treated with Tec and Tal, pt experience associated with these novel BsAb therapies is relatively unexplored. Methods HealthTree Foundation, a multiple myeloma pt advocacy group which provides enrolled pts with information on treatments, community groups, and research participation, surveyed RRMM patients who have received Tec or Tal. Eligible pts who completed the treatment experience survey had at least 4 months of follow-up after starting BsAb. The survey was fielded from May 2024 through June 2025. Data collection followed IRB-exempt protocols with informed consent. Results A total of 32 patients (24 Tec, 8 Tal) completed the survey. The median age was 70 years, 50% were male, and 84% were white. Most pts (n=24; 75%) received SUD at their primary oncology clinic (n=19, 59% at an academic center; n=5, 16% at local community center), and 8 (25%) at an academic center which was not their primary oncology clinic. All pts who received SUD at an academic center that was not their primary oncology clinic later transitioned to their local community clinic post-SUD and reported being satisfied or very satisfied with their transition of care experience. Overall, most pts (n= 21; 66%) received their entire step-up dosing during a single hospitalization, while some (n=6; 19%) received all doses of the SUD during separate hospitalizations for each dose. About 13% (n=4) received all SUD in an OP setting, and 3% (n=1) received SUD in a hybrid setting (mix of IP and OP). Although 85% (n=27) of the pts received IP SUD, 66% (n=21) would have preferred IP SUD in one hospitalization, while the remaining 34% (n=11) would have preferred OP or hybrid SUD. Among pts who received IP SUD (n=27), almost a quarter reported a preference for either OP (n=4; 15%) or hybrid SUD (n=2; 7%) and 78% (n=21) preferred one IP hospitalization for SUD. The factors influencing their preference for the setting of SUD in this IP sub-group were feeling more secure with IP monitoring (78%), convenience (26%), less worry about staying near healthcare centers (15%), being able to stay with their local physician (11%), staying closer to home (7%), and lower costs to the pt (4%). Among pts receiving OP SUD (n=4), 75% (n=3) preferred fully OP SUD and 25% (n=1) preferred hybrid SUD because of convenience (n=2; 50%), lower cost to pt (n=1; 25%), flexible dosing schedule (n=1; 25%), and feeling of security with IP monitoring (n=1; 25%). All the pts receiving hybrid SUD (n=1) preferred fully OP SUD due to convenience. Although Tec and Tal are subcutaneous (SC) injections, when patients were asked to compare the options of BsAbs with comparable efficacy and safety profile, they favored SC injection (n= 22; 69%) over intravenous infusion (n = 3; 9%), while 22% (n=7) had no preference for mode of drug administration. The challenges that impacted pt experience with Tec or Tal were treatment side effects (Tal pts: n=6, 75%; Tec pts: n=9, 38%) and distance or travel time to the treatment facility (Tal pts: n=2, 25%; Tec pts: n=4; 17%). Other reasons included caring for others, continuing to work, cost and insurance, lack of caregiver/care partner, being away from home, unavailability of the therapy in community setting near home, and eligibility criteria. Conclusions Most pts in this study received SUD at their primary oncology clinic. While most pts received IP SUD and preferred a single planned IP visit, one third preferred OP or hybrid SUD due to convenience. As the field moves toward OP-only SUD, this study underscores the need to consider pt preferences. There is an unmet need for community clinics providing SUD options closer to pt homes.

Abstract Introduction: DRd is the standard of care for frontline (FL) treatment (tx) of transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). This is supported by its superior efficacy and tolerable safety profile vs lenalidomide and dexamethasone (Rd) and vs bortezomib plus Rd (VRd) per the phase 3 MAIA clinical trial and real-world data. However, based on recent phase 3 CEPHEUS and IMROZ trial data, the tx paradigm is shifting toward the use of quadruplets for suitable TIE patients with NDMM. CEPHEUS demonstrated the superior efficacy of DVRd vs VRd in TIE and transplant-deferred patients with NDMM. DVRd-treated patients achieved significantly higher rates of minimal residual disease negativity and significantly improved progression-free survival vs VRd-treated patients. DVRd is listed as a National Comprehensive Cancer Network (NCCN) Category 1 preferred regimen in this setting and is therefore used in US real-world clinical practice. The objective of this study was to evaluate real-world usage patterns of FL DVRd and FL DRd in nontransplanted patients with NDMM and to assess the characteristics of patients treated with these regimens. Methods:Data from the Flatiron Health Research database were used for this retrospective observational study. Patients were included in this analysis if they received FL tx with DVRd or DRd for NDMM between Jan 1, 2019, and Dec 31, 2024. The index date was defined as the initiation date of FL DVRd or FL DRd. As the Flatiron database does not capture transplant eligibility status, the analysis excluded all patients who underwent hematopoietic stem cell transplantation at any time during the study period. Patients were also excluded if they were <18 years of age, enrolled in a clinical trial, had presence of other cancers, received chimeric antigen receptor T-cell therapy, or were diagnosed with amyloid light-chain amyloidosis before the index date. High cytogenetic risk was defined as the presence of abnormalities including del(17p), t(4;14), or t(14;16). Descriptive statistics were used to report demographic and clinical characteristics. Kaplan-Meier methods were used to estimate duration of therapy. Results: Among the nontransplanted NDMM cohort, 704 FL DVRd-treated patients and 396 FL DRd-treated patients were identified. At index, FL DVRd patients were generally younger than FL DRd patients (median age, 68 vs 78 years, respectively), more likely to be male (55.3% vs 49.5%), and less likely to have Medicare coverage (8.4% vs 17.2%). The 2 cohorts had similar proportions of Black/African American patients (18.9% and 18.7%). Among patients with available data, high cytogenetic risk was more frequently observed in FL DVRd (29.2%) vs FL DRd (17.5%) patients; a lower proportion of FL DVRd patients had International Staging System (ISS) stage III disease (27.1%) than ISS stage I disease (39.9%), whereas a higher proportion of FL DRd patients had ISS stage III disease (32.9%) than ISS stage I disease (25.5%). FL DVRd patients were more likely to be nonfrail (Intergroupe Francophone du Myélome simplified frailty score <2) vs FL DRd patients (64.6% vs 28.2%). Use of both DVRd and DRd increased during the study period; however, the increase was greater for DVRd, particularly in the later years. Notably, FL DVRd was started in 10 patients in 2019, increasing to 146 in 2022 and 222 in 2024. By comparison, FL DRd was initiated in 17 patients in 2019, increasing to 85 in 2022 and 97 in 2024. Median follow-up was 15.6 mo in the DVRd cohort and 20.3 mo in the DRd cohort. Median duration of DVRd therapy was 18.5 mo (95% CI, 14.8–22.7) and was 23.5 mo (95% CI, 19.0–31.7) for DRd therapy. Bortezomib as part of the DVRd regimen was given once weekly or less frequently in the majority (65.6%) of patients. Conclusions: These real-world data show the increasing FL use of the daratumumab-based quadruplet regimen DVRd among nontransplanted patients with NDMM. FL DVRd patients were generally younger and less frail but more likely to have high cytogenetic risk than those treated with DRd. These data also show that daratumumab-based regimens, either as a triplet (DRd) or a quadruplet (DVRd), are increasingly adopted over time in real-world clinical practice. These data further suggest that DRd and DVRd may be considered foundational for the tx of nontransplanted patients with NDMM regardless of patient characteristics, including age, frailty, cytogenetic risk, and ISS stage.

Abstract Introduction: Lutetium-177 DOTATATE peptide receptor radionuclide therapy (PRRT) is an effective treatment for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). While generally well tolerated, PRRT can result in hematologic toxicity ranging from mild cytopenias to therapy-related myeloid neoplasms (t-MNs). Understanding the incidence, severity, and clinical consequences of hematologic toxicity is essential for optimizing treatment decisions and establishing effective monitoring strategies. This study aimed to characterize hematologic toxicity patterns, severity, and recovery profiles in GEP-NET patients treated with Lutetium-177 DOTATATE PRRT and to determine the frequency of cytopenia-related treatment discontinuation. Methods: We conducted a retrospective analysis of 160 consecutive GEP-NET patients who underwent PRRT. Hematologic parameters (hemoglobin, white blood cell count, absolute neutrophil count, platelet count, and lymphocyte count) were assessed at baseline, mid-treatment (post-cycle 2), and post-treatment (post-cycle 4). Cytopenias were graded using Common Terminology Criteria for Adverse Events version 4.03 and categorized as never (grade <2 throughout), transient (grade ≥2 mid-treatment, resolving post-treatment), persistent (grade ≥2 at both timepoints), or late-onset (grade <2 mid-treatment, grade ≥2 post-treatment). Treatment completion rates and discontinuation reasons were documented. Results: Overall, 73% of patients (117/160) completed all planned PRRT cycles. Among the 43 patients who discontinued treatment early, only 4 (2.5% of total cohort) discontinued specifically due to cytopenia, while the remainder discontinued for other reasons. Post-treatment grade ≥2 cytopenias were uncommon: lymphocytes (4.4%), hemoglobin (2.5%), neutrophils (1.9%), white blood cells (1.3%), and platelets (1.3%). The majority of patients (≥85%) never experienced grade ≥2 cytopenia throughout treatment. When cytopenias occurred, they were predominantly transient (8-10% of patients) with complete recovery by treatment completion. Persistent cytopenias were rare (<5% across all cell lines), while late-onset cytopenia occurred most frequently with neutrophils (14%). Conclusion: Lutetium-177 DOTATATE PRRT demonstrates an excellent hematologic safety profile in GEP-NET patients. Severe cytopenias are uncommon, predominantly transient, and rarely necessitate treatment discontinuation. These findings support the continued use of PRRT in appropriate candidates, with cytopenia-related discontinuation occurring in fewer than 3% of cases. Long-term follow-up remains essential to monitor delayed hematologic effects, including t-MNs. Future research should evaluate baseline predictors such as prior chemotherapy, renal function, and marrow reserve to identify patients at higher risk who may benefit from closer hematologic surveillance.

Abstract Abstract Introduction: Leukemia, a heterogeneous group of hematologic malignancies, has established associations with modifiable risk factors such as tobacco use. Despite the widespread implementation of tobacco control measures over the past three decades, disparities persist in tobacco-attributable leukemia mortality across sex and socio- demographic strata. This study aimed to quantify and compare long-term global and regional trends in mortality due to tobacco-associated leukemia between 1990 and 2021, with a focus on sex-based and income-level disparities. Methods: We obtained age-standardized mortality rates (ASMRs) for leukemia attributable to tobacco use from the Global Burden of Disease (GBD) 2021 dataset for 204 countries and territories. ASMRs were analyzed for the years 1990 and 2021 and stratified by sex (male, female, both) and socio-demographic index (SDI) regions (high, high-middle, middle, low- middle, low). Temporal trends were assessed using Average Annual Percent Change (AAPC) with corresponding 95% confidence intervals (CI). Additionally, univariate linear regressions by location were conducted to quantify associations between time and mortality. Results: Globally, tobacco-related leukemia mortality decreased substantially between 1990 and 2021. The overall ASMR declined from 0.64 to 0.40 per 100,000 population (AAPC: –1.51%; 95% CI: –1.59 to –1.43). Sex-disaggregated data revealed a more favorable reduction in females (from 0.23 to 0.12; AAPC: –2.25%; 95% CI: –2.41 to –2.09) compared to males (from 1.20 to 0.77; AAPC: –1.45%; 95% CI: –1.51 to –1.39), suggesting persistent gender disparities in tobacco exposure and/or access to care. These trends were statistically significant (p < 0.001), and global univariate regression confirmed a significant negative slope (–0.0088; p = 0.021). Marked regional differences emerged by SDI status. High-SDI countries experienced the steepest declines in mortality. In these regions, ASMRs dropped from 1.16 to 0.69 among both sexes combined (AAPC: –1.70%; 95% CI: –1.80 to –1.61), with females improving from 0.56 to 0.31 (AAPC: –1.90%; 95% CI: –2.03 to –1.76) and males from 2.07 to 1.17 (AAPC: –1.88%; 95% CI: –1.96 to –1.80). The associated regression slope (–0.0183) was statistically significant (p = 0.0014), with an R² of 0.10, indicating a strong temporal association. High-middle SDI regions showed moderate progress: ASMRs declined from 0.62 to 0.45 among both sexes (AAPC: –0.99%; 95% CI: –1.10 to –0.88). Reductions were steeper in females (0.12 to 0.07; AAPC: –1.32%; 95% CI: –1.55 to –1.09) than in males (1.40 to 0.96; AAPC –1.19%; 95% CI: –1.29 to –1.09). However, regression slopes were not statistically significant (p = 0.18), suggesting heterogeneous trends within this group. Low-SDI regions, in stark contrast, exhibited minimal improvements. Between 1990 and 2021, ASMRs decreased marginally from 0.098 to 0.074 (AAPC: –1.01%; 95% CI: –1.10 to –0.91), with male mortality decreasing from 0.17 to 0.12 (AAPC: –1.22%; 95% CI: –1.32 to –1.13) and female rates from 0.037 to 0.027 (AAPC: –0.88%; 95% CI: –1.04 to –0.72). However, the regression slope (–0.00084) was not statistically significant (p = 0.17), and the effect size (R² = 0.02) suggested only a weak temporal association. Middle and low-middle SDI countries also demonstrated underwhelming progress. In low- middle SDI settings, the combined-sex ASMR dropped from 0.21 to 0.16 per 100,000, with a weak negative slope (–0.0012; p = 0.43), and an AAPC of –0.83% (95% CI: –0.95 to –0.71). These results highlight stagnation and growing inequities in health burden mitigation. Conclusion: From 1990 to 2021, global mortality due to tobacco-attributable leukemia significantly declined, with the greatest improvements seen in high-SDI countries and among females. However, regions with lower income levels lagged, showing minimal or no significant decline in mortality despite decades of global tobacco control efforts. The pronounced disparities by sex and socioeconomic status underscore the need for context- specific, equity-focused tobacco cessation initiatives and leukemia screening programs, especially in underserved populations. Without urgent intervention, the global burden of leukemia attributable to tobacco may continue to disproportionately affect those with the fewest resources and weakest health infrastructure.

Abstract Background: Patients with myelodysplastic syndromes (MDS) are at heightened risk for severe infections, including sepsis, due to underlying cytopenias and immune dysregulation. Hospital-level characteristics, including size and available resources, may influence clinical outcomes in these patients, but data remain limited. This study examines the association between hospital bed size and sepsis-related complications in patients with MDS using a nationally representative dataset. Methods: We conducted a retrospective cohort analysis using the National Inpatient Sample (NIS) from 2016 to 2022, identifying adult hospitalizations with co-diagnoses of MDS and sepsis. Hospitalizations were stratified by hospital bed size: small (n = 15,490), medium (n = 22,815), and large (n = 40,245). Multivariable logistic regression, adjusted for patient demographics, comorbidities, and hospital characteristics, was used to assess associations between hospital bed size and eight clinical outcomes: in-hospital mortality, septic shock, acute renal failure, respiratory failure, encephalopathy, disseminated intravascular coagulation (DIC), Clostridioides difficile infection (CDI), and fungal sepsis. Results: Compared to small hospitals, patients treated at large hospitals had significantly higher odds of in-hospital mortality (OR 1.43, p < 0.001), septic shock (OR 1.25, p < 0.001), acute renal failure (OR 1.10, p < 0.001), encephalopathy (OR 1.11, p = 0.004), DIC (OR 1.48, p = 0.007), and fungal sepsis (OR 2.13, p = 0.028). Medium-sized hospitals were also associated with increased odds of mortality (OR 1.16, p = 0.021) and septic shock (OR 1.13, p = 0.038). No statistically significant differences were found in rates of CDI across hospital sizes. Respiratory failure showed a borderline association in medium hospitals (OR 1.05, p = 0.082) but not in large hospitals. Conclusion: Hospital bed size is independently associated with important variations in sepsis-related outcomes among patients with MDS. Large hospitals demonstrated significantly increased odds of multiple complications and mortality, possibly reflecting referral bias, higher disease acuity, or institutional coding practices. These findings underscore the importance of hospital-level factors in evaluating outcomes and resource planning for high-risk hematologic populations. Keywords: Myelodysplastic syndromes, hospital bed size, sepsis, mortality, ICU complications, NIS