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OBJECTIVE Spinal cord stimulation (SCS) at 10 kHz (10-kHz SCS) is a safe and effective therapy for treatment of chronic low-back pain. However, it is unclear from existing evidence whether these findings can be generalized to patients with chronic back pain that is refractory to conventional medical management (CMM) and who have no history of spine surgery and are not acceptable candidates for spine surgery. The authors have termed this condition "nonsurgical refractory back pain" (NSRBP) and conducted a multicenter, randomized controlled trial to compare CMM with and without 10-kHz SCS in this population. METHODS Patients with NSRBP, as defined above and with a spine surgeon consultation required for confirmation, were randomized 1:1 to patients undergoing CMM with and without 10-kHz SCS. CMM included nonsurgical treatment for back pain, according to physicians’ best practices and clinical guidelines. Primary and secondary endpoints included the responder rate (≥ 50% pain relief), disability (Oswestry Disability Index [ODI]), global impression of change, quality of life (EQ-5D-5L), and change in daily opioid use and were analyzed 3 and 6 months after randomization. The protocol allowed for an optional crossover at 6 months for both arms, with observational follow-up over 12 months. RESULTS In total, 159 patients were randomized; 76 received CMM, and 69 (83.1%) of the 83 patients who were assigned to the 10-kHz SCS group received a permanent implant. At the 3-month follow-up, 80.9% of patients who received stimulation and 1.3% of those who received CMM were found to be study responders (primary outcome, ≥ 50% pain relief; p < 0.001). There was also a significant difference between the treatment groups in all secondary outcomes at 6 months (p < 0.001). In the 10-kHz SCS arm, outcomes were sustained, including a mean 10-cm visual analog scale score of 2.1 ± 2.3 and 2.1 ± 2.2 and mean ODI score of 24.1 ± 16.1 and 24.0 ± 17.0 at 6 and 12 months, respectively (p = 0.9). In the CMM arm, 74.7% (56/75) of patients met the criteria for crossover and received an implant. The crossover arm obtained a 78.2% responder rate 6 months postimplantation. Five serious adverse events occurred (procedure-related, of 125 total permanent implants), all of which resolved without sequelae. CONCLUSIONS The study results, which included follow-up over 12 months, provide important insights into the durability of 10-kHz SCS therapy with respect to chronic refractory back pain, physical function, quality of life, and opioid use, informing the current clinical practice for pain management in patients with NSRBP.

80 Background: Higher baseline body mass index is associated with improved survival in metastatic CRC (mCRC). Whether weight gain or loss after mCRC diagnosis is associated with survival remains largely unknown. Methods: We analyzed individual patient data from 3504 patients with previously untreated mCRC enrolled in five phase III randomized trials (AVF2017g, AVF2192g, CRYSTAL, N9741, OPUS) conducted between 2000 and 2006. Weight measurements were prospectively collected at 3 months after diagnosis and then up to 5 years. Patients were categorized into three groups based on the percent weight change at 3 months: stable weight or gain, weight loss up to 5% of baseline weight, and ≥5% weight loss of baseline weight. Cox models were used to assess the prognostic associations of weight change at 3 months with overall survival (OS) and progression-free survival (PFS), adjusting for baseline BMI, age, sex, performance score, chemotherapy backbone (oxaliplatin vs. irinotecan), and biologics type (cetuximab vs. bevacizumab). Sub-analyses included Cox models adjusted for additional clinical-pathological factors (primary tumor sidedness [right colon vs. left colon-rectum], and BRAF status; N=1,511). Results: Median percent weight change at 3 months was -0.5% (IQR -4.0 to+1.6%). OS was better in patients with weight stability or gain than in those with weight loss (up to 5% or ≥5%; (Table). Results were consistent for PFS for patients with ≥5% weight loss of baseline weight, as well as for sub-analyses. Conclusions: Patients losing weight during the first 3 months of systemic therapy for metastatic colorectal cancer have significantly shorter overall survival than those with stable or increasing weight. Degree of weight loss is proportional to the observed increased risk of death and remains evident among underweight, normal weight and obese individuals. Further studies examining possible usefulness of on-treatment early weight loss as a novel intermediary end-point are needed.[Table: see text]

Abstract Background: Somatic EGFR mutations define a subset of non–small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74–0.77) in the training and 0.77 (95% CI, 0.74–0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

Abstract Background The detrimental effect of leukocytosis on survival in myeloproliferative neoplasms (MPN) has been well established for primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET ) (JCO. 2018;36:310; BJH. 2020;189:291) Previous studies have also implicated leukocytosis as a risk factor for leukemic transformation (Mayo Clin Proc. 2017;92:1118) and thrombosis in MPN (Blood Adv. 2019;3:1729). However, it is currently not clear as to which component(s) of white blood cells is responsible for these observations. In the current study, we sought to examine the individual prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC) and monocyte (AMC) counts, on overall (OS), leukemia-free (LFS), and myelofibrosis-free (MFFS) survival and in ET. Methods Study patients (n=349) were retrospectively recruited from the Mayo Clinic MPN database of 1,249 WHO-defined ET patients, evaluated over five decades (1967-2021), based on availability of information on ANC, ALC and AMC. Conventional criteria were used for diagnosis and definitions of major complications, including leukemic or fibrotic transformation (Blood 2016;127:2391). Conventional statistical methods were applied using JMP Pro 14.0.0 software package, SAS Institute, Cary, NC. Multivariable analyses included previously established risk factors for survival. Results 349 patients (median age 57 years, range 18-89; females 61%) with ET were included in the study: 46% JAK2, 34% CALR, 16% triple-negative and 4% MPL mutated; IPSET risk category high 24%, intermediate 41%, and low 35%; presenting median (range) values were 13.8 g/dL (11.1-16.4) for hemoglobin, 8.2 x 10(9)/L (3.2-52) for leukocyte count, and 859 x 10(9)/L (451-3460) for platelet count; palpable splenomegaly was present in 48 (14%); median followup was 10 years (range 0-47), during which time 118 deaths, 52 fibrotic progressions, and 14 leukemic transformations were documented. Multivariable analysis identified older age (p&lt;0.001), increased ANC (p&lt;0.001), decreased ALC (p=0.03), and male sex (p=0.04), but not AMC (p=0.8), venous thrombosis (p=0.4), or arterial thrombosis (p=0.4), as independent risk factors for OS. ANC of ≥8 x 10(9)/L and ALC of &lt;1.8 x 10(9)/L were determined as appropriate cut-off values by ROC analysis. Subsequent multivariable analysis using these cut-off values resulted in HR (95% CI) of 5.2 (3.4-7.9; p&lt;0.001) for age &gt;60 years, 3.1 (2.1-4.6; p&lt;0.001) for ANC, and 2.0 (1.4-3.0; p&lt;0.001) for ALC; male sex was no longer significant in this analysis (p=0.14). An operational HR-based risk score assigned 3 adverse risk points for older age (&gt;60 years), 2 for increased ANC (≥8 x 10(9)/L) and 1 for ALC (&lt;1.8 x 10(9)/L), resulting in an new Age Anc Alc (AAA; triple A) risk model for survival in ET with estimates of median survival ranging from 9.7 to 36.6 years (Figure 1). In addition, ALC &lt;1.8 x 10(9)/L was associated with inferior LFS (p=0.06) and MFFS (p=0.07) while AMC as a continuous variable showed borderline significance for MFFS (p=0.18). In univariate analysis, JAK2V617F allele burden showed significant association with OS (p=0.02), LFS (p=0.05) and MFFS (p=0.001); however significance for OS was lost in mutivariable analysis that included ANC and ALC. An external validation cohort from the University of Florence (n=485) confirmed the independent survival risk contribution from age &gt;60 years (p&lt;0.001; HR 9.9, 95% CI 5.4-18.0), ANC ≥8 x 10(9)/L (p=0.02; 1.9, 1.1-3.5) and ALC &lt;1.8 x 10(9)/L (p&lt;0.001; 2.0, 1.3-3.0). The Triple A risk model was also effectively applied on the Florence validation cohort (Figure 1): median follow-up 8.4 years; 87 deaths; 43 fibrotic progression; 12 leukemic transformations. The association of ALC &lt;1.8 x 10(9)/L (p=0.04) and AMC (p=0.002) with fibrotic transformation was also validated in the Florence cohort. Conclusions: The current study identifies increased ANC and decreased ALC as age-independent risk factors for survival in ET, thus allowing the development of a globally applicable simple to use "Triple A" risk model that is based on Age, ANC and ALC. Decreased ALC also predicted fibrotic and leukemic progression. Our observations suggest potential value for immune profiling as an additional prognostic tool in MPN. Figure 1 Figure 1. Disclosures Szuber: Novartis: Honoraria. Vannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Platelet-activating anti-PF4 antibodies that cause thrombocytopenia and thrombosis are implicated in Heparin-induced thrombocytopenia (HIT) and, more recently, in a newly recognized entity, vaccine-induced immune thrombotic thrombocytopenia (VITT). Current frontline PF4-Polyanion ELISAs utilize simple techniques but are highly non-specific. Functional gold-standard assays such as the serotonin-release assay (SRA) and PF4-dependent P-selectin expression assay (PEA) have limited availability due to technical complexity and the requirement for freshly-drawn normal donor platelets which results in significant delays in diagnosis. Thus, there is an unmet need for near-patient, functional assays for HIT/VITT diagnosis. Aim: To develop a highly sensitive and specific functional assay to detect platelet-activating antibodies associated with HIT and VITT using long-term stored platelets. The assay should be technically simple, avoiding current functional HIT testing endpoints such as aggregometry, radioactivity measurement or flow cytometry. Methods: Platelets were subjected to controlled-rate freezing in a trehalose-based buffer. Cryopreserved platelets were then thawed after variable storage periods, incubated with platelet factor 4 (PF4), and sera from HIT or VITT suspected patients. Thrombospondin-1 (TSP1), a protein highly expressed in platelet α-granules, was quantified from activated platelet supernatants in an ELISA-based assay as a measure of platelet activation. Results: In initial studies, p-selectin expression was induced by platelet-activating HIT antibodies using cryopreserved platelets and the TSP1-release assay (TRA) detected HIT antibody-mediated PF4-dependent cryopreserved platelet activation across 20 different platelet lots (data not shown). A representative study using platelets stored for 11 months is shown in Figure 1A. A cohort of thirty-six HIT-suspected patient sera, half with PF4-dependent platelet-activating antibodies (PEA+) and without (PEA-), were used to evaluate the diagnostic accuracy of the TRA (Figure 1B). All 18 PEA+ samples activated platelets strongly with a mean TSP1 concentration of 147 µg/mL measured in the supernatant compared to a mean of 43 µg/mL obtained with non-activating samples. TSP1 release in a subgroup of 7 PEA+/SRA+/ELISA+ and 4 PEA-/SRA-/ELISA+ samples that were matched for ELISA Optical Density was examined (Figure 1C). Results demonstrated that even strong ELISA+ samples that were non-activating (PEA-/SRA-) did not induce platelet activation in the TRA, confirming high specificity of the assay. The TRA was tested for its ability to detect platelet-activating antibodies in four patients who developed VITT after the Janssen vaccine (Ad26.COV2.S). All samples induced high levels of TSP1 release from cryopreserved platelets (Figure 1D). Conclusions: Our results demonstrate that cryopreserved platelets stored for several months are viable and capable of degranulation upon activation. Further, we demonstrate that measurement of TSP-1 released from cryopreserved, PF4-treated platelets is highly accurate for detecting platelet-activating HIT and VITT anti-PF4 antibodies. Specificity and sensitivity were both 100% even with samples that were strongly false-positive in the HIT ELISA. Coupling cryopreserved platelet activation to a simple ELISA endpoint, as demonstrated here, precludes the need for fresh platelets and complex testing techniques. Thus, the TRA has the potential to transform the diagnostic testing paradigm in HIT and VITT by making near-patient in-hospital functional testing available for rapid and accurate diagnosis. Figure Legend: Figure 1. TSP-1 quantification of (A) 3 HIT patient samples (closed circles) relative to 3 normal control samples (open circles) after 11-months of frozen platelet storage. (B) Thirty-six HIT-suspected patient samples: 18 PEA+ samples (closed circles), and 18 PEA- samples (open squares). Data are compared using two-tailed, unpaired Student's t test. **** P&lt;0.0001. (C) Eleven high optical density matched HIT ELISA patient sera: 7 PEA+/SRA+ samples (closed circles) and 4 PEA-/SRA- samples (open squares). (D) TSP-1 quantification of VITT patient sera. NC-normal control. Figure 1 Figure 1. Disclosures Pruthi: Instrumentation Laboratory: Honoraria; HEMA Biologics: Honoraria; Bayer Healthcare AG: Honoraria; Genentech: Honoraria; CSL Behring: Honoraria; Merck: Honoraria. Padmanabhan: Veralox Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Myelofibrosis (MF) is characterized by progressive bone marrow (BM) fibrosis resulting from aberrant megakaryopoiesis and expression of pro-inflammatory cytokines. These processes, heavily influenced by bromodomain and extraterminal domain (BET) protein-mediated gene regulation, lead to myeloproliferation and cytopenias. There is a high unmet need for a treatment that can potentially delay or reverse BM fibrosis in patients (pts) with MF. Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule BET inhibitor, which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in pts with MF. Pelabresib is currently being investigated as a monotherapy and in combination with the JAK inhibitor (JAKi) ruxolitinib (RUX), in the ongoing MANIFEST Phase 2 study (NCT02158858). Methods: In arm 1 of MANIFEST, pelabresib is administered as monotherapy to pts with MF who are intolerant/refractory to, or ineligible for RUX; in arm 2, as an 'add-on' to RUX in pts with MF who have suboptimal/lost response; and in arm 3 as combination therapy with RUX in JAKi treatment-naïve pts with MF. To evaluate the effects of pelabresib on BM biology, analyses were conducted using BM biopsy samples obtained pre-treatment and at 24 weeks post-treatment during the MANIFEST trial. Central pathology review of reticulin staining was conducted to evaluate BM fibrosis (BMF) grading and immunohistochemistry staining for changes in erythroids (ERY) and megakaryocytes (MK), respectively. Independent digital images of stained BM slides were also evaluated with a semi-quantitative cell-specific detection algorithm for reticulin density, percentage CD71+ ERY, mean number of CD61+ MK and mean distance between nuclei for CD61+ MK. Results: Exploratory analyses across the three treatment arms showed BM improvements after 24 weeks of treatment. Paired comparison by digital analysis of baseline and 24-week treatment BM biopsies from 29 pts showed reduction (range 67%-15.5%) in reticulin intersections per field in 45% (13/29) pts. Furthermore, digital analysis of CD71+ ERY and CD61+ MK from paired biopsies showed increased ERY progenitors in 50% (16/32) pts, decreased MK density in 57% (15/26) pts and decreased MK clustering in 46% (12/26) pts at 24 weeks. Decreased MK clustering correlated with decreased density of CD61+ MK in 75% pts (9/12). Correlative analysis between observed clinical responses and bone marrow improvements are ongoing and will be available for presentation at the conference. We previously reported (Talpaz M, et al. ASH 2020; Abstract 2163) that in pts with MF, pelabresib can reduce spleen volume, improve symptoms, improve bone marrow fibrosis, demonstrate increase in hemoglobin levels, and reduce transfusion burden. Updated 24-week data reflecting a higher number of evaluable pts and new long-term data at 48 weeks across the MANIFEST trial, will be presented. Conclusions: Treatment with pelabresib as monotherapy or in combination with RUX, in both RUX treatment-naïve and -experienced pts with MF, resulted in increased ERY progenitors, decreased MK density and reduction of BM fibrosis, as assessed by digital pathology. These data suggest possible disease-modifying potential for pelabresib by improving BM histology and function, leading to potential clinical benefits. Disclosures Verstovsek: Roche: Research Funding; Promedior: Research Funding; Blueprint Medicines Corp: Research Funding; Incyte Corporation: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Ital Pharma: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Salama: Mayo Clinic: Current Employment, Other: Mayo Clinic had the contractual work for the central pathology review for this study and I was one of the reviewing pathologists; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Mascarenhas: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy, Research Funding; Prelude: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Galecto: Consultancy; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merus: Research Funding; Forbius: Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz: Celgene: Consultancy; Imago: Consultancy; Takeda: Other: Grant/research support ; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa: La Jolla Pharma: Consultancy; Samus: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Pharma: Consultancy; CTI: Research Funding; Abbvie: Research Funding; CTI: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; AOP: Consultancy. Vannucchi: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rampal: Incyte: Consultancy, Research Funding; Pharmaessentia: Consultancy; Blueprint: Consultancy; Disc Medicine: Consultancy; Stemline: Consultancy, Research Funding; BMS/Celgene: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Constellation: Research Funding; Memorial Sloan Kettering: Current Employment; Kartos: Consultancy. Oh: Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Celgene Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Membership on an entity's Board of Directors or advisory committees; PharamaEssentia: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. Taverna: Constellation Pharmaceuticals: Current Employment. Cui: Constellation Pharmaceuticals: Current Employment. Zavidij: Constellation Pharmaceuticals: Current Employment. Chen: Constellation Pharmaceuticals: Current Employment. Colak: Constellation Pharmaceuticals: Current Employment. Efuni: Constellation Pharmaceuticals: Current Employment. Keller: Constellation Pharmaceuticals: Current Employment. Trojer: Constellation Pharmaceuticals: Current Employment. Harrison: Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Sierra Oncology: Honoraria; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Monoclonal B-cell lymphocytosis (MBL) is one of the most common pre-malignant conditions and is characterized by a circulating population of clonal B-cells with an absolute clonal B-cell count &lt; 5x10 9/L and no evidence of lymphadenopathy, organomegaly, or cytopenias. MBL can be classified by the immunophenotype: CLL-like MBL (CD5+, CD20dim), atypical MBL (CD5+, CD20+), or non-CLL-like MBL (CD5-, CD20+), as well as by the size of the clone (low-count or high-count) with low-count MBL (LC-MBL) defined as clonal B-cell &lt;0.5x10 9/L or percent clonal B-cell count &lt;85% out of total B-cell count. The prevalence of MBL varies depending on detection methods and population tested. In a Spanish screening study of 608 individuals, they identified 73 MBLs (12%) with CLL-like MBL; moreover, these authors also evaluated overall survival (OS) compared to 290 individuals without MBL and found a significantly shorter OS among these predominantly LC-MBLs. Here, we evaluate the prevalence and OS of LC-MBL in a large screening cohort of 8,297 individuals. Study participants from the Mayo Clinic Biobank, a large-scale biorepository of adult patients, who had no prior history of hematologic malignancy, provided blood samples between 7/2009 to 4/2021. Stored peripheral blood mononuclear cells were screened for MBL with an eight-color flow cytometry assay capable of detecting clonal B-cell event to the 0.005% level. We classified each MBL by immunophenotype as CLL-like MBL, atypical MBL, and non-CLL-like MBL. Individuals with more than one immunophenotype were classified into one immunophenotype based on the following hierarchy: CLL-like MBL, then atypical MBL, then non-CLL like MBL. Based on previously published evidence, individuals were also classified by clonal counts using the percent clonal B-cell count &lt;85% out of the total B-cell count to define LC-MBL. Individuals were followed from sample date to the earliest of death, loss to follow-up, or 5/31/2021. OS for LC-MBL and controls (individuals who screened negative for MBL) was assessed by Kaplan-Meier method. Age- and sex-adjusted OS was analyzed using inverse weights methods. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs), adjusted for age and sex. We screened 8,297 individuals 40 years or older (median age 67 years, 39% male) and identified 1,326 (16%) with LC-MBL and 6,651 (80%) controls. Those individuals detected with high-count MBL (N=90, 1%) or individuals who had insufficient cells for flow cytometry interpretation (N=230, 3%) were excluded from subsequent analyses. The prevalence of LC-MBL was higher in males (21%) than females (14%; p&lt;0.01) and significantly increased with age (p&lt;0.01) ranging from 3% among those 40-49 years, 10% among those 50-59 years, 15% among those 60-69 years, 23% among those 70-79 years, and 29% for those 80+ years. Sixty-one individuals had clones with more than one type of immunophenotype. Based on our hierarchy, CLL-like MBL was the most common (N=1,155), followed by non-CLL-like (N=168) and atypical MBL (N=67). The median follow-up time in our cohort was 26 months (range 0-142), and 432 individuals had subsequently died. The 5-year and 10-year OS adjusted for age and sex among LC-MBLs was 95% and 87%, respectively; control estimates were 95% and 84%, respectively. We did not observe a significant difference in OS between those individuals with LC-MBL versus controls (HR=0.98, CI=0.77-1.24, P=0.84, Fig 1a), nor when we stratified individuals by age &lt;65 (P=0.77) or age &gt;= 65 (P=0.68). Among females, OS was longer among LC-MBL compared to controls (HR=0.61, CI=0.38-0.97, P=0.04); but no evidence of a difference in OS among males was observed (HR=1.22, CI=0.92-1.62, P=0.17). When we evaluated OS by MBL immunophenotype, we observed no statistically significant difference (Fig 1b, log rank P=0.44). When we stratified the MBLs by immunophenotype versus controls, we also did not observe a difference: CLL-like (HR=0.91, CI=0.71-1.18, P=0.5), atypical (HR=1.73, CI=0.92-3.27, P=0.09), non-CLL like (HR=0.98, CI=0.58-1.66, P=0.95). In the largest MBL screening cohort to date, LC-MBL was a common condition among adults 40 years or older reaching a prevalence as high as 29% among individuals 80 years of age or older. OS among those with and without LC-MBL was similar, regardless of immunophenotype and age. The longer survival in females with MBL versus controls requires further evaluation. Figure 1 Figure 1. Disclosures Parikh: Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding. Kay: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; MEI Pharma: Research Funding; Tolero Pharmaceuticals: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees. Shanafelt: Genentech, Pharmacyclics: Research Funding.