Hanson, Curtis A.

Abstract BACKGROUND Early disease progression within 24 months following chemoimmunotherapy (CIT) is an established adverse prognostic factor for overall survival (OS) in patients (pts) with indolent non-Hodgkin lymphomas. Initially reported in pts with follicular lymphoma, progression of disease (PD) within 24 months in pts with CLL treated with CIT (occurring in ~1-out-of-4 pts) is also associated with inferior OS. The prognostic utility of early event status in pts with CLL treated with targeted therapies is unknown. Recently, we reported worse than expected outcomes with BCL2 inhibitor (BCL2i) treatments in an international cohort of pts with covalent BTK inhibitor (BTKi)-resistant, CIT-naïve CLL. We hypothesize that early disease progression on first-line (1L) targeted agent treatment will identify additional pts with high-risk disease beyond conventional prognostics in the current era. METHODS We identified pts in the Mayo Clinic CLL Database with the following 1L treatments a) BTKi (+/- anti-CD20 monoclonal antibody [CD20mAb]); b) BCL2i + CD20mAb; c) BTKi + BCL2i +/- CD20mAb. PD was defined by a) new or progressive lymphadenopathy or splenomegaly; and/or b) ≥ 50% increase from nadir absolute lymphocyte count (ALC) with persistent (>2 months), and otherwise unexplained ALC ≥ 10x109/L; and/or c) Richter transformation. Logistic regression model evaluated association between clinical factors and POD36 status. OS in pts with PD within 36 months of 1L start (POD36) was evaluated and compared to those without early PD (non-POD36) with analyses: a) starting from time of PD (POD36) and starting from 3 years after 1L initiation (non-POD36); and b) Kaplan-Meier landmark analysis amongst pts alive 3 years post 1L initiation. Cox regression analyses compared a) OS from POD36 by groups and b) OS from 1L treatment with POD36 as a time-dependent covariate. RESULTS A total of 787 pts with CLL initiated 1L targeted therapy (n=538 [68%] BTKi +/- CD20mAb; n=151 [19%] BCL2i + CD20mAb; n=98 [13%] BTKi + BCL2i +/- CD20mAb. The median age at 1L start was 67 years (range 26-92 years), and 67% of pts were male. Among pts with complete CLL-IPI data (n=519), 44% and 15% had high- and very high-risk CLL-IPI risk scores, respectively. Specific pre-1L treatment disease characteristics included TP53 disruption (del17p or TP53 mutation) in 120/639 (19%), del11q in 103/634 (16%), unmutated IGHV in 406/591 (69%), complex karyotype (≥3 clonal structural or numerical abnormalities on karyotype) in 70/273 (26%), and positive CD49d expression in 229/449 (46%). The median pre-treatment beta-2-microglobulin level was 3.3 mcg/mL (range 1.2-24.4 mcg/mL). The median follow-up from 1L start was 50 months (95% CI 46-54 months). 496 pts met criteria for defining POD36 status; 72 (15%) had PD, and 424 did not. TP53 disruption (OR 2.9; 95% CI 1.5-5.7, P=0.001) was associated with POD36 on univariate analysis; complex karyotype, unmutated IGHV status, elevated serum lactate dehydrogenase level, age, sex, and inclusion of CD20mAb were not associated with POD36 status. Median OS from the time of determination of POD36 status was not reached. OS was significantly shorter after POD36 compared to non-POD36 pts (HR 3.5; 95%CI 2.1-6.0, P<0.0001), with 4-year OS estimates of 65% and 88%, respectively. When assessed by landmark analysis at the 3-year timepoint following 1L start (n=50 POD36), OS was also shorter in pts with POD36 compared to non-POD36 pts (HR 3.5; 95%CI 1.8-6.8, P=0.0002). In the overall cohort (n=787), when evaluating OS from 1L treatment with POD36 as a time-dependent covariate, POD36 status was associated with an increased risk of death (HR 4.3; 95% CI 2.6-7.1, P<0.0001) on univariable analysis; and remained an independent marker of shorter OS in multivariable analyses after adjusting for age, sex, TP53 disruption status, and IGHV status (HR 4.2; 95% CI 2.1-8.4, P<0.0001). CONCLUSIONMost pts achieved durable CLL disease control with 1L targeted treatments, and early PD occurs much less frequently than previously reported with CIT. However, among pts who receive 1L targeted therapies for CLL, PD within 36 months is associated with a ~4-fold higher risk of death. These results, if validated in larger data sets, will provide a practical measure for identifying a high-risk subgroup of pts in need of novel treatment strategies in future trials.

Abstract Introduction: Pirtobrutinib, a highly selective non-covalent BTK inhibitor, demonstrated encouraging efficacy in Richter transformation (RT) of chronic lymphocytic leukemia (CLL) in the BRUIN trial (Wierda et al, Lancet Haematology, 2024). However, a control arm was not included in this phase 1/2 trial, and how pirtobrutinib compares to usual care is unknown. To address this gap of knowledge, we sought to compare efficacy outcomes in BRUIN to that in a control cohort consisting of RT patients treated with usual care at Mayo Clinic. Methods: The study was approved by the Mayo Clinic IRB. Patient-level data from BRUIN (n=79; investigator-assessed) were obtained from the study sponsor. Patients with histologically confirmed RT (large B-cell lymphoma) who received at least one line of therapy (n=230) were identified from the Mayo Clinic CLL Database. Multivariable logistic regression was employed to calculate propensity scores for baseline covariates (ie, age at RT treatment line, number of prior lines of CLL treatment [truncated at 3], number of prior lines of RT treatment [truncated at 3], and LDH). For each Mayo patient, propensity scores for each line of RT therapy were calculated, and the line with the highest propensity score was chosen as the index RT treatment line. Using the inverse probability treatment weighting (IPTW) methodology, individual weights were computed, and standardized mean differences (SMDs) were examined for each of the unadjusted and weighted baseline covariates to ensure that balance was obtained between BRUIN cases and Mayo controls. Overall survival (OS; the primary endpoint) and progression-free survival (PFS) were analyzed using unweighted and weighted Cox proportional hazards models. Unweighted and weighted overall response rates (ORRs) and complete response (CR) rates were analyzed using logistic regression. Results: The final analysis dataset contained 79 BRUIN cases (median age 67 [range 26-95], 66% male) and 204 Mayo controls (median age 69 [range 30-89], 74% male). The BRUIN cohort had more patients with ECOG PS ≥1 (61% vs 40%, p=0.001) and elevated LDH (81% vs 63%, p=0.003) than the Mayo cohort. The proportion of patients with TP53 aberration was not statistically different in both cohorts (57% vs. 44%, p=0.15). The index line of RT treatment in the Mayo cohort included chemoimmunotherapy (n=167, 80%) and novel agent-based therapy (eg, cBTKi, venetoclax, PI3Ki, immune checkpoint inhibitor, etc; n=42, 20%). Median lines of prior CLL therapy were 2 (IQR 1-4) vs 1 (IQR 0-3) in the BRUIN and Mayo cohorts, respectively; median lines of prior RT therapy were 2 (IQR 1-2) vs 0 (IQR 0-2). The SMDs of the weighted baseline factors met pre-determined criteria (-0.25≤SMD≤0.25), indicating that balance between the two cohorts was achieved. The median follow-up was 18.3 months (range 0.7-32.9) in the BRUIN cohort and 122.8 months (range 0-280.2) in the Mayo cohort. The unweighted median OS was 12.5 months (95% CI 7.0-20.6) in the BRUIN cohort and 5.7 months (95% CI 3.9-10.7) in the Mayo cohort. The unweighted HR was 0.76 (95% CI 0.54-1.07, p=0.12). After IPTW, the weighted HR was 0.63 (95% CI 0.50-0.78, p<0.001), significantly favoring the BRUIN cohort. The unweighted median PFS was 3.6 months (95% CI 2.8-5.1) in the BRUIN cohort and 3.1 months (95% CI 2.5-4.3) in the Mayo cohort. The unweighted HR was 0.98 (95%CI 0.72-1.34, p=0.92). After IPTW, the weighted HR was 0.78 (95% CI 0.64-0.95, p=0.01), again favoring the BRUIN cohort. Response was evaluable/available in 69 patients in BRUIN and 182 patients in Mayo cohort. The unweighted ORR was 58% vs 53% in BRUIN and Mayo cohorts, respectively (OR=0.83, 95% CI 0.47-1.45, p=0.51), and the CR rate was 16% vs 36% (OR=2.94, 95% CI 1.43-5.88, p=0.003). After IPTW, the weighted OR was 0.65 (95% CI 0.45-0.93, p=0.02) for ORR, favoring the BRUIN cohort, and 1.89 (95%CI 1.23-2.86, p=0.02) for CR rate, favoring the Mayo cohort. Conclusions: This individual patient-level IPTW-based analysis demonstrated that single agent pirtobrutinib is associated with improved OS, PFS, and ORR compared to usual care in patients with RT. These results support the choice of pirtobrutinib over traditional therapies for RT. Although these results are encouraging, the durability of response to pirtobrutinib remains suboptimal. Ongoing trials and other future research will evaluate the efficacy of pirtobrutinib in combination with other treatments in this setting.

Abstract Background: Monoclonal B-cell lymphocytosis (MBL), a precursor to chronic lymphocytic leukemia (CLL), is an understudied yet common premalignant condition present in ~8 million adults in the United States. Based on flow cytometry, MBL can be classified into two immunophenotypes: CLL-type (CD5, CD23, and CD20 co-expression) and non-CLL-type (CD5-negative). While the majority of the data to date pertains to CLL-type MBL, the available evidence indicates non-CLL-type MBL is also associated with an increased risk of hematologic malignancies. Clonal hematopoiesis of indeterminate potential (CHIP) is another precursor condition associated with hematologic malignancies. The relationship between non-CLL-type MBL and CHIP and their combined effect remains unknown. Herein, we report findings on these two precursor conditions in the largest screening cohort to date. Methods: Using flow cytometry, we screened for MBL in the Mayo Clinic Biobank participants who were 40 years or older with no prior history of hematologic cancers. Using whole-exome sequencing of whole-blood DNA, CHIP was screened on 291 genes related to myeloid (56 genes) or lymphoid malignancies (235 genes). Incident hematologic malignancies were detected during follow-up using International Classification of Diseases (ICD) codes in the medical record. All diagnoses were manually reviewed for confirmation. Multivariable logistic regression was used to evaluate the association between non-CLL-type MBL and CHIP. Time to incident hematologic malignancy was calculated from date of MBL screening to the earliest date of incident malignancy, withdrawal, death, last medical visit, or study end. Overall survival (OS) was calculated from date of MBL screening to date of death or last known alive. Multivariable Cox regression, adjusted for age, sex and residency, was used to investigate associations between non-CLL-type MBL and CHIP with clinical outcomes; with results reported using hazard ratios (HR) and 95% confidence intervals (CI). Results: In total, 8,802 individuals with MBL screening and CHIP data were analyzed. Non-CLL-type MBL was detected in 249 (2.8%) individuals; 121 (49%) were male, and median age was 78 years (range, 47-95). We identified 757 (8.6%) individuals with CHIP in at least one of the 291 genes tested. The most frequently mutated CHIP genes were DNMT3A, TET2, ASXL1, PPM1D, and TP53. A total of 47 (0.5%) individuals had both non-CLL-type MBL and CHIP; the four genes with the highest number of CHIP variants in these individuals were DNMT3A (n=16), TET2 (n=10), ASXL1 (n=3), and ATM (n=3). An association between non-CLL-type MBL and any CHIP (OR=1.6, 95%CI:1.2-2.3, P=0.006) was observed. When analyzing CHIP in genes related to myeloid malignancies, the association with non-CLL-type MBL was also significant (OR=1.6, 95%CI:1.1-2.3, P=0.012); however, the association was not statistically significant for genes related to lymphoid malignancies (OR=1.6, 95%CI:0.8-3.3, P=0.165). With a median follow-up of 5.4 years, 104 individuals developed incident hematologic malignancies (66 lymphoid and 38 myeloid malignancies). Non-CLL-type MBL (HR=3.5, 95%CI:1.9-6.5, P<0.001) and CHIP (HR=3.2, 95%CI:2.1-5.1, P<0.001) were each associated with increased risk of incident hematologic malignancies. Co-existence of both precursor conditions was associated with a substantially higher risk of incident hematologic malignancies (HR=10.3, 95%CI:4.0-26.2, P<0.001) compared to individuals with neither precursor condition. Among individuals with non-CLL-like MBL, any CHIP was a borderline significant predictor for incident hematologic malignancy (HR=3.6, 95%CI:1.0-12.9, P=0.049). Compared to individuals with no precursor conditions, OS was not significantly different in those with non-CLL-type MBL-only (HR=1.1, 95%CI:0.8-1.5, P=0.40), those with CHIP-only (HR=1.2, 95%CI:0.99-1.4, P=0.06), or those with both CHIP and non-CLL-type MBL (HR=1.3, 95%CI:0.8-2.1, P=0.39). Conclusions: In the largest screening cohort to date evaluating the relationship of CHIP and non-CLL-type MBL, we found that non-CLL-type MBL and CHIP are associated with each other. Individuals with non-CLL-type MBL were more likely to have CHIP variants in DNMT3A, TET2, ASXL1, and ATM. Among individuals with non-CLL-type MBL, the presence of any CHIP was associated with increased risk of developing hematologic malignancy.

Abstract Background: The synergistic mechanisms of BCL-2 inhibitors and CD20-directed antibodies in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) often lead to deep and durable responses. Although the use of venetoclax-obinutuzumab (Ven-O) in the frontline setting (1L) for CLL/SLL has led to a paradigm shift in the disease management, there are limited data on its efficacy in the relapsed/refractory (R/R) setting. In this study, we evaluated the efficacy and safety of Ven-O in both 1L and R/R CLL among patients treated outside the context of clinical trials at our institution. Methods We used the Mayo Clinic CLL Database to identify patients with CLL who were treated with Ven-O, both in 1L and R/R settings. Patients seen at Mayo Clinic Rochester between 2017 and 2025 were included. Overall survival (OS) was calculated from date of Ven-O initiation until last known alive date. Event-free survival (EFS) was calculated from date of Ven-O initiation until the next line of treatment or last known alive date. Kaplan-Meier methods estimated EFS and OS rates at 1, 3, and 5 years. Cox proportional hazards models were used to explore the association between baseline factors and EFS and OS; results are reported as hazard ratios (HR) and 95% confidence intervals (95%CI). Finally, we compared the OS to the age- and sex-matched general population of the state of Minnesota. Results A total of 154 patients (91 1L, 63 R/R) were included in the study. The median age was 68 years (69 1L, 68 R/R), and 68% were male (64% 1L, 73% R/R). Overall, TP53 disruptions (either del17p by FISH or TP53 mutation) were noted in 22 (15%) patients (9% 1L, 23% R/R). CLL FISH findings demonstrated del11q in 24 (19%) patients (19% 1L, 18% R/R), del13q in 46 (36%) patients (36% 1L, 36% R/R), and trisomy 12 in 21 (16%) patients (16% 1L, 18% R/R). IGHV genes were unmutated in 95 (68%) patients (60% 1L, 80% R/R). The CLL-IPI risk score was high in 54 (51%) patients (51% 1L, 53% R/R) and very-high in 18 (17%) patients (8% 1L, 34% R/R). A total of 121 (89%) patients completed planned treatment (1 year of venetoclax in 73 [90%] 1L and 2 years of venetoclax in 48 [87%] R/R). Median follow-up for the entire cohort was 1.8 years (2.2 1L, 1.5 R/R). Neither median EFS nor OS was reached for the overall cohort or within the 1L and R/R subgroups. The 1, 3, and 5-year EFS estimates for the overall cohort were 91% (86-96%), 85% (78-92%), and 67% (51-89%), respectively; corresponding EFS values for the 1L subgroup were 95% (91-100%), 89% (82-98%), and 67% (47-95%), respectively; and for the R/R subgroup were 85% (76-95%), 77% (65-92%), and 77% (65-92%), respectively. The 1, 3, and 5-year OS estimates were 98% (95-100%), 95% (91-99%), and 88% (76%-100%), respectively; corresponding OS values for the 1L subgroup were 99% (96-100%), 97% (94-100%), and 97% (94-100%) and for the R/R subgroup were 96% (91-100%), 91% (82-100%), and 61% (27-100%), respectively. Univariable analyses showed that TP53 disruption was associated with shorter EFS (HR 3.8, 95%CI 1.4-10.2, p=0.01), although IGHV mutation status was not associated with shorter EFS. A higher level of serum beta-2 microglobulin (HR 1.27, 95%CI 1.01-1.59, p=0.04) and R/R status (HR 4.9, 95%CI 0.9-25.8, p=0.06) were associated with a shorter OS. Interestingly, TP53 mutation status and IGHV mutation status were not associated with inferior OS. There was no difference in the observed and expected OS for both the 1L (p-0.23) and R/R (p=0.14) Ven-O treated cohorts compared to the age- and sex-matched general population of the state of Minnesota. Conclusions Our study shows that Ven-O is a well-tolerated regimen with demonstration of durable treatment responses both in the 1L and R/R groups, when used outside the context of a clinical trial. To the best of our knowledge, these data for the first time demonstrate no difference in OS of patients treated with Ven-O compared to age- and sex-matched general population, in both the 1L and R/R settings.

Abstract Background Mosaic chromosomal alterations (mCAs) are large-scale somatic gains, losses, or copy-neutral loss of heterozygosity (CNLOH) detectable by genotyping of peripheral blood DNA. They represent a form of clonal hematopoiesis and are observed in 0.5-5% of cancer-free individuals. The presence of any autosomal mCA has been associated with >3-fold risk of hematological malignancies. In particular, mCAs occurring in regions related to lymphoid malignancies have an 11-fold increased risk of lymphoid malignancies and a 68.6-fold risk for chronic lymphocytic leukemia (CLL). Monoclonal B-cell lymphocytosis (MBL), the precursor state to CLL, is defined by <5×10⁹/L clonal B cells in otherwise healthy individuals and is classified as low-count (<0.5x109/L) or high-count (0.5-5x10⁹/L) based on clonal B-cell count. MBL is also associated with increased risk of lymphoid malignancy (beyond CLL), with 4.3-fold and 74-fold risk in individuals with low- and high-count MBL, respectively. We previously reported a significant enrichment of autosomal mCAs in MBL, demonstrating a 1.7-fold association in those with low-count MBL and a 50.5-fold association in those with high-count MBL. Whether mCAs independently predict lymphoid malignancy risk after accounting for MBL status is unknown. Here, we evaluated the impact of mCAs on risk of incident lymphoid malignancies in individuals with MBL and in individuals screened negative for MBL. Methods CLL-type MBL (CD5 positive) was identified using flow cytometry assay on peripheral blood. Participants were age ≥40, had no prior hematologic malignancy, and were enrolled through the Mayo Clinic Biobank or the Division of Hematology at Mayo Clinic, Rochester. Participants were followed for incident lymphoid malignancy, including CLL, with diagnoses confirmed by medical record review. mCAs with cell fraction >1% were detected from array-based genotyping of whole blood DNA. Cox proportional hazards models, adjusted for age and sex, estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of developing an incident lymphoid malignancy in individuals with autosomal mCA versus those without an autosomal mCA. Results In 4,331 participants with available MBL and mCA status, the median age was 67 years, and 45% were male. Flow cytometry identified 3,231 individuals who screened negative for MBL, 754 individuals with low-count MBL, and 346 individuals with high-count MBL. Autosomal mCAs were present in 6.5% of individuals without MBL, 7.6% with low-count MBL, and 71.1% with high-count MBL. Over a median follow-up of 6.9 years, 237 individuals developed an incident lymphoid malignancy. The most common types were CLL, multiple myeloma, and diffuse large B-cell lymphoma. Ignoring MBL status, the presence of an autosomal mCA was associated with increased risk of lymphoid malignancy (HR = 2.65; 95% CI: 1.45–4.86; P = 0.002), replicating previous results. However, after excluding individuals with MBL, this association attenuated; those with mCA alone did not have a significantly elevated risk (HR = 1.60; 95% CI: 0.57-4.52; P = 0.38) compared to individuals without MBL or mCA. We next examined the effect of mCAs among individuals with MBL. In those with low-count MBL, the most frequent mCA events were 13q loss (2.1%), 12 gain (1.9%), and 4q CNLOH (1.2%), and individuals with an mCA had a borderline significant risk of developing a lymphoid malignancy (HR = 2.78; 95% CI: 1.01–7.67; P = 0.049) compared to those without an mCA. Similarly, in those with high-count MBL, the most frequent mCA events were 13q loss/CNLOH (31.2%), 12 gain (13.0%), and 11q loss (4.9%), and the presence of an mCA conferred an increased risk compared to those without mCA (HR = 1.51; 95% CI: 1.09-2.08; P = 0.012). Conclusions Autosomal mCAs were more frequent in individuals with high-count MBL compared to those with low-count or no MBL. mCAs showed limited predictive value for lymphoid malignancy among individuals without MBL. In contrast, in individuals with low-count MBL, autosomal mCAs emerged as a potential biomarker for identifying those at risk of developing a lymphoid malignancy. In high-count MBL, mCAs were also a biomarker, but were driven by known chromosomal abnormalities identified through clinical testing. These findings suggest that the utility of mCAs as a predictive marker for lymphoid malignancy is contingent on the presence of MBL and may inform risk stratification and surveillance strategies in this population.

SummaryIn individuals with high‐count monoclonal B‐cell lymphocytosis (MBL), we investigated if lymphadenopathy or splenomegaly found by imaging was associated with shorter time to first chronic lymphocytic leukaemia (CLL) therapy (TTFT) and overall survival (OS). Individuals with MBL seen at Mayo Clinic (2002–2019) were retrospectively divided into three cohorts based on imaging studies within 1 year of diagnosis: no imaging studies (Cohort A); imaging with no evidence of lymphadenopathy/splenomegaly (Cohort B); imaging with evidence of lymphadenopathy/splenomegaly (Cohort C). We compared baseline characteristics, TTFT and OS across the MBL cohorts to a cohort of individuals with small lymphocytic lymphoma (SLL). A total of 1078 patients were included: 640 with MBL and 438 with SLL. Compared to Cohort B, individuals in Cohort C were more likely to have unmutated immunoglobulin heavy chain variable region (IGHV) (43% vs. 25% p = 0.016), high‐risk fluorescence in situ hybridization (FISH) (del17p and del11q in 15% vs. 4%, p = 0.038) and higher expression of CD38 (31% vs. 16%; p = 0.011). After adjusting for sex and CLL‐International Prognostic Index (IPI), lymphadenopathy/splenomegaly was associated with a shorter TTFT (hazard ratio [HR] = 2.04, 95% confidence interval [CI]: 1.02–4.04, p = 0.042) but not OS (HR = 1.09, 95% CI: 0.62–1.92, p = 0.775). Lymphadenopathy/splenomegaly on imaging in individuals with high‐count MBL is associated with a more unfavourable risk profile and shorter time to first CLL‐directed therapy.

Background: Monoclonal B-cell lymphocytosis (MBL) is a common premalignant condition that can be classified into chronic lymphocytic leukemia (CLL)-type (CD5, CD23, and CD20 co-expression), and non-CLL-type (CD5-negative) based on flow cytometry immunophenotypes. CLL-type MBL is relatively well characterized with increased risk of hematologic (especially lymphoid) malignancies, serious infections, and decreased response to vaccinations. However, the prevalence, genetic predispositions, and clinical consequences of non-CLL-type MBL remain to be fully elucidated. Herein, we report findings in non-CLL-type MBL in a large screening cohort. Methods: We screened 10,330 individuals (40 years or older with no prior history of hematologic cancers) for MBL with highly sensitive flow cytometry, in the Mayo Clinic Biobank, with patients recruited from primary care-based clinics. Individuals were genotyped by Regeneron Genetics. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Among those individuals residing in the 27 counties surrounding Rochester, Minnesota, we identified incident hematologic malignancies and melanomas using ICD codes and the Rochester Epidemiology Project, a population based medical records linkage system. All diagnoses were manually reviewed for confirmation. Cox regression was used to calculate hazard ratios (HR) and 95% CIs, adjusted for age and sex. Results: We identified 1,736 individuals with MBL and 8,341 individuals without MBL. Among those with MBL, 246 (14.2%) had non-CLL-type MBL as the major clone. The median age of non-CLL-type MBL was 77 years (range, 47-95). The prevalence of non-CLL-type MBL significantly increased with age, with 0.5% prevalence among those between 40 to 59 years of age, 2.3% prevalence among those between 60 and 79 years, and 7.8% prevalence in those 80 years of age or older. The prevalence of non-CLL-type MBL was significantly higher (P < .001) among males (3.1%) than females (2.0%). Using the genome-wide complex trait analysis tool, the heritability of non-CLL-type MBL was estimated to be ~26%, suggesting inherited genetics plays a role in etiology. To identify common inherited variants, we first evaluated the known CLL susceptibility variants, many of which also associated with CLL-type MBL. Among the 42 variants, none were statistically associated (all P > .05) with non-CLL-type MBL. We next conducted a genome-wide association study to identify novel variants, and the most significant variant resided in 10q26.3 (minor allele frequency [MAF]control = 0.7%, MAFMBL = 3.5%, OR = 6.4, 95% CI 3.6-11.3, P = 5.7 * 10-8). Among the 6,478 individuals (192 with non-CLL-type MBL and 6,286 without MBL) followed for incident hematologic malignancies, 36 developed lymphoid and 23 developed myeloid malignancies after a median of 4.2 years of follow up. Similar to CLL-type MBL, non-CLL-type MBL was associated with a 5.2-fold risk for lymphoid malignancies (95% CI 2.0-13.0, P < .001). Elevated but not significant risks were observed for myeloid malignancies (HR = 2.3, 95% CI 0.5-10.3, P = 0.27). The lymphoid malignancies developed by individuals with non-CLL-type MBL included diffuse large B-cell lymphoma, multiple myeloma, marginal zone lymphoma, and other low-grade lymphomas. We recently reported that individuals with CLL-type MBL are at higher risk for developing melanoma (HR = 1.9, 95% CI 1.3-2.8). Interestingly, non-CLL-type MBL had no evidence of an association with melanoma risk (HR = 0.4, 95% CI 0.1-1.8). We did not observe a significant difference in overall survival between individuals with non-CLL-type MBL vs those without MBL. Conclusions: In the largest screening cohort to date, we evaluated the etiology and clinical outcomes of non-CLL-type MBL, an understudied yet common condition that occurs in ~4 million adults in the United States. Non-CLL-type MBL is more common in men and older individuals, and evidence supports that inherited genetics plays an etiological role with 10q26.3 locus identified as a novel susceptibility locus. Individuals with non-CLL-type MBL had significantly increased risk of lymphoid malignancies, similar to CLL-type MBL, but, distinct from CLL-type MBL, no evidence of an increased risk of melanoma. Our study provides insights into the prevalence, genetic predispositions and clinical consequences of non-CLL-type MBL and how it differs from the classic CLL-type MBL.